Countries with BCG Vaccinations and COVID-19 Deaths

An interesting study, examining the association of BCG vaccination and risk of COVID-19 deaths using country level data. Authors make a compelling case that there is an association using data from a large number of countries.

Such studies have potential for ecological fallacy – however, there is underlying biological plausibility and further, as we are collecting data on these cases, knowing about patients who had BCG vaccination versus those who did not may help to solidify the evidence in support of BCG. In other words, the evidence in not solid but need further study.

Indeed, clinical trial examining the role of BCG in stimulating immunity and generating resistance is ongoing Australia where they are planning to enroll approximately 4,000 healthcare workers at hospitals across Australia.

Hydrate or not to Hydrate that is the Question

A large amount of previous evidence have suggested that hydration of patients undergoing an intravenous contrast study reduces the risk of kidney injury. However, recently some data suggests that the contrast induced injury may simply be because patients who are undergoing emergent intravenous contrast study are sicker patients and are likely to develop kidney injury irrespective of getting contrast.

Timal and colleagues conducted a randomized controlled trial enrolling 523 patients with stage 2 chronic kidney disease and found that there was no benefit of giving intravenous fluids to patients who were getting intravenous contrast. The study details are here

Another Drug (Interferon beta-1A) is Found to be Ineffective in Patients with Acute Respiratory Distress Syndrome

Acute respiratory distress syndrome (ARDS) is a life-threatening disease. It is characterized by leaky lungs blood vessels resulting in fluid in the lungs (pulmonary edema) which results in low oxygenation of the blood flowing through lungs. Usually, there is an underlying severe disease, often sepsis, that results in ARDS. Currently, the treatment of patients with ARDS is treatment of the underlying cause and supportive care with a hope that lungs will recover on their own.

The main mechanisms underlying underlying ARDS is an uncontrolled inflammatory response resulting in injury to the walls of the lung blood vessels leading to increased leakage of fluids into the lung alveoli. Interferon beta-1A (IBA) has been shown to reduce leakage from blood vessels and dampen inflammatory response. An early study showed some benefit.

A recently reported randomized controlled trial found no benefit of the drug. Investigators did not find any benefit with regard to ventilator free days or 28-day mortality. In fact, if anything, significant number of patients suffered adverse effects. While the study was not effective in showing a benefit, it raised important question about possibility of other therapies affecting the beneficial effect of this drug. In conclusion, more research is needed for this disease for which we have no therapies available.

Time Sucked Away from Patients by EHRs

Sticking results from this descriptive study – on an average physicians are spending 16 minutes per encounter working with electronic health record. Now you know why your physicians are spending little time with you and always appear in a hurry. They are still very busy, reviewing the chart, ordering tests, and documenting the encounter. Machine has taken over the space between a doctor and a patient.

Obviously, very few (likely none) physicians enjoy spending time away from their patients. However, the regulatory burdens, some national mandates,some state mandates, some regulatory body mandates, and some institutional mandates require increasing documentation. All this increased documentation requirement has been placed without providing any additional time to a physician. As a result, physicians decreased the only discrete time they had – time with the patient.

Most of these mandates are there to make sure that the quality of care delivered is adequate. However, these mandates have worsened physician burnout and are perhaps not improving overall care except only those processes that are being measured.

The Saga of Vitamin C and Septic Shock

Vitamin C has been proposed as a drug that may help patients with sepsis due to its antioxidant effects. Earlier studies have been inconclusive. Another randomized trial was reported this week. Investigators wanted to examine if the combination of vitamin C, hydrocortisone, and thiamine, compared with hydrocortisone alone, improves the duration of time alive and free of vasopressor administration in patients with septic shock.

This was a multicenter studies conducted in 10 ICU in Australia, New Zealand, and Brazil. The study was open label (treating physicians were aware of the therapy), randomized (patients were allocated to the treatment or control arm randomly) clinical trial.  Investigators recruited 216 patients fulfilling the Sepsis-3 definition of septic shock.

