Autophagy and senescence facilitate the development of antiestrogen resistance in ER positive breast cancer.

Estrogen receptor positive (ER+) breast cancer is the most common breast cancer diagnosed annually in the US with endocrine-based therapy as standard-of-care for this breast cancer subtype. Endocrine therapy includes treatment with antiestrogens, such as selective estrogen receptor modulators (SERMs), selective estrogen receptor downregulators (SERDs), and aromatase inhibitors (AIs). Despite the appreciable remission achievable with these treatments, a substantial cohort of women will experience primary tumor recurrence, subsequent metastasis, and eventual death due to their disease. In these cases, the breast cancer cells have become resistant to endocrine therapy, with endocrine resistance identified as the major obstacle to the medical oncologist and patient. To combat the development of endocrine resistance, the treatment options for ER+, HER2 negative breast cancer now include CDK4/6 inhibitors used as adjuvants to antiestrogen treatment. In addition to the dysregulated activity of CDK4/6, a plethora of genetic and biochemical mechanisms have been identified that contribute to endocrine resistance. These mechanisms, which have been identified by lab-based studies utilizing appropriate cell and animal models of breast cancer, and by clinical studies in which gene expression profiles identify candidate endocrine resistance genes, are the subject of this review. In addition, we will discuss molecular targeting strategies now utilized in conjunction with endocrine therapy to combat the development of resistance or target resistant breast cancer cells. Of approaches currently being explored to improve endocrine treatment efficacy and patient outcome, two adaptive cell survival mechanisms, autophagy, and "reversible" senescence, are considered molecular targets. Autophagy and/or senescence induction have been identified in response to most antiestrogen treatments currently being used for the treatment of ER+ breast cancer and are often induced in response to CDK4/6 inhibitors. Unfortunately, effective strategies to target these cell survival pathways have not yet been successfully developed. Thus, there is an urgent need for the continued interrogation of autophagy and "reversible" senescence in clinically relevant breast cancer models with the long-term goal of identifying new molecular targets for improved treatment of ER+ breast cancer.

Using ambulance surveillance data to characterise blood-borne viral infection histories among patients presenting with acute alcohol and other drug-related harms.

OBJECTIVE: Preventable transmission of blood-borne viruses (BBV), including human immunodeficiency virus (HIV), hepatitis C virus (HCV) and hepatitis B virus (HBV), continue in at-risk populations, including people who use alcohol and drugs (AODs). To our knowledge, no studies have explored the use of ambulance data for surveillance of AOD harms in patients with BBV infections. METHODS: We used electronic patient care records from the National Ambulance Surveillance System for people who were attended by an ambulance in Victoria, Australia between July 2015 and July 2016 for AOD-related harms, and with identified history of a BBV infection. Descriptive and geospatial analyses explored the epidemiological and psychosocial characteristics of patients for these attendances. RESULTS: The present study included 1832 patients with a history of a BBV infection who required an ambulance for AOD-related harms. Amphetamines were reported in 24.7% of attendances where the patient identified HIV history, and heroin was reported more often for patients with viral hepatitis history (HCV: 19.2%; HBV: 12.7%). Higher proportions of attendances with a viral hepatitis history were observed in patients from the most socially disadvantaged areas. Geospatial analyses revealed higher concentrations of AOD attendances with a BBV history occurring in metropolitan Melbourne. CONCLUSIONS: Our study describes the utility of ambulance data to identify a sub-population of patients with a BBV history and complex medical and social characteristics. Repeat attendances of BBV history patients to paramedics could present an opportunity for ongoing surveillance using ambulance data and possible paramedic intervention, with potential linkage to appropriate BBV services.

Adolescent Suicidal Behaviors During the COVID-19 Pandemic in Australia: Analysis of Acute Harms Assessed via Ambulance Data.

