Grantblanchard3720

These alternate transcripts were expressed at very low levels in the wild-type mice and were significantly upregulated in the mutant mice, indicating that pre-translational splicing defects may be a critical component of the disease mechanism associated with the mutation. Evidence of reduced expression of the full-length CFL2 transcript was also observed in the muscle biopsy sample of the patient with p.A35T mutation. © The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email journals.permissions@oup.com.Up till now, research on inflammatory bowel disease [IBD] has mainly been focused on the immune cells present in the gastrointestinal tract. However, recent insights indicate that stromal cells also play an important and significant role in IBD pathogenesis. Stromal cells in the intestines regulate both intestinal epithelial and immune cell homeostasis. Different subsets of stromal cells have been found to play a role in other inflammatory diseases [e.g. DS-8201 Antibody-Drug Conjug chemical rheumatoid arthritis], and these various stromal subsets now appear to carry out also specific functions in the inflamed gut in IBD. Novel potential therapies for IBD utilize, as well as target, these pathogenic stromal cells. Injection of mesenchymal stromal cells [MSCs] into fistula tracts of Crohn's disease patients is already approved and used in clinical settings. In this review we discuss the current knowledge of the role of stromal cells in IBD pathogenesis. We further outline recent attempts to modify the stromal compartment in IBD with agents that target or replace the pathogenic stroma. © European Crohn’s and Colitis Organisation (ECCO) 2020.Inflammatory bowel disease, including ulcerative colitis and Crohn's disease, are chronic inflammatory disorders of the gastrointestinal tract which are characterised, in part, by an imbalance in the production of several pro- and anti-inflammatory cytokines. Although various agents are effective for inducing and maintaining remission, approximately 20% of patients are treatment-refractory and require surgery. Parenterally administered monoclonal antibody-based biologics are associated with adverse effects resulting in treatment discontinuation and/or immunogenicity, leading to loss of response to therapy. Approximately 50% of patients who initially respond to treatment with tumour necrosis factor antagonists lose response to therapy within the 1st year of treatment. Incidence of immunogenicity tends to decrease over time, but once present can persist for years, even after treatment discontinuation. Nonimmunogenic oral small molecule therapies, including Janus kinase inhibitors, are currently being developed and have demonstrated efficacy in early phase clinical trials, which has already led to regulatory approval of tofacitinib for the treatment of patients with moderate-to-severe ulcerative colitis. Differentiation of T cells into T helper cells, which are mediators of the inflammatory response in inflammatory bowel disease, is mediated by the Janus kinase signal transducer and activator of the transcription signalling pathway. Absorption and distribution of Janus kinase inhibitors occurs at the site of action in the gastrointestinal tract, and newer compounds are being developed with limited systemic absorption, potentially reducing the risk of adverse effects. The current review describes the clinical pharmacology of approved Janus kinase inhibitors, as well as those in clinical development for the treatment of inflammatory bowel disease. © European Crohn’s and Colitis Organisation (ECCO) 2020.BACKGROUND Diphtheria is a vaccine-preventable disease that persists as a global health problem. An understanding of the pattern of disease is lacking in low- and middle-income countries such as the Philippines. METHODS We conducted a retrospective review of the clinical, microbiological, and epidemiological features of patients admitted with a clinical diagnosis of diphtheria to an infectious disease referral hospital in Metro Manila, the Philippines, between 2006 and 2017. Cases were mapped and the distribution was compared with population density. Corynebacterium diphtheriae isolates from between 2015 and 2017 were examined by multilocus sequence typing (MLST). RESULTS We studied 267 patients (range12-54 cases/year) admitted between 2006 and 2017. The case fatality rate (CFR) was 43.8% (95% confidence interval, 37.8-50.0%). A higher number of cases and CFR was observed among children less then 10 years. Mortality was associated with a delayed admission to hospital and a lack of diphtheria antitoxin. Between 2015 and 2017 there were 42 laboratory-confirmed cases. We identified 6 multilocus sequence types (STs). ST-302 was the most common (17/34, 48.6%), followed by ST67 (7/34, 20%) and ST458 (5/34, 14%). Case mapping showed a wide distribution of diphtheria patients in Metro Manila. Higher case numbers were found in densely populated areas but with no apparent clustering of ST types. CONCLUSIONS Our analysis indicates that diphtheria remains endemic in Metro Manila and that the infection is frequently fatal in young children. Improved vaccine coverage and a sustainable supply of diphtheria antitoxin should be prioritized. link2 © The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.Context Recreational use of opioids is a growing problem in the United States, particularly in the Midwest. Educators have called for inclusion of pain- and opioid-specific courses in health professional school curricula, yet more research