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Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders with strong genetic heterogeneity and more prevalent in males than females. We and others hypothesize that diminished activity-dependent neural signaling is a common molecular pathway dysregulated in ASD caused by diverse genetic mutations. Brain-derived neurotrophic factor (BDNF) is a key growth factor mediating activity-dependent neural signaling in the brain. A common single nucleotide polymorphism (SNP) in the pro-domain of the human BDNF gene that leads to a methionine (Met) substitution for valine (Val) at codon 66 (Val66Met) significantly decreases activity-dependent BDNF release without affecting basal BDNF secretion. By using mice with genetic knock-in of this human BDNF methionine (Met) allele, our previous studies have shown differential severity of autism-like social deficits in male and female BDNF +/Met mice. Pyramidal neurons are the principal neurons in the prefrontal cortex (PFC), a key brain region for social behaviors. Here, we investigated the impact of diminished activity-dependent BDNF signaling on the intrinsic excitability of pyramidal neurons in the PFC. Surprisingly, diminished activity-dependent BDNF signaling significantly increased the intrinsic excitability of pyramidal neurons in male mice, but not in female mice. Notably, significantly decreased thresholds of action potentials were observed in male BDNF +/Met mice, but not in female BDNF +/Met mice. Voltage-clamp recordings revealed that the sodium current densities were significantly increased in the pyramidal neurons of male BDNF +/Met mice, which were mediated by increased transcriptional level of Scn2a encoding sodium channel Na V 1.2. Medium after hyperpolarization (mAHP), another important parameter to determine intrinsic neuronal excitability, is strongly associated with neuronal firing frequency. Further, the amplitudes of mAHP were significantly decreased in male BDNF +/Met mice only, which were mediated by the downregulation of Kcnn2 encoding small conductance calcium-activated potassium channel 2 (SK2). This study reveals a sexually dimorphic signature of diminished activity-dependent BDNF signaling on the intrinsic neuronal excitability of pyramidal neurons in the PFC, which provides possible cellular and molecular mechanisms underpinning the sex differences in idiopathic ASD patients and human autism victims who carry BDNF Val66Met SNP., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Ma, Zhang, McDaniel, Webb, Newton, Lee and Qin.)

Glioblastoma (GBM) is a rare brain cancer with an exceptionally high mortality rate, which illustrates the pressing demand for more effective therapeutic options. Despite considerable research efforts on GBM, its underlying biological mechanisms remain unclear. Furthermore, none of the United States Food and Drug Administration (FDA) approved drugs used for GBM deliver satisfactory survival improvement. This study presents a novel computational pipeline by utilizing gene expression data analysis for GBM for drug repurposing to address the challenges in rare disease drug development, particularly focusing on GBM. The GBM Gene Expression Profile (GGEP) was constructed with multi-omics data to identify drugs with reversal gene expression to GGEP from the Integrated Network-Based Cellular Signatures (iLINCS) database. We prioritized the candidates via hierarchical clustering of their expression signatures and quantification of their reversal strength by calculating two self-defined indices based on the GGEP genes' log 2 foldchange (LFCs) that the drug candidates could induce. Among eight prioritized candidates, in-vitro experiments validated Clofarabine and Ciclopirox as highly efficacious in selectively targeting GBM cancer cells. The success of this study illustrated a promising avenue for accelerating drug development by uncovering underlying gene expression effect between drugs and diseases, which can be extended to other rare diseases and non-rare diseases., Competing Interests: Competing interests The authors declare no conflicts of interests.

Hepatitis C virus (HCV) causes significant mortality worldwide. HCV is highly curable but access to care is limited for many patients. The Grady Liver Clinic (GLC), a primary care-based HCV clinic, utilizes a multidisciplinary team to provide comprehensive care for a medically underserved patient population in Atlanta, Georgia. The GLC added a telehealth option for HCV treatment at the start of the COVID-19 pandemic. We describe the outcomes of utilizing telehealth in this population. We performed a retrospective chart review of patients who initiated HCV treatment from March 2019 to February 2020 (pre-pandemic) and March 2020 to February 2021 (pandemic). Charts were abstracted for patient demographics and characteristics, treatment regimen, and treatment outcomes. Our primary outcome was HCV cure rate of the pre-pandemic compared to the pandemic cohorts and within the different pandemic cohort visit types. We performed an intention-to-treat (ITT) analysis for all patients who took at least one dose of a direct-acting antiviral (DAA) regardless of therapy completion, and a per-protocol (PP) analysis of those who completed treatment and were tested for HCV cure. SVR12 rates were >95% on ITT analysis, with no significant difference between pre-pandemic and pandemic cohorts. There was also no significant difference within the pandemic group when treatment was provided traditionally, via telehealth, or via a hybrid of these. Our findings support the use of telehealth as a tool to expand access to HCV treatment in a medically underserved patient population., (© 2024 John Wiley & Sons Ltd.)

Hepatitis C virus (HCV) infection is a critical public health concern in the United States. HCV is highly curable, but access to care is limited for many patients. Primary care models can expand access to HCV care. The Grady Liver Clinic (GLC) is a primary care-based HCV clinic founded in 2002. During 20 years, using a multidisciplinary team, the GLC expanded its operations in response to advances in HCV screening and treatment. We describe the clinic model, patient population, and treatment outcomes of the clinic from 2015 through 2019. During this period, 2689 patients were seen in the GLC, and 77% (n = 2083) initiated treatment. Eighty-five percent (1779 of 2083) of patients who started treatment completed treatment and were tested for cure, and 1723 (83% of the total treated cohort, 97% of those tested for cure) were cured. Building on a successful primary care-based treatment model, the GLC dynamically responded to the changes in HCV screening and treatment guidelines, continually increasing access to HCV care. The GLC serves as a model of primary care-based HCV care that aims to achieve HCV microelimination in a safety-net health system. Our findings support the notion that for the United States to achieve elimination of HCV by 2030, generalists can and should provide HCV care, particularly in medically underserved patient populations., Competing Interests: Declaration of Conflicting InterestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr Miller receives grant funding through Emory University from Gilead Sciences and consulting fees from AbbVie.