PURPOSE: This study investigated changes in suicidal ideation, attempts, and nonsuicidal self-injury (NSSI)-related ambulance attendances among adolescents during the COVID-19 pandemic. METHODS: An interrupted time series analysis using data from the National Ambulance Surveillance System, a globally unique mental health and suicide surveillance system. Patients aged 12-17 years from the state of Victoria, Australia who were attended by ambulance for suicide attempts, suicide ideation, and NSSI between January 2016 and October 2021 were included. Monthly ambulance attendances during the pre-COVID period (January 2016-March 2020) were compared to those in the peak period of COVID-19 (April 2020-October 2021). RESULTS: There were 20,125 ambulance attendances for suicide ideation, suicide attempt, and NSSI in adolescents over the study period. During the pre-COVID period, the number of suicide ideation, attempts, and NSSI attendances was increasing by 1.1% per month (incidence rate ratio [IRR]:1.011; 95% confidence interval [1.009-1.013], p < .001). There was no change in the rate of all suicide ideation, attempt, and NSSI for all adolescents during the period of COVID-19. However, when disaggregated by gender, there was a 0.7% increase in the monthly rate of attendances for females (IRR: 1.007 [1.001-1.013], p = .029), and a 3.0% decrease for males (IRR: 0.970 [0.964-0.975], p < .001). DISCUSSION: Adolescent female suicide ideation, attempt, and NSSI attendances increased during the COVID-19 period, compared with males in the same time period. These findings suggest tailored intervention strategies may be needed to address the increasing trends of self-harm among young people.

Cannabis and Driving in Older Adults.

Importance: Epidemiological studies have found that cannabis increases the risk of a motor vehicle collision. Cannabis use is increasing in older adults, but laboratory studies of the association between cannabis and driving in people aged older than 65 years are lacking. Objective: To investigate the association between cannabis, simulated driving, and concurrent blood tetrahydrocannabinol (THC) levels in older adults. Design, Setting, and Participants: Using an ecologically valid counterbalanced design, in this cohort study, regular cannabis users operated a driving simulator before, 30 minutes after, and 180 minutes after smoking their preferred legal cannabis or after resting. This study was conducted in Toronto, Canada, between March and November 2022 with no follow-up period. Data were analyzed from December 2022 to February 2023. Exposures: Most participants chose THC-dominant cannabis with a mean (SD) content of 18.74% (6.12%) THC and 1.46% (3.37%) cannabidiol (CBD). Main outcomes and measures: The primary end point was SD of lateral position (SDLP, or weaving). Secondary outcomes were mean speed (MS), maximum speed, SD of speed, and reaction time. Driving was assessed under both single-task and dual-task (distracted) conditions. Blood THC and metabolites of THC and CBD were also measured at the time of the drives. Results: A total of 31 participants (21 male [68%]; 29 White [94%], 1 Latin American [3%], and 1 mixed race [3%]; mean [SD] age, 68.7 [3.5] years), completed all study procedures. SDLP was increased and MS was decreased at 30 but not 180 minutes after smoking cannabis compared with the control condition in both the single-task (SDLP effect size [ES], 0.30; b = 1.65; 95% CI, 0.37 to 2.93; MS ES, -0.58; b = -2.46; 95% CI, -3.56 to -1.36) and dual-task (SDLP ES, 0.27; b = 1.75; 95% CI, 0.21 to 3.28; MS ES, -0.47; b = -3.15; 95% CI, -5.05 to -1.24) conditions. Blood THC levels were significantly increased at 30 minutes but not 180 minutes. Blood THC was not correlated with SDLP or MS at 30 minutes, and SDLP was not correlated with MS. Subjective ratings remained elevated for 5 hours and participants reported that they were less willing to drive at 3 hours after smoking. Conclusions and relevance: In this cohort study, the findings suggested that older drivers should exercise caution after smoking cannabis.

Opioid-related ambulance attendances during the first 2 years of the COVID-19 pandemic in Victoria, Australia.

