Citations

Abstract More than 5 million Americans are living with Alzheimer's disease (AD) today, and nearly two‐thirds of Americans with AD are women. This sex difference may be due to the higher longevity women generally experience; however, increasing evidence suggests that longevity alone is not a sufficient explanation and there may be other factors at play. The Alzheimer's Association convened an expert think tank to focus on the state of the science and level of evidence around gender and biological sex differences for AD, including the knowledge gaps and areas of science that need to be more fully addressed. This article summarizes the think tank discussion, moving forward a research agenda and funding program to better understand the biological underpinnings of sex‐ and gender‐related disparities of risk for AD.

Background and purpose The clinical characteristics of colony stimulating factor 1 receptor ( CSF 1R) related adult‐onset leukoencephalopathy with axonal spheroids and pigmented glia ( ALSP ) have been only partially elucidated. Methods Clinical data from CSF 1R mutation carriers who had been seen at our institutions or reported elsewhere were collected and analysed using a specific investigation sheet to standardize the data. Results In all, 122 cases from 90 families with CSF 1R mutations were identified. The mean age of onset was 43 years (range 18–78 years), the mean age at death was 53 years (range 23–84 years) and the mean disease duration was 6.8 years (range 1–29 years). Women had a significantly younger age of onset than men (40 vs. 47 years, P = 0.0006, 95% confidence interval 3.158–11.177). There was an age‐dependent penetrance that was significantly different between the sexes ( P = 0.0013). Motor dysfunctions were the most frequent initial symptom in women whose diseases began in their 20s. Thinning of the corpus callosum, abnormal signalling in pyramidal tracts, diffusion‐restricted lesions and calcifications in the white matter were characteristic imaging findings of ALSP . The calcifications were more frequently reported in our case series than in the literature (54% vs. 3%). Seventy‐nine per cent of the mutations were located in the distal part of the tyrosine kinase domain of CSF 1R (102 cases). There were no apparent phenotype−genotype correlations. Conclusions The characteristics of ALSP were clarified. The phenotype of ALSP caused by CSF 1R mutations is affected by sex.

Abstract Introduction. A KRAS mutation represented the first genomic biomarker to predict lack of benefit from anti-epidermal growth factor receptor (EGFR) antibody therapy in advanced colorectal cancer (CRC). Expanded RAS testing has further refined the treatment approach, but understanding of genomic alterations underlying primary and acquired resistance is limited and further study is needed. Materials and Methods. We prospectively analyzed 4,422 clinical samples from patients with advanced CRC, using hybrid-capture based comprehensive genomic profiling (CGP) at the request of the individual treating physicians. Comparison with prior molecular testing results, when available, was performed to assess concordance. Results. We identified a RAS/RAF pathway mutation or amplification in 62% of cases, including samples harboring KRAS mutations outside of the codon 12/13 hotspot region in 6.4% of cases. Among cases with KRAS non-codon 12/13 alterations for which prior test results were available, 79 of 90 (88%) were not identified by focused testing. Of 1,644 RAS/RAF wild-type cases analyzed by CGP, 31% harbored a genomic alteration (GA) associated with resistance to anti-EGFR therapy in advanced CRC including mutations in PIK3CA, PTEN, EGFR, and ERBB2. We also identified other targetable GA, including novel kinase fusions, receptor tyrosine kinase amplification, activating point mutations, as well as microsatellite instability. Conclusion. Extended genomic profiling reliably detects alterations associated with lack of benefit to anti-EGFR therapy in advanced CRC, while simultaneously identifying alterations potentially important in guiding treatment. The use of CGP during the course of clinical care allows for the refined selection of appropriate targeted therapies and clinical trials, increasing the chance of clinical benefit and avoiding therapeutic futility.

In June 2015, the National Institutes of Health (NIH) released a Guide notice (NOT‐OD‐15–102) that highlighted the expectation of the NIH that the possible role of sex as a biologic variable be factored into research design, analyses, and reporting of vertebrate animal and human studies. Anticipating these guidelines, the NIH Office of Research on Women's Health, in October 2014, convened key stakeholders to discuss methods and techniques for integrating sex as a biologic variable in preclinical research. The workshop focused on practical methods, experimental design, and approaches to statistical analyses in the use of both male and female animals, cells, and tissues in preclinical research. Workshop participants also considered gender as a modifier of biology. This article builds on the workshop and is meant as a guide to preclinical investigators as they consider methods and techniques for inclusion of both sexes in preclinical research and is not intended to prescribe exhaustive/specific approaches for compliance with the new NIH policy.—Miller, L. R., Marks, C., Becker, J.B., Hurn, P.D., Chen, W.‐J., Woodruff, T., McCarthy, M.M., Sohrabji, F., Schiebinger, L., Wetherington, C.L., Makris, S., Arnold, A. P., Einstein, G., Miller, V. M., Sandberg, K., Maier, S., Cornelison, T. L., Clayton, J. A. Considering sex as a biological variable in preclinical research. FASEB J. 31, 29–34 (2017) www.fasebj.org

