Delocalized quinolinium-macrocyclic peptides, an atypical chemotype for CNS penetration.

Macrocyclic drugs can address an increasing range of molecular targets but enabling central nervous system (CNS) access to these drugs has been viewed as an intractable problem. We designed and synthesized a series of quinolinium-modified cyclosporine derivatives targeted to the mitochondrial cyclophilin D protein. Modification of the cation to enable greater delocalization was confirmed by x-ray crystallography of the cations. Critically, greater delocalization improved brain concentrations. Assessment of the compounds in preclinical assays and for pharmacokinetics identified a molecule JP1-138 with at least 20 times the brain levels of a non-delocalized compound or those reported for cyclosporine. Levels were maintained over 24 hours together with low hERG potential. The paradigm outlined here could have widespread utility in the treatment of CNS diseases.

Barriers and Facilitators to Accessing and Utilizing Medicaid Smartphone Services: Perspectives of Peer Support Specialists and Patients with a Diagnosis of a Serious Mental Illness.

Access to smartphone and data plan services may impact levels of connection and opportunities for health management for patients with a diagnosis of a serious mental illness. Such smartphone-based services provide opportunities that extend the reach of physical and mental health care programs. The purpose of this study was to explore barriers and facilitators faced by individuals with mental health challenges when accessing Medicaid SafeLink smartphones and data plans. Interview guides were developed using the Consolidated Framework for Implementation Research. Individual semi-structured interviews were conducted to collect qualitative data on 18 participants' experiences with SafeLink services. Two main themes were identified- barriers and facilitators. Sub-themes included monthly data limits, followed by account management (barriers), opportunities for safety, and connection (facilitators). Massachusetts SafeLink policies provide individuals with an opportunity for smartphone ownership. However, results imply that expanding the current policy's usage limits may provide additional opportunities for connection and access to health services.

Factors influencing imaging clinical decision-making in low back pain management. A scoping review.

BACKGROUND: The use of diagnostic imaging in low back pain (LBP) management is often inappropriate, despite recommendations from clinical practice guidelines. There is a limited understanding of factors that influence the imaging clinical decision-making (CDM) process. AIM: Explore the literature on factors influencing imaging CDM for people with LBP and consider how these findings could be used to reduce inappropriate use of imaging in LBP management. DESIGN: Scoping review. METHOD: This review followed the Preferred Reporting Items for Systematic Review extension for scoping reviews. A digital search was conducted in Medline, the Cumulative Index of Nursing and Allied Health Literature, Scopus, and the Cochrane Central Register of Controlled Trials for eligible studies published between January 2010-2023. Data reporting influences on imaging CDM were extracted. Data were then analysed through an inductive process to group the influencing factors into categories. RESULTS: After screening, 35 studies (5 qualitative and 30 quantitative) were included in the review, which reported factors influencing imaging CDM. Three categories were developed: clinical features (such as red flags, pain, and neurological deficit), non-modifiable factors (such as age, sex, and ethnicity) and modifiable factors (such as beliefs about consequences and clinical practice). Most studies reported non-modifiable factors. CONCLUSIONS: The results of this scoping review challenge the perception that imaging CDM is purely based on clinical history and objective findings. There is a complex interplay between clinical features, patient and clinician characteristics, beliefs, and environment. These findings should be considered when designing strategies to address inappropriate imaging behaviour.

Effectiveness of non-pharmacological interventions delivered at home for urinary and faecal incontinence with homebound older people: systematic review of randomised controlled trials.

