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Why neurotrophins and their Trk receptors promote neuronal differentiation and survival whereas receptor tyrosine kinases for other growth factors, such as EGF, do not, has been a long-standing question in neurobiology. We provide evidence that one difference lies in the selective ability of Trk to generate long-lived signaling endosomes. We show that Trk endocytosis is distinguished from the classical clathrin-based endocytosis of EGF receptor (EGFR). Although Trk and EGFR each stimulate membrane ruffling, only Trk undergoes both selective and specific macroendocytosis at ruffles, which uniquely requires the Rho-GTPase, Rac, and the trafficking protein, Pincher. This process leads to Trk-signaling endosomes, which are immature multivesicular bodies that retain Rab5. In contrast, EGFR endosomes rapidly exchange Rab5 for Rab7, thereby transiting into late-endosomes/lysosomes for degradation. Sustained endosomal signaling by Trk does not reflect intrinsic differences between Trk and EGFR, because each elicits long-term Erk-kinase activation from the cell surface. Thus, a population of stable Trk endosomes, formed by specialized macroendocytosis in neurons, provides a privileged endosome-based system for propagation of signals to the nucleus.

In a split-voice narrative, the author details the dual focus of her days as a doctor teaching in a primary care internal residency program and as a mother. Despite her multiple responsibilities at home and the office, each work day is bounded by the transitions where the author transfers her children to and from the care of others. Even on days when her husband helps, which he does several times a week, she still attends to many of the details. The author entered medicine at a time when opportunities for women in the profession were soaring. She benefits from an institution that takes part-time work seriously, allowing her progression on her academic clock to be prorated and where she received an additional year in her current term when she had her baby. According to the author, many women desire flexibility and alternative pathways, but also not to be discounted or undervalued simply because they are also mothers.

Limited health literacy is associated with worse health outcomes. It is standard practice in many primary care clinics to provide patients with written patient education materials (PEM), which often come directly from an electronic health record (EHR). We compared the health literacy of patients in a primary care residency clinic with EHR PEM readability by grade level. We assessed health literacy using the Rapid Estimate of Adult Literacy in Medicine-Short Form (REALM-SF), and determined grade level readability for the PEM distributed for the five most common clinical diagnoses using the Simple Measure of Gobbledygook (SMOG) and Flesch-Kincaid metrics. Among 175 participants, health literacy was ≥9th grade for 76 patients (43.4%), 7th to 8th grade for 66 patients (37.7%), and ≤6th grade for 30 patients (17.1%). Average standard PEM readability by SMOG was grade 9.2 and easy-to-read PEM readability was grade 6.8. These findings suggest a discrepancy between the health literacy of most patients who were surveyed and standard PEM readability. Despite national guidelines encouraging clinicians to provide PEM at an appropriate reading level, our results indicate that PEM from EHR may not be readable for many patients. [ Health Literacy Research and Practice . 2017;1(4):e203–e207.]

BackgroundProfessionalism standards encourage physicians to participate in public advocacy on behalf of societal health and well-being. While the number of publications of advocacy curricula for GME-level trainees has increased, there has been no formal effort to catalog them.ObjectiveTo systematically review the existing literature on curricula for teaching advocacy to GME-level trainees and synthesize the results to provide a resource for programs interested in developing advocacy curricula.MethodsA systematic literature review was conducted to identify articles published in English that describe advocacy curricula for graduate medical education trainees in the USA and Canada current to September 2017. Two reviewers independently screened titles, abstracts, and full texts to identify articles meeting our inclusion and exclusion criteria, with disagreements resolved by a third reviewer. We abstracted information and themes on curriculum development, implementation, and sustainability. Learning objectives, educational content, teaching methods, and evaluations for each curriculum were also extracted.ResultsAfter reviewing 884 articles, we identified 38 articles meeting our inclusion and exclusion criteria. Curricula were offered across a variety of specialties, with 84% offered in primary care specialties. There was considerable heterogeneity in the educational content of included advocacy curriculum, ranging from community partnership to legislative advocacy. Common facilitators of curriculum implementation included the American Council for Graduate Medical Education requirements, institutional support, and preexisting faculty experience. Common barriers were competing curricular demands, time constraints, and turnover in volunteer faculty and community partners. Formal evaluation revealed that advocacy curricula were acceptable to trainees and improved knowledge, attitudes, and reported self-efficacy around advocacy.DiscussionOur systematic review of the medical education literature identified several advocacy curricula for graduate medical education trainees. These curricula provide templates for integrating advocacy education into GME-level training programs across specialties, but more work needs to be done to define standards and expectations around GME training for this professional activity.

