A Few Favorite Articles From 2022

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Check out the following summaries of a few of Cam and Chelsea’s favorite articles from 2022:

“Percentage of Heavy Drinking Days Following Psilocybin-Assisted Psychotherapy vs Placebo in the Treatment of Adult Patients With Alcohol Use Disorder: A Randomized Clinical Trial” by Bogunshutz et al, published in JAMA Psychiatry

Historical context:

  • Since their discovery, hallucinogens have been of interest to researchers, notably for their possible use in psychiatric disorders
  • In the 1950s and 1960s, LSD was studied specifically for alcohol use disorder (AUD), and showed an average rate of remission double that of placebo
  • Then, with the passage of the Controlled Substances Act (1971; the start of the War on Drugs), all studies halted for essentially 40 years
  • More recently, Johns Hopkins received research grants to study psilocybin with small studies showing effectiveness in depression; however, hallucinogens in AUD have not been studied since 1971

Key points from the study:

  • Question: Does psilocybin-assisted treatment improve drinking outcomes in patients with AUD relative to outcomes observed with active placebo medication?
  • Trial overview:
    • Qualifying participants were randomly assigned in a 1:1 ratio to receive either psilocybin or diphenhydramine, administered in two sessions at weeks 4 and 8.
    • All participants were offered a total of 12 psychotherapy sessions from a team of 2 therapists, including a licensed psychiatrist: 4 before the first medication session, 4 between the first and second medication sessions, and 4 in the month following the second medication session.
  • Findings: In this double-blind randomized clinical trial with 93 participants, the percentage of heavy drinking days during 32 weeks of follow-up was significantly lower in the psilocybin group than in the diphenhydramine group.
  • Significance: The results in this trial showed that psilocybin administered in combination with psychotherapy produced robust decreases in the percentage of heavy drinking days compared with those produced by active placebo and psychotherapy.

“Percentage of heavy drinking days among participants treated with psilocybin was 41% of that observed in the diphenhydramine-treated group. Exploratory analyses confirmed a between-group effect across a range of secondary drinking measures. Although this was, to our knowledge, the first controlled trial of psilocybin for AUD, these findings are consistent with a meta-analysis of trials conducted in the 1960s evaluating LSD as a treatment for AUD.”

Bogunshutz et al. JAMA Psychiatry. 2022

Cam’s take-away points:

  • Limited study under very specific conditions, but promising results!
  • 32-week follow-up is fairly extensive, but still raises the question if a longer duration would be needed, noting that AUD often has a chronic, relapsing course
  • Difficult to attain true double blinding
  • Many limitations in how and in whom we can study the use of psilocybin, thus limiting generalization

“Butyrylcholinesterase is a potential biomarker for Sudden Infant Death Syndrome” by Harrington et al, published in eBioMedicine

Quick background on SIDS:

  • Sudden Infant Death Syndrome (SIDS) is the sudden death of an infant <1yo, which remains unexplained after a thorough case investigation, including performance of a complete autopsy, examination of the death scene, and review of the clinical history
  • We don’t know what causes SIDS, but several risk factors are known (e.g., prematurity, smoke exposure, unsafe sleeping habits, etc.)
  • One theory is the triple-risk model, consisting of an infant with an underlying vulnerability (e.g., genetic pattern, brainstem abnormality) who experiences a trigger event (e.g., airflow obstruction, smoking exposure) at a vulnerable developmental stage of the central nervous system or immune system

Key points from the study:

  • Methods: In this case-control study we measured butyrylcholinesterase activity and total protein from dried blood spots taken at birth as part of the newborn screening program. Results for each of 67 sudden unexpected deaths classified by the coroner (aged 1 week to 104 weeks) were compared to 10 date of birth- and gender-matched surviving controls, with 5 cases reclassified to meet criteria for SIDS, including the criterion of age 3 weeks to 1 year.
  • Findings: Conditional logistic regression showed that in groups where cases were reported as “SIDS death” there was strong evidence that lower butyrylcholinesterase specific activity was associated with death (OR = 0.73 per U/mg, 95% CI 0.60-0.89, P=0.0014), whereas in groups with a “Non-SIDS death” as the case there was no evidence of a linear association between butyrylcholinesterase specific activity and death (OR = 1.001 per U/mg, 95% CI 0.89-1.13, P=0.99).
  • Interpretation: Butyrylcholinesterase specific activity, measured in dried blood spots taken 2-3 days after birth, was lower in babies who subsequently died of SIDS compared to surviving controls and other Non-SIDS deaths. We conclude that a previously unidentified cholinergic deficit, identifiable by abnormal butyrylcholinesterase specific activity, is present at birth in SIDS babies and represents a measurable, specific vulnerability prior to their death.