INTRODUCTION: Incontinence is a common, distressing condition, most prevalent in older people. There is an unmet need for effective interventions to support continence. This review focuses on non-pharmacological interventions to reduce incontinence among homebound older people. Aim: to identify interventions with potential to be delivered by care workers, nurses or family members in a person's home. METHODS: Multiple databases were searched until 15 September 2023 for randomised controlled trials reporting home-based interventions for incontinence for older people (≥65 years) living at home. Two reviewers independently screened titles, abstracts and papers against inclusion criteria, then assessed for the Risk of Bias (RoB2). A third reviewer resolved the discrepancies. Primary data were extracted and synthesised. RESULTS: A full-text review of 81 papers identified seven eligible papers (1996-2022, all USA), including n = 636 participants (561 women and 75 men). Two studies focusing on multicomponent behavioural interventions showed benefit, as did one study of transcutaneous tibial nerve stimulation self-administered through electrode-embedded socks. Three, which included cognitively impaired people, reported improvement with toileting assistance programmes, but the effects were not all significant. Results were inconclusive from a study examining the effects of fluid intake adjustments. Interventions were delivered by nurses, three in collaboration with family caregivers. No faecal incontinence interventions met the criteria. CONCLUSION: There is scant evidence for continence supporting interventions delivered in older people's own homes. With an ageing population often reliant on family or social care workers well-placed to support continence promotion and policy drives for services to support older people remaining at home, this evidence gap needs addressing.

New Zealanders with low back pain seeking health care: a retrospective descriptive analysis of Accident Compensation Corporation-funded low back pain healthcare service usage.

Introduction Most New Zealanders experience low back pain (LBP) at least once throughout their lifetime and many seek help from the large range of health providers in primary care. Accident Compensation Corporation (ACC) funds a significant proportion of those claims, but which services are they funding and what are the costs? Method This was a retrospective audit and descriptive analysis of ACC-funded, non-public hospital healthcare service use by people with LBP in New Zealand (NZ). Outcome measures were the healthcare services accessed by people with ACC-funded LBP,the claims (all occurrences for a service that has generated a payment/year), single contact (with a service), and costs (NZ$) for services between 2009 and 2020. Results The number of claims for services were 129 000 for physiotherapy, 105 000 for general practitioner and 59 000 for radiology services. Per single contact, elective surgery and radiology services were the most expensive. During 2009-2020, there were 3.3 million ACC claims for LBP with a total cost of NZ$4 billion. Over this time, there was an increase in claims, costs and single contacts. Costs decreased slightly during 2010 due to changes in healthcare funding and in 2020 due to the COVID-19 pandemic. Discussion Consumers have considerable choice in where they access health care for ACC-funded LBP services. This study shows the services they use most frequently and the cost to NZ for those services. These data can inform service planning for ACC-funded LBP health care in NZ.

Prospective Association Between Video and Computer Game Use During Adolescence and Incidence of Metabolic Health Risks: Secondary Data Analysis.

BACKGROUND: Video and computer games are popular activities, with 72% of adolescents aged 13 to 17 years reporting video game use on either a computer, game console, or portable device. Despite high levels of video and computer game use in adolescence, relatively little scientific literature exists examining the association and effects of video and computer games on adolescents. OBJECTIVE: The objective of this study was to examine the prevalence of video and computer game use among US adolescents and rates of positive screens for obesity, diabetes, high blood pressure (BP), and high cholesterol. METHODS: A secondary data analysis was conducted using the National Longitudinal Study of Adolescent to Adult Health (Add Health) data, including adolescents aged 12 to 19 years between 1994 and 2018. RESULTS: Respondents (n=4190) who played the most video and computer games had a significantly (P=.02) higher BMI and were more likely to self-report having at least one of the evaluated metabolic disorders: obesity (BMI >30 kg/m2), diabetes, high BP (BP >140/90), and high cholesterol (>240). With increased video or computer game use, there was a statistically significant increase in high BP rates in each quartile, with those with more frequent use also having higher rates of high BP. A similar trend was observed for diabetes, though the association did not reach statistical significance. No significant association was observed between video or computer game use and diagnoses of dyslipidemia, eating disorders, or depression. CONCLUSIONS: Frequency of video and computer game use is associated with obesity, diabetes, high BP, and high cholesterol in adolescents aged 12 to 19 years. Adolescents who play the most video and computer games have a significantly higher BMI. They are more likely to have at least one of the evaluated metabolic disorders: diabetes, high BP, or high cholesterol. Public health interventions designed to target modifiable disease states through health promotion and self-management may support the health of adolescents aged 12 to 19 years. Video and computer games can integrate health promotion interventions in gameplay. This is an important area for future research as video and computer games are integrated into the lives of adolescents.