In laboratory animals, there are numerous demonstrations that past exposure to drugs of abuse can lead to devaluation impairments weeks after the final drug exposure, with the majority of these demonstrations examining effects of exposure to psychostimulants. There has been minimal investigation into whether prior exposure to opiates can lead to devaluation impairments. Here, we first trained female rats that two separate cuelights predicted two different foods and measured Pavlovian goal-tracking responses (Experiment 1) or trained female rats to press two levers to earn two different foods and measured this operant response (Experiment 2). In both experiments, we subsequently gave the rats injections of fentanyl twice daily for 6 days, and then tested rats for conditioned responses after satiation on one of the foods 48-h after the final injection. We found that rats were impaired in the expression of devaluation in the Pavlovian task after fentanyl exposure, but were unimpaired in the expression of devaluation in the operant task. The pattern of results is most consistent with an impairment in lateral orbitofrontal cortex function, but additional research is needed to determine the neurobiological cause of this pattern of results., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Purpose: Heplisav-B is a novel recombinant adjuvanted vaccine for hepatitis B virus (HBV) that has been approved as a 2-dose regimen and shown to have similar seroconversion rates in healthy adults as single-antigen HBV vaccines. More data are needed to determine whether similarly high rates of seroconversion and immunity are observed in immunocompromised patient populations such as in patients with end-stage renal disease (ESRD) on hemodialysis., Methods: Patients with ESRD who presented for emergency-only hemodialysis and either were HBV vaccine naive or had a hepatitis B surface antibody (anti-HBs) titer of less than 10 IU/mL received 3 standard 20-μg doses of Heplisav-B at week 0, week 4 (±2 weeks), and week 24 (±2 weeks), with anti-HBs titer measured at week 28 (±2 weeks)., Results: Thirty-two patients received at least one dose in the study timeframe, with 24 patients completing the vaccine series and measurement of anti-HBs titer. The mean age of the patients was 46 years, and 58% of patients were male. Of the 24 patients who completed the vaccine series, 20 (83%) seroconverted after the third dose. Three of the 4 patients who did not seroconvert after 3 doses were revaccinated with an additional 20-μg dose, and 2 of the 3 patients had an anti-HBs titer of greater than 10 IU/mL 4 weeks after this dose., Conclusion: Patients with ESRD who received three 20-μg doses of recombinant HBV vaccine had a seroconversion rate of 83%, representing a similar seroconversion rate and fewer doses of vaccine as compared to the standard HBV vaccine regimen for patients with ESRD., (© American Society of Health-System Pharmacists 2023. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Latinx populations have been more heavily impacted by the COVID-19 pandemic than the general population of the US, including higher rates of hospitalization due to COVID-19 in eastern Massachusetts. We conducted a qualitative study to better understand the experiences of Latinx and Spanish-speaking patients who had clinically significant COVID-19 in the early months of the pandemic., Methods: Thirteen qualitative, semistructured, phone interviews were conducted between December 2020 and April 2021 with Latinx and Spanish-speaking patients who had experienced clinically significant COVID-19 in the metro-north Boston area. Interviews were recorded and transcribed in their original languages. An a priori code tree was developed which was later iteratively revised based on emerging themes. Transcripts were thematically analyzed., Results: Participants discussed their overall experiences contracting the COVID-19 infection, as well as their experiences with the disease and with being hospitalized and the months after in recovery. Family and social networks were a common support, both emotional and financial. Although they survived the disease, hospitalization had serious impacts on the mental and physical health of participants, including the remnants of trauma from hospitalization itself., Implications: Latinx and Spanish-speaking patients in eastern Massachusetts had specific experiences in the early months of the COVID-19 pandemic that were shaped by their living conditions and culture. It is important for health care professionals to understand these experiences so that they can design appropriate medical interventions as well as target outreach efforts that are culturally appropriate. Finally, serious attention should be paid to the mental health-related consequences of hospitalization and policies that can alleviate them., Competing Interests: Conflict of interest: None., (© Copyright by the American Board of Family Medicine.)

Objectives: To determine the accuracy, precision, and clinical applicability of the ICare® TONOVET Plus (TVP) in cats., Animals and Procedures: IOP readings obtained with the TVP were compared to values obtained concurrently with the original TONOVET (TV01) and Tono-Pen Vet™ (TP) in 12 normal cats (24 eyes) and 8 glaucomatous LTBP2-mutant cats (13 eyes) in vivo. Reproducibility of TVP readings was also assessed for three observers in the above cats. The anterior chambers of five different normal cat eyes were cannulated ex vivo. IOP was measured with the TVP, TV01, and TP at manometric IOPs ranging from 5 to 70 mmHg. Data were analyzed by linear regression, ANOVA and Bland-Altman plots. ANOVA was used to assess reproducibility of TVP readings obtained by different observers and an ANCOVA model controlled for variation of individual cats. p < .05 was considered significant., Results: TVP values strongly correlated with TV01 values (y = 1.045x + 1.443, R 2  = .9667). The TP significantly underestimated IOP relative to the TVP and TV01, particularly at high IOP. IOP values obtained by 1 observer were significantly higher (~1 mmHg average) compared to the other 2 observers via ANCOVA analysis (p = .0006479 and p = .0203). Relative to manometry, the TVP and TV01 were significantly more accurate (p < .0001) and precise (p < .0070) than the TP in ex vivo eyes., Conclusions: IOP readings obtained with the TVP and TV01 are broadly interchangeable between models and between observers, but subtle differences may be important in a research context. TP readings vastly underestimate high IOP in feline glaucoma., (© 2023 The Authors. Veterinary Ophthalmology published by Wiley Periodicals LLC on behalf of American College of Veterinary Ophthalmologists.)

Introduction: Emerging research suggests insufficient sleep can heighten the risk of poor mental health among adolescents. We examined the relationship between sleep, depressive symptoms, and suicidal thoughts and behaviors among Florida high school students., Methods: Data were from the 2021 Florida High School Youth Risk Behavior Survey, a statewide representative sample of students in grades 9 to 12. We estimated prevalence of 1 indicator of depressive symptoms - feeling sad or hopeless for 2 or more weeks - and 2 indicators of suicidality - having considered attempting suicide and making a suicide plan - by insufficient sleep status (<8 h of sleep on an average school night). Multivariate logistic regressions were used to calculate odds ratios measuring the association between insufficient sleep, poor mental health, and suicidality., Results: Compared with students reporting sufficient sleep, those with insufficient sleep were more likely to feel sad or hopeless (42.7% vs 28.1%), have considered suicide (19.1% vs 12.5%), or have made a suicide plan (14.8% vs 9.6%). In adjusted multivariate models, compared with students with sufficient sleep, students with insufficient sleep had higher odds of feeling sad or hopeless (adjusted odds ratio [AOR] = 1.83; 95% CI 1.54-2.17), and having made a plan about how they would attempt suicide (AOR = 1.32; 95% CI, 1.00-1.74), but did not have significantly higher odds of having seriously considered suicide., Conclusion: Increased attention to sleep as a modifiable risk factor for mental health among adolescents is particularly important because of the many less modifiable factors that contribute to mental health difficulties in this population. Adolescent mental health programs should consider sleep an important factor in suicide prevention.

Objective: To evaluate dogs with total hypercalcemia, azotemia, and normal serum phosphorus concentrations to determine whether a calcium-to-phosphorus ratio (Ca:P) or ionized Ca:P (iCa:P) could be utilized to predict underlying neoplasia., Animals: 105 dogs were included in the study. Thirty-seven percent (n = 39) had known neoplasia, and 63% (66) had no evidence of neoplasia., Procedures: A retrospective medical records search was performed. An observational cutoff of 2.5 for Ca:P and 0.33 for iCa:P was used for determining sensitivity and specificity between the neoplasia and nonneoplasia groups., Results: Total hypercalcemia was higher in dogs with neoplasia compared to nonneoplastic cases of hypercalcemia. Ca:P of 2.5 had an 80% sensitivity and 46% specificity for predicting neoplasia. iCa:P of 0.33 had a 92% sensitivity and 77% specificity for predicting neoplasia in azotemic dogs., Clinical Relevance: The sensitivity and specificity of Ca:P was low, making it an unreliable tool to predict neoplasia in this specific study population. However, iCa:P may have some usefulness in determining presence of neoplasia in patients with high calcium, azotemia, and normal phosphorus.