BACKGROUND AND AIMS: Public health measures introduced to contain the spread of the SARS-CoV-2 virus likely affected opioid supply and demand, as well as the patterns and contexts of opioid use. We measured opioid-related harms during the first 2 years of COVID-19 restrictions in Victoria, Australia. DESIGN: We adopted an interrupted time series analysis design using interventional autoregressive integrated moving average (ARIMA) models. Opioid-related ambulance attendance data between January 2015 and March 2022 were extracted from the National Ambulance Surveillance System. SETTING: Victoria, Australia. PARTICIPANTS: Patients (≥15 years) attended to by an ambulance for opioid-related harms. MEASUREMENTS: Monthly opioid-related ambulance attendances for three drug types: heroin, prescription opioids and opioid agonist therapy (OAT) medications. FINDINGS: The monthly rate of heroin-related attendances fell by 26% immediately after the introduction of COVID-19 restrictions. A reduced rate of heroin-related attendances was observed during COVID-19 restrictions, resulting in 2578 averted heroin-related attendances. There was no change in the rate of attendances for extra-medical OAT medications or prescription opioids. CONCLUSIONS: Strict COVID-19 restrictions in Victoria, Australia appear to have resulted in a substantial reduction in heroin-related ambulance attendances, perhaps because of border closures and restrictions on movement affecting supply, changing patterns of drug consumption, and efforts to improve access to OAT. Despite policy changes allowing longer OAT prescriptions and an increased number of unsupervised doses, we found no evidence of increased harms related to the extra-medical use of these medications.

Testing the effectiveness and acceptability of online supportive supervision for mental health practitioners in humanitarian settings: a study protocol for the caring for carers project.

BACKGROUND: Local humanitarian workers in low and middle-income countries must often contend with potentially morally injurious situations, often with limited resources. This creates barriers to providing sustainable mental health and psychosocial support (MHPSS) to displaced individuals. Clinical supervision is an often neglected part of ensuring high-quality, sustainable care. The Caring for Carers (C4C) project aims to test the effectiveness and acceptability of online group-based supportive supervision on the well-being of MHPSS practitioners, as well as service-user-reported service satisfaction and quality when working with displaced communities in Türkiye, Syria, and Bangladesh. This protocol paper describes the aim, design, and methodology of the C4C project. METHOD: A quasi-experimental, mixed-method, community-based participatory research study will be conducted to test the effectiveness of online group-based supportive clinical supervision provided to 50 Syrian and 50 Bangladeshi MHPSS practitioners working with Syrian and Rohingya displaced communities. Monthly data will be collected from the practitioners and their beneficiaries during the active control (six months) and supervision period (16 months over two terms). Outcomes are psychological distress (Kessler-6), burnout (the Copenhagen Burnout Inventory), compassion fatigue, compassion satisfaction, and secondary traumatic stress (Professional Quality of Life Scale), perceived injustice, clinical self-efficacy (Counseling Activity Self-Efficacy Scale), service satisfaction, and quality (Client Satisfaction Questionnaire and an 18-item measure developed in this project). A realist evaluation framework will be used to elucidate the contextual factors, mechanisms, and outcomes of the supervision intervention. DISCUSSION: There is a scarcity of evidence on the role of clinical supervision in improving the well-being of MHPSS practitioners and the quality of service they provide to displaced people. By combining qualitative and quantitative data collection, the C4C project will address the long-standing question of the effectiveness and acceptability of clinical supervision in humanitarian settings.

HIV-1 subtypes maintain distinctive physicochemical signatures in Nef domains associated with immunoregulation.