Introduction to the Coproduction of Supervision Standards for Digital Peer Support: Qualitative Study.

BACKGROUND: Digital peer support enhances engagement in mental and physical health services despite barriers such as location, transportation, and other accessibility constraints. Digital peer support involves live or automated peer support services delivered through technology media such as peer-to-peer networks, smartphone apps, and asynchronous and synchronous technologies. Supervision standards for digital peer support can determine important administrative, educative, and supportive guidelines for supervisors to maintain the practice of competent digital peer support, develop knowledgeable and skilled digital peer support specialists, clarify the role and responsibility of digital peer support specialists, and support specialists in both an emotional and developmental capacity. OBJECTIVE: Although digital peer support has expanded recently, there are no formal digital supervision standards. The aim of this study is to inform the development of supervision standards for digital peer support and introduce guidelines that supervisors can use to support, guide, and develop competencies in digital peer support specialists. METHODS: Peer support specialists that currently offer digital peer support services were recruited via an international email listserv of 1500 peer support specialists. Four 1-hour focus groups, with a total of 59 participants, took place in October 2020. Researchers used Rapid and Rigorous Qualitative Data Analysis methods. Researchers presented data transcripts to focus group participants for feedback and to determine if the researcher's interpretation of the data match their intended meanings. RESULTS: We identified 51 codes and 11 themes related to the development of supervision standards for digital peer support. Themes included (1) education on technology competency (43/197, 21.8%), (2) education on privacy, security, and confidentiality in digital devices and platforms (33/197, 16.8%), (3) education on peer support competencies and how they relate to digital peer support (25/197, 12.7%), (4) administrative guidelines (21/197, 10.7%), (5) education on the digital delivery of peer support (18/197, 9.1%), (6) education on technology access (17/197, 8.6%), (7) supervisor support of work-life balance (17/197, 8.6%), (8) emotional support (9/197, 4.6%), (9) administrative documentation (6/197, 3%), (10) education on suicide and crisis intervention (5/197, 2.5%), and (11) feedback (3/197, 1.5%). CONCLUSIONS: Currently, supervision standards from the Substance Abuse and Mental Health Services Administration (SAMHSA) for in-person peer support include administrative, educative, and supportive functions. However, digital peer support has necessitated supervision standard subthemes such as education on technology and privacy, support of work-life balance, and emotional support. Lack of digital supervision standards may lead to a breach in ethics and confidentiality, workforce stress, loss of productivity, loss of boundaries, and ineffectively serving users who participate in digital peer support services. Digital peer support specialists require specific knowledge and skills to communicate with service users and deliver peer support effectively, while supervisors require new knowledge and skills to effectively develop, support, and manage the digital peer support role.

Lived Experience-Led Research Agenda to Address Early Death in People With a Diagnosis of a Serious Mental Illness: A Consensus Statement.

Importance: People with serious mental illness (SMI), defined as a diagnosis of schizophrenia spectrum disorder, bipolar disorder, or disabling major depressive disorder) die approximately 10 to 25 years earlier than the general population. Objective: To develop the first-ever lived experience-led research agenda to address early mortality in people with SMI. Evidence Review: A virtual 2-day roundtable comprising 40 individuals convened on May 24 and May 26, 2022, and used a virtual Delphi method to arrive at expert group consensus. Participants responded to 6 rounds of virtual Delphi discussion via email that prioritized research topics and agreement on recommendations. The roundtable was composed of individuals with lived experience of mental health and/or substance misuse, peer support specialists, recovery coaches, parents and caregivers of people with SMI, researchers and clinician-scientists with and without lived experience, policy makers, and patient-led organizations. Twenty-two of 28 (78.6%) of the authors who provided data represented people with lived experiences. Roundtable members were selected by reviewing the peer-reviewed and gray literature on early mortality and SMI, direct email, and snowball sampling. Findings: The following recommendations are presented in order of priority as identified by the roundtable participants: (1) improve the empirical understanding of the direct and indirect social and biological contributions of trauma on morbidity and early mortality; (2) advance the role of family, extended families, and informal supporters; (3) recognize the importance of co-occurring disorders and early mortality; (4) redefine clinical education to reduce stigma and support clinicians through technological advancements to improve diagnostic accuracy; (5) examine outcomes meaningful to people with an SMI diagnosis, such as loneliness and sense of belonging, and stigma and their complex relationship with early mortality; (6) advance the science of pharmaceuticals, drug discovery, and choice in medication use; (7) use precision medicine to inform treatment; and (8) redefine the terms system literacy and health literacy. Conclusions and Relevance: The recommendations of this roundtable are a starting point for changing practice and highlighting lived experience-led research priorities as an option to move the field forward.

