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Dapagliflozin, a sodium-glucose cotransporter-2 inhibitor, reduces cardiovascular death and worsening heart failure in patients with chronic heart failure and reduced ejection fraction. Early initiation during an acute heart failure (AHF) hospitalization may facilitate decongestion, improve natriuresis, and facilitate safe transition to a beneficial outpatient therapy for both diabetes and heart failure. The objective is to assess the efficacy and safety of initiating dapagliflozin within the first 24 hours of hospitalization in patients with AHF compared to usual care. DICTATE-AHF is a prospective, multicenter, open-label, randomized trial enrolling a planned 240 patients in the United States. Patients with type 2 diabetes hospitalized with hypervolemic AHF and an estimated glomerular filtration rate of at least 30 mL/min/1.73m2 are eligible for participation. Patients are randomly assigned 1:1 to dapagliflozin 10 mg once daily or structured usual care until day 5 or hospital discharge. Both treatment arms receive protocolized diuretic and insulin therapies. The primary endpoint is diuretic response expressed as the cumulative change in weight per cumulative loop diuretic dose in 40 mg intravenous furosemide equivalents. Secondary and exploratory endpoints include inpatient worsening AHF, 30-day hospital readmission for AHF or diabetic reasons, change in NT-proBNP, and measures of natriuresis. Safety endpoints include the incidence of hyper/hypoglycemia, ketoacidosis, worsening kidney function, hypovolemic hypotension, and inpatient mortality. The DICTATE-AHF trial will establish the efficacy and safety of early initiation of dapagliflozin during AHF across both AHF and diabetic outcomes in patients with diabetes.

Autistic Individuals with or without co-occurring Mental Health Conditions Experience Challenges with Community Participation that can Affect Quality of life. These Challenges Involve, but are not Limited to, Transportation, Finances, Accessibility, Attitude towards Participation, and Infrastructure Issues. COVID-19 Added a new Layer of Community Participation Barriers for all Individuals, Especially Autistic Individuals. The purpose of this study is to understand the perceived community participation barriers and facilitators encountered by autistic individuals during a public health crisis using the Photovoice methodology. The study will compare these perceptions of autistic individuals with and without co-occurring mental health conditions during a public health crisis to determine if any distinctions can be determined. Photovoice, an established qualitative outreach methodology, was the foundation for the methods. Participants completed a narrative answering the question “what is a barrier or facilitator to your community participation?” Data were analyzed using grounded theory. Seventeen autistic participants with a mean age of 23 completed the Photovoice study. Eleven (65%) reported at least one co- occurring mental health condition. Data analysis resulted in two major themes COVID-19 and Transportation; and six subthemes access, safety, technology, leisure, shared experiences, and sensory. Autistic individuals with and without co-occurring mental health conditions chose to identify barriers more than facilitators. Participants without co-occurring mental health conditions viewed COVID-19 as a facilitator almost twice as often as those without. Participants with co-occurring mental health conditions reported transportation more as a barrier than those without. In this study conducted during COVID-19 regulations, autistic individuals identified COVID-19 and transportation as the primary barriers to community participation. COVID-19 was identified as both a barrier and a facilitator. Autistic individuals identified that COVID-19 enabled more on-line participation. Autistic individuals with co-occurring mental health conditions can experience a greater increase in symptoms when daily routines and participation are affected. Disruption and changes in participation for the autistic community during the COVID-19 pandemic can have future implications on this population’s ability to reintroduce themselves into community participation. Identified facilitators; technology, shared experiences, and leisure are useful tools to combat the participation barriers.

Huntington’s Disease (HD) is a progressive neurodegenerative disorder caused by CAG trinucleotide repeat expansions in exon 1 of the huntingtin ( HTT ) gene. The mutant HTT (mHTT) protein causes neuronal dysfunction, causing progressive motor, cognitive and behavioral abnormalities. Current treatments for HD only alleviate symptoms, but cerebral spinal fluid (CSF) or central nervous system (CNS) delivery of antisense oligonucleotides (ASOs) or virus vectors expressing RNA-induced silencing (RNAi) moieties designed to induce mHTT mRNA lowering have progressed to clinical trials. Here, we present an alternative disease modifying therapy the orally available, brain penetrant small molecule branaplam. By promoting inclusion of a pseudoexon in the primary transcript, branaplam lowers mHTT protein levels in HD patient cells, in an HD mouse model and in blood samples from Spinal Muscular Atrophy (SMA) Type I patients dosed orally for SMA (NCT02268552). Our work paves the way for evaluating branaplam’s utility as an  HD therapy, leveraging small molecule splicing modulators to reduce expression of dominant disease genes by driving pseudoexon inclusion. Huntington’s disease (HD) results from the abnormal expansion of CAG repeats in exon 1 of the HTT gene. Here, the authors show that orally available, brain penetrant molecule branaplam lowers HTT transcript by promoting inclusion of a poison exon or pseudoexon.

