Genetic variants are associated with severe cutaneous reactions to phenytoin

A number of SNPs were identified in this study:

Design, Setting, and Participants Case-control study conducted in 2002-2014 among 105 cases with phenytoin-related severe cutaneous adverse reactions (n=61 Stevens-Johnson syndrome/toxic epidermal necrolysis and n=44 drug reactions with eosinophilia and systemic symptoms), 78 cases with maculopapular exanthema, 130 phenytoin-tolerant control participants, and 3655 population controls from Taiwan, Japan, and Malaysia. A genome-wide association study (GWAS), direct sequencing of the associated loci, and replication analysis were conducted using the samples from Taiwan. The initial GWAS included samples of 60 cases with phenytoin-related severe cutaneous adverse reactions and 412 population controls from Taiwan. The results were validated in (1) 30 cases with severe cutaneous adverse reactions and 130 phenytoin-tolerant controls from Taiwan, (2) 9 patients with Stevens-Johnson syndrome/toxic epidermal necrolysis and 2869 population controls from Japan, and (3) 6 cases and 374 population controls from Malaysia.

Main Outcomes and Measures Specific genetic factors associated with phenytoin-related severe cutaneous adverse reactions.

Results The GWAS discovered a cluster of 16 single-nucleotide polymorphisms in CYP2C genes at 10q23.33 that reached genome-wide significance. Direct sequencing of CYP2C identified missense variant rs1057910 (CYP2C9*3) that showed significant association with phenytoin-related severe cutaneous adverse reactions (odds ratio, 12; 95% CI, 6.6-20; P=1.1 × 10−17). The statistically significant association between CYP2C9*3 and phenytoin-related severe cutaneous adverse reactions was observed in additional samples from Taiwan, Japan, and Malaysia. A meta-analysis using the data from the 3 populations showed an overall odds ratio of 11 (95% CI, 6.2-18; z=8.58; P less than .00001) for CYP2C9*3 association with phenytoin-related severe cutaneous adverse reactions. Delayed clearance of plasma phenytoin was detected in patients with severe cutaneous adverse reactions, especially CYP2C9*3 carriers, providing a functional link of the associated variants to the disease.

Fruit and vegetable servings and mortality

From a recent BMJ meta-analysis:

Results Sixteen prospective cohort studies were eligible in this meta-analysis. During follow-up periods ranging from 4.6 to 26 years there were 56 423 deaths (11 512 from cardiovascular disease and 16 817 from cancer) among 833 234 participants. Higher consumption of fruit and vegetables was significantly associated with a lower risk of all cause mortality. Pooled hazard ratios of all cause mortality were 0.95 (95% confidence interval 0.92 to 0.98) for an increment of one serving a day of fruit and vegetables (P=0.001), 0.94 (0.90 to 0.98) for fruit (P=0.002), and 0.95 (0.92 to 0.99) for vegetables (P=0.006). There was a threshold around five servings of fruit and vegetables a day, after which the risk of all cause mortality did not reduce further. A significant inverse association was observed for cardiovascular mortality (hazard ratio for each additional serving a day of fruit and vegetables 0.96, 95% confidence interval 0.92 to 0.99), while higher consumption of fruit and vegetables was not appreciably associated with risk of cancer mortality.

It looks like the five serving rule still holds!

Volume controlled versus pressure controlled ventilation in ARDS

Given that treatment needs to be individualized, there is insufficient evidence to tell whether one is better than the other across the board according to a Cochrane review.

Via Hospital Medicine Virtual Journal Club.

Relationships between exercise, hunger and energy balance

Interesting article in the American Journal of Lifestyle Medicine:

High-intensity exercise causes a short-term suppression of hunger of approximately 15 to 60 minutes. Although there is evidence for compensatory food consumption, it usually does not make up for the energy deficit created by exercise. The exception occurs when individuals consume or reward themselves with energy-dense foods or drink. Because people tend to eat the same volume of food each day, on days when they exercise, they will remain in an energy deficit. However, on sedentary days, a positive energy balance is likely if caloric restriction is not imposed, which could result in weight gain. Caloric restriction alone leads to loss of lean body mass, while the inclusion of exercise with an energy deficit helps conserve lean tissue.

What’s new in the management of acute severe asthma?

From a recently published update:

Recent findings: β2-agonist heliox-driven nebulization significantly increased by 17% [95% confidence interval (CI) 5.2–29.4] peak expiratory flow, and decreased the rate of hospital admissions (risk ratio 0.77, 95% CI 0.62–0.98), compared with oxygen-driven nebulization. Other findings indicate that there is no robust evidence to support the use of intravenous or nebulized magnesium sulphate in adults with severe acute asthma, and that levalbuterol was not superior to albuterol regarding efficacy and safety in individuals with acute asthma. Finally, hyperlactatemia developed during the first hours of acute asthma treatment has a high prevalence, is related with the use of β2-agonists and had no clinical consequences.