Certified Peer Support Specialists Training in Technology and Delivery of Digital Peer Support Services: Cross-sectional Study.

BACKGROUND: When the COVID-19 pandemic lockdown measures were instituted, the wide-scale necessity for remote mental health care increased among professional clinicians, such as psychiatrists, psychologists, social workers, and certified peer support (CPS) specialists. Factors contributing to increased demand include concern for the safety of loved ones, the safety of oneself, overall well-being, unemployment, and loneliness for older individuals. While demand continues to increase and a shortage of mental health professionals persists, understanding the training, technology, media, and delivery of digital peer support services can facilitate community-based support services to assist patients in coping with mental health symptoms between clinical encounters with licensed professionals. Digital peer support consists of asynchronous and synchronous, live or automated, peer support services such as applications, social media, and phone calls. OBJECTIVE: The purpose of this cross-sectional study is to determine how digital peer support is delivered, by which technologies it is delivered, and how certified digital peer supporters are trained within the United States to inform future delivery of digital peer support. METHODS: We used an online cross-sectional self-report survey developed alongside certified peer specialists. The study included questions regarding the types of peer support training and the delivery methods used within their practices. We advertised the survey through a certified peer support specialist listserve, Facebook, and Twitter. RESULTS: Certified peer specialists provide mutual social emotional support to those with a similar mental health condition. Of certified peer specialists trained in CPS, the majority of CPS specialists were trained in peer support (418/426, 98.1%). Peer support specialists deliver services via telephone calls (182/293, 62.1%), via videoconference-based services (160/293, 54.6%), via SMS text messages (123/293, 42%), via smartphone apps (68/293, 23.2%), and via social media (65/293, 22.2%). Certified peer specialists deliver services through virtual reality (11/293, 3.8%) and through video games (6/293, 2%). Virtual reality and video games may represent emerging technologies to develop and deliver community-based support. CONCLUSIONS: This study examined the modes of digital peer support intervention as well as the training and demographic background of peer supporters. Given the demand for mental health care, digital peer support emerges as one option to increase access. These results suggest that CPS specialists commonly use SMS text messaging, phone calls, and videoconferences to engage in peer support. Less frequently, they may use diverse modes such as apps, social media, and video games. It is important to consider the backgrounds of peer supporters and the mediums of communication to best accommodate areas where access to peer support is emerging. Larger longitudinal studies and a variety of experimental designs may be considered to understand the efficacy of digital interventions and digital peer support training to direct optimal care.

Perspectives and experiences of physiotherapists and general practitioners in the use of the STarT Back Tool: a review and meta-synthesis.

Introduction The STarT Back Tool (SBT) is used to triage people with acute low back pain (LBP) into treatment groups, matched to their risk of chronicity. It was developed in the UK where it has been shown to improve clinical outcomes, patient satisfaction, and reduce time off work. Successful implementation of the SBT outside the UK is dependent on health practitioner's attitudes and the healthcare system in which they work. Gaining health practitioners' perspectives on the SBT is an important step in implementation. Methods A computerised search of qualitative literature was conducted across seven databases in March 2021 using keywords to identify studies investigating the perspectives of physiotherapists and general practitioners on the use of the SBT in primary health care. Study quality was assessed using the Critical Appraisal Skills Programme (CASP) tool. Data were coded and analysed using reflexive thematic analysis. Results Eight articles met inclusion criteria and included the views of 76 physiotherapists and 65 general practitioners, working in primary health care in four countries. Three themes were created from the data: 'Making it work', identifies factors that influence implementation and continued use of the SBT. The second 'will I do it?', captured potential consequences of adopting the SBT, and the third, 'it's all about the patient' emphasised how the SBT may  affect patients. Discussion Physiotherapists and general practitioners found using the SBT frequently enhanced practice. General practitioners expressed concerns about time constraints and the SBT's potential to undermine clinical experience. Findings from this study will inform modifications to contextualise the tool to each healthcare environment.