BACKGROUND: HIV subtype is associated with varied rates of disease progression. The HIV accessory protein, Nef, continues to be present during antiretroviral therapy (ART) where it has numerous immunoregulatory effects. In this study, we analyzed Nef sequences from HIV subtypes A1, B, C, and D using a machine learning approach that integrates functional amino acid information to identify if unique physicochemical features are associated with Nef functional/structural domains in a subtype-specific manner. METHODS: 2253 sequences representing subtypes A1, B, C, and D were aligned and domains with known functional properties were scored based on amino acid physicochemical properties. Following feature generation, we used statistical pruning and evolved neural networks (ENNs) to determine if we could successfully classify subtypes. Next, we used ENNs to identify the top five key Nef physicochemical features applied to specific immunoregulatory domains that differentiated subtypes. A signature pattern analysis was performed to the assess amino acid diversity in sub-domains that differentiated each subtype. RESULTS: In validation studies, ENNs successfully differentiated each subtype at A1 (87.2%), subtype B (89.5%), subtype C (91.7%), and subtype D (85.1%). Our feature-based domain scoring, followed by t-tests, and a similar ENN identified subtype-specific domain-associated features. Subtype A1 was associated with alterations in Nef CD4 binding domain; subtype B was associated with alterations with the AP-2 Binding domain; subtype C was associated with alterations in a structural Alpha Helix domain; and, subtype D was associated with alterations in a Beta-Sheet domain. CONCLUSIONS: Recent studies have focused on HIV Nef as a driver of immunoregulatory disease in those HIV infected and on ART. Nef acts through a complex mixture of interactions that are directly linked to the key features of the subtype-specific domains we identified with the ENN. The study supports the hypothesis that varied Nef subtypes contribute to subtype-specific disease progression.

BRD4 Inhibition as a Strategy to Prolong the Response to Standard of Care in Estrogen Receptor-Positive Breast Cancer.

Breast cancer is the most commonly occurring malignancy in women and the second most common cause of cancer-related deaths. ER+ breast cancer constitutes approximately 70% of all breast cancer cases. The standard of care for ER+ breast cancer involves estrogen antagonists such as tamoxifen or fulvestrant in combination with CDK4/6 inhibitors such as palbociclib. However, these treatments are often not curative, with disease recurrence and metastasis being responsible for patient mortality. Overexpression of the epigenetic regulator, BRD4, has been shown to be a negative prognostic indicator in breast cancer, and BET family inhibitors such as ARV-825 and ABBV-744 have garnered interest for their potential to improve and prolong the response to current therapeutic strategies. The current work examined the potential of utilizing ARV-825 and ABBV-744 to increase the effectiveness of tamoxifen or fulvestrant plus palbociclib. ARV-825 was effective in both p53 wild-type (WT) breast tumor cells and in cells lacking functional p53 either alone or in combination with tamoxifen, while the effectiveness of ABBV-744 was limited to fulvestrant plus palbociclib in p53 WT cells. These differential effects may be related to the capacity to suppress c-Myc, a downstream target of BRD4.

Regulation of the Innate Immune System as a Therapeutic Approach to Supporting Respiratory Function in ALS.

Amyotrophic lateral sclerosis (ALS) is a clinical diagnosis used to define a neurodegenerative process that involves progressive loss of voluntary muscle function and leads to death within 2-5 years after diagnosis, in most cases because of respiratory function failure. Respiratory vital capacity (VC) measurements are reproducible and strong predictors of survival. To understand the role of the innate immune response in progressive VC loss we evaluated ALS clinical trial and biomarker results from a 6-month phase 2 study of NP001, a regulator of innate immune function. All ALS baseline values were similar between treated and controls except for those > 65 years old who were excluded from analysis. Treated patients with plasma CRP ≥ 1.13 mg/L (high CRP) showed a 64% slower rate of VC decline compared with placebo and those with plasma CRP < 1.13 mg/L (low CRP) who showed no response. High CRP patients showed no age associated loss of VC whereas low CRP patients showed an age dependent loss of VC function. Plasma levels of serum amyloid A (SAA) were similarly elevated in high CRP patients consistent with ongoing innate immune activation. Plasma TGFB1 in high CRP treated patients was 95% higher than placebo at 6-months, confirming the activation and release of this anti-inflammatory factor by the innate immune alpha 2 macroglobulin (A2M) system. This report is the first to link a biomarker confirmed regulation of the innate immune system with a therapeutic approach for controlling VC loss in ALS patients.