Scalable technologies to sequence the transcriptomes and epigenomes of single cells are transforming our understanding of cell types and cell states. The Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative Cell Census Network (BICCN) is applying these technologies at unprecedented scale to map the cell types in the mammalian brain. In an effort to increase data FAIRness (Findable, Accessible, Interoperable, Reusable), the NIH has established repositories to make data generated by the BICCN and related BRAIN Initiative projects accessible to the broader research community. Here, we describe the Neuroscience Multi-Omic Archive (NeMO Archive; nemoarchive.org), which serves as the primary repository for genomics data from the BRAIN Initiative. Working closely with other BRAIN Initiative researchers, we have organized these data into a continually expanding, curated repository, which contains transcriptomic and epigenomic data from over 50 million brain cells, including single-cell genomic data from all of the major regions of the adult and prenatal human and mouse brains, as well as substantial single-cell genomic data from non-human primates. We make available several tools for accessing these data, including a searchable web portal, a cloud-computing interface for large-scale data processing (implemented on Terra, terra.bio), and a visualization and analysis platform, NeMO Analytics (nemoanalytics.org)., (© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Treatment for hepatitis C virus (HCV) with direct-acting antivirals (DAA) is advantageous over previous treatment options due to high efficacy, short treatment duration, and relatively few drug interactions. Similarly, direct oral anticoagulants (DOAC) are generally preferred over warfarin for the management of thrombosis and atrial fibrillation due to a favourable safety profile. Direct-acting antivirals inhibit DOAC transport through P-glycoprotein inhibition leading to a theoretical increase in bleeding risk. We evaluated the incidence of bleeding in patients who received concurrent DAA and DOAC therapy and stratified the analysis based on the patient's cirrhosis status. We conducted a multicenter, retrospective cohort study to evaluate bleeding in patients with HCV and cirrhosis compared to patients with HCV without cirrhosis. Patients receiving at least 1 month of overlapping DAA and DOAC therapy between May 2017 and August 2020 at 11 medical centers in the United Kingdom and three medical centers in the United States were included. Charts were manually reviewed to identify baseline characteristics as well as thromboembolic or bleeding events. Bleeding events were categorized as major bleeding (MB) and clinically relevant non-major bleeding (CRNMB). Of 204 total patients, 36 patients (18%) had cirrhosis and 168 patients (82%) did not have cirrhosis. The majority of patients were male (79%) and Caucasian (75%). Sofosbuvir/velpatasvir (32%) and rivaroxaban (57%) were the most commonly prescribed DAA and DOAC, respectively. Leading indications for anticoagulation included thrombosis (75%) and atrial fibrillation (21%). There were three MB events (1.5%) all of which occurred in patients with additional risk factors (age over 65 and on antiplatelet therapy) and no CRNMB occurred while on DOAC and DAA therapy. Of the three MB, one occurred in a patient with cirrhosis and two in patients without cirrhosis, RR 1.23 (0.56-2.76). In conclusion, in this multicenter cohort study of concurrent DAA and DOAC use, MB was uncommon and there was no CRNMB. There was no significant difference in bleeding events among patients with cirrhosis compared to those without cirrhosis. These findings support the use of DAA among patients requiring DOAC., (© 2022 John Wiley & Sons Ltd.)

Objective: Prior literature has shown improved outcomes in morbidity and mortality for admitted patients cared for by female physicians. One theory is that female physicians adhere closely to guideline recommendations. We sought to determine whether patients who have out-of-hospital cardiac arrest (OHCA) experience more guideline-concordant postcardiac arrest care and potentially better outcomes based on the gender of their treating physician and gender distribution of the treatment teams. Methods: This study is a retrospective cohort study from the Colorado Cardiac Arrest Registry, local registry of OHCA patients treated at one academic urban tertiary care hospital. We analyzed adult OHCA patients who survived to hospital admission but were comatose. Patient demographic data and arrest characteristics were abstracted for subjects, and the gender of the provider was abstracted from the medical record. Results: Patients were admitted by a female attending in 28.5% of the cohort. The difference in guideline-concordant care between male and female providers was not significant. No statistical difference was found between all-male or mixed gender teams in adherence to guideline-concordant care. No patient was cared for by an all-female team. Neither gender of the admitting physician nor gender of the physician who led the family meeting to discuss prognosis was associated with a survival difference. Conclusions: Prior literature has described differences in outcome based on gender of the treating physician. Our analysis targeted a similar question in a cohort of OHCA patients with survival to hospital admission. We determined that there was no difference in postcardiac arrest guideline concordance and survival to hospital discharge based on treating physician gender. This finding differs from the prior literature and supports the importance of diverse clinical teams in medicine.

Type 1 diabetes is a polygenic disease that results in an autoimmune response directed against insulin-producing beta cells. PTPN2 is a known high-risk type 1 diabetes associated gene expressed in both immune- and pancreatic beta cells, but how genes affect the development of autoimmune diabetes is largely unknown. We employed CRISPR/Cas9 technology to generate a functional knockout of PTPN2 in human pluripotent stem cells (hPSC) followed by differentiating stem-cell-derived beta-like cells (sBC) and detailed phenotypical analyses. The differentiation efficiency of PTPN2 knockout (PTPN2 KO) sBC is comparable to wild-type (WT) control sBC. Global transcriptomics and protein assays revealed the increased expression of HLA Class I molecules in PTPN2 KO sBC at a steady state and upon exposure to proinflammatory culture conditions, indicating a potential for the increased immune recognition of human beta cells upon differential PTPN2 expression. sBC co-culture with autoreactive preproinsulin-reactive T cell transductants confirmed increased immune stimulations by PTPN2 KO sBC compared to WT sBC. Taken together, our results suggest that the dysregulation of PTPN2 expression in human beta cell may prime autoimmune T cell reactivity and thereby contribute to the development of type 1 diabetes.

High-income country (HIC) trainees are participating in research in low- and middle-income countries (LMIC) in increasing numbers, yet the ethical challenges they face have not been well described. We conducted a mixed methods study of U.S. graduate and undergraduate students who conducted research in LMIC, including an online survey and semi-structured interviews. Among 123 online survey respondents, 31% reported ethical challenges and nearly two-thirds of respondents did not feel well prepared to deal with ethical challenges. Qualitative analysis of the 17 semi-structure interviews and narrative survey responses revealed many themes of 'ethics in practice': challenges in setting research priorities, navigating relationships with host country partners, scope of research practice, and human subject protections. Respondents reported that pre-departure trainings were not reflective of ethical frameworks or research contexts in LMIC, and few described seeking host mentor help in addressing ethical challenges. These results suggest a need for improvements in training, oversight and mentorship of trainee researchers, and to further engage both HIC and LMIC institutions, educators and researchers in addressing ethical issues.

Melanoma is the third most common skin malignancy across all racial groups in the United States.1 While non-Hispanic white patients comprise the overwhelming majority of cases, morbidity and mortality remain disproportionately higher in minority populations.

Over the past decade, what is known about skin of color in the field of dermatology has gained an increasing amount of attention among both clinicians and the general public. Recent efforts have continued to shed light on the role of skin color in health disparities and the development of actionable strategies to improve outcomes for patients of color. While research has largely focused on conditions such as atopic dermatitis, psoriasis, and skin cancer, uncommon dermatologic conditions have been less emphasized in skin of color discussions thus far.