Sensitivity of Acute Myelocytic Leukemia Cells to the Dienone Compound VLX1570 Is Associated with Inhibition of the Ubiquitin-Proteasome System.

Dienone compounds with a 1,5-diaryl-3-oxo-1,4-pentadienyl pharmacophore have been widely reported to show tumor cell selectivity. These compounds target the ubiquitin-proteasome system (UPS), known to be essential for the viability of tumor cells. The induction of oxidative stress, depletion of glutathione, and induction of high-molecular-weight (HMW) complexes have also been reported. We here examined the response of acute myeloid leukemia (AML) cells to the dienone compound VLX1570. AML cells have relatively high protein turnover rates and have also been reported to be sensitive to depletion of reduced glutathione. We found AML cells of diverse cytogenetic backgrounds to be sensitive to VLX1570, with drug exposure resulting in an accumulation of ubiquitin complexes, induction of ER stress, and the loss of cell viability in a dose-dependent manner. Caspase activation was observed but was not required for the loss of cell viability. Glutathione depletion was also observed but did not correlate to VLX1570 sensitivity. Formation of HMW complexes occurred at higher concentrations of VLX1570 than those required for the loss of cell viability and was not enhanced by glutathione depletion. To study the effect of VLX1570 we developed a zebrafish PDX model of AML and confirmed antigrowth activity in vivo. Our results show that VLX1570 induces UPS inhibition in AML cells and encourage further work in developing compounds useful for cancer therapeutics.

Identification and functional validation of FDA-approved positive and negative modulators of the mitochondrial calcium uniporter.

The mitochondrial calcium uniporter (MCU), the highly selective channel responsible for mitochondrial Ca2+ entry, plays important roles in physiology and pathology. However, only few pharmacological compounds directly and selectively modulate its activity. Here, we perform high-throughput screening on a US Food and Drug Administration (FDA)-approved drug library comprising 1,600 compounds to identify molecules modulating mitochondrial Ca2+ uptake. We find amorolfine and benzethonium to be positive and negative MCU modulators, respectively. In agreement with the positive effect of MCU in muscle trophism, amorolfine increases muscle size, and MCU silencing is sufficient to blunt amorolfine-induced hypertrophy. Conversely, in the triple-negative breast cancer cell line MDA-MB-231, benzethonium delays cell growth and migration in an MCU-dependent manner and protects from ceramide-induced apoptosis, in line with the role of mitochondrial Ca2+ uptake in cancer progression. Overall, we identify amorolfine and benzethonium as effective MCU-targeting drugs applicable to a wide array of experimental and disease conditions.

Reasons for discontinuing oral anticoagulation therapy for atrial fibrillation: a systematic review.

INTRODUCTION: Atrial fibrillation (AF) is the most common cardiac arrhythmia and can lead to significant comorbidities and mortality. Persistence with oral anticoagulation (OAC) is crucial to prevent stroke but rates of discontinuation are high. This systematic review explored underlying reasons for OAC discontinuation. METHODS: A systematic review was undertaken to identify studies that reported factors influencing discontinuation of OAC in AF, in 11 databases, grey literature and backwards citations from eligible studies published between 2000 and 2019. Two reviewers independently screened titles, abstracts and papers against inclusion criteria and extracted data. Study quality was appraised using Gough's weight of evidence framework. Data were synthesised narratively. RESULTS: Of 6,619 sources identified, 10 full studies and 2 abstracts met the inclusion criteria. Overall, these provided moderate appropriateness to answer the review question. Four reported clinical registry data, six were retrospective reviews of patients' medical records and two studies reported interviews and surveys. Nine studies evaluated outcomes relating to dabigatran and/or warfarin and three included rivaroxaban (n = 3), apixaban (n = 3) and edoxaban (n = 1). Bleeding complications and gastrointestinal events were the most common factors associated with discontinuation, followed by frailty and risk of falling. Patients' perspectives were seldom specifically assessed. Influence of family carers in decisions regarding OAC discontinuation was not examined. CONCLUSION: The available evidence is derived from heterogeneous studies with few relevant data for the newer direct oral anticoagulants. Reasons underpinning decision-making to discontinue OAC from the perspective of patients, family carers and clinicians is poorly understood.