Exercise to improve cognitive function

This review focuses on the cognitive impairment associated with heart failure. Neurophysiologic mechanisms are discussed.

When hypersensitivity pneumonitis enters the fibrotic stage

---it can mimic many other diffuse ILDs as outlined in this review.

Via Hospital Medicine Virtual Journal Club.

Whole bowel irrigation for overdose patients

A recent literature review found that it may facilitate removal in selected patients but is not supported by convincing evidence of improved outcomes.

Exercise as treatment for depression

From a JAMAClinical Evidence Synopsis:

Bottom Line Exercise is associated with a greater reduction in depression symptoms compared with no treatment, placebo, or active control interventions, such as relaxation or meditation. However, analysis of high-quality studies alone suggests only small benefits.

Endurance exercise and atrial fibrillation risk

From a recent review:

Endurance exercise, despite a plethora of proven health benefits, is increasingly recognized as a potential cause of lone atrial fibrillation. Moderate exercise reduces all-cause mortality and protects against developing atrial fibrillation. However, more intense exercise regimes confer modest incremental health benefits, induce cardiac remodelling and negate some of the cardiovascular benefits of exercise. The implications of endurance exercise and athletic heart are becoming increasingly relevant as the popularity of endurance exercise has increased 20-fold within a generation.

Recent findings: An apparent dose–response relationship exists between endurance exercise and left atrial dilatation. Repeated strenuous endurance exercise overloads atria, resulting in stretch-induced ‘microtears’, inflammation and endocardial scarring. Although these findings are observational in humans, similar mechanisms have recently been confirmed in animal models suggesting causation.

The toxic alcohol work up

A case presentation and some tips from Emergency Physicians Monthly.

Is therapeutic hypothermia associated with more bleeding after cardiac arrest?

Not according to this systematicreview and meta-analysis.

Toxic epidermal necrolysis

A brief review in the American Journal of Medicine. Free full text.

TB or not TB? Tips for the evaluation of hospitalized patients

Here is a recent update from CCJM.

Adult cases of group A strep meningitis

From a recent report:

RESULTS:

GAS was identified in 26 of 1322 patients with community-acquired bacterial meningitis (2%); 9 cases (35%) occurred in the first four months of 2013. GAS meningitis was often preceded by otitis or sinusitis (24 of 26 [92%]) and a high proportion of patients developed complications during clinical course (19 of 26 [73%]). Subdural empyema occurred in 8 of 26 patients (35%). Nine patients underwent mastoidectomy and in 5 patients neurosurgical evacuation of the subdural empyema was performed. Five of 26 patients (19%) died and 11 of 21 surviving patient had neurologic sequelae (52%). Infection with the emm1 and cc28 GAS genotype was associated with subdural empyema (both 4 of 6 [67%] vs. 2 of 14 [14%]; P = 0.037).

CONCLUSIONS:

GAS meningitis is an uncommon but severe disease. Patients are at risk for empyema, which is associated with infection with the emm1 and cc28 genotype.

Via Hospital Medicine VirtualJournal Club.

Is statin myalgia associated with decreased muscle strength?

Not in this study.

Carbamazepine poisoning

Here is a systematic review with a focus on extracorporeal removal. From the review:

The workgroup concluded that carbamazepine is moderately dialyzable and made the following recommendations: ECTR is suggested in severe carbamazepine poisoning (2D). ECTR is recommended if multiple seizures occur and are refractory to treatment (1D), or if life-threatening dysrhythmias occur (1D). ECTR is suggested if prolonged coma or respiratory depression requiring mechanical ventilation are present (2D) or if significant toxicity persists, particularly when carbamazepine concentrations rise or remain elevated, despite using multiple-dose activated charcoal (MDAC) and supportive measures (2D). ECTR should be continued until clinical improvement is apparent (1D) or the serum carbamazepine concentration is below 10 mg/L (42 the μ in μmol/L looks weird.) (2D). Intermittent hemodialysis is the preferred ECTR (1D), but both intermittent hemoperfusion (1D) or continuous renal replacement therapies (3D) are alternatives if hemodialysis is not available. MDAC therapy should be continued during ECTR (1D). Conclusion. Despite the low quality of the available clinical evidence and the high protein binding capacity of carbamazepine, the workgroup suggested extracorporeal removal in cases of severe carbamazepine poisoning.

Tylenol and benadryl before transfusions

Very commonly done but not evidence based in the least. If this is not on someone’s choosing wisely list it should be.

Sleep deprivation caused endothelial dysfunction

---in this small study.

Tigecycline activity against Clostridium difficile

New study here.

Via Hospital Medicine Virtual Journal Club.