The Utility of THC Cutoff Levels in Blood and Saliva for Detection of Impaired Driving.

Background: Δ9-Tetrahydrocannabinol (THC) is the psychoactive component in cannabis and a relationship of THC to driving impairment is expected. Despite this, there are discrepant findings with respect to the relationship of blood THC to driving. This study investigated the relationship of blood, urine, and saliva THC/THC-COOH levels to "weaving," as measured by a driving simulator. Methods: Participants smoked cannabis alone or with alcohol. THC/THC-COOH levels in blood, urine, and saliva were correlated with standard deviation of lateral position (SDLP), measuring "weaving." In addition, SDLP after cannabis and/or alcohol were compared with SDLP after placebo when THC/THC-COOH levels were above or below specified thresholds in blood (5 ng/mL), urine (50 ng/mL), or saliva (25 ng/mL). Results: A clear linear relationship between blood THC concentration and SDLP was not observed based on calculation of Spearman coefficients. When compared with placebo, SDLP was significantly increased after cannabis and cannabis combined with alcohol when THC in the blood was above the legal limit. SDLP was increased in drug conditions when saliva cutoffs were above the legal limit. Conclusions: The findings of this study suggest that specified thresholds for THC in blood and saliva may be able to detect driving impairment, but future studies are needed. ClinicalTrials.gov ID: NCT03106363.

An Upper Bound Visualization of Design Trade-Offs in Adsorbent Materials for Gas Separations: CO2 , N2 , CH4 , H2 , O2 , Xe, Kr, and Ar Adsorbents.

The last 20 years have seen many publications investigating porous solids for gas adsorption and separation. The abundance of adsorbent materials (this work identifies 1608 materials for CO2 /N2 separation alone) provides a challenge to obtaining a comprehensive view of the field, identifying leading design strategies, and selecting materials for process modeling. In 2021, the empirical bound visualization technique was applied, analogous to the Robeson upper bound from membrane science, to alkane/alkene adsorbents. These bound visualizations reveal that adsorbent materials are limited by design trade-offs between capacity, selectivity, and heat of adsorption. The current work applies the bound visualization to adsorbents for a wider range of gas pairs, including CO2 , N2 , CH4 , H2 , Xe, O2 , and Kr. How this visual tool can identify leading materials and place new material discoveries in the context of the wider field is presented. The most promising current strategies for breaking design trade-offs are discussed, along with reproducibility of published adsorption literature, and the limitations of bound visualizations. It is hoped that this work inspires new materials that push the bounds of traditional trade-offs while also considering practical aspects critical to the use of materials on an industrial scale such as cost, stability, and sustainability.

Upregulation of the EGFR/MEK1/MAPK1/2 signaling axis as a mechanism of resistance to antiestrogen­induced BimEL dependent apoptosis in ER+ breast cancer cells.

The epidermal growth factor receptor (EGFR) is commonly upregulated in multiple cancer types, including breast cancer. In the present study, evidence is provided in support of the premise that upregulation of the EGFR/MEK1/MAPK1/2 signaling axis during antiestrogen treatment facilitates the escape of breast cancer cells from BimEL­dependent apoptosis, conferring resistance to therapy. This conclusion is based on the findings that ectopic BimEL cDNA overexpression and confocal imaging studies confirm the pro­apoptotic role of BimEL in ERα expressing breast cancer cells and that upregulated EGFR/MEK1/MAPK1/2 signaling blocks BimEL pro­apoptotic action in an antiestrogen­resistant breast cancer cell model. In addition, the present study identified a pro­survival role for autophagy in antiestrogen resistance while EGFR inhibitor studies demonstrated that a significant percentage of antiestrogen­resistant breast cancer cells survive EGFR targeting by pro­survival autophagy. These pre­clinical studies establish the possibility that targeting both the MEK1/MAPK1/2 signaling axis and pro­survival autophagy may be required to eradicate breast cancer cell survival and prevent the development of antiestrogen resistance following hormone treatments. The present study uniquely identified EGFR upregulation as one of the mechanisms breast cancer cells utilize to evade the cytotoxic effects of antiestrogens mediated through BimEL­dependent apoptosis.