Niemann-Pick disease, type C1 (NPC1) is a lysosomal storage disorder characterised by progressive neurodegeneration. In preclinical testing, 2-hydroxypropyl-β-cyclodextrins (HPβCD) significantly delayed cerebellar Purkinje cell loss, slowed progression of neurological manifestations, and increased lifespan in mouse and cat models of NPC1. The aim of this study was to assess the safety and efficacy of lumbar intrathecal HPβCD. In this open-label, dose-escalation phase 1–2a study, we gave monthly intrathecal HPβCD to participants with NPC1 with neurological manifestation at the National Institutes of Health (NIH), Bethesda, MD, USA. To explore the potential effect of 2-week dosing, three additional participants were enrolled in a parallel study at Rush University Medical Center (RUMC), Chicago, IL, USA. Participants from the NIH were non-randomly, sequentially assigned in cohorts of three to receive monthly initial intrathecal HPβCD at doses of 50, 200, 300, or 400 mg per month. A fifth cohort of two participants received initial doses of 900 mg. Participants from RUMC initially received 200 or 400 mg every 2 weeks. The dose was escalated based on tolerance or safety data from higher dose cohorts. Serum and CSF 24(S)-hydroxycholesterol (24[S]-HC), which serves as a biomarker of target engagement, and CSF protein biomarkers were evaluated. NPC Neurological Severity Scores (NNSS) were used to compare disease progression in HPβCD-treated participants relative to a historical comparison cohort of 21 NPC1 participants of similar age range. Between Sept 21, 2013, and Jan 19, 2015, 32 participants with NPC1 were assessed for eligibility at the National Institutes of Health. 18 patients were excluded due to inclusion criteria not met (six patients), declined to participate (three patients), pursued independent expanded access and obtained the drug outside of the study (three patients), enrolled in the RUMC cohort (one patient), or too late for the trial enrolment (five patients). 14 patients were enrolled and sequentially assigned to receive intrathecal HPβCD at a starting dose of 50 mg per month (three patients), 200 mg per month (three patients), 300 mg per month (three patients), 400 mg per month (three patients), or 900 mg per month (two patients). During the first year, two patients had treatment interrupted for one dose, based on grade 1 ototoxicity. All 14 patients were assessed at 12 months. Between 12 and 18 months, one participant had treatment interrupted at 17 months due to hepatocellular carcinoma, one patient had dose interruption for 2 doses based on caregiver hardship and one patient had treatment interrupted for 1 dose for mastoiditis. 11 patients were assessed at 18 months. Between Dec 11, 2013, and June 25, 2014, three participants were assessed for eligibility and enrolled at RUMC, and were assigned to receive intrathecal HPβCD at a starting dose of 200 mg every 2 weeks (two patients), or 400 mg every two weeks (one patient). There were no dropouts in this group and all 3 patients were assessed at 18 months. Biomarker studies were consistent with improved neuronal cholesterol homoeostasis and decreased neuronal pathology. Post-drug plasma 24(S)-HC area under the curve (AUC8-72) values, an indicator of neuronal cholesterol homoeostasis, were significantly higher than post-saline plasma 24(S)-HC AUC8-72 after doses of 900 mg (p=0·0063) and 1200 mg (p=0·0037). CSF 24(S)-HC concentrations in three participants given either 600 or 900 mg of HPβCD were increased about two fold (p=0·0032) after drug administration. No drug-related serious adverse events were observed. Mid-frequency to high-frequency hearing loss, an expected adverse event, was documented in all participants. When managed with hearing aids, this did not have an appreciable effect on daily communication. The NNSS for the 14 participants treated monthly increased at a rate of 1·22, SEM 0·34 points per year compared with 2·92, SEM 0·27 points per year (p=0·0002) for the 21 patient comparison group. Decreased progression was observed for NNSS domains of ambulation (p=0·0622), cognition (p=0·0040) and speech (p=0·0423). Patients with NPC1 treated with intrathecal HPβCD had slowed disease progression with an acceptable safety profile. These data support the initiation of a multinational, randomised, controlled trial of intrathecal HPβCD. National Institutes of Health, Dana's Angels Research Trust, Ara Parseghian Medical Research Foundation, Hope for Haley, Samantha's Search for the Cure Foundation, National Niemann-Pick Disease Foundation, Support of Accelerated Research for NPC Disease, Vtesse, Janssen Research and Development, a Johnson & Johnson company, and Johnson & Johnson.