“This is the first study to identify a measurable biochemical marker in infants who succumb to SIDS, during their newborn period while they are still alive, and one that could plausibly produce functional alterations to an infant’s autonomic and arousal responses to an exogenous stressor leaving them vulnerable to sudden death. Further work investigating this area needs to be undertaken with urgency, to determine if specific activity of butyrylcholinesterase could potentially be used as a biomarker to identify and prevent future SIDS deaths.”

Harrington et al. EBioMedicine. 2022

Cam’s take-away points:

“Aggressive or Moderate Fluid Resuscitation in Acute Pancreatitis” by de-Madaria et al, published in NEJM

Background:

  • Traditional treatment of acute pancreatitis focused on pancreatic rest (making the patient NPO, at least until recently) while providing ample IV fluids
  • Why IV fluids? Studies in the early 2000s showed that hemoconcentration was a main risk factor for developing necrotizing pancreatitis and multiorgan failure
  • Later studies suggested that aggressive fluids lead to worse outcomes, particularly for severe pancreatitis

Study details:

  • Type of study: open-label randomized control trial across 18 sites in India, Mexico, Italy, and Spain
  • Study population: 249 adults with acute pancreatitis, diagnosed in the prior 8 hours
  • Primary outcome: development of moderately severe or severe acute pancreatitis
  • Trial ended early by the safety monitoring board at the first interim safety analysis (⅓ of the expected way through) on the basis of clear harm in the aggressive fluid group

Cam’s take-away points:

  • Though most volume overload not severe, not balanced by any improvement in outcomes with aggressive hydration
  • Strong study given carefully defined variables, including not only mild pancreatitis (though not severe or in shock) and used relevant hydration strategies in the groups
  • Adds to growing body of evidence arguing against early aggressive hydration for these patients

“Effect of Calorie-Unrestricted Low-Carbohydrate, High-Fat Diet Versus High-Carbohydrate, Low-Fat Diet on Type 2 Diabetes and Nonalcoholic Fatty Liver Disease: A Randomized Controlled Trial” by Hansen et al, published in the Annals of Internal Medicine

Study details:

  • Purpose: Compare “isocaloric” low-carb high-fat (LCHF) intake with high-carb low-fat (HCLF) in patients with T2DM
  • Type of study: prospective, parallel-group, unblinded (open-label) randomized control trial in Denmark; ITT analysis
  • Study population: 165 adults with T2DM
  • Outcomes: glycemic control, lipid levels, metabolic markers, and liver biopsies
  • Duration: 6-month intervention with additional follow-up at 9 months
  • Intervention (2 calorie-unrestricted diets):
    • LCHF diet with 50-60 energy percent (E%) fat, less than 20E% carbohydrates, and 25-30E% proteins
    • HCLF diet with 50-60E% carbohydrates, 20-30E% fats, and 20-25E% proteins
  • Intake set at calculated TEE, participants instructed to maintain same level of physical activity
    • LCHF diet had greater improvements in A1C (mean difference in change, -6.1 mmol/mol [95% CI, -9.2 to -3.0 mmol/mol] or -0.59% [CI, -0.87% to -0.30%]) and lost more weight (mean difference in change, -3.8 kg [CI, -6.2 to -1.4 kg]).
    • Both groups had higher HDL and lower triglycerides at 6 months. Changes in LDL were less favorable in the LCHF diet group than in the HCLF diet group (mean difference in change, 0.37 mmol/L [CI, 0.17 to 0.58 mmol/L] or 14.3 mg/dL [CI, 6.6 to 22.4 mg/dL]).
    • No statistically significant between-group changes were detected in the assessment of NAFLD. Changes were not sustained at the 9-month follow-up.
  • Adverse events: LCHF group experienced more nausea, fatigue, headache, and dizziness in the first two weeks; constipation and diarrhea throughout; and self-reported hypoglycemic events, but there were no severe hypoglycemic events

Chelsea’s take-away points:

  • Isocaloric diet modification with LCHF may be beneficial for glycemic control and metabolic risk factors, with tolerance of possible small increases in LDL/apolipoprotein-B
  • May be confounded by weight loss in both groups
  • No meaningful change in NAFLD, HDL or triglycerides in either group
  • Changes from dietary measures last only as long as the dietary measures themselves – need to focus on sustainable nutrition!

