CDK12 phosphorylates 4E-BP1 to enable mTORC1-dependent translation and mitotic genome stability.

The RNA polymerase II (RNAPII) C-terminal domain kinase, CDK12, regulates genome stability, expression of DNA repair genes, and cancer cell resistance to chemotherapy and immunotherapy. In addition to its role in mRNA biosynthesis of DNA repair genes, we show here that CDK12 phosphorylates the mRNA 5' cap-binding repressor, 4E-BP1, to promote translation of mTORC1-dependent mRNAs. In particular, we found that phosphorylation of 4E-BP1 by mTORC1 (T37 and T46) facilitates subsequent CDK12 phosphorylation at two Ser-Pro sites (S65 and T70) that control the exchange of 4E-BP1 with eIF4G at the 5' cap of CHK1 and other target mRNAs. RNA immunoprecipitation coupled with deep sequencing (RIP-seq) revealed that CDK12 regulates release of 4E-BP1, and binding of eIF4G, to many mTORC1 target mRNAs, including those needed for MYC transformation. Genome-wide ribosome profiling (Ribo-seq) further identified specific CDK12 "translation-only" target mRNAs, including many mTORC1 target mRNAs as well as many subunits of mitotic and centromere/centrosome complexes. Accordingly, confocal imaging analyses revealed severe chromosome misalignment, bridging, and segregation defects in cells deprived of CDK12 or CCNK. We conclude that the nuclear RNAPII-CTD kinase CDK12 cooperates with mTORC1, and controls a specialized translation network that is essential for mitotic chromosome stability.

YAP repression of the WNT3 gene controls hESC differentiation along the cardiac mesoderm lineage.

Activin/SMAD signaling in human embryonic stem cells (hESCs) ensures NANOG expression and stem cell pluripotency. In the presence of Wnt ligand, the Activin/SMAD transcription network switches to cooperate with Wnt/ß-catenin and induce mesendodermal (ME) differentiation genes. We show here that the Hippo effector YAP binds to the WNT3 gene enhancer and prevents the gene from being induced by Activin in proliferating hESCs. ChIP-seq (chromatin immunoprecipitation [ChIP] combined with high-throughput sequencing) data show that YAP impairs SMAD recruitment and the accumulation of P-TEFb-associated RNA polymerase II (RNAPII) C-terminal domain (CTD)-Ser7 phosphorylation at the WNT3 gene. CRISPR/CAS9 knockout of YAP in hESCs enables Activin to induce Wnt3 expression and stabilize ß-catenin, which then synergizes with Activin-induced SMADs to activate a subset of ME genes that is required to form cardiac mesoderm. Interestingly, exposure of YAP-/- hESCs to Activin induces cardiac mesoderm markers (BAF60c and HAND1) without activating Wnt-dependent cardiac inhibitor genes (CDX2 and MSX1). Moreover, canonical Wnt target genes are up-regulated only modestly, if at all, under these conditions. Consequently, YAP-null hESCs exposed to Activin differentiate precisely into beating cardiomyocytes without further treatment. We conclude that YAP maintains hESC pluripotency by preventing WNT3 expression in response to Activin, thereby blocking a direct route to embryonic cardiac mesoderm formation.

The effect of dietary anthocyanins on biochemical, physiological, and subjective exercise recovery: a systematic review and meta-analysis.

Anthocyanins (ACN), the sub-class of (poly)phenols responsible for the red-blue-purple pigmentation of fruit and vegetables, have gained considerable interest in sport and exercise research due to their potential to facilitate exercise recovery. A systematic literature search was performed using PubMed, The Cochrane Library, MEDLINE, SPORTDiscus and CINAHL. Thirty nine studies were included and the standardized mean difference (Hedges g) for creatine kinase (CK), anti-oxidative and inflammatory markers, strength, power and delayed onset muscle soreness (DOMS) indices were pooled in separate meta-analyses; meta-regression was also performed on reported ACN dose. Immediately post-exercise there was an increase in antioxidant capacity (g: 0.56) and reduced C reactive protein (g: -0.24) and tumor necrosis factor α (g: -40); p ≤ 0.02. Strength was improved with ACN at all time points (g: 0.45-0.67). DOMS (g: -0.23) was lower 24 hours post-exercise and power was improved 24 hours (g: 0.62) and 48 hours (g: 0.57) post exercise. The CK was lower 48 hours post-exercise (g: -0.31) and there was a trend for a positive association with ACN dose (p = 0.057). This systematic review provides new data showing ACN-rich foods promote functional and subjective recovery likely due to the antioxidant and anti-inflammatory properties of ACN.

SMADs and YAP compete to control elongation of ß-catenin:LEF-1-recruited RNAPII during hESC differentiation.

