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ABSTRACTIntroductionSuccessful neuropharmacology requires optimization of CNS drug delivery and, by extension, free drug concentrations at brain molecular targets. Detailed assessment of blood–brain barrier (BBB) physiological characteristics is necessary to achieve this goal. The ‘next frontier’ in CNS drug delivery is targeting BBB uptake transporters, an approach that requires evaluation of brain endothelial cell transport processes so that effective drug accumulation and improved therapeutic efficacy can occur.Areas coveredBBB permeability of drugs is governed by tight junction protein complexes (i.e., physical barrier) and transporters/enzymes (i.e., biochemical barrier). For most therapeutics, a component of blood-to-brain transport involves passive transcellular diffusion. Small molecule drugs that do not possess acceptable physicochemical characteristics for passive permeability may utilize putative membrane transporters for CNS uptake. While both uptake and efflux transport mechanisms are expressed at the brain microvascular endothelium, uptake transporters can be targeted for optimization of brain drug delivery and improved treatment of neurological disease states.Expert opinionUptake transporters represent a unique opportunity to optimize brain drug delivery by leveraging the endogenous biology of the BBB. A rigorous understanding of these transporters is required to improve translation from the bench to clinical trials and stimulate the development of new treatment paradigms for neurological diseases.

Recovery colleges were developed in England to support the recovery of individuals who have mental health symptoms or mental illness. They have been founded in many countries but there has been little international research on recovery colleges and no studies investigating their staffing, fidelity, or costs. We aimed to characterise recovery colleges internationally, to understand organisational and student characteristics, fidelity, and budget.

Aim To review the cost-effectiveness of strategies to improve participant recruitment and retention in randomised controlled trials.Methods All included studies from the latest Cochrane recruitment and retention reviews were considered. To identify articles published since the Cochrane reviews, electronic databases were searched until March 2021. Hand searching of conference databases and journals was also undertaken. The inclusion criteria included Studies within a Trial (SWATs). The main outcome was the incremental cost-effectiveness ratio (ICER). Quality assessment of papers used the Cochrane risk of bias 1 tool. The CRD guidance was used to assess the quality of economic evaluation. Random-effect meta-analyses were undertaken. The GRADE certainty of evidence was applied for each strategy, and Trial Forge Guidance 2 was used for strategies included in meta-analyses to evaluate the uncertainty of the findings. Cost-effectiveness ranks summarise the cost-effectiveness of all strategies.Results We identified 6569 records and included 29 SWATs (earliest conducted in 1999 and latest in 2021) including more than 35,800 participants. There is no strategy we would recommend trial teams and researchers adopt with complete statistical certainty. Recruitment strategies which could be cost-effective include financial incentives, trial-branded pens, telephone reminders and pre-notification leaflets. Retention strategies which could be cost-effective include vouchers and trial-branded pens.Conclusion Future SWATs should replicate existing recruitment and retention strategies, rather than evaluate novel ones. We recommend that economic evaluations be carried out alongside all future SWATs, costs and benefits be recorded transparently, and the cost-effectiveness of existing recruitment or retention strategies be evaluated.