BACKGROUNDChildren and adolescents with autism spectrum disorder (ASD) have many well-known health concerns, yet health conditions in adults with ASD remain poorly defined.OBJECTIVETo examine health conditions and functional status in adults with ASD and identify factors associated with health and functional status across age cohorts.DESIGN AND SUBJECTSWe collected cross-sectional data from 255 adult subjects aged 18 to 71 years with ASD using the Rochester Health Status Survey IV (RHSS-IV), a 58-item validated survey instrument. We used the National Health and Nutritional Examination Survey and National Health Interview Survey to provide comparative prevalence rates in the general population.RESULTSCompared to the general population, young adults aged 18–29 with ASD had a substantially higher prevalence of seizure disorder (11.2 % vs. 1.4 %; p = 0.002), depression (16.4 % vs. 6.4 %; p = 0.007), hypertension (12.9 % vs. 6.3 %; p = 0.05), and allergies (39.7 % vs. 8.4 %; p < 0.001). In contrast, young adults with ASD had considerably lower rates of sexually transmitted illness (STI) (0.9 % vs. 4.3 %; p = 0.03), tobacco use (5.2 % vs. 31.9 %; p < 0.001), and alcohol misuse (0.9 % vs. 11.9 %; p < 0.001). Adults 40 and over with ASD also had higher rates of seizure disorder (29.2 % vs. 1.7 %; p < 0.001), lower tobacco use (2.8 % vs. 24.5 %; p < 0.001), and lower alcohol misuse (1.4 % vs. 18.2 %; p < 0.001) compared to the general population. Amongst the 55 % of participants with a documented IQ score, 91 % had an intellectual disability (IQ < 70). Within the cohort aged 40 years old and older, only 54.2 % were independent with eating, 43.0 % independent with dressing, and 43.1 % independent with bathing. Lower IQ and depression were associated with lower functional status.CONCLUSIONSAdults with ASD have a high prevalence of seizure disorders and depression, but low rates of STIs, tobacco use, and alcohol misuse. Within our cohort, the majority of older adults with ASD required some assistance with activities of daily living.

High resource expenditure on acute care is a challenge for mental health services aiming to focus on supporting recovery, and relapse after an acute crisis episode is common. Some evidence supports self-management interventions to prevent such relapses, but their effect on readmissions to acute care following a crisis is untested. We tested whether a self-management intervention facilitated by peer support workers could reduce rates of readmission to acute care for people discharged from crisis resolution teams, which provide intensive home treatment following a crisis. We did a randomised controlled superiority trial recruiting participants from six crisis resolution teams in England. Eligible participants had been on crisis resolution team caseloads for at least a week, and had capacity to give informed consent. Participants were randomly assigned to intervention and control groups by an unmasked data manager. Those collecting and analysing data were masked to allocation, but participants were not. Participants in the intervention group were offered up to ten sessions with a peer support worker who supported them in completing a personal recovery workbook, including formulation of personal recovery goals and crisis plans. The control group received the personal recovery workbook by post. The primary outcome was readmission to acute care within 1 year. This trial is registered with ISRCTN, number 01027104. 221 participants were assigned to the intervention group versus 220 to the control group; primary outcome data were obtained for 218 versus 216. 64 (29%) of 218 participants in the intervention versus 83 (38%) of 216 in the control group were readmitted to acute care within 1 year (odds ratio 0·66, 95% CI 0·43–0·99; p=0·0438). 71 serious adverse events were identified in the trial (29 in the treatment group; 42 in the control group). Our findings suggest that peer-delivered self-management reduces readmission to acute care, although admission rates were lower than anticipated and confidence intervals were relatively wide. The complexity of the study intervention limits interpretability, but assessment is warranted of whether implementing this intervention in routine settings reduces acute care readmission. National Institute for Health Research.