The Persistence of HIV Diversity, Transcription, and Nef Protein in Kaposi's Sarcoma Tumors during Antiretroviral Therapy.

Epidemic Kaposi's sarcoma (KS), defined by co-infection with Human Herpes Virus 8 (HHV-8) and the Human Immunodeficiency Virus (HIV), is a major cause of mortality in sub-Saharan Africa. Antiretroviral therapy (ART) significantly reduces the risk of developing KS, and for those with KS, tumors frequently resolve with ART alone. However, for unknown reasons, a significant number of KS cases do not resolve and can progress to death. To explore how HIV responds to ART in the KS tumor microenvironment, we sequenced HIV env-nef found in DNA and RNA isolated from plasma, peripheral blood mononuclear cells, and tumor biopsies, before and after ART, in four Ugandan study participants who had unresponsive or progressive KS after 180-250 days of ART. We performed immunohistochemistry experiments to detect viral proteins in matched formalin-fixed tumor biopsies. Our sequencing results showed that HIV diversity and RNA expression in KS tumors are maintained after ART, despite undetectable plasma viral loads. The presence of spliced HIV transcripts in KS tumors after ART was consistent with a transcriptionally active viral reservoir. Immunohistochemistry staining found colocalization of HIV Nef protein and tissue-resident macrophages in the KS tumors. Overall, our results demonstrated that even after ART reduced plasma HIV viral load to undetectable levels and restored immune function, HIV in KS tumors continues to be transcriptionally and translationally active, which could influence tumor maintenance and progression.

Macrophage-Targeted Sodium Chlorite (NP001) Slows Progression of Amyotrophic Lateral Sclerosis (ALS) through Regulation of Microbial Translocation.

Amyotrophic lateral sclerosis (ALS) is a heterogeneous, progressive, and universally fatal neurodegenerative disease. A subset of ALS patients has measurable plasma levels of lipopolysaccharide (LPS) and C-reactive protein (CRP) consistent with low-grade microbial translocation (MT). Unless interrupted, MT sets up a self-perpetuating loop of inflammation associated with systemic macrophage activation. To test whether MT contributed to ALS progression, blood specimens from a phase 2 study of NP001 in ALS patients were evaluated for changes in activity in treated patients as compared to controls over the 6-month study. In this post hoc analysis, plasma specimens from baseline and six-month timepoints were analyzed. Compared with baseline values, biomarkers related to MT were significantly decreased (LPS, LPS binding protein (LBP), IL-18, Hepatocyte growth factor (HGF), soluble CD163 (sCD163)) in NP001-treated patients as compared to controls, whereas wound healing and immunoregulatory factors were increased (IL-10, Epidermal growth factor (EGF), neopterin) by the end of study. These biomarker results linked to the positive clinical trial outcome confirm that regulation of macrophage activation may be an effective approach for the treatment of ALS and, potentially, other neuroinflammatory diseases related to MT.

Can microprocessor knees reduce the disparity in trips and falls risks between above and below knee prosthesis users?

