Predicting residents' performance: A prospective study

BACKGROUND: Objective criteria for predicting residents' performance do not exist. The purpose of this study was to test the hypothesis that global assessment by an intern selection committee (ISC) would correlate with the future performance of residents. METHODS: A prospective study of 277 residents between 1992 and 1999. Global assessment at the time of interview was compared to subsequent clinical (assessed by chief residents) and cognitive performance (assessed by the American Board of Pediatrics in-service training examination). RESULTS: ISC ratings correlated significantly with clinical performance at 24 and 36 months of training (r = 0.58, P < .001; and r = 0.60, P < .001 respectively). ISC ratings also correlated significantly with in-service exam scores in the 1(st), 2(nd), and 3(rd) years of training (r = 0.35, P = .0016; r = 0.39, P = 0.0003; r = 0.50, P = 0.005 respectively). CONCLUSIONS: Global assessment by an ISC predicted residents' clinical and cognitive performances

Findings from the Peutz-Jeghers Syndrome Registry of Uruguay

Background: Peutz-Jeghers syndrome (PJS) is characterized by intestinal polyposis, mucocutaneous pigmentation and an increased cancer risk, usually caused by mutations of the STK11 gene. This study collected epidemiological, clinical and genetic data from all Uruguayan PJS patients. Methods: Clinical data were obtained from public and private medical centers and updated annually. Sequencing of the STK11 gene in one member of each family was performed. Results and discussion: 25 cases in 11 unrelated families were registered (15 males, 10 females). The average age of diagnosis and death was 18 and 41 years respectively. All patients had characteristic PJS pigmentation and gastrointestinal polyps. 72% required urgent surgery due to intestinal obstruction. 3 families had multiple cases of seizure disorder, representing 20% of cases. 28% developed cancer and two patients had more than one cancer. An STK11 mutation was found in 8 of the 9 families analyzed. A unique M136K missense mutation was noted in one family. Comparing annual live births and PJS birth records from 1970 to 2009 yielded an incidence of 1 in 155,000. Conclusion: The Uruguayan Registry for Peutz-Jeghers patients showed a high chance of emergent surgery, epilepsy, cancer and shortened life expectancy. The M136K missense mutation is a newly reported STK 11 mutation

Never Resting Brain: Simultaneous Representation of Two Alpha Related Processes in Humans

Brain activity is continuously modulated, even at “rest”. The alpha rhythm (8–12 Hz) has been known as the hallmark of the brain's idle-state. However, it is still debated if the alpha rhythm reflects synchronization in a distributed network or focal generator and whether it occurs spontaneously or is driven by a stimulus. This EEG/fMRI study aimed to explore the source of alpha modulations and their distribution in the resting brain. By serendipity, while computing the individually defined power modulations of the alpha-band, two simultaneously occurring components of these modulations were found. An ‘induced alpha’ that was correlated with the paradigm (eyes open/ eyes closed), and a ‘spontaneous alpha’ that was on-going and unrelated to the paradigm. These alpha components when used as regressors for BOLD activation revealed two segregated activation maps: the ‘induced map’ included left lateral temporal cortical regions and the hippocampus; the ‘spontaneous map’ included prefrontal cortical regions and the thalamus. Our combined fMRI/EEG approach allowed to computationally untangle two parallel patterns of alpha modulations and underpin their anatomical basis in the human brain. These findings suggest that the human alpha rhythm represents at least two simultaneously occurring processes which characterize the ‘resting brain’; one is related to expected change in sensory information, while the other is endogenous and independent of stimulus change

Path to Facilitate the Prediction of Functional Amino Acid Substitutions in Red Blood Cell Disorders – A Computational Approach

A major area of effort in current genomics is to distinguish mutations that are functionally neutral from those that contribute to disease. Single Nucleotide Polymorphisms (SNPs) are amino acid substitutions that currently account for approximately half of the known gene lesions responsible for human inherited diseases. As a result, the prediction of non-synonymous SNPs (nsSNPs) that affect protein functions and relate to disease is an important task.In this study, we performed a comprehensive analysis of deleterious SNPs at both functional and structural level in the respective genes associated with red blood cell metabolism disorders using bioinformatics tools. We analyzed the variants in Glucose-6-phosphate dehydrogenase (G6PD) and isoforms of Pyruvate Kinase (PKLR & PKM2) genes responsible for major red blood cell disorders. Deleterious nsSNPs were categorized based on empirical rule and support vector machine based methods to predict the impact on protein functions. Furthermore, we modeled mutant proteins and compared them with the native protein for evaluation of protein structure stability.We argue here that bioinformatics tools can play an important role in addressing the complexity of the underlying genetic basis of Red Blood Cell disorders. Based on our investigation, we report here the potential candidate SNPs, for future studies in human Red Blood Cell disorders. Current study also demonstrates the presence of other deleterious mutations and also endorses with in vivo experimental studies. Our approach will present the application of computational tools in understanding functional variation from the perspective of structure, expression, evolution and phenotype