Brain magnetic resonance (MR) represents a useful and feasible tool for the differential diagnosis of Parkinson’s disease. Conventional MR may reveal secondary forms of parkinsonism and may show peculiar brain alterations of atypical parkinsonian syndromes. Furthermore, advanced MR techniques, such as morphometric-volumetric analyses, diffusion-weighted imaging, diffusion tensor imaging, tractography, proton MR spectroscopy, and iron-content sensitive imaging, have been used to obtain quantitative parameters useful to increase the diagnostic accuracy. Currently, many MR studies have provided both qualitative and quantitative findings, reflecting the underlying neuropathological pattern of the different degenerative parkinsonian syndromes. Although the variability in the methods and results across the studies limits the conclusion about which technique is the best, specific radiologic phenotypes may be identified. Qualitative/quantitative MR changes in the substantia nigra do not discriminate between different parkinsonisms. In the absence of extranigral abnormalities, the diagnosis of PD is more probable, whereas basal ganglia changes (mainly in the putamen) suggest the diagnosis of an atypical parkinsonian syndrome. In this context, changes in pons, middle cerebellar peduncles, and cerebellum suggest the diagnosis of MSA, in midbrain and superior cerebellar peduncles the diagnosis of PSP, and in whole cerebral hemispheres (mainly in frontoparietal cortex with asymmetric distribution) the diagnosis of Corticobasal Syndrome.

Purpose The flipped classroom (FC), in which instructional content is delivered before class with class time devoted to knowledge application, has the potential to engage residents. A Mayo Clinic Internal Medicine Residency Program study was conducted to validate an FC perception instrument (FCPI); determine whether participation improved FC perceptions; and determine associations between resident characteristics, change in quality improvement (QI) knowledge, and FC perception scores. Method All 143 internal medicine residents at Mayo Clinic, Rochester participated from 2014 to 2015; some experienced a flipped QI curriculum and others completed the traditional nonflipped course. The FCPI was developed, and factor analysis revealed an intuitive two-factor structure: preclass activity and in-class application. Residents were surveyed before and after the monthlong curriculum to measure changes in perception, and the QI Knowledge Assessment Tool was employed to measure knowledge improvement. Results Postcourse FCPI scores significantly increased for three of the eight items. QI knowledge increased significantly among residents who experienced the FC compared with residents who completed the non-FC curriculum. Those without prior FC exposure demonstrated a significant increase in QI knowledge compared with those with previous FC experience. The FCPI had compelling validity evidence with improved scores after curriculum exposure and associations with greater engagement in online modules. Conclusions Residents who participated in the FC demonstrated improved QI knowledge compared with the control group. Residents valued the in-class application sessions more than the online component. These findings have important implications for graduate medical education as residency training programs increasingly use FC models.

BackgroundCardiac infiltration is an important cause of death in sarcoidosis. Transthoracic echocardiography (TTE) has limited sensitivity for the detection of cardiac sarcoidosis (CS). Late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) is used to diagnose CS but has limitations of cost and availability. We sought to determine whether TTE‐derived global longitudinal strain (GLS) may be used to identify individuals with CS, despite preserved left ventricular ejection fraction (LVEF), and whether abnormal GLS is associated with major cardiovascular events (MCE).MethodsWe studied 31 patients with biopsy‐proven extra‐cardiac sarcoidosis, LVEF>50% and LGE on CMR (CS+ group), and 31 patients without LGE (CS− group), matched by age, sex, and severity of lung disease. GLS was measured using vendor‐independent speckle tracking software. Parameters of left and right ventricular systolic and diastolic function were also studied. Receiver‐operating characteristic curves were used to identify GLS cutoff for CS detection, and Kaplan–Meier plots to determine the ability of GLS to predict MCE.ResultsLGE was associated with reduced GLS (−19.6±1.9% in CS− vs −14.7±2.4% in CS+, P<.01) and with reduced E/A ratio (1.1±0.3 vs 0.9±0.3, respectively, P =.01). No differences were noted in other TTE parameters. GLS magnitude inversely correlated with LGE burden (r=−.59). GLS cutoff of −17% showed sensitivity and specificity 94% for detecting CS. Patients who experienced MCE had worse GLS than those who did not (−13.4±0.9% vs −17.7±0.4%, P=.0003).ConclusionsCS is associated with significantly reduced GLS in the presence of preserved LVEF. GLS measurements may become part of the TTE study performed to screen for CS.