While all lower limb prosthesis walkers have a high risk of tripping and/or falling, above knee prosthesis users are reported to fall more frequently. Recognising this, engineers designed microprocessor knees (MPK) to help mitigate these risks, but to what extent these devices reduce this disparity between above and below knee users is unclear. A service review was carried out in a prosthetic limb centre regarding the frequency of trips and falls in the previous four weeks. Data from unilateral, community ambulators were extracted. Ordered logistic regressions were applied to investigate whether MPKs mitigated the increased risk of trips and falls for prosthetic knee users, compared to below knee prosthesis users. Socio-demographics (sex, age), prosthesis (prosthesis type, years of use), health (comorbidities, vision, contralateral limb status, medication), and physical function (use of additional walking aids, activity level) were included as covariates. Of the 315 participants in the analysis, 57.5% reported tripping and 20.3% reported falling. Non-microprocessor prosthetic knee (non-MPK) users were shown to trip significantly more than below knee prosthesis users (OR = 1.96, 95% CI = 1.17-3.28). Other covariates showing a significant association included contralateral limb injuries (OR = 1.91, 95% CI = 1.15-3.18) and using an additional walking aid (OR = 1.99, 95% CI = 1.13-3.50). Non-MPK users were also shown to fall significantly more than below knee prosthesis users (OR = 3.34, 95% CI = 1.73-6.45), with no other covariates showing a significant association. MPK users did not show an increased frequency of trips (OR = 0.74, 95% CI = 0.33-1.64) or falls (OR = 0.34, 95% CI = 0.18-2.62), compared to below knee prosthesis users. Of those who tripped at least once in the previous four weeks, those using a non-MPK (OR = 2.73, 95% CI = 1.30-5.74) presented an increased frequency of falling. These findings provide evidence to suggest that the use of MPKs reduces the difference in falls risk between above knee and below knee prosthesis users, providing justification for their provision.

Conceptualising public mental health: development of a conceptual framework for public mental health.

BACKGROUND: Numerous determinants have been linked to public mental health; however, they have not been brought together in a comprehensive conceptual framework. The goal of this work was to bring together academic research, practitioner expertise, and public perspectives to create a public mental health conceptual framework. METHODS: The development process proceeded in four stages. First, we identified a comprehensive list of potential determinants through a state-of-the-art academic literature review, grey literature review, and created mind maps created by peer researchers. Next, we conducted in-person workshops, consultations, and an online survey with academics, practitioners, policy makers, and members of the public to review the potential determinants, nominate additional determinants, and prioritise determinants by importance for understanding public mental health. This iterative process resulted in the final list of determinants contained in the framework. We then conducted rapid reviews to define each determinant and to identify key research, interventions, and resources. Finally, we worked with a design team to visualise the conceptual framework as an online tool and printable infographic. RESULTS: We found substantial overlap between sources reflecting a shared understanding of the key drivers of public mental health. The unique determinants that emerged from each data source highlighted the importance of using multiple sources to create a comprehensive model. 72 potential determinants were prioritised through stakeholder consultations, resulting in a final list of 55 determinants and organised into four levels: individual, family, community, and structural. CONCLUSIONS: This is the most complete conceptual framework for public mental health to date, bringing together academic research, policy and practitioner views, and lived experience perspectives. The co-production processes and tools we used provides a template for researchers looking to include multiple perspectives in their research. The conceptual framework draws together current knowledge on each determinant, but also highlights areas where further research is needed to better understand the relationship between each factor and mental health, which can inform the research agenda. This online tool and infographic can be used by practitioners to identify interventions for promoting mental health, and by the general public as a resource to increase awareness of the broad factors which shape public mental health.

Analysis of lower limb prosthetic socket interface based on stress and motion measurements.

The study was designed to establish a biomechanical assessment platform for the lower limb residuum/socket interface as a function of duration and speed of movement. The approach exploits an interface sensor which measures multi-directional stresses at the interface. The corresponding interface coupling motion was assessed using a 3D motion capture system. A longitudinal study, involving a trans-femoral amputee, was conducted with nine repeated level walking sessions over a 12-month period. The effect of walking speed on interface biomechanics was also assessed. Interface peak pressures and shear stresses in the range of 55-59 kPa and 12-19 kPa were measured, respectively, over all sessions in the 12 months study period at the posterior-proximal location of the residuum. The peak pressure and longitudinal shear values were found to fluctuate approximately 11% and 40% as against its maximum value, respectively, over 12 months. In addition, up to 12° of angular coupling and up to 28 mm of pistoning were recorded over a gait cycle, which was found to change by 29% and 45% respectively over the study period. The variation in walking speed, by altering self-selected cadence, resulted in changes of pressure and shear stresses at mid-stance of the gait cycle. In particular, as compared with self-selected cadence, for fast speed, peak pressure and peak longitudinal shear stress decreased by 5% and 33%, respectively. For slow speed, peak pressure and peak longitudinal shear stress increased by 7% and 17%, respectively. The corresponding angular and pistoning revealed a variation of up to 29% and 45%, respectively. This biomechanical assessment approach shows promise in the quantitative assessment of interface kinematics and kinetics for lower limb prosthetics, the usage of which could assist the clinical assessment of prosthetic socket fit.