is needed to address future prescribers' beliefs, experiences, and postgraduate plans related to opioids. Objective To examine health professional students' perceived severity of the opioid crisis and opioid-related beliefs, experiences, and postgraduate plans. Methods Using a descriptive, cross-sectional design, researchers evaluated health professional students from 3 academic programs (nurse practitioner [NP], physician assistant [PA], and doctor of osteopathic medicine [DO]) using a 25-item survey that assessed perceived opioid crisis severity and opioid-related beliefs, experiences, and postgraduate plans. Demographics of respondents were assessed using descriptive statistics and frequencies. Responses were compared between academic programs with 1-way analysis of vari5, Z=5.92, P less then .001; U=25,346.0, Z=4.94, P less then .001) and confidence in treating patients with opioid addictions (U=36,806.5, Z=4.96, P less then .001; U=23,765.5, Z=3.66, P less then .001). Conclusion Although health professional students had similar beliefs and perceptions regarding the opioid crisis, there were notable differences between academic programs. Students with clinical opioid experiences were more likely to plan on working with patients addicted to opioids and be confident in treating these patients. Thus, the inclusion of experiential learning in the medical curricula may be beneficial for both students and their future patients.Adult T cell leukemia/lymphoma (ATL) is an aggressive hematological malignancy caused by Human T-cell leukemia virus type-1 (HTLV-1). ATL is preceded by decades of chronic HTLV-1 infection, and the tumors carry both somatic mutations and proviral DNA integrated into the tumor genome. In order to gain insight into the oncogenic process, we used targeted sequencing to track the evolution of the malignant clone in six individuals, 2-10 years before the diagnosis of ATL. Clones of premalignant HTLV-1-infected cells bearing known driver mutations were detected in the blood up to 10 years before individuals developed acute and lymphoma subtype ATL. Six months before diagnosis, the total number and variant allele fraction of mutations increased in the blood. Peripheral blood mononuclear cells from premalignant cases (1 year pre-diagnosis) had significantly higher mutational burden in genes frequently mutated in ATL than did high risk, age-matched HTLV-1-carriers who remained ATL-free after a median of 10 years of follow up. These data show that HTLV-1-infected T cell clones carrying key oncogenic driver mutations can be detected in cases of ATL years before the onset of symptoms. Early detection of such mutations may enable earlier and more effective intervention to prevent the development of ATL. Copyright © 2020 American Society of Hematology.Glutaric aciduria type 1 (GA1) is an inborn error of lysine degradation characterized by a specific encephalopathy that is caused by toxic accumulation of lysine degradation intermediates. Substrate reduction through inhibition of DHTKD1, an enzyme upstream of the defective glutaryl-CoA dehydrogenase, has been investigated as a potential therapy, but revealed the existence of an alternative enzymatic source of glutaryl-CoA. Here we show that loss of DHTKD1 in GCDH-deficient HEK-293 cells leads to a 2-fold decrease in the established GA1 clinical biomarker glutarylcarnitine, and demonstrate that OGDH is responsible for this remaining glutarylcarnitine production. We furthermore show that DHTKD1 interacts with OGDH, DLST and DLD to form a hybrid 2-oxoglutaric and 2-oxoadipic acid dehydrogenase complex. In summary, 2-oxoadipic acid is a substrate for DHTKD1, but also for OGDH in a cell model system. The classical 2-oxoglutaric dehydrogenase complex can exist as a previously undiscovered hybrid containing DHTKD1 displaying improved kinetics towards 2-oxoadipic acid. © The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email journals.permissions@oup.com.PURPOSE To develop and implement an interprofessional framework to increase the capture of health system-generated prescriptions within health system-owned pharmacies. SUMMARY Low prescription capture rates within a health system's internal pharmacies led to an interdisciplinary process improvement effort. A framework was developed to assess the baseline prescription capture rate, select clinics for improvement, understand clinic workflows and key drivers of pharmacy selection, design strategies to increase prescription capture, implement targeted efforts, and measure the effectiveness of the intervention(s). Employing this framework provided revised workflows for nursing and medical assistant staff scripting and for referral of patients to internal pharmacies. These workflows were pilot tested at 3 system clinics. link3 Results indicated that overall prescription capture increased 2.9% to by 2.9 to 4.1 percentage points (range, 10 to 86 prescriptions per month) and specialty prescription capture increased 11.6 to 26.7 percentage points (range, 4 to 26 prescriptions per month) for each clinic within the first 2 months. A total of 99 new patients were referred to internal pharmacies within the first month. CONCLUSION Development and implementation of a framework to increase prescription capture from health system clinics helped increase capture, enhanced clinic engagement and knowledge about pharmacy services, and supported positive clinic-pharmacy relationships. © American Society of Health-System Pharmacists 2020. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.