The Wnt3a/ß-catenin and Activin/SMAD2,3 signaling pathways synergize to induce endodermal differentiation of human embryonic stem cells; however, the underlying mechanism is not well understood. Using ChIP-seq and GRO-seq analyses, we show here that Wnt3a-induced ß-catenin:LEF-1 enhancers recruit cohesin to direct enhancer-promoter looping and activate mesendodermal (ME) lineage genes. Moreover, we find that LEF-1 and other hESC enhancers recruit RNAPII complexes (eRNAPII) that are highly phosphorylated at Ser5, but not Ser7. Wnt3a signaling further increases Ser5P-RNAPII at LEF-1 sites and ME gene promoters, indicating that elongation remains limiting. However, subsequent Activin/SMAD2,3 signaling selectively increases transcription elongation, P-TEFb occupancy, and Ser7P-RNAPII levels at these genes. Finally, we show that the Hippo regulator, YAP, functions with TEAD to regulate binding of the NELF negative elongation factor and block SMAD2,3 induction of ME genes. Thus, the Wnt3a/ß-catenin and Activin/SMAD2,3 pathways act in concert to counteract YAP repression and upregulate ME genes during early hESC differentiation.

"My body tends to betray me sometimes": a Qualitative Analysis of Affective and Perceptual Body Image in Individuals Living with Endometriosis.

BACKGROUND: Endometriosis is a chronic reproductive disease manifesting in physical symptoms including pain, abdominal swelling, altered bowel and bladder function, and fatigue. These symptoms potentially threaten body image regarding subjective perceptions of functional, appearance, and sensory aspects of one's body. The aim of this study was to qualitatively understand how endometriosis impacts on affective and perceptual aspects of body image. METHOD: Participants (N = 40) were recruited through endometriosis consumer organizations. In an online survey, participants completed demographic and health history questions, then provided written narratives about body image-related impacts of their endometriosis in response to open-ended questions. These data were thematically analyzed using the template approach. FINDINGS: The majority of participants (Mage = 28.3 years) were employed part-time, diagnosed on average for 4.2 years, and reported pelvic pain and bloating, fatigue, and nausea symptoms. Thematic analysis yielded three themes including My Body is a Barrier, Needing to Hide Myself, and Body as Healer and Teacher, all of which reflected affective and perceptual aspects of body image. CONCLUSION: These findings highlight wide-ranging body image-related impacts of endometriosis, suggesting the need for targeted interventions to address these concerns.

Racial and Ethnic Differences Among Active-Duty Service Members in Use of Mental Health Care and Perceived Mental Health Stigma: Results From the 2018 Health Related Behaviors Survey.

INTRODUCTION: The prevalence of mental health disorders is rising among US service members; however, research is limited on their use of mental health care. The objective of our study was to determine whether racial and ethnic disparities exist in the use of mental health care and perceived mental health stigma among active-duty service members. METHODS: We obtained data from a sample of 17,166 active-duty service members who participated in the 2018 Department of Defense Health Related Behavior Survey (HRBS). Racial and ethnic groups included Black, Hispanic, White, and other. Yes-no questions about use of mental health care and perceived mental health stigma were our outcome variables. We used multiple logistic regression to assess racial and ethnic differences in mental health care use and perceived mental health stigma by service members. Significance was set at P <.05. RESULTS: In 2018, approximately 25.5% of service members self-reported using mental health services, and 34.2% self-reported perceived mental health stigma. Hispanic service members (AOR = 0.78) and service members in the "other" racial and ethnic group (AOR = 0.81) were less likely than their White counterparts to have used mental health care. Black (AOR = 0.68) and Hispanic (AOR = 0.86) service members were less likely than their White counterparts to self-report perceived mental health stigma. CONCLUSION: The 2018 HRBS showed racial and ethnic differences in mental health care use and perceived stigma among US active-duty service members. Perceived stigma was a barrier to use of mental health care among service members with a mental health condition. Culture-sensitive programs customized for different racial and ethnic groups are needed to promote mental health care and reduce perceptions of stigma associated with its use.

Heterogeneity in how women value risk-stratified breast screening.

PURPOSE: Risk-stratified screening has potential to improve the cost effectiveness of national breast cancer screening programs. This study aimed to inform a socially acceptable and equitable implementation framework by determining what influences a woman's decision to accept a personalized breast cancer risk assessment and what the relative impact of these key determinants is. METHODS: Multicriteria decision analysis was used to elicit the relative weights for 8 criteria that women reported influenced their decision. Preference heterogeneity was explored through cluster analysis. RESULTS: The 2 criteria valued most by the 347 participants related to program access, "Mode of invitation" and "Testing process". Both criteria significantly influenced participation (P < .001). A total of 73% preferred communication by letter/online. Almost all women preferred a multidisease risk assessment with potential for a familial high-risk result. Four preference-based subgroups were identified. Membership to the largest subgroup was predicted by lower educational attainment, and women in this subgroup were concerned with program access. Higher relative perceived breast cancer risk predicted membership to the smallest subgroup that was focused on test parameters, namely "Scope of test" and "Test specificity". CONCLUSION: Overall, Australian women would accept a personalized multidisease risk assessment, but when aligning with their preferences, it will necessitate a focus on program access and the development of online communication frameworks.