Phase 2B randomized controlled trial of NP001 in amyotrophic lateral sclerosis: Pre-specified and post hoc analyses.

INTRODUCTION/AIMS: ALS is a heterogeneous disease that may be complicated or in part driven by inflammation. NP001, a regulator of macrophage activation, was associated with slowing disease progression in those with higher levels of the plasma inflammatory marker C-reactive protein (CRP) in phase 2A studies in ALS. Here, we evaluate the effects of NP001 in a phase 2B trial, and perform a post hoc analysis with combined data from the preceding phase 2A trial. METHODS: The phase 2B trial enrolled 138 participants within 3 y of symptom onset and with plasma hs-CRP values >1.13 mg/L. They were randomized 1:1 to receive either placebo or NP001 for 6 mo. Change from baseline ALSFRS-R scores was the primary efficacy endpoint. Secondary endpoints included vital capacity (VC) change from baseline and percentage of participants showing no decline of ALSFRS-R score over 6 mo (non-progressor). RESULTS: The phase 2B study did not show significant differences between placebo and active treatment with respect to change in ALSFRS-R scores, or VC. The drug was safe and well tolerated. A post hoc analysis identified a 40- to 65-y-old subset in which NP001-treated patients demonstrated slower declines in ALSFRS-R score by 36% and VC loss by 51% compared with placebo. A greater number of non-progressors were NP001-treated compared with placebo (p = .004). DISCUSSION: Although the phase 2B trial failed to meet its primary endpoints, post hoc analyses identified a subgroup whose decline in ALSFRS-R and VC scores were significantly slower than placebo. Further studies will be required to validate these findings.

What are the expectations and experiences of a GMH research programme delivered in Bosnia-Herzegovina, Colombia and Uganda? A prospective longitudinal qualitative study.

OBJECTIVES: Global health research collaborations between partners in high-income countries and low-income and middle-income countries (LMICs) aim to generate new evidence, strengthen research capacity, tackle health inequalities and improve outcomes. Previous evaluations of such programmes have identified areas for improvement but consisted only of retrospective experiences. We conducted the first prospective study to assess the initial expectations as well as the final experiences of participants of a global health research programme. DESIGN, SETTINGS AND PARTICIPANTS: This study adopted a prospective longitudinal qualitative study, 38 participants of a global mental health research programme with partners in Bosnia-Herzegovina, Colombia, Uganda and the (UK). The interviewees included senior investigators, coordinators and researchers. Framework analysis was used to analyse the data. OUTCOME MEASURES: Participants were interviewed about their initial expectations at the inception of the research programme and their final experiences at the end. RESULTS: Many of the original expectations were later reported as met or even exceeded. They included experiences of communication, relationships, developed research expertise, further research opportunities and extending networks. However, other expectations were not met or only partially met, mainly on developing local leadership, strengthening institutional research capacity and opportunities for innovation and for mutual learning. Around equity of partnership and ownership of research the views of participants in the UK tended to be more critical than those of partners in LMICs. CONCLUSIONS: The findings suggest that global health research programmes can achieve several of their aims, and that partners in LMICs feel equity has been established in the partnership despite the imbalance of the funding arrangement. Aims of global health research projects should have a realistic focus and be proportionate to the parameters of the funding arrangement. More resources and longer time scales may be required to address sustainable structural capacity and long-standing local leadership sufficiently.