IMPORTANCE: Falls and fractures are frequent and deleterious to the health of older people. Aspirin has been reported to reduce bone fragility and slow bone loss. OBJECTIVE: To determine if daily low-dose aspirin (100 mg) reduces the risk of fractures or serious falls (fall-related hospital presentations) in healthy older men and women. DESIGN, SETTING, AND PARTICIPANTS: This substudy of a double-blind, randomized, placebo-controlled trial studied older adult men and women in 16 major sites across southeastern Australia. The ASPREE-FRACTURE substudy was conducted as part of the Australian component of the ASPREE trial. Between 2010 and 2014 healthy (free of cardiovascular disease, dementia or physical disability), community-dwelling volunteers aged 70 years or older were recruited to participate in the ASPREE trial. Potentially eligible participants were identified by medical practitioners and trial personnel and were then sent a letter of invitation to participate. Interested participants were screened for suitability. Eligible participants with medical practitioner authorization and adherent to a 4-week run-in medication trial were randomized. Data were analyzed from October 17, 2019, to August 31, 2022. INTERVENTIONS: Participants in the intervention group received a daily dose of oral 100 mg enteric-coated (low-dose) aspirin. The control group received a daily identical enteric-coated placebo tablet. MAIN OUTCOMES AND MEASURES: The primary outcome of ASPREE-FRACTURE was the occurrence of any fracture. The secondary outcome was serious fall resulting in hospital presentation. RESULTS: In total, 16 703 people with a median (IQR) age of 74 (72-78) years were recruited, and 9179 (55.0%) were women. There were 8322 intervention participants and 8381 control participants included in the primary and secondary outcome analysis of 2865 fractures and 1688 serious falls over the median follow-up of 4.6 years. While there was no difference in the risk of first fracture between the intervention and control participants (hazard ratio, 0.97; 95% CI, 0.87-1.06; P = .50), aspirin was associated with a higher risk of serious falls (total falls 884 vs 804; incidence rate ratio, 1.17; 95% CI, 1.03-1.33; P = .01). Results remained unchanged in analyses that adjusted for covariates known to influence fracture and fall risk. CONCLUSIONS AND RELEVANCE: In this substudy of a randomized clinical trial, the failure of low-dose aspirin to reduce the risk of fractures while increasing the risk of serious falls adds to evidence that this agent provides little favorable benefit in a healthy, White older adult population. TRIAL REGISTRATION: This substudy is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12615000347561).

AbstractAimsThe associations of prior homelessness with current health are unknown. Using nationally representative data collected in private households in England, this study aimed to examine Common Mental Disorders (CMDs), physical health, alcohol/substance dependence, and multimorbidities in people who formerly experienced homelessness compared to people who never experienced homelessness.MethodsThis cross-sectional study utilised data from the 2007 and 2014 Adult Psychiatric Morbidity Surveys. Former homelessness and current physical health problems were self-reported. Current CMDs, alcohol dependence and substance dependence were ascertained using structured validated scales. Survey-weighted logistic regression was used to compare multimorbidities (conditions in combination) for participants who formerly experienced homelessness with those who had never experienced homelessness, adjusting for sociodemographic characteristics, smoking status and adverse experiences. Population attributable fractions (PAFs) were calculated.ResultsOf 13,859 people in the sample, 535 formerly experienced homelessness (3.6%, 95% CI 3.2–4.0). 44.8% of people who formerly experienced homelessness had CMDs (95% CI 40.2–49.5), compared to 15.0% (95% CI 14.3–15.7) for those who had never experienced homelessness. There were substantial associations between prior homelessness and physical multimorbidity (adjusted odds ratio [aOR] 1.98, 95% CI 1.53–2.57), CMD–physical multimorbidity (aOR 3.43, 95% CI 2.77–4.25), CMD–alcohol/substance multimorbidity (aOR 3.53, 95% CI 2.49–5.01) and trimorbidity (CMD–alcohol/substance–physical multimorbidity) (aOR 3.26, 95% CI 2.20–4.83), in models adjusting for sociodemographic characteristics and smoking. After further adjustment for adverse experiences, associations attenuated but persisted for physical multimorbidity (aOR 1.40, 95% CI 1.10–1.79) and CMD–physical multimorbidity (aOR 1.55, 95% CI 1.20–2.00). The largest PAFs were observed for CMD–alcohol/substance multimorbidity (17%) and trimorbidity (16%).ConclusionsEven in people currently rehoused, marked inequities across multimorbidities remained evident, highlighting the need for longer-term integrated support for people who have previously experienced homelessness.

•COVID-19 demands exposed and amplified hazards related to disposable glove manufacturing.•Glove contamination at production is consequential for users, and food or healthcare endpoints.•Loosely regulated safety and quality standards are causative factors within the glove industry.•Glove physical failures are pivotal in release of sweat build-up and liquefaction of chemical residues.•Incubation of microbial contaminants from hands and gloves can represent an additional hazard.