Patient Acceptability of a Novel Technological Solution (Ambient Intelligent Geriatric Management System) to Prevent Falls in Geriatric and General Medicine Wards: A Mixed-Methods Study.

INTRODUCTION: As effective interventions to prevent inpatient falls are lacking, a novel technological intervention was trialed. The Ambient Intelligent Geriatric Management (AmbIGeM) system used wearable sensors that detected and alerted staff of patient movements requiring supervision. While the system did not reduce falls rate, it is important to evaluate the acceptability, usability, and safety of the AmbIGeM system, from the perspectives of patients and informal carers. METHODS: We conducted a mixed-methods study using semistructured interviews, a pre-survey and post-survey. The AmbIGeM clinical trial was conducted in two geriatric evaluation and management units and a general medical ward, in two Australian hospitals, and a subset of participants were recruited. Within 3 days of being admitted to the study wards and enrolling in the trial, 31 participants completed the pre-survey. Prior to discharge (post-intervention), 30 participants completed the post-survey and 27 participants were interviewed. Interview data were thematically analyzed and survey data were descriptively analyzed. RESULTS: Survey and interview participants had an average age of 83 (SD 9) years, 65% were female, and 41% were admitted with a fall. Participants considered the AmbIGeM system a good idea. Most but not all thought the singlet and sensor component as acceptable and comfortable, with no privacy concerns. Participants felt reassured with extra monitoring, although sometimes misunderstood the purpose of AmbIGeM as detecting patient falls. Participants' acceptability was strongly positive, with median 8+ (0-10 scale) on pre- and post-surveys. DISCUSSION/CONCLUSION: Patients' acceptability is important to optimize outcomes. Overall older patients considered the AmbIGeM system as acceptable, usable, and improving safety. The findings will be important to guide refinement of this and other similar technology developments.

A gene-specific role for the Ssu72 RNAPII CTD phosphatase in HIV-1 Tat transactivation.

HIV-1 Tat stimulates transcription elongation by recruiting the P-TEFb (positive transcription elongation factor-b) (CycT1:CDK9) C-terminal domain (CTD) kinase to the HIV-1 promoter. Here we show that Tat transactivation also requires the Ssu72 CTD Ser5P (S5P)-specific phosphatase, which mediates transcription termination and intragenic looping at eukaryotic genes. Importantly, HIV-1 Tat interacts directly with Ssu72 and strongly stimulates its CTD phosphatase activity. We found that Ssu72 is essential for Tat:P-TEFb-mediated phosphorylation of the S5P-CTD in vitro. Interestingly, Ssu72 also stimulates nascent HIV-1 transcription in a phosphatase-dependent manner in vivo. Chromatin immunoprecipitation (ChIP) experiments reveal that Ssu72, like P-TEFb and AFF4, is recruited by Tat to the integrated HIV-1 proviral promoter in TNF-α signaling 2D10 T cells and leaves the elongation complex prior to the termination site. ChIP-seq (ChIP combined with deep sequencing) and GRO-seq (genome-wide nuclear run-on [GRO] combined with deep sequencing) analysis further reveals that Ssu72 predominantly colocalizes with S5P-RNAPII (RNA polymerase II) at promoters in human embryonic stem cells, with a minor peak in the terminator region. A few genes, like NANOG, also have high Ssu72 at the terminator. Ssu72 is not required for transcription at most cellular genes but has a modest effect on cotranscriptional termination. We conclude that Tat alters the cellular function of Ssu72 to stimulate viral gene expression and facilitate the early S5P-S2P transition at the integrated HIV-1 promoter.

The Impact of NC Statewide Telepsychiatry Program (NC-STeP) on Cost Savings by Reducing Unnecessary Psychiatric Hospitalizations During a 6½ Year Period.

OBJECTIVE: To study the impact of the North Carolina Statewide Telepsychiatry Program in reducing unnecessary psychiatric hospitalizations and cost savings during a 6½ year period. METHODS: Patient encounter data was extracted from the NC-STeP database that captured records of 19,383 patients who received services over a 6½ -years' period. We analyzed the data to calculate the total number of patient encounters, the number of encounters with an IVC, and the number of encounters with an IVC that was overturned. For encounters with an overturned IVC, we also determined the patient discharge disposition. We estimated the cost of a typical mental health hospitalization to measure the savings generated by the overturned IVCs in the NC-STeP program. RESULTS: Over the 6½ year period there were 19,383 NC-STeP patient encounters at partner hospital emergency departments. There were 13,537 encounters where the patient had an IVC in place during the ED stay, and 4,627 where the IVC was overturned (34 %). For patients where there was an IVC that was overturned, 85.9 % of those patients were ultimately discharged home. Using the "three-way bed" cost estimate of $ 4,500 for each overturned IVC, the cost savings generated by the NC-STeP program from November 2013 to June 2020 were $ 20,821,500. CONCLUSIONS: Telepsychiatry consultation services in the emergency departments can decrease unnecessary psychiatric hospitalizations and contribute to significant cost savings to the healthcare system and society and improve the outcomes for patients and families by decreasing financial burden and stress associated with a hospital stay.

Study of Impact of Telehealth Use on Clinic "No Show" Rates at an Academic Practice.

OBJECTIVE: To examine the clinic no-show rate across different modalities of care delivery (Face to Face, Telephone visits and Audio-Video visits). METHODS: Clinic no show data for adult patients was extracted from the electronic health records used by the psychiatry clinic for 10 months before pandemic and 10 months during pandemic. No show rate was analyzed by visits type (new vs return) and across different modalities (face-to-face vs Telephone vs Audio-Video) before and during COVID pandemic. RESULTS: There were 13,916 scheduled visits during the 10-month period before the pandemic of which 2,522 were no show. There were 13,251 scheduled visits during the 10-month period during the COVID pandemic of which 2,029 were no show. The overall clinic no show rate decreased from pre pandemic to pandemic period (18.1% vs 15.3%) after transitioning to telehealth. Across different modalities during the pandemic, the no-show rate for Telephone visits was significantly lower than for face- to-face visits. No difference was identified for no-show rates between face-to-face visits and audio-video visits during the pandemic. The no-show rate for face-to-face visits before the pandemic compared to during the pandemic also showed no difference. CONCLUSION: Using technology in health care delivery can decrease the clinic no show rate. Digital literacy for patients and providers is critical for successful utilization of telehealth.

Function-Oriented and Modular (+/-)-cis-Pseudoguaianolide Synthesis: Discovery of New Nrf2 Activators and NF-κB Inhibitors.

Described herein is a function-oriented synthesis route and biological evaluation of pseudoguaianolide analogues. The 10-step synthetic route developed retains the topological complexity of the natural product, installs functional handles for late-stage diversification, and forges the key bioactive Michael acceptors early in the synthesis. The analogues were found to be low-micromolar Nrf2 activators and micromolar NF-κB inhibitors and dependent on the local environment of the Michael acceptor moieties.

Cardiopulmonary exercise performance and factors associated with aerobic capacity in neuromuscular diseases.

INTRODUCTION/AIMS: Aerobic deconditioning, due to lower levels of physical activity, could impact independence for people with neuromuscular conditions. We report the maximal cardiopulmonary response in a cohort of people with Charcot Marie Tooth disease type 1A (CMT 1A) and inclusion body myositis (IBM). We also explored potential predictors of aerobic capacity with measures of physical impairment and functional performance. METHODS: Participants underwent maximal cardiopulmonary exercise testing (CPET) using a semi-recumbent cycle ergometer. Data were analyzed to determine the peak O2 consumption (VO2 peak), anaerobic threshold (AT), maximum heart rate (MHR), ventilatory equivalent for CO2 slope (VE /VCO2 ), and respiratory exchange ratio (RER). Impairment, functional and patient reported measures were also recorded. Predicted CPET variables were calculated based on published normative data for age, gender, and weight. RESULTS: Twenty-two people with CMT and 17 people with IBM were recruited. Both groups showed significantly lower VO2 peak, MHR, AT, and VE /VCO2 . The CMT group overall performed better than the IBM group, with significantly higher VO2 peak, MHR, and AT, but lower VE /VCO2. Linear regression analysis demonstrated that VO2 peak was related to body fat percentage and 6-min walk distance for both groups, and steps per day for the IBM group. DISCUSSION: Lower than predicted CPET variables were observed that were not explained by cardiopulmonary limitations or reduced effort, implicating peripheral factors in limiting the cycling task. Regression analysis implied prediction of VO2 peak by body fat percentage and 6-min walk distance. Six-minute walk distance could be a potential proxy measure of cardiopulmonary fitness.

Anti-seizure medications for Lennox-Gastaut syndrome.

