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A 36-year-old man with schizophrenia, on two times per day clozapine, presented with a 2-year history of diffuse intermittent body pain.Per chart review—and on presentation—his physical examination had been consistently unremarkable, without point-tenderness elicited at any major muscle groups or focal neurological deficits. Workup for myopathy, neuropathy and supratherapeutic clozapine levels had similarly been unrevealing.Given that prior interventions had been unsuccessful in alleviating these symptoms, we queried whether clozapine might have been contributory. As a result, we adopted a previously described strategy of scheduling the bulk of patients’ medication during non-waking hours.At 1-month follow-up, the patient reported about a 50% improvement in his symptoms. At 6-month follow-up, this improvement in symptoms had been sustained.Our findings add to the limited anecdotal reports of this side effect whose true prevalence remains unknown. Timely recognition has the potential to promote adherence to therapy among patients in the maintenance phase.

INTRODUCTION Risk stratification has been proposed as a strategy to improve participation in colorectal cancer (CRC) screening, but evidence is lacking. We performed a randomized controlled trial of risk stratification using the National Cancer Institute's Colorectal Cancer Risk Assessment Tool (CCRAT) on screening intent and completion. METHODS A total of 230 primary care patients eligible for first-time CRC screening were randomized to risk assessment via CCRAT or education control. Follow-up of screening intent and completion was performed by record review and phone at 6 and 12 months. We analyzed change in intent after intervention, time to screening, overall screening completion rates, and screening completion by CCRAT risk score tertile. RESULTS Of the patients, 61.7% of patients were aged

Descriptive and translational investigations into the human gut microbiome (GM) are rapidly expanding; however, studies are largely restricted to industrialized populations in the USA and Europe. Little is known about microbial variability and its implications for health and disease in other parts of the world. Populations in Africa are particularly underrepresented. What limited research has been performed has focused on a few subject domains, including the impact of long-term lifestyle and dietary factors on GM ecology, its maturation during infancy, and the interrelationships between the microbiome, infectious disease, and undernutrition. Recently, international consortia have laid the groundwork for large-scale genomics and microbiome studies on the continent, with a particular interest in the epidemiologic transition to noncommunicable disease. Here, we survey the current landscape of GM scholarship in Africa and propose actionable recommendations to improve research capacity and output.

Ras-dependent signaling is an important regulator of cell cycle progression, proliferation, senescence, and apoptosis. Several of the downstream effectors of Ras play dual roles in each of these processes. Under one set of conditions, they promote cell cycle progression and proliferation; yet, in a different paradigm, they drive cell cycle arrest and apoptosis. Furthermore, there is cross talk between certain downstream effectors of Ras including the PI3K-AKT and Raf-MEK-ERK pathways. Here we describe a series of experiments used to dissect the effect of different Ras-dependent signaling pathways on cell cycle progression, proliferation, senescence, and apoptosis. Furthermore, we highlight the importance of consistent growth conditions of cells in culture when studying Ras-dependent signaling as we show that the activation of downstream effectors of Ras changes with the confluency at which the cells are grown.

Chiari Type I Malformation (CMI) is characterized by displacement of the cerebellar tonsils below the base of the skull, resulting in significant neurologic morbidity. Although multiple lines of evidence support a genetic contribution to disease, no genes have been identified. We therefore conducted the largest whole genome linkage screen to date using 367 individuals from 66 families with at least two individuals presenting with nonsyndromic CMI with or without syringomyelia. Initial findings across all 66 families showed minimal evidence for linkage due to suspected genetic heterogeneity. In order to improve power to localize susceptibility genes, stratified linkage analyses were performed using clinical criteria to differentiate families based on etiologic factors. Families were stratified on the presence or absence of clinical features associated with connective tissue disorders (CTDs) since CMI and CTDs frequently co-occur and it has been proposed that CMI patients with CTDs represent a distinct class of patients with a different underlying disease mechanism. Stratified linkage analyses resulted in a marked increase in evidence of linkage to multiple genomic regions consistent with reduced genetic heterogeneity. Of particular interest were two regions (Chr8, Max LOD = 3.04; Chr12, Max LOD = 2.09) identified within the subset of "CTD-negative" families, both of which harbor growth differentiation factors (GDF6, GDF3) implicated in the development of Klippel-Feil syndrome (KFS). Interestingly, roughly 3-5% of CMI patients are diagnosed with KFS. In order to investigate the possibility that CMI and KFS are allelic, GDF3 and GDF6 were sequenced leading to the identification of a previously known KFS missense mutation and potential regulatory variants in GDF6. This study has demonstrated the value of reducing genetic heterogeneity by clinical stratification implicating several convincing biological candidates and further supporting the hypothesis that multiple, distinct mechanisms are responsible for CMI.