The development, reliability, and validity of the Facilitator Assessment Tool: An implementation fidelity measure used in Parenting for Lifelong Health for Young Children.

BACKGROUND: The Parenting for Lifelong Health for Young Children (PLH-YC) programme aims to reduce violence against children and child behaviour problems among families in low- and middle-income countries (LMICs). Although the programme has been tested in four randomised controlled trials and delivered in over 25 countries, there are gaps in understanding regarding the programme's implementation fidelity and, more generally, concerning the implementation fidelity of parenting programmes in LMICs. AIMS: This study aims to address these gaps by examining the psychometric properties of the PLH-YC-Facilitator Assessment Tool (FAT)-an observational tool used to measure the competent adherence of PLH-YC facilitators. Examining the psychometric properties of the FAT is important in order to determine whether there is an association between facilitator competent adherence and programme outcomes and, if correlated, to improve facilitator performance. It is also important to develop the implementation literature among parenting interventions in LMICs. METHODS: The study examined the content validity, intra-rater reliability, and inter-rater reliability of the FAT. Revision of the tool was based on consultation with programme trainers, experts, and assessors. A training curriculum and assessment manual was created. Assessors were trained in Southeastern Europe and their assessments of facilitator delivery were analysed as part of a large-scale factorial experiment (N = 79 facilitators). RESULTS: The content validity process with PLH-YC trainers, experts, and assessors resulted in substantial improvements to the tool. Analyses of percentage agreements and intraclass correlations found that, even with practical challenges, assessments were completed with adequate yet not strong intra- and inter-rater reliability. CONCLUSIONS: This study contributes to the literature on the implementation of parenting programmes in LMICs. The study found that the FAT appears to capture its intended constructs and can be used with an acceptable degree of consistency. Further research on the tool's reliability and validity-specifically, its internal consistency, construct validity, and predictive validity-is recommended.

Calcium dysregulation potentiates wild-type myocilin misfolding: implications for glaucoma pathogenesis.

Myocilin is secreted from trabecular meshwork cells to an eponymous extracellular matrix that is critical for maintaining intraocular pressure. Missense mutations found in the myocilin olfactomedin domain (OLF) lead to intracellular myocilin misfolding and are causative for the heritable form of early-onset glaucoma. The OLF domain contains a unique internal, hetero-dinuclear calcium site. Here, we tested the hypothesis that calcium dysregulation causes wild-type (WT) myocilin misfolding reminiscent of that observed for disease variants. Using two cellular models expressing WT myocilin, we show that the Ca2+ ATPase channel blocker thapsigargin inhibits WT myocilin secretion. Intracellular WT myocilin is at least partly insoluble and aggregated in the endoplasmic reticulum (ER), and stains positively with an amyloid dye. By comparing the effect of thapsigargin on WT myocilin to that on a de novo secretion-competent Ca2+-free variant D478S, we discern that non-secretion of WT myocilin is due initially to calcium dysregulation, and is potentiated further by resultant ER stress. In E. coli, depletion of calcium leads to recombinant expression of misfolded isolated WT OLF but the D478S variant is still produced as a folded monomer. Treatment of cells expressing a double mutant composed of D478S and either disease variants P370L or Y437H with thapsigargin promotes its misfolding and aggregation, demonstrating the limits of D478S to correct secretion defects. Taken together, the heterodinuclear calcium site is a liability for proper folding of myocilin. Our study suggests a molecular mechanism by which WT myocilin misfolding may contribute broadly to glaucoma-associated ER stress. This study explores the effect of calcium depletion on myocilin olfactomedin domain folding.

Acne treatment review and future perspectives.

Acne affects approximately 9% of people worldwide and is the most common skin condition in the USA. There are abundant topical and oral treatment options available for patients with acne. First-line agents include topical retinoids, azelaic acid, benzoyl peroxide, and combinations of these agents. For recalcitrant or more severe acne, oral medications, including oral antibiotics, isotretinoin, or hormonal therapy, may be considered. This review will also discuss the many advances being made in the treatment of acne vulgaris, from the development of microencapsulated medications to targeted treatments.

Molecular architecture and modifications of full-length myocilin.

