Causal Assessment of Income Inequality on Self-Rated Health and All-Cause Mortality: A Systematic Review and Meta-Analysis.

Policy Points Income is thought to impact a broad range of health outcomes. However, whether income inequality (how unequal the distribution of income is in a population) has an additional impact on health is extensively debated. Studies that use multilevel data, which have recently increased in popularity, are necessary to separate the contextual effects of income inequality on health from the effects of individual income on health. Our systematic review found only small associations between income inequality and poor self-rated health and all-cause mortality. The available evidence does not suggest causality, although it remains methodologically flawed and limited, with very few studies using natural experimental approaches or examining income inequality at the national level. CONTEXT: Whether income inequality has a direct effect on health or is only associated because of the effect of individual income has long been debated. We aimed to understand the association between income inequality and self-rated health (SRH) and all-cause mortality (mortality) and assess if these relationships are likely to be causal. METHODS: We searched Medline, ISI Web of Science, Embase, and EconLit (PROSPERO: CRD42021252791) for studies considering income inequality and SRH or mortality using multilevel data and adjusting for individual-level socioeconomic position. We calculated pooled odds ratios (ORs) for poor SRH and relative risk ratios (RRs) for mortality from random-effects meta-analyses. We critically appraised included studies using the Risk of Bias in Nonrandomized Studies - of Interventions tool. We assessed certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation framework and causality using Bradford Hill (BH) viewpoints. FINDINGS: The primary meta-analyses included 2,916,576 participants in 38 cross-sectional studies assessing SRH and 10,727,470 participants in 14 cohort studies of mortality. Per 0.05-unit increase in the Gini coefficient, a measure of income inequality, the ORs and RRs (95% confidence intervals) for SRH and mortality were 1.06 (1.03-1.08) and 1.02 (1.00-1.04), respectively. A total of 63.2% of SRH and 50.0% of mortality studies were at serious risk of bias (RoB), resulting in very low and low certainty ratings, respectively. For SRH and mortality, we did not identify relevant evidence to assess the specificity or, for SRH only, the experiment BH viewpoints; evidence for strength of association and dose-response gradient was inconclusive because of the high RoB; we found evidence in support of temporality and plausibility. CONCLUSIONS: Increased income inequality is only marginally associated with SRH and mortality, but the current evidence base is too methodologically limited to support a causal relationship. To address the gaps we identified, future research should focus on income inequality measured at the national level and addressing confounding with natural experiment approaches.

Adolescents' interactive electronic device use, sleep and mental health: a systematic review of prospective studies.

Optimal sleep, both in terms of duration and quality, is important for adolescent health. However, young people's sleeping habits have worsened over recent years. Access to and use of interactive electronic devices (e.g., smartphones, tablets, portable gaming devices) and social media have become deep-rooted elements of adolescents' lives and are associated with poor sleep. Additionally, there is evidence of increases in poor mental health and well-being disorders in adolescents; further linked to poor sleep. This review aimed to summarise the longitudinal and experimental evidence of the impact of device use on adolescents' sleep and subsequent mental health. Nine electronic bibliographical databases were searched for this narrative systematic review in October 2022. Of 5779 identified unique records, 28 studies were selected for inclusion. A total of 26 studies examined the direct link between device use and sleep outcomes, and four reported the indirect link between device use and mental health, with sleep as a mediator. The methodological quality of the studies was generally poor. Results demonstrated that adverse implications of device use (i.e., overuse, problematic use, telepressure, and cyber-victimisation) impacted sleep quality and duration; however, relationships with other types of device use were unclear. A small but consistent body of evidence showed sleep mediates the relationship between device use and mental health and well-being in adolescents. Increasing our understanding of the complexities of device use, sleep, and mental health in adolescents are important contributions to the development of future interventions and guidelines to prevent or increase resilience to cyber-bullying and ensure adequate sleep.

The effect of school summer holidays on inequalities in children and young people's mental health and cognitive ability in the UK using data from the millennium cohort study.