BACKGROUND: Lennox-Gastaut syndrome (LGS) is an age-specific epilepsy syndrome characterised by multiple seizure types, including drop seizures. LGS has a characteristic electroencephalogram, an onset before age eight years and an association with drug resistance. This is an updated version of the Cochrane Review published in 2013. OBJECTIVES: To assess the efficacy and tolerability of anti-seizure medications (ASMs) for LGS. SEARCH METHODS: We searched the Cochrane Register of Studies (CRS Web) and MEDLINE (Ovid, 1946 to 28 February 2020) on 2 March 2020. CRS Web includes randomised controlled trials (RCTs) or quasi-RCTs from the Cochrane Central Register of Controlled Trials (CENTRAL); the Specialised Registers of Cochrane Review Groups, including Cochrane Epilepsy; PubMed; Embase; ClinicalTrials.gov; and the World Health Organization's International Clinical Trials Registry Platform (ICTRP). We imposed no language restrictions. We contacted pharmaceutical companies and colleagues in the field to seek any unpublished or ongoing studies. SELECTION CRITERIA: We considered RCTs, including cross-over trials, of ASMs for LGS in children and adults. We included studies of ASMs used as either monotherapy or as an add-on (adjunctive) therapy. We excluded studies comparing different doses of the same ASM. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures, including independent, dual assessment for risk of bias and application of the GRADE approach to rate the evidence certainty for outcomes. MAIN RESULTS: We found no trials of ASM monotherapy. The review included 11 trials (1277 participants; approximately 11 weeks to 112 weeks follow-up after randomisation) using add-on ASMs for LGS in children, adolescents and adults. Two studies compared add-on cannabidiol (two doses) with add-on placebo in children and adolescents only. Neither study reported overall seizure cessation or reduction. We found high-certainty evidence that 72 more people per 1000 (confidence interval (CI) 4 more to 351 more) had adverse events (AE) leading to study discontinuation with add-on cannabidiol, compared to add-on placebo (two studies; 396 participants; risk ratio (RR) 4.90, 95% CI 1.21 to 19.87). One study compared add-on cinromide with add-on placebo in children and adolescents only. We found very low-certainty evidence that 35 more people per 1000 (CI 123 fewer to 434 more) had 50% or greater average reduction of overall seizures with add-on cinromide compared to add-on placebo (one study; 56 participants; RR 1.15, 95% CI 0.47 to 2.86). This study did not report participants with AE leading to study discontinuation. One study compared add-on clobazam (three doses) with add-on placebo. This study did not report overall seizure cessation or reduction. We found high-certainty evidence that 106 more people per 1000 (CI 0 more to 538 more) had AE leading to study discontinuation with add-on clobazam compared to add-on placebo (one study; 238 participants; RR 4.12, 95% CI 1.01 to 16.87). One study compared add-on felbamate with add-on placebo. No cases of seizure cessation occurred in either regimen during the treatment phase (one study; 73 participants; low-certainty evidence). There was low-certainty evidence that 53 more people per 1000 (CI 19 fewer to 716 more) with add-on felbamate were seizure-free during an EEG recording at the end of the treatment phase, compared to add-on placebo (RR 2.92, 95% CI 0.32 to 26.77). The study did not report overall seizure reduction. We found low-certainty evidence that one fewer person per 1000 (CI 26 fewer to 388 more) with add-on felbamate had AE leading to study discontinuation compared to add-on placebo (one study, 73 participants; RR 0.97, 95% CI 0.06 to 14.97). Two studies compared add-on lamotrigine with add-on placebo. Neither study reported overall seizure cessation. We found high-certainty evidence that 176 more people per 1000 (CI 30 more to 434 more) had ≥ 50% average seizure reduction with add-on lamotrigine compared to add-on placebo (one study; 167 participants; RR 2.12, 95% CI 1.19 to 3.76). We found low-certainty evidence that 40 fewer people per 1000 (CI 68 fewer to 64 more) had AE leading to study-discontinuation with add-on lamotrigine compared to add-on placebo (one study; 169 participants; RR 0.49, 95% CI 0.13 to 1.82). Two studies compared add-on rufinamide with add-on placebo. Neither study reported seizure cessation. We found high-certainty evidence that 202 more people per 1000 (CI 34 to 567 more) had ≥ 50% average seizure reduction (one study; 138 participants; RR 2.84, 95% CI 1.31 to 6.18). We found low-certainty evidence that 105 more people per 1000 (CI 17 fewer to 967 more) had AE leading to study discontinuation with add-on rufinamide compared to add-on placebo (one study; 59 participants; RR 4.14, 95% CI 0.49 to 34.86). One study compared add-on rufinamide with another add-on ASM. This study did not report overall seizure cessation or reduction. We found low-certainty evidence that three fewer people per 1000 (CI 75 fewer to 715 more) had AE leading to study discontinuation with add-on rufinamide compared to another add-on ASM (one study; 37 participants; RR 0.96, 95% CI 0.10 to 9.57). One study compared add-on topiramate with add-on placebo. This study did not report overall seizure cessation. We found low-certainty evidence for ≥ 75% average seizure reduction with add-on topiramate (one study; 98 participants; Peto odds ratio (Peto OR) 8.22, 99% CI 0.60 to 112.62) and little or no difference to AE leading to study discontinuation compared to add-on placebo; no participants experienced AE leading to study discontinuation (one study; 98 participants; low-certainty evidence). AUTHORS' CONCLUSIONS: RCTs of monotherapy and head-to-head comparison of add-on ASMs are currently lacking. However, we found high-certainty evidence for overall seizure reduction with add-on lamotrigine and rufinamide, with low-certainty evidence for AE leading to study discontinuation compared with add-on placebo or another add-on ASM. The evidence for other add-on ASMs for overall seizure cessation or reduction was low to very low with high- to low-certainty evidence for AE leading to study discontinuation. Future research should consider outcome reporting of overall seizure reduction (applying automated seizure detection devices), impact on development, cognition and behaviour; future research should also investigate age-specific efficacy of ASMs and target underlying aetiologies.