Importance: Antibiotics are commonly used to treat and prevent urinary tract infection (UTI), but resistance is growing. Nonantibiotic prophylaxis such as methenamine hippurate (MH) shows clinical promise, but its impact on bladder factors influencing recurrent UTIs (rUTIs) is not well described., Objective: The aim of the study was to examine the effect of MH on bladder inflammation and barrier function in aged mice and women with rUTI., Study Design: This study included urine samples from an experimental study involving aged female mice with and without methenamine treatment as well as women with rUTI who received either no prophylaxis, MH alone, vaginal estrogen therapy and/or d-mannose alone, or MH in addition to vaginal estrogen therapy and/or d-mannose. We performed a comprehensive cytopathological analysis, which included enzyme-linked immunosorbent assay for immunoglobulin A (IgA), interleukin 6 (in human samples), and fluorescein isothiocyanate-conjugated-dextran permeability assay (in mice) to assess for urothelial permeability., Results: In the aged mice model, there was a decreased urothelial permeability (as seen by retention of fluorescein isothiocyanate-conjugated-dextran fluorescence in superficial cells) and increased urinary IgA in mice treated with MH compared with controls. There was no significant difference in urothelial shedding (P > 0.05). In human samples, there was significantly increased urinary IgA in those taking MH alone compared with no prophylaxis (830.1 vs 540.1 ng/mL, P = 0.04), but no significant difference in interleukin 6., Conclusions: Methenamine hippurate seems to enhance barrier function as evidenced by decreased urothelial permeability and increased urinary IgA levels, without worsening inflammation. This may reflect another beneficial mechanism by which MH helps prevent rUTI., Competing Interests: The authors have declared they have no conflicts of interest., (Copyright © 2022 American Urogynecologic Society. All rights reserved.)

The developmental effects of chemicals that co-occur in vulnerable populations with elevated psychological stress are of increasing concern to the public. To investigate these concerns, we developed a rodent model of co-occurring perinatal manipulations and conducted a series of cognitive assessments in male and female offspring. Manganese (Mn), a neurodevelopmental toxicant when exceeding physiological requirements, was delivered in the drinking water (0, 2, or 4 mg Mn/mL) of rats from gestational day (GD) 7 to postnatal day (PND) 22. A variable perinatal stress paradigm was applied to half of the animals from GD13 to PND9. Novel object recognition (NOR), Morris water maze (MWM), differential reinforcement of low-rates procedure (DRL) and cued and uncued choice reaction time (CRT) tests were used to assess cognitive functions in offspring. Mn (4 mg/mL) and stress impaired NOR in adolescent males but facilitated NOR performance in females. However, when stress and Mn were combined these effects were attenuated in both sexes. During training for the DRL, Mn (2 mg/mL) facilitated, while stress impaired, lever press learning in both sexes. Few effects related to the treatments were found on DRL or MWM. During cued CRT, Mn (2 and 4 mg/mL) and stress reduced accuracy in males, while stress and Mn (2 mg/mL) increased anticipatory responding and slowed decision time in both sexes. Stress combined with Mn (2 mg/mL) improved cued accuracy and decision time, and Mn attenuated the effect of stress on anticipatory responding in both sexes. Stress slowed female movement time but when combined with Mn (4 mg/mL) the effect of stress was attenuated. During uncued CRT, except for decision time (which replicated effects observed with the cued task), no other effects of Mn or its combination with stress occurred. Females remained negatively affected by stress in most uncued CRT performance measures, while stressed improved male uncued accuracy. Taken together these data do not support increased cognitive impairment produced by Mn when combined with stress. However, the effects of perinatal stress alone, on these cognitive functions may hinder the detection of effects due to chemical exposures and underscores the need to consider the psychological health and wellbeing of the mother and her environment in risk assessment for developmental neurotoxicity of chemicals., (Published by Elsevier Inc.)

Introduction: Trauma is ubiquitous and associated with negative effects on physical and mental health. Trauma-informed care (TIC) is a framework for mitigating these health effects and improving patients' engagement with medical care. Despite these clinical benefits, TIC is not routinely taught in undergraduate medical education., Methods: We designed a session for first-year medical and dental students to introduce TIC principles and their application in patient care. The session focused on screening for and inquiring about trauma and responding to disclosures of trauma. Using live patient interviews, small-group discussions, and case-based role-plays, the session offered expert instruction and hands-on practice. Students completed pre- and postsession surveys and a 5-month follow-up survey. Students reported their comfort with screening for trauma and responding to disclosures of trauma before and after the session and at 5 months following the session., Results: Of the 164 student participants, 76% completed surveys during the session, and 50% completed the follow-up survey. More than one-third (34%) of respondents reported having received at least one disclosure of trauma from a patient within the first 5 months of medical school. Students' comfort with screening for trauma increased from 30% to 56%, and their comfort with responding to disclosure of trauma increased from 35% to 55%. These improvements persisted on reevaluation at 5 months., Discussion: We present a model for teaching trauma-informed communication skills to first-year medical and dental students. The intervention significantly increased students' comfort level and self-reported clinical skills, and benefits persisted at 5 months., (© 2021 Brown et al.)

The majority of patients and medical students experience some form of psychological trauma or adversity across their life course. All forms of trauma can be associated with adverse health consequences and can negatively affect learning and professional development. Trauma-informed care (TIC) offers a framework to address and mitigate these consequences and promote safety and health. The Substance Abuse and Mental Health Services Administration describes 6 domains of TIC: safety; trust and transparency; peer support; collaboration and mutuality; empowerment, voice, and choice; and cultural, historic, and gender issues. At present, TIC is not taught routinely in undergraduate medical education (UME)-a crucial educational gap given that UME grounds the development of key perspectives and practices that students use throughout their careers. Further, given the prevalence of preexisting trauma among learners and the likelihood of new traumatic exposures during training, medical schools' processes, practices, and learning environments may risk exacerbating or even causing trauma. To address this educational need and support students and their future patients, the authors propose a trauma-informed medical education (TIME) framework. TIME informs medical schools' curricular content and educational context. In UME, curricular content should address trauma epidemiology, physiology, and effects; trauma-informed clinical skills including sensitive communication and physical exam techniques; and trauma-informed self-care techniques including education on organizational resources, how to elicit supports, and personal self-care practices. A trauma-informed educational context encompasses curricular development, including student-faculty coproduction of educational content; curricular delivery, including faculty development on TIC principles; and learning environment, including trauma-informed educational practices, medical student advising, institutional policies, and recruitment. TIME offers practical strategies to support teaching, learning, educational administration, and professional development and aims to inspire new strategies for effective learner and faculty engagement. TIME aims to foster students' development of competency in TIC and promote student engagement, learning, health, and well-being., (Copyright © 2020 by the Association of American Medical Colleges.)

Objective: To evaluate the impact of visually significant blepharoptosis and dermatochalasis on driving safety and performance. Patients with visually significant blepharoptosis often complain of difficulty with driving, but the impact of blepharoptosis on driving has not been evaluated in a real-world setting., Methods: Retrospective cohort study of 610 consecutive adult patients undergoing bilateral functional blepharoplasty or ptosis repair surgery at a single, University-based practice between 2014 and 2017. This cohort had a median age of 65 and was predominantly female. Pre-operative rates of motor vehicle collisions (MVCs) and moving violations (MVs) extracted from state Department of Transportation (DOT) records were compared with post-operative rates, using each patient as their own control. Poisson models were used for analysis., Results: Subjects were included in the study for a median of 730 days before eyelid surgery (IQR 346 - 730) and 783 days after surgery (IQR 449 - 1176). There were 30 total MVCs before surgery (0.024 per subject, per year) and 48 after surgery (0.036 per subject, per year) (p = 0.08). There were 81 MVs before surgery (0.065 per subject, per year) and 66 after (0.049 per subject, per year) (p = 0.11). The multivariable model comparing MVCs pre- versus post-surgery adjusting for age, ptosis severity, gender, and comorbidities yields a rate ratio of 0.63 (p = 0.05). The multivariable model comparing MVs pre- versus post-surgery demonstrates a rate-ratio of 1.2 (p = 0.20). Older age was associated with lower rates of moving violations (coefficient of -0.03, p < 0.01). None of the other variables included in the final models had a significant association with MVCs or MVs., Conclusions: In this cohort, visually significant blepharoptosis and dermatochalasis were not associated with rates of MVCs or MVs. Further work is needed to study the impact of these common conditions on driving, for example adjusting MVC and MV rates by miles driven, which may influence decisions about when to operate on ptotic eyelids.