Objectives:We have shown that transforming growth factor-β (TGF-β)/activin-like kinase 1 (ALK1) signaling at the blood-brain barrier (BBB) can regulate organic anion transporting polypeptide 1a4 (Oatp1a4), a transporter involved in brain uptake of drugs relevant to stroke pharmacotherapy (i.e., 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (statins)). To date, the involvement of endoglin (ENG), a co-receptor that can modulate the TGF-β/ALK1 pathway, in regulation of Oatp1a4 expression/activity has not been elucidated. The objective of this study is to evaluate whether ENG plays a role in the control of BBB transport mechanisms for stroke therapeutics.Methods:Our studies were conducted using the immortalized mouse brain endothelial cell line bEnd.3. Endoglin knockdown mutants were generated through lentiviral transfection of ENG-shRNA and validated using confocal microscopy and western blot analysis. Cells were then treated with bone morphogenetic protein-9 (BMP-9; 1 nM), a known TGF-β/ALK1 agonist. Oatp1a4 protein expression and transport activity were measured using western blot analysis and in vitrouptake assays using the known Oatp substrate drug [3H]atorvastatin. Additionally, ENG expression in bEnd.3 cells was assessed under normoxic and oxygen/glucose deprivation (OGD) conditions (i.e., 1% O2in glucose-free medium).Results:BMP-9 treatment in non-transfected bEnd.3 cells resulted in increased Oatp1a4 protein expression and increased cellular uptake of [3H]atorvastatin. These enhancements in Oatp1a4 functional expression were attenuated in ENG-shRNA knockdown bEnd.3 cells treated with BMP-9. Confocal microscopy and western blot analysis confirmed decreased ENG protein expression following shRNA transfection. Under OGD conditions, expression of ENG in bEnd.3 cells was significantly increased.Conclusions:Our data provide the first evidence for involvement of ENG in regulation of Oatp1a4 by TGF-β/ALK1 signaling in brain microvessel endothelial cells. These observations have clear implications for CNS delivery of drugs relevant to treatment of stroke. Studies are ongoing in our laboratory to fully evaluate ENG regulation of BBB transport mechanisms in the setting of ischemic stroke.

Purpose:Cationic drugs have often been considered for stroke treatment but their utility is dependent upondelivery across the blood-brain barrier (BBB). This process can involve transporters for cationic substratessuch as organic cation transporters 1 and 2 (Oct1 and Oct2) as well as the multidrug and toxin extruder 1(Mate1). The goal of this study was to show that the Oct/Mate system at the BBB represents an endogenoustransporter mechanism that can be exploited for efficient brain delivery of cationic drugs relevant to stroketherapy.Methods:Male Sprague-Dawley rats (200-250 g) were subjected to middle cerebral artery occlusion (MCAO;90 minutes) followed by reperfusion. Sham-operated rats were used as controls. Memantine (5 mg/kg, i.v.), arepresentative cationic neuroprotective drug, was injected 2 h following intraluminal suture removal in thepresence and absence of cimetidine (15 mg/kg, i.v.), an inhibitor of cation transporters. Localization andprotein expression of Oct1, Oct2, and Mate1 were evaluated by confocal microscopy and western blottingrespectively. Progression of cerebral infarction volume was determined via TTC-stained brain slices.Neurological and motor outcomes during the acute (1 day) and subacute (3-7 days) recovery period post-stroke were assessed using functional neuroscores (i.e., based upon the modified Rankin Scale) and rotorodanalysis.Results:Localization and protein expression of Oct1, Oct2, and Mate1 were confirmed in cerebralmicrovessels isolated from Sprague-Dawley rats subjected to MCAO and in Sham controls. Memantinereduced progression of cerebral infarction, reduced neurological scores, and improved rotorod performanceduring the acute and subacute recovery periods following MCAO. Pharmacological effectiveness of memantinewas decreased in the presence of cimetidine.Conclusions:Our data show that memantine cannot exert beneficial effects during acute and subacute post-stroke recovery without functional expression of endogenous transporters for organic cations (i.e., Oct1, Oct2,and Mate1) at the BBB. This work is highly translational and emphasizes the critical need to evaluate BBBtransport mechanisms during preclinical development of drugs for ischemic stroke treatment.

