Open Access Journal of Medical andClinical Surgery

Abstract

Unplanned pregnancies are a major public health issue globally causing poor maternal and foetal outcomes. The objective of this study was to determine the prevalence of unplanned pregnancies & their associated factors among antenatal clinic attendees in Thimbirigasyaya Divisional Secretariat Division, Colombo, Sri Lanka. A cross-sectional study was conducted in three randomly selected antenatal clinics of the Thimbirigasyaya Divisional Secretariat Division of the Colombo Municipal Council. A total of 425 antenatal mothers were included in the study using a consecutive sampling method. Data collection was done using interviewer-administered questionnaires. Statistical analysis was done using the Chi-Square test, Odds Ratio and 95% confidence interval. The prevalence of unplanned pregnancies was 32.7% in the study population. The 95 % confidence interval was 28.26 – 37.39. Being married, the mother being employed in the preceding 12 months, the number of past conceptions being two or less & intake of folic acid before pregnancy had statistically significant associations with planned pregnancies at 95% confidence interval (p < 0.05). Marital age less than 20 years, highest education level of the mother being less than Grade 11, highest education level of the spouse being less than Grade 11, monthly household income of less than LKR 25,000, the interpregnancy interval of fewer than 24 months, using family planning practices in the past, never wanting or expecting the current pregnancy and not planning for another pregnancy had statistically significant associations with unplanned pregnancies at 95% confidence interval (p < 0.05). According to the study, one-third of the pregnancies were unplanned & a statistical significance at 95% confidence interval was seen between the planning status of the current pregnancy and twelve of the eighteen variables studied.

Keywords: Prevalence, unplanned pregnancies, associated factors, antenatal mothers, Sri Lanka

Introduction

Data on prevalence is important to help in resource allocation and prioritisation of activities by relevant stakeholders. The prevalence data would also help to identify the magnitude of the problem related to unplanned pregnancies in a given population under study by assessing its overall burden. It would also support the process of identification of priorities in healthcare, preventive activities and policymaking which is needed to develop a health economics model to address issues related to unplanned pregnancies.

There is a lack of recent data on the prevalence of unplanned pregnancies in this study population in an urban community setting in Thimbirigasyaya Divisional Secretariat Division which falls under the Colombo Municipal Council. It is important to identify associated factors for any public health problem, as it would provide data on the most important associated factors to be addressed and would help to prioritise them. Identifying and addressing associated factors for unplanned pregnancies among the targeted population would improve their sexual and reproductive health and help to implement necessary interventions and provide health-related services on unplanned pregnancies.

Lay Summary

This study is a retrospective chart review of the electronic medical records of 68 patients diagnosed with acute appendicitis (AA) and admitted to the general surgery department of Dubai Hospital, UAE, for conservative or surgical management of acute appendicitis between March 1 and December 31, 2020. Conservative treatment was defined as treatment with antibiotics and supportive management alone. Ethical approval was obtained from the Dubai Scientific Research Ethics Committee (DSREC). Patients admitted within this time period without a nasopharyngeal RT-PCR swab for COVID-19 on admission were excluded from the study. All demographic, clinical, radiological, and laboratory data was retrieved from the SALAMA electronic file system.

Variables evaluated for each patient include: age, sex, COVID-19 status, modality of management (conservative or operative), incidence of complications, type of surgical technique if managed operatively (open or laparoscopic appendicectomy), past medical and drug history, presence of pre-existing comorbidities, smoking status, preoperative vital signs (temperature, heart rate, respiratory rate, and blood pressure), radiological findings on chest x-ray if COVID-19 positive, preoperative laboratory markers, and length of hospital stay. The data was entered into the data collection tool (Microsoft Excel spreadsheet), exported, and analyzed in SPSS Version 22 software using Fisher’s exact test. The analysis was carried out in accordance with the Strengthening the Reporting of Observational studies in Epidemiology (STROBE) guidelines for observational studies.

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Introduction

Unplanned pregnancies: Pregnancies can be broadly divided into planned/wanted pregnancies and unplanned pregnancies. Unplanned pregnancy is a major public health issue the world over. In unplanned pregnancies, conception has occurred not at the desired time and was expected later or was never expected or wanted.

Associated factors for unplanned pregnancies: The common cause of unplanned pregnancies has been identified as not using contraception or due to not using a contraceptive method consistently or correctly or both [1]. Marital age, marital status, age at first pregnancy, education level of the couple, employment status of the mother, monthly household income, interpregnancy interval, disrupted marital life and gender-based issues are some of the factors associated with unplanned pregnancies [2].

Adverse outcomes of unplanned pregnancies: Unplanned pregnancies have been a major cause of induced abortions the world over and have been linked to poor maternal and child health outcomes causing an increased risk of abortion-related death and morbidity, especially in countries where abortion is illegal [3]. Women with unplanned pregnancies are more vulnerable to committing suicide, have poor nutrition during gestation, and have adverse mental health issues, unstable family relationships, experience physical and psychological violence, risk of bad pregnancy outcomes and delay in seeking prenatal care [4].

The children born of mothers with unplanned pregnancies are at risk for low birth weight, poor academic performance, violence and neglect [5]. These children are exposed to greater risk factors, hence are more likely to experience negative psychological and physical health issues, increased school dropouts and tend to show delinquent behaviour during their adolescent period. A study conducted in Australia showed higher levels of depression, delinquency and anxiety among children born out of unplanned pregnancies as compared to planned pregnancies [6].

The global situation on unplanned pregnancies: Unplanned pregnancies can negatively affect women physically, emotionally and financially. Effective, equitable and easier access to effective contraception methods, especially to long-acting reversible contraception, would certainly help to address this issue of public health concern [7].

Between 2015 to 2019, there had been 121 million unplanned pregnancies annually the world over (80% confidence interval of 112.8-131.5) which corresponds to a global rate of 64 unplanned pregnancies per 1000 women aged 15 - 49 years. Out of this amount, 61% of the unplanned pregnancies ended in abortions, which accounts for an abortion rate of 39 abortions per 1000 women aged 15 - 49 years [8]. According to the latest estimates by the World Health Organisation, almost half the pregnancies between 2015 to 2019 in low and low middle-income countries had been unplanned. Women living in the poorest regions are almost three times likely to have unplanned pregnancies than women from wealthier regions [9].

Sri Lankan situation on unplanned pregnancies

In Sri Lanka, approximately 360,000 women become pregnant annually, of which one in three (33.3%) are estimated to have an unplanned pregnancy. Demographic and Health Survey (DHS) of 2016 reports that 35% of married women in Sri Lanka do not use any form of contraception and teenage pregnancies are around 4.6% [10]. Approximately 150,000 to 175,000 abortions are expected to take place annually in Sri Lanka [11], with no recent data indicating any decrease. According to the National Post Abortion Care Guideline of 2015, unsafe abortion is responsible for 10% to 13% of maternal deaths in Sri Lanka, making it the second leading cause of maternal mortality in the country (Family Health Bureau, 2015). In 2017, approximately 326,000 live births had taken place in Sri Lanka, along with 127 reported maternal deaths in that same year. Among the 127 maternal deaths, 28 were due to unplanned pregnancies (Family Health Bureau, 2015). Another study concluded that 23.3% of pregnancies in Sri Lanka were unplanned [12].

Methods

A descriptive cross-sectional study was conducted between April 2020 and January 2021 in three randomly Medical Officer of Health areas in the Thimbirigasyaya Divisional Secretariat Division of the Colombo Municipal Council. A total of 425 antenatal mothers who fulfilled the inclusion criteria were included in the study. Any antenatal mother who had difficulties in hearing the questions asked or difficulties in speaking in response to the questions asked by the interviewer, antenatal mothers residing in that area for less than six months duration and mothers who visited the clinics while being registered in antenatal clinics not belonging to the study setting were excluded from the study. The sample size was calculated using the formula by Lwanga & Lemeshow [13]. Since the exact prevalence of the main outcome variable (prevalence of unplanned pregnancies) is not available and since there were no recent (within 5 years) literature or studies done on this topic in this setting, prevalence (p) was assumed as 50% to calculate the sample size.

The consecutive sampling method was used and the final sample size included 425 antenatal mothers from three antenatal clinics in the Thimbirigasyaya Divisional Secretariat. There were no nonresponders as all antenatal mothers who fulfilled the inclusion criteria were willing to participate in the study. Interviewer administered questionnaire was used for data collection. Construction of the interviewer-administered questionnaire was done by doing a thorough literature review and analysing the variables and associated factors for unplanned pregnancies. Pre-testing of the questionnaire was done at the antenatal clinic in Slave Island which belongs to the Colombo Divisional Secretariat Division of the Colombo Municipal Council. Following the pretesting, some questions were modified to make it more easily understood by antenatal mothers with basic educational levels by reducing scientific and technical terms. Prior permission had been obtained from relevant authorities to carry out this study. On each day of data collection, the principal investigator clearly explained the purpose of the study to the antenatal mothers in the waiting area of the clinic. Thereafter information sheets were distributed for further information. Subsequently, consent forms were given to obtain written consent from mothers willing to participate in the study who fulfilled the inclusion criteria. Duplication of data was prevented by taking note of the pregnancy record registration numbers of antenatal mothers who had attended the clinic during the previous week or weeks.

Interviewer bias was nil as only the principal investigator was involved in data collection, analysis, and interpretation. Recall bias was kept to a minimum by asking the antenatal mothers about their most recent pregnancies. Perusing pregnancy records for additional information on the current pregnancy was used to minimise information bias. Selection bias was kept to a minimum, as all antenatal mothers attending the respective antenatal clinics on the day of data collection, who fulfilled the inclusion criteria were included in the study. The reliability of the questionnaire was checked by translating it from English to Sinhala and Tamil and then translating it back to English. Statistical analysis of the data was done using Chi-Square testing and p values at a 95% confidence interval. Odds Ratio was used to assess the strength of association between the planning status of the pregnancy and its associated factors. Data analysis was conducted using the Statistical Package for Social Sciences (SPSS) version 21.

Ethical clearance was obtained from the Ethics Review Committee of the Postgraduate Institute of Medicine, University of Colombo, Sri Lanka (Approval Number: ERC/PGIM/2020/091).

There was no lack in antenatal care for the study participants by withdrawing from data collection. Data collection was carried out thus maintaining the privacy of the participant while giving them all the necessary information about the study. They had full control over their decision-making ability, autonomy and enrolment in the study. The knowledge obtained from the data collection was only used for research purposes and all study participants were made aware of it. There are no conflicts of interest.

Results

The total sample size was 425 and there were no non responders as all participants were willing to join the study. The age distribution was between 15 to 44 years. The age group of 22 to 34 years included 83.2% of the total study population. There were 37.2% Sinhalese, 33.9% Moors and 28.9% Tamils in the study sample. The prevalence of unplanned pregnancies was 32.7% in the study population. The 95 % confidence interval was 28.26 – 37.39. Being married (p = <0.05, OR = 3.08, CI. = 1.15-8.3), mother being employed in the preceding 12 months (p = <0.001, OR = 4.18, CI. = 2.32-7.53), number of past conceptions being two or less (p = <0.05, OR = 2.1, CI. = 1.06-4.12), intake of folic acid before pregnancy (p = <0.001, OR = 2.27, CI. = 1.5-3.43) had statistically significant associations with planned pregnancies at 95% confidence interval (p < 0.05). Marital age less than 20 years (p = <0.001, OR = 0.3, CI. = 0.19-0.47), highest education level of mother being less than Grade 11 (p = < 0.001, OR = 0.42, CI. = 0.25-0.68), highest education level of spouse being less than Grade 11 (p = <0.05, OR = 0.48, CI. = 0.29-0.79), monthly household income of less than LKR 25,000 (p = <0.001, OR = 0.47, CI. = 0.31-0.72), interpregnancy interval of less than 24 months (p = <0.001, OR = 0.25, CI. = 0.12-0.53), using family planning practices in the past (p = <0.05, OR = 0.62, CI. = 0.4-0.94), never wanting or expecting the current pregnancy (p = <0.001, OR = 0.02, CI. = 0.0096-0.064) and not planning for another pregnancy (p = <0.001, OR = 0.31, CI. = 0.2-0.47) had statistically significant associations with unplanned pregnancies at 95% confidence interval (p < 0.05).

Being less than 20 years of age at first pregnancy (OR = 0.67, CI. = 0.36-1.24), contraception use in the month of pregnancy (OR = 0.57, CI. = 0.32-1.05), time of first antenatal clinic registration within 12 weeks of gestation (OR = 1.5, CI. = 0.88-2.56), number of children expected after marriage being two or less (OR = 1.04, CI. = 0.61-1.74), having home visits by health care workers during antenatal period (OR = 0.79, CI. = 0.53-1.19) and mother visiting the hospital for any other medical condition during the pre-pregnancy period (OR = 0.66, CI. = 0.39-1.13) did not show any statistically significant association with planning status of the current pregnancy at 95% confidence interval (p > 0.05).

Discussion

Unplanned pregnancy is either unwanted, such as one that occurs when there are no other children or when no further children are desired, or the pregnancy was mistimed, with the baby arriving earlier than expected (Centers for Disease Control & Prevention, 2021). The prevalence of unplanned pregnancies in the Thimbirigasyaya Divisional Secretariat Division of the Colombo Municipal Council was 32.7% (139 out 425 study participants) and the 95 % confidence interval was 28.26 – 37.39.  There is a statistically significant association between the planning status of the current pregnancy and the marital status of the mother at a 95% confidence interval (p < 0.05). Being married is three times more likely to have a planned pregnancy (OR = 3.08, 95% CI: 1.15-8.3). Similar findings were seen in studies conducted in South Africa and Kenya. In South Africa, those married or living with their partners are more likely to have planned pregnancies and a significant association between marital status and unplanned pregnancies (p < 0.001) was seen [14].

There is a statistically significant association between the planning status of the current pregnancy and marital age at a 95% confidence interval (p < 0.001). Marital age of fewer than 20 years is 70% less likely to be associated with a planned pregnancy (OR = 0.3. 95% CI: 0.19-0.47). In a study done in Kenya, the prevalence of unplanned pregnancies was 51% between the ages of 15 and 19 years and 31% between the ages of 20 and 22 years [15].

The association between the planning status of the current pregnancy and the highest maternal education is statistically significant at a 95 % confidence interval (p < 0.001). The highest education level of the mother being less than Grade 11 shows a 58% less likelihood of having a planned pregnancy (OR = 0.42, 95% CI: 0.25-0.68). A sub–Saharan African multi-country analysis of the Demographic and Health Surveys of 29 countries showed that women with primary (OR = 0.74, CI = 0.69–0.80) and secondary (OR = 0.71, CI = 0.65–0.77) levels of education had fewer chances of unplanned pregnancies as compared to women with no education (Ameyaw et al., 2019). A statistically significant association between the planning status of the current pregnancy and maternal employment in the last 12 months is seen at a 95% confidence interval (p < 0.001). The antenatal mother being employed in the preceding 12 months has a four-time likelihood of having a planned pregnancy (OR = 4.18, 95% CI: 2.32-7.53). Similar findings were seen in a study done in Western Iran where unplanned pregnancies were 5.08 times more among housewives (p < 0.001) as compared to employed women [16].

There is a statistically significant association between the planning status of the current pregnancy and the husband’s education at a 95% confidence interval (p < 0.05). The highest education level of the spouse being less than Grade 11 is 52% less likely to have a planned pregnancy with his spouse (OR = 0.48, 95% CI: 0.29-0.79). There were more spouses among the planned pregnancy group who had completed Tertiary education as compared to the unplanned pregnancy category. Unplanned pregnancies were less common and least likely to occur (p < 0.05) among women who had husbands with some College or University education according to a study done in Southern Ethiopia [17]. There is a statistically significant association at a 95% confidence interval between the planning status of the current pregnancy and monthly household income (p < 0.001). Antenatal mothers having a monthly household income of less than LKR 25,000 are 53% less likely to have planned pregnancies (OR = 0.47, 95% CI: 0.31-0.72). Poor household income has been shown to cause unplanned pregnancies (p < 0.001) with an odds ratio of 1.7 in a study conducted in Canada [18].

There is a statistically significant association between the planning status of the current pregnancy and the interpregnancy interval of the mother at a 95% confidence interval (p < 0.001) in this study. Having an interpregnancy interval of fewer than 24 months has a 75% less likelihood of having a planned pregnancy (OR = 0.25, 95% CI: 0.12-0.53). The National Survey of Family Growth conducted in the United States of America showed that of the 40% of unplanned pregnancies, 36% had an interpregnancy interval of fewer than 18 months. It also concluded that as the interpregnancy interval increased, the prevalence of unplanned pregnancies decreased [19]. The association between the planning status of the current pregnancy and the timing of folic acid intake is statistically significant at a 95% confidence interval (p < 0.001). Antenatal mothers who had consumed folic acid before the current pregnancy have more than twice the chance of having a planned pregnancy (OR = 2.27, 95% CI: 1.5-3.43). A study done in the United States of America showed that women who said that their pregnancies were planned are more likely to confirm taking folic acid in the preconception period, with an odds ratio of 3.7 (95% confidence interval: 2.38 – 5.56) after controlling for maternal age and income [20].

A statistically significant association is seen at a 95% confidence interval between the planning status of the current pregnancy and the number of past conceptions (p < 0.05). Having less than two past conceptions is twice as more likely to have a planned pregnancy (OR = 2.1, 95% CI: 1.6-4.12). A case-control study in Western Iran revealed a significant association between unplanned pregnancies and previous live births (p < 0.001), with risk increasing by 2.97 per one already living child. A statistically significant association is not seen between the planning status of the current pregnancy and maternal age at birth of the first child at a 95% confidence interval (p > 0.05). In a community-based cross-sectional study done in Nepal, 60.5% of unplanned pregnancies were among women who had delivered their first child at or before they were 20 years of age [21]. As only mothers having at least one live birth were considered, and a significant amount of the study population (204 out of 425) were either having their first pregnancy or not having a live birth in the past, a statistically significant association with the planning status of the current pregnancy was not found.

There is no statistically significant association between the planning status of the current pregnancy and the time of first antenatal clinic registration by the antenatal mothers at a 95 % confidence interval (p > 0.05). Though there is no statistically significant association in this study, a systematic review and meta-analysis done in 2013 on the effects of pregnancy intention on the use of antenatal care services showed that a significantly higher number of women with unplanned pregnancies not attending their first antenatal care clinics on time as compared to women with planned pregnancies (Odds ratio: 1.42, 95% confidence interval: 1.27 – 1.59) [22]. In the above systematic review, the median duration of pregnancy at the time of the first antenatal clinic registration by the pregnant mother was five months, as compared to Sri Lanka, where antenatal mothers register by 12 weeks. The meta-analysis included only 32 articles though 422 were initially identified through searches and was conducted in a rural population in Ethiopia as compared to this study which was done in an urban setting. These could be reasons for the difference in the findings between this study and the systematic review [23,24] Table 1.

There is no statistically significant association at a 95% confidence interval between the planning status of the current pregnancy and home visits by health care workers in the antenatal period (p > 0.05). According to data from the Family Health Bureau, the percentage of pregnant women having at least one home visit by a Public Health Midwife (PHM) was 91.9% (Family Health Bureau, 2015). As most antenatal mothers in Sri Lanka receive at least one home visit during their antenatal period by a health care worker, there is no statistically significant association with the planning status of pregnancy.

Declaration of interest

No conflict of interest could be perceived as prejudicing the impartiality of the research reported.

Funding

This research did not receive any specific grant from any funding agency in the public, commercial or not for profit sector.

Author contribution

Psn was the principal investigator in the study and was involved in data collection, analysis and report writing.

Acknowledgements

The dissertation was mainly based on the experience the principal investigator had while working as a Senior House Officer in Obstetrics and Gynaecology at Teaching Hospital Batticaloa between the years of 2014 to 2017. The principal investigator, especially among antenatal mothers who attended the hospital antenatal clinics, observed unplanned pregnancies and their adverse outcomes. It is also a major public health problem all over the world and hence the principal investigator thought it would be an ideal topic to do a dissertation on, especially at a time when there is a COVID 19 pandemic. The principal investigator would also like to thank the various officials who were involved in permitting to collect data at Borella, Kirula and Wellawatte antenatal clinics, especially during the COVID 19 pandemic. Many people were very helpful during the period of data collection, analysis, and dissertation writing. The principal investigator would like to thank all of them.

There was no funding, grants or equipment provided as a source of support for this study. There are no conflicts of interest.

Abstract

Introduction: It is important to note the risk COVID-19 poses to the demographic of recovering postoperative patients and ascertain identifiable factors which may reflect on their prognosis.

Aim: To explore the 30-day postoperative outcomes among COVID-19 positive patients operated for acute appendicitis (AA) in Dubai Hospital while surveying their relation to age, gender, modality of management, type of operative technique, presence of pre-existing conditions, smoking habits, preoperative vital signs and laboratory results, and other variables. In addition, we aim to assess the relation of length of hospital stay with the aforementioned variables.

Methods: Our study is a retrospective electronic medical record (EMR) review of 68 patients admitted to the general surgery department of Dubai Hospital and who underwent conservative or surgical management of acute appendicitis between March 1 and December 31, 2020. Analysis was performed with a 30-day follow up. The data was retrieved from electronic medical records (EMR) via the SALAMA (EPIC) system and then recorded using a Microsoft Excel spreadsheet.

Results: Our results showed that, out of the 68 patients included in the study, 6 (9%) patients were found to be COVID-19 positive. 7 patients (10%) were managed conservatively, 1 of which was COVID-19 positive, while the remaining 61 (90%) patients underwent operative management. Only 1 (1.5%) patient (COVID-19 negative) developed complications requiring ventilation and ICU (intensive care unit) admission. Length of hospital stay (LOS) for COVID-19 positive patients was 6.5 days ±4.57 while LOS for COVID-19 negative patients was shorter at 3.8 days ±2.14.

Discussion/Conclusion: Our data revealed no significant complications in COVID-19 positive patients who were diagnosed with AA regardless of the method of treatment adopted. However, LOS was prolonged for these patients in comparison to the COVID-19 negative group. Therefore, we recommend that the choice of treatment be made on a case-by-case basis.

Keywords: perioperative COVID-19, COVID-19, acute appendicitis, appendectomy

Introduction

COVID-19, or Coronavirus disease 2019, caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), was declared a global pandemic by the WHO on March 11, 2020 [1]. Since then, the virus has spread across the globe, causing significant financial and economic burden. This has been in part due to the creation of qualified and specialized medical teams, COVID-19 units, increase in ICU beds, enhancement of medical supply chains, increased requirements for personal protective equipment, creation of field hospitals, production and use of PCR swab tests, and rising health insurance costs. With nearly 90 per cent of the global economy being affected during lockdown [2], any means of alleviating the financial burden of healthcare during the pandemic are of paramount importance.

In order to cope with the increased medical demand in the initial phase of the COVID-19 pandemic, many hospitals and medical centers elected to suspend non-emergent and elective surgeries to reduce the transmission of COVID-19 between infected individuals, patients, and staff  [3]. During this time, only emergent surgeries were performed. The most common surgical emergency, acute appendicitis, serves as an excellent target for assessing differences in surgical outcomes between SARS-CoV-2 negative and positive patients. Additionally, numerous factors may affect perioperative morbidity and mortality rates among this group of patients, such as changes in clinical presentation and severity [4], conversion of laparoscopic to an open surgical approach due to poor early guidelines [5] and fear of aerosolization of blood borne viruses [6], and delay in initiation of surgical management in favor of non-operative management (NOM) [7].

Surgical patients are especially vulnerable to SARS-CoV-2 infection as the derangements of metabolic and physiological processes linked to surgically-induced stress response can lead to deviations in acute phase inflammatory responses. Hypermetabolism and hypercatabolism associated with this stress response can lead to impaired immune function through elevations of catecholamines, cortisol, and inflammatory cytokines. In addition, this group of patients is at a higher risk of pulmonary complications due to immunosuppressive responses to mechanical ventilation [8]. It is imperative that measures are taken to identify predictors of perioperative morbidity and mortality in COVID-19 positive patients, in order to reduce patient suffering, mortality rates, and the national financial and medical burden.

Materials and Methods

This study is a retrospective chart review of the electronic medical records of 68 patients diagnosed with acute appendicitis (AA) and admitted to the general surgery department of Dubai Hospital, UAE, for conservative or surgical management of acute appendicitis between March 1 and December 31, 2020. Conservative treatment was defined as treatment with antibiotics and supportive management alone. Ethical approval was obtained from the Dubai Scientific Research Ethics Committee (DSREC). Patients admitted within this time period without a nasopharyngeal RT-PCR swab for COVID-19 on admission were excluded from the study. All demographic, clinical, radiological, and laboratory data was retrieved from the SALAMA electronic file system.

Variables evaluated for each patient include: age, sex, COVID-19 status, modality of management (conservative or operative), incidence of complications, type of surgical technique if managed operatively (open or laparoscopic appendicectomy), past medical and drug history, presence of pre-existing comorbidities, smoking status, preoperative vital signs (temperature, heart rate, respiratory rate, and blood pressure), radiological findings on chest x-ray if COVID-19 positive, preoperative laboratory markers, and length of hospital stay. The data was entered into the data collection tool (Microsoft Excel spreadsheet), exported, and analyzed in SPSS Version 22 software using Fisher’s exact test. The analysis was carried out in accordance with the Strengthening the Reporting of Observational studies in Epidemiology (STROBE) guidelines for observational studies.

Statistical Data and Analysis

This study is a retrospective chart review of the electronic medical records of 68 patients diagnosed with acute appendicitis (AA) and admitted to the general surgery department of Dubai Hospital, UAE, for conservative or surgical management of acute appendicitis between March 1 and December 31, 2020. Conservative treatment was defined as treatment with antibiotics and supportive management alone. Ethical approval was obtained from the Dubai Scientific Research Ethics Committee (DSREC). Patients admitted within this time period without a nasopharyngeal RT-PCR swab for COVID-19 on admission were excluded from the study. All demographic, clinical, radiological, and laboratory data was retrieved from the SALAMA electronic file system.

Variables evaluated for each patient include: age, sex, COVID-19 status, modality of management (conservative or operative), incidence of complications, type of surgical technique if managed operatively (open or laparoscopic appendicectomy), past medical and drug history, presence of pre-existing comorbidities, smoking status, preoperative vital signs (temperature, heart rate, respiratory rate, and blood pressure), radiological findings on chest x-ray if COVID-19 positive, preoperative laboratory markers, and length of hospital stay. The data was entered into the data collection tool (Microsoft Excel spreadsheet), exported, and analyzed in SPSS Version 22 software using Fisher’s exact test. The analysis was carried out in accordance with the Strengthening the Reporting of Observational studies in Epidemiology (STROBE) guidelines for observational studies.

Results

84 patients were diagnosed with acute appendicitis between March 1 and December 31, 2020. Most patients were diagnosed clinically. Out of this group, 16 patients were excluded due to lack of nasopharyngeal RT-PCR COVID-19 swab on admission. The remaining 68 patients were entered in the study. 20 (30%) patients were female and 48 (70%) patients were male. 6 (9%) patients were found to be COVID-19 positive. Analysis of the demographic characteristics revealed no significant difference in the age or sex between both groups (conservative or operative). 7 (10%) patients were managed conservatively with antibiotics alone, 1 of them was COVID-19 positive. 61 (90%) patients underwent operative management, of which 8 (13%) patients had an open appendicectomy - 3 (4.4%) of them were COVID-19 positive - and 53 (87%) patients had a laparoscopic appendicectomy.

Figure 1: Flow chart for recruitment of patients in retrospective chart review.

Figure 2: Percentage of patients treated conservatively (blue), or operatively with open appendicectomy (orange), and with laparoscopic appendicectomy (grey) on a monthly basis during the study period.

Table 1: Comparison of patient characteristics by treatment group. Continuous data is presented as a mean with standard deviation. Categorical data are presented as numbers/denominators.

7 (10%) patients were found to have pre-existing comorbidities, none of which were respiratory in nature. 10 (15%) patients were found to be current smokers. Only 1 (1.5%) patient, COVID-19 negative, developed complications requiring ventilation and ICU (intensive care unit) admission. There were no mortalities among this patient group.

Preoperative vital signs were analyzed for all patients. 17 (25%) patients were febrile on pre-operative assessment, of which 2 were COVID-19 positive. 9 (13%) patients were tachycardic, of which 1 was COVID-19 positive. 6 (9%) patients had an elevated blood pressure. 1 (1.5%) patient was tachypneic. C-Reactive Protein (CRP) was elevated in 48 (71%) patients, of which 5 were COVID-19 positive. White blood cell count was elevated in 51 (75%) patients, of which 5 were COVID-19 positive. Neutrophil value was elevated in 54 (79%) patients, of which 5 were COVID-19 positive. Laboratory reference ranges are shown in Table 2. Among those testing COVID-19 positive, 6 (100%) patients had positive radiological findings on chest x-ray, 3 (50%) had elevated ferritin levels, 2 (33.3%) had elevated d-dimer levels, and 1 (16.67%) had elevated lactate dehydrogenase (LDH). Laboratory reference ranges are shown in Table 2.

Table 2: Laboratory markers reference ranges and units.

There was no significant difference in the length of hospital stay (LOS) between the conservatively and operatively managed groups; the LOS in conservatively managed patients was 4.43 days ±5.29. The LOS in operatively managed patients was 4.00 days ±2.16. However, LOS for COVID-19 positive patients was 6.5 days ±4.57 while LOS for COVID-19 negative patients was shorter at 3.8 days ±2.14. Furthermore, the mean hospital stay for those who swabbed positive and underwent open laparotomy was 5.3±2.05 in comparison to a mean of 4±2.68 in those who were negative. As for laparoscopic appendicectomy, there was less difference in the LOS, with the LOS for COVID-19 positive patients at 3.5±0.5 in contrast to 3.94±2.09 for negative patients.

Discussion

Appendicitis is defined as an inflammation of the vermiform appendix which results from an obstruction of the appendix lumen either mechanically or through fecalith impaction resulting in bacterial overgrowth. It is one of the most common surgical emergencies with a global incidence rate of 1%. [9] The classical presentation of the disease manifests as periumbilical abdominal pain that migrates to the right lower quadrant, in association with anorexia, nausea, vomiting, and fever. Appendicitis is most often diagnosed clinically, however, a diagnostic computed tomography (CT) scan of the abdomen carries a sensitivity of 98.5% [10]. Management is typically surgical, either through laparoscopy, or through open laparotomy reserved for complicated cases. Furthermore, conservative management through antibiotics and supportive measures can also be adopted. Complications may include appendicular abscess, perforation, and peritonitis. Following the emergence of SARS-CoV-2, the declaration of the COVID-19 pandemic had an immense impact on healthcare systems worldwide. Surgical procedures were affected through major delays or cancellations as hospitals sought to decrease surgical caseload and capacity pressures as a result of the pandemic. Non-emergent or elective surgeries were similarly cancelled in our facilities due to the emergence of COVID-19 cases. However, appendicitis was managed in a very compelling way. Diagnosis was reliant on CT scans rather than clinical diagnosis and scans were performed for every patient regardless of their age group, in an effort to treat the case appropriately.

A conservative approach using antibiotics was instilled in our facility whenever possible in treating uncomplicated cases of acute appendicitis in accordance with national guidelines [11]. On the other hand, complicated cases, along with those patients who did not respond to conservative management, were treated operatively with appendicectomy. Patients managed conservatively were given empiric broad-spectrum antibiotics (metronidazole and ceftriaxone) for a duration of 10 days.  86% of patients in this group were COVID-19 negative; with 50% of them being hemodynamically unstable, according to the normal ranges of vital signs established by the American College of Emergency Physicians (ACEP) guidelines. The mean LOS was 2.5± 1.38. The remaining 14% of patients were COVID-19 positive, hemodynamically stable, with normal laboratory parameters and a mean LOS of 16 days due to the isolation period of 14 days being included in the calculation. Furthermore, both groups had abnormal inflammatory marker values and neither group had long lasting complications. These findings are consistent with existing published articles stating that conservative management is an effective means of treating appendicitis in patients that are COVID-19 positive [12-14].

50% of the population who tested positive underwent open laparotomy in comparison to only 9% of those who did not. This notable difference could be attributed to early guidelines set in place during the start of the pandemic, as many sources encouraged surgeons to minimize laparoscopic procedures for COVID-19 positive patients in fear of viral transmission through aerosolization. However, as ongoing research is being conducted regarding the matter, many recent publications have since revealed that there is no strong evidence of increased risk [15-17]. Our data revealed only one COVID-19 negative patient who developed postoperative complications out of all the patients included in this study who were surgically managed for AA, regardless of COVID status. The patient, a 71 years old male known to have diabetes mellitus and hypertension treated with regular medication, developed pulmonary complications requiring ventilation and ICU admission which increased his length of hospital stay to 12 days. This comes in contrast to the expected outcomes of increased postoperative complications in COVID-19 positive patients who underwent emergency surgery according to a report [18]. However, it is worth noting that most of our patients are young and had no previous comorbidities, therefore, decreasing their chance of developing postoperative morbidity or mortality.

Keeping in mind that open appendicectomy can increase the length of hospital stay, thus placing COVID-19 negative patients at an increased risk of developing the infection during hospitalization, we recommend that the length of hospital stay be reduced to the minimum to decrease this risk. In addition, as our results show no difference in outcome between conservative and surgical management, we also recommend that the choice of treatment be made on a case-by-case basis and evaluation of the risk-to-benefit ratio for each individual, as well as taking into consideration the performing surgeon's expertise and comfort. As is now standard in many hospitals, incorporating pre-operative swabbing as part of routine procedures allows the physician to plan accordingly. Furthermore, we highly recommend for surgeons to adamantly follow protective measures to reduce the risk of contracting the virus as much as possible; this includes proper handwashing and hygiene as well as the proper use of personal protective equipment (PPE). Limitations in our research included lack of postoperative follow up and inadequate information about the patients’ past medical and social history.

Conclusion

Our retrospective chart review of patients diagnosed with and treated for acute appendicitis between March 1 and December 31, 2020 in Dubai Hospital included a total of 68 patients. Cases of acute uncomplicated appendicitis were managed conservatively, while complicated cases or those who failed to respond to medical management were operated. In summary, our data revealed no significant postoperative complications in COVID-19 positive patients undergoing appendectomy regardless of the method of treatment adopted (open vs. laparoscopic). However, the LOS was prolonged for these patients in comparison to the COVID-19 negative group. Therefore, COVID-19 infection should not be used as a singular variable when deciding the modality of treatment, but rather each case should be considered independently to assess existing risk factors, deliver the best management plan, and avoid complications.

Abstract

Objective: The penis fracture is indeed growing in incidence, of various causes, the most frequent of which in the Maghreb is the manipulation of an erect penis. Its management aims at both anatomical and functional restitution of the penis because the evolution can be crowned with complications. The purpose of our study was to assess the condition of the penis after its fracture.

Patients and methods: We report a mono-centric cross-sectional study from January 2015 to December 2019 in the fracture surgery department. The parameters studied were: age, mechanism of occurrence, clinical and surgical data, and then postoperative follow-up. Checks had been carried out on the 1st and 2ed week and 1st, 3rd, 6th and 12th month. The complications were: aesthetic (repair scar and restain of penis curvature) and functional (discomfort during sexual intercourse and erectile dysfunction); erectile dysfunction was assessed according to the International Erectile Function Index (IIEF-5).

Results: One hundred and seventy-one patients had operated with an average age of 99 years. Forced maneuver on the erect penis was predominant (40%) followed by missteps by coitus (27%). The doggy position was in the majority (46.81%). The coronal first was in the majority (120 cases); the frequency of short- and long-term complications was 18.71% after a 15-month decline; the majority of patients (123 cases) had a duration of abstinence between 1 and 2 months. No patient had a penile fibrosis plaque and three had a penis curvature of less than 15° without sexual impact. The mean IIEF5 score was 18, two patients had severe erectile dysfunction. There were correlations between duration of abstinence and IIEF5 score (P < 0.05). The time of consultation, the duration of abstinence, and the length of the fracture line as well as the duration of surgical management were factors influencing the occurrence of complications (P < 0.05).

Conclusion: In short, with 18.71% of the complications of penis fracture, it is necessary to proceed to primary management (eviction of forced maneuver on the erect penis, of certain sexual postures), secondary (early and adequate surgical intervention), or even tertiary (respect of the abstinence period) to preserve or restore the anatomy see the functioning of the penis.

Introduction

The fracture of the corpora cavernous is a rare urological emergency but emerging from the point of view of incidence. It is defined by the rupture of the albuginea of the cavernous bodies during erections. Of various causes, the fracture of the penis is often due, in the Maghreb, to forced manipulations either during masturbatory maneuvers or to reduce or disguise an embarrassing erection. Surgery stays the indisputable treatment either elective or coronal, however, any delay or non-use of surgery is a source of complications (functional or aesthetic). Thus the purpose of our study was to assess the state of the penis after the fracturing of the cavernous body.

Patients and Methods

From January 2015 to December 2019 (5 years), we conducted, within the urology department of the Ibn Rochd University Hospital in Casablanca, a monocentric transversal study on fractures of the cavernous bodies of the penis. All patients aged at least 15 years with a cavernous body fracture were included, all were consenting to the study. Patients who had ruptured albuginea by self-harm, as well as those with a particular history (of cavernous body fracture, pre-existing erectile dysfunction, penis curvature), were not included (5 patients). Several parameters were studied: age, marital status, mechanisms of occurrence, consultation time, clinical data (cracking sensation, penis pain, hematoma, penis curvature, urethritis) ultrasound, and surgical than the evolutionary results of treatment taking into account the duration of abstinence after surgery(in months). The mechanisms of occurrence were classified as follows: masturbation, shock on erect penis, turning on erect penis during sleep, forced maneuver on erect penis, coitus misstep (Andromachus, and vaginal doggie, men on top, women on top, missionary). All patients had been operated on within 24 hours of admission, under spinal anesthesia. The way first was either elective or coronal. A braided thread 3.0 and 4.0 raphie with rapid resorption had been made in all our patients respectively on the albuginea and the urethra (in case of lesions), they had all been put on analgesics and anti-edematous. They had been reviewed post-operatively on the 7th,15th day (for the removal of the bladder probe in case of associated urethral rupture) and 1st 3rd, 6th, and 12th months (in search of complications, see references).

The complications were grouped into two groups: (E) aesthetic (repair scar and restain of penis curvature) and (F) functional (discomfort during sexual intercourse and erectile dysfunction); erectile dysfunction was assessed according to the International Five-Point Erectile Function Index (IIEF-5) and intracavernous injection of prostaglandin (Caverject 20μg) or saline in patients reporting a deviation or curvature of the penis during an erection in order to objectify this deviation. Due to the lack of flowmetry in our department, we used the urinary symptom profile (USP)score alone for the evaluation of lower urinary tract disorders in the follow-up of patients with a repaired urethral lesion, followed by the realization of retrograde urethrocystography at six months.

The analysis of the data was done by the epi software info.7, the ki2 test was used to compare them with a significant threshold ˂5%.

Results

We analyzed 176 files, 171 cases had been retained. The mean age was 35.99 years (extremes 15 to 67 years). There were 87 married (50.88%) and 84 single (49.12%).The majority of our patients had consulted within the first 24 hours(76% of cases), and in 24% of cases after 24 hours. Yard hematoma was the predominant symptom (Figure1) and forced maneuver on the erect penis was the most frequently encountered mechanism of occurrence (Figure2). Among the mechanisms of interrupted coitus, we noted: the position doggy style (22 cases) including 20 vaginal and 2 cases of, the position  ̋ andromache ̋ (14 cases) and the position ̏missionary ̋ (11 cases). The study was more oriented to the right than to the left in 77.78% and 22.22% respectively.

The hematoma was over the entire penis, at the proximal, distal, and scrotal levels respectively in 72.51%, 16.96% 7.02%, and 3.51% of cases. Ninety-seven patients had an ultrasound of the penis and the fracture was objectified in 73 patients. The fracture trait was proximal, distal, and mid axial respectively in 46, 7, and 20% of cases. Of the 120 coronal incisions, 78 were longitudinal and 42 transverse and the selective incision was made in 51 patients. The predominant fracture line length was between [1 and 2]cm (Figure3). The type of sutures of the albuginea was overjet, single stitches, and inverted stitches in 1.94%, 7.74%, and 90.32% respectively.

The average duration of intervention was 49 min (extremes of 30 and 90 min), and that of hospitalization of 26.54 hours (extremes of 24 and 72 h). There was an average pick-up time of 2.5hours (extremes of 45 minutes and 15 hours). No complications were noted intraoperatively or in the immediate post-operative period. However, Thirty-two patients had short- and long-term complications at near an average decline of 15 months [extremes of 9 and 68 months] or 18.71%, distributed as follows: 15 cases of aesthetics, 9 cases of functional, and 8 cases were aesthetic associated with functional. During the evolutionary phase, discomfort during the sexual intercourse was the predominant functional complication (Table 1). No patient had a fibrosis plaque on the penis and three had a penis curvature whose angle was less than 15 ° without impact during sexual intercourse (see Table 1). Erectile dysfunction accounted for 25% of complications and 5% in the overall study population.

The average time of abstinence after surgery was 2.5 months, the majority of our patients had a duration of abstinence between one to two months in 72% of cases, and less than a month and beyond 2 months there were respectively 10 and 18% of cases.­ There was a correlation between the occurrence of complications and the duration of sexual abstinence (Table 2). There was no causal link between the type of suture, the type of coitus misstep, and the occurrence of complications (P>0.05). Similarly, no type of coitus misstep had an impact on the length of the penis fracture line (P>0.05, ki(2)=12.79). However, we have identified correlations between fracture length and the occurrence of complications (Table 3) then the occurrence of erectile dysfunction, and the time to sexual abstinence (Table 4).

USP score

The USP score of the patient who had a urethral rupture does not show dysuria and his reteograde urethrograme was normal at the 6th month.

Annex: Appearance of the penis at 3 months of follow-up after fracture of cavernous body

Discussion

Many authors note a significant frequency of fracture of cavernous bodies related to forced maneuvers of an erect penis in Maghreb and Eastern countries [1-3], however, it is no less in case of interrupted coitus [4], such as the case of our series. The latter can be explained by the fact that our study population was so young with an average age of 35.99 years and the majority of whom were married, therefore in full sexual activity. The doggy position was the most predominant of the mechanisms in case of interrupted coitus followed by the Andromachus; our results corroborate those of some authors [5-6]. This is explained on the one hand when the man is in a dominant position and very excited, sexual intercourse can become extremely vigorous, triggering a greater impact at the moment when the penis slides out of the vagina and hits against the perineum or pubic symphysis. On the other hand when the woman is on the man and then inadvertently lands all her weight on the erect penis if it slips out of the vagina.

Although it is recognized that clinical history and genital examination are the mainstays of diagnosis, there is no consensus on how to exclude a concomitant urethral lesion, which can be present in almost a third of cases. Most authors agree that urethral catheterization should be avoided when a urethral injury is suspected and a suprapubic catheter should be inserted for drainage [7-8]. No correlation was noted between sexual position and penile injury severity in our study, as is the case in a meta-analysis in which no impact of relative risk was objectified [9].

The diagnosis of penile fracture was essentially clinical, based on the stereotypical history of the accident and physical examination. No paraclinical examination is required for diagnosis in typical forms [10-12]. However, in frustrated or late-sighted forms some authors recommend Color Doppler ultrasound, retrograde urethrocystography, cavernography, or magnetic resonance imaging (MRI) [11-13]. Retrograde urethrocystography finds its only indication in the rupture of the associated urethra. MRI makes a precise lesion assessment on the location and extent of the rupture of the albuginea of the cavernous body as well as the associated lesions such as a rupture of the spongy body or urethra [14]. Its disadvantage is related to its cost and availability. Doppler ultrasound is a non-invasive examination, less expensive than MRI, reliable when performed by experienced hands, which can highlight the rupture of the albuginea and hematoma even under albuginea [11,15-16]. In our case,­we have not used any of these examinations because of their unavailability as a matter of urgency.

The coronal approach was the most used in our study, it is the preferred route because it allows better exposure and exploration, it is the gold standard in case of bilateral lesion or complete urethral involvement [17-18].

However, several authors report the risk of edema, infection, and skin necrosis during the coronal approach of penis fracture [19]. We have not had any cases of infection or edema of the penis, this can be administered to all our patients of antioedematous. Some authors state that the lateral and longitudinal incision in front of one of the cavernous bodies allows an elective approach to the focus of fracture without skin risk but sometimes at the cost of an unsightly scar [4].

We noted a short- and long-term complication rate of 18.71% in our study with a predominance of discomfort during sexual intercourse and erectile dysfunction, similar to those of many authors [20]. This frequency in our series can be explained by the non-respect of the required period of abstinence in post-operative in some because we note a correlation between the time of abstinence and the occurrence of complications (P<0.05). The erectile dysfunction observed after penile fracture appears to be more related to a venous cause (leakage of venous blood into the spongy body) than to an arterial cause due to cavernous artery failure [21-23].

The origin of this dysfunction in our series was not known, because we have not resorted to echo-Doppler in the search for etiology. However Rajkumar, in a series of 18 cases of penis fractures, had objectified to Doppler an insufficiency of the cavernous artery in one of the patients who had erectile dysfunction after a follow-up of 3 months [22]. In our series, we have highlighted a correlation between the length of the fracture line and the occurrence of short- and long-term complications (P<0.05). We think that the size of the fracture line would be at the origin of huge fibrosis of the albuginea therefore source of stretch curvature and on the other hand of significant leakage of cavernous venous blood in the spongy, the cause of erectile dysfunction. The subjectivity of questionnaire responses is also a bias in the assessment of sexual function in our patients.

Conclusion

The penis fracture (Although rare) is a pathological entity due mainly to the forced maneuver of an erect penis and by the sexual act, whose inadequate or delayed management can be enameled with both functional and aesthetic complications, reaching   18.71% in our series, with a correlation to the time of abstinence and the length of the fracture line. Thus the therapeutic base is based on preventive, secondary, and tertiary care adequate to maintain or restore the functional anatomy of the patient.

Summary

We are presenting a case of a venous thrombosis (VTE) caused by two very rare & more importantly surgically correctible co-existing factors. A proximal left lower limb deep vein thrombosis (DVT) and pulmonary embolisms (PE)s with lung infarcts - secondary to an abdominal aortic aneurysm (AAA) causing inferior vena cava (IVC) compression and venous stasis  with a coexisting May - Thurner  variant too, in case things weren’t interesting enough. Beware of the occasional Zebras (they do exist) when you are surrounded by horses. The patient underwent a successful open repair of both with a satisfactory outcome.

Background: Venous thrombo-embolism (VTE) is a common and significant cause of morbidity and mortality in our current day to-day clinical practice and the need to further investigate unprovoked VTEs still remains very controversial despite many cohorts, reviews and meta analysis publications. Seek and thou shall find the unexpected sometimes - and looking further in unprovoked VTEs may lead on to not only diagnosing the underlying occult malignancies, but also reversible surgical pathologies as in this case.

Case Presentation

A 57 years old gentleman was referred to our Deep Vein Thrombosis (DVT) clinic with the history of left lower limb pain and swelling of one week duration, having already been started on Rivaroxaban by his General Practitioner. His past medical history was unremarkable, apart from a 100 pack-years smoking history. There were no obvious precipitating factors for a venous thrombo-embolism (VTE) nor red flags of an underlying malignancy. He was referred to our Ambulatory Emergency Care Unit (AECU) as he has also started complaining of dyspnoea at that point in time. Physical examination was unremarkable apart from the swollen left leg.

Investigations and Differential Diagnosis IF Relevant

A Doppler ultrasound of the left lower limb confirmed thrombus in all major deep veins of the left leg, extending to the left external iliac vein. An electrocardiogram(ECG) showed inverted T waves in anterior leads V1 to V3 (Figure 1), which was attributed to a right heart strain secondary to a possible pulmonary embolism (PE) in this clinical context. A chest X-ray was done which showed a Hampton’s hump (Figure 2), suggesting an underlying pulmonary infarction [1,2]. A computed tomography of pulmonary angiogram (CTPA) along with the computed tomography (CT) of the chest, abdomen and pelvis confirmed large bilateral pulmonary emboli (Figure 3) with suggestion of Right heart strain along with foci of consolidation in the upper lobe of the left lung likely secondary to haemorrhage or infarction (Figure 4). Although CT of abdomen and pelvis did not reveal any occult malignancy for which it was originally requested, surprisingly it did show an incidental 7cm abdominal aortic aneurysm (AAA) which was compressing and displacing the inferior vena cava (IVC), causing venous stasis (Figures 5 and 6), and a left common iliac artery compressing the left iliac vein separately (Figure 7), as picked up by the vascular team.

Figure 1: Electrocardiogram suggesting possible right ventricle strain.

Figure 2: Chest radiography showing Hampton's hump - Upper lobe of left lung.

Figure 3: Transverse CT pulmonary angiogram showing a large embolus in segmental branch of left pulmonary artery.

Figure 4: Transverse CT Chest showing peripheral pulmonary infarct in the left upper lobe abutting the oblique fissure.

Figure 5: Transverse CT Abdomen showing abdominal aortic aneurysm with displacement and compression of inferior vena cava lumen.

Figure 6: Coronal CT abdomen showing abdominal aortic aneurysm causing mass effect on the inferior vena cava and deep vein thrombosis in left common femoral vein.

Figure 7: Transverse CT Abdomen-Pelvis showing compression of left common iliac vein by the left common iliac artery.

Treatment if relevant

Patient was promptly referred to vascular surgeons team and the risk of anticoagulation in the context of aortic aneurysm was explained. When the vascular team reviewed the patient and the CT images, they were also concerned about an element of May-Thurner syndrome variant, specifically left common iliac artery compressing on the left common iliac vein, along with the AAA compressing the IVC possibly causing venous stasis at both sites.

Outcome and Follow-Up

He was treated with anticoagulation and he later underwent an open repair of the aortic aneurysm successfully. He made a complete recovery.

Discussion Include a very brief review of similar published cases

Venous thromboses are historically due to the Virchow’s triad of stasis, hyper-coagulability and lumen injury. Unruptured abdominal aortic aneurysm compressing and displacing the IVC causing venous stasis has been well described in literature [3,4,5]. May-Thurner syndrome, which is a rarely diagnosed condition in which patients develop iliofemoral deep venous thrombosis (DVT) due to an anatomical variant in which the right common iliac artery overlies and compresses the left common iliac vein against the lumbar spine, has also been well described as a cause of deep vein thrombosis in left lower limb [6,7]. in this specific case, what we have is a variant – left common Iliac artery causing compression and resultant venous stasis, of the  left common iliac vein, contributing additionally (and separately) to the left lower limb DVT. The management of abdominal aortic aneurysm usually varies between an Endovascular repair (EVAR) versus an open repair,[8,9], while the surgical options in May- Thurner syndrome may include Endo-vascular stenting plus or minus thrombectomy or bypass grafting or arterial repositioning in certain instances [7,10]. Having both pathologies contributing to DVT and PE at the same time, in the same patient is exceptionally rare. This rare combination often necessitates an open repair rather than endovascular approach and EVAR is often reserved only for those who are frail with co-morbidities, in whom an open approach isn't feasible [11]. The detection and treatment of venous thromboses and underlying pathologies have tremendously improved over the years. This case highlights and demonstrates the need of imaging in excluding underlying malignancies, as well as ruling out surgical causes / structural anomalies, especially with the current NICE guidelines moving further and further away from imaging in unprovoked VTEs [12]. The potential benefit of extensive screening over limited screening to no screening at all if they have no red flags of an underlying neoplasm have been heavily debated over the past two decades, with the occurrence of underlying occult malignancies generally being thought to being anywhere between 4 to 9 % according to current studies [13].

Learning Points/Take Home Messages 3-5 bullet points

The relevance of ruling out reversible surgical causes / anatomical anomalies in unprovoked VTEs.

The role of imaging in unprovoked VTEs – further need to reassess this controversial topic.

The importance of having an open approach - to analyse and investigate each case on its own merit, often above and beyond the restraints of formulaic guidelines - often if you venture to explore further in unexplained scenarios, you shall find the rare and unexpected, yet potentially reversible causes, as in this instance.

Acknowledgment

The relevance of ruling out reversible surgical causes / anatomical anomalies in unprovoked VTEs.

The role of imaging in unprovoked VTEs – further need to reassess this controversial topic.

The importance of having an open approach - to analyse and investigate each case on its own merit, often above and beyond the restraints of formulaic guidelines - often if you venture to explore further in unexplained scenarios, you shall find the rare and unexpected, yet potentially reversible causes, as in this instance.

Regarding our Journal: https://oajclinicalsurgery.com/

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Abstract

Unplanned pregnancies are a major public health issue globally causing poor maternal and foetal outcomes. The objective of this study was to determine the prevalence of unplanned pregnancies & their associated factors among antenatal clinic attendees in Thimbirigasyaya Divisional Secretariat Division, Colombo, Sri Lanka. A cross-sectional study was conducted in three randomly selected antenatal clinics of the Thimbirigasyaya Divisional Secretariat Division of the Colombo Municipal Council. A total of 425 antenatal mothers were included in the study using a consecutive sampling method. Data collection was done using interviewer-administered questionnaires. Statistical analysis was done using the Chi-Square test, Odds Ratio and 95% confidence interval. The prevalence of unplanned pregnancies was 32.7% in the study population. The 95 % confidence interval was 28.26 – 37.39. Being married, the mother being employed in the preceding 12 months, the number of past conceptions being two or less & intake of folic acid before pregnancy had statistically significant associations with planned pregnancies at 95% confidence interval (p < 0.05). Marital age less than 20 years, highest education level of the mother being less than Grade 11, highest education level of the spouse being less than Grade 11, monthly household income of less than LKR 25,000, the interpregnancy interval of fewer than 24 months, using family planning practices in the past, never wanting or expecting the current pregnancy and not planning for another pregnancy had statistically significant associations with unplanned pregnancies at 95% confidence interval (p < 0.05). According to the study, one-third of the pregnancies were unplanned & a statistical significance at 95% confidence interval was seen between the planning status of the current pregnancy and twelve of the eighteen variables studied.

Keywords: prevalence, unplanned pregnancies, associated factors, antenatal mothers, Sri Lanka

Lay Summary

Data on prevalence is important to help in resource allocation and prioritisation of activities by relevant stakeholders. The prevalence data would also help to identify the magnitude of the problem related to unplanned pregnancies in a given population under study by assessing its overall burden. It would also support the process of identification of priorities in healthcare, preventive activities and policymaking which is needed to develop a health economics model to address issues related to unplanned pregnancies.

There is a lack of recent data on the prevalence of unplanned pregnancies in this study population in an urban community setting in Thimbirigasyaya Divisional Secretariat Division which falls under the Colombo Municipal Council. It is important to identify associated factors for any public health problem, as it would provide data on the most important associated factors to be addressed and would help to prioritise them. Identifying and addressing associated factors for unplanned pregnancies among the targeted population would improve their sexual and reproductive health and help to implement necessary interventions and provide health-related services on unplanned pregnancies.

Introduction

Unplanned pregnancies

Pregnancies can be broadly divided into planned/wanted pregnancies and unplanned pregnancies. Unplanned pregnancy is a major public health issue the world over. In unplanned pregnancies, conception has occurred not at the desired time and was expected later or was never expected or wanted.

Associated factors for unplanned pregnancies

The common cause of unplanned pregnancies has been identified as not using contraception or due to not using a contraceptive method consistently or correctly or both [1]. Marital age, marital status, age at first pregnancy, education level of the couple, employment status of the mother, monthly household income, interpregnancy interval, disrupted marital life and gender-based issues are some of the factors associated with unplanned pregnancies [2].

Adverse outcomes of unplanned pregnancies

Unplanned pregnancies have been a major cause of induced abortions the world over and have been linked to poor maternal and child health outcomes causing an increased risk of abortion-related death and morbidity, especially in countries where abortion is illegal [3]. Women with unplanned pregnancies are more vulnerable to committing suicide, have poor nutrition during gestation, and have adverse mental health issues, unstable family relationships, experience physical and psychological violence, risk of bad pregnancy outcomes and delay in seeking prenatal care [4]. The children born of mothers with unplanned pregnancies are at risk for low birth weight, poor academic performance, violence and neglect [5]. These children are exposed to greater risk factors, hence are more likely to experience negative psychological and physical health issues, increased school dropouts and tend to show delinquent behaviour during their adolescent period. A study conducted in Australia showed higher levels of depression, delinquency and anxiety among children born out of unplanned pregnancies as compared to planned pregnancies [6].

The global situation on unplanned pregnancies

Unplanned pregnancies can negatively affect women physically, emotionally and financially. Effective, equitable and easier access to effective contraception methods, especially to long-acting reversible contraception, would certainly help to address this issue of public health concern [7]. Between 2015 to 2019, there had been 121 million unplanned pregnancies annually the world over (80% confidence interval of 112.8-131.5) which corresponds to a global rate of 64 unplanned pregnancies per 1000 women aged 15 - 49 years. Out of this amount, 61% of the unplanned pregnancies ended in abortions, which accounts for an abortion rate of 39 abortions per 1000 women aged 15 - 49 years [8]. According to the latest estimates by the World Health Organisation, almost half the pregnancies between 2015 to 2019 in low and low middle-income countries had been unplanned. Women living in the poorest regions are almost three times likely to have unplanned pregnancies than women from wealthier regions [9].

Sri Lankan situation on unplanned pregnancies

In Sri Lanka, approximately 360,000 women become pregnant annually, of which one in three (33.3%) are estimated to have an unplanned pregnancy. Demographic and Health Survey (DHS) of 2016 reports that 35% of married women in Sri Lanka do not use any form of contraception and teenage pregnancies are around 4.6% [10]. Approximately 150,000 to 175,000 abortions are expected to take place annually in Sri Lanka [11], with no recent data indicating any decrease. According to the National Post Abortion Care Guideline of 2015, unsafe abortion is responsible for 10% to 13% of maternal deaths in Sri Lanka, making it the second leading cause of maternal mortality in the country [12]. In 2017, approximately 326,000 live births had taken place in Sri Lanka, along with 127 reported maternal deaths in that same year. Among the 127 maternal deaths, 28 were due to unplanned pregnancies [12]. Another study concluded that 23.3% of pregnancies in Sri Lanka were unplanned [13].

Methods

A descriptive cross-sectional study was conducted between April 2020 and January 2021 in three randomly Medical Officer of Health areas in the Thimbirigasyaya Divisional Secretariat Division of the Colombo Municipal Council. A total of 425 antenatal mothers who fulfilled the inclusion criteria were included in the study. Any antenatal mother who had difficulties in hearing the questions asked or difficulties in speaking in response to the questions asked by the interviewer, antenatal mothers residing in that area for less than six months duration and mothers who visited the clinics while being registered in antenatal clinics not belonging to the study setting were excluded from the study. The sample size was calculated using the formula by Lwanga & Lemeshow [14]. Since the exact prevalence of the main outcome variable (prevalence of unplanned pregnancies) is not available and since there were no recent (within 5 years) literature or studies done on this topic in this setting, prevalence (p) was assumed as 50% to calculate the sample size. The consecutive sampling method was used and the final sample size included 425 antenatal mothers from three antenatal clinics in the Thimbirigasyaya Divisional Secretariat. There were no non responders as all antenatal mothers who fulfilled the inclusion criteria were willing to participate in the study.

Interviewer administered questionnaire was used for data collection. Construction of the interviewer-administered questionnaire was done by doing a thorough literature review and analysing the variables and associated factors for unplanned pregnancies. Pre-testing of the questionnaire was done at the antenatal clinic in Slave Island which belongs to the Colombo Divisional Secretariat Division of the Colombo Municipal Council. Following the pretesting, some questions were modified to make it more easily understood by antenatal mothers with basic educational levels by reducing scientific and technical terms.

Prior permission had been obtained from relevant authorities to carry out this study. On each day of data collection, the principal investigator clearly explained the purpose of the study to the antenatal mothers in the waiting area of the clinic. Thereafter information sheets were distributed for further information. Subsequently, consent forms were given to obtain written consent from mothers willing to participate in the study who fulfilled the inclusion criteria. Duplication of data was prevented by taking note of the pregnancy record registration numbers of antenatal mothers who had attended the clinic during the previous week or weeks.

Interviewer bias was nil as only the principal investigator was involved in data collection, analysis, and interpretation. Recall bias was kept to a minimum by asking the antenatal mothers about their most recent pregnancies. Perusing pregnancy records for additional information on the current pregnancy was used to minimise information bias. Selection bias was kept to a minimum, as all antenatal mothers attending the respective antenatal clinics on the day of data collection, who fulfilled the inclusion criteria were included in the study. The reliability of the questionnaire was checked by translating it from English to Sinhala and Tamil and then translating it back to English. Statistical analysis of the data was done using Chi-Square testing and p values at a 95% confidence interval. Odds Ratio was used to assess the strength of association between the planning status of the pregnancy and its associated factors. Data analysis was conducted using the Statistical Package for Social Sciences (SPSS) version 21.

Ethical clearance was obtained from the Ethics Review Committee of the Postgraduate Institute of Medicine, University of Colombo, Sri Lanka (Approval Number: ERC/PGIM/2020/091). There was no lack in antenatal care for the study participants by withdrawing from data collection. Data collection was carried out thus maintaining the privacy of the participant while giving them all the necessary information about the study. They had full control over their decision-making ability, autonomy and enrolment in the study. The knowledge obtained from the data collection was only used for research purposes and all study participants were made aware of it. There are no conflicts of interest.

Results

The total sample size was 425 and there were no no responders as all participants were willing to join the study. The age distribution was between 15 to 44 years. The age group of 22 to 34 years included 83.2% of the total study population. There were 37.2% Sinhalese, 33.9% Moors and 28.9% Tamils in the study sample. The prevalence of unplanned pregnancies was 32.7% in the study population. The 95 % confidence interval was 28.26 – 37.39.

Being married (p = <0.05, OR = 3.08, CI. = 1.15-8.3), mother being employed in the preceding 12 months (p = <0.001, OR = 4.18, CI. = 2.32-7.53), number of past conceptions being two or less (p = <0.05, OR = 2.1, CI. = 1.06-4.12), intake of folic acid before pregnancy (p = <0.001, OR = 2.27, CI. = 1.5-3.43) had statistically significant associations with planned pregnancies at 95% confidence interval (p < 0.05). Marital age less than 20 years (p = <0.001, OR = 0.3, CI. = 0.19-0.47), highest education level of mother being less than Grade 11 (p = < 0.001, OR = 0.42, CI. = 0.25-0.68), highest education level of spouse being less than Grade 11 (p = <0.05, OR = 0.48, CI. = 0.29-0.79), monthly household income of less than LKR 25,000 (p = <0.001, OR = 0.47, CI. = 0.31-0.72), interpregnancy interval of less than 24 months (p = <0.001, OR = 0.25, CI. = 0.12-0.53), using family planning practices in the past (p = <0.05, OR = 0.62, CI. = 0.4-0.94), never wanting or expecting the current pregnancy (p = <0.001, OR = 0.02, CI. = 0.0096-0.064) and not planning for another pregnancy (p = <0.001, OR = 0.31, CI. = 0.2-0.47) had statistically significant associations with unplanned pregnancies at 95% confidence interval (p < 0.05).

Being less than 20 years of age at first pregnancy (OR = 0.67, CI. = 0.36-1.24), contraception use in the month of pregnancy (OR = 0.57, CI. = 0.32-1.05), time of first antenatal clinic registration within 12 weeks of gestation (OR = 1.5, CI. = 0.88-2.56), number of children expected after marriage being two or less (OR = 1.04, CI. = 0.61-1.74), having home visits by health care workers during antenatal period (OR = 0.79, CI. = 0.53-1.19) and mother visiting the hospital for any other medical condition during the pre-pregnancy period (OR = 0.66, CI. = 0.39-1.13) did not show any statistically significant association with planning status of the current pregnancy at 95% confidence interval (p > 0.05).

Table 1: Associated factors for planning status of pregnancy and statistical significance at 95% confidence interval.

Discussion

Unplanned pregnancy is either unwanted, such as one that occurs when there are no other children or when no further children are desired, or the pregnancy was mistimed, with the baby arriving earlier than expected (Centers for Disease Control & Prevention, 2021). The prevalence of unplanned pregnancies in the Thimbirigasyaya Divisional Secretariat Division of the Colombo Municipal Council was 32.7% (139 out 425 study participants) and the 95 % confidence interval was 28.26 – 37.39.

There is a statistically significant association between the planning status of the current pregnancy and the marital status of the mother at a 95% confidence interval (p < 0.05). Being married is three times more likely to have a planned pregnancy (OR = 3.08, 95% CI: 1.15-8.3). Similar findings were seen in studies conducted in South Africa and Kenya. In South Africa, those married or living with their partners are more likely to have planned pregnancies and a significant association between marital status and unplanned pregnancies (p < 0.001) was seen [15].

There is a statistically significant association between the planning status of the current pregnancy and marital age at a 95% confidence interval (p < 0.001). Marital age of fewer than 20 years is 70% less likely to be associated with a planned pregnancy (OR = 0.3. 95% CI: 0.19-0.47). In a study done in Kenya, the prevalence of unplanned pregnancies was 51% between the ages of 15 and 19 years and 31% between the ages of 20 and 22 years [16]. The association between the planning status of the current pregnancy and the highest maternal education is statistically significant at a 95 % confidence interval (p < 0.001). The highest education level of the mother being less than Grade 11 shows a 58% less likelihood of having a planned pregnancy (OR = 0.42, 95% CI: 0.25-0.68). A sub–Saharan African multi-country analysis of the Demographic and Health Surveys of 29 countries showed that women with primary (OR = 0.74, CI = 0.69–0.80) and secondary (OR = 0.71, CI = 0.65–0.77) levels of education had fewer chances of unplanned pregnancies as compared to women with no education [17].

A statistically significant association between the planning status of the current pregnancy and maternal employment in the last 12 months is seen at a 95% confidence interval (p < 0.001). The antenatal mother being employed in the preceding 12 months has a four-time likelihood of having a planned pregnancy (OR = 4.18, 95% CI: 2.32-7.53). Similar findings were seen in a study done in Western Iran where unplanned pregnancies were 5.08 times more among housewives (p < 0.001) as compared to employed women [18]. There is a statistically significant association between the planning status of the current pregnancy and the husband’s education at a 95% confidence interval (p < 0.05). The highest education level of the spouse being less than Grade 11 is 52% less likely to have a planned pregnancy with his spouse (OR = 0.48, 95% CI: 0.29-0.79). There were more spouses among the planned pregnancy group who had completed Tertiary education as compared to the unplanned pregnancy category. Unplanned pregnancies were less common and least likely to occur (p < 0.05) among women who had husbands with some College or University education according to a study done in Southern Ethiopia [19].

There is a statistically significant association at a 95% confidence interval between the planning status of the current pregnancy and monthly household income (p < 0.001). Antenatal mothers having a monthly household income of less than LKR 25,000 are 53% less likely to have planned pregnancies (OR = 0.47, 95% CI: 0.31-0.72). Poor household income has been shown to cause unplanned pregnancies (p < 0.001) with an odds ratio of 1.7 in a study conducted in Canada [20]. There is a statistically significant association between the planning status of the current pregnancy and the interpregnancy interval of the mother at a 95% confidence interval (p < 0.001) in this study. Having an interpregnancy interval of fewer than 24 months has a 75% less likelihood of having a planned pregnancy (OR = 0.25, 95% CI: 0.12-0.53). The National Survey of Family Growth conducted in the United States of America showed that of the 40% of unplanned pregnancies, 36% had an interpregnancy interval of fewer than 18 months. It also concluded that as the interpregnancy interval increased, the prevalence of unplanned pregnancies decreased [21].

The association between the planning status of the current pregnancy and the timing of folic acid intake is statistically significant at a 95% confidence interval (p < 0.001). Antenatal mothers who had consumed folic acid before the current pregnancy have more than twice the chance of having a planned pregnancy (OR = 2.27, 95% CI: 1.5-3.43). A study done in the United States of America showed that women who said that their pregnancies were planned are more likely to confirm taking folic acid in the preconception period, with an odds ratio of 3.7 (95% confidence interval: 2.38 – 5.56) after controlling for maternal age and income [22]. A statistically significant association is seen at a 95% confidence interval between the planning status of the current pregnancy and the number of past conceptions (p < 0.05). Having less than two past conceptions is twice as more likely to have a planned pregnancy (OR = 2.1, 95% CI: 1.6-4.12). A case-control study in Western Iran revealed a significant association between unplanned pregnancies and previous live births (p < 0.001), with risk increasing by 2.97 per one already living child [18].

A statistically significant association is not seen between the planning status of the current pregnancy and maternal age at birth of the first child at a 95% confidence interval (p > 0.05). In a community-based cross-sectional study done in Nepal, 60.5% of unplanned pregnancies were among women who had delivered their first child at or before they were 20 years of age [23]. As only mothers having at least one live birth were considered, and a significant amount of the study population (204 out of 425) were either having their first pregnancy or not having a live birth in the past, a statistically significant association with the planning status of the current pregnancy was not found.

There is no statistically significant association between the planning status of the current pregnancy and the time of first antenatal clinic registration by the antenatal mothers at a 95 % confidence interval (p > 0.05). Though there is no statistically significant association in this study, a systematic review and meta-analysis done in 2013 on the effects of pregnancy intention on the use of antenatal care services showed that a significantly higher number of women with unplanned pregnancies not attending their first antenatal care clinics on time as compared to women with planned pregnancies (Odds ratio: 1.42, 95% confidence interval: 1.27 – 1.59) [24,25]. In the above systematic review, the median duration of pregnancy at the time of the first antenatal clinic registration by the pregnant mother was five months, as compared to Sri Lanka, where antenatal mothers register by 12 weeks. The meta-analysis included only 32 articles though 422 were initially identified through searches and was conducted in a rural population in Ethiopia as compared to this study which was done in an urban setting. These could be reasons for the difference in the findings between this study and the systematic review.

There is no statistically significant association at a 95% confidence interval between the planning status of the current pregnancy and home visits by health care workers in the antenatal period (p > 0.05). According to data from the Family Health Bureau, the percentage of pregnant women having at least one home visit by a Public Health Midwife (PHM) was 91.9% (Family Health Bureau, 2015). As most antenatal mothers in Sri Lanka receive at least one home visit during their antenatal period by a health care worker, there is no statistically significant association with the planning status of pregnancy.

Declaration of Interest

No conflict of interest could be perceived as prejudicing the impartiality of the research reported.

Funding

This research did not receive any specific grant from any funding agency in the public, commercial or not for profit sector.

Author Contribution

psn was the principal investigator in the study and was involved in data collection, analysis and report writing.

Acknowledgements

The dissertation was mainly based on the experience the principal investigator had while working as a Senior House Officer in Obstetrics and Gynaecology at Teaching Hospital Batticaloa between the years of 2014 to 2017. The principal investigator, especially among antenatal mothers who attended the hospital antenatal clinics, observed unplanned pregnancies and their adverse outcomes. It is also a major public health problem all over the world and hence the principal investigator thought it would be an ideal topic to do a dissertation on, especially at a time when there is a COVID 19 pandemic. The principal investigator would also like to thank the various officials who were involved in permitting to collect data at Borella, Kirula and Wellawatte antenatal clinics, especially during the COVID 19 pandemic. Many people were very helpful during the period of data collection, analysis, and dissertation writing. The principal investigator would like to thank all of them.

Abstract

Cancer is a dreadful disease responsible for taking millions of lives from all over the world every year. Disturbance during the cell cycle results in the abnormal growth of the tissues in the body.  Body’s immune system is expected to identify these abnormal cells and kill them though cancer cells have been observed to weaken the immune system on many occasions. Development of immunotherapy to treat cancer is a breakthrough to bypass the side effects of the other treatment modalities available now, since immune cells also has the capability to identify and kill cancer cells. Biological drugs include antibodies, vaccines and non-specific immunotherapy such as Interferon and interleukins are available fall under this category. But cancer cells have their own hide and seek game to escape from the eyes of the immune system. Cancer cells evade immune cells by producing several immune suppressive cytokines checkpoints to inactivate the immune cells or change their local environment, so it becomes a hostile place for immune cells to work. Possible mechanisms operated by the cancer cells to evade from immune system are discussed.

Keywords: Immunotherapy; cancer escaping from immune cells; possible mechanisms by cancer cells

Introduction

Cancer is a disease in which the body's normal control mechanism stops and abnormal cells divide uncontrollably. Old cells do not die and instead grow out of control, forming new, abnormal cells. These extra cells may form a mass of tissue, called a tumour which in turn destroys body’s healthy tissues by encroaching nearby tissues. Cancer cells can also spread to other parts of the body through the blood and lymphatic systems. Many patients are treated for cancer, and spent rest of their life, and die of other causes. Many others are treated for cancer and still die from it, although treatment may give them more time: even years or decades. Millions of human lives are lost due to cancer every year and possible causal factors responsible for the development of the disease  are identified such as overexposure to  light due to modern lifestyle [1- 4], synthetic chemicals [5] and some virus and microorganisms [6]. The list increases in length every year due to the focus by the scientist to save mankind from this dreadful disease.

Chemotherapy and radiation therapy are the two most common types of cancer treatment. They destroy these fast-growing cells including other types of fast-growing healthy cells [such as blood, sperm and hair root cells], causing adverse reactions, or side effects. The immune system also helps to fight cancer. Many new methods of treatment based on immunology were evolved.  Some of those became a sort of "game changers'' in cancer therapy. The immune system is an in built protection system from illness and infection that reacts and gives responses to “non self” in the body, for example, damaged cells or infections. Some immune cells can recognise cancer cells as well as abnormal cells and kill them and so immune system is important to patients who suffer with cancer though this may not be enough to get rid of a cancer altogether. Different types of immunotherapy adopt different strategies. Some immunotherapy treatments help the immune system stop or slow the growth of cancer cells. Others help the immune system to destroy cancer cells or stop the cancer from spreading to other parts of the body. Immunotherapy treatments can be used alone or combined with other cancer treatments.  Nevertheless, cancer is also "Smart" and capable of escaping immune system that can fight cancers.

Understanding Immune System

Two different types of the immune system operate in our body. One that works from birth [in built immune protection, innate immunity] and the second what we develop after having certain diseases [acquired immunity].

Innate immunity

The innate immunity is always ready and prepared to defend the body from infection immediately. This inbuilt protection system comes from  a barrier formed by the skin around the body, the inner linings of the gut and lungs, which produce mucus and trap invading bacteria, hairs that move the mucus and trapped bacteria out of the lungs, stomach acid which kills bacteria, helpful bacteria growing in the bowel, which prevent other bacteria from taking over, urine flow which flushes bacteria out of the bladder and urethra, white blood cells called neutrophils, which can identify and kill bacteria. Many factors can overcome and damage these natural protection mechanisms. For example: something may break the skin barrier, such as having a drip in the arm or a wound from surgery, a catheter into your bladder can become a route for bacteria to get inside the bladder and cause infection antacid medicines for heart burn may neutralise the stomach acid that kills bacteria.

Adaptive Immunity

Adaptive immunity is a defence mechanism which our body builds when it meets and remembers the antigens [another name for germs and other foreign substances] in the body. Antibodies are produced to fight against the antigens though 14 days are needed for our body to make specific antibodies. More importantly, the body memorizes this fight so that if its meets the same antigen again, it can recognize and attack more quickly. Antibody production is one of the most important ways to develop immunity. There are two types of adaptive immunity:

Active Immunity - antibodies that develop in a person's own immune system after the body is exposed to an antigen through a disease or when we get an immunization [e. a flu shot]. This type of immunity lasts for a long time.

Passive Immunity - antibodies given to a person to prevent disease or to treat disease after the body is exposed to an antigen. Passive immunity is given from mother to child through the placenta before birth and through breast milk after birth. It can also be given medically through blood products that contain antibodies, such as immune- globulins. This type of immunity is fast acting but lasts only a few weeks or months.

Vaccines provide active immunity to the disease. Vaccines do not make sick, but they can trick our body into believing to have a disease, so it can fight the disease.

Here is how a vaccination works:

The vaccine is administered antigens to a specific disease.

The immune system identifies the antigens in the vaccine as foreign invaders.

The immune system then develops antibodies to neutralize the antigens.

The immune system stores these antibodies for future use in case the person is ever exposed to the disease. Vaccines are given to prevent and eventually wipe out diseases. When a vaccine is given to a significant portion of the population, it protects those who receive the vaccine as well as those who cannot receive the vaccine. This concept is called "herd immunity." When a high percentage of the population is vaccinated and immune to a disease, they do not get sick and so there is no one to spread the disease to others. This herd immunity protects the unvaccinated population from contagious [spread from person to person] diseases for which there are a vaccine [7; 8].

Cancer may weaken immunity

Cancer can weaken the immune system by spreading into the bone marrow that makes blood cells to fight infection. This happens most often in leukaemia or lymphoma, but it can happen with other cancers too. The cancer can stop the bone marrow from making so many blood cells. Certain cancer treatments can temporarily weaken the immune system by a drop in the number of white blood cells from bone marrow. Cancer treatments that are more likely to weaken the immune system are:

chemotherapy

targeted cancer drugs

radiotherapy

high dose of steroids

Highlights of Cancer Immunotherapy

In the recent past cancer immunotherapy is an innovative treatment in vogue for cancer treatment [9-11]. Immune system efficiently fights off cancer or pre-cancer conditions on a regular basis without even bringing it to our notice. The types of immunotherapy include:

immune checkpoint inhibitors [ICIs],

cellular immunotherapy,

exosome immunotherapy [12].

These therapies create an immune microenvironment and modulate intestinal microbiota and tumour gene mutation. By employing these therapies drug resistance and adverse drug reactions are avoided. However, there is still a lot of scope to reduce side effects and improve the targeting of the therapy [13]. Unlike chemotherapy, which targets directly on cancerous tumours, immunotherapy treats patients by acting on their immune system. Immunotherapy can boost the immune response in the body as well as teach the immune system how to identify and destroy cancer cells [14].  Fewer side effects are observed than other treatments, because it targets just the immune system and not all the cells in the body so cancer may be less likely to return. The immune system can clearly recognize cancer cells as different, yet often it is unable to stop them from growing. Scientists have made a breakthrough in the development novel   potential drugs that can kill cancer cells. They have discovered a method of synthesizing organic compounds that are four times more fatal to cancer cells and leave non-cancerous cells unharmed. Their research can assist in the creation of new anticancer drugs with minimal side effects. In the laboratory scientists can produce different chemicals that are part of the immune response.  Monoclonal antibodies and tumour-agnostic treatments are by administering:

Checkpoint inhibitors

oncolytic virus therapy

T-cell therapy

cancer vaccines

The immune system fights with cancer

The immune system consists of a complex process to make “biological” which are used   in the prevention, diagnosis, or treatment of cancer and other diseases. Biological drugs include antibodies, vaccines and non-specific immunotherapy such as Interferon and interleukins [15; 16].This process involves the organs, cells and proteins. Monoclonal antibodies are made in a laboratory to boost your body’s natural antibodies or act as antibodies themselves. Monoclonal antibodies can help fight cancer in different ways. For example, they can be used to block the activity of abnormal proteins in cancer cells. This is also known as a targeted therapy, or cancer treatment that targets a cancer’s specific genes, proteins, or the tissue environment that helps the tumour to grow and survive. Other types of monoclonal antibodies boost your immune system by inhibiting or stopping immune checkpoints. An immune checkpoint is normally used by the body to naturally stop the immune system’s response and prevent it from attacking healthy cells.

Cancers escaping the immune system

Cancer cells can find ways to hide from the immune system by activating the checkpoints [17].  The cytotoxic T-lymphocyte–associated antigen 4 [CTLA-4] and programmed death 1 [18] immune checkpoints are negative regulators of T-cell immune function.   The cancer cells that have reached the “escape” stage no longer possess the molecules that show any danger. The B cells and phagocytes then fail to recognize them as a result the T cells are not activated and the cancer cells are not destroyed. Marasco and colleagues have discovered a key protein that is needed to activate this escape process [19,20].

During depth study to find out the failure of suppressor genes to destroy cancer cells, Stephen Elledge team identified more than 100 mutated tumour suppressor genes: genes that regulate cells during cell division and replication. The mutated genes can prevent the immune system from spotting and destroying malignant cells in mouse models. This observation challenges the conventional idea that the majority of mutations in tumour suppressor genes cause cells to divide and grow uncontrollably. More over this behaviour of the immune system doesn't do more to fight early-stage tumours [21]. Stephen Elledge said that "The shock was that these genes are all about getting around the immune system, as opposed to simply saying 'grow, grow, grow!" Immune cells recognize danger through a group of molecules found on the surface of all cells in the body [22]. This helps them inspect potential problems closely and decide whether to attack. The 'cancer immune-editing phase' or the "Escape phase" in which tumours can evade immune by producing several immune suppressive cytokines, either by the cancer cells or by the non-cancerous cells present in the tumour microenvironment [23]. The molecules that would otherwise reveal the cancer to the immune system are lost, and killer T cells move past, unaware of the danger the cancer cell could cause. “Cancer cells also develop ways to inactivate immune cells by producing molecules that make them stop working.” They also change their local environment, so it becomes a hostile place for immune cells to work [24; 25]. Tumour cells that evade detection can be explained by the following proposed mechanisms: down regulation of major histocompatibility class [MHC] I expression - allowing antigen to go unrecognised. The main reason the human body is unable to fight cancer is because it cannot differentiate between patient’s own DNA and cancer cell DNA and so taken for granted as its own [26]. A new mouse study by researchers at the Francis Crick Institute uncovered a protein that aids tumours evade the immune system. It’s exciting to find a previously unknown mechanism for how our body recognizes and tackles tumours. This opens new avenues for developing drugs that increase the number of patients with different types of cancer who might benefit from innovative immune-therapies [27]. The scientists also identified gasoline, a protein that is present in blood plasma secreted by cancer cells, and the mechanism of interfering with the immune system’s defences by blocking a receptor inside dendritic cells. Clinical data and samples from cancer patients with 10 different types of the disease were analyzed, and the researchers observed that individuals with liver, head and neck, and stomach cancers, who have lower levels of this protein in their tumours had higher chances of survival [28].

Chronic inflammation is a critical hallmark of cancer, with at least 25% of cancers associated with it, and possible underlying causes include microbial infections, autoimmunity, and immune deregulation [29;30].Whether or not inflammation is a cause or a consequence, the tumour microenvironment [TME] is compromised, triggering an immune inflammatory response, and histopathological analyses provide evidence for the presence of innate and adaptive immune cells in most human tumours, which are characterized as features of cancer progression [31]. It is currently accepted that an aberrant innate and adaptive immune response contributes to tumorigenesis by selecting aggressive clones, inducing immune suppression, and stimulating cancer cell proliferation and metastasis [32]. During the early stages of tumour development, cytotoxic immune cells such as natural killer [NK] and CD8+ T cells recognize and eliminate the more immunogenic cancer cells [33]. This first phase of elimination selects the proliferation of cancer cell variants that are less immunogenic and therefore invisible to immune detection. As the neoplastic tissue evolves to a clinically detectable tumour, different subsets of inflammatory cells impact tumour fate. For example, high levels of tumour-infiltrated T cells correlate with good prognosis in many solid cancers [34 -36].

On the other hand, high levels of macrophage infiltration correlate with a worse prognosis [37-39]. Involvement of macrophages has been described in every step of cancer progression, from early neoplastic transformation throughout metastatic progression to therapy resistance [40 - 42]. During carcinogenesis, anti-tumour macrophages display an M1-like polarization that plays a relevant role in the elimination of more immunogenic cancer cells. As the tumour progresses, the TME elicits an M2-like polarization of Tumour-associated macrophages [TAMs] that is protumorigenic [43]. TAMs promote tumour progression in different ways, such as stimulating angiogenesis and lymphangiogenesis, stimulating both cancer cell proliferation and epithelial–mesenchymal transition, limiting the efficacy of therapies, remodeling the extracellular matrix [ECM], promoting metastasis, and inducing immunosuppression of anti-tumour effector immune cells [44;45;39]. TAMs also directly stimulate cancer cell proliferation through the secretion of epidermal growth factor [EGF] [46], promote tumour angiogenesis by vascular endothelial growth factor [VEGF]  secretion [47], and remodel the ECM by secreting metalloproteinases [MMPs] [48]. Although TAMs mostly play protumorigenic roles, they can also sometimes exert anti-tumoral roles. Additionally, TAMs mediate the efficacy of the anti-tumor and anti-metastatic effects of the histone deacetylase inhibitor TMP195, which reprograms TAMs to a highly phagocytic phenotype [49]. Similar to the M1/M2 phenotype of macrophages, it has been proposed that tumour-associated neutrophils [TANs]  which exist in two polarization states, called “N1” and “N2,” to describe protumor and anti-tumour populations, respectively [50]. Cancer cells exploit the immunosuppressive properties of T cells while impairing the effect or functions of anti-tumor T cells, such as their ability to infiltrate tumours and their survival, proliferation, and cytotoxicity [51]. The antigen-dependent nature of the effector T cells implies that the effectiveness of the anti-tumour T-cell immune response depends on both the ability of the tumour antigen to induce an immune response [immunogenic] and the presence or absence—of inhibitory signals that can impair the T cells’ functions [52]. Accordingly, it is widely accepted that, in a T-cell-dependent process, most neoplastic cells expressing highly immunogenic antigens will be recognized and killed during the early stages of tumour development [53].

The less immunogenic cancer cells escape the immune control of T cells and survive, a process termed cancer immune editing [34]. The final outcome is that the surviving cancer cells adopt an immune-resistant phenotype. In parallel, during tumor development, cancer cells evolve mechanisms that mimic peripheral tolerance and are able to prevent the local cytotoxic response of effector T cells as well as those of other cells, such as TAMs, NK cells, and TANs [33].

Introduction

In almost 80%, bladder tumors are those that do not infiltrate the detrusor muscle, only the epithelium or the chorion is invaded. Its management is currently well codified with the development of new diagnostic techniques for early management. Immunotherapy, particularly the BCG vaccine, is one of the most used means in NIMBC therapy and the indications for which are well known [1-2]. Urinary cytology is, along with cystoscopy, one of the benchmark examinations for the detection and monitoring of NIMBC, especially of high grade [3]. This surveillance for NIMBC is essential because the risk of recurrence is high with a risk of progression of 10-20% and a mortality of 3% of cancer deaths, then an increasing incidence of about 1% per year. Few data exist in the literature mentioning the place of post-BCG bladder biopsies up to date. So should you do it? As a result, we carried out this study to assess the place of post-BCG bladder biopsies.

Patients and Methods

We conducted a retrospective study in the urology department of CHU Bichat-Claude-Bernard from January 2016 to December 2019 at (i.e. 4 years) in patients followed for high risk muscle bladder tumor that did not infiltrate BCG post-instillation biopsies. We included all patients with non-infiltrating bladder tumors and we did bladder biopsies after the induction phase of BCG instillation, who then had urine cytology. Our variables were clinical, paraclinical, therapeutic as well as prognostic. Clavien Dindo's classification had been used for possible post-operative complications.

The categorical and continuous data were compared respectively to the chi-square and Student t tests. Sensitivity, specificity, positive predictive value, negative predictive value, positive and negative likelihood ratios and diagnostic accuracy were calculated for cystoscopy and cytology separately and in combination. One and more variable logistic regression models assessed the factors associated with the occurrence of a positive biopsy. The analyzes were carried out with SPSS (v24) and R, version 2.10.1.

Results

A total of 62 patients were included, including 47 men (76%) and 15 women (24%). The median age was 71 years (IQR 13). Urothelial carcinoma was the only histological type noted before biopsy with a predominance of pT1 (Figure 1) and a concomitant Cis was detected in 32 patients (52%). After BCG, a total of 342 bladder biopsy were taken with a median of 5 (IQR 2) per case. The biopsy was positive in 13 patients (21%). The median number of positive biopsy was 2 (IQR 1) and the total number of positive biopsy was 27 (8%).

The biopsy was positive at the initial tumor site in 8 patients (61.5%). the only histologic type noted after the biopsy was urothelial carcinoma and the high pTa stage was predominant after biopsy (Table 1). No complications of Clavien III to V have been reported. Out of 62 patients who underwent systematic transurethral biopsy, only 3 (5%) presented complications from grade I to II. Two patients (3%) had prolonged hematuria requiring bladder irrigation, one patient (2%) presented with acute urinary retention requiring the placement of a bladder catheter. No perforation of the bladder was recorded. We found a significant association of positive biopsy with positive urinary cytology (p <0.001) and the presence of erythematous lesions (p <0.02) or visible tumors (p <0.001) at cystoscopy. The pre-BCG stage T (p = 0.32), the presence of CIS (p = 0.71), the multifocal tumor (p = 0.41) and the size (p = 0.52) were not associated with a positive biopsy occurrence.

Discussion

One of the most important features of urothelial cancer is the formation of tumors in multiple foci throughout the urinary tract, synchronously and / or metachronically. In fact, intravesical recurrence after TURBT has been reported in 30 to 80% of patients with NMIBC, which could be explained in part by the presence of malignant lesions of normal appearance at the time of endoscopy [4]. To detect such concomitant urothelial cancers during NMIBC endoscopy, random biopsies targeting normal-looking urothelial mucosa were performed. However, there have been few large series studies assessing the importance of random bladder biopsies, and they have presented conflicting conclusions [5-6]. In this context, several authors have suggested that in the presence of negative cystoscopy and cytology, biopsies are not guaranteed [7-8]. Dalbagni et al. were the first to suggest that routine biopsies were not warranted in normal office cystoscopy or cystoscopy with signs of erythema in the presence of normal bladder cytology [9].­­ Limitations of this study included a lack of description of the biopsies and the fact that the cytology of the isolated upper tract was not evaluated.

In contrast, our study showed that pre-BCG stage pathologies and the presence of Tis were not associated with the positive results of the biopsy. Only cystoscopy and urinary cytology which have been identified as significant variables. However, the positivity of urinary cytology should be interpreted with caution, since several cytological changes induced by BCG are easily detectable in the first 3 months after the last instillation, including enlarged hyperchromatic nuclei with prominent nucleoli, anisokaryosis, and increased granulocytes [10-11]. These cellular changes can be interpreted as positive.

We have objectified a correlation between the presence of erythema of the bladder mucosa / tumor lesions (seen on cystoscopy) to the positivity of biopsies, which is noted by several authors in the literature [12-13]. We have a rate of 5% of complications in our series and lower than those found by other authors [14]. To our knowledge, perioperative complications of transurethral biopsy have not yet been analyzed according to the modified Clavian classification.

It has been recognized that performing bladder biopsies is associated with certain risks, including bleeding, perforation, infection and spread of cancer [15]; therefore, it is necessary to develop new strategies to avoid this procedure. One strategy is to accumulate a much larger number of patients with NMIBC undergoing random biopsies of the bladder prospectively and to identify predictive parameters with acceptable sensitivity as well as specificity in each group classified according to the risk tables of the EORTC [16]. Another approach is to introduce new diagnostic methods for concomitant urothelial cancer, such as fluorescence cystoscopy [17]. However, the substantial costs of.

CONCLUSION

In summary, routine transurethral bladder biopsies are not required after induction therapy for BCG. However, a personalized approach is recommended based on cystoscopy and cytology. the pace and the means of surveillance (cytology, fibroscopy, uro-CT) of NMIBC must be adapted to the risk of recurrence and progression defined according to the tables of the EORTC.

Summary

Objective:To analyze the clinical, pathological spectrum andprognosis of patients with monoclonal gammopathy of renal significance (MGRS).

Methods:Patients with kidney biopsy-proven MGRS at Dr Lütfi Kırdar City Hospital between 2015 and 2019 wereincluded, clinical data, kidney pathology type, treatment and prognosis were collected.

Results: Thirteen patients, constituting 0.77% of kidneybiopsies, were recorded. Eight MGRS patients had amyloidosis. Two patients (%) had monoclonal immunoglobulin deposition disease. 1 patient (%) with proliferative glomerulonephritis with monoclonal immunoglobulin (G) deposit, 1 patient (%) withcryoglobulinemic glomerulonephritis. and one patient (%) with C3 glomerulonephritis. All of our patients were treatedwith chemotherapy and/or stem cell transplantation. The meanfollow-up period was 26 ± 34 months. Multiple myeloma developed in one patient at 19 months during follow-up. At the end of the follow-up, 2 patients (%) died, 3 patients (%) developed end-stage renal disease (ESRD).

Conclusion: MGRS is a rare form of hematological disorderthat causes kidney damage presenting with a wide range of pathological lesions. Amyloidosis is the most common form. Early diagnosis and close follow-up are important becauserenal survival of MGRS patients can be improved with early treatment.

Keywords: monoklonal gamopaties, renal injury, proteinüria

Objectives

Monoclonal gammopathies are a group of diseases that are formed by the activation of plasma cells, in which plasma cells secrete a certain type of immunoglobulin called M protein. This accumulation may progress over time and cause organ damage. The most common form of monoclonal gammopathies, monoclonal gammopathy of unknown importance (MGUS), may be associated with premalignant and nonmalignant diseases. Its frequency increases with age. Its prevalence reaches 3% in the population over the age of 50. Diagnosis is made by monitoring less than 10% plasma cells in the bone marrow [1].

Renal damage was observed in some of the patients with a diagnosis of MGUS followed, and it was observed that these patients did not meet the criteria for myeloma in the bone marrow evaluation [2,3]. Therefore, International Kidney and Monoclonal Gammopathy Research Group proposed to use the term monoclonal gammopathy (MGRS) with renal significance in 2012 [7]. This definition was suggested in patients with MGUS who did not meet the criteria for multiple myeloma, and in the group of patients with secondary renal damage due to M protein [4-9].

Classification in MGRS is based on the type and distribution of monoclonal deposits:

Organized: fibrillary deposits (Ig-associated amyloidosis (AL,AH,AHL), fibrillary glomerulonephritis); microtubular deposits (monoclonal cryoglobulinemia, immunotactoid glomerulopathy); crystal inclusions (light chain proximal tubulopathy, crystal-deposit histiocytosis)[10,12,13,14] Non-organized: Ig-related (monoclonal immunoglobulin storage disease and monoclonal gammopathy-associated proliferative glomerulonephritis), non-Ig (C3 glomerulopathy with monoclonal gammopathy).

Most of the patients with MGRS are at risk of progressive renal disease and end-stage renal disease develops in later periods. In addition, the risk of recurrence is high in renal transplant. Therefore, aggressive treatment is recommended for these patients, unlike patients with MGUS who are only followed up with periodic follow-ups. Renal biopsy is mandatory in patients with MGUS with renal findings. In patients with MGRS, treatment is based on the type of renal injury and the immunoglobulin-producing b-cell clone. Eradication of monoclonal proliferating plasma cells should be aimed in treatment [15,16]. In this article, we reviewed the literature in company with our four patients diagnosed with MGRS, whom we followed in our outpatient clinic.

METHODS

The cases who underwent kidney biopsy and followed up in our hospital's Nephrology Outpatient Clinic between 2015 and 2019 were retrospectively analyzed. Patients with malignancy and patients with multiple myeloma overt bone marrow biopsy were not included in the study. Demographic characteristics such as age, gender, basal creatinine and post-treatment creatinine, additional diseases and habits, treatments and renal biopsy results of cases with MGRS were recorded.

Our study is a retrospective study and descriptive statistics were performed using SPSS software (SPSS Inc, Chicago, IL) version 16.0. Variables were defined as the mean standard deviation. Variables that did not show normal distribution were defined as median (min-max). Bone marrow biopsy was performed in all patients to exclude multiple myeloma. Renal survival and overall survival of the patients were evaluated.

Renal biopsies were evaluated by experienced pathologists by light microscopy and immunofluorescence examination.

Results

Clinical and demographic pathological data:

Thirteen patients, constituting 0.77% of kidney biopsies, were recorded. 4 out of 13 patients were women. The mean age of the patients was 48± 12 years. Eight MGRS patients had amyloidosis (62%). Two patients (15%) had monoclonal immunoglobulin deposition disease. 1 patient (10%) with proliferative glomerulonephritis (MPGNID) with monoclonal immunoglobulin (G) deposits, 1 patient (1%) with cryoglobulinemic glomerulonephritis. and one patient (1%) with C3 glomerulonephritis. The mean 24-hour proteinuria level was 6560 mg/day. His serum albumin level was 2.8gr/dl. The mean creatinine level was 5.2 mg/dl. The mean e GFR level was 57ml/min. Two patients were undergoing hemodialysis at the time of diagnosis. After treatment, one patient was weaned from hemodialysis. 5 patients (40%) had microscopic hematuria. There was no patient with macroscopic hematuria. Two of the patients had cardiac involvement and one had liver involvement. Serum C3 level was low in two patients. No monoclonal band was detected in serum in 5 patients. Monoclonal band was observed in serum protein electrophoresis and immunoelectrophoresis in 4 patients. Serum free light chain level was found to be high in 3 patients.

Treatment and prognosis

In our study, we examined our patients diagnosed with MGRS who applied to my center. The most common subtype associated with monoclonal gammopathies is AL amyloidosis. The clinical presentation of approximately 75% of patients with AL amyloidosis, a subtype of MGRS, is edema and proteinuria. Plasma creatinine concentration is usually normal. ESRD develops in 20% of cases. There is no correlation between glomerular amyloid staining intensity and proteinuria in biopsies. Diffuse amorphous staining hyaline material is observed in light microscope examination. In immunofluorescence examination, lambda or kappa light chains are positively stained [14]. Although there is clonal proliferation of renal AL amyloidosis plasma cells, most patients do not develop multiple myeloma; Although light chain overproduction is present in most patients with multiple myeloma, renal amyloidosis does not develop [15]. International Kidney and Monoclonal Gammopathy Research Group suggested in 2012 to use the term monoclonal gammopathy (MGRS) with renal significance in such patients [7]. This term was suggested in the group of patients who did not meet criteria for multiple myeloma but had secondary renal damage due to M protein. Our patients did not meet the criteria for multiple myeloma by bone marrow examination and were diagnosed with MGRS by renal biopsy. In the study of Shaik et al., 6% of the patients followed up with the diagnosis of MGUS were diagnosed with MGRS [16]. In a study by Steiner et al., 2935 patients with a diagnosis of MGUS were examined and 1.5% of those diagnosed with MGRS [17]. In a study evaluating patients who started dialysis in the Netherlands in 2016, it was reported that 1.1 percent of patients were diagnosed with MGRS [18]. In a study examining patients with biopsy-proven AL amyloidosis, lambda light chain amyloidosis was observed 12 times more [19]. Renal involvement was observed 4 times more in lambda amyloidosis cases. In this study, it was observed that the amount of proteinuria was higher in patients with renal amyloidosis diagnosed with lambda amyloidosis. Our patients were also diagnosed with lambda amyloidosis and their proteinuria levels were at nephrotic level in line with the literature. In another study in which a patient diagnosed with MGRS with monoclonal gammopathy and renal disease was examined, the renal disease of approximately half of the patients was found to be associated with monoclonal gammopathy [20,21]. In patients with MGRS, treatment is based on the type of renal injury and the B cell clone that produces immunoglobulin. Eradication of monoclonal proliferating plasma cells should be aimed in the treatment [22].

Ten of our patients were treated with bortezomib-based chemotherapy. One of the patients was given lenalidomide. Autologous bone marrow was additionally performed in two patients. The mean follow-up period was 26 ± 34 months. Multiple myeloma developed in one patient at 19 months during follow-up. At the end of the follow-up, 2 patients (%) died, 3 patients (%) developed end-stage renal disease (ESRD).

Discussion

MGRS is a rare form of hematological disorder that causes kidney damage presenting with a wide range of pathological lesions. Amyloidosis is the most common form. Even with mild clinical findings, serum protein electrophoresis and immune electrophoresis should be performed in patients who present with abnormal findings in the urine and mildly elevated creatinine. In patients with monoclonal bands and multiple myeloma diagnosis excluded, a detailed renal evaluation for MGRS must be performed before MGUS is diagnosed. Early consideration of performing renal biopsy in such patients prevents delay in the diagnosis of MGRS, provides early treatment and close follow-up of renal reserve functions, thus slowing the progression to end-stage renal disease. Early diagnosis and close follow-up are important because renal survival of MGRS patients can be improved with early treatment. More clinical studies are needed on this subject.

Histopathological studies were not carried out, nor were chemical mediators related to the inflammation process characteristic of wound healing.

Abstract

Introduction: There is a global level the need to create new and effective therapeutic strategies that improve and accelerate the scarring processes of chronic ulcers, it is possible that the components of the Gestation of T. Penetrans could generate or promote the healing process.

Methods: A controlled experimental study was carried out in a cutaneous wound a mixture of eggs and abdominal membrane of T. penetrans, which was obtained from a T. gravid penetrans (8 days) that was on the skin from the foot of the same individual and was extracted by means of surgical decapitation of the cutaneous ampoule, said biological material was deposited in a recent sterile glass that with subtle circular movements partially homogenized.

Results: In the experimental wound, the formation of an initial brown yellow crust was observed in a period of 6 hours. At 48 hours, the crust was thick and very dark, which rose above the surface of the skin. In the HC the coast is still yellowed remained below the surface of the brink of healthy skin. At 5th day of evolution, the retraction of the crust was greater in the HE as well as the edges of the injury. Both wounds heal in equal time, however it could be appreciated that there was a slight depression in the control while in the experimental wound the neoformation tissue was at the level of the surrounding skin.

Conclusions: The properties of a mixture of eggs and abdominal membrane of T. penetrans are demonstrated to stimulate the effective healing of a cutaneous wound.

KEYWORDS: Tunga penetra; Healing; Inflammation; Wound; Eggs

Introduction

While most chronic wound treatments are related to wound bandages, [1] active treatment such as enzymes, skin grafts and growth factors are emerging with great potential as they improve the healing process [2].Motivated by finding new therapeutic strategies that improve and accelerate the healing processes, a first experimental trial was performed in vivo in which Eggs and abdominal membrane of Tunga Penetrans were applied in a cutaneous wound and healing was compared with a control wound to the which only general measures of asepsy were applied. This hypothesis, that the components of the Gestation of T [3]. Penetrans could generate or promote the healing process arose after observing in dozens of patients the natural evolution of lesions by tungiasis, once these ectoparasites die or are extracted, producing A thick and hard black crust (Figure 1) [6-7].

T.Penetrans is an ectoparasite of a millimeter long (Figure 2), it is endemic in countries of Latin America, the Caribbean and Sub-Saharan Africa,[4] whose permanent penetration in the skin produces the tungiasis [5].The periungueal region of the fingers of the feet is the preferred site by the flea, although the infestation can also occur in the hands, elbows and the genital and anal region.6 After penetrating the host epidermis, the flea suffers a peculiar hypertrophy as eggs are They develop within their abdomen to become a globular neosome,7,8 in a period of 3 weeks, hundreds of eggs are produced and expelled through the subsequent abdominal segments protruding in the corneous stratum [9].

METHODS

Study Design and Population

An experimental controlled study was carried out in which 3 male individuals, white skin without personal pathological history of diabetes mellitus or venous insufficiency were performed in lower limbs. In each individual, a surgical wound was performed in the middle third of the anterior face of each thigh, in the form of an eyelet of 1.2 x 0.5 cm with a depth of 0.3 cm.

After ASEPSIA of the area, 1 cc Lidocaine was administered to 2% and subsequently incision was made with scalpel n ° 22, compressive hemostasis was then performed and then occluded with sterile and adhesive Gaza for a period of 6 hours. Subsequently, the wound was uncovered and when corroborating the ceasefire, a mixture of eggs and abdominal membrane of T. penetra (Figure 3) was applied, which was obtained from a T. GRAVIDA T. PRANS (8 days) That was in the skin of the foot of the same individual and extracted by means of surgical decapitation of the cutaneous ampoule, said biological material was deposited in a recent sterile glass that with subtle circular movements partially homogenized. At 72 hours and at 6 days applied, the egg mixture and abdominal membrane of T. penetrans was carried out culture of the surface of the wounds [8].

Data Collection

The wound was evaluated daily, with measurements of its dimensions with a militheld rule. As well as direct observation of the characteristics of the scarring crust: appearance, color and retraction of the crust, retraction of the edges, pigmentation and size of the wound. Signs of inflammation (increase in temperature and volume, pain, flushing and swelling) and infection of the surrounding wound or tissues, systemic effects were also evaluated as a fever, regional adoiners (inguinal) [10].

Ethical Consideration

Each individual was carried out detailed explanation of the proceedings and on the topical application of a mixture of eggs and abdominal membrane of T. penetrans. The acceptance to participate in the experimental study was formalized with the signing of a document called informed consent, which each participant read and after his understanding, signed [11].

Results

On both thighs, a surgical wound was performed in the shape of 1 x 0.5 x 0.3 cm; The one on the right side was selected to be the experimental wound (HE) on which the mixture of eggs and abdominal membrane of T. penetrans was applied; and that of the left thigh represented the control wound (HC) on which only general measures were applied. After a period of 6 hours of applied the mixture of eggs and abdominal membrane of T. penetrans was observed the formation of an initial brown yellow crust in the HE with slight retraction of the edges of the lesion, while in the HC the Formation of a yellowish moist layer [12].

At 48 hours in the HA, the crust was thick and very dark, which rose above the surface of the skin. In the HC, the coast still yellow remained below the surface of the brink of healthy skin (Figure 4). At 5th day of evolution, the retraction of the crust was greater in the HE as well as the edges of the injury. At 10 days of evolution, in both wounds the crust was reduced; And at 14 days the scientist of the HC had fallen and in HE I still persisted a small central crust. The valuation of day 18 allowed us to observe that both wounds had scarred, however it could be appreciated that in the HC there was a slight depression while in the wound I have the neoformation tissue was at the level of the surface of the surrounding skin (Figure 5) [13].

Discussion

Once the penetration is completed, T. Penetrans begins its feeding and the hypertrophic enlargement of the abdomen,11 called neosomy or new body,12,13 which is completed on day 6, when it begins to expel the eggs, which are ovoids and They measure around 600 x 320 μm11 that are "expelled one after another, like the cartridges of a machine gun connected together by a viscose substance";14 or one by one in Rachas [15-18].After the death of the flea (as part of its life cycle or surgical extraction), the lesion is covered by a thick black crust, leaving an epidermal scar,16 that microscopically corresponds to acantosis and parakeratotic hyperkeratosis, as well as areas Multifocals of moderate epidermal and dermal necrosis.17 This fact was the one that I call the attention of the researcher to plant the hypothesis that it was possible to reproduce that cicatrization process in cutaneous wounds [19].

In the present study, in the wound in which the mixture of eggs and abdominal membrane of T. penetrans was applied, a thick crust of considerable consistency was formed in a short period (6 hours), which represent a protection of the external environment favoring the creation of a humid environment that promotes scarring.

In addition, in one of the individuals, the mixture of eggs and abdominal membrane of T. penetrans was observed after 24 hours of applied, the formation of a slight erythema with 0.5 cm diameter, accompanied by pruritus, which is It corresponds with an inflammatory reaction that coincided with the inflammatory phase of healing [20].

This inflammatory reaction that could be favoring the highly orchestrated sequence of events that occur during healing, is quite possibly promoted by the components of T. penetrans, such as:

-Eggs, exoskeleton formed by a coarse eosinophilic cuticle that delimits the body cavity.

The different components of the digestive tract that includes rarestone muscle beams and a simple cubic epithelium coating with irregular granular content pardusco.17

- Ovaries with sizes 155 to 220 μm diameter.17

- The saliva could be playing an important role, since Verardi et al.18 propose the hypothesis that the ampoule is produced as a result of a reaction to unknown flea antigens contained in its saliva. Therefore, it is necessary to isolate the flea saliva to perform trials on the promoted immune response.

- Wolbachia SPP: The presence of this endoscopinte in the Ovaries of T. Penetrans has been associated with abnormal immunological responses in diseases such as onchocerciasis,3,19 according to Heukelbach et al.20, the accumulation of neutrophils and macrophages in the Immediates of neosomical fleas infected with Wolbachia embedded in human tissue. The prevalence of this endobacteria in T. penetrans is 100%,20 being found in fleas in Ghana, East Africa and Fortaleza, Brazil, South America [21]. One aspect to be highlighted is that no infections were observed, checked by the clinic and by cultivation of the surface of the wounds from the application of the egg mixture and abdominal membrane of T. penetrans to the closure of the wound. One infection could be expected since it is described that, in the skin lesions by tungiasis, cases of erysis, tetanus, cellulite, gaseous gangrene, necrosis, septicemia, and even death of the patient can be expected [22]. This finding shows that the application of mixing of eggs and abdominal membrane of T. penetrans is a safe treatment in patients with cutaneous wounds.

LIMITATIONS

Histopathological studies were not carried out, nor were chemical mediators related to the inflammation process characteristic of wound healing.

CONCLUSION

In this small experimental trial, the properties of a mixture of eggs and abdominal membrane of T. penetrans were demonstrated to stimulate the effective healing of a cutaneous wound. Studies must be carried out to clarify the possible mechanisms by which the mixture of eggs and abdominal membrane of T. penetrans contributes to healing.

Abstract

Objective: The aim of this study was to assess the success of bone regeneration in infected and non-infected human dental defects, wtih respect to biological properties of bone remodeling.

Background: Treatment with dental implants occasionally requires a preliminary procedure of bone augmentation. The use of platelet concentrates such as platelet-rich plasma (PRP) or platelet-rich fibrin (PRF) in the dental field has been shown to facilitate implant osseointegration and promote healing. However, bone healing in infected sites differs from that which occurs in non-infected sites: most notably, the healing phase is prolonged in infected sites due to the coinciding inflammation.

Methods: Thirty-eight operated sites, consisting of twelve non-infected sites and twenty-six infected sites, from twenty-eight patients were included in this study. Bone regeneration was performed using particulate bovine-derived xenograft mixed with PRP derived from the patient's blood, covered by platelet-poor plasma (PPP) and/or a collagen membrane. At 6±1.8-months post augmentation, re-entry surgery was performed and bone samples were harvested at implant locations prior to implantation.

Results: Histomorphometric analysis of bone biopsies was used to evaluate new bone formation, soft tissue, and residual biomaterial in infected and non-infected sites. In all samples, the biomaterial particles were surrounded by newly generated bone. Among factors that were analyzed, gender, medical state, and smoking had no significant effect on bone regeneration. Variables including tooth location, platelet concentrate, and protective membrane addition were also analyzed for their effects on bone regeneration.

Conclusion: The results clearly demonstrate that both infected and non-infected sites were clinically successful in terms of bone regeneration geared for implantation, yet infected sites tend to exhibit delayed remodeling, resulting in higher levels of soft tissue and biomaterial remains.

Introduction

The unveiling of osseointegration, recent progress in biomaterials and implant techniques, as well as the increased longevity, esthetic and functional demands, have contributed to an increased application of dental implants in restoration for partially and completely edentulous patients. The main reasons for tooth or implant loss are progressive periodontitis and peri-implantitis [1]. These dental inflammatory conditions are characterized by alveolar bone loss, which occurs either directly due to the colonization of bone by microorganisms, or indirectly, due to the local inflammatory response in the gingival soft tissues and periodontium [2]. The inflammatory environment initiates osteoclast activity and leads to excessive bone resorption [3-5]. This prevents positioning of dental implants and requires bone augmentation prior to the implant insertion [6,7]. The success of bone augmentation is assessed by the sufficient presence of alveolar bone and by the degree of remodeling and mineralization to provide an effective structure for implant placement.

Various techniques for augmentation are currently in use to treat bone atrophy [8]. One of the most common techniques for ridge augmentation is guided bone regeneration (GBR) with particulate bone graft substitutes, covered by a membrane (non-resorbable membrane or resorbable collagen membrane) to prevent ingrowth of soft tissue into the augmented site [9-12]. Bone healing involves interactions among numerous cell types and microenvironments. The monocyte–macrophage–osteoclast lineage, the mesenchymal stem cell–osteoblast lineage, along with early and transient inflammatory signals are essential for proper bone healing [13].

Whole blood-derived products, such as platelet-rich plasma (PRP) and platelet-poor plasma (PPP), have been in use for decades. PRP, and in some cases PPP, were demonstrated to facilitate angiogenesis, soft tissue repair, and bone regeneration in alveolar bone augmentation [14-19]. However, contradicting reports are present regarding the long-term beneficial use of PRP, thus additional studies are crucial.

The current study includes consecutive patients that underwent bone augmentation following tooth extraction or implant removal, due to endo-perio lesions or chronic peri-implantitis. Our aim was to assess the clinical and histological success of bone augmentation in infected sites relative to healthy, atrophied sites.

Materials and Methods

Patients

The study was conducted on successive patients that underwent bone augmentation following tooth extraction or implant removal, due to endo-perio lesions or chronic peri-implantitis. The control group includes patients that required bone augmentation in healthy, edentulous sites prior to implantation. The study was composed of 28 healthy individuals and 38 operated sites (12 non-infected sites and 26 infected sites).

Sites of extraction and implant removal were disinfected prior to the augmentation procedure. After a healing period of six months, bone samples were collected from the implantation site. DSA performed all surgeries at the Schwartz-Arad Surgical Center between 2014 and 2016 under local or general anesthesia. Preoperative clinical examination, panoramic and CT scans of the operated area were performed. One hour before the surgical procedure, prophylactic antibiotics (Amoxicillin 1 g or Clindamycin 600 mg for penicillin-sensitive patients), and dexamethasone (8 mg) were administered. Rinsing with 0.5% chlorohexidine for 1-2 minutes was performed prior to surgery. Data collection and analysis were performed by independent researchers. Informed consent for the surgical procedure and study was obtained from the patients prior to procedure. The study was approved by research ethics committee of Tel Aviv University #0000993.

Tooth Extraction and Implant removal

Tooth extraction: Indications for tooth extraction were the appearance of chronic infection due to extensive untreatable periodontal or endodontic disease or presence of a pathological process (i.e. cysts).

Implant removal: Implant removal was determined necessary by chronic, untreatable peri-implantitis with extensive cervical bone loss.

After tooth or implant removal, the defects were disinfected with Iodine solution (Medi-market, Netanya, Israel) and hydrogen peroxide 3% (Medi-market, Netanya, Israel) and irrigated with cold sterile 0.9% saline (Medi-market, Netanya, Israel).

Augmentation procedure

Augmentation of the alveolar process was performed with the combination of a bone substitute (Bio-Oss ®, Geistlich Sons, Wolhusen, Switzerland) saturated in Metronidazole® (Medi-market, Netanya, Israel) and PRP and and covered with PPP, both obtained from patient's own blood (see below for details). Immediately after the augmentation procedure, panoramic imaging was obtained; all patients were prescribed oral antibiotics (amoxicillin 1.5 g for five days) or clindamycin (1.2 g for four days) and dexamethasone (4 mg for two days). Rinsing with 0.25% chlorohexidine was recommended twice a day for 10 days follow the procedure. Naproxen sodium was prescribed twice a day. Sutures were removed 3 weeks post-surgery and panoramic and CT scans of the operated sites were obtained after a waiting period of 5.86 ± 1.38 months prior to implantation. Non-infected sites were treated using the same augmentation procedure.

PRP and PPP preparation

The preparation of PRP and PPP was performed using the Harvest SmartPReP2® Multicellular Processing System (Harvest Terumo BCT, Inc. Lakewood, Colorado). The bone substitute was first saturated in the PRP activated by 20 mM CaCl2 plus 25 IU/ml human plasma thrombin (Omrix Biopharmaceutical Ltd., Israel). This mixture was used as a filling material in both tested and control sites. Occasionally, PPP (also activated by thrombin and CaCl2) was gently placed over the operated site with or without a collagen membrane.

Sample harvesting and preparation

Directly preceding implantation, bone samples were collected from the augmentation sites. A surgical trephine drill (Ø =3mm) (Ofek Frides Ltd., Petah-Tikva, Israel) was used to harvest a small bone sample. Bone core biopsies were immediately stored in 10% buffered formaldehyde (Fisher Scientific, Atlanta, Georgia) and subsequently processed to obtain thin ground sections (Precise 1 Automated System, Assing, Rome, Italy). The specimens were dehydrated in an ascending series of alcohol rinses and embedded in glycol methacrylate resin (Technovit 7200 VLC, Heraeus Kulzer GmbH & Co, Wehrheim, Germany). Specimens were then sectioned along the longer axis using a high-precision diamond disc to approximately 150 microns and ground down to about 30 microns. From each specimen, two slides were obtained and stained with basic fuchsin and toluidine blue.

Histological and histomorphometric evaluation

Histomorphometry of newly formed bone, marrow spaces, and residual graft material were carried out on each specimen using a light microscope at low magnification (325) (Laborlux S, Ernst Leitz GmbH, Wetzlar, Germany) connected to a high-resolution video camera (3CCD, JVC KY-F55B, JVC, Yokohama, Japan) and interfaced to a monitor and personal computer (Intel Pentium III 1200 MMX, Intel Corporation, Santa Clara, Calif). This optical system was linked to a digitizing pad (MatrixVision GmbH, Oppenweiler, Germany) and a histometry software package with image-capturing capabilities (ImagePro Plus Version 4.5, Media Cybernetics Inc, Silver Spring, Md). The values for marrow space/soft tissue, residual graft material, and newly formed bone were recorded exactly 1 mm from the pre-existing bone, and the mean percentage values were calculated.

Statistics

Continuous variables were expressed as mean ± standard deviation (SD) and analyzed with Student’s t test or the Mann Whitney test when appropriate. Categorical variables were analyzed using the chi-square test. Analyses were performed with SPSS V.25 for Windows.

Results

Bone samples from 38 sites obtained from 28 patients were quantitatively analyzed for the presence of soft tissue and residual biomaterial, and bone formation. Sites that displayed infection markers such bleeding on probe, gingivitis, or deep periodontal pockets were included in the study group. The control group was composed of patients that required alveolar bone augmentation in non-infected sites.

A prevalent reason for tooth extraction in this cohort was untreatable periodontitis (16.67%), and for implant removal was peri-implantitis (45.83%, Figure 2A). However, there were no differences in the levels of newly formed bone, biomaterial, or soft tissue found among the various cases (Figure 2B). was required mainly in the posterior mandible (Figure 3A). Yet, no marked differences in bone augmentation and regeneration were observed between the maxilla and mandible (Figure 3B). Out of the patients, 40.12% were male and 59.88% were female, with ages ranging from 33 to 85 years (mean 59.38 ± 11.57 years). Comparison between bone regeneration in infected sites showed no difference between genders (Figure 3C).

There is an ongoing debate regarding the contribution of PPP in promoting bone regeneration: studies have shown that PPP could improve wound healing and reduce pain [20, 21]. In this study, we evaluated the effect of PPP addition compared to alternative treatments (Figure 4). The results show no significant differences in bone regeneration among sites covered by PPP alone versus sites covered by a resorbable membrane with or without PPP.

Crucially, the histological analysis also shows that the Bio-Oss particles appear to fuse with newly formed bone (stained in red), revealing intimate contact between bone and grafted particles (Figure 5 A,B).

The environmental signals around healthy, atrophied sites allow improved bone-remodeling compared to infected sites. As shown in Figure 5C, new bone around biomaterial particles was 45% lower in chronic infected sites compared to non-infected sites (p=0.0001). In contrast, both the soft tissue levels and biomaterial remnants were significantly higher in infected sites relative to non-infected sites by 69% (p=0.002) and 37% (p=0.036) respectively.

Discussion

Tooth extraction is one of the most frequent procedures in oral and maxillofacial surgery. Ridge preservation procedures performed at the time of extraction aim to maximize bone formation and minimize the soft tissue expansion within the socket. We hypothesized that augmentation in infected sites with biomaterial will not differ significantly from the same augmentation procedure in non-infected sites: therefore, we evaluated the potential amount of bone formation following volume preservation using bone substitutes in infected and non-infected sites as well as the influence of different factors on the outcome of bone regeneration. Out of the 28 patients included in the study, the majority of extractions and implant removals were performed in the posterior mandibular (46%). It is well established that the posterior mandible has several disadvantages in the placement of dental implants. The posterior mandible is limited by the mental foramen anteriorly and the caudal inferior alveolar nerve, and usually suffers extensive bone deficiency [22]. Despite the high incidence of tooth extraction at the posterior mandible, the rates of bone regeneration were similar in the mandible and maxilla.

Failing implants are usually removed due to progressive peri-implantitis and subsequent bone loss [4]. According to the 2012 European academy of osseointegration (EAO) the prevalence of peri‐implantitis is 10% in regards to implants and 20% in patients within 5 to 10 years after implant placement [23].

Indeed, most of the studied cases suffered from peri-implantitis and bone loss (45.83%). Socket preservation is used to minimize the dimensional changes in soft and hard tissues after tooth extraction [24-26]. Currently, a variety of bone substitutes are available, many of them lacking optimal functionality. Bone substitutes used for socket preservation must have excellent osteo-conductive properties and appropriate strength, and ideally the material will participate in bone remodeling, gradually replacing the bone graft substitute over time. Chronic inflammation leads to the secretion of pro-inflammatory cytokines, which are primarily responsible for the activation of osteoclasts and the subsequent bone destruction. In the current study extracted sites were preserved by using bovine-derived bone substitute (Bio-Oss) saturated with platelet concentrate. Histological analysis of the samples indicated an intimate contact between new bone and biomaterial particles generating an alveolar ridge adequate for implantation. The bone quality in infected sites was lower than in not-infected sites as demonstrated by significantly low levels of new bone in adittion to high levels of soft tissue and biomaterial remains. These parameters reveal a potential for improved bone remodeling in non- infected sites relative to infected sites and emphasize that local inflammatory effects of the infected environment and should be taken under consideration when performing ridge preservation.

Abstract

Introduction: Surgical site infections (SSIs) represent index of healthcare system and are third most commonly reported nosocomial infection. SSIs are responsible for high morbidity and mortality ratio and account round about 1/4 of hospital acquired infections which produce adverse impacts on patients. Moreover, they increase patient stay in hospital resultantly responsible for economical loss of patient and family.

Objective: The aim of present review is to assemble already known information regarding incidence of SSIs, pathological as well as microbiological risk factors and mitigation strategies (pre-operative, intraoperative and postoperative) for patients posted for any surgery in hospital. Additionally, importance of SSIs related preventive measures and prophylactic antibiotic therapy for better healthcare is also highlighted.

Methodology: Several research, review articles, clinical reports and survey-based reports were searched by using different databases to gather the information regarding SSIs.

Results: Complete ten published clinical studies were thorough reviewed to highlight importance of operation theater quality management to prevent SSIs. Data obtained showed that implementation of pre, intra and postoperative strategies can cut down mortality rate associated with SSIs around the world. Moreover, surveillance of SSIs risk factors and decline in them may also decrease nosocomial infections.

Conclusion: SSIs surveillance is a well-established and comprehensive approach to reduce incidence of SSIs. Along with, maintenance of operation theater quality is hallmark for reduction in SSIs. However, further studies are still required to improve standards for periodic surveillance and management of hospital acquired infections.

Keywords: SSIs, operation theater, pre-operative, nosocomial infection, surveillance programs

Introduction

Surgical site infections (SSIs) represent major health care complications and account for 38% of hospital acquired infections. SSIs usually occur within one month of procedure execution or maximum in 1 year in patients who has received implants [1]. These contaminations could be deep or superficial incisional infections and generally involve body organs/spaces. In particular, superficial diseases that affect skin only can be SSIs such as operative wounds (involvement of surface tissues, organs, or soft masses) [2]. Extreme SSIs account for about half of all SSIs in deep incisions or organ gaps [3]. One clinical study has reported that an estimated 11% of entire disease burden were associated with operating procedure [4]. Moreover, 1 in 10 patients admitted to hospital face nosocomial infection. Among all on them, majority of in-hospital events are linked to surgical incisions and administration of medications [5]. SSIs are responsible for high morbidity and mortality ratio as SSI patients remain 2-11 times more expected to die than non-SSI patients therefore, management of SSIs is a significant clinical concern globally. Moreover, surgical site infected patients stay in hospital for around 7-10 additional days which resultantly drop economic conditions of patients [6].

According to Centers for Disease Control National Nosocomial Infections Surveillance (CDCNNIS) system four major types of risk of injuries related to operating procedure are categorized as 1) clean wounds, an uninfected operational wound in which no inflammation is observed and alimentary, respiratory, genital, or uninfected urinary tract is not accessed; 2) operative incisional wounds that accompany blunt trauma; 3) clean-contaminated wounds, a surgical wound in which gastrointestinal, respiratory, genital, or urinary tracts are entered under sterile environments and without unusual contamination and 4) contaminated wounds including open, fresh or accidental wounds. For example, procedures with major disruptions due to leakage from GIT tract and the incisions in which non-purulent, acute inflammation is encountered mainly involve dirty-infected wounds, traumatic wounds and lacerated viscera [2,7,8] (Figure 1).

Besides this, risk of developing SSI differs considerably depending on procedure type and individual’s characteristics undertaking surgery [9]. Different studies have reported both internal (related to patient i.e. dehydration, older age, co-existing disease and diabetes) and external (related to procedure i.e. length of procedure, working ethics of surgeon, stability of pre-operative skin preparation, adequacy of antimicrobial prophylaxis and addition of foreign objects) factors responsible for SSIs [10]. A research conducted by Dominioni et al. has shown that serum albumin accumulation, older age and standard of operation theater can increase chances of SSIs [11]. Various studies have been revealed prominent role of microorganisms in surgical site infections. Findings showed Staphylococcus aureus and methicillin-resistant staphylococcus aureus (MRSA) strains related medical complications which consequently increase post-operative medical stay and related hospital expenses [12]. Likewise, occurrence of concomitant infections due to inevitable growth of bacterial species (e.g., S. aureus, coagulase-negative staphylococci (CoNS), Enterococcus and Escherichia coli) are accountable for SSIs in patients undergoing any implantation or other prosthesis. Hence, use of prophylaxis antibiotic may significantly reduce rate of nosocomial infections [13]. Considering this all information, operating care has become an integral measure of global health care with approximately 234 million procedures per year.

Rarely, pathogenic microorganisms are originated from an exogenous source like operating theatre (OT) environment, surgical personnel or employees [9] and total tools including instruments as well as materials used during a surgery [10,14]. Giacometti et al. studied 676 patients of surgery with signs and symptoms suggestive of wound infections, who presented over course of six years. Findings showed bacterial pathogens in 614 victims and most of them were aerobic bacteria (S. aureus, P. aeruginosa, E. coli, S. epidermidis and Enterococcus faecalis) with percentages of 28.2, 25.2, 7.8, 7.1 and 5.6 respectively (Table 1) [15].

Methodology

Numerous numbers of research and review articles have been analyzed for acquisition of information about surgical site infections and their remedial measures especially concerning operation theater quality. Different databases have been investigated to find out the information about respective topic. Keywords used were “surgical site infection”, surgical site prevention”, “operation theater infections”, risk factors responsible for SSIs”, strategies to reduce SSIs”, “SSIs related complications”, “etiology of SSIs”, “intra-operative SSIs”, “post-surgical site infections”, “exposure time for surgical site treatment”, “nosocomial infection types” and so on. It was a qualitative type of review so no specific software was used for data analysis. Articles having supposititious and un-authentic information regarding SSIs were excluded from the review process.

Results and Discussion

For the avoidance of surgical site infections, few strategies are adopted including preoperative, intra-operative and post-operative strategies as summarized in Figure 2.

Pre-operative strategies

For pre-operative preparation of skin, most commonly used agents are alcohol-containing products, iodophors, and chlorhexidine gluconate. According to FDA, alcohol is well-established agent having active constituents including ethyl alcohol (C2H5OH) 60-95% or isopropyl alcohol 50-91.3% by volume [16]. Alcohol remains most effective, readily available, inexpensive, rapidly acting agent and have bactericidal, fungicidal and virucidal activity, but spores can show resistance [17]. The technique for application of antiseptic is in concentric circle, starting from area of supposed incisional site to periphery [18]. According to Center for Disease Control (CDC) guidelines maintenance of “hand hygiene” including trimming of nails, use of proper antiseptic agent for scrubbing and drying can help to reduce pathogen transfer from medical workers to patients [10]. For removing hairs, shaving of surgical site causes a significant increase in SSI (5.6%) as compared to other hair removal agents (0.6%). Shaving causes microscopic traumas in skin that later act as a center for replication of bacteria [19].

OT workers may have interactions during medical procedures with individual skin and/or mucous membranes and there is a chance of sharp injury leads towards chronic infections. Sharp wounds placed employees at threat of exposure to blood-borne diseases as well [20]. Proper educational programmers and policies must be developed among health sector personals in order to limit chances of pathogen transfer to patients which in turn decreases hospital acquired infections among post-surgery patients. Before surgery, administration of antimicrobial prophylaxis has been shown to significantly decrease severity of wound infections associated with surgical procedures. The usage of antibiotic drug prophylactically prior to surgery allow availability of appropriate concentration in tissue thus, reduce microbial concentration and occupancy at incisional site [21].

Intra-operative Strategies

SSIs may result from bacteria surviving on surgical tools or penetrating directly into operational site [22]. Ventilation and humidity in the OT are important factors to minimize chance of infection. In order to avoid getting potentially polluted air to reach surgical suite, surgical operation room (SOR) must be hold on to positive pressures in comparison to the hallways outside the room [23]. As best practice, there must also be at least 15 air changes per hour (3 of fresh air). To stop development of molds and fungi, humidity should be conserved at a definite level [24]. The Ventilation health care facility suggests that the OT must be managed at 20-24oC, with positive pressure and humidity of 20-60% [25]. Flash sterilization is a procedure designed for instant use of instruments (e.g., for reprocessing of an accidentally dropped instrument). However, it is not recommended for implants because of a viable risk of infection [26]. Various studies did not prefer this method as a routine sterilization for convenience, to save time and to minimize sterilization cycle factors (i.e., temperature and time) [27] (Table 2).

Environmental surfaces are hardly concerned for expansion of SSIs. When surfaces get visibly soiled during a procedure, a hospital disinfectant approved by environmental protection agency (EPA) would be used before next procedure [28]. According to Occupational Safety and Health Administration (OSHA) requirement, environmental surfaces should be disinfected after interaction with infectious material or blood [29]. After the end of night or day, a disinfectant approved from environmental protection agency (EPA) is used on regular basis for wet-vacuuming of floor of operating room [30]. The tacky mats have not been played significant role in reduction of microorganism present on stretcher wheels or shoes. So, there is no need to use them for controlling infection [31].

Microbiological sampling and counting can regularly be used to determine condition of air in OTs, but the relationship between two approaches has rarely been tested. A study indicated that there is no need to substitute microbiological sampling with particle counting in conventionally ventilated operating theatres for routine assessment of pathogenic organisms [32]. Surgical attire is worn to minimize release of microbes into atmosphere of operation theater. Clean, freshly washed scrubs should be worn by each medical staff member  [33] just to prevent spread of possible pathogens to the wounds. In addition, sterile drapes can also be used for the same purpose [34].

Strict obedience to codes of asepsis by scrubbed staff as well as by anesthesia personnel is base for controlling SSIs. Different surveys related to operation theater visits revealed that anesthesia personnel were involved as source of pathogen when placing intra-vascular devices, endotracheal tubes (ETT), and when administrating intravenous (IV) drugs [35]. Improper implementation of aseptic-principles throughout performance is associated with outbreaks of post-operative infections. It is believed that risk of SSIs can be reduced through application of surgical technique in operation theatre [36]. Presence of some type of foreign body like suture material, an implant, or drain, might stimulate inflammation at surgical site and may enhance chance of SSIs [37]. Moreover, studies have been showed that risk of SSIs drop when closed suction drains are used instead of open drains [38] (Table 3).

Post-operative strategies

After performing a surgery, the care of surgical site incision is mandatory depending upon the type of incision the patient had. There are three forms of incision sites including closed skin edges incision, open edges incision which is closed later and open incision site for healing purpose. Postoperative incision care in case of closed edges, the incision is covered with germ free bandage for up to 48 hours [39]. In case of open edges incision, it must be packed with sterile dressing for minimizing the contamination of surgical site. When the incision site left open for healing purpose, it is also filled with germ free damped gauze and covered with bandage. The American College of Surgeons (ACS) and other authorities have suggested usage of germ-free gloves and tools while exchanging dressings of surgical incision [40] .

Presently, patients are discharged momentarily even afore surgical incisions have restored. Physician will provide specific instructions about when and how to adjust it. After a few days, most wounds do not require taking off the gauze but wrapping of area and change dressing on regular basis by maintaining proper hand hygiene it may help to protect cut from infection and it may heal more quickly. The discharge planning intent is to sustain reliability of restorative incision, let the patient to know almost signs and symptoms of infection and direct patient about whom to interact to account any issues [41]. Previous studies which have worked to identify the risk factors responsible for surgical site infections and strategies for preventing them are summarized below (Table 4).

Data obtained exhibited that an area where all contaminating factors and micro-environmental changes are kept under controlled supervision is considered as a safe operating unit. By giving thorough attention, this task can be done by proper management and frequent inspections, as well as by adequate ongoing employee training [42]. Indeed, OT is an extremely complex environment in which there are various risk factors, including not only infrastructure characteristics and its equipment but also the administration and actions of workers in healthcare system [43]. Design of OT is one of the most important parameters to maintain quality of procedure. In specific description, it is essential to separate clean and dirty areas and maintain organized and logical movement of patients from their entrance to exit. For execution of medical procedures and for preparation of equipment separate rooms should be allocated. In these rooms, it is essential to limit the level of movement and activities of people as both factors can manipulate microbial contents and therefore can influence possibility of infections. The size of storage area should be determined according to workload and types of materials need to be placed in it. Windows of operating room (OR) should have a surface that are easy to clean and free from collecting dust [44]. Design of operation room, furniture, floor finishing and its covering will influence cleaning condition of operation room. In order to assist infection control, surface of floor should be impermeable, easy to clean, anti-stain and suitable for moving equipment’s of operating room [45-55].

Conclusion

To summarize, surgical site infections can be avoided through implementation of well-planned pre-operative, intra-operative and post-operative strategies as well as by practicing infection management through execution of sterile technique while conducting procedures. It's important to remember that much of the morbidity and mortality ratio associated with SSIs can be reduced by modifying a variety of variables, including surgical environment, patient-related or procedure-related risk factors along with personnel behavior. Furthermore, SSIs surveillance is a well-documented and well-established method of reducing incidence of SSIs. Despite its usefulness, many hospitals continue to ignore this advice. The importance of good patient preparation, aseptic conditions and adherence to sterile surgical procedure are highlighted in the CDC guidelines for prevention of SSIs and antimicrobial prophylaxis is also guided in particular circumstances. Altogether, SSIs prevention necessitates a comprehensive approach and the contribution of all individuals involved, including those responsible for the design, layout, and management of operating rooms. However, further research into prevention strategies, as well as strict adherence to the implementation of established evidence-based methods to mitigate SSIs is still required to reduce infection even more.

Mini Review

As survival after pancreatectomy for pancreatic adenocarcinoma (PDAC) has significantly improved with modern chemotherapy protocols and more aggressive surgery including vascular resections, more patients may live long enough to develop locoregional recurrence, but not diffusely metastatic disease. Due to the rarity of such cases, even in major pancreas referral centers, no prospective randomized studies exist and published experience includes only descriptive studies with small number of patients. It is important to analyze and dissect such studies in order to extract as reliable conclusions as possible, so optimal management can be offered to these patients, especially in the context where resection of recurrent disease is not included in any set of guidelines.

Local recurrence (pancreatic bed, peripancreatic lymph nodes, solitary metastases to the mesentery): Eighteen studies (with at least 5 patients each) have been published describing surgery, chemotherapy or radiation treatment [1]. They collectively include 313 patients. Eight studies with 100 patients describe surgical treatment, but only two presented survival data. Median survival was 25 and 26 months [2,3]. Major postoperative morbidity was 29% [1]. In 7 studies with 153 patients, chemotherapy was offered and median survival was 10, 12, 16, 16, 17, 18, and 19 months. In the remaining 4 studies, 60 patients were subjected to radiation therapy resulting to median survival of 9, 12, 13, and 16 months. In most studies, longer disease-free interval was associated with longer survival after treatment of recurrence.

Local recurrence - pancreatic remnant:  Fifteen studies with 52 patients have been published [4], but 7 of those are single case reports. Five studies (with at least 6 patients each) sum up the experience on 36 patients. Completion pancreatectomy was performed in 92% and median survival was 15, 16, 28, 28, and 31 months.

Recurrence to the liver:  Surgery has been considered only in oligometastatic liver recurrence (up to 3 lesions). The majority of studies describe treatment of oligometastatic synchronous disease; not recurrent disease. The latter is the topic of only 3 studies [5-7] with 52 patients altogether, but only one [5] presented median survival of 31 months.

The limited descriptive published experience suggests that any treatment of locoregional recurrent disease leads to survival benefit (around 1.5 year) compared to palliative management alone. Authors believe that specifically resection of recurrent disease is associated with longer survival, around 2 years, despite some postoperative morbidity. However, it is of paramount importance to understand that patients included in these studies were very highly selected with both limited bulk of recurrent disease and good performance status. This combination occurs only rarely in recurrent PDAC, so it is essential not to generalize the previously stated assessments.

Generally, recurrent PDAC behaves as a systemic disease requiring systemic treatment. Patients with recurrence generally present with diffuse metastatic involvement and significantly impaired performance status, implying rather aggressive biology of the recurrent disease, which may often limit any form of systemic chemotherapy. Very rarely however, recurrence may be more indolent: disease free interval after pancreatectomy may be longer (9-20 months), metastatic involvement may be limited based on modern imaging, and performance status not declined. Such a combination alludes to a more “mild PDAC biology” and leads to patient “self-selection”. Still, systemic chemotherapy is the mainstay of treatment in this minority of patients, but if the disease remains under control after its completion and performance status continues to be good, resection may be considered.

Due to the striking scarcity of such “self-selected” patients with recurrent PDAC, no definitive conclusions for surgical treatment can be drawn until multi-institutional prospective studies are conducted by major pancreas referral centers. Accordingly, although surgery may be reasonable to offer under the restrictions stated above, it still remains “out of the box” and no scientifically based prognosis is currently available.

Mini Review

It is well known that DVT formation increases with age. The risk is estimated to increase at 1% per year in the elderly. Since the cause for thrombus formation is known to be multifactorial, there are many risk factors associated with it. Commonly studied DVT risk factors are sarcopenia, malignancy, congestive heart failure, chronic medical conditions and hormone replacement therapy [1].

In geriatric population, sarcopenia is common. Lack of exercise, handicapped to perform physical activity, loss of interest to engage in social networks and hormonal imbalances all contribute to development of sarcopenia. Sarcopenia does not only affect physical activity status but is also associated with blood circulation, specifically venous blood return to heart [2]. With decrease in muscle mass vessels surrounding, it cannot be squeezed properly leading to hemodynamic insufficiency and therefore more prone to thrombus formation.

Inner walls of vessels are also known to change with aging. There are studies pointing out that patients with VTE (spontaneous venous thromboembolism) have impaired endothelial function. Impaired endothelium leads to inappropriate secretion of vWf (von willibrand factor) and P-selectin, both of which contribute to a prothrombotic status [3]. Patient with VTE also commonly have venous insufficiency. Valves on venous walls begins to have more collagen deposits and lose smooth muscle cells leading to prothrombotic status [4].

Immobilization also leads to prothrombotic status. According to one study, residents in nursing homes had 8-fold more risk of VT as compared to not institutionalized [1]. Formation of DVT sometimes does not end with swollen and painful legs, it can sometimes be devastating. Thrombus can travel to the heart or to the brain resulting in ischemic heart disease or stroke.

Current guidelines on use of antiplatelet and anticoagulation therapy mainly focuses on the extent of CAD (coronary artery disease) or ACS (Acute coronary syndrome) and is dependent on treatment options such as PCI (Percutaneous coronary interventions), CABG (Coronary artery bipass grafting) or medical treatment. But not much attention is given to DVT prophylaxis [5].

There are several risk assessment scoring system for guidance of DVT　prophylaxis. Most commonly recognized scoring system is Well’s criteria, others are ASH (Amerian Society of Hematology) guidelines, NICE (National Institue for Health and Care Excellence), ACCP (American College of Clinical Pharmacy) guidelines and CHEST (American College of Chest Physicians) guidelines. Each guidelines have different risk assessments systems but overall follow some common treatment guidelines. Most guidelines recommend the use of VKA (Vitamin K Antagonist), LMWH (Low Molecular Weight Heparin), IV unfractionated heparin or DOAC (Direct Oral Anticoagulant) for the treatment of DVT [6].

Generally for inpatient treatments VKA and LMWH is preferred and for outpatient treatments DOAC is preferred. But LMWH treatment is only available at inpatient hospital settings. VKA treatment requires INR monitoring and for those with renal impairments or in the elderly, frequency of INR monitoring is increased. For the above reasons there are studies favoring the use of DOAC due to its predictable pharmacokinetics and pharmacodynamics profile [7,8].

Differences in metabolism of medications also play a role in deciding which antiplatelet or anticoagulation therapy to use. Studies suggest that there is a difference among ethinicity in dosing of antiplatelet or anticoagulants to meet the anti-ischemic purposes [9]. Studies have shown that levels of active metabolite concentrations in asians were lower for clopidogrel, higher for prasugrel, ticagrelor, dabigatran, rivaroxaban [10]. Apixaban metabolite levels were relatively the same between east asians and caucasians. Edoxaban metabolite levels were lower in east asians compared to Caucasians [11]. There are studies suggesting higher rate of aspirin resistance in asians and also higher rate of genetic polymorphism [12].

Clinically, there are laboratory tests that can be useful in detection of prothrombotic status. When D-dimer is elevated, it favors prothrombotic status, when BUN is elevated with no definite dehydation sign or without concurrent Cr elevation and it favors prothrombotic status, when BNP is markedly elevated it favors prothrombotic status. In nursing hospitals or long-term care hospitals, many patients are on aspirin and clopidogrel dual anti platelet therapy. Still, with the onset of infection or development of cancer, signs of DVT or ischemia develop and physicians have to decide whether to add another type of anticoagulant or not. When bleeding risk assessments are done, LMWH or DOAC is administered depending on the severity of thrombosis. There seems to be a better outcome in patients using LMWH or DOAC agents in means of faster decrease in CRP and heart rate normalization.

Since there are different metabolism of medications between each individuals, physicians should carefully decide when and how to start anticoagulation and antiplatelet therapy for the better outcome of their patients.

Mini Review

It is well known that DVT formation increases with age. The risk is estimated to increase at 1% per year in the elderly. Since the cause for thrombus formation is known to be multifactorial, there are many risk factors associated with it. Commonly studied DVT risk factors are sarcopenia, malignancy, congestive heart failure, chronic medical conditions and hormone replacement therapy [1].

In geriatric population, sarcopenia is common. Lack of exercise, handicapped to perform physical activity, loss of interest to engage in social networks and hormonal imbalances all contribute to development of sarcopenia. Sarcopenia does not only affect physical activity status but is also associated with blood circulation, specifically venous blood return to heart [2]. With decrease in muscle mass vessels surrounding, it cannot be squeezed properly leading to hemodynamic insufficiency and therefore more prone to thrombus formation.

Inner walls of vessels are also known to change with aging. There are studies pointing out that patients with VTE (spontaneous venous thromboembolism) have impaired endothelial function. Impaired endothelium leads to inappropriate secretion of vWf (von willibrand factor) and P-selectin, both of which contribute to a prothrombotic status [3]. Patient with VTE also commonly have venous insufficiency. Valves on venous walls begins to have more collagen deposits and lose smooth muscle cells leading to prothrombotic status [4].

Immobilization also leads to prothrombotic status. According to one study, residents in nursing homes had 8-fold more risk of VT as compared to not institutionalized [1]. Formation of DVT sometimes does not end with swollen and painful legs, it can sometimes be devastating. Thrombus can travel to the heart or to the brain resulting in ischemic heart disease or stroke.

Current guidelines on use of antiplatelet and anticoagulation therapy mainly focuses on the extent of CAD (coronary artery disease) or ACS (Acute coronary syndrome) and is dependent on treatment options such as PCI (Percutaneous coronary interventions), CABG (Coronary artery bipass grafting) or medical treatment. But not much attention is given to DVT prophylaxis [5].

There are several risk assessment scoring system for guidance of DVT　prophylaxis. Most commonly recognized scoring system is Well’s criteria, others are ASH (Amerian Society of Hematology) guidelines, NICE (National Institue for Health and Care Excellence), ACCP (American College of Clinical Pharmacy) guidelines and CHEST (American College of Chest Physicians) guidelines. Each guidelines have different risk assessments systems but overall follow some common treatment guidelines. Most guidelines recommend the use of VKA (Vitamin K Antagonist), LMWH (Low Molecular Weight Heparin), IV unfractionated heparin or DOAC (Direct Oral Anticoagulant) for the treatment of DVT [6].

Generally for inpatient treatments VKA and LMWH is preferred and for outpatient treatments DOAC is preferred. But LMWH treatment is only available at inpatient hospital settings. VKA treatment requires INR monitoring and for those with renal impairments or in the elderly, frequency of INR monitoring is increased. For the above reasons there are studies favoring the use of DOAC due to its predictable pharmacokinetics and pharmacodynamics profile [7,8].

Differences in metabolism of medications also play a role in deciding which antiplatelet or anticoagulation therapy to use. Studies suggest that there is a difference among ethinicity in dosing of antiplatelet or anticoagulants to meet the anti-ischemic purposes [9]. Studies have shown that levels of active metabolite concentrations in asians were lower for clopidogrel, higher for prasugrel, ticagrelor, dabigatran, rivaroxaban [10]. Apixaban metabolite levels were relatively the same between east asians and caucasians. Edoxaban metabolite levels were lower in east asians compared to Caucasians [11]. There are studies suggesting higher rate of aspirin resistance in asians and also higher rate of genetic polymorphism [12].

Clinically, there are laboratory tests that can be useful in detection of prothrombotic status. When D-dimer is elevated, it favors prothrombotic status, when BUN is elevated with no definite dehydation sign or without concurrent Cr elevation and it favors prothrombotic status, when BNP is markedly elevated it favors prothrombotic status. In nursing hospitals or long-term care hospitals, many patients are on aspirin and clopidogrel dual anti platelet therapy. Still, with the onset of infection or development of cancer, signs of DVT or ischemia develop and physicians have to decide whether to add another type of anticoagulant or not. When bleeding risk assessments are done, LMWH or DOAC is administered depending on the severity of thrombosis. There seems to be a better outcome in patients using LMWH or DOAC agents in means of faster decrease in CRP and heart rate normalization.

Since there are different metabolism of medications between each individuals, physicians should carefully decide when and how to start anticoagulation and antiplatelet therapy for the better outcome of their patients.

Abstract

Introduction: Percutaneous Cholecystostomy (PC) is a radiological intervention used in the management of high risk or critically ill patients with acute cholecystitis (AC)

Method: A retrospective study of outcomes following PC, including success rates, rates of res-olution of AC, complication rates, readmissions rates, post-procedure endoscopic retrograde cholangiopancreatography (ERCP) rates and rates of subsequent cholecystectomy.

Results: Our database identified 28 patients (14M;14F), median age 73 (range 40-93). 82% were ASA III/IV. Median follow-up was 2 (range 0-8) years. Imaging suggested AC in 61% and empyema in 39%. 86% were calculous. All procedures were USS-guided with 100% success. Resolution of AC occurred in 89.3%. Of three unresolved, there was 1 death day-1 post-PC (non-procedure related), 1 index cholecystectomy, 1 chronic complicated cholecystitis. 28.6% devel-oped complications, 2 major (1 late biliary peritonitis with subphrenic abscess, and 1 cholecys-to-cutaneous fistula with abdominal wall abscess), 17.9% had dislodged drains, and 14.3% had other minor complications. 20 (71.4%) patients had bile cultures taken, of which 60% were posi-tive. 17.9% patients were readmitted with AC, 1 had repeat PC. 21.4% had subsequent ERCP. 32.1% underwent subsequent cholecystectomy, of which there was 1 laparoscopic cholecystec-tomy (LC) index, 4 elective (3 LC, 1 open) and 4 emergencies (2 LC, 1 LC subtotal, 1 failed open with drain insertion). There were no procedure related mortalities although 39.3% patients died during the follow-up period, a reflection of their pre-existing multi-morbidity.

Conclusion: PC is both safe and effective with significant procedural success rates and resolu-tion rates. There are few major complications but significant morbidities including high rates of dislodged drains. There is a high readmission rate with further biliary disease and high rates of subsequent choledocholithiasis requiring subsequent ERCP. Only one-third of patients have subsequent cholecystectomy. Further RCTs are required to determine whether PC or LC is a su-perior option in high-risk patients.

Background and Indications

Gallstone (GS) related diseases, of which AC is the most common, are some of the most fre-quently encountered acute surgical emergencies. 10-15% of the adult population in developed countries is affected by gallstones, with 20% of symptomatic patients presenting as AC [1]. The incidence of gallstone disease increases with age [2], as do co-morbidities, making management of AC challenging.

AC can be calculous (approximately 90% cases) or acalculous. Acute Calculous Cholecystitis (ACC) results from gallstone impaction either at the neck of the gallbladder (GB) or in the cystic duct. This results in obstruction to the outflow of bile, with subsequent distension, oedema and inflammation of the GB wall. If the obstruction persists, bacterial superinfection occurs leading to AC, which can progress to empyema. Ischaemia and necrosis can also supervene, leading to a gangrenous GB. Subsequent perforation can lead to localized abscess formation or even peri-tonitis. Patients may become critically ill from sepsis and its sequelae if left untreated. Acute acalculous cholecystitis (AAC) occurs in absence of GS. It occurs in the critically ill and is thought to be related to either bile stasis or ischaemia of the GB.

Laparoscopic cholecystectomy (LC) under general anaesthetic is the standard treatment of ACC and is performed in the early acute phase of the disease, in patients fit to undergo the proce-dure. However, in high-risk critically ill patients where operative intervention poses a significant mortality risk, PC has an established role. PC can be used with two intentions. Firstly, it is most commonly used as a bridge or temporizing measure in AC, allowing elective planned cholecystectomy when the patient is more stable. Secondly, it can be used as a definitive treatment in multi-morbid patients who are unfit for surgery. Thirdly, in patients with AAC, it is the definitive procedure.

The Tokyo Guidelines recommend appropriate intervention for different grades of AC (see Table 1) [3].  The severity of inflammation of the GB is associated with the difficulty of LC and carries in-creased risks of bile leak, common bile duct injury or conversion to an open procedure, espe-cially if LC is performed for severe AC beyond one week after the onset of symptoms. Grade I ACC (mild) is associated with no organ dysfunction and limited disease in the gallbladder, grade II (moderate) is associated with no organ dysfunction but extensive inflammatory gallbladder disease, making cholecystectomy difficult, whilst Grade III is associated with organ failure. Grade I patients are candidates for early LC; grade II patients could have either LC or PC (also called percutaneous transhepatic gallbladder drainage - PTGBD); immediate PC/PTGBD is strongly recommended for grade III patients.

The Technique

PC was initially described in 1867 but was first performed under USS guidance in 1980. It is a minimally invasive radiological procedure that involves placement of a drainage catheter into the lumen of the GB, under aseptic conditions. It is performed under image guidance via either the trocar or modified Seldinger technique. Indications of PC include calculous or acalculous cholecystitis, cholangitis, and biliary obstruction. The majority of patients undergoing PC are generally unfit for a cholecystectomy at initial presentation (Figure 1) [4].

There are 2 approaches, trans-hepatic and trans-peritoneal, each with its own advantages and disadvantages.  With the trans-hepatic route the catheter is passed through the liver (extra-peritoneal) into the gallbladder. This theoretically not only reduces the risk of bile peritonitis but gives greater stability to the catheter. If the gallbladder is significantly distended, the trans-peritoneal route becomes more feasible. Since the trans-peritoneal approach carries the risk of bile peritonitis however, the trans-hepatic route is generally preferred (Figure 2). Ultrasound-guided cholecystostomy with an 8-French drainage catheter (white arrow) placed into the gallbladder using the trocar tech-nique (same patient with Figure 1). White asterisk indicates posterior acoustic shadowing from gallstones [5].

There are usually no absolute contraindications to PC, but relative contraindications include co-agulopathy (needs correction), ascites, GB full of stones preventing access, and GB tumor. Complications associated with PC either are immediate or can occur within days. These include haemorrhage, bile leak/bile peritonitis, pneumothorax, bowel perforation (usually via the trans-peritoneal route), colonization of the GB, infection/abscesses and catheter displace-ment/migration (most common).

AIM

The main aim of this study was to evaluate outcomes following PC at our Health Board. Primary outcomes were success rates, rate of resolution of AC, complications, readmission rates and subsequent cholecystectomy performed. Secondary outcomes were bile cultures, repeat proce-dures and other procedures performed.

Methods

A total of 28 patients were identified on WelshPAS (Digital Patient Record System) as having undergone PC between 2011 and August 2020. Patient data was extracted for retrospective analysis using Welsh Clinical Portal and patient medical notes. Data collected included patient demographics, ASA grades, calculous vs acalculous cholecystitis, procedural success rates, reso-lution rates, complications, bile cultures taken (and organisms cultured), re-admissions rates, further procedures and subsequent cholecystectomy.

Results

The database identified 28 patients (14 male and 14 female) with an age range of 40 to 93 years (median age 73). 82% of patients were of an ASA grade of III or IV (18 patients grade III, 5 patients grade IV). The median patient follow-up was 2 years (ranging from 0 - 8 years). Ultra-sound and/or CT imaging indicated severe AC in 61% of patients (with 86% being calculous) and AC with associated empyema in 39% of patients (Table 2).

All cholecystostomies were ultrasound-guided with a 100% success rate. Resolution of acute cholecystitis occurred in 25 (89.3%) patients. Of the three unresolved patients, there was one chronic complicated cholecystitis, one index cholecystectomy and one death day-1 post chole-cystostomy (due to a cardiac cause). 28.6% of patients developed complications due to the PC, some of whom had more than one complication. Two major complications included one late biliary peritonitis (including subphrenic abscess), and one cholecysto-cutaneous fistula with abdominal wall abscess. Both these patients had sur-gical intervention and recovered [5]. (17.9%) patients had dislodged drains (with one patient re-quiring a repeat procedure within 1 week), whilst 3 other complications were blocked drain, excessive granulation of drain site and abdominal wall cellulitis (Table 3).

20 (71.4%) patients had bile cultures taken, with 70% of these being positive. Gram-negative organisms were cultured in 8 patients (mainly coliform) whilst gram-positive organisms (3 En-terococcus, 1 Aerococus, 1 Streptococcus viridans) were cultured in 7 patients (Table 4).  17.9% of patients were readmitted with further acute cholecystitis, with one patient having a repeat PC one week after the primary procedure, and another patient having a second PC pro-cedure 2 years after the first. 21.4% of patients had subsequent endoscopic retrograde cholan-gio-pancreatography (ERCP).  32.1% of patients underwent subsequent cholecystectomy. Of these, one was an index procedure, four were elective procedures (3 laparoscopic, 1 open), and four were emergency procedures (2 laparoscopic, 1 laparoscopic subtotal, and one failed open with open cholecystostomy tube drain inserted) (Table 5 & 6). While there were no procedure-related mortalities, 11 patients (39.3%) died during the follow-up period due to pre-existing morbidities as reflected by their ASA classifications.

Discussion

PC is a minimally invasive procedure that can be lifesaving for patients who are critically ill from severe AC. PC leads to resolution of AC in most cases, with high success rates and minimal mortality. It is reliable, cost effective and can be easily performed. There are associated significant morbidities however, and it does not deal with the primary source of the problem, which is gallstones.

A systematic review conducted by Winbladh et al in 2007 [6]  analysed the safety and efficacy of PC in elderly and critically ill patients. It reported a success rate of 91% in patients with con-firmed ACC and a procedure related mortality of 0.4%. The overall complication rate was low (6.2%). Our overall complication rate was much higher than this (28.6% of patients), although the majority of these were minor complications.

Bundy et al reported technical success and resolution rates of 100% [7]. Other studies report reso-lution rates of around 90%. Our study had similar outcomes. Furtado et al showed a 29% rate of subsequent cholecystectomy, [8] similar to our study.  The study also found that although PC was a life-saving procedure, there was significant associated morbidity, with 44% rate of choledocho-lithiasis, 27% rate tube dislodgment, and 23% rate postoperative abscess.  Our results were also comparable to this.

There have been few RCTs comparing PC to emergency cholecystectomy (EC). A multi-centre RCT Netherlands [9] very interestingly showed LC as superior to PC drainage in treatment of high-risk patients with ACC. It demonstrated no difference in mortality between LC and PC (3% vs 9%, P=0.27) in high-risk patients with ACC. However, LC had a significantly lower major compli-cation rate than PC (12% vs 65%, P<0.001). Recurrent biliary disease occurred more often in the PC group compared to the LC group (53% vs 5%, P<0.001). In this RCT, LC not only reduced rate of major complications but also need for re-intervention for recurrent biliary disease.

Our study failed to correlate with the high mortality rate for PC in severe disease compared to the RCT, although we do acknowledge that our study was limited by low patient numbers. Our rate of major complications was also significantly lower that in this study. However, our study did show significant rates of readmissions with biliary disease as well as a high rate of chole-docholithiasis requiring ERCP.

A study by Schlottmann et al in 2018 [10] used a retrospective population base analysis of over 200,000 elderly patients (7516 PC vs 193,399 cholecystectomy). This study showed that there was a higher incidence of post-procedural morbidity and mortality in the PC group compared to the cholecystectomy group and concluded that elderly patients with AC should undergo chole-cystectomy. However, in 2011 Melloul et al [11] found that although PC and EC were both effective in the resolution of AAC sepsis, EC was associated with a higher procedure-related mortality and conversion rate and concluded that PC remains a valuable intervention.

There were some obvious limitations with our study, such as low patient numbers even though this represented a ten-year review. Additionally, patients were not necessarily graded as per Tokyo Guidelines for severity since the study period pre-dates the publication of the guidelines. As most patients were ASA III/IV, we presume they all fell into AAC grades II and III.

Conclusion

Our study demonstrated that PC is both safe and effective in the treatment of severe acute cholecystitis. PC was associated with a high procedural success rate and high-resolution rate, with no procedure related mortalities. There were few major complications, however a significant rate of overall complications. We found PC to be associated with significant readmission rates with further biliary disease and high rates of choledocoholithiasis requiring subsequent ERCP. Only one third of patients had subsequent cholecystectomy. In view of significant overall complication rates and recurrent biliary disease, further RCTs need to be conducted in order to determine whether LC or PC is a superior intervention in these high-risk patients. PC, however, remains an invaluable treatment option.

Abstract

The aim of this study was to identify genes of the HT29 cell line, whose transcription occurs in response to infection by pathogenic strains of E. coli UM146 and E. coli UM147 isolated from individuals with CD and UC, respectively and in response to the presence of non-pathogenic strain of E. coli Nissle 1917, for better understanding of the mechanism of IBD. General findings from our experiments are related to protective action of chemokine ligand 6 indicating very important role of IL6 in inducing inflammation processes driven by two pathogenic E. coli strains used in our study. We also determined important role of molecules participating in transport of ions, carbohydrates, mRNAs and proteins as well as higher expression levels for molecules involved in RNA modification processes. Those expression differences may somehow influence host-pathogen interaction differences for two pathogenic strains with different toxin types versus one non-pathogenic E. coli.

Keywords: Inflammatory bowel Disease; Microarray; HT-29 cell line; Escherichia coli

Abbreviations: CD: Crohn’s Disease; IBD: Inflammatory Bowel Disease; PCR: Polymerase chain; reaction;   RMA: Robust MultiChip Average; RNA: Ribonucleic acid; SPATE: Serine Protease Autotransporters; t-RNA:   Transporting ribonucleic acid; UC: Ulcerative Colitis

Introduction

Crohn's disease (CD) and Ulcerative Colitis (UC) are most common diseases in the group of inflammatory bowel diseases (IBD). One of the features characteristics to both diseases is as yet undetermined etiology. Usually, patients with CD or UC have mutations in the genes engaged in the immune responses [1,2], and epithelial gaps shown by sophisticated microscopic examination [3]. It has also been found that the levels of expression of Secretory Leukocyte Protease Inhibitor (SLPI) can contribute to healing of lesions [4]. Likewise, protease inhibitors may also regulate the inflammation [5]. Furthermore, point mutations in the nod2 gene particularly in patients with CD decrease expression of proinflammatory cytokines, antimicrobial peptides including defensins [1]. In addition, studies on intestinal microflora composition [6,7] and pure Lipopolysaccharide (LPS) use [8] confirmed the involvement of microorganisms in IBD. Kind of treatments against excessive apoptosis postulated in IBD patients together with factors involved in IBD is presented in Table 1.

Material consisted of two pathogenic strains of E. coli, UM146 and UM147, isolated from patients with CD and UC, respectively, non-pathogenic strain of E. coli Nissle 1917, and human colon adenocarcinoma cell line HT-29. The common feature of both strains is the presence of S-fimbriae, a vacuolating autotransporter toxin belonging to Serine Protease Autotransporters (SPATE) and antigen 43. In addition, E. coli UM146 is P-fimbriae positive in the PCR test and E. coli UM147 has a sort of trypsin activity. Single colonies of the bacteria were cultured at 37° C for 18 h in 10 ml LB broth (Part No. 1427-500 BP) from Fisher Scientific. In order to determine the level of gene transcription of the HT29 line in response to bacterial infection, 1 ml of bacterial culture (ca. 107 CFU) was added to a flat-bottomed vessel with a bottom area equal to 75 cm2, in which HT-29 were cultured until cells became confluent and grew on the 70% area of the bottom. The samples after the addition of the bacteria were incubated for 3 hours at 37 °C in the presence of 5% CO2, after which a trypsin-containing solution was added in order to separate the cell line from the bottom surface - the resulting cell suspension was transferred into centrifuge tubes. Cells were centrifuged at 1.000 rpm for 10 min at 4°C. RNA isolation was performed by extraction with guanidine thiocyanate, phenol and chloroform (3). Hybridization of RNA to immobilized probes of single-stranded DNA on a GeneChip HG-U133A Plus 2.0 microarray and the detection of biotinylated RNA sequences were carried out according to the recommendations of Affymetrix®. Cultures of HT29 cells and E. coli as well as experiments involving microarrays were performed in a single experiment due to reproducibility difficulties. The results of the microarray were normalized using Robust MultiChip Average (RMA) using the Affymetrix® Expression Console™, and selection of line HT-29 genes differing from one another depending on the strain of E. coli, were determined using the equations from Table 2.

Table 2: Selection of most significant results for RNA transcripts of HT-29 cell line.

Only results with %-difference values higher than ±10 were collected in Table 3 as supplementary material, while additional information concerning ontology terms and involvement in Reactome pathways in Table 4 as supplementary material. Presented in Tables 3 results are divided into three groups of RNA transcripts grouped based on %-differences and skewness values in comparison to the reference results. In the first group characterized by negative %-difference and positive skewness values 4 out of 5 ID-probes were identified: (I.) Heterogeneous nuclear ribonucleoprotein U (scaffold attachment factor A) – HNRNPU mainly involved in mRNA spicing; (II.) Chemokine (C-X-C motif) ligand 6 - CXCL6 involved in neutrophil mediated immunity; (III.) Mir210 host gene - MIR210HG with unknown function and (IV.) Zinc finger protein 207 - ZNF207 participating in regulation of chromosome segregation in mitotic cell division were identified. To the second group characterized by positive %-difference and positive skewness only four out of nine ID-probes were identified. These are: (I.) Midasin AAAATP-ase 1 - MDN1 involved in ribosomal large subunit protein complex assembly; (II.) Small nuclear ribonucleoprotein polypeptide A' - SNRPA1 participating in mRNA splicing, via spliceosome; (III.) Nucleoporin 58 kDa - NUP58 involved mainly in mitotic cell cycle, t-RNA processing transmembrane transport of carbohydrates, mRNA and proteins as well as regulation of cellular response to heat and (IV.) Solute carrier family 20, SLC20A1 is responsible for phosphate-containing compound metabolic processes like phosphate and sodium ions transmembrane transport and positive regulation of I-kappaB kinase/NF-kappaB signaling. Third group we found constitute 46 ID Probes, and their characteristics are presented in Table 5. The most repeated function for this group is mediation of RNA processing connected with the gene expression of HT-29 cells in the response to pathogenic E. coli strains in terms of elevated level of RNA transcripts [9,10].

Declarations

Ethics approval and consent to participate

Not applicable

Consent for publication

Author agrees for publication of the manuscript.

Availability of data and materials

All results of our experimental and bioinformatics approaches are included in the manuscript and as supplementary materials.

Competing Interests

The authors declare that they do not have any competing interests.

Funding

Not applicable

Acknowledgements

Not applicable

Abstract

The aim of this investigation was to study patient characteristics and long and short-term results specifically in patients primarily admitted to a neurosurgical department and operated acutely for acute subdural hematoma (ASDH) or epidural hematoma (EDH). Forty-five patients operated at Uppsala university hospital 2008-2019 were included (ASDH=39 and EDH=6): 28 men and 17 women, mean age 61 years (range 8-93), 76% >1 co-morbidity, 44% on anticoagulants/antiplatelets, mean hematoma width 20mm (range 7-37) and mean midline shift 9mm (range 0-26). Seventy-three percent had >3 characteristics indicating vital surgical indication, i.e preoperative unconsciousness (GCSM <5), pupillary dilation (one or both eyes), lucid interval, hematoma width >10 mm, midline shift >5 mm. Postoperative CT was improved in all cases. Proportion of patients responding on commands increased from 36% at admission to 69% at discharge. Favorable outcome was seen in 36% and 31% died (all ASDH, mean width 21mm, range 12-35, mean shift 13mm, range 4-26; mean age 70 years, range 43-87; 64% not responding to commands and 57% abnormal pupils on admission). In conclusion, substantial mortality and morbidity were found in patients operated for ASDH and EDH even if primarily admitted to a university hospital and operated by a neurosurgeon. Taking into consideration the substantial presence of negative pre-operative prognostic characteristics, the results may afterall be interpreted as relatively favorable. An important observation was that also patients with poor prognostic factors may sometimes have favorable outcome when operated without delay. The proportion of favorable outcome achived despite that many patients displayed features related to poor prognosis, indicates that the decision making to operate was appropriate, accepting also patients indicative of having relatively poor prognosis.

Keywords: Traumatic brain injury; Acute subdural hematoma; Epidural haematoma; Acute neurosurgery

Introduction

Acute subdural hematoma (ASDH) and epidural hematoma (EDH) are common types of traumatic brain injury (TBI). ASDH comprised 30% and EDH 22.5% of 13,962 TBI patients registered in an European database 2001-2008 [1]. The corresponding figures for Sweden were 46% and 6%, respectively, among in-hospital treated patients 1987-2000 [2]. A review of the literature made for the Brain trauma foundation found mortality rates between 40-60% for ASDH [3] and around 10% for EDH [4]. It is well known that a delay of surgical evacuation may be detrimental both in ASDH and EDH, especially in patients losing consciousness [5-9]. In Sweden, as well as in many other countries, there may be long distances to the nearest neurosurgical department and many patients are primarily admitted to local hospitals and transferred secondarily to neurosurgical departments. When patients are admitted primarily to a university hospital with neurosurgery the time factor is usually limited and one are probably more inclined to take the chance to operate even patients with less favourble prognostic factors.  It would be of interest to particularly study this group of patients. The aim of this investigation was therefore to study patient characteristics and long- and short-term results specifically in patients primarily admitted to a neurosurgical department and operated acutely for EDH or ASDH.

Materials and Methods

The Department of Neurosurgery at Uppsala University Hospital (UUH) provides neurosurgical care for 6 counties with one another university hospital, 5 county hospital and various smaller local hosptals. The total catchment area includes around 2 milj inhabitants of which 200,000 live in the Uppsala county region and are referred primarily to UUH. The longest distance from the most distant local hospital within the catchment area is 300 km. TBI patients treated between 2008 and 2019 at the Department of Neurosurgery, UUH, were selected from the Uppsala TBI register [10]. Inclusion criterion were: 1. ASDH or EDH (dominating injury); 2. acute admittance primarily to UUH and 3. acute neurosurgery performed at UUH. During this time 1102 TBI patients treated in Uppsala were included in the TBI registry. From this population, 391 patients were identified with ASDH or EDH as the dominating injury. Three-hundred-forty-six patients were primarily admitted to a local hospital and therefore excluded from further analysis, leaving us with 45 patients in the final study population. The following parameters were analyzed: age, gender, former and ongoing diseases, use of anticoagulants/antiplatelets, type of trauma, intoxication, lucid interval, major extracranial injury (requiring hospital care itself), global ischemia (circulatory or respiratory); and neurological reaction grade based on the Reaction Level Scale 85 (RLS) [11,12], presence of pupillary dilatation and paresis, at admission and at discharge from the neurointensive care (NIC) unit or step down unit, respectively. The correspondence between RLS and Glasgow coma scale motor score (GCS M) is described in Table 1.

Factors indicating vital indication for surgery were evaluated [13]: 1. Preoperative unconsciousness (RLS 4-8), 2. Pupillary dilation (one or both eyes), 3. Lucid interval, 4. Hematoma width >10 mm, 5. Midline shift >5 mm. Lucid interval was defined as when the patient was awake after the injury and later became unconscious.  ICP monitoring, type of ICP monitoring, re-operation <24h and additional surgery during NIC (>24h) were investigated. The hematomas were analyzed regarding type, width, and midline shift on the CT-scans. The radiological outcome of surgery was assessed as improved, unchanged, or worsened by comparing the midline shift and the width of the hematoma between the latest preoperative and first postoperative CT-scan.

Clinical outcome was measured using the Glasgow Outcome Scale Extended (GOSE) after around six months [14]. GOSE categories between 8-5 were assessed as favorable outcome and categories between 4-1 as unfavorable. Unknown or missing data were reported as unknown.

Statistical Analysis

The statistical methods were mainly descriptive.  The data analysis was done in Prism Graph Pad 8. Fisher´s exact test was used for a significance assessment of the difference between groups. P-values <0.05 was considered statistically significant.

Results

Demographics

The demographics are presented in Table 2. There were 28 men (62%) and 17 women (38%), and the mean age was 61 years (range 8-93 years). Twenty-seven (60%) of the patients were >60 years. Thirty-four (76%) of the patients had one or more co-morbidity: hypertension or cardiac disease in 49% of all cases, past brain trauma or brain disease in 27%, history of alcohol abuse in 11%. Intoxication at the time of trauma was confirmed in 6 of the cases (13%). Twenty patients (44%) were on anticoagulants/antiplatelets.

The dominating types of trauma were fall accidents (71%) and traffic accidents (20%) (Table 2). Seven of the patients (16%) had one or more major extracranial injury (Table 2), i.e. extremity injury (n=3), facial fractures (n=2), spinal injury (n=2), thoracic injury (n=2), pelvic fractures (n=2), and extensive hemorrhage (n=1).

Preoperative CT-scan findings

The dominant finding on the preoperative CT scan was ASDH in 39 cases (87%) and EDH in 6 cases (13%). The mean hematoma width was 20 mm (range 7-37) and the mean midline shift was 9 mm (range 0-26).

Preoperative neurological status

Preoperatively, 29 patients (64%) did not respond to commands (RLS 3B-8/GCS M 5-1) (Figure 1), 17 patients had pupillary dilatation (38%; 1 unknown) (Figure 2) and 13 patients had paresis (29%; 2 unknown; > RLS 6/flexion not evaluated) (Figure 3).

Presence of vital indication

Preoperative unconsciousness (RLS 4-8/GCS M 5-1) existed in 20 patients (44%), pupillary dilation (uni- or bilateral) in 17 (38%; 1 unknown), lucid interval in 11 (24%; 6 unknown), hematoma width >10 mm in 39 (87%), midline shift >5 mm in 37 (82%) (Table 3). One factor indicating vital indication for surgery was present in 7 patients (16%), 2 factors in 17 (38%), 3 factors in 4 (9%), 4 factors in 15 (33%) and 5 factors in 2 (4%) (Table 3).

ICP monitoring

ICP was monitored in 32 patients (71%); 29 received an intraparenchymal pressure device, one received an external ventricular drain, and two received both.

Radiological outcome

Postoperative CT showed improvement in all patients who performed a postoperative scan CT examination (2 patients deteriorated and died before this was done).

Reoperation

A reoperation < 24 h was performed in one patient with removal av remaining hematoma and 5 patients had additional surgery later during NIC.

Short term neurological outcome

The mean duration from admission to discharge from the NIC unit or step down unit was 19 days (range 1-93). The proportion of patients responding on commands (RLS 1-3A/GCS M 6) increased from 36% (16/45) to 69% (31/45) at discharge (p=0.0029) (Figure 1). There were no obvious improvements regarding presence of pupillary abnormality (Figure 2) and presence of paresis (Figure 3).

Long term neurological outcome

Clinical outcome was assessed in mean after 7 months (range 5-10). Fifteen patients (33%) had good recovery, 1 (2%) moderate disability, 12 (27%) severe disability, 1 (2%) vegetative state, 14 (31%) had died and 2 patients (4%) were lost to follow-up (Figure 4). The outcome was classified as favorable (good recovery and moderate disability) in 16 patients (36%) and unfavorable (severe, vegetative, and dead) in 27 (60%). The 14 patients who died, had all ASDH and they died within 21 days after the trauma, 8 before discharge from NIC and 6 after discharge.  When different potential prognostic factors were related to outcome (favorable and unfavorable), age >65 years and ASDH were significant negative prognostic factors and use of anticoagulants/antiplateles showed a tendency to be related to unfavorable outcome (Table 3). The patients who died had a mean age of 70 years (range 43-87), 36% (5/14) were RLS 7-8, 57% (8/14) had abnormal pupils, and the mean width of the hematomas was 21 mm (range 12-35) and the mean midline shift was 13mm (range 4-26) on CT (Table 4).

Discussion

In this study of patients primarily admitted to a neurosurgical department and operated acutely for an EDH or ASDH, we found that ASDH was more common than EDH and associated with a significantly worse outcome. We also found that males were overrepresented and that traffic accidents and falls were the most common causes of trauma. Hence, our cohort was similar to those in other comparable studies with regard to these results [1,15,16]. However, our patient cohort showed a high prevalence of unfavorable prognostic factors. The prognostic factor that most clearly differed from other studies [1,15,16] was age; the median age in our cohort was 68 years, and 60% of the patients were older than 60 years and 55% were older than 65 years. Furthermore, 76% had a previous disease/comorbidity, and 44% used anticoagulants/antiplatelets.  Since age, history of prior disease, and use of anticoagulants/antiplatelets contribute to poor clinical outcome [1,15,17,18], our cohort was more likely to have less favorable outcome.

Overall, 37%  (16/43; 2 unknown) of the patients showed favorable outcome in the particular group of patients studied (EDH: 5/5, one unknown; ASDH: 11/38, 29%, one unknown), which is within the ranges reported by others  [7,14,15,19-24]. It is important to analyse the outcome results in detail in order to evaluate whether the decision to operate appears to be reasonable or too optimistic in acute patients admitted primarily to our hospital and if one can identify reliable prognostic predictors. The proportion of favorable outcome achived, despite that many patients displayed features related to poor prognosis, indicates that the decision making to to operate were indeed appropriate. When different potential prognostic factors were related to outcome, we found that age >65 years and ASDH were significant negative prognostic factors, and use of anticoagulants/antiplateles showed a tendency to be related to unfavorable outcome (Table 3). However, the predictive value of those factors were low because a considerable number of patients with age >65 years, ASDH and anticoagulants/antiplatelses had favorable outcome. This finding underline that a judgement that surgery are without chances should be based on a multifactorial analysis.

When evaluating the results, it is also important to look on the degree of vital indication, i.e. how urgent surgery was. With this purpose, five characteristics indicating vital indication were evaluated [13].  It was found that all patients included in the study had at least one parameter that indicated vital indication and a large majority (73%) had three or more (Table 3). Neither any specific characteristic of vital indication nor the number of vital indications showed significant relation to outcome, which was expected since precence of characteristics indicating vital indication was so common. It is, however, notable that also patients with 4-5 characteristics of vital indications had favorable outcome, which shows that such patients may have favorable outcome if acute surgery can be performed without delay. Furthermore, the outcome in relation to presence of vital indications further support that the decision making to operate was appropriate.

The overall mortality rate in this study was 33% (14/43; 2 unknown), all due to ASDH (14/37, 36%; one unknown),  which can be compared with the mortality rates of 40-60% in ASDH [3] and around 10% in EDH (4) reported by the Brain trauma foundation. Detailed analysis of patients who died in our study showed a mean age of 70 years and large proportions of patients in RLS 7-8 with abnormal pupils and large hematomas with extensive midline shift on CT (Table 4). Overall, the characteristics of the patients who died indicate that they all had very poor chances to survive, except one 43-year-old man in RLS 3B on admission, although he had abnormal pupil reactions (Table 4). Thus, no obvious potentially avoidable deaths were observed.

When the distances from local hospitals to university hospitals with neurosurgery are long, there has been a tradition in some countries, including e.g. Sweden and Norway, that life-saving evacuations of ASDHs and EDHs may be performed by general surgeons at local hospitals. An earlier regional study in Norway, indicated that the clinical outcome was suboptimal for patients operated at regional hospitals, suggesting that perhaps all patients should be transferred to a university hospital for surgery despite the time delay [25]. In the region where we provide neurosurgical service, we have had a long-standing working routine that a general surgeon with neurosurgical training may perform an acute evacuation of an ASDH or EDH at a local hospital, after consultation of the neurosurgeon on call in Uppsala, if the operation is life-saving and the patient judget not to survive a delay of surgery [13]. The policy includes also that the patient after surgery should be referred to Uppsala for NIC [13]. When we evaluated the results 2005-2010 we found, on the contrary to the Norwegian study [25], relatively favorable results after acute evacuations of extracerebral hematomas performed in the local hospitals [13]. The results of the present study shows that the rate of favorable clinical outcome was even higher (51%) and mortality rate lower (18%) in the local hospitals. It is however important to highlight the differences with younger patients, more cases of  EDH, less co-morbidity and less use of anticoagulants/antiplatelets in the local hospital series [13]. Even if the patient materials differ and are difficult to compare, we do think the results of this study concerning patients primarily admitted to a neurosurgical department not in any way contradict continuing the practice of acute evacuation in local hospitals when there is a clear vital indication in our health care reagion. It is however important to underline that the patient should be transferred for NIC after a life saving operation in a local hospital.

There are some methodolocical issues of this study which need to be considered. There were a limited number of patients studied and therefore multivariate statistical analysis or applying statistical model grading systems for outcome prediction was not possible. Detailed information about time courses, e.g. time from detoriation to surgery, was lacking. On the other hand, a strength was that a large proportion of patients with a considerable number of negative prognostic factors were operated, included and analysed, which provided the valuable information that relatively favourable results may be obtained also despite these conditions.

In conclusion, substantial mortality and morbidity were found overall in patients with ASDH and EDH even if they were primarily admitted to a university hospital and operated by a neurosurgeon. Poor results could to a large extent be explained by considerable presence of negative prognostic characteristics, e.g. poor neurological grade, high age, co-morbidity, anticoagulants, and preoperative indications of a clear need for instant surgical evacuation on vital indication. Taking these conditions into consideration, the results may afterall be interpreted as relatively favorable. An important observation was that also patients with poor prognostic factors may sometimes have favorable outcome when operated without delay. The proportion of favorable outcome achived (37%) despite that many patients displayed features related to poor prognosis, indicates that the decision making to to operate was appropriate accepting also patients indicative of having relatively poor prognosis.