Interventions for promoting physical activity in people with neuromuscular disease.

BACKGROUND: The World Health Organization (WHO) recommends that people of all ages take regular and adequate physical activity. If unable to meet the recommendations due to health conditions, international guidance advises being as physically active as possible. Evidence from community interventions of physical activity indicate that people living with medical conditions are sometimes excluded from participation in studies. In this review, we considered the effects of activity-promoting interventions on physical activity and well-being in studies, as well as any adverse events experienced by participants living with inherited or acquired neuromuscular diseases (NMDs).  OBJECTIVES: To assess the effects of interventions designed to promote physical activity in people with NMD compared with no intervention or alternative interventions. SEARCH METHODS: On 30 April 2020, we searched Cochrane Neuromuscular Specialised Register, CENTRAL, Embase, MEDLINE, and ClinicalTrials.Gov. WHO ICTRP was not accessible at the time. SELECTION CRITERIA: We considered randomised or quasi-randomised trials, including cross-over trials, of interventions designed to promote physical activity in people with NMD compared to no intervention or alternative interventions. We specifically included studies that reported physical activity as an outcome measure. Our main focus was studies in which promoting physical activity was a stated aim but we also included studies in which physical activity was assessed as a secondary or exploratory outcome. DATA COLLECTION AND ANALYSIS: We used standard Cochrane procedures. MAIN RESULTS: The review included 13 studies (795 randomised participants from 12 studies; number of participants unclear in one study) of different interventions to promote physical activity. Most studies randomised a minority of invited participants. No study involved children or adolescents and nine studies reported minimal entry criteria for walking. Participants had one of nine inherited or acquired NMDs. Types of intervention included structured physical activity support, exercise support (as a specific form of physical activity), and behaviour change support that included physical activity or exercise. Only one included study clearly reported that the aim of intervention was to increase physical activity. Other studies reported or planned to analyse the effects of intervention on physical activity as a secondary or exploratory outcome measure. Six studies did not report results for physical activity outcomes, or the data were not usable. We judged 10 of the 13 included studies at high or unclear risk of bias from incomplete physical activity outcome reporting. We did not perform a meta-analysis for any comparison because of differences in interventions and in usual care. We also found considerable variation in how studies reported physical activity as an outcome measure. The studies that reported physical activity measurement did not always clearly report intention-to-treat (ITT) analysis or whether final assessments occurred during or after intervention. Based on prespecified measures, we included three comparisons in our summary of findings. A physical activity programme (weight-bearing) compared to no physical activity programme One study involved adults with diabetic peripheral neuropathy (DPN) and reported weekly duration of walking during and at the end of a one-year intervention using a StepWatch ankle accelerometer. Based on the point estimate and low-certainty evidence, intervention may have led to an important increase in physical activity per week; however, the 95% confidence interval (CI) included the possibility of no difference or an effect in either direction at three months (mean difference (MD) 34 minutes per week, 95% CI -92.19 to 160.19; 69 participants), six months (MD 68 minutes per week, 95% CI -55.35 to 191.35; 74 participants), and 12 months (MD 49 minutes per week, 95% CI -75.73 to 173.73; 70 participants). Study-reported effect estimates for foot lesions and full-thickness ulcers also included the possibility of no difference, a higher, or lower risk with intervention. A sensor-based, interactive exercise programme compared to no sensor-based, interactive exercise programme One study involved adults with DPN and reported duration of walking over 48 hours at the end of four weeks' intervention using a t-shirt embedded PAMSys sensor. It was not possible to draw conclusions about the effectiveness of the intervention from the very low-certainty evidence (MD -0.64 hours per 48 hours, 95% CI -2.42 to 1.13; 25 participants). We were also unable to draw conclusions about impact on the Physical Component Score (PCS) for quality of life (MD 0.24 points, 95% CI -5.98 to 6.46; 35 participants; very low-certainty evidence), although intervention may have made little or no difference to the Mental Component Score (MCS) for quality of life (MD 5.10 points, 95% CI -0.58 to 10.78; 35 participants; low-certainty evidence). A functional exercise programme compared to a stretching exercise programme One study involved adults with spinal and bulbar muscular atrophy and reported a daily physical activity count at the end of 12 weeks' intervention using an Actical accelerometer. It was not possible to draw conclusions about the effectiveness of either intervention (requiring compliance) due to low-certainty evidence and unconfirmed measurement units (MD -8701, 95% CI -38,293.30 to 20,891.30; 43 participants). Functional exercise may have made little or no difference to quality of life compared to stretching (PCS: MD -1.10 points, 95% CI -5.22 to 3.02; MCS: MD -1.10 points, 95% CI -6.79 to 4.59; 49 participants; low-certainty evidence). Although studies reported adverse events incompletely, we found no evidence of supported activity increasing the risk of serious adverse events. AUTHORS' CONCLUSIONS: We found a lack of evidence relating to children, adolescents, and non-ambulant people of any age. Many people living with NMD did not meet randomised controlled trial eligibility criteria. There was variation in the components of supported activity intervention and usual care, such as physical therapy provision. We identified variation among studies in how physical activity was monitored, analysed, and reported. We remain uncertain of the effectiveness of promotional intervention for physical activity and its impact on quality of life and adverse events. More information is needed on the ITT population, as well as more complete reporting of outcomes. While there may be no single objective measure of physical activity, the study of qualitative and dichotomous change in self-reported overall physical activity might offer a pragmatic approach to capturing important change at an individual and population level.