“Association of “Weekend Warrior” and Other Leisure Time Physical Activity Patterns With Risks for All-Cause, Cardiovascular Disease, and Cancer Mortality” by O’Donovan et al, published in JAMA Internal Medicine

Background:

  • For 18-64yo, WHO recommends at least 150 min/wk of moderate aerobic activity or at least 75 min/wk of vigorous aerobic activity
  • Those who choose to do all their exercise on 1 or 2 days of the week have been termed weekend warriors

Study details:

  • Purpose: To investigate associations between the weekend warrior and other physical activity patterns and the risks for all-cause, cardiovascular disease (CVD), and cancer mortality
  • Type of study: Pooled analysis of household-based survey including 63,591 respondents to the Health Survey for England (HSE) and Scottish Health Survey (SHS) with prospective linkage to mortality records
  • Study population: adults ≥40yo; data collected from 1994 to 2012
  • Outcomes: All-cause, CVD, and cancer mortality ascertained from death certificates
  • Findings:
    • Compared with the inactive participants, the hazard ratio (HR) for all-cause mortality was 0.66 (95% CI, 0.62-0.72) in insufficiently active participants who reported 1 to 2 sessions per week, 0.70 (95% CI, 0.60-0.82) in weekend warrior participants, and 0.65 (95% CI, 0.58-0.73) in regularly active participants.
    • Compared with the inactive participants, the HR for CVD mortality was 0.60 (95% CI, 0.52-0.69) in insufficiently active participants who reported 1 or 2 sessions per week, 0.60 (95% CI, 0.45-0.82) in weekend warrior participants, and 0.59 (95% CI, 0.48-0.73) in regularly active participants.
    • Compared with the inactive participants, the HR for cancer mortality was 0.83 (95% CI, 0.73-0.94) in insufficiently active participants who reported 1 or 2 sessions per week, 0.82 (95% CI, 0.63-1.06) in weekend warrior participants, and 0.79 (95% CI, 0.66-0.94) in regularly active participants.
  • Conclusion: Weekend warrior and other leisure time physical activity patterns characterized by 1 or 2 sessions per week may be sufficient to reduce all-cause, CVD, and cancer mortality risks regardless of adherence to prevailing physical activity guidelines.

Chelsea’s take-home points:

  • All activity groups (insufficiently active, weekend warrior, regularly active) had significantly lower risk of all-cause mortality compared to the inactive group (i.e., any activity is better than none!)
  • Even 1 or 2 sessions per week of moderate/vigorous physical activity may reduce mortality
  • Regular activity might be the best

“The SGLT2 inhibitor empagliflozin in patients hospitalized for acute heart failure: a multinational randomized trial” by Voors et al, published in Nature Medicine

Background:

  • DAPA-HF (2019) and EMPEROR-Reduced (2020): Comparing SGLT2i vs placebo, in pts with HFrEF, SGLT2i reduced composite of cardiovascular death or HF hospitalization by 25%, reduced risk of CV death by 18% and all-cause mortality by 17% regardless of diabetes status.
  • SOLOIST-WHF (2021): Sotagliflozin reduced the combined endpoint of cardiovascular death, HF hospitalization, or urgent HF visits by 33% in patients with diabetes and LVEF <50%.
  • EMPEROR-Preserved (2021): SGLT2i showed 21% reduction in composite endpoint of time to HF hospitalization or cardiovascular death in patients with LVEF >40% and elevated BNP, driven mostly by a 29% reduction in time to HF hospitalization; no benefit on all-cause mortality.

Study details:

  • Purpose: To assess the benefit and safety of SGLT-2i therapy for patients admitted with acute heart failure, both new (excluded from prior studies) and decompensated
  • Type of study: Double-blind, placebo controlled trial; ITT analysis
  • Study population: 530 inpatients with primary diagnosis of new or decompensated heart failure, regardless of EF or diabetes
  • Outcomes: Composite endpoint of “clinical benefit” defined as hierarchical composite of death from any cause, number of HF events, time to first HF event, or ≥5 point difference from baseline symptom score at 90 days
  • Findings:
    • More patients treated with empagliflozin had clinical benefit compared with placebo (stratified win ratio, 1.36; 95% confidence interval, 1.09–1.68; P = 0.0054), meeting the primary endpoint.
    • Clinical benefit was observed for both acute de novo and decompensated HF and was observed regardless of EF or the presence or absence of diabetes.
    • Empagliflozin was well tolerated; serious adverse events were reported in 32.3% and 43.6% of the empagliflozin- and placebo-treated patients, respectively.
    • These findings indicate that initiation of empagliflozin in patients hospitalized for acute heart failure is well tolerated and results in significant clinical benefit in the 90 days after starting treatment.

Chelsea’s take-away points:

  • Initiation of SGLT2i in patients hospitalized for acute heart failure reduced all-cause mortality and HF exacerbations as well as improved quality of life
  • Benefits seen in both new and decompensated HF, reduced and preserved EF, diabetes and no diabetes
  • Fewer adverse events in SGLT2i group

Blog post based on Med-Peds Forum talk by Chelsea Boyd, PGY4, and Cam Ulmer, PGY3

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