Bovine respiratory disease (BRD) is the costliest disease affecting the cattle industry globally. Orthomyxoviruses, influenza C virus (ICV) and influenza D virus (IDV) have recently been implicated to play a role in BRD. However, there are contradicting reports about the association of IDV and ICV to BRD. Using the largest cohort study (cattle, n = 599) to date we investigated the association of influenza viruses in cattle with BRD. Cattle were scored for respiratory symptoms and pooled nasal and pharyngeal swabs were tested for bovine viral diarrhea virus, bovine herpesvirus 1, bovine respiratory syncytial virus, bovine coronavirus, ICV and IDV by real-time PCR. Cattle that have higher viral loads of IDV and ICV also have greater numbers of co-infecting viruses than controls. More strikingly, 2 logs higher IDV viral RNA in BRD-symptomatic cattle that are co-infected animals than those infected with IDV alone. Our results strongly suggest that ICV and IDV may be significant contributors to BRD., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: Metoprolol succinate is a long-acting beta-blocker prescribed for the management of hypertension (HTN) and other cardiovascular diseases. Metabolomics, the study of end-stage metabolites of upstream biologic processes, yield insight into mechanisms of drug effectiveness and safety. Our aim was to determine metabolomic profiles associated with metoprolol effectiveness for the treatment of hypertension., Methods: We performed a prospective pragmatic trial (NCT02293096) that enrolled patients between 30 and 80 years with uncontrolled HTN. Patients were started on metoprolol succinate at a dose based upon systolic blood pressure (SBP). Urine and blood pressure measurements were collected weekly. Individuals with a 10% decline in SBP or heart rate (HR) were considered responsive. Genotype for the CYP2D6 enzyme, the primary metabolic pathway for metoprolol, was evaluated for each subject. Unbiased metabolomic analyses were performed on urine samples using UPLC-QTOF mass spectrometry., Results: Urinary metoprolol metabolite ratios are indicative of patient CYP2D6 genotypes. Patients taking metoprolol had significantly higher urinary levels of many gut microbiota-dependent metabolites including hydroxyhippuric acid, hippuric acid, and methyluric acid. Urinary metoprolol metabolite profiles of normal metabolizer (NM) patients more closely correlate to ultra-rapid metabolizer (UM) patients than NM patients. Metabolites did not predict either 10% SBP or HR decline., Conclusion: In summary, urinary metabolites predict CYP2D6 genotype in hypertensive patients taking metoprolol. Metoprolol succinate therapy affects the microbiome-derived metabolites.

Objective: The incidence of type 1 diabetes (T1D) is increasing, most notably in young children and in racial and ethnic minorities. Historically, screening for risk with T1D-associated antibodies has been limited to those with a family history, while up to 90% of newly diagnosed patients lack such a family history. To address the needs to screen diverse ethnic groups in the general population, we screened children for T1D-associated antibodies in the Denver, Colorado metro area at community health fairs., Methods: Children attending health fairs from 2015 to 2018 were offered free T1D screening by measuring the four prototypical T1D-associated antibodies. A finger stick capillary puncture was performed to collect blood spots on filter paper. Dried blood spots (DBSs) were eluted and antibodies were measured using fluid-phase radio-binding assays., Results: At 39 health fairs, children were educated on the signs and symptoms of diabetes, and screened for T1D-associated antibodies (n = 478), which represented 90% of those that attended. Median age was 9.0 years (range of 1-18) with diverse ethnic backgrounds: 37% Hispanic, 31% Caucasian, 20% African American, and 12% other. Nine children screened positive for antibodies, single n = 8 and multiple n = 1, and confirmation with serum samples showed excellent correlation to the measurements from DBSs for antibodies directed against GAD, IA-2, and ZnT8 (P < .01 for each)., Conclusions: Screening for T1D risk at community health fairs using DBSs on filter paper is feasible and provides an avenue to screen children from ethnically diverse backgrounds., (© 2019 The Authors. Pediatric Diabetes published by John Wiley & Sons Ltd.)

Gallbladder mucocele (GBM) is a common extra-hepatic biliary syndrome in dogs with death rates ranging from 7 to 45%. Therefore, the aim of this study was to identify the association of survival with variables that could be utilized to improve clinical decisions. A total of 1194 dogs with a gross and histopathological diagnosis of GBM were included from 41 veterinary referral hospitals in this retrospective study. Dogs with GBM that demonstrated abnormal clinical signs had significantly greater odds of death than subclinical dogs in a univariable analysis (OR, 4.2; 95% CI, 2.14-8.23; P<0.001). The multivariable model indicated that categorical variables including owner recognition of jaundice (OR, 2.12; 95% CI, 1.19-3.77; P=0.011), concurrent hyperadrenocorticism (OR 1.94; 95% CI, 1.08-3.47; P=0.026), and Pomeranian breed (OR, 2.46; 95% CI 1.10-5.50; P=0.029) were associated with increased odds of death, and vomiting was associated with decreased odds of death (OR, 0.48; 95% CI, 0.30-0.72; P=0.001). Continuous variables in the multivariable model, total serum/plasma bilirubin concentration (OR, 1.03; 95% CI, 1.01-1.04; P<0.001) and age (OR, 1.17; 95% CI, 1.08-1.26; P<0.001), were associated with increased odds of death. The clinical utility of total serum/plasma bilirubin concentration as a biomarker to predict death was poor with a sensitivity of 0.61 (95% CI, 0.54-0.69) and a specificity of 0.63 (95% CI, 0.59-0.66). This study identified several prognostic variables in dogs with GBM including total serum/plasma bilirubin concentration, age, clinical signs, concurrent hyperadrenocorticism, and the Pomeranian breed. The presence of hypothyroidism or diabetes mellitus did not impact outcome in this study., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Purpose: To identify the incidence of endophthalmitis and visual outcomes in eyes with Boston type 1 keratoprosthesis combined with pars plana vitrectomy and silicone oil insertion (KPro + PPV + SOI) as compared to eyes receiving Boston type 1 keratoprosthesis (KPro) alone., Patients and Methods: Retrospective chart review of 29 eyes of 27 patients with KPro having at least 12-month follow-up. Thirteen of these eyes had hypotony and/or retinal detachment in addition to corneal pathology and thus received KPro + PPV + SOI. Polymyxin-trimethoprim with a quinolone was used as chronic topical antibiotic prophylaxis in both groups after the first postoperative month. Outcome measures recorded at the 1-, 3-, 6-, 12-, and 24-month follow-up visits included best-corrected visual acuity (BCVA) and rates of postoperative complications., Results: All the patients had completed 24-month follow-up except one case in the KPro group who lost to follow-up after 12-month visit. In the KPro + PPV + SOI group, no eyes had developed endophthalmitis by the 24-month follow-up visit versus 5 eyes of 5 patients in the uncombined KPro group ( P =0.048). The 2-year cumulative endophthalmitis incidence was 31.2% in the KPro group versus zero in the KPro + PPV + SOI group ( P =0.030). Four of these 5 eyes had vitreous taps with positive cultures; 2 were positive with Staphylococcus aureus , 1 with coagulase-negative staphylococci, and 1 with Streptococcus pneumoniae . Other complications included KPro extrusion (1 in each group), retinal detachment (2 in the KPro and 1 in the KPro + PPV + SOI group), newly developed glaucoma (2 in each group), and retroprosthetic membrane (9 in the KPro and 5 in the KPro + PPV + SOI group). The KPro group had better average preoperative BCVA compared to those of the KPro + PPV + SOI group (-2.29 ± 0.72 LogMAR, versus -2.95 ± 0.30 LogMAR; P =0.004). No statistically significant difference in BCVA was noted in subsequent follow-up visits., Conclusion: The addition of PPV and SOI to the KPro implantation in the eyes with corneal pathology, as well as hypotony and/or retinal detachment, is a safe and effective procedure for visual rehabilitation. Pars plana vitrectomy and silicone oil insertion may have a protective effect against the development of postoperative endophthalmitis in eyes receiving KPro., Competing Interests: The authors declare that there are no conflicts of interest.

