A new look at an old well-being construct: evaluating the psychometric properties of 9, 5, and 1-item versions of emotional exhaustion metrics

ObjectiveTo compare the relative strengths (psychometric and convergent validity) of four emotional exhaustion (EE) measures: 9- and 5-item scales and two 1-item metrics.Patients and methodsThis was a national cross-sectional survey study of 1409 US physicians in 2013. Psychometric properties were compared using Cronbach’s alpha, Confirmatory Factor Analysis (CFA), Exploratory Factor Analysis (EFA), and Spearman’s Correlations. Convergent validity with subjective happiness (SHS), depression (CES-D10), work-life integration (WLI), and intention to leave current position (ITL) was assessed using Spearman’s Correlations and Fisher’s R-to-Z.ResultsThe 5-item EE scale correlated highly with the 9-item scale (Spearman’s rho = 0.828), demonstrated excellent internal reliability (alpha = 0.87), and relative to the 9-item, exhibited superior CFA model fit (RMSEA = 0.082, CFI = 0.986, TLI = 0.972). The 5-item EE scale correlated as highly as the 9-item scale with SHS, CES-D10, and WLI, and significantly stronger than the 9-item scale to ITL. Both 1-item EE metrics had significantly weaker correlation with SHS, CES-D10, WLI, and ITL (Fisher’s R-to-Z; p < 0.05) than the 5- and 9-item EE scales.ConclusionThe 5-item EE scale was repeatedly found equivalent or superior to the 9-item version across analyses, particularly with respect to the CFA results. As there is no cost to using the briefer 5-item EE scale, the burden on respondents is smaller, and widespread access to administering and interpreting an excellent wellbeing metric is enhanced at a critical time in global wellbeing research. The single item EE metrics exhibited lower convergent validity than the 5- and 9-item scales, but are acceptable for detecting a signal of EE when using a validated EE scale is not feasible. Replication of psychometrics and open-access benchmarking results for use of the 5-tem EE scale further enhance access and utility of this metric

Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis

Importance: Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation.Objective: To identify the genetic variants associated with juvenile ALS.Design, Setting, and Participants: In this multicenter family-based genetic study, trio whole-exome sequencing was performed to identify the disease-associated gene in a case series of unrelated patients diagnosed with juvenile ALS and severe growth retardation. The patients and their family members were enrolled at academic hospitals and a government research facility between March 1, 2016, and March 13, 2020, and were observed until October 1, 2020. Whole-exome sequencing was also performed in a series of patients with juvenile ALS. A total of 66 patients with juvenile ALS and 6258 adult patients with ALS participated in the study. Patients were selected for the study based on their diagnosis, and all eligible participants were enrolled in the study. None of the participants had a family history of neurological disorders, suggesting de novo variants as the underlying genetic mechanism.Main Outcomes and Measures: De novo variants present only in the index case and not in unaffected family members.Results: Trio whole-exome sequencing was performed in 3 patients diagnosed with juvenile ALS and their parents. An additional 63 patients with juvenile ALS and 6258 adult patients with ALS were subsequently screened for variants in the SPTLC1 gene. De novo variants in SPTLC1 (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive. A fourth variant (p.Leu39del) was identified in a patient with juvenile ALS where parental DNA was unavailable. Variants in this gene have been previously shown to be associated with autosomal-dominant hereditary sensory autonomic neuropathy, type 1A, by disrupting an essential enzyme complex in the sphingolipid synthesis pathway.Conclusions and Relevance: These data broaden the phenotype associated with SPTLC1 and suggest that patients presenting with juvenile ALS should be screened for variants in this gene.</p

Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.Peer reviewe

Effects of torcetrapib in patients at high risk for coronary events

BACKGROUND: Inhibition of cholesteryl ester transfer protein (CETP) has been shown to have a substantial effect on plasma lipoprotein levels. We investigated whether torcetrapib, a potent CETP inhibitor, might reduce major cardiovascular events. The trial was terminated prematurely because of an increased risk of death and cardiac events in patients receiving torcetrapib. METHODS: We conducted a randomized, double-blind study involving 15,067 patients at high cardiovascular risk. The patients received either torcetrapib plus atorvastatin or atorvastatin alone. The primary outcome was the time to the first major cardiovascular event, which was defined as death from coronary heart disease, nonfatal myocardial infarction, stroke, or hospitalization for unstable angina. RESULTS: At 12 months in patients who received torcetrapib, there was an increase of 72.1% in high-density lipoprotein cholesterol and a decrease of 24.9% in low-density lipoprotein cholesterol, as compared with baseline (P <0.001 for both comparisons), in addition to an increase of 5.4 mm Hg in systolic blood pressure, a decrease in serum potassium, and increases in serum sodium, bicarbonate, and aldosterone (P <0.001 for all comparisons). There was also an increased risk of cardiovascular events (hazard ratio, 1.25; 95% confidence interval [CI], 1.09 to 1.44; P=0.001) and death from any cause (hazard ratio, 1.58; 95% CI, 1.14 to 2.19; P=0.006). Post hoc analyses showed an increased risk of death in patients treated with torcetrapib whose reduction in potassium or increase in bicarbonate was greater than the median change. CONCLUSIONS: Torcetrapib therapy resulted in an increased risk of mortality and morbidity of unknown mechanism. Although there was evidence of an off-target effect of torcetrapib, we cannot rule out adverse effects related to CETP inhibition. (ClinicalTrials.gov number, NCT00134264 [ClinicalTrials.gov].

Mises’ democracy–dictatorship equivalence theorem: A critique

Democracy, Dictatorship, Public opinion, Revolution, D72, D74, D70,