Myocilin, a modular multidomain protein, is expressed broadly in the human body but is best known for its presence in the trabecular meshwork extracellular matrix, and myocilin misfolding is associated with glaucoma. Despite progress in comprehending the structure and misfolding of the myocilin olfactomedin domain, the structure and function of full-length myocilin, and contextual changes in glaucoma, remain unknown. Here we expressed and purified milligram-scale quantities of full-length myocilin from suspension mammalian cell culture (Expi293F), enabling molecular characterization in detail not previously accessible. We systematically characterized disulfide-dependent and -independent oligomerization as well as confirmed glycosylation and susceptibility to proteolysis. We identified oligomeric states with glycosylation sites that are inaccessible to enzymatic removal. Low-resolution single particle 2D class averaging from conventional transmission electron microscopy imaging confirms an extended arrangement of tetramers, truncated products consistent with dimers, and a higher-ordered state consistent with octamer. Taken together, our study reveals new myocilin misfolded states and layers of intrinsic heterogeneity, expands our knowledge of olfactomedin-family proteins and lays the foundation for a better molecular understanding of myocilin structure and its still enigmatic biological function.

Stable calcium-free myocilin olfactomedin domain variants reveal challenges in differentiating between benign and glaucoma-causing mutations.

Nonsynonymous gene mutations can be beneficial, neutral, or detrimental to the stability, structure, and biological function of the encoded protein, but the effects of these mutations are often not readily predictable. For example, the ß-propeller olfactomedin domain of myocilin (mOLF) exhibits a complex interrelationship among structure(s), stability, and aggregation. Numerous mutations within mOLF are linked to glaucoma; the resulting variants are less stable, aggregation-prone, and sequestered intracellularly, causing cytotoxicity. Here, we report the first stable mOLF variants carrying substitutions in the calcium-binding site that exhibit solution characteristics indistinguishable from those of glaucoma variants. Crystal structures of these stable variants at 1.8-2.0-Å resolution revealed features that we could not predict by molecular dynamics simulations, including loss of loop structure, helix unwinding, and a blade shift. Double mutants that combined a stabilizing substitution and a selected glaucoma-causing single-point mutant rescued in vitro folding and stability defects. In the context of full-length myocilin, secretion of stable single variants was indistinguishable from that of the WT protein, and the double mutants were secreted to varying extents. In summary, our finding that mOLF can tolerate particular substitutions that render the protein stable despite a conformational switch emphasizes the complexities in differentiating between benign and glaucoma-causing variants and provides new insight into the possible biological function of myocilin.

DnaJ/Hsc70 chaperone complexes control the extracellular release of neurodegenerative-associated proteins.

It is now known that proteins associated with neurodegenerative disease can spread throughout the brain in a prionlike manner. However, the mechanisms regulating the trans-synaptic spread propagation, including the neuronal release of these proteins, remain unknown. The interaction of neurodegenerative disease-associated proteins with the molecular chaperone Hsc70 is well known, and we hypothesized that much like disaggregation, refolding, degradation, and even normal function, Hsc70 may dictate the extracellular fate of these proteins. Here, we show that several proteins, including TDP-43, α-synuclein, and the microtubule-associated protein tau, can be driven out of the cell by an Hsc70 co-chaperone, DnaJC5. In fact, DnaJC5 overexpression induced tau release in cells, neurons, and brain tissue, but only when activity of the chaperone Hsc70 was intact and when tau was able to associate with this chaperone. Moreover, release of tau from neurons was reduced in mice lacking the DnaJC5 gene and when the complement of DnaJs in the cell was altered. These results demonstrate that the dynamics of DnaJ/Hsc70 complexes are critically involved in the release of neurodegenerative disease proteins.

Human cyclophilin 40 unravels neurotoxic amyloids.

The accumulation of amyloidogenic proteins is a pathological hallmark of neurodegenerative disorders. The aberrant accumulation of the microtubule associating protein tau (MAPT, tau) into toxic oligomers and amyloid deposits is a primary pathology in tauopathies, the most common of which is Alzheimer's disease (AD). Intrinsically disordered proteins, like tau, are enriched with proline residues that regulate both secondary structure and aggregation propensity. The orientation of proline residues is regulated by cis/trans peptidyl-prolyl isomerases (PPIases). Here we show that cyclophilin 40 (CyP40), a PPIase, dissolves tau amyloids in vitro. Additionally, CyP40 ameliorated silver-positive and oligomeric tau species in a mouse model of tau accumulation, preserving neuronal health and cognition. Nuclear magnetic resonance (NMR) revealed that CyP40 interacts with tau at sites rich in proline residues. CyP40 was also able to interact with and disaggregate other aggregating proteins that contain prolines. Moreover, CyP40 lