Study the Clinical Studies

TAILORx: Trial Assigning IndividuaLized Options for treatment = Tailor Rx

1. What is the proportion of the women with hormone-receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative, armpit node–negative early breast cancer who don't need chemo after primary surgery?

The 10,273 participants were divided into 3 classes first by Recurrence Score (0-100), and this was a non-randomized process. Then, 6,907 participants whose scores were 11-25 were randomly assigned to a group without or with chemo.

It's known: Recurrence Score ≤10 not need chemo & ≥26 need chemo. How about 11-25? This trial tries to answer this.

There were 9719 eligible patients with follow-up information who were included in the main analysis set. (1619 + 3399 + 3312 + 1389)

Figure 1. Registration, Randomization, and Follow-up.

CONCLUSIONS Chemo had no added efficacy in women with hormone-receptor-positive, human epidermal growth factor receptor 2-negative, armpit node–negative breast cancer who had a mid-range 21-gene recurrence score (11-25), although some benefit of chemo was found in women 50 years of age or younger with a recurrence score of 16-25.

Figure S11. Recurrence Score 11 to 25: Subgroup Analysis for Comparison of Assigned Treatment Arms. DFS, invasive disease-free survival; RS = Recurrence Score; Pre, premeno, pre-menopause; post, post-menopause

[9719 - 1389 - (923 + 492)]/9719 × 100% ≈ 71%

2. Most readers could associate 18-50 years old with menstruation, but is there an association between menstruation/menopause and young women scored 16-25 needing chemo? From the Fig above, we can't see such an association because [Pre, RS 21-25] shows no added  benefit of chemo. See more of Fig S11:

Fig S11. More. DRFI (distant recurrence-free interval), freedom from breast cancer recurrence at a distant site

Fig S11. More. RFI (recurrence-free interval), freedom from breast cancer recurrence at a distant or local-regional site

From Fig S11 More, an weak association between [Pre, RS 21-25] and chemo need appears, but which is weakened further by the weird results from first analysis. Still, the authors wrote about it:

A greater treatment effect from adjuvant chemotherapy has been noted in younger women,7 which may be at least partly explained by an antiestrogenic effect associated with premature menopause induced by chemotherapy.27

A lady who wants to have a boy eventually has vaginal yeast infection after she washed her vagina with sodium bicarbonate solution for a time. So sad a true story.

It is impossible to take a randomized clinical trial to test this method, but of which the effect is bad according to medical knowledge. Vaginal acidity is necessary to prevent infections and the normal pH value shouldn't be changed purposely.

Why is there such a horrific method for gender selection?  Let's see an animal experiment in 1934, which type of research can't produce evidence directly for human beings.

EFFECTS OF FEEDING SODIUM BICARBONATE OR LACTIC ACID UPON THE SEX RATIO IN RATS

SEVERAL articles have appeared recently in the newspapers to the effect that the ingestion of sodium bicarbonate during pregnancy influences the sex of the offspring both in the human and in the dog, males being produced exclusively.

We conclude that, for the rat at least, the sex ratio is not affected by the feeding of base or acid.

Further, more targeted animal experiments happened inevitably in the late 1930s.

THE EFFECT OF LACTIC ACID AND SODIUM BICARBONATE ON THE SEX RATIO

Douching females with lactic acid before mating was effective in increasing the proportion of females, while the use of sodium bicarbonate increased the proportion of males.

However, human ≠ experiment using rat. Now see an in vitro laboratory study in 2017, which type of research can't produce evidence directly for or against any lifestyle change for sex selection, but which often also provides a review of its topic.

Environmental Exposure of Sperm Sex-Chromosomes: A Gender Selection Technique

(Introduction) Sex selection can be achieved through natural conception, although this option is not well-established yet and therefore, remains quite speculative. However, influencing the timing of fertilization with regard to ovulation is one of the natural methods believed to be effective. Sex selection through timely intercourse is based on the respective characteristics of the X- and Y-chromosome-bearing spermatozoa, favoring one or the other toward reaching and fertilizing the egg.

The results indicated enrichment of Y-sperm at pH 6.5, 8.5, or 9.5, but poverty at pH 5.5 (neutral 7.5), increased temperatures, and elevated H2O2.

Preconceptual sex selection… X- and Y-chromosome-bearing spermatozoa (motile sperm cell) are isolated prior to fertilization of the oocyte (egg cell).

The aim of this study was to separate X- and Y-chromosome-bearing spermatozoa using methods based on the viability difference between the X- and Y-chromosome-bearing spermatozoa.