Six things you need to know about low back pain.

Low back pain (LBP) is the leading contributor to years lived with disability, and imposes an enormous burden on individuals and on health-care systems. General practitioners and physiotherapists are generally the front-line health professionals dealing with patients with LBP, and have a key role in minimising its effect. Here we review six key issues associated with LBP including its effects, diagnosis and management in primary care, and highlight the importance of the biopsychosocial model and matched care for patients with LBP.

TrkB Signaling Influences Gene Expression in Cortistatin-Expressing Interneurons.

Brain-derived neurotrophic factor (BDNF) signals through its cognate receptor tropomyosin receptor kinase B (TrkB) to promote the function of several classes of inhibitory interneurons. We previously reported that loss of BDNF-TrkB signaling in cortistatin (Cort)-expressing interneurons leads to behavioral hyperactivity and spontaneous seizures in mice. We performed bulk RNA sequencing (RNA-seq) from the cortex of mice with disruption of BDNF-TrkB signaling in cortistatin interneurons, and identified differential expression of genes important for excitatory neuron function. Using translating ribosome affinity purification and RNA-seq, we define a molecular profile for Cort-expressing inhibitory neurons and subsequently compare the translatome of normal and TrkB-depleted Cort neurons, revealing alterations in calcium signaling and axon development. Several of the genes enriched in Cort neurons and differentially expressed in TrkB-depleted neurons are also implicated in autism and epilepsy. Our findings highlight TrkB-dependent molecular pathways as critical for the maturation of inhibitory interneurons and support the hypothesis that loss of BDNF signaling in Cort interneurons leads to altered excitatory/inhibitory balance.

Manipulation of a genetically and spatially defined sub-population of BDNF-expressing neurons potentiates learned fear and decreases hippocampal-prefrontal synchrony in mice.

Brain-derived neurotrophic factor (BDNF) signaling regulates synaptic plasticity in the hippocampus (HC) and prefrontal cortex (PFC), and has been extensively linked with fear memory expression in rodents. Notably, disrupting BDNF production from promoter IV-derived transcripts enhances fear expression in mice, and decreases fear-associated HC-PFC synchrony, suggesting that Bdnf transcription from promoter IV plays a key role in HC-PFC function during fear memory retrieval. To better understand how promoter IV-derived BDNF controls HC-PFC connectivity and fear expression, we generated a viral construct that selectively targets cells expressing promoter IV-derived Bdnf transcripts ("p4-cells") for tamoxifen-inducible Cre-mediated recombination (AAV8-p4Bdnf-ERT2CreERT2-PEST). Using this construct, we found that ventral hippocampal (vHC) p4-cells are recruited during fear expression, and that activation of these cells causes exaggerated fear expression that co-occurs with disrupted vHC-PFC synchrony in mice. Our data highlight how this novel construct can be used to interrogate genetically defined cell types that selectively contribute to BDNF-dependent behaviors.

Prevalence, distribution, and diversity of cryptic piroplasm infections in raccoons from selected areas of the United States and Canada.