Whole exome sequencing has proven to be a powerful tool for understanding the genetic architecture of human disease. Here we apply it to more than 2,500 simplex families, each having a child with an autistic spectrum disorder. By comparing affected to unaffected siblings, we show that 13% of de novo missense mutations and 43% of de novo likely gene-disrupting (LGD) mutations contribute to 12% and 9% of diagnoses, respectively. Including copy number variants, coding de novo mutations contribute to about 30% of all simplex and 45% of female diagnoses. Almost all LGD mutations occur opposite wild-type alleles. LGD targets in affected females significantly overlap the targets in males of lower intelligence quotient (IQ), but neither overlaps significantly with targets in males of higher IQ. We estimate that LGD mutation in about 400 genes can contribute to the joint class of affected females and males of lower IQ, with an overlapping and similar number of genes vulnerable to contributory missense mutation. LGD targets in the joint class overlap with published targets for intellectual disability and schizophrenia, and are enriched for chromatin modifiers, FMRP-associated genes and embryonically expressed genes. Most of the significance for the latter comes from affected females. Family-based exome sequencing in a large autism study has identified 27 high-confidence gene targets and accurately estimates the contribution of both de novo gene-disrupting and missense mutations to the incidence of simplex autism, with target genes in affected females overlapping those in males of lower but not higher IQ; targets also overlap known targets for intellectual disability and schizophrenia, and are enriched for chromatin modifiers, FMRP-associated genes and embryonically expressed genes. Autism-linked genetic factors analysed Autism spectrum disorder (ASD) is a broad group of brain development disorders, including autism, childhood disintegrative disorder and Asperger's syndrome, characterized by impaired social interaction and communication, repetitive behaviour and restricted interests. Two groups reporting in this issue of Nature have used large-scale whole-exome sequencing to examine the contribution of inherited and germline de novo mutations to ASD risk. Silvia De Rubeis et al . analysed DNA samples from 3,871 autism cases and 9,937 ancestry-matched or parental controls and identify more than 100 autosomal genes that are likely to affect risk for the disease. De novo loss-of-function mutations were detected in more than 5% of autistic subjects. Many of the associated gene products appear to function in synaptic, transcriptional, and chromatin remodelling pathways. Ivan Iossifov et al . sequenced exomes from more than 2,500 families, each with one child with ASD. They identify 27 high-confidence gene targets and estimate that 13% of de novo missense mutations and 43% of de novo 'likely gene-disrupting' (LGD) mutations contribute to 12% and 9% of diagnoses, respectively.

To determine whether altruism as reason for participation in research is independently associated with adherence to a medical regimen in a clinical trial. Participants were 475 participants in the Women's Estrogen for Stroke Trial. Before randomization to estrogen or placebo, all women were questioned about reason for participation and baseline features that may contribute to adherence. Adherence was defined as completion of at least 80% of expected pill intake during the trial. Women who reported at least one altruistic reason for participation were more likely to be college educated, have a higher level of social support, and a better functional status. They were also more likely to be adherent to their study medication {155 of 212 (73%) vs. 158 of 253 (62.5%), P < .01}. On stratified analysis and multivariable regression, the relationship between altruism as reason for participation and adherence was independent of other sociodemographic, psychosocial, and clinical features (relative risk 1.17, Confidence interval 1.03–1.32). Altruism may explain a small portion of the variation in adherence among research participants. This relationship may have implications for recruitment of participants in clinical research. The possible contribution of altruism to the relationship between adherence and outcomes in clinical trials is worthy of further investigation.

The staff nurse at the facility had asked Jeff over the phone if she should send Mom to the hospital for evaluation, but this clinical pattern had occurred many times before without incident and without necessitating a hospital visit. When he walked into her room that morning to visit, he found her skin warm with a low-grade fever. Even when a patient's status is clear and the family's consensus unified, the moment of decision can be clouded with doubt and uncertainty.

Fang et al . describe a computational protocol to accurately call indels from whole-genome and whole-exome sequencing data using Scalpel. Important issues for indel identification, such as short repeat regions and varying sequencing coverage, are discussed. As the second most common type of variation in the human genome, insertions and deletions (indels) have been linked to many diseases, but the discovery of indels of more than a few bases in size from short-read sequencing data remains challenging. Scalpel ( http://scalpel.sourceforge.net ) is an open-source software for reliable indel detection based on the microassembly technique. It has been successfully used to discover mutations in novel candidate genes for autism, and it is extensively used in other large-scale studies of human diseases. This protocol gives an overview of the algorithm and describes how to use Scalpel to perform highly accurate indel calling from whole-genome and whole-exome sequencing data. We provide detailed instructions for an exemplary family-based de novo study, but we also characterize the other two supported modes of operation: single-sample and somatic analysis. Indel normalization, visualization and annotation of the mutations are also illustrated. Using a standard server, indel discovery and characterization in the exonic regions of the example sequencing data can be completed in ∼5 h after read mapping.

The USA is unique among industrialized nations in its dramatic rate of firearm violence. Unfortunately, firearm-related issues in America are politically divisive and fraught with controversy, thus impeding the study and implementation of safety strategies. Despite the lack of consensus, there is agreement that firearms should be kept away from individuals with criminal intent and those who are dangerous due to medical impairment. While predicting criminal intent remains challenging, assessment of medical impairment remains a viable target. One approach in which physicians could contribute their expertise includes training a subset of doctors to perform specialized medical evaluations as a prerequisite for gun ownership. Such a process is not unprecedented, as physicians currently have a role in protecting the public’s safety through assessments for commercial drivers, pilots, and train operators. Certified physician examiners could conduct these evaluations with a focus on evaluating objective, skill-based metrics to limit potential evaluator bias. The results of the medical evaluation would then be considered by an existing regulatory body to determine if disqualifying criteria are present. This proposal provides a mechanism for trained physicians to meaningfully participate in addressing an alarming public health issue, while still working within existing legal frameworks.

OBJECTIVE: The authors sought to determine the effect of an educational seminar on interactions with pharmaceutical representatives on residents' attitudes and behavior. METHOD: A controlled trial of an educational intervention was conducted. Residents at a university-affiliated residency program (N=32) were divided into two groups: one group (N=18) received a 1-hour educational intervention, while the other group (N=14) served as a control. Both groups completed a 33-item survey before the intervention and 2 months after the intervention. RESULTS: Residents interacted substantially with pharmaceutical representatives. The majority of residents found the interactions and gifts useful and believed their prescribing practices were not influenced. Compared to the comparison group, the intervention group significantly decreased the reported number of office supplies and noneducational gifts, but showed no change in attitude toward pharmaceutical representatives and their gifts. CONCLUSION: One-time educational interventions may have significant impact on psychiatric residents' targeted gift-accepting behavior but little effect on attitudes.