This initiative increased patient acceptance of controlled substance agreements and random urine drug screening, and it led many patients to discontinue opioid therapy.

Cholangiopathies are diseases that affect cholangiocytes, the cells lining the biliary tract. Liver stem cells (LSCs) are able to differentiate into all cells of the liver and possibly influence the surrounding liver tissue by secretion of signaling molecules. One way in which cells can interact is through secretion of extracellular vesicles (EVs), which are small membrane-bound vesicles that contain proteins, microRNAs (miRNAs), and cytokines. We evaluated the contents of liver stem cell-derived EVs (LSCEVs), compared their miRNA contents to those of EVs isolated from hepatocytes, and evaluated the downstream targets of these miRNAs. We finally evaluated the crosstalk among LSCs, cholangiocytes, and human hepatic stellate cells (HSCs). We showed that LSCEVs were able to reduce ductular reaction and biliary fibrosis in multidrug resistance protein 2 (MDR2) -/- mice. Additionally, we showed that cholangiocyte growth was reduced and HSCs were deactivated in LSCEV-treated mice. Evaluation of LSCEV contents compared with EVs derived from hepatocytes showed a large increase in the miRNA, lethal-7 (let-7). Further evaluation of let-7 in MDR2 -/- mice and human primary sclerosing cholangitis samples showed reduced levels of let-7 compared with controls. In liver tissues and isolated cholangiocytes, downstream targets of let-7 (identified by ingenuity pathway analysis), Lin28a (Lin28 homolog A), Lin28b (Lin28 homolog B), IL-13 (interleukin 13), NR1H4 (nuclear receptor subfamily 1 group H member 4) and NF-κB (nuclear factor kappa B), are elevated in MDR2 -/- mice, but treatment with LSCEVs reduced levels of these mediators of ductular reaction and biliary fibrosis through the inhibition of NF-κB and IL-13 signaling pathways. Evaluation of crosstalk using cholangiocyte supernatants from LSCEV-treated cells on cultured HSCs showed that HSCs had reduced levels of fibrosis and increased senescence. Conclusion: Our studies indicate that LSCEVs could be a possible treatment for cholangiopathies or could be used for target validation for future therapies., (© 2019 by the American Association for the Study of Liver Diseases.)

Background & Aims: Transmembrane protein 173 (TMEM173 or STING) signaling by macrophage activates the type I interferon-mediated innate immune response. The innate immune response contributes to hepatic steatosis and non-alcoholic fatty liver disease (NAFLD). We investigated whether STING regulates diet-induced in hepatic steatosis, inflammation, and liver fibrosis in mice., Methods: Mice with disruption of Tmem173 (STING gt ) on a C57BL/6J background, mice without disruption of this gene (controls), and mice with disruption of Tmem173 only in myeloid cells were fed a standard chow diet, a high-fat diet (HFD; 60% fat calories), or a methionine- and choline-deficient diet (MCD). Liver tissues were collected and analyzed by histology and immunohistochemistry. Bone marrow cells were isolated from mice, differentiated into macrophages, and incubated with 5,6-dimethylxanthenone-4-acetic acid (DMXAA; an activator of STING) or cyclic guanosine monophosphate-adenosine monophosphate (cGAMP). Macrophages or their media were applied to mouse hepatocytes or human hepatic stellate cells (LX2) cells, which were analyzed for cytokine expression, protein phosphorylation, and fat deposition (by oil red O staining after incubation with palmitate). We obtained liver tissues from patients with and without NAFLD and analyzed these by immunohistochemistry., Results: Non-parenchymal cells of liver tissues from patients with NAFLD had higher levels of STING than cells of liver tissues from patients without NAFLD. STING gt mice and mice with disruption only in myeloid cells developed less severe hepatic steatosis, inflammation, and/or fibrosis after the HFD or MCD than control mice. Levels of phosphorylated c-Jun N-terminal kinase and p65 and mRNAs encoding tumor necrosis factor and interleukins 1B and 6 (markers of inflammation) were significantly lower in liver tissues from STING gt mice vs control mice after the HFD or MCD. Transplantation of bone marrow cells from control mice to STING gt mice restored the severity of steatosis and inflammation after the HFD. Macrophages from control, but not STING gt , mice increased markers of inflammation in response to lipopolysaccharide and cGAMP. Hepatocytes and stellate cells cocultured with STING gt macrophages in the presence of DMXAA or incubated with the medium collected from these macrophages had decreased fat deposition and markers of inflammation compared with hepatocytes or stellate cells incubated with control macrophages., Conclusions: Levels of STING were increased in liver tissues from patients with NAFLD and mice with HFD-induced steatosis. In mice, loss of STING from macrophages decreased the severity of liver fibrosis and the inflammatory response. STING might be a therapeutic target for NAFLD., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Adenosine 2A receptor (A2AR) exerts anti-inflammatory effects. However, the role of A2AR in obesity-associated adipose tissue inflammation remains to be elucidated. The present study examined the expression of A2AR in adipose tissue of mice with diet-induced obesity and determined the effect of A2AR disruption on the status of obesity-associated adipose tissue inflammation. WT C57BL/6J mice and A2AR-disrupted mice were fed a high-fat diet (HFD) for 12 weeks to induce obesity and adipose tissue inflammation. In vitro, bone marrow-derived macrophages from A2AR-disrupted mice and WT control mice were treated with palmitate and examined for macrophage proinflammatory activation. Compared with that of low-fat diet (LFD)-fed WT mice, A2AR expression in adipose tissue of HFD-fed WT mice was increased significantly and was present predominantly in adipose tissue macrophages. The increase in adipose tissue A2AR expression in HFD-fed mice was accompanied with increased phosphorylation states of c-Jun N-terminal kinase 1 p46 and nuclear factor kappa B p65 and mRNA levels of interleukin (Il)-1beta, Il6 and tumor necrosis factor alpha. In A2AR-disrupted mice, HFD feeding induced significant increases in adipose tissue inflammation, indicated by enhanced proinflammatory signaling and increased proinflammatory cytokine expression, and adipose tissue insulin resistance, indicated by a decrease in insulin-stimulated Akt phosphorylation relative to those in WT mice. Lastly, A2AR disruption enhanced palmitate-induced macrophage proinflammatory activation. Taken together, these results suggest that A2AR plays a protective role in obesity-associated adipose tissue inflammation, which is attributable to, in large part, A2AR suppression of macrophage proinflammatory activation.

