A systematic review of existing national priorities for child health research in sub-Saharan Africa

BACKGROUND: We systematically reviewed existing national child health research priorities in Sub-Saharan Africa, and the processes used to determine them. METHODS: Collaborators from a purposive sample of 20 WHO-AFRO Region countries, assisted by key informants from a range of governmental, non-governmental, research and funding organisations and universities, identified and located potentially eligible prioritisation documents. Included documents were those published between 1990 and 2002 from national or nationally accredited institutions describing national health research priorities for child health, alone or as part of a broader report in which children were a clearly identifiable group. Laboratory, clinical, public health and policy research were included. Two reviewers independently assessed eligibility for inclusion and extracted data. RESULTS: Eight of 33 potentially eligible reports were included. Five reports focused on limited areas of child health. The remaining three included child-specific categories in reports of general research priorities, with two such child-specific categories limited to reproductive health. In a secondary analysis of Essential National Health Research reports that included children, though not necessarily as an identifiable group, the reporting of priorities varied markedly in format and numbers of priorities listed, despite a standard recommended approach. Comparison and synthesis of reported priorities was not possible. CONCLUSION: Few systematically developed national research priorities for child health exist in sub-Saharan Africa. Children's interests may be distorted in prioritisation processes that combine all age groups. Future development of priorities requires a common reporting framework and specific consideration of childhood priorities

Prefrontal cortical activation associated with prospective memory while walking around a real-world street environment

Rostral PFC (area 10) activation is common during prospective memory (PM) tasks. But it is not clear what mental processes these activations index. Three candidate explanations from cognitive neuroscience theory are: (i) monitoring of the environment; (ii) spontaneous intention retrieval; (iii) a combination of the two. These explanations make different predictions about the temporal and spatial patterns of activation that would be seen in rostral PFC in naturalistic settings. Accordingly, we plotted functional events in PFC using portable fNIRS while people were carrying out a PM task outside the lab and responding to cues when they were encountered, to decide between these explanations. Nineteen people were asked to walk around a street in London, U.K. and perform various tasks while also remembering to respond to prospective memory (PM) cues when they detected them. The prospective memory cues could be either social (involving greeting a person) or non-social (interacting with a parking meter) in nature. There were also a number of contrast conditions which allowed us to determine activation specifically related to the prospective memory components of the tasks. We found that maintaining both social and non-social intentions was associated with widespread activation within medial and right hemisphere rostral prefrontal cortex (BA 10), in agreement with numerous previous lab-based fMRI studies of prospective memory. In addition, increased activation was found within lateral prefrontal cortex (BA 45 and 46) when people were maintaining a social intention compared to a non-social one. The data were then subjected to a GLM-based method for automatic identification of functional events (AIDE), and the position of the participants at the time of the activation events were located on a map of the physical space. The results showed that the spatial and temporal distribution of these events was not random, but aggregated around areas in which the participants appeared to retrieve their future intentions (i.e., where they saw intentional cues), as well as where they executed them. Functional events were detected most frequently in BA 10 during the PM conditions compared to other regions and tasks. Mobile fNIRS can be used to measure higher cognitive functions of the prefrontal cortex in “real world” situations outside the laboratory in freely ambulant individuals. The addition of a “brain-first” approach to the data permits the experimenter to determine not only when haemodynamic changes occur, but also where the participant was when it happened. This can be extremely valuable when trying to link brain and cognition

Text Messages With Financial Incentives for Men With Obesity : A Randomized Clinical Trial

Peer reviewe

Safety and efficacy of memantine and trazodone versus placebo for motor neuron disease (MND SMART): stage two interim analysis from the first cycle of a phase 3, multiarm, multistage, randomised, adaptive platform trial