BACKGROUND: Summer learning loss has been the subject of longstanding concern among researchers, the public and policy makers. The aim of the current research was to investigate inequality changes in children's mental health and cognitive ability across the summer holidays. METHODS: We conducted linear and logistic regression analysis of mental health (borderline-abnormal total difficulty and prosocial scores on the strengths and difficulties questionnaire (SDQ)) and verbal cognitive ability (reading, verbal reasoning or vocabulary) at ages 7, 11 and 14, comparing UK Millennium Cohort Study members who were interviewed before and after the school summer holidays. Inequalities were assessed by including interaction terms in the outcome models between a discrete binary variable with values representing time periods and maternal academic qualifications. Coefficients of the interaction terms were interpreted as changes from the pre- to post-holiday period in the extent of inequality in the outcome between participants whose mothers had high or low educational qualifications. Separate models were fitted for each age group and outcome. We used inverse probability weights to allow for differences in the characteristics of cohort members assessed before and after the summer holidays. RESULTS: Mental health (borderline/abnormal SDQ total and prosocial scores) at ages 7 and 14 worsened and verbal cognitive ability scores at age 7 were lower among those surveyed after the summer holidays. Mental health inequalities were larger after the holidays at age 7 ([OR = 1.4; 95%CI (0.6, 3.2) and 14: [OR = 1.5; 95%CI (0.7, 3.2)], but changed little at age 11 (OR = 0.9; 95%CI (0.4, 2.6)]. There were differences in pro-social behaviours among those surveyed before/after the school holidays at age 14 [OR = 1.2; 95%CI (0.5, 3.5)] but not at age 7 or 11. There was little change in inequalities in verbal cognitive ability scores over the school holidays [Age 7: b = 1.3; 95%CI (- 3.3, 6.0); Age 11: b = - 0.7; 95%CI (- 4.3, 2.8); Age 14: b = - 0.3; 95%CI (- 1.0, 0.4)]. CONCLUSION: We found inequalities in mental health and cognitive ability according to maternal education, and some evidence or worsening mental health and mental health inequalities across school summer holidays. We found little evidence of widening inequalities in verbal cognitive ability. Widespread school closures during the COVID-19 restrictions have prompted concerns that prolonged closures may widen health and educational inequalities. Management of school closures should focus on preventing or mitigating inequalities that may arise from differences in the support for mental health and learning provided during closures by schools serving more or less disadvantaged children.

Sourcing the immune system to induce immunogenic cell death in Kras-colorectal cancer cells.

BACKGROUND: Current approaches aimed at inducing immunogenic cell death (ICD) to incite an immune response against cancer neoantigens are based on the use of chemotherapeutics and other agents. Results are hampered by issues of efficacy, combinatorial approaches, dosing and toxicity. Here, we adopted a strategy based on the use of an immunomolecule that overcomes pharmachemical limitations. METHODS: Cytofluorometry, electron microscopy, RT-PCR, western blotting, apotome immunofluorescence, MLR and xenografts. RESULTS: We report that an ICD process can be activated without the use of pharmacological compounds. We show that in Kras-mut/TP53-mut colorectal cancer cells the 15 kDa ßGBP cytokine, a T cell effector with onco-suppressor properties and a potential role in cancer immunosurveillance, induces key canonical events required for ICD induction. We document ER stress, autophagy that extends from cancer cells to the corresponding xenograft tumours, CRT cell surface shifting, ATP release and evidence of dendritic cell activation, a process required for priming cytotoxic T cells into a specific anticancer immunogenic response. CONCLUSIONS: Our findings provide experimental evidence for a rationale to explore a strategy based on the use of an immunomolecule that as a single agent couples oncosuppression with the activation of procedures necessary for the induction of long term response to cancer.

Adaptation of complex interventions for people with long-term conditions: a scoping review.

Adaptation seeks to transfer and implement healthcare interventions developed and evaluated in one context to another. The aim of this scoping review was to understand current approaches to the adaptation of complex interventions for people with long-term conditions (LTCs) and to identify issues for studies performed in low- and middle-income countries (LMICs). Bibliographic databases were searched from 2000 to October 2022. This review involved five stages: (i) definition of the research question(s); (ii) identifying relevant studies; (iii) study selection; (iv) data charting; and (v) data synthesis. Extraction included an assessment of the: rationale for adaptation; stages and levels of adaptation; use of theoretical frameworks, and quality of reporting using a checklist based on the 2021 ADAPT guidance. Twenty-five studies were included from across 21 LTCs and a range of complex interventions. The majority (16 studies) focused on macro (national or international) level interventions. The rationale for adaptation included intervention transfer across geographical settings [high-income country (HIC) to LMIC: six studies, one HIC to another: eight studies, one LMIC to another: two studies], or transfer across socio-economic/racial groups (five studies), or transfer between different health settings within a single country (one study). Overall, studies were judged to be of moderate reporting quality (median score 23, maximum 46), and typically focused on early stages of adaptation (identification and development) with limited outcome evaluation or implementation assessment of the adapted version of the intervention. Improved reporting of the adaptation for complex interventions targeted at LTCs is needed. Development of future adaptation methods guidance needs to consider the needs and priorities of the LMIC context.