Developmental Stability Covaries with Genome-Wide and Single-Locus Heterozygosity in House Sparrows

Fluctuating asymmetry (FA), a measure of developmental instability, has been hypothesized to increase with genetic stress. Despite numerous studies providing empirical evidence for associations between FA and genome-wide properties such as multi-locus heterozygosity, support for single-locus effects remains scant. Here we test if, and to what extent, FA co-varies with single- and multilocus markers of genetic diversity in house sparrow (Passer domesticus) populations along an urban gradient. In line with theoretical expectations, FA was inversely correlated with genetic diversity estimated at genome level. However, this relationship was largely driven by variation at a single key locus. Contrary to our expectations, relationships between FA and genetic diversity were not stronger in individuals from urban populations that experience higher nutritional stress. We conclude that loss of genetic diversity adversely affects developmental stability in P. domesticus, and more generally, that the molecular basis of developmental stability may involve complex interactions between local and genome-wide effects. Further study on the relative effects of single-locus and genome-wide effects on the developmental stability of populations with different genetic properties is therefore needed

Circulating inflammatory cytokines and risk of five cancers: a Mendelian randomization analysis

Background: Epidemiological and experimental evidence has linked chronic inflammation to cancer aetiology. It is unclear whether associations for specific inflammatory biomarkers are causal or due to bias. In order to examine whether altered genetically predicted concentration of circulating cytokines are associated with cancer development, we performed a two-sample Mendelian randomisation (MR) analysis.Methods: Up to 31,112 individuals of European descent were included in genome-wide association study (GWAS) meta-analyses of 47 circulating cytokines. Single nucleotide polymorphisms (SNPs) robustly associated with the cytokines, located in or close to their coding gene (cis), were used as instrumental variables. Inverse-variance weighted MR was used as the primary analysis, and the MR assumptions were evaluated in sensitivity and colocalization analyses and a false discovery rate (FDR) correction for multiple comparisons was applied. Corresponding germline GWAS summary data for five cancer outcomes (breast, endometrial, lung, ovarian, and prostate), and their subtypes were selected from the largest cancer-specific GWASs available (cases ranging from 12,906 for endometrial to 133,384 for breast cancer).Results: There was evidence of inverse associations of macrophage migration inhibitory factor with breast cancer (OR per SD = 0.88, 95% CI 0.83 to 0.94), interleukin-1 receptor antagonist with endometrial cancer (0.86, 0.80 to 0.93), interleukin-18 with lung cancer (0.87, 0.81 to 0.93), and beta-chemokine-RANTES with ovarian cancer (0.70, 0.57 to 0.85) and positive associations of monokine induced by gamma interferon with endometrial cancer (3.73, 1.86 to 7.47) and cutaneous T-cell attracting chemokine with lung cancer (1.51, 1.22 to 1.87). These associations were similar in sensitivity analyses and supported in colocalization analyses.Conclusions: Our study adds to current knowledge on the role of specific inflammatory biomarker pathways in cancer aetiology. Further validation is needed to assess the potential of these cytokines as pharmacological or lifestyle targets for cancer prevention.</p

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Measurement of the energy asymmetry in t(t)over-barj production at 13 TeV with the ATLAS experiment and interpretation in the SMEFT framework

A measurement of the energy asymmetry in jet-associated top-quark pair production is presented using $$139\,{\mathrm {fb}}^{-1}$$ 139 fb - 1 of data collected by the ATLAS detector at the Large Hadron Collider during pp collisions at $$\sqrt{s}=13\,\text {TeV}$$ s = 13 TeV . The observable measures the different probability of top and antitop quarks to have the higher energy as a function of the jet scattering angle with respect to the beam axis. The energy asymmetry is measured in the semileptonic $$t{\bar{t}}$$ t t ¯ decay channel, and the hadronically decaying top quark must have transverse momentum above $$350\,\text {GeV}$$ 350 GeV . The results are corrected for detector effects to particle level in three bins of the scattering angle of the associated jet. The measurement agrees with the SM prediction at next-to-leading-order accuracy in quantum chromodynamics in all three bins. In the bin with the largest expected asymmetry, where the jet is emitted perpendicular to the beam, the energy asymmetry is measured to be $$-0.043\pm 0.020$$ - 0.043 ± 0.020 , in agreement with the SM prediction of $$-0.037\pm 0.003$$ - 0.037 ± 0.003 . Interpreting this result in the framework of the Standard Model effective field theory (SMEFT), it is shown that the energy asymmetry is sensitive to the top-quark chirality in four-quark operators and is therefore a valuable new observable in global SMEFT fits