BackgroundMotor neuron disease represents a group of progressive and incurable diseases that are characterised by selective loss of motor neurons, resulting in an urgent need for rapid identification of effective disease-modifying therapies. The MND SMART trial aims to test the safety and efficacy of promising interventions efficiently and definitively against a single contemporaneous placebo control group. We now report results of the stage two interim analysis for memantine and trazodone.MethodsMND SMART is an investigator-led, phase 3, double-blind, placebo-controlled, multiarm, multistage, randomised, adaptive platform trial recruiting at 20 hospital centres in the UK. Individuals older than 18 years with a confirmed diagnosis of either amyotrophic lateral sclerosis classified by the revised El Escorial criteria, primary lateral sclerosis, progressive muscular atrophy, or progressive bulbar palsy, regardless of disease duration, were eligible for screening. Participants were randomised (1:1:1) to receive oral trazodone 200 mg once a day, oral memantine 20 mg once a day, or matched placebo using a computer-generated minimisation algorithm delivered via a secure web-based system. Co-primary outcome measures were clinical functioning, measured by rate of change in the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R), and survival. Comparisons were conducted in four stages, with predefined criteria for stopping at the end of stages one and two. We report interim analysis from the stage two results, which was done when 100 participants per group (excluding long survivors, defined as >8 years since diagnosis at baseline) completed a minimum of 12 months of follow-up for the candidate investigational medicinal products. The trial is registered on the European Clinical Trials Registry, 2019–000099–41, and ClinicalTrials.gov, NCT04302870, and is ongoing.FindingsBetween Feb 27, 2020, and July 24, 2023 (database lock for interim analysis two), 554 people with a motor neuron disease were randomly allocated to memantine (183 [33%]), trazodone (185 [33%]), or placebo (186 [34%]). The primary interim analysis population comprised 530 participants, of whom 175 (33%) had been allocated memantine, 175 (33%) had been allocated trazodone, and 180 (34%) had been allocated placebo. Over 12 months of follow-up, the mean rate of change per month in ALSFRS-R was –0·650 for memantine, –0·625 for trazodone, and –0·655 for placebo (memantine versus placebo estimated mean difference 0·033, one-sided 90% CI lower level –0·085; one-sided p=0·36; trazodone vs placebo: 0·065, –0·051; one-sided p=0·24). The one-sided p values were both above the significance threshold of 10%, indicating that neither memantine nor trazodone groups met the criteria for continuation. There were 483 participants with at least one adverse event (145 [77%] on placebo, 170 [91%] on memantine, and 168 [90%] on trazodone). There were 88 participants with at least one serious adverse event (37 [20%] on memantine, 27 [14%] on trazodone, and 24 [13%] on placebo). A total of 11 serious adverse event led to treatment discontinuation. There was no survival difference between comparisons, with 49 deaths in the memantine group, 52 deaths in the trazodone group, and 48 deaths in the placebo group.InterpretationNeither memantine nor trazodone improved efficacy outcomes compared with placebo. This result is sufficiently powered to warrant no further testing of trazodone or memantine in motor neuron disease at the doses evaluated in this study. The multiarm multistage design shows important benefits in reducing the time, cost, and participant numbers to reach a definitive result

Safety and efficacy of memantine and trazodone versus placebo for motor neuron disease (MND SMART): stage two interim analysis from the first cycle of a phase 3, multiarm, multistage, randomised, adaptive platform trial

Background: Motor neuron disease represents a group of progressive and incurable diseases that are characterised by selective loss of motor neurons, resulting in an urgent need for rapid identification of effective disease-modifying therapies. The MND SMART trial aims to test the safety and efficacy of promising interventions efficiently and definitively against a single contemporaneous placebo control group. We now report results of the stage two interim analysis for memantine and trazodone. // Methods: MND SMART is an investigator-led, phase 3, double-blind, placebo-controlled, multiarm, multistage, randomised, adaptive platform trial recruiting at 20 hospital centres in the UK. Individuals older than 18 years with a confirmed diagnosis of either amyotrophic lateral sclerosis classified by the revised El Escorial criteria, primary lateral sclerosis, progressive muscular atrophy, or progressive bulbar palsy, regardless of disease duration, were eligible for screening. Participants were randomised (1:1:1) to receive oral trazodone 200 mg once a day, oral memantine 20 mg once a day, or matched placebo using a computer-generated minimisation algorithm delivered via a secure web-based system. Co-primary outcome measures were clinical functioning, measured by rate of change in the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R), and survival. Comparisons were conducted in four stages, with predefined criteria for stopping at the end of stages one and two. We report interim analysis from the stage two results, which was done when 100 participants per group (excluding long survivors, defined as >8 years since diagnosis at baseline) completed a minimum of 12 months of follow-up for the candidate investigational medicinal products. The trial is registered on the European Clinical Trials Registry, 2019–000099–41, and ClinicalTrials.gov , NCT04302870 , and is ongoing. // Findings: Between Feb 27, 2020, and July 24, 2023 (database lock for interim analysis two), 554 people with a motor neuron disease were randomly allocated to memantine (183 [33%]), trazodone (185 [33%]), or placebo (186 [34%]). The primary interim analysis population comprised 530 participants, of whom 175 (33%) had been allocated memantine, 175 (33%) had been allocated trazodone, and 180 (34%) had been allocated placebo. Over 12 months of follow-up, the mean rate of change per month in ALSFRS-R was –0·650 for memantine, –0·625 for trazodone, and –0·655 for placebo (memantine versus placebo estimated mean difference 0·033, one-sided 90% CI lower level –0·085; one-sided p=0·36; trazodone vs placebo: 0·065, –0·051; one-sided p=0·24). The one-sided p values were both above the significance threshold of 10%, indicating that neither memantine nor trazodone groups met the criteria for continuation. There were 483 participants with at least one adverse event (145 [77%] on placebo, 170 [91%] on memantine, and 168 [90%] on trazodone). There were 88 participants with at least one serious adverse event (37 [20%] on memantine, 27 [14%] on trazodone, and 24 [13%] on placebo). A total of 11 serious adverse event led to treatment discontinuation. There was no survival difference between comparisons, with 49 deaths in the memantine group, 52 deaths in the trazodone group, and 48 deaths in the placebo group. // Interpretation: Neither memantine nor trazodone improved efficacy outcomes compared with placebo. This result is sufficiently powered to warrant no further testing of trazodone or memantine in motor neuron disease at the doses evaluated in this study. The multiarm multistage design shows important benefits in reducing the time, cost, and participant numbers to reach a definitive result. // Funding: The Euan MacDonald Centre, MND Scotland, My Name'5 Doddie Foundation, and Baillie Gifford

