The Complete Spectrum of Yeast Chromosome Instability Genes Identifies Candidate CIN Cancer Genes and Functional Roles for ASTRA Complex Components

Chromosome instability (CIN) is observed in most solid tumors and is linked to somatic mutations in genome integrity maintenance genes. The spectrum of mutations that cause CIN is only partly known and it is not possible to predict a priori all pathways whose disruption might lead to CIN. To address this issue, we generated a catalogue of CIN genes and pathways by screening ∼2,000 reduction-of-function alleles for 90% of essential genes in Saccharomyces cerevisiae. Integrating this with published CIN phenotypes for other yeast genes generated a systematic CIN gene dataset comprised of 692 genes. Enriched gene ontology terms defined cellular CIN pathways that, together with sequence orthologs, created a list of human CIN candidate genes, which we cross-referenced to published somatic mutation databases revealing hundreds of mutated CIN candidate genes. Characterization of some poorly characterized CIN genes revealed short telomeres in mutants of the ASTRA/TTT components TTI1 and ASA1. High-throughput phenotypic profiling links ASA1 to TTT (Tel2-Tti1-Tti2) complex function and to TORC1 signaling via Tor1p stability, consistent with the role of TTT in PI3-kinase related kinase biogenesis. The comprehensive CIN gene list presented here in principle comprises all conserved eukaryotic genome integrity pathways. Deriving human CIN candidate genes from the list allows direct cross-referencing with tumor mutational data and thus candidate mutations potentially driving CIN in tumors. Overall, the CIN gene spectrum reveals new chromosome biology and will help us to understand CIN phenotypes in human disease

Robust estimation of bacterial cell count from optical density

Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals <1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data

Impact of Scribes on Physician Satisfaction, Patient Satisfaction, and Charting Efficiency: A Randomized Controlled Trial

PurposeScribes are increasingly being used in clinical practice despite a lack of high-quality evidence regarding their effects. Our objective was to evaluate the effect of medical scribes on physician satisfaction, patient satisfaction, and charting efficiency.MethodsWe conducted a randomized controlled trial in which physicians in an academic family medicine clinic were randomized to 1 week with a scribe then 1 week without a scribe for the course of 1 year. Scribes drafted all relevant documentation, which was reviewed by the physician before attestation and signing. In encounters without a scribe, the physician performed all charting duties. Our outcomes were physician satisfaction, measured by a 5-item instrument that included physicians' perceptions of chart quality and chart accuracy; patient satisfaction, measured by a 6-item instrument; and charting efficiency, measured by time to chart close.ResultsScribes improved all aspects of physician satisfaction, including overall satisfaction with clinic (OR = 10.75), having enough face time with patients (OR = 3.71), time spent charting (OR = 86.09), chart quality (OR = 7.25), and chart accuracy (OR = 4.61) (all P values <.001). Scribes had no effect on patient satisfaction. Scribes increased the proportion of charts that were closed within 48 hours (OR =1.18, P =.028).ConclusionsTo our knowledge, we have conducted the first randomized controlled trial of scribes. We found that scribes produced significant improvements in overall physician satisfaction, satisfaction with chart quality and accuracy, and charting efficiency without detracting from patient satisfaction. Scribes appear to be a promising strategy to improve health care efficiency and reduce physician burnout

Impact of High Intensity Interval Training Versus Moderate Intensity Continuous Training on Critical Power

Critical Power (PCRIT) is the greatest power that a person can sustain for prolonged periods of time while maintaining steady-state, submaximal aerobic conditions. Work-prime (W’) is the amount of work that can be tolerated when exercising in non-steady-state conditions above PCRIT. PURPOSE: Compare the effect of equal amounts of moderate intensity continuous training (MICT) and high intensity interval training (HIIT) on PCRIT and W’. METHODS: Twenty-two (10 female) untrained, young adults completed 8 weeks of cycling training (40 minutes, 3x per week) administered as either MICT (44% max power achieved during a graded exercise test; PGXT) or HIIT (4 bouts at 80% PGXT for 4 minutes with recovery intervals between). PCRIT, W’ and other physiological variables were determined before and after training. RESULTS: PCRIT significantly increased in both groups, but to a greater extent in the HIIT group (MICT: 15.7 ± 3.1% vs. HIIT: 27.5 ± 4.3%; P=0.04). W’ was not consistently impacted by training (P=0.76). The training-induced change in PCRIT was not significantly related to the training-induced change in V̇O2MAX. The training-induced increase in PCRIT was related to how intense the training was relative to PCRIT, with those performing the same workout at a greater % PCRIT exhibiting greater training-induced increases in PCRIT (R2=0.49, PCONCLUSION: HIIT elicits approximately twice the increase in PCRIT than an equal amount of MICT in untrained young adults. Training-induced increases in PCRIT are not dependent upon changes in V̇O2MAX. Exercise may be more effectively prescribed and described relative to PCRIT, rather than V̇O2MAX or PGXT

Early-onset lymphoproliferation and autoimmunity caused by germline STAT3 gain-of-function mutations

Germline loss-of-function mutations in the transcription factor signal transducer and activator of transcription 3 (STAT3) cause immunodeficiency, whereas somatic gain-of-function mutations in STAT3 are associated with large granular lymphocytic leukemic, myelodysplastic syndrome, and aplastic anemia. Recently, germline mutations in STAT3 have also been associated with autoimmune disease. Here, we report on 13 individuals from 10 families with lymphoproliferation and early-onset solid-organ autoimmunity associated with 9 different germline heterozygous mutations in STAT3. Patients exhibited a variety of clinical features, with most having lymphadenopathy, autoimmune cytopenias, multiorgan autoimmunity (lung, gastrointestinal, hepatic, and/or endocrine dysfunction), infections, and short stature. Functional analyses demonstrate that these mutations confer a gain-of-function in STAT3 leading to secondary defects in STAT5 and STAT1 phosphorylation and the regulatory T-cell compartment. Treatment targeting a cytokine pathway that signals through STAT3 led to clinical improvement in 1 patient, suggesting a potential therapeutic option for such patients. These results suggest that there is a broad range of autoimmunity caused by germline STAT3 gain-of-function mutations, and that hematologic autoimmunity is a major component of this newly described disorder. Some patients for this study were enrolled in a trial registered at www.clinicaltrials.gov as #NCT00001350