A systematic review and meta-analysis of the prevalence of left ventricular non-compaction in adults.

AIMS: To assess the reported prevalence of left ventricular non-compaction (LVNC) in different adult cohorts, taking in to consideration the role of diagnostic criteria and imaging modalities used. METHODS AND RESULTS: A systematic review and meta-analysis of studies reporting LVNC prevalence in adults. Studies were sourced from Pre-Medline, Medline, and Embase and assessed for eligibility according to inclusion criteria. Eligible studies provided a prevalence of LVNC in adult populations (≥12 years). Studies were assessed, and data extracted by two independent reviewers. Fifty-nine eligible studies documenting LVNC in 67 unique cohorts were included. The majority of studies were assessed as moderate or high risk of bias. The pooled prevalence estimates for LVNC were consistently higher amongst cohorts diagnosed on cardiac magnetic resonance (CMR) imaging (14.79%, n = 26; I2 = 99.45%) compared with echocardiogram (1.28%, n = 36; I2 = 98.17%). This finding was unchanged when analysis was restricted to studies at low or moderate risk of bias. The prevalence of LVNC varied between disease and population representative cohorts. Athletic cohorts demonstrated high pooled prevalence estimates on echocardiogram (3.16%, n = 5; I2 = 97.37%) and CMR imaging (27.29%, n = 2). CONCLUSION: Left ventricular non-compaction in adult populations is a poorly defined entity which likely encompasses both physiological adaptation and pathological disease. There is a higher prevalence with the introduction of newer imaging technologies, specifically CMR imaging, which identify LVNC changes more readily. The clinical significance of these findings remains unclear; however, there is significant potential for overdiagnosis, overtreatment, and unnecessary follow-up.

α-Catenin interacts with APC to regulate ß-catenin proteolysis and transcriptional repression of Wnt target genes.

Mutation of the adenomatous polyposis coli (APC) tumor suppressor stabilizes ß-catenin and aberrantly reactivates Wnt/ß-catenin target genes in colon cancer. APC mutants in cancer frequently lack the conserved catenin inhibitory domain (CID), which is essential for ß-catenin proteolysis. Here we show that the APC CID interacts with α-catenin, a Hippo signaling regulator and heterodimeric partner of ß-catenin at cell:cell adherens junctions. Importantly, α-catenin promotes ß-catenin ubiquitylation and proteolysis by stabilizing its association with APC and protecting the phosphodegron. Moreover, ß-catenin ubiquitylation requires binding to α-catenin. Multidimensional protein identification technology (MudPIT) proteomics of multiple Wnt regulatory complexes reveals that α-catenin binds with ß-catenin to LEF-1/TCF DNA-binding proteins in Wnt3a signaling cells and recruits APC in a complex with the CtBP:CoREST:LSD1 histone H3K4 demethylase to regulate transcription and ß-catenin occupancy at Wnt target genes. Interestingly, tyrosine phosphorylation of α-catenin at Y177 disrupts binding to APC but not ß-catenin and prevents repression of Wnt target genes in transformed cells. Chromatin immunoprecipitation studies further show that α-catenin and APC are recruited with ß-catenin to Wnt response elements in human embryonic stem cells (hESCs). Knockdown of α-catenin in hESCs prevents the switch-off of Wnt/ß-catenin transcription and promotes endodermal differentiation. Our findings indicate a role for α-catenin in the APC destruction complex and at Wnt target genes.