Spermatozoa were exposed to different pH values (5.5, 6.5, 7.5, 8.5, and 9.5), increased temperatures (37°C, 41°C, and 45°C) and ROS (reactive oxygen species) level (50 μM, 750 μM, and 1,000 μM).

Fig. 1. Effect of pH on the sex-chromosome ratios in spermatozoa.

At any rate, listening to a specialist of OB/GYN is necessary:

Is there any way to influence a baby's sex?

The short answer is no — there's not much the average couple can do to affect a baby's sex.

Can sleeping in on the weekends compensate for lack of sleep during the week? The study about this question hadn’t produced any practical significance:

due to the low number of subjects in the categories SML and LS, we could not differentiate the effect between short sleep during the week and medium or long sleep during the weekend…

SML = Short weekday sleep and Medium/Long weekend sleep

【SML ==?== death rate】 Is there any association between “weekend compensation” and death rate? The information became undefined from the summary to the full text.

Another ambiguousness had confused NHS Choices/Behind the Headlines. What is long sleep duration in 6 sleep patterns such as SML and LS? Pics above give the answer. Also, the paper:

we observed a detrimental association with consistently sleeping ≤5 hr (hazard ratios 1.65; 95% confidence intervals 1.22–2.23) 【SS】 or ≥8 hr (hazard ratios 1.25; 95% confidence intervals 1.05–1.50), 【LL】 compared with consistently sleeping 6–7 hr per day (reference). 【MM】

A higher risk was also observed for individuals with consistently long sleep (LL; HR 1.25; 95% CI 1.05–1.50).

What confused Behind the Headlines?

For the study of weekend sleep we defined short sleep as ≤5 hr, and weekend long sleep as ≥9 hr, with 7 hr being the reference category. The former is a common definition (Cappuccio et al., 2010) and the one used in the largest study (Kripke, Garfinkel, Wingard, Klauber, & Marler, 2002). The definition of long sleep as ≥9 hr is the most common one (Cappuccio et al., 2010), and the one used in the largest study (Kripke et al., 2002).

BUT:

Sleep duration was self-reported through two questions at baseline: “How many hours, approximately, do you usually sleep during a workday/weekday night?” and “How many hours, approximately, do you usually sleep per night on days off?” The response alternatives were: <5, 5, 6, 7, 8 or ≥9 hr …

For the analysis of both weekend and weekday sleep duration we collapsed the two highest categories to ensure enough participants with long weekday sleep (which is shorter than weekday sleep).

Collapsing 8 and  ≥9 produced  ≥8, which is the definition of Long sleep for the analysis of not only weekend sleep but also weekday sleep.

Two definitions of long sleep for two analyses made some specialists dizzy, and“weekend sleep compensation” effect to prevent death is just a rumor.

Does fever help fight Infection? Should I avoid fever-reducing drugs? They are important questions which are often given a harmful answer by  intellectuals. 

NYT ASK WELL gave an answer with caution, quoted as below. In fact, 

1. the Ibuprofen RCT tell us that in patients with sepsis, treatment with ibuprofen reduces tachycardia, oxygen consumption, and lactic acidosis without increased  adverse events 

2. the Acetaminophen RCT tell us that  ICU and hospital length of stay were longer with acetaminophen than with placebo among patients who died, i.e., acetaminophen might prolong their lives — consistent with other studies, While survivors shorter, i.e.,  acetaminophen might make them improve more quickly

2.1 “Our observation that early administration of acetaminophen to treat fever is associated with a longer ICU stay than placebo among nonsurvivors and a shorter stay among survivors must be regarded as hypothesis-generating, thereby requiring caution in interpretation,” the researchers wrote.

2.2 No adverse events increased

So it is probably safe for you to defer taking anti-fever medicines for minor illnesses. On the other hand, since rigorous clinical trials have shown that these drugs do not worsen outcomes, why not make yourself comfortable?

Harrison's Principles of Internal Medicine, 19th Edition:

Most fevers are associated with self-limited infections, such as common viral diseases. The use of antipyretics is not contraindicated in these infections: no significant clinical evidence indicates either that antipyretics delay the resolution of viral or bacterial infections or that fever facilitates recovery from infection or acts as an adjuvant to the immune system. In short, treatment of fever and its symptoms with routine antipyretics does no harm and does not slow the resolution of common viral and bacterial infections.

Reducing fever with antipyretics also reduces systemic symptoms of headache, myalgias (muscle pain), and arthralgias (joint pain).

In hyperpyrexia, the use of cooling blankets facilitates the reduction of temperature; however, cooling blankets should not be used without oral antipyretics.

