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A primary barrier to translation of clinical research discoveries into care delivery and population health is the lack of sustainable infrastructure bringing researchers, policymakers, practitioners, and communities together to reduce silos in knowledge and action. As National Institutes of Healthʼs (NIH) mechanism to advance translational research, Clinical and Translational Science Award (CTSA) awardees are uniquely positioned to bridge this gap. Delivering on this promise requires sustained collaboration and alignment between research institutions and public health and healthcare programs and services. We describe the collaboration of seven CTSA hubs with city, county, and state healthcare and public health organizations striving to realize this vision together. Partnership representatives convened monthly to identify key components, common and unique themes, and barriers in academic–public collaborations. All partnerships aligned the activities of the CTSA programs with the needs of the city/county/state partners, by sharing resources, responding to real-time policy questions and training needs, promoting best practices, and advancing community-engaged research, and dissemination and implementation science to narrow the knowledge-to-practice gap. Barriers included competing priorities, differing timelines, bureaucratic hurdles, and unstable funding. Academic–public health/health system partnerships represent a unique and underutilized model with potential to enhance community and population health.

ABSTRACT IMPACT: Effective healthcare interventions improve access, quality of care, and health outcomes for underserved, high-disparity populations of Los Angeles county and beyond. OBJECTIVES/GOALS: We will expand our successful, Los Angeles-based public-academic partnership to develop and evaluate health system interventions aimed at improving healthcare for underserved communities, as well as develop workforce skilled in healthcare delivery science. METHODS/STUDY POPULATION: Together with the LA County Department of Health Services, the two LA-based CTSA hubs at USC and UCLA have established critical infrastructure for effective cross-sector translational research: (1) New funding mechanisms to evaluate health system interventions in county hospitals and clinics in areas of mutual interest; (2) Specialized research service cores (Safety-net Health Innovation core, Clinical Research Informatics core, and Healthcare Delivery Science core), and (3) Training and mentorship programs tailored for healthcare delivery scientists. RESULTS/ANTICIPATED RESULTS: Outcomes from the first four years of the partnership include: (1) Significant impact on health outcomes from eight funded projects, e.g., lowered A1c levels by 0.9%; (2) Successful, coordinated service to dozens of research projects, e.g., a teleretinal screening program decreased ophthalmology visit wait times from 158 to 17 days; (3) New virtual coursework in seven domains (healthcare delivery science, dissemination and implementation science, systems engineering, behavioral economics, informatics, team science, and community engagement); (4) A published ‘synergy paper’ w/ CTSA hubs in three other urban cities examining common themes of academic-public partnerships; and (5) Rapid and streamlined COVID-19 research policy setting with county leadership. DISCUSSION/SIGNIFICANCE OF FINDINGS: Our sustainable infrastructure is effectively bridging research-policy-practice gaps in Los Angeles and addressing patients’ and the health system’s priorities.

[This corrects the article DOI: 10.1017/cts.2020.23.].