Heart failure (HF) is a chronic syndrome that is associated with frequent rehospitalization. Patient-focused research suggests that increased health-management activation may lead to favorable clinical outcomes. This article introduces a case study of the development of a patient education and activation tool for use by HF-specialist clinicians, “ENGAGE in HF,” and advocates for wider adoption of co-creation involving people living with HF. Following a behavioral assessment of unmet needs in the HF-patient population in scientific literature, people living with HF were invited to comment on the content plan and excerpts from the tool. Afterwards, HF-specialist clinicians provided their scientific perspective and assessed the content's practical utility. The co-created tool aims to improve dialogue between clinicians and patients. It allows clinicians to personalize conversations, considering each patient's capacity to integrate information and their readiness to engage in shared decision making. Feedback from initial dissemination of the ENGAGE in HF tool among cardiologists in China suggests that use of such tools may lead to improvements in patient education, symptom management, and adherence to medication.

Acute kidney injury (AKI) is a serious disorder for which there are limited treatment options. Following injury, native nephrons display limited regenerative capabilities, relying on the dedifferentiation and proliferation of renal tubular epithelial cells (RTECs) that survive the insult. Previously, we identified 4-(phenylthio)butanoic acid (PTBA), a histone deacetylase inhibitor (HDI), as an enhancer of renal recovery, and showed that PTBA treatment increased RTEC proliferation and reduced renal fibrosis. Here, we investigated the regenerative mechanisms of PTBA in zebrafish models of larval renal injury and adult cardiac injury. With respect to renal injury, we showed that delivery of PTBA using an esterified prodrug (UPHD25) increases the reactivation of the renal progenitor gene Pax2a, enhances dedifferentiation of RTECs, reduces Kidney injury molecule-1 (Kim-1) expression, and lowers the number of infiltrating macrophages. Further, we found that the effects of PTBA on RTEC proliferation depend upon retinoic acid signaling and demonstrate that the therapeutic properties of PTBA are not restricted to the kidney but also increase cardiomyocyte proliferation and decrease fibrosis following cardiac injury in adult zebrafish. These studies provide key mechanistic insights into how PTBA enhances tissue repair in models of acute injury and lay the groundwork for translating this novel HDI into the clinic. This article has an associated First Person interview with the joint first authors of the paper.

Endothelial cells (ECs) respond to concurrent stimulation by biochemical factors and wall shear stress (SS) exerted by blood flow. Disruptions in flow-induced responses can result in remodeling issues and cardiovascular diseases, but the detailed mechanisms linking flow-mechanical cues and biochemical signaling remain unclear. Activin receptor-like kinase 1 (ALK1) integrates SS and ALK1-ligand cues in ECs; ALK1 mutations cause hereditary hemorrhagic telangiectasia (HHT), marked by arteriovenous malformation (AVM) development. However, the mechanistic underpinnings of ALK1 signaling modulation by fluid flow and the link to AVMs remain uncertain. We recorded EC responses under varying SS magnitudes and ALK1 ligand concentrations by assaying pSMAD1/5/9 nuclear localization using a custom multi-SS microfluidic device and a custom image analysis pipeline. We extended the previously reported synergy between SS and BMP9 to include BMP10 and BMP9/10. Moreover, we demonstrated that this synergy is effective even at extremely low SS magnitudes (0.4 dyn/cm2) and ALK1 ligand range (femtogram/mL). The synergistic response to ALK1 ligands and SS requires the kinase activity of ALK1. Moreover, ALK1’s basal activity and response to minimal ligand levels depend on endocytosis, distinct from cell–cell junctions, cytoskeleton-mediated mechanosensing, or cholesterol-enriched microdomains. However, an in-depth analysis of ALK1 receptor trafficking’s molecular mechanisms requires further investigation.

To calculate the burden of 2009 pandemic influenza A (pH1N1) in the United States, we extrapolated from the Centers for Disease Control and Prevention's Emerging Infections Program laboratory-confirmed hospitalizations across the entire United States, and then corrected for underreporting. From 12 April 2009 to 10 April 2010, we estimate that approximately 60.8 million cases (range: 43.3-89.3 million), 274 304 hospitalizations (195 086—402 719), and 12 469 deaths (8868-18 306) occurred in the United States due to pH1N1. Eighty-seven percent of deaths occurred in those under 65 years of age with children and working adults having risks of hospitalization and death 4 to 7 times and 8 to 12 times greater, respectively, than estimates of impact due to seasonal influenza covering the years 1976—2001. In our study, adults 65 years of age or older were found to have rates of hospitalization and death that were up to 75% and 81%, respectively, lower than seasonal influenza. These results confirm the necessity of a concerted public health response to pH1N1.