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.

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.

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.

Removal of user fees and system strengthening improves access to maternity care, reducing neonatal mortality in a district hospital in Lesotho.

OBJECTIVE: Lesotho has one of the highest maternal mortality rates in the world. While at primary health care (PHC) level maternity care is free, at hospital level co-payments are required from patients. We describe service utilisation and delivery outcomes before and after removal of user fees and quality of delivery care, and associated costs, at St Joseph's Hospital (SJH) in Roma, Lesotho. METHODS: We compared utilisation of delivery services, stillbirths and maternal and neonatal mortality for the periods before (1 July 2012 to 31 December 2013) and after (1 January 2014 to 30 June 2015) user fee removal through a retrospective chart review and estimated additional costs attributed to user fee removal from provider (hospital) and patient perspectives. RESULTS: Of 4715 deliveries 3855 were at SJH and 860 at PHC centres. Of women delivering at SJH 684 (18.5%) were ≤19 years and 894 (23.6%) were HIV positive. After user fee removal hospital deliveries increased by 49% - from 1547 to 2308 - and neonatal mortality decreased from 4.8 to 1.3 per 1000 live births (P = 0.033). Extrapolating costs to the entire country, 1 USD per capita per year would allow user fee removal at hospital level, the provision of free transport to/from and accommodation at hospital. CONCLUSION: Removing user fees for hospital delivery care in Lesotho is feasible and affordable, and has the potential to improve maternal and neonatal outcomes by removing financial barriers to skilled birth attendants and increasing coverage of institutional deliveries.

Trauma-Induced Uveitis and Free Air in the Anterior Chamber of Three Eastern Screech Owls (Megascops asio).

Unusual ocular abnormalities were documented in 3 wild eastern screech owls (Megascops asio) presented to a wildlife rehabilitation hospital after vehicular strike-induced trauma to the head. All 3 had anterior uveitis and free air bubbles in the anterior chamber, but none of the cases had any discernable corneal damage, either grossly or with fluorescein stain technique. Perforation of the globe at the level of the scleral ossicle was considered a possible cause. All 3 cases recovered with standard treatment for anterior uveitis, and the free air was absorbed within 10-14 days and did not appear to cause any lingering complications. The owls were later released back into the wild after demonstrating the ability to navigate obstacles in a flight cage and capture live prey.

Selective Inhibition of the Mitochondrial Permeability Transition Pore Protects against Neurodegeneration in Experimental Multiple Sclerosis.

The mitochondrial permeability transition pore is a recognized drug target for neurodegenerative conditions such as multiple sclerosis and for ischemia-reperfusion injury in the brain and heart. The peptidylprolyl isomerase, cyclophilin D (CypD, PPIF), is a positive regulator of the pore, and genetic down-regulation or knock-out improves outcomes in disease models. Current inhibitors of peptidylprolyl isomerases show no selectivity between the tightly conserved cyclophilin paralogs and exhibit significant off-target effects, immunosuppression, and toxicity. We therefore designed and synthesized a new mitochondrially targeted CypD inhibitor, JW47, using a quinolinium cation tethered to cyclosporine. X-ray analysis was used to validate the design concept, and biological evaluation revealed selective cellular inhibition of CypD and the permeability transition pore with reduced cellular toxicity compared with cyclosporine. In an experimental autoimmune encephalomyelitis disease model of neurodegeneration in multiple sclerosis, JW47 demonstrated significant protection of axons and improved motor assessments with minimal immunosuppression. These findings suggest that selective CypD inhibition may represent a viable therapeutic strategy for MS and identify quinolinium as a mitochondrial targeting group for in vivo use.

Traumatic brain injury decreases AMP-activated protein kinase activity and pharmacological enhancement of its activity improves cognitive outcome.

Prolonged metabolic suppression in the brain is a well-characterized secondary pathology of both experimental and clinical traumatic brain injury (TBI). AMP-activated kinase (AMPK) acts as a cellular energy sensor that, when activated, regulates various metabolic and catabolic pathways to decrease ATP consumption and increase ATP synthesis. As energy availability after TBI is suppressed, we questioned if increasing AMPK activity after TBI would improve cognitive outcome. TBI was delivered using the electromagnetic controlled cortical impact model on male Sprague-Dawley rats (275-300 g) and C57BL/6 mice (20-25 g). AMPK activity within the injured parietal cortex and ipsilateral hippocampus was inferred by western blots using phospho-specific antibodies. The consequences of acute manipulation of AMPK signaling on cognitive function were assessed using the Morris water maze task. We found that AMPK activity is decreased as a result of injury, as indicated by reduced AMPK phosphorylation and corresponding changes in the phosphorylation of its downstream targets: ribosomal protein S6 and Akt Substrate of 160 kDa (AS160). Increasing AMPK activity after injury using the drugs 5-amino-1-ß-d-ribofuranosyl-imidazole-4-carboxamide or metformin did not affect spatial learning, but significantly improved spatial memory. Taken together, our results suggest that decreased AMPK activity after TBI may contribute to the cellular energy crisis in the injured brain, and that AMPK activators may have therapeutic utility. Increased phosphorylation of Thr172 activates AMP-activated protein kinase (AMPK) under conditions of low cellular energy availability. This leads to inhibition of energy consuming, while activating energy generating, processes. Hill et al., present data to indicate that TBI decreases Thr172 phosphorylation and that its stimulation by pharmacological agents offers neuroprotection and improves memory. These results suggest that decreased AMPK phosphorylation after TBI incorrectly signals the injured brain that excess energy is available, thereby contributing to the cellular energy crisis and memory impairments.

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.

Tuberculosis and HIV co-infection, California, USA, 1993­2008.

To understand the epidemiology of tuberculosis (TB) and HIV co-infection in California, we cross-matched incident TB cases reported to state surveillance systems during 1993­2008 with cases in the state HIV/AIDS registry. Of 57,527 TB case-patients, 3,904 (7%) had known HIV infection. TB rates for persons with HIV declined from 437 to 126 cases/100,000 persons during 1993­2008; rates were highest for Hispanics (225/100,000) and Blacks (148/100,000). Patients co-infected with TB­HIV during 2001­2008 were significantly more likely than those infected before highly active antiretroviral therapy became available to be foreign born, Hispanic, or Asian/Pacific Islander and to have pyrazinamide-monoresistant TB. Death rates decreased after highly active antiretroviral therapy became available but remained twice that for TB patients without HIV infection and higher for women. In California, HIV-associated TB has concentrated among persons from low- and middle-income countries who often acquire HIV infection in the peri-immigration period.

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.

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.

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.

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.

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.