Patients in the vitamin C arm (n = 109) received intravenous vitamin C (1.5 g every 6 hours), hydrocortisone (50 mg every 6 hours), and thiamine (200 mg every 12 hours). Patients in the control arm (n = 107) received only intravenous hydrocortisone (50 mg every 6 hours) alone until shock resolution or up to 10 days.

Median time alive and vasopressor free up to day 7 was 122.1 hours (interquartile range [IQR], 76.3-145.4 hours) in the intervention group and 124.6 hours (IQR, 82.1-147.0 hours) in the control group; the median of all paired differences was –0.6 hours (95% CI, –8.3 to 7.2 hours; P = .83). Ninety-day mortality was 30/105 (28.6%) in the intervention group and 25/102 (24.5%) in the control group (hazard ratio, 1.18; 95% CI, 0.69-2.00). No serious adverse events were reported.

The findings strengthen the clinical data, which is in contrast to the basic science data, that vitamin C may have clinical benefit in septic patients. At the minimum, the study findings suggest that treatment with intravenous vitamin C, hydrocortisone, and thiamine does not lead to a more rapid resolution of septic shock compared with intravenous hydrocortisone alone. For some, this might be end of vitamin C story, others may still want to examine vitamin C potential little more.

Vitamin D, Calcium Supplementation, and Bone Fracture Risk

Osteoporosis can be considered an aging process. In a lifetime, osteoporotic fracture affects about 1 in 2 women and 1 in 5 men aged 50 years or older with hip fracture being the most serious type of osteoporotic fracture. Vitamin D is essential for optimal musculoskeletal health because it promotes calcium absorption, mineralization of bone, and maintenance of muscle function. Vitamin D supplementation in several observational studies have been shown to decrease the risk of fracture. Similarly, calcium supplementation has also been shown to be preventive. However, results from the randomized clinical trials, the gold standard for determining if a given therapy is effective or not are lacking.

Yao and colleagues published a systematic review and meta-analysis and pooled data from large observation studies and randomized clinical trials to answer some key questions. In particular, they wanted to assess the risks of fracture associated with supplementation with vitamin D alone or in combination with calcium in RCTs. To identify relevant studies, they searched several medical literature databases: PubMed, EMBASE, Cochrane Library, and other randomized controlled trial databases. The search was from the start of database until December 31, 2018. They selected observational studies involving at least 200 fracture cases and randomized clinical trials enrolling at least 500 participants and reporting at least 10 incident fractures were included.

They identified 11 observational studies with a total number of 39 141 participants who had total of 6278 fractures, out of which 2367 were hip fractures. When they pooled the study results, they found that each increase of 10.0 ng/mL (ie, 25 nmol/L) in vitamin D was associated with an adjusted rate ratio for any fracture of 0.93 (95% CI, 0.89-0.96) and an adjusted rate ratio for hip fracture of 0.80 (95% CI, 0.75-0.86).

They also identified 11 RCTs of vitamin D supplementation alone enrolling 34 243 participants, 2843 fractures of which 740 were hip fractures. These trials did not find any decrease in risk of any fracture with Vitamin D supplementation alone (rate ratio, 1.06; 95% CI, 0.98-1.14). Similarly, there was no decrease in risk of hip fracture (rate ratio, 1.14; 95% CI, 0.98-1.32).

In contrast, a meta-analysis of 6 RCTs (49 282 participants, 5449 fractures, 730 hip fractures) of combined supplementation with daily vitamin D (daily doses of 400-800 IU) and daily calcium (daily doses of 1000-1200 mg) found a 6% reduced risk of any fracture (rate ratio, 0.94; 95% CI, 0.89-0.99) and a 16% reduced risk of hip fracture (rate ratio, 0.84; 95% CI, 0.72-0.97).

The final word: If you take vitamin D and/or calcium to reduce the risk of osteoporosis and osteoporotic fractures, you should take both calcium and vitamin D supplements together. Taking just one medication is unlikely to decrease fracture risk.