Differential Inhibition of APOBEC3 DNA-Mutator Isozymes by Fluoro- and Non-Fluoro-Substituted 2'-Deoxyzebularine Embedded in Single-Stranded DNA.

The APOBEC3 (APOBEC3A-H) enzyme family is part of the human innate immune system that restricts pathogens by scrambling pathogenic single-stranded (ss) DNA by deamination of cytosines to produce uracil residues. However, APOBEC3-mediated mutagenesis of viral and cancer DNA promotes its evolution, thus enabling disease progression and the development of drug resistance. Therefore, APOBEC3 inhibition offers a new strategy to complement existing antiviral and anticancer therapies by making such therapies effective for longer periods of time, thereby preventing the emergence of drug resistance. Here, we have synthesised 2'-deoxynucleoside forms of several known inhibitors of cytidine deaminase (CDA), incorporated them into oligodeoxynucleotides (oligos) in place of 2'-deoxycytidine in the preferred substrates of APOBEC3A, APOBEC3B, and APOBEC3G, and evaluated their inhibitory potential against these enzymes. An oligo containing a 5-fluoro-2'-deoxyzebularine (5FdZ) motif exhibited an inhibition constant against APOBEC3B 3.5 times better than that of the comparable 2'-deoxyzebularine-containing (dZ-containing) oligo. A similar inhibition trend was observed for wild-type APOBEC3A. In contrast, use of the 5FdZ motif in an oligo designed for APOBEC3G inhibition resulted in an inhibitor that was less potent than the dZ-containing oligo both in the case of APOBEC3GCTD and in that of full-length wild-type APOBEC3G.

SHMT2 and the BRCC36/BRISC deubiquitinase regulate HIV-1 Tat K63-ubiquitylation and destruction by autophagy.

HIV-1 Tat is a key regulator of viral transcription, however little is known about the mechanisms that control its turnover in T cells. Here we use a novel proteomics technique, called DiffPOP, to identify the molecular target of JIB-04, a small molecule compound that potently and selectively blocks HIV-1 Tat expression, transactivation, and virus replication in T cell lines. Mass-spectrometry analysis of whole-cell extracts from 2D10 Jurkat T cells revealed that JIB-04 targets Serine Hydroxymethyltransferase 2 (SHMT2), a regulator of glycine biosynthesis and an adaptor for the BRCC36 K63Ub-specific deubiquitinase in the BRISC complex. Importantly, knockdown of SHMT1,2 or BRCC36, or exposure of cells to JIB-04, strongly increased Tat K63Ub-dependent destruction via autophagy. Moreover, point mutation of multiple lysines in Tat, or knockdown of BRCC36 or SHMT1,2, was sufficient to prevent destruction of Tat by JIB-04. We conclude that HIV-1 Tat levels are regulated through K63Ub-selective autophagy mediated through SHMT1,2 and the BRCC36 deubiquitinase.

Asthma deaths in North Carolina: 1999-2016.

Introduction: Despite the significant decline in overall death rates in the U.S. over the past decade, many asthma deaths could have been avoided. Eastern North Carolina (N.C.) is an economically challenged region with significant health disparities and a high prevalence of asthma. Objective: The primary purpose of this project was to examine trends of asthma deaths across N.C. and identify counties in the state with the highest mortality rates over an 18-year period. Methods: CDC WONDER was used to query and evaluate age-adjusted asthma mortality rates from 1999 to 2016 among residents in N.C., greater than 1 year of age. Asthma death data were derived from death certificates using ICD-10 underlying cause-of-death codes J45 (asthma) and J46 (status asthmaticus). The Join point regression program was used to test statistical significance in age-adjusted rates for the U.S. and N.C. over the entire study period. Results: N.C. experienced a total of 2,066 decedents assigned as the underlying cause of deaths for an overall death rate of 12.5 per 1,000,000 persons. Death rates were highest among females (14.6 deaths per 1,000,000) and black or African Americans (24.7 per 1,000,000). Discussion: Overall asthma mortality rates in N.C. decreased. However, several rural and impoverished counties in eastern N.C. with a large percent of blacks or African-Americans, had the highest asthma death rates in the state. Conclusion: Healthcare providers should remain highly cognizant to provide optimal asthma management, education, and follow-up with asthma patients to help avoid unnecessary asthma related deaths.