For Children, Review Guidelines:

This cross-sectional study interests a psychologist for its small OR

However, these ORs, etc, represent associations between only a One-Quintile reduction in relative amplitude, a measure of the extent to which circadian rhythmicity of rest–activity cycles is disrupted, and mood disorders, etc. 

1/5 full body clock disruption ==?== mood disorders

UK residents aged 37–73 years were recruited into the UK Biobank general population cohort from 2006 to 2010. We used data from a subset of participants whose activity levels were recorded by wearing a wrist-worn accelerometer for 7 days. 

From these data, we derived a circadian relative amplitude variable, which is a measure of the extent to which circadian rhythmicity of rest–activity cycles is disrupted. 

In the same sample, we examined cross-sectional associations between low relative amplitude and mood disorder…  A one-quintile reduction in relative amplitude was associated with … 

Article Summary

Your grandpa probably complained that rain was coming—he could feel it in his knees. Dr. Elaine Husni says that many, but not all, of her osteoarthritis patients complain that weather does influence their pain levels,  【which is different from what grandpa complained.】 

Dr. Husni points out that clinical studies have been conducted to find direct correlations between patients with hip or knee pain and changes in the weather, but the results were mixed. “There does seem to be a loose association between certain temperature variables like barometric pressure, cold temperatures and humidity and increased joint pain, but it isn’t so easy for patients to say with precision, ‘It will be 60 degrees and rainy tomorrow,’” she says. While many patients do feel more pain when it gets cold or humid, “they’re not psychic. In studies, they couldn’t predict the weather with accuracy.”

The probably most valuable research, a multicenter prospective cohort study

The Influence of Weather Conditions on Joint Pain in Older People with Osteoarthritis: Results from the European Project on OSteoArthritis

significant associations of joint pain with daily average humidity (B = 0.004, p < 0.01) and 3-day… A significant interaction effect was found between daily average humidity and temperature on joint pain. The effect of humidity on pain was stronger in relatively cold weather conditions.

Changes in weather variables between 2 consecutive days were not significantly associated with reported joint pain. 【weather change ==||== pain change, so joint pain can’t predict weather change】

Obesity paradox may exist theoretically in patients with chronic wasting diseases & without ability to reduce BMI. However, that’s somewhat meaningless. Prevention and reversion of overweight and obesity is very important to your health.

New research

Association of Body Mass Index With Lifetime Risk of Cardiovascular Disease and Compression of Morbidity

In this study, obesity was associated with shorter longevity and significantly increased risk of cardiovascular morbidity and mortality compared with normal BMI. 

Despite similar longevity compared with normal BMI, overweight was associated with significantly increased risk of developing cardiovascular disease (CVD) at an earlier age, resulting in a greater proportion of life lived with CVD morbidity. 

About obesity paradox, Harrison's Principles of Internal Medicine, 19th Edition

Not all patients who are deemed obese by BMI alone need to be treated, as exemplified by the concepts of obesity paradox or the metabolically healthy obese. However, patients who present with obesity-related comorbidities and who would benefit from weight loss intervention should be managed proactively.

Goldman-Cecil Medicine, 25th Edition

Interestingly, some obese individuals have apparently normal insulin sensitivity and glucose metabolism, sometimes referred to as the obesity paradox. The mechanisms that may protect someone from the diabetogenic effects of excess adiposity are not known, but intact cardiorespiratory fitness may play a role.

Braunwald's Heart Disease, 10th Edition

Although obesity is a risk factor for the development of HF, obese patients with HF seem to enjoy a more favorable clinical prognosis. The association between obesity, a traditional cardiovascular risk factor, and improved clinical outcomes in patients with HF (i.e., reverse epidemiology) has been called the “obesity paradox.”

These are only the most efficient information of the literature. In a word, whether obesity paradox exists is controversial and you can neglect this term.

Paper Abstract | We recruited 86 participants for our study. Of these, 40 patients were randomly allocated to the control group, and 46 were randomly allocated to the tonsillectomy group. One patient in the control group and no patients in the tonsillectomy group had a severe episode of pharyngitis (difference 3%, 95% confidence interval [CI] −2% to 7%).

This, in a nutshell, is an RCT with a primary outcome as 1/40 vs. 0/46.