Physician Burnout and Self-perception of Medical Errors

Another study was just published examining the relationship between surgeon burnout and self-perceived medical errors. As expected, they found a strong correlation between the two. It is pretty well-known that when a physician is burned out, his/her own perception of quality of work goes down.In other words, finding a relationship between burnout and self-perception of medical errors is an issue of physician’s perception and not that actually medical errors occurred. To be confident, we need to objectively measure medical errors.

High Utilizers and Social Support

There is a common theme within the readmission reduction community that a large number of readmissions are due to limited social network around patients and only if we can provide patients with resources in community, we will be able to decrease these readmissions. Some observations studies have noticed a decrease in readmissions when patients are provided access to social/community resources, however, such studies are limited by risk of bias due to the ‘regression to the mean’ phenomenon.

Regression to mean phenomenon stipulates that if we examine participants once only performing a certain activity (or for an outcome), some of them will perform better while others will perform poorly simply due to some random factors. If we observe these participants longitudinally, we will find that those who performed well will perform poorly while those who performed poorly will perform better than their initial performance. Both groups will try to reach towards their mean (or true value).

Similarly, when we examine high-utilizer patients of health care services during a given period, those patients are likely at their worst and will do better anyway during the follow-up. This has nothing to do with the intervention but rather due to the regression to mean phenomenon. The way to address this problem is either to have several longitudinal measurements of the whole cohort where we can identify regression to the mean or to conduct a randomized clinical trial.

Finkelstein et al., conducted such a trial. They randomly assigned 800 hospitalized patients with medically and socially complex conditions with at least one additional hospitalization in the preceding 6 months, to either usual care (control group) or to the intervention group where social workers and community health workers coordinated and helped patients to access community resources.

To their, and frankly everyone else’s, surprise, they found to benefit of all the efforts of social workers and community health workers in reducing readmissions. The 180-day readmission rate was 62.3% in the intervention group and 61.7% in the control group. The adjusted between-group difference was not significant (0.82 percentage points; 95% confidence interval, −5.97 to 7.61).

More importantly, study highlighted the phenomenon of regression to the mean showing that the patients with high readmission rates resulting in enrollment generally had a decline in their readmission rate irrespective of whether they received intervention or not.

The study has few caveats but still raises very important questions – what should hospitals, healthcare systems, physicians, and other healthcare team members do to reduce readmissions and healthcare resource utilization in a very vulnerable population.

Are Young Women Getting Unnecessary Medical Care?

The annual pelvic examination in otherwise healthy women is considered part of the well-woman visit. Similarly, Pap-smear is performed for cervical cancer screening among sexually active women. Screening for cervical cancer is not recommended for women younger than 21 years, a consensus reached by the US Preventive Services Task Force, the American College of Obstetricians and Gynecologists, and American Cancer Society. The general recommendation is against performing pelvic examinations in asymptomatic, nonpregnant women younger than 21 years. However, young women are still undergoing such exams during their physical examinations.

How big is the problem of these unnecessary exams? Qin et al has recently published their findings using the National Survey of Family Growth. They estimated that between 2011 and 2017, an estimated 2.6 million women aged 15 to 20 years in the United States (22.9%) received a pelvic examination in the past year, and 54.4% of these examinations were potentially unnecessary. Further, an estimated 2.2 million young women (19.2%) received a Pap-smear test in the past year, and 71.9% of these tests were potentially unnecessary.

The Best Time to Take Your Blood Pressure Pills

Majority of blood pressure medicines are one daily and people take their blood pressure medicines often in the morning. There have been some data based on our understanding of the diurnal variations or circadian rhythms that taking medications at bedtime may work better. For example, peak activity of the renin–angiotensin–aldosterone system (RAAS) occurs during sleep. Further, data from some uncontrolled studies have suggested that taking blood pressure medications at evening (or bedtime) may be beneficial. However, a randomized controlled clinical trial (the gold standard for scientific evidence) has been lacking. That is until now!

A recent study published in the European Heart Journal, by Hermida et al, addressed this very same question. Investigators enrolled 19 084 hypertensive patients (10 614 men and 8470 women) and assigned patients to take the entire dose of their blood pressure pills at bedtime or in the morning. Of all the patients, 1752 experienced either a death due to heart attack, heart attack without death, had stent placed in their heart blood vessels, developed new heart failure, or a stroke. Patients who were taking their medications had 45% lower risk of all outcomes combined, 56% lower risk of heart attach death, 34% lower risk of heart attack, 40% lower risk of stents in their heart blood vessels, 42% lower risk of heart failure, and 49% lower risk of stroke.

Note, these are large differences – these patients were taking their blood pressure pills but just taking pills at a different time made a huge difference. The difference is larger than many other pills that are often prescribed by physicians. If you, or your loved one, takes blood pressure pills, consider talking to your doctor if you should take your pills at bed-time.

Tele-Health and Liver Transplant

Liver transplantation is the only treatment that increases survival times of patients with decompensated cirrhosis. Patients who live further away from a transplant center are disadvantaged. Health care delivery via telehealth is an effective way to remotely manage patients with decompensated cirrhosis. Authors investigated the effects of telehealth on the liver transplant evaluation process.

Using regression models, authors evaluated the differential effects of telehealth vs. usual care on placement on the liver transplant waitlist. We also investigated the effects of telehealth on time from referral to initial evaluation by a transplant hepatologist, liver transplantation, and mortality.

Authors found that the use of telehealth was associated with a substantial reduction in time from referral to initial evaluation by a hepatologist and placement on the liver transplant waitlist-especially for patients with low MELD scores, with no changes in time to transplantation or pre-transplant mortality.

Fragility Index for Randomized Controlled Trials

An interesting question – how ‘fragile’ are the results of a randomized controlled trial (RCT)?

RCTs are gold-standard for determining the efficacy of a treatment. RCTs randomly assigned patients to an intervention arm or to a placebo (or standard of care or active treatment) arm. Because patients are randomly assigned, we expect that all patient characteristics (genetic, environmental etc.) would be balanced in the two groups. RCTs are often published with significant results – small RCTs without significant results are generally either not published or published in low-tier journals and don’t get prominence

Even when we randomly assign patients to a treatment arm or control arm, there is always a possibility that the two arm may be imbalanced by chance on measured or unmeasured variables. Further, it is also possible that just by chance one group may have statistically significant result than the other group without any true benefit (or harm) of the treatment. While we generally use a p-value of less than 0.05 (which says that there is a 1 in 20 probability that the results are observed due to chance only – not the right definition but its simple!), there remains a small chance that results will be not significant.

In comes ‘Fragility Index’, a measure of determining the robustness of results. Fragility index is the minimum number of patients who must be moved from the nonevent group to the event group to turn a significant result nonsignificant. The fragility index is an easy to calculate index that provides an intuitive way to understand the precision of trial results. Knowing the fragility index and comparing it to the number of patients lost to follow-up can help to understand the uncertainty in evidence even when a study has positive results.

Khan et al, examined cardiovascular clinical trials published between 2007-17 in major Cardiology journals. All trials were large with >500 patient enrollment. Among the 123 RCTs the median fragility index was 13.In almost 1/3rd of trials, the number of patients lost to follow-up was more than the fragility index.

In another study Gaudino et al examined the clinical trials used to support evidence in cardiology guidelines and determined the fragility index. They found that more than a quarter of RCTs supporting current guidelines on myocardial revascularization have a fragility index 3 or lower. Further over 40% of trials had a fragility index which was lower than the number of patients lost to follow-up.

Physician Burnout & Patient Satisfaction/Experience

There have been concerns that physician burnout leads to lower patient satisfaction. In fact, some studies have found that patient satisfaction is lower among physicians with higher levels of burnout. A meta-analysis published in 2018 assimilated data and reached to the same conclusion. However, the quality of data, and studies, is questionable and there is a need for better conducted studies to examine this relationship.

A recently published article, by Howell et al., in the Journal of Patient Experience found no relationship between patient satisfaction and physician burnout domains of exhaustion and disengagement. This is an interesting finding and has strong implications. What it shows is that despite having high levels of burnout, physicians are able to function in a way that their patients don’t see a difference based on their burnout level. The brunt of burnout is faced by physicians and they shield their patients from its effects, likely at high personal cost.

Obviously, there may be other explanations – for example, the tools used to measure physician burnout are not reliably measuring burnout or that the tools to measure patient satisfaction with physicians are inaccurate and have large measurement bias. Both of these two explanations are possible but less plausible.

Artificial Intelligence in a Smartwatch for Atrial Fibrillation

An interesting study by Perez et al in NEJM found some very interesting things:

1. A large number of people opted-in to be part of the study (over 400K)
2. In about 4 months, about 0.5% participants were noted to have irregular heart rate – a relatively small percentage than one would expect.
3. Of the people who returned 7-day monitoring after being notified of irregular heart beat, about one-third had atrial fibrillation. This is a significant number of atrial fibrillation in otherwise asymptomatic individuals.

The study highlights several important things, some noted above. However, what it does not tell us if the use of smartwatch to identify atrial fibrillation in otherwise healthy people results in improved health outcomes or not. A future study should be able to evaluate this question. For now, at least we know we can depend on smartwatch to identify atrial fibrillation.

Should Older Patients with Subclinical Hypothyroidism be Treated with Thyroid Replacement?

With increasing age, many patients develop subclinical hypothyroidism. Subclinical hypothyroidism is defined by the presence of elevated thyroid stimulating hormone (TSH) but normal free T4 levels. Some patients with subclinical hypothyroidism also have symptoms that are not uncommon with increasing age such as constipation, tiredness, mental slowness, and fatigue.

Prior studies have found no association between treating patients with subclinical hypothyroidism with thyroid replacement therapy and resolution of symptoms. However, very old individuals (older than 80 years) are often not included in the studies.

To examine if treatment of subclinical hypothyroidism with thyroid replacement therapy results in resolution of such symptoms, Moojiraat et al. combined data from two randomized controlled trials. Combining data from two trials results in increased number of patients above 80 (and hence power of the study to detect a difference).

Contrary to expectations, but consistent with previous findings, thyroid replacement therapy does not result in resolution of symptoms in patients with subclinical hypothyroidism. Instead, there may be some increase in adverse events.

Prediction of COPD Exacerbations – ACCEPT Tool

Preventing exacerbations in patients with COPD is a major goal. If we can identify patients who are at higher risk of exacerbations, we may be able to tailor more aggressive therapy to such patients. This will result in better utilization of resources, improved risk/benefit ratio, and will not expose low-risk patients to the adverse effects of aggressive therapies. Thus, predicting exacerbation risk in individual patients can guide these clinical decisions. Unfortunately, there are no externally validated and implementable tools to predict COPD exacerbation.

That is until now: Adibi and colleagues have uploaded their manuscript to a preprint server (bioRxiv) which used data from three randomized trials to develop ACCEPT, a clinical prediction tool based on routinely available predictors for COPD exacerbations. Authors externally validated ACCEPT in a large, multinational prospective cohort. ACCEPT appears to be the first COPD exacerbation prediction tool that jointly estimates the individualized rate and severity of exacerbations. The tool is designed to be easily applicable in clinical practice and is accessible as a web application.

Issues with Current Physician Burnout Research

The relationship of physician burnout with patient outcomes has been often reported but the studies have been of poor quality and/or report the outcomes as perceived by physicians. Obviously, using physician’s perception of burnout and physician’s perception of patient outcomes is circular in nature; a burnout physician may be likely to think that the patient care provided by her is of lower quality.