Green Space and Internalizing or Externalizing Symptoms Among Children

Importance: Evidence suggests that living near green space supports mental health, but studies examining the association of green space with early mental health symptoms among children are rare. Objective: To evaluate the association between residential green space and early internalizing (eg, anxiety and depression) and externalizing (eg, aggression and rule-breaking) symptoms. Design, Setting, and Participants: Data for this cohort study were drawn from the Environmental Influences on Child Health Outcomes cohort; analysis was conducted from July to October 2023. Children born between 2007 and 2013 with outcome data in early (aged 2-5 years) and/or middle (aged 6-11 years) childhood who resided in 41 states across the US, drawing from clinic, hospital, and community-based cohorts, were included. Cohort sites were eligible if they recruited general population participants and if at least 30 children had outcome and residential address data to measure green space exposure. Nine cohorts with 13 sites met these criteria. Children diagnosed with autism or developmental delay were excluded, and 1 child per family was included. Exposures: Green space exposure was measured using a biannual (ie, summer and winter) Normalized Difference Vegetation Index, a satellite image-based indicator of vegetation density assigned to monthly residential history from birth to outcome assessment. Main Outcome and Measures: Child internalizing and externalizing symptoms were assessed using the Child Behavior Checklist for Ages 1½ to 5 or 6 to 18. The association between green space and internalizing and externalizing symptoms was modeled with multivariable linear regression using generalized estimating equations, adjusting for birthing parent educational level, age at delivery, child sex, prematurity, and neighborhood socioeconomic vulnerability. Models were estimated separately for early and middle childhood samples. Results: Among 2103 children included, 1061 (50.5%) were male; 606 (29.1%) identified as Black, 1094 (52.5%) as White, 248 (11.9%) as multiple races, and 137 (6.6%) as other races. Outcomes were assessed at mean (SD) ages of 4.2 (0.6) years in 1469 children aged 2 to 5 years and 7.8 (1.6) years in 1173 children aged 6 to 11 years. Greater green space exposure was associated with fewer early childhood internalizing symptoms in fully adjusted models (b = -1.29; 95% CI, -1.62 to -0.97). No associations were observed between residential green space and internalizing or externalizing symptoms in middle childhood. Conclusions and Relevance: In this study of residential green space and children's mental health, the association of green space with fewer internalizing symptoms was observed only in early childhood, suggesting a sensitive period for nature exposure. Policies protecting and promoting access to green space may help alleviate early mental health risk

Text messages with financial incentives for men with obesity. A randomized clinical trial

Importance: Effective weight loss interventions are needed for men with obesity. Objective : To determine whether an intervention that combined text messaging with financial incentives attained significant weight loss at the 12-month follow-up compared with the control group and whether an intervention of text messaging alone attained significant weight loss at the 12-month follow-up compared with the control group. Design, Setting, and Participants: An assessor-blinded randomized clinical trial conducted in Belfast, Bristol, and Glasgow areas in the UK. A total of 585 men with body mass index (BMI) of 30 or more were enrolled between July 2021 and May 2022. Final follow-up occurred June 2023. Interventions: Participants were randomly assigned to 12 months of behavioral focused text messages combined with financial incentives (n = 196), 12 months of behavioral focused text messages alone (n= 194), or a waiting list (control group; n= 195). The financial incentive consisted of a monetary reward that was lost if weight loss targets were not met. All participants received weight management information and a pedometer at baseline. Main Outcomes and Measures: The 2 primary comparisons were the 12-month comparison of within-participant weight change between the text messaging with financial incentive group and the control group and the comparison between the text messaging alone group and the control group (minimum clinically important difference, 3%). The P value defined for statistical significance was P < .025 for each comparison. Results: Of the 585 men (mean [SD] age, 50.7 [13.3] years; mean weight, 118.5 [19.9] kg; mean BMI, 37.7 [5.7]; 525 [90%] White), 227 (39%) lived in postal code areas with lower socioeconomic status, and 426 (73%) completed the 12-month follow-up. At the 12-month follow-up, compared with the control group, the mean percent weight change was significantly greater in the text messaging with financial incentive group (mean difference, −3.2%; 97.5% CI, −4.6% to −1.9%; P < .001) but was not significantly greater in the text messaging alone group (mean difference, −1.4%; 97.5% CI, −2.9% to 0.0, P = .05). The mean (SD) weight changes were −5.7 (7.4) kg for the text messaging with financial incentives group, −3.0 (7.5) kg for the text messaging alone group, and −1.5 (6.6) kg for the control group. The 12-month mean (SD) percentage weight changes from baseline were −4.8% (6.1%) for the text messaging with financial incentives group, −2.7% (6.3%) for text messaging alone group, and −1.3% (5.5%) for the control group. Of 366 adverse events reported, the most common were infections (83 [23%]). Of the 23 serious adverse events (6.3%), 12 (52%) occurred in the text messaging with financial incentives group, 5 (22%) in the texts messaging alone group, and 6 (26%) in the control group. None were considered related to participating in a trial group. Conclusion and Relevance: Among men with obesity, an intervention with text messaging with financial incentive significantly improved weight loss compared with a control group, whereas text messaging alone was not significantly better than the control condition. These findings support text messaging combined with financial incentives to attain weight loss in men with obesityOutput Status: Forthcoming/Available Onlin

ADAMTS and ADAM metalloproteinases in osteoarthritis - looking beyond the 'usual suspects'

INTRODUCTION: Matrix metalloproteinases (MMPs) and 'aggrecanase' a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs) are well established to play key roles in osteoarthritis (OA) through degradation of extracellular matrix (ECM) type II collagen and aggrecan, and are thus potential targets for development of OA therapies. OBJECTIVE: This paper aims to provide a comprehensive review of the expression and potential roles of other, lesser-known ADAMTSs and related adamalysins (or a disintegrin and metalloproteinases (ADAMs)) in cartilage, with a view to identifying potentially protective or homeostatic metalloproteinases in the joint and informing consequent selective inhibitor design. DESIGN: A comprehensive literature search was performed using PubMed terms 'osteoarthritis' and 'ADAMTS' or 'ADAM'. RESULTS: Several ADAMTSs and ADAMs were identified as having reportedly increased expression in OA. These include enzymes likely to play roles in cartilage matrix anabolism (e.g., the procollagen N-proteinases ADAMTS-2, ADAMTS-3 and ADAMTS-14), chondrocyte differentiation and proliferation (e.g., ADAM9, ADAM10, ADAM12), as well as enzymes contributing to cartilage catabolism (e.g., Cartilage oligomeric protein (COMP)-degrading ADAMTS-7 and ADAMTS-12). CONCLUSIONS: In addition to the well-characterised MMPs, ADAMTS-4 and ADAMTS-5, many other ADAMTSs and ADAMs are expressed in cartilage and several show significantly altered expression in OA. Studies aimed at elucidating the pathophysiological roles of these enzymes in cartilage will contribute to our understanding of OA pathogenesis and enable design of targeted inhibitors that effectively target metalloproteinase-mediated cartilage degradation while sparing cartilage repair pathways

Systematic, comprehensive, evidence-based approach to identify neuroprotective interventions for motor neuron disease: using systematic reviews to inform expert consensus