microRNA-21 (miRNA) is one of the most abundant miRNAs in chronic liver injuries including alcoholic liver injury. Previous studies have demonstrated that miR-21 plays a role in inflammation in the liver and functions in hepatic stellate cells (HSCs), which reside in the perisinusoidal space between sinusoidal endothelial cells and hepatocytes and regulate sinusoidal circulation. HSCs integrate cytokine-mediated inflammatory responses in the sinusoids and relay them to the liver parenchyma. Here, we showed that the activation of Von Hippel-Lindau (VHL) expression, by miR-21 knockout in vivo and anti-miR-21 or VHL overexpression in vitro, suppressed the production of proinflammatory cytokines, such as interleukin (IL)-6, monocyte chemoattractant protein-1, and IL-1β, in human HSCs during alcoholic liver injury. Sequence and functional analyses confirmed that miR-21 directly targeted the 3'-untranslated region of VHL. Immunofluorescence and real-time PCR analysis revealed that miR-21 depletion blocked NF-κB activation in human HSCs both in cultured HSCs as well as HSCs isolated from alcohol-related liver disease mice liver by laser capture microdissection. We also showed that conditioned medium from anti-miR-21-transfected HSCs suppressed human monocyte-derived THP-1 cell migration. Taken together, our study indicates that depletion of miR-21 may downregulate cytokine production in HSCs and macrophage chemotaxis during alcoholic liver injury and that the targeting of miR-21 may have therapeutic potential for preventing the progression of alcoholic liver diseases. NEW & NOTEWORTHY This study demonstrates that silencing microRNA-21 can inhibit cytokine production and inflammatory responses in human hepatic stellate cells during alcoholic liver injury and that the targeting of microR-21 in hepatic stellate cells may have therapeutic potential for prevention and treatment of alcoholic liver diseases.

Myopericytomas are rare benign tumors that show a distinctive, concentric perivascular proliferation of oval to spindle-shaped myoid-appearing cells that are predominantly arranged concentrically around thin-walled vascular channels. These lesions are similar in histologic appearance to hemangiopericytomas, myofibromas, and glomus tumors. The myopericytoma is usually found in the distal extremities, but a handful of reports have shown the lesion to be present in the oral cavity. A review of the literature to date shows only 4 other reported cases of myopericytomas occurring in the lips. We describe a case of myopericytoma in the lower lip of a 42-year-old woman., (Published by Elsevier Inc.)

The development of the peripheral nervous system relies on long-distance signaling from target organs back to the soma. In sympathetic neurons, this long-distance signaling is mediated by target derived Nerve Growth Factor (NGF) interacting with its axonal receptor, TrkA. This ligand receptor complex internalizes into what is commonly referred to as the signaling endosome which is transported retrogradely to the soma and dendrites to mediate survival signaling and synapse formation, respectively. The molecular identity of signaling endosomes in dendrites has not yet been determined. Here, we perform a detailed analysis of TrkA endosomal compartments and trafficking patterns. We find that signaling endosomes are not uniform but molecularly diversified into Rab7 (late endosome) and Rab11 (recycling endosome) populations in axons and dendrites in vitro and in the soma in vivo. Surprisingly, TrkA-NGF signaling endosomes in dendrites undergo dynamic trafficking events, including putative fusion and fission. Overall, we find that signaling endosomes do not remain as a singular endosomal subtype but instead exist in multiple populations that undergo dynamic endosomal trafficking events. These dynamic events might drive functional diversification of the signaling endosome.

Background: Use of new psychoactive substances (NPS) has increased over the last decade. During this period, variability of both clinical presentations and chemical compositions of these compounds has increased. Synthetic cannabinoids (SCs) are the most commonly used NPS and there are more than 100 documented unique molecules in this class. "Black Mamba", often associated to ADB-FUBINACA, is the most commonly used SC in Colorado. It has been linked to kidney injury, myocardial toxicity, seizures, and death., Objectives: We aim to identify the chemical constituents and quantification of eight cases of reported "Black Mamba" use in order to further understand the clinical variability in patients presenting for emergency stabilization., Methods: We report data from eight cases of reported "Black Mamba" use prospectively captured through the Colorado site of the Psychoactive Surveilance Consortium and Analysis Network (P SCAN). P SCAN is a geographically representative group of academic hospitals that capture clinical presentation, outcome, and biologic samples from patients that present for emergency stabilization following NPS use. Serum and urine samples were analyzed and quantified by liquid chromatography-quadrupole time-of-flight mass spectrometry after a qualitative screen for over 600 unique NPS compounds., Results: In the reported eight cases, the median age was 28 years old. There were four male and four females. Four patients had agitation/delirium and four patients had chest pain. Normal saline, benzodiazepines and ondansetron were the common treatment provided in the emergency department (ED). Two patients were discharged from the ED and six patients being admitted for emergency observation with a median length of stay (LOS) of six hours. No deaths were reported. Confirmatory testing revealed that only five patients (62.5%) had SCs found in blood or urine samples. Cocaine, NRG-3, 3-methoxyphencyclidine hydrochloride (MeO-PCP), and methamfetamine were identified in other presentations., Conclusions: The wide range of clinical presentations from "Black Mamba" use may be explained by the wide variability of chemical constituents found by laboratory analysis.

ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/) is a freely available, public archive of human genetic variants and interpretations of their significance to disease, maintained at the National Institutes of Health. Interpretations of the clinical significance of variants are submitted by clinical testing laboratories, research laboratories, expert panels and other groups. ClinVar aggregates data by variant-disease pairs, and by variant (or set of variants). Data aggregated by variant are accessible on the website, in an improved set of variant call format files and as a new comprehensive XML report. ClinVar recently started accepting submissions that are focused primarily on providing phenotypic information for individuals who have had genetic testing. Submissions may come from clinical providers providing their own interpretation of the variant ('provider interpretation') or from groups such as patient registries that primarily provide phenotypic information from patients ('phenotyping only'). ClinVar continues to make improvements to its search and retrieval functions. Several new fields are now indexed for more precise searching, and filters allow the user to narrow down a large set of search results., (Published by Oxford University Press on behalf of Nucleic Acids Research 2017.)

Purpose: Undergraduate capstone courses are culminating experiences that allow seniors to integrate and demonstrate the knowledge and skills gained during undergraduate studies. To date, there are no published studies about capstone course standards/designs in the discipline of communication sciences and disorders (CSD). The purpose of this study was to determine what capstone experiences are considered critical for CSD undergraduates., Method: Faculty from CSD programs nationwide were asked to rank-order 15 potential learning objectives (suitable to a senior capstone) based on their relative importance from most important to least important. Some respondents provided feedback, which was optional., Results: Sixty-four CSD faculty responded to the nationally distributed survey. The three highest ranked objectives for capstone courses were: written and oral communication proficiency, understanding of human communication, and understanding theories of learning from a multidisciplinary perspective. Undergraduate research experiences received the lowest rankings., Conclusion: Survey results and faculty feedback are discussed in the context of the standards expected of a capstone course, undergraduate requirements in CSD, and enhancing student interest in research. The degree to which students are being prepared for evidence-based practice, the doctoral shortage, and the challenges to master's programs are also discussed.