The order Piroplasmida contains a diverse group of intracellular parasites, many of which can cause significant disease in humans, domestic animals, and wildlife. Two piroplasm species have been reported from raccoons (Procyon lotor), Babesia lotori (Babesia sensu stricto clade) and a species related to Babesia microti (called B. microti-like sp.). The goal of this study was to investigate prevalence, distribution, and diversity of Babesia in raccoons. We tested raccoons from selected regions in the United States and Canada for the presence of Babesia sensu stricto and Babesia microti-like sp. piroplasms. Infections of Babesia microti-like sp. were found in nearly all locations sampled, often with high prevalence, while Babesia sensu stricto infections had higher prevalence in the Southeastern United States (20-45% prevalence). Co-infections with both Babesia sp. were common. Sequencing of the partial 18S rRNA and cytochrome oxidase subunit 1 (cox1) genes led to the discovery of two new Babesia species, both found in several locations in the eastern and western United States. One novel Babesia sensu stricto sp. was most similar to Babesia gibsoni while the other Babesia species was present in the 'western piroplasm' group and was related to Babesia conradae. Phylogenetic analysis of the cox1 sequences indicated possible eastern and western genetic variants for the three Babesia sensu stricto species. Additional analyses are needed to characterize these novel species; however, this study indicates there are now at least four species of piroplasms infecting raccoons in the United States and Canada (Babesia microti-like sp., Babesia lotori, a novel Babesia sensu stricto sp., a novel western Babesia sp.) and a possible fifth species (Babesia sensu stricto) in raccoons in Japan.

Stock-outs of antiretroviral and tuberculosis medicines in South Africa: A national cross-sectional survey.

BACKGROUND: HIV and TB programs have rapidly scaled-up over the past decade in Sub-Saharan Africa and uninterrupted supplies of those medicines are critical to their success. However, estimates of stock-outs are largely unknown. This survey aimed to estimate the extent of stock-outs of antiretroviral and TB medicines in public health facilities across South Africa, which has the world's largest antiretroviral treatment (ART) program and a rising multidrug-resistant TB epidemic. METHODS: We conducted a cross-sectional telephonic survey (October-December 2015) of public health facilities. Facilities were asked about the prevalence of stock-outs on the day of the survey and in the preceding three months, their duration and impact. RESULTS: Nationwide, of 3547 eligible health facilities, 79% (2804) could be reached telephonically. 88% (2463) participated and 4% (93) were excluded as they did not provide ART or TB treatment. Of the 2370 included facilities, 20% (485) reported a stock-out of at least 1 ARV and/or TB-related medicine on the day of contact and 36% (864) during the three months prior to contact, ranging from 74% (163/220) of health facilities in Mpumalanga to 12% (32/261) in the Western Cape province. These 864 facilities reported 1475 individual stock-outs, with one to fourteen different medicines out of stock per facility. Information on impact was provided in 98% (1449/1475) of stock-outs: 25% (366) resulted in a high impact outcome, where patients left the facility without medicine or were provided with an incomplete regimen. Of the 757 stock-outs that were resolved 70% (527) lasted longer than one month. INTERPRETATION: There was a high prevalence of stock-outs nationwide. Large interprovincial differences in stock-out occurrence, duration, and impact suggest differences in provincial ability to prevent, mitigate and cope within the same framework. End-user monitoring of the supply chain by patients and civil society has the potential to increase transparency and complement public sector monitoring systems.

Patterns of adherence to diuretics, dietary sodium and fluid intake recommendations in adults with heart failure.

BACKGROUND: Three behaviors advocated to minimize fluid-related hospitalizations in patients with heart failure (HF) are restricted sodium and fluid intake and consistent oral diuretic use. Adherence to behaviors intended to decrease risk of hospitalization is believed to vary over time, but surprisingly little research has addressed patterns of adherence in HF patients. OBJECTIVE: To describe patterns over time of 3 recommended self-care behaviors (i.e., diet, fluid intake, and diuretic dosing) in adults with HF and to determine how time and behavior influenced adherence rates. METHODS: We enrolled 24 adults hospitalized for a HF exacerbation and discharged on a loop diuretic into a descriptive, longitudinal pilot study. Over 3-months, diuretic use was measured using electronic event monitoring, and participants were telephoned regularly to assess sodium and fluid intake. Data were summarized for each 2-week intervals. RESULTS: The overall adherence rates were 42.4% for low sodium diet, 96.4% for fluid restriction, and 84.7% for the diuretic regimen. Early after hospital discharge, medication adherence was the highest, and dietary adherence was the lowest, but adherence to diet and diuretic use decreased significantly over time. CONCLUSION: Although participants were just discharged from the hospital after an acute exacerbation of HF, all three behavioral patterns decreased markedly over the 3-month follow-up period.