Objectives: Motor neuron disease (MND) is an incurable progressive neurodegenerative disease with limited treatment options. There is a pressing need for innovation in identifying therapies to take to clinical trial. Here, we detail a systematic and structured evidence-based approach to inform consensus decision making to select the first two drugs for evaluation in Motor Neuron Disease-Systematic Multi-arm Adaptive Randomised Trial (MND-SMART: NCT04302870), an adaptive platform trial. We aim to identify and prioritise candidate drugs which have the best available evidence for efficacy, acceptable safety profiles and are feasible for evaluation within the trial protocol. Methods: We conducted a two-stage systematic review to identify potential neuroprotective interventions. First, we reviewed clinical studies in MND, Alzheimer’s disease, Huntington’s disease, Parkinson’s disease and multiple sclerosis, identifying drugs described in at least one MND publication or publications in two or more other diseases. We scored and ranked drugs using a metric evaluating safety, efficacy, study size and study quality. In stage two, we reviewed efficacy of drugs in MND animal models, multicellular eukaryotic models and human induced pluripotent stem cell (iPSC) studies. An expert panel reviewed candidate drugs over two shortlisting rounds and a final selection round, considering the systematic review findings, late breaking evidence, mechanistic plausibility, safety, tolerability and feasibility of evaluation in MND-SMART. Results: From the clinical review, we identified 595 interventions. 66 drugs met our drug/disease logic. Of these, 22 drugs with supportive clinical and preclinical evidence were shortlisted at round 1. Seven drugs proceeded to round 2. The panel reached a consensus to evaluate memantine and trazodone as the first two arms of MND-SMART. Discussion: For future drug selection, we will incorporate automation tools, text-mining and machine learning techniques to the systematic reviews and consider data generated from other domains, including high-throughput phenotypic screening of human iPSCs

Text messages with financial incentives for men with obesity. A randomized clinical trial

Importance: Effective weight loss interventions are needed for men with obesity. Objective : To determine whether an intervention that combined text messaging with financial incentives attained significant weight loss at the 12-month follow-up compared with the control group and whether an intervention of text messaging alone attained significant weight loss at the 12-month follow-up compared with the control group. Design, Setting, and Participants: An assessor-blinded randomized clinical trial conducted in Belfast, Bristol, and Glasgow areas in the UK. A total of 585 men with body mass index (BMI) of 30 or more were enrolled between July 2021 and May 2022. Final follow-up occurred June 2023. Interventions: Participants were randomly assigned to 12 months of behavioral focused text messages combined with financial incentives (n = 196), 12 months of behavioral focused text messages alone (n= 194), or a waiting list (control group; n= 195). The financial incentive consisted of a monetary reward that was lost if weight loss targets were not met. All participants received weight management information and a pedometer at baseline. Main Outcomes and Measures: The 2 primary comparisons were the 12-month comparison of within-participant weight change between the text messaging with financial incentive group and the control group and the comparison between the text messaging alone group and the control group (minimum clinically important difference, 3%). The P value defined for statistical significance was P < .025 for each comparison. Results: Of the 585 men (mean [SD] age, 50.7 [13.3] years; mean weight, 118.5 [19.9] kg; mean BMI, 37.7 [5.7]; 525 [90%] White), 227 (39%) lived in postal code areas with lower socioeconomic status, and 426 (73%) completed the 12-month follow-up. At the 12-month follow-up, compared with the control group, the mean percent weight change was significantly greater in the text messaging with financial incentive group (mean difference, −3.2%; 97.5% CI, −4.6% to −1.9%; P < .001) but was not significantly greater in the text messaging alone group (mean difference, −1.4%; 97.5% CI, −2.9% to 0.0, P = .05). The mean (SD) weight changes were −5.7 (7.4) kg for the text messaging with financial incentives group, −3.0 (7.5) kg for the text messaging alone group, and −1.5 (6.6) kg for the control group. The 12-month mean (SD) percentage weight changes from baseline were −4.8% (6.1%) for the text messaging with financial incentives group, −2.7% (6.3%) for text messaging alone group, and −1.3% (5.5%) for the control group. Of 366 adverse events reported, the most common were infections (83 [23%]). Of the 23 serious adverse events (6.3%), 12 (52%) occurred in the text messaging with financial incentives group, 5 (22%) in the texts messaging alone group, and 6 (26%) in the control group. None were considered related to participating in a trial group. Conclusion and Relevance: Among men with obesity, an intervention with text messaging with financial incentive significantly improved weight loss compared with a control group, whereas text messaging alone was not significantly better than the control condition. These findings support text messaging combined with financial incentives to attain weight loss in men with obesit