Clinical development of new drugs for ischemic stroke has been challenging. In contrast, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (i.e., statins) are routinely administered to stroke patients because they improve neurological outcomes. This property of statins requires delivery across the blood-brain barrier (BBB). We have uncovered a BBB uptake transporter for statins: organic anion transporting polypeptide 1a4 (Oatp1a4). Our goal was to determine whether Oatp-mediated transport at the BBB is a required mechanism for a commonly prescribed statin (i.e., atorvastatin; ATV) to exert neuroprotective effects following ischemic stroke.Methods:Male Sprague-Dawley rats (200-250 g) were subjected to middle cerebral artery occlusion (MCAO; 90 min) followed by reperfusion. ATV (20 mg/kg, i.v.) was administered 2 h following intraluminal suture removal. Involvement of Oatp-mediated transport was determined using fexofenadine (FEX; 3.2 mg/kg, i.v.), a competitive Oatp inhibitor. Oatp1a4 transport activity was measured by in situbrain perfusion. Following MCAO/reperfusion, infarction volumes and brain edema ratios were calculated from TTC-stained brain tissue slices. Hippocampal neuronal cell numbers were assessed by immunofluorescence imaging of neuronal nuclei (NeuN) staining. Post-stroke functional outcomes were assessed via neurological deficit scores and rotarod analysis. At 2 h post-MCAO, ATV uptake was increased in ischemic brain tissue. FEX blocked blood-to-brain uptake of ATV, which confirmed involvement of an Oatp-mediated transport mechanism. ATV reduced post-MCAO infarction volume and brain edema ratio, increased hippocampal NeuN staining, and improved neurological outcomes. All positive effects of ATV were attenuated by co-administration of FEX.Conclusions:Our data demonstrate ATV requires functional expression of an endogenous BBB transporter (i.e., Oatp1a4) to exert neuroprotective effects and promote post-stroke recovery. These novel and translational findings provide mechanistic evidence on the critical role of BBB transporters in delivery of stroke drugs to the ischemic brain, information that can facilitate therapeutic advancement in clinical trials.

BackgroundLittle is known about the role of air pollution in how people with dementia use mental health services.ObjectiveWe examined longitudinal associations between air pollution exposure and mental health service use in people with dementia.MethodsIn 5024 people aged 65 years or older with dementia in South London, high resolution estimates of nitrogen dioxide (NO2) and particulate matter (PM2.5and PM10) levels in ambient air were linked to residential addresses. Associations between air pollution and Community Mental Health Team (CMHT) events (recorded over 9 years) were examined using negative binomial regression models. Cognitive function was measured using the Mini Mental State Examination (MMSE) and health and social functioning was measured using the Health of the Nation Outcomes Scale (HoNOS65+). Associations between air pollution and both MMSE and HoNOS65+ scores were assessed using linear regression models.FindingsIn the first year of follow-up, increased exposure to all air pollutants was associated with an increase in the use of CMHTs in a dose-response manner. These associations were strongest when we compared the highest air pollution quartile (quartile 4: Q4) with the lowest quartile (Q1) (eg, NO2: adjusted incidence rate ratio (aIRR) 1.27, 95% CI 1.11 to 1.45, p<0.001). Dose-response patterns between PM2.5and CMHT events remained at 5 and 9 years. Associations were strongest for patients with vascular dementia. NO2levels were linked with poor functional status, but not cognitive function.ConclusionsResidential air pollution exposure is associated with increased CMHT usage among people with dementia.Clinical implicationsEfforts to reduce pollutant exposures in urban settings might reduce the use of mental health services in people with dementia, freeing up resources in already considerably stretched psychiatric services.