A systemic review, in Annals of Internal Medicine highlights the similar issue. Moreover, it also shows that where a relationship is shown, the effect sizes tend to be larger suggesting that publication bias may be contributing to preponderance of studies showing an effect (because studies showing no effect are not getting published.

The physician burnout research (and researchers) should start using rigorous scientific methods to define outcomes, predictors, associations, and evaluation of interventions. Otherwise, such an important topic will get a poor reputation due to low-quality research.

National Academy of Medicine Talks about Physician Burnout

In response to concerning rates of depression, stress, and burnout among US medical students and clinicians, the National Academy of Medicine (formerly Institute of Medicine) launched the Action Collaborative on Clinician Well-Being and Resilience in 2017.

Incorporating input from experts in human factors and systems engineering and health informatics, as well as medical, nursing, pharmacy, and dentistry experts and educators, the committee took a systems approach to clinician burnout.

The committee’s systems model for professional well-being and clinician burnout has 3 levels: frontline care delivery, health care organization, and external environment, which together influence the work system factors that contribute to clinician burnout and professional well-being. The work system factors often extend across more than 1 system level (care delivery, health care organization, and external environment), and improvement can occur at every level to relieve workplace stress. The recommendations from the report, organized under 6 overarching goals, reflect the crosscutting nature of the identified factors contributing to clinician burnout and professional well-being.

1. Create positive work environments

2. Create positive learning environments

3. Reduce administrative burden

4. Enable technology solutions

5. Provide support to clinicians and students

6. Invest in research

Angiotensin Receptor Blockers and Suicide Risk

Interesting conclusions in a study reported in the JAMA Network Open:

The use of ARBs may be associated with an increased risk of suicide compared with ACEIs.

Investigators matched 964 cases to 3856 controls. Compared to ACE inhibitors, ARBs were associated with 63% higher risk of death by suicide. The results remained significant (60% increase) when individuals with history of self-harm were excluded.

Proliferation of Risk Factors for Physician Burnout

Several authors have promoted various risk factors for physician burnout. Below are some that I noticed in my email:

Moral Injury:

Kopacz MS, Ames D, Koenig HG. It's time to talk about physician burnout and moral injury. Lancet Psychiatry. 2019 Nov;6(11):e28. doi:10.1016/S2215-0366(19)30385-2. PubMed PMID: 31631880.

Low or lack of Mindfulness:

Lebares CC et al. Key factors for implementing mindfulness-based burnout interventions in surgery. The American Journal of Surgery (in Press)

Lack of Resilience and Grit

Shakir HJ, Cappuzzo JM, Shallwani H, Kwasnicki A, Bullis C, Wang J, Hess RM,Levy EI. Relationship of Grit and Resilience to Burnout Among US NeurosurgeryResidents. World Neurosurg. 2019 Oct 16. pii: S1878- 750(19)32658-0. doi:10.1016/j.wneu.2019.10.043. [Epub ahead of print]  PubMed PMID: 31629138.

Attacks on the Calling of Medicine

Stewart MT, Serwint JR. Burning without burning out: A call to protect thecalling of medicine. Curr Probl Pediatr Adolesc Health Care. 2019 Oct 17:100655. doi: 10.1016/j.cppeds.2019.100655. [Epub ahead of print] PubMed PMID: 31631025

Above are some of the examples of risk factors cited in literature and the list continues to grow with each passing day. There are folks who have developed ‘Burnout Prevention Programs’ around these risk factors. Some even market these programs and make money.

My concern stems from the fact that while there may be strong conceptual underpinnings for at least some of these risk factors, rigorous studies examining the relationship are missing. The current state of evidence is so poor that a clinician will not take seriously risk factors with such limited evidence when managing a patient. Then, why, physicians doing this to themselves.

In particular, the worrisome part is the so-called prevention programs. Where is the evidence to support that such interventions work? If we don’t accept evidence for our patients without randomized clinical trials or at least strong observational studies, why we accept such intervention programs without evidence of efficacy?