When any number of the four (as to this RCT primary outcome, they're  1, 39; 0, 46) greater than 5, we can use the normal approximation to solve a binomial distribution problem. The researchers use this method without the premise. Let's recreate their calculation by online calculators. (Upper Left. http://www.rossmanchance.com/ISIapplets.html Theory-Based Inference)

The right methods are Newcombe's method for 95% CI & Fisher's exact test for p-value. (Lower Right. http://vassarstats.net/prop2_ind.html )

Paper Short-term outcomes of tonsillectomy in adult patients with recurrent pharyngitis: a randomized controlled trial （Free Full Text）

Risk of stroke and transient ischaemic attack (TIA) in patients with a diagnosis of resolved atrial fibrillation (AF) Remained high? That's in accordance with our present knowledge. Were anticoagulants useless for patients with a diagnosis of resolved AF to prevent stroke and TIA? This conclusion can't be drawn from the new research.

Paper Abstract | Adjusted incidence rate ratios for stroke or TIA inpatients with resolved atrial fibrillation were 0.76 (95% confidence interval 0.67 to 0.85, P<0.001) versus controls with AF & 1.63 (1.46 to 1.83, P<0.001) versus controls without AF.

That is, as to Stroke/TIA, patients with resolved AF were only 24% safer than with current AF, but 63% riskier than without AF. Why？

Besides causing stroke, AF may also be associated with other factors that cause stroke.

Age, male sex, hypertension, diabetes mellitus, valvular heart disease, heart failure, coronary heart disease, chronic kidney disease, inflammatory disorders, sleep apnea, and tobacco use are risk factors for both AF and stroke.

Confounding in the AF–stroke association is indicated by its attenuation as more shared risk factors are accounted for.

That is, AF resolved but Other risk factors for stroke/TIA not resolved. However—

AF remains independently associated with stroke even after seemingly thorough adjustment for shared risk factors. And AF is associated not just with stroke in general, but most strongly with strokes whose neuroimaging patterns resemble that of cardiac embolism.

That is, AF —> Stroke relationship is very very strong though accompanying risk factors exist (and Stroke —>AF may occur).

OK. The second key point.

Paper Full Text | The adjusted incidence of stroke or TIA was 14% lower in patients with a current prescription for an anticoagulant compared with those without, but this result was not statistically significant: adjusted incidence rate ratio 0.86 (95% confidence interval 0.62 to 1.18).

This comparison isn't a purpose of the research, and most patients with a current prescription for an anticoagulant (a prescription of any anticoagulant up to 90 days before census date; up to 90 days before index, equivalent to 90-180 days after the atrial fibrillation resolved record. Study start date = one year before the first index or census date) couldn't stick to anticoagulants too long:

Paper Full Text | In total, 17.4% (95% confidence interval 16.7% to 18.1%; 1943/11 159) of patients with coded atrial fibrillation resolved had a current prescription for anticoagulant at the time the diagnosis of resolved atrial fibrillation was recorded. Of the 1943 (17.4%) patients with a current prescription for anticoagulant at the time the diagnosis of resolved atrial fibrillation was recorded, 44.9% (42.7% to 47.1%; 872/1943) were still receiving anticoagulant treatment up to 90 days later, and 32.9% (30.8% to 35.0%; 639/1943) were still receiving treatment up to 180 days later.

Taking the medications too short may cause that taking was equal to not taking, and the researcher advocate continued use of anticoagulants in patients with resolved AF.

After all, this is a retrospective cohort study, which can't be overinterpreted.

Reference Superlinks

Risk of stroke and transient ischaemic attack in patients with a diagnosis of resolved atrial fibrillation: retrospective cohort studies (BMJ, free full text)

People no longer being treated for irregular pulse 'may still have stroke risk' (Behind the Headlines - NHS Choices)

The viewpoint of the news title may be right. However, the research reported wasn't about this.

According to the presentation at AGS 2018 Annual Scientific Meeting, the LINK is between Antihypertensive Drug De-Intensification and Recurrent Falls in Long-Term Care (presented by Kenneth Boockvar, MD, MS), not between Aggressive BP Lowering and Falls in Older Patients.

"Little is known, however, about links between recurrent falls and less stringent blood pressure targets pursued through “de-intensified” blood pressure treatment. To explore that connection … According to the researchers, findings suggest that blood pressure medication de-intensification may reduce recurrent falls in some nursing home residents with more aggressive blood pressure targets." the presentation said.

So the News Title should have been BP Medication De-intensification Linked to Reduced Recurrent Falls in Older Patients

However, the news provided some useful information, which may be used to correct its errors. *^____^*

The team identified veterans who had fallen in the 3 days after a systolic blood pressure reading no higher than 120 mm Hg, which suggests that they were receiving aggressive blood pressure management.