Dipeptidyl peptidase-IV (DPP-IV) inhibitorsrepresent a new class of oral antihyperglycemic agents. Sitagliptin is an orally active and selective DPP-IV inhibitor currently in Phase III development for the treatment of type 2 diabetes mellitus. The aim of this study was to assess the pharmacokinetic and pharmacodynamic (PK/PD) properties and tolerability of multiple oral once-daily or twice-daily doses of sitagliptin. This double-blind, randomized, placebo-controlled,incremental oral-dose study was conducted at SGS Biopharma, Antwerp, Belgium. Healthy, nonsmoking male volunteers aged 18 to 45 years with a creatinine clearance rate of >80 mL/min and normoglycemia and weighing within 15% of their ideal height/weight range were randomly assigned to 1 of 8 treatment groups: sitagliptin 25, 50, 100, 200, or 400 mg or placebo, QD for 10 days; a single dose of sitagliptin 800 mg administered on day 1 followed by 600 mg QD on days 3 to 10; or sitagliptin 300 mg BID for 10 days. For analysis of PK properties, plasma and urine samples were obtained before study drug administration on day 1 and at 0.5, 1, 2, 4, 6, 8, 10, 12, and 16 hours after study drug administration on day 1; before study drug administration on days 2 to 9; and every 24 hours for 96 hours after the last dose on day 10, and analyzed for sitagliptin concentrations. Assays were used to measure inhibition of plasma DPP-IV activity and plasma concentrations of active and total glucagon-like peptide-1 (GLP-1), glucose, and glucagon, and serum concentrations of insulin, C-peptide, insulin-like growth factor-1, and insulin like growth factor binding protein-3. Tolerability was assessed throughout the study using physical examination, including vital sign measurements; 12-lead electrocardiography; and laboratory analysis, including hematology, biochemistry (hepatic aminotransferase and creatine phosphokinase), and urinalysis. Seventy subjects were enrolled (mean age, 32.9 years [range, 18–45 years]; mean weight, 79.7 kg [range, 63.4–97.7 kg]; 8 patients per sitagliptin study group and 14 patients in the control group). In the sitagliptin groups, the plasma concentration-time profiles and principal PK parameters (T max, C max, and t ½) were statistically similar at days 1 (single dose) and 10 (steady state). In the groups receiving sitagliptin QD doses, accumulation of sitagliptin was modest (AUC accumulation ratio [day 10/day 1] range, 1.05–1.29), and the apparent terminal elimination t ½ was 11.8 to 14.4 hours. At steady state in the sitagliptin QD groups, the mean proportion of drug excreted unchanged in the urine was ∼70.6%. Dose-dependent inhibition of plasma DPP-IV activity was apparent, and the pattern of inhibition at steady state (day 10) was statistically similar to that observed on day 1. Day-10 weighted mean inhibition of plasma DPP-IV activity over 24 hours was ≥ 80% for doses of ≥ 50 mg QD. After a standard meal, active GLP-1 concentrations were significantly increased in the sitagliptin groups by ∼2-fold compared with that in the control group, a finding consistent with near-maximal acute glucose lowering in preclinical studies. Across doses, no apparent adverse effects, including hypoglycemia, were found or reported. The results from this study in a select population of healthy male volunteers suggest that multiple oral doses of sitagliptin inhibited plasma DPP-IV activity and affected active GLP-1 concentrations in a dose-dependent manner, without producing hypoglycemia. Multiple dosing of sitagliptin exhibited a PK/PD profile consistent with that of a QD regimen and was well tolerated.

Lavinia Paternoster and colleagues report the results of a large, multi-ancestry genome-wide association study of atopic dermatitis. They identify ten new susceptibility loci harboring candidate genes involved in innate host defense and T cell function. Genetic association studies have identified 21 loci associated with atopic dermatitis risk predominantly in populations of European ancestry. To identify further susceptibility loci for this common, complex skin disease, we performed a meta-analysis of >15 million genetic variants in 21,399 cases and 95,464 controls from populations of European, African, Japanese and Latino ancestry, followed by replication in 32,059 cases and 228,628 controls from 18 studies. We identified ten new risk loci, bringing the total number of known atopic dermatitis risk loci to 31 (with new secondary signals at four of these loci). Notably, the new loci include candidate genes with roles in the regulation of innate host defenses and T cell function, underscoring the important contribution of (auto)immune mechanisms to atopic dermatitis pathogenesis.

AbstractObjectiveTo determine if virtual care with remote automated monitoring (RAM) technology versus standard care increases days alive at home among adults discharged after non-elective surgery during the covid-19 pandemic.DesignMulticentre randomised controlled trial.Setting8 acute care hospitals in Canada.Participants905 adults (≥40 years) who resided in areas with mobile phone coverage and were to be discharged from hospital after non-elective surgery were randomised either to virtual care and RAM (n=451) or to standard care (n=454). 903 participants (99.8%) completed the 31 day follow-up.InterventionParticipants in the experimental group received a tablet computer and RAM technology that measured blood pressure, heart rate, respiratory rate, oxygen saturation, temperature, and body weight. For 30 days the participants took daily biophysical measurements and photographs of their wound and interacted with nurses virtually. Participants in the standard care group received post-hospital discharge management according to the centre’s usual care. Patients, healthcare providers, and data collectors were aware of patients’ group allocations. Outcome adjudicators were blinded to group allocation.Main outcome measuresThe primary outcome was days alive at home during 31 days of follow-up. The 12 secondary outcomes included acute hospital care, detection and correction of drug errors, and pain at 7, 15, and 30 days after randomisation.ResultsAll 905 participants (mean age 63.1 years) were analysed in the groups to which they were randomised. Days alive at home during 31 days of follow-up were 29.7 in the virtual care group and 29.5 in the standard care group: relative risk 1.01 (95% confidence interval 0.99 to 1.02); absolute difference 0.2% (95% confidence interval −0.5% to 0.9%). 99 participants (22.0%) in the virtual care group and 124 (27.3%) in the standard care group required acute hospital care: relative risk 0.80 (0.64 to 1.01); absolute difference 5.3% (−0.3% to 10.9%). More participants in the virtual care group than standard care group had a drug error detected (134 (29.7%) v 25 (5.5%); absolute difference 24.2%, 19.5% to 28.9%) and a drug error corrected (absolute difference 24.4%, 19.9% to 28.9%). Fewer participants in the virtual care group than standard care group reported pain at 7, 15, and 30 days after randomisation: absolute differences 13.9% (7.4% to 20.4%), 11.9% (5.1% to 18.7%), and 9.6% (2.9% to 16.3%), respectively. Beneficial effects proved substantially larger in centres with a higher rate of care escalation.ConclusionVirtual care with RAM shows promise in improving outcomes important to patients and to optimal health system function.Trial registrationClinicalTrials.gov NCT04344665.