Limited finance and human capacity may reduce access to new treatments for people with long-term conditions. This is especially true in low- and middle-income countries. One solution is to transfer treatments developed in one place for use in other areas. This paper provides a current summary of international research on adapting treatments. We used a checklist to assess study reporting quality, based on published advice. Our findings showed the need for better conduct and reporting of adaptation. Future guidance should consider the specific needs of low- and middle-income countries.

Wildfire, deforestation and health in tropical rainforest areas: a scoping review protocol.

INTRODUCTION: Wildfires and deforestation potentially have direct effects on multiple health outcomes as well as indirect consequences for climate change. Tropical rainforest areas are characterised by high rainfall, humidity and temperature, and they are predominantly found in low-income and middle-income countries. This study aims to synthesise the methods, data and health outcomes reported in scientific papers on wildfires and deforestation in these locations. METHODS AND ANALYSIS: We will carry out a scoping review according to the Joanna Briggs Institute's (JBI) manual for scoping reviews and the framework proposed by Arksey and O'Malley, and Levac et al. The search for articles was performed on 18 August 2023, in 16 electronic databases using Medical Subject Headings terms and adaptations for each database from database inception. The search for local studies will be complemented by the manual search in the list of references of the studies selected to compose this review. We screened studies written in English, French, Portuguese and Spanish. We included quantitative studies assessing any human disease outcome, hospitalisation and vital statistics in regions of tropical rainforest. We exclude qualitative studies and quantitative studies whose outcomes do not cover those of interest. The text screening was done by two independent reviewers. Subsequently, we will tabulate the data by the origin of the data source used, the methods and the main findings on health impacts of the extracted data. The results will provide descriptive statistics, along with visual representations in diagrams and tables, complemented by narrative summaries as detailed in the JBI guidelines. ETHICS AND DISSEMINATION: The study does not require an ethical review as it is meta-research and uses published, deidentified secondary data sources. The submission of results for publication in a peer-reviewed journal and presentation at scientific and policymakers' conferences is expected. STUDY REGISTRATION: Open Science Framework (https://osf.io/pnqc7/).

Evolution of 'whole institution' approaches to improving health in tertiary education settings: a critical scoping review.

In recent decades, 'whole school' approaches to improving health have gained traction, based on settings-based health promotion understandings which view a setting, its actors and processes as an integrated 'whole' system with multiple intervention opportunities. Much less is known about 'whole institution' approaches to improving health in tertiary education settings. We conducted a scoping review to describe both empirical and non-empirical (e.g. websites) publications relating to 'whole settings', 'complex systems' and 'participatory'/'action' approaches to improving the health of students and staff within tertiary education settings. English-language publications were identified by searching five academic and four grey literature databases and via the reference lists of studies read for eligibility. We identified 101 publications with marked UK overrepresentation. Since the 1970s, publications have increased, spanning a gradual shift in focus from 'aspirational' to 'conceptual' to 'evaluative'. Terminology is geographically siloed (e.g., 'healthy university' (UK), 'healthy campus' (USA)). Publications tend to focus on 'health' generally rather than specific health dimensions (e.g. diet). Policies, arguably crucial for cascading systemic change, were not the most frequently implemented intervention elements. We conclude that, despite the field's evolution, key questions (e.g., insights into who needs to do what, with whom, where and when; or efficacy) remain unanswered.

Social support, educational, and behavioral modification interventions for improving household disaster preparedness in the general community-dwelling population: a systematic review and meta-analysis.

Background: The efficacy of household emergency preparedness interventions for community-dwelling, non-institutionalized people is largely unknown. Objective: To ascertain the state of the science on social support, educational, and behavioral modification interventions to improve all-hazard household disaster preparedness. Design: Systematic review and meta-analysis. Methods: Databases, trial registers, reports, and websites were searched, and citation trails followed utilizing replicable methods. Individual, cluster, and cross-over randomized controlled trials of non-institutionalized, community-dwelling populations and non-randomized controlled trials, controlled before-after, and program evaluation studies were included. At least two review authors independently screened each potentially relevant study for inclusion, extracted data, and assessed the risk of bias. Risk of bias was assessed using Cochrane's RoB2 tool for randomized studies and ROBINS-I tool for nonrandomized studies. Meta-analyses were applied using a random-effects model. Where meta-analysis was not indicated, results were synthesized using summary statistics of intervention effect estimates and vote counting based on effect direction. The evidence was rated using GRADE. Results: 17 studies were included with substantial methodological and clinical diversity. No intervention effect was observed for preparedness supplies (OR = 6.12, 95% 0.13 to 284.37) or knowledge (SMD = 0.96, 95% CI -0.15 to 2.08) outcomes. A small positive effect (SMD = 0.53, 95% CI 0.16 to 0.91) was observed for preparedness behaviors, with very low certainty of evidence. No studies reported adverse effects from the interventions. Conclusion: Research designs elucidating the efficacy of practical yet complex and multi- faceted social support, educational, and behavioral modification interventions present substantial methodological challenges where rigorous study design elements may not match the contextual public health priority needs and resources where interventions were delivered. While the overall strength of the evidence was evaluated as low to very low, we acknowledge the valuable and informative work of the included studies. The research represents the seminal work in this field and provides an important foundation for the state of the science of household emergency preparedness intervention effectiveness and efficacy. The findings are relevant to disaster preparedness practice and research, and we encourage researchers to continue this line of research, using these studies and this review to inform ongoing improvements in study designs.

Definitions, acceptability, limitations, and guidance in the use and reporting of surrogate end points in trials: a scoping review.

OBJECTIVE: To synthesize the current literature on the use of surrogate end points, including definitions, acceptability, and limitations of surrogate end points and guidance for their design/reporting, into trial reporting items. STUDY DESIGN AND SETTING: Literature was identified through searching bibliographic databases (until March 1, 2022) and gray literature sources (until May 27, 2022). Data were thematically analyzed into four categories: (1) definitions, (2) acceptability, (3) limitations and challenges, and (4) guidance, and synthesized into reporting guidance items. RESULTS: After screening, 90 documents were included: 79% (n = 71) had data on definitions, 77% (n = 69) on acceptability, 72% (n = 65) on limitations and challenges, and 61% (n = 55) on guidance. Data were synthesized into 17 potential trial reporting items: explicit statements on the use of surrogate end point(s) and justification for their use (items 1-6); methodological considerations, including whether sample size calculations were informed by surrogate validity (items 7-9); reporting of results for composite outcomes containing a surrogate end point (item 10); discussion and interpretation of findings (items 11-14); plans for confirmatory studies, collecting data on the surrogate end point and target outcome, and data sharing (items 15-16); and informing trial participants about using surrogate end points (item 17). CONCLUSION: The review identified and synthesized items on the use of surrogate end points in trials; these will inform the development of the Standard Protocol Items: Recommendations for Interventional Trials-SURROGATE and Consolidated Standards of Reporting Trials-SURROGATE extensions.

Acceptability of Single-dose Clindamycin Gel for Bacterial Vaginosis: A Randomized Controlled Trial.

PURPOSE: The goal of this study was to assess the acceptability of a single-dose bioadhesive 2% clindamycin vaginal gel for bacterial vaginosis (BV). METHODS: This double-blind, placebo-controlled, randomized study compared a new clindamycin gel with placebo gel (2:1 ratio). The primary objective was efficacy; secondary objectives were safety and acceptability. Subjects were evaluated at screening, days 7 to 14 (Day 7-14), and days 21 to 30 (test-of-cure [TOC]). An acceptability questionnaire with 9 questions was administered at the Day 7-14 visit, and a subset of questions (#7-#9) was asked again at the TOC visit. At Visit 1, subjects were provided with a daily electronic diary (e-Diary) to collect information regarding study drug administration, vaginal discharge, odor, itching, and any other treatments used. Study site staff reviewed e-Diaries at the Day 7-14 and TOC visits. FINDINGS: A total of 307 women with BV were randomized to treatment (204 to the clindamycin gel group and 103 to the placebo gel group). Most (88.3%) reported at least one previously diagnosed BV episode, and more than one half (55.4%) had experience with other vaginal treatments for BV. At the TOC visit, almost all (91.1%) of the clindamycin gel subjects described their overall experience with the study drug as "satisfied" or "very satisfied," 95.8% indicated that they would be "likely" or "very likely" to use the product again if it became available after the study and they had BV again, and 93.7% would be "likely" or "very likely" to recommend their treatment to a friend who had BV. Almost all (90.2%) clindamycin-treated subjects responded that application was "clean" or "fairly clean," as opposed to "neither clean nor messy," "fairly messy," or "messy." Although 55.4% experienced leakage in the days after application, only 26.9% of those indicated that it was bothersome. Subjects receiving clindamycin gel also reported improvement in both odor and discharge, commencing shortly after dosing and continuing through the assessment period, regardless of whether they met the critical cure criteria. IMPLICATIONS: A single dose of a new bioadhesive 2% clindamycin vaginal gel showed rapid resolution of symptoms and was highly acceptable as a treatment for bacterial vaginosis. CLINICALTRIALS: gov identifier: NCT04370548.

Intrinsic S phase checkpoint enforced by an antiproliferative oncosuppressor cytokine.

The cell cycle is strictly programmed with control mechanisms that dictate order in cell cycle progression to ensure faithful DNA replication, whose deviance may lead to cancer. Checkpoint control at the G1/S, S/G2 and G2/M portals have been defined but no statutory time-programmed control for securing orderly transition through S phase has so far been identified. Here we report that in normal cells DNA synthesis is controlled by a checkpoint sited within the early part of S phase, enforced by the ßGBP cytokine an antiproliferative molecule otherwise known for its oncosuppressor properties that normal cells constitutively produce for self-regulation. Suppression of active Ras and active MAPK, block of cyclin A gene expression and suppression of CDK2-cyclin A activity are events which while specific to the control of a cell cycle phase in normal cells are part of the apoptotic network in cancer cells.

The Impacts of Benefit Sanctions: A Scoping Review of the Quantitative Research Evidence.

In recent decades, the use of conditionality backed by benefit sanctions for those claiming unemployment and related benefits has become widespread in the social security systems of high-income countries. Critics argue that sanctions may be ineffective in bringing people back to employment or indeed harmful in a range of ways. Existing reviews largely assess the labour market impacts of sanctions but our understanding of the wider impacts is more limited. We report results from a scoping review of the international quantitative research evidence on both labour market and wider impacts of benefit sanctions. Following systematic search and screening, we extract data for 94 studies reporting on 253 outcome measures. We provide a narrative summary, paying attention to the ability of the studies to support causal inference. Despite variation in the evidence base and study designs, we found that labour market studies, covering two thirds of our sample, consistently reported positive impacts for employment but negative impacts for job quality and stability in the longer term, along with increased transitions to non-employment or economic inactivity. Although largely relying on non-experimental designs, wider-outcome studies reported significant associations with increased material hardship and health problems. There was also some evidence that sanctions were associated with increased child maltreatment and poorer child well-being. Lastly, the review highlights the generally poor quality of the evidence base in this area, with few studies employing research methods designed to identify the causal impact of sanctions, especially in relation to wider impacts.

Nature-Based Early Childhood Education and Children's Social, Emotional and Cognitive Development: A Mixed-Methods Systematic Review.

This systematic review synthesised evidence on associations between nature-based early childhood education (ECE) and children's social, emotional, and cognitive development. A search of nine databases was concluded in August 2020. Studies were eligible if: (a) children (2-7 years) attended ECE, (b) ECE integrated nature, and (c) assessed child-level outcomes. Two reviewers independently screened full-text articles and assessed study quality. Synthesis included effect direction, thematic analysis, and results-based convergent synthesis. One thousand three hundred and seventy full-text articles were screened, and 36 (26 quantitative; 9 qualitative; 1 mixed-methods) studies were eligible. Quantitative outcomes were cognitive (n = 11), social and emotional (n = 13), nature connectedness (n = 9), and play (n = 10). Studies included controlled (n = 6)/uncontrolled (n = 6) before-after, and cross-sectional (n = 15) designs. Based on very low certainty of the evidence, there were positive associations between nature-based ECE and self-regulation, social skills, social and emotional development, nature relatedness, awareness of nature, and play interaction. Inconsistent associations were found for attention, attachment, initiative, environmentally responsible behaviour, and play disruption/disconnection. Qualitative studies (n = 10) noted that nature-based ECE afforded opportunities for play, socialising, and creativity. Nature-based ECE may improve some childhood development outcomes, however, high-quality experimental designs describing the dose and quality of nature are needed to explore the hypothesised pathways connecting nature-based ECE to childhood development (Systematic Review Registration: CRD42019152582).

Nature-Based Early Childhood Education and Children's Physical Activity, Sedentary Behavior, Motor Competence, and Other Physical Health Outcomes: A Mixed-Methods Systematic Review.

BACKGROUND: The purpose was to synthesize evidence on the association between nature-based Early Childhood Education (ECE) and children's physical activity (PA) and motor competence (MC). METHODS: A literature search of 9 databases was concluded in August 2020. Studies were eligible if (1) children were aged 2-7 years old and attending ECE, (2) ECE settings integrated nature, and (3) assessed physical outcomes. Two reviewers independently screened full-text articles and assessed study quality. Synthesis was conducted using effect direction (quantitative), thematic analysis (qualitative), and combined using a results-based convergent synthesis. RESULTS: 1370 full-text articles were screened and 39 (31 quantitative and 8 qualitative) studies were eligible; 20 quantitative studies assessed PA and 6 assessed MC. Findings indicated inconsistent associations between nature-based ECE and increased moderate to vigorous PA, and improved speed/agility and object control skills. There were positive associations between nature-based ECE and reduced sedentary time and improved balance. From the qualitative analysis, nature-based ECE affords higher intensity PA and risky play, which could improve some MC domains. The quality of 28/31 studies was weak. CONCLUSIONS: More controlled experimental designs that describe the dose and quality of nature are needed to better inform the effectiveness of nature-based ECE on PA and MC.

Scoping and targeted reviews to support development of SPIRIT and CONSORT extensions for randomised controlled trials with surrogate primary endpoints: protocol.

INTRODUCTION: Using a surrogate endpoint as a substitute for a primary patient-relevant outcome enables randomised controlled trials (RCTs) to be conducted more efficiently, that is, with shorter time, smaller sample size and lower cost. However, there is currently no consensus-driven guideline for the reporting of RCTs using a surrogate endpoint as a primary outcome; therefore, we seek to develop SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) and CONSORT (Consolidated Standards of Reporting Trials) extensions to improve the design and reporting of these trials. As an initial step, scoping and targeted reviews will identify potential items for inclusion in the extensions and participants to contribute to a Delphi consensus process. METHODS AND ANALYSIS: The scoping review will search and include literature reporting on the current understanding, limitations and guidance on using surrogate endpoints in trials. Relevant literature will be identified through: (1) bibliographic databases; (2) grey literature; (3) handsearching of reference lists and (4) solicitation from experts. Data from eligible records will be thematically analysed into potential items for inclusion in extensions. The targeted review will search for RCT reports and protocols published from 2017 to 2021 in six high impact general medical journals. Trial corresponding author contacts will be listed as potential participants for the Delphi exercise. ETHICS AND DISSEMINATION: Ethical approval is not required. The reviews will support the development of SPIRIT and CONSORT extensions for reporting surrogate primary endpoints (surrogate endpoint as the primary outcome). The findings will be published in open-access publications.This review has been prospectively registered in the OSF Registration DOI: 10.17605/OSF.IO/WP3QH.

Single-Dose, Bioadhesive Clindamycin 2% Gel for Bacterial Vaginosis: A Randomized Controlled Trial.

OBJECTIVE: To assess efficacy and safety of a single-dose vaginal clindamycin gel for bacterial vaginosis treatment. METHODS: We conducted a double-blind, placebo-controlled, randomized study comparing clindamycin gel with placebo (2:1 ratio). Entry required clinical diagnosis of bacterial vaginosis, that is, all four Amsel's criteria, without other genital infections. Nugent scores of 7-10 were required for efficacy assessment, per updated 2019 U.S. Food and Drug Administration guidance. Patients were evaluated at screening, day 7-14, and day 21-30 (test of cure). Clinical cure was defined as resolution of three of four Amsel's criteria. Bacteriologic cure was defined as Nugent score lower than 4. Therapeutic cure was both clinical and bacteriologic cure. Primary outcome was clinical cure at the test-of-cure visit. Secondary endpoints were clinical cure at day 7-14, and bacteriologic and therapeutic cures at day 7-14 and test of cure. A sample size of 188 patients in the clindamycin group compared with 94 patients in the placebo group had 90% power to detect statistically significant difference (P=.05, 2-tailed). RESULTS: Participants were seen between July 9, 2020, and November 12, 2020. Of 307 randomized women, 56.0% were Black and 88.3% reported one or more previous bacterial vaginosis episodes. In the modified intention-to-treat population, 70.5% of patients in the clindamycin group and 35.6% in the placebo group achieved clinical cure at test of cure (primary outcome) (difference of 34.9, 95% CI 19.0-50.8), as did 77.5% of patients in the clindamycin group and 42.6% of patients in the placebo group in the per-protocol population (difference of 34.9, 95% CI 17.0-52.7). Statistically significant differences between groups were seen for all secondary endpoints. Clinical cure rate in patients in the clindamycin group with more than three bacterial vaginosis episodes in the prior year was 70.0%. Approximately 15% (15.3%) of patients in the clindamycin group experienced one or more treatment-emergent adverse events related to study treatment, as did 9.7% of patients in the placebo group. The most frequent treatment-related, treatment-emergent adverse event was vulvovaginal candidiasis. CONCLUSION: A new, single-dose clindamycin vaginal gel was highly effective, with excellent safety, in women disproportionately affected by bacterial vaginosis, with Nugent scores of 7-10 at study entry. FUNDING SOURCE: The study was funded by Daré Bioscience, Inc. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov, NCT04370548.

Barriers and facilitators of successful weight loss during participation in behavioural weight management programmes: a protocol for a systematic review.

BACKGROUND: Behavioural weight management programmes are effective in assisting people with overweight or obesity to lose excess body weight. Yet, many still struggle to attain their weight loss goals in such programmes. Little is understood about the factors which impact success in these programmes. Synthesising this data will allow for theory to be developed on how to improve success in such programmes. The main aim of this review will be to extract and synthesise the barriers and facilitators of successful weight loss during participation of behavioural weight loss programmes in adults living with overweight and obesity. METHODS: A systematic search of MEDLINE, Embase, PsycINFO, The Cochrane Library and CINAHL will be performed from inception onwards. Studies will also be sought by contacting experts in the field, reference and website searching. Studies will be eligible if the participants are adults living with obesity (population) undertaking or recently completed behavioural weight loss programmes (intervention) with the primary focus of weight loss (outcome). The primary outcomes will be amount of weight lost and information on barriers and/or facilitators to success. The secondary outcomes will be reasons or factors related to attrition and adherence and behaviour change techniques used in programmes. Two reviewers will screen citations and full-text data. Reviewer 1 will screen all, and reviewer 2 will screen a random 50% of articles. Data extraction will be completed by reviewer 1, and 10% will be checked by the research team. Potential conflicts will be resolved through discussion. Data will be synthesised and described narratively to show the characteristics of each study, levels of success and barriers and facilitators during programme participation. A thematic approach will be taken, and themes will be coded against the levels of the socioecological model. Quantitative data will be extracted and categorised according to these themes and presented alongside the qualitative data. DISCUSSION: Our findings can be used to inform how weight loss programmes can be improved to facilitate success in those at risk of failure. Results will be published in a peer-reviewed journal. SYSTEMATIC REVIEW REGISTRATION: ( PROSPERO CRD42019148158 ).

Nature-based early childhood education for child health, wellbeing and development: a mixed-methods systematic review protocol.

BACKGROUND: Several systematic reviews have reviewed the evidence relating to nature on aspects of children and adolescent's health and wellbeing; however, none have looked at the associations or effectiveness of attending nature-based early childhood education (ECE). The main objective is to systematically review and synthesise the evidence to determine if nature-based ECE enhances children's health, wellbeing and development. METHODS: We will search the following electronic databases (from inception onwards): MEDLINE, Scopus, PsycINFO, ERIC, SportDiscus, Australian Education Index, British Education Index, Child Development and Adolescent studies, and Applied Social Sciences Index and Abstracts. Grey literature will be identified searching dissertations and reports (e.g. Open Grey, Dissertations Theses Database [ProQuest], and Google Scholar). All types of studies (quantitative and qualitative) conducted in children (aged 2-7 years old) attending ECE who had not started education at primary or elementary school will be included. The exposure of interest will be nature-based ECE settings that integrate nature into their philosophy and/or curriculum and environment. The outcomes of interest will be all aspects of the child's physical, cognitive, social and emotional health wellbeing and development. Two reviewers will independently screen full-text articles. The study methodological quality (or bias) will be appraised using appropriate tools. If feasible, a meta-analysis will be conducted using a random-effect model for studies similar in exposure and outcome. Where studies cannot be included in a meta-analysis, findings will be summarised based on the effect directions and a thematic analysis will be conducted for qualitative studies. DISCUSSION: This systematic review will capture the state of the current literature on nature-based ECE for child health, wellbeing and development. The results of this study will be of interest to multiple audiences (including researchers and policy makers). Results will be published in a peer-reviewed journal. Gaps for future research will be identified and discussed. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42019152582.

Phosphoinositide 3-kinase targeting by the beta galactoside binding protein cytokine negates akt gene expression and leads aggressive breast cancer cells to apoptotic death.

INTRODUCTION: Phosphoinositide 3-kinase (PI3K)-activated signalling has a critical role in the evolution of aggressive tumourigenesis and is therefore a prime target for anticancer therapy. Previously we have shown that the beta galactoside binding protein (betaGBP) cytokine, an antiproliferative molecule, induces functional inhibition of class 1A and class 1B PI3K. Here, we have investigated whether, by targeting PI3K, betaGBP has therapeutic efficacy in aggressive breast cancer cells where strong mitogenic input is fuelled by overexpression of the ErbB2 (also known as HER/neu, for human epidermal growth factor receptor 2) oncoprotein receptor and have used immortalised ductal cells and non-aggressive mammary cancer cells, which express ErbB2 at low levels, as controls. METHODS: Aggressive BT474 and SKBR3 cancer cells where ErbB2 is overexpressed, MCF10A immortalised ductal cells and non-invasive MCF-7 cancer cells which express low levels of ErbB2, both in their naive state and when forced to mimic aggressive behaviour, were used. Class IA PI3K was immunoprecipitated and the conversion of phosphatidylinositol (4,5)-biphosphate (PIP2) to phosphatidylinositol (3,4,5)-trisphosphate (PIP3) assessed by ELISA. The consequences of PI3K inhibition by betaGBP were analysed at proliferation level, by extracellular signal-regulated kinase (ERK) activation, by akt gene expression and by apoptosis. Apoptosis was documented by changes in mitochondrial membrane potential, alteration of the plasma membrane, caspase 3 activation and DNA fragmentation. Phosphorylated and total ERK were measured by Western blot analysis and akt mRNA levels by Northern blot analysis. The results obtained with the BT474 and SKBR3 cells were validated in the MCF10A ductal cells and in non-invasive MCF-7 breast cancer cells forced into mimicking the in vitro behaviour of the BT474 and SKBR3 cells. RESULTS: In aggressive breast cancer cells, where mitogenic signalling is enforced by the ErbB2 oncoprotein receptor, functional inhibition of the catalytic activity of PI3K by the betaGBP cytokine and loss of akt mRNA results in apoptotic death. A functional correlation between ERK and the kt gene was also found. The relationship between ERK, akt mRNA, PI3K and cell vulnerability to betaGBP challenge was sustained both in mammary ductal cells forced to mimic an aggressive behaviour and in non-aggressive breast cancer cells undergoing an enforced shift into an aggressive phenotype. CONCLUSIONS: betaGBP, a newly discovered physiological inhibitor of PI3K, is a selective and potent inducer of apoptosis in aggressive breast cancer cells. Due to its physiological nature, which carries no chemotherapeutic disadvantages, betaGBP has the potential to be safely tested in clinical trials.

Tregs utilize beta-galactoside-binding protein to transiently inhibit PI3K/p21ras activity of human CD8+ T cells to block their TCR-mediated ERK activity and proliferation.

Regulatory T cells (Tregs) and beta-galactoside-binding protein (betaGBP), a regulatory protein often found expressed at sites of immunological privilege, have similar functions. Their presence affects the outcome of harmful autoimmunity and cancers, including experimental autoimmune encephalomyelitis and malignant gliomas. Here we report a novel pathway by which Tregs express and utilize betaGBP to control CD8(+) T cell responses partially activating TCR signaling but blocking PI3K activity. As a result, this leads to a loss of p21(ras), ERK and Akt activities despite activation of TCR proximal signals, such as phosphorylation of CD3zeta, Zap70, Lat and PKCtheta. Although non-processive TCR signaling often leads to cell anergy, Tregs/betaGBP did not affect cell viability. Instead, betaGBP/Tregs transiently prevented activation of CD8(+) T cells with self-antigens, while keeping their responses to xenogeneic antigens unaffected.