They then looked at whether treatment had been eased — with a dose decrease or the discontinuation of a medication — in the 7 days after the fall, and assessed the 30-day risk for subsequent falls.

Fall Risk

The median nursing home stay of the 3436 veterans who fell was 611.5 days.

Of the 730 falls that were preceded by a systolic blood pressure reading of 80 to 100 mg Hg, 245 veterans (33.6%) had had their antihypertensive treatment eased.

Of the 1528 falls that were preceded by a systolic reading of 101 to 120 mg Hg, 381 veterans (24.9%) had had their treatment eased.

Age and physical function were similar, whether or not treatments had been changed. However, Elixhauser Comorbidity Index score was higher with medication easing than without (6.4 vs 5.9; P = .004), and the rate of dementia was lower (53% vs 61%; P = .008).

In addition, the risk for 30-day subsequent falls was lower after treatment changes.

"However, the findings will need to be replicated in women in long-term care settings, given that veterans are predominately men," she pointed out.

=============Meeting Presentation=================

Antihypertensive Drug De-Intensification and Recurrent Falls in Long-Term Care (presented by Kenneth Boockvar, MD, MS)

So beloved by many beautiful ladies, skin tight pants and other tight clothes probably do them more harm than good. Of course, gentlemen are no exception.

Tight trousers can cause meralgia paresthetica (skinny pants syndrome).

https://jamanetwork.com/journals/jama/article-abstract/392023

A very tight bra can cause Mondor's syndrome of superficial thrombophlebitis.

https://www.breastcancercare.org.uk/information-support/have-i-got-breast-cancer/benign-breast-conditions/mondor%E2%80%99s-disease

Vulval non-obstetric trauma may be due to tight clothing.

https://onlinelibrary.wiley.com/doi/abs/10.1111/1742-6723.12016

Burn the bra! (and men’s tight underpants too): compromised ‘chaotic’ cooling by constrictive clothing in the causation of testicular and breast cancers

This cross-sectional study merely tell us Correlations between IQ and some characteristics of neurons. Causal relationship？ Premature to chat. Let alone cause or effect.

"What makes some people smarter than others? It Could 【=possibly】 come down to your individual brain cells – the bigger and faster your neurons, the higher your IQ. IF Confirmed, 【i.e., NOT confirmed】 the finding…" Reported New Scientist accurately.

A cellular basis of human intelligence

Why to lower p-value？ Is lowering p-value to .005 reasonable？

The Paper  （free PDF） 

The News （login needed）

The ASA's Statement on p-Values: Context, Process, and Purpose （free PDF）　

Executive Summary

P values and accompanying methods of statistical significance testing are creating challenges in biomedical science and other disciplines. The status quo is widely believed to be problematic, but how exactly to fix the problem is far more contentious.

P values are misinterpreted, overtrusted, and misused. These 3 major problems mean that passing a statistical significance threshold (traditionally P = .05) is wrongly equated with a finding or an outcome (eg, an association or a treatment effect) being true, valid, and worth acting on.

Overtrust ensues when it is forgotten that “proper inference requires full reporting and transparency.” P-values and related analyses should not be reported selectively. Conducting multiple analyses of the data and reporting only those with certain p-values (typically those passing a significance　threshold) renders the reported p-values essentially uninterpretable. Researchers should disclose the number of hypotheses　explored during the study, all data collection decisions, all statistical analyses conducted and all p-values computed.

Better-looking (smaller) P values alone do not guarantee full reporting and transparency. In fact, smaller P values may hint to selective reporting and nontransparency.

The most common misuse of the P value is to make “scientific conclusions and　business or policy decisions” based on “whether a P value passes a specific threshold” even though “a P value, or　statistical significance, does not measure the size of an effect or the importance of a result,” and “by itself,　a　P value does not provide a good measure.”

Any effect, no matter how tiny, can produce a small p-value if the sample size or measurement precision is high enough, and large effects may produce unimpressive p－values if the sample size is small or measurements are imprecise. Similarly, identical estimated effects will have different p-values if the precision of the estimates differs.

Researchers should recognize that a p-value without context or other evidence provides limited information. For example, a p-value near 0.05 taken by itself offers　only weak evidence against the null hypothesis. Likewise, a relatively large p-value does not imply evidence in favor of the null hypothesis; many other hypotheses may be equally or more consistent with the observed data. For these reasons, data analysis should not end with the calculation of a p-value when other approaches are appropriate and feasible.

My Opinion

Misinterpretations of P values don't matter if accompanying methods are selected correctly according to authorized textbooks.