Alcoholic liver disease remains a major cause of liver-related morbidity and mortality, which ranges from alcoholic steatohepatitis to fibrosis/cirrhosis and hepatocellular carcinoma, and the related mechanisms are understood poorly. In this study, we aimed to investigate the role of miR-34a in alcohol-induced cellular senescence and liver fibrosis. We found that hepatic miR-34a expression was upregulated in ethanol-fed mice and heavy drinkers with steatohepatitis compared with respective controls. Mice treated with miR-34a Vivo-Morpholino developed less severe liver fibrosis than wild-type mice after 5 weeks of ethanol feeding. Further mechanism exploration showed that inhibition of miR-34a increased cellular senescence of hepatic stellate cells (HSCs) in ethanol-fed mice, although it decreased senescence in total liver and hepatocytes, which was verified by the changes of senescence-associated β-galactosidase and gene expression. Furthermore, enhanced cellular senescence was observed in liver tissues from steatohepatitis patients compared with healthy controls. In addition, the expression of transforming growth factor-β1, drosophila mothers against decapentaplegic protein 2 (Smad2), and Smad3 was decreased after inhibition of miR-34a in ethanol-fed mice. Our in vitro experiments showed that silencing of miR-34a partially blocked activation of HSCs by lipopolysaccharide and enhanced senescence of HSCs. Furthermore, inhibition of miR-34a decreased lipopolysaccharide-induced fibrotic gene expression in cultured hepatocytes. In conclusion, our data suggest that miR-34a functions as a profibrotic factor that promotes alcohol-induced liver fibrosis by reducing HSC senescence and increasing the senescence of hepatocytes., (Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Background: The prevalence of sexual dysfunction (SDx) diagnoses in primary care settings is not well known, which is a concern because of the high prevalence of comorbid chronic health conditions in patients diagnosed with SDx., Aim: To explore the relation of SDx diagnosis, chronic health conditions, and prescription medications commonly associated with SDx for men and women in primary care using medical records diagnoses., Methods: Exploratory descriptive analyses were used to interpret secondary data from a primary care patient database. The database included patient data from 3 family and internal medicine clinics in the St Louis metropolitan area from July 1, 2008 to June 30, 2015. Analysis included key demographic variables, chronic illness, and health conditions of hypertension, pain, prostate disorder, menopause, substance abuse, depression, anxiety, and associated medications. Analysis of the database yielded 30,627 adult patients (men: n = 12,097, mean age = 46.8 years, 65.6% white race; women: n = 18,530, mean age = 46.6 years, 59.2% white race) with significant comorbid associations between SDx and other chronic illness, health conditions, and medication prescription., Results: Depression, anxiety, pain, hypertension, diabetes, and psychotropic medication use were significantly associated with SDx for men and women. Examination of specific SDx diagnoses showed erectile dysfunction to be significantly associated with all tested variables for men. For women, pain-related SDx diagnoses were associated more with chronic illness, health conditions, and medication use than were psychosexual SDx diagnoses (eg, orgasm), except for menopause. Prevalence varied by sex, with a higher prevalence rate of any SDx for men (13.5%) than for women (1.0%), although sex comparisons were not part of the analytics., Clinical Translation: This study suggests the diagnosis of SDx is closely associated with other common chronic illness and health conditions and could go underdiagnosed in women in primary care., Strengths and Limitations: The cross-sectional nature of the study limits the ability to draw causal conclusions related to the nature of the associated conditions with SDx diagnoses. The generalizability of the findings also might be limited given the specific demographic or health makeup of the St Louis area where the study was conducted., Conclusion: The high comorbidity of SDx with mental health, chronic pain and illnesses, and medication use adds to the growing evidence that sexual health and functioning are essential components of overall well-being and holistic care for men and women. Heiden-Rootes KM, Salas J, Gebauer S, et al. Sexual Dysfunction in Primary Care: An Exploratory Descriptive Analysis of Medical Record Diagnoses. J Sex Med 2017;14:1318-1326., (Copyright © 2017 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Potential cost-effective barriers in cost-effectiveness studies mean that budgetary impact analyses should also be included in post-2015 Sustainable Development Goal projects says Joshua Salomon and colleagues.

The let-7/Lin28 axis is associated with the regulation of key cellular regulatory genes known as microRNAs in various human disorders and cancer development. This study evaluated the role of the let-7/Lin28 axis in regulating a mesenchymal phenotype of hepatic stellate cells in alcoholic liver injury. We identified that ethanol feeding significantly down-regulated several members of the let-7 family in mouse liver, including let-7a and let-7b. Similarly, the treatment of human hepatic stellate cells (HSCs) with lipopolysaccharide (LPS) and transforming growth factor-β (TGF-β) significantly decreased the expressions of let-7a and let-7b. Conversely, overexpression of let-7a and let-7b suppressed the myofibroblastic activation of cultured human HSCs induced by LPS and TGF-β, as evidenced by repressed ACTA2 (α-actin 2), COL1A1 (collagen 1A1), TIMP1 (TIMP metallopeptidase inhibitor 1), and FN1 (fibronectin 1); this supports the notion that HSC activation is controlled by let-7. A combination of bioinformatics, dual-luciferase reporter assay, and Western blot analysis revealed that Lin28B and high-mobility group AT-hook (HMGA2) were the direct targets of let-7a and let-7b. Furthermore, Lin28B deficiency increased the expression of let-7a/let-7b as well as reduced HSC activation and liver fibrosis in mice with alcoholic liver injury. This feedback regulation of let-7 by Lin28B is verified in hepatic stellate cells isolated by laser capture microdissection from the model. The identification of the let-7/Lin28 axis as an important regulator of HSC activation as well as its upstream modulators and down-stream targets will provide insights into the involvement of altered microRNA expression in contributing to the pathogenesis of alcoholic liver fibrosis and novel therapeutic approaches for human alcoholic liver diseases., (© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.)

Hepatic fibrosis occurs during the progression of primary sclerosing cholangitis (PSC) and is characterized by accumulation of extracellular matrix proteins. Proliferating cholangiocytes and activated hepatic stellate cells (HSCs) participate in the promotion of liver fibrosis during cholestasis. Gonadotropin-releasing hormone (GnRH) is a trophic peptide hormone synthesized by hypothalamic neurons and the biliary epithelium and exerts its biological effects on cholangiocytes by interaction with the receptor subtype (GnRHR 1 ) expressed by cholangiocytes and HSCs. Previously, we demonstrated that administration of GnRH to normal rats increased intrahepatic biliary mass (IBDM) and hepatic fibrosis. Also, miR-200b is associated with the progression of hepatic fibrosis; however, the role of the GnRH/GnRHR 1 /miR-200b axis in the development of hepatic fibrosis in PSC is unknown. Herein, using the mouse model of PSC (multidrug resistance gene 2 knockout), the hepatic knockdown of GnRH decreased IBDM and liver fibrosis. In vivo and in vitro administration of GnRH increased the expression of miR-200b and fibrosis markers. The GnRH/GnRHR 1 axis and miR-200b were up-regulated in human PSC samples. Cetrorelix, a GnRHR 1 antagonist, inhibited the expression of fibrotic genes in vitro and decreased IBDM and hepatic fibrosis in vivo. Inhibition of miR-200b decreased the expression of fibrosis genes in vitro in cholangiocyte and HSC lines. Targeting the GnRH/GnRHR 1 /miR-200b axis may be key for the management of hepatic fibrosis during the progression of PSC., (Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)