BACE1 is a key enzyme for amyloid-β (Aβ) production, and an attractive therapeutic target in Alzheimer's disease (AD). Here we report that BACE1 inhibitors have distinct effects on neuronal Aβ metabolism, inducing a unique pattern of secreted Aβ peptides, analyzed in cell media from amyloid precursor protein (APP) transfected cells and in cerebrospinal fluid (CSF) from dogs by immunoprecipitation-mass spectrometry, using several different BACE1 inhibitors. Besides the expected reductions in Aβ1-40 and Aβ1-42, treatment also changed the relative levels of several other Aβ isoforms. In particular Aβ1-34 decreased, while Aβ5-40 increased, and these changes were more sensitive to BACE1 inhibition than the changes in Aβ1-40 and Aβ1-42. The effects on Aβ5-40 indicate the presence of a BACE1 independent pathway of APP degradation. The described CSF Aβ pattern may be used as a pharmacodynamic fingerprint to detect biochemical effects of BACE1-therapies in clinical trials, which might accelerate development of novel therapies.

ObjectivePharmacokinetic variability drives tuberculosis (TB) treatment outcomes but measurement of serum drug concentrations for personalised dosing is inaccessible for children in TB-endemic settings. We compared rifampin urine excretion for prediction of a serum target associated with treatment outcome.DesignProspective diagnostic accuracy study.SettingInpatient wards and outpatient clinics, northern Tanzania.PatientsChildren aged 4–17 years were consecutively recruited on initiation of WHO-approved treatment regimens.InterventionsSamples were collected after directly observed therapy at least 2 weeks after initiation in the intensive phase: serum at pre-dose and 1, 2 and 6 hours post-dose, later analysed by liquid chromatography-tandem mass spectrometry for calculation of rifampin total exposure or area under the concentration time curve (AUC0-24); urine at post-dose intervals of 0–4, 4–8 and 8–24 hours, with rifampin excretion amount measured onsite by spectrophotometry.Main outcome measuresReceiver operating characteristic (ROC) curve for percentage of rifampin dose excreted in urine measured by spectrophotometry to predict serum rifampin AUC0–24 target of 31.7 mg*hour/L.Results89 children, 52 (58%) female, with median age of 9.1 years, had both serum and urine collection. Only 59 (66%) reached the serum AUC0–24 target, reflected by a range of urine excretion patterns. Area under the ROC curve for percentage of rifampin dose excreted in urine over 24 hours predicting serum AUC0–24 target was 69.3% (95% CI 56.7% to 81.8%), p=0.007.ConclusionsUrine spectrophotometry correlated with a clinically relevant serum target for rifampin, representing a step toward personalised dosing for children in TB-endemic settings.

Affiliation: Department of Public Health, Neglected Tropical Diseases Division, Federal Ministry of Health, Abuja, Nigeria Wilfred Etienne Batcho ¶‡ These authors also contributed equally to this work. Affiliation: Disease Control Division, Ministry of Health, Putrajaya, Malaysia Ibrahim J. Kargbo-Labour ¶‡ These authors also contributed equally to this work. Since the London Declaration in 2012, about 31 countries have eliminated at least one NTD [2]. [...]of Merck’s commitment and the partnerships developed to distribute ivermectin, mass drug administration (MDA) has emerged as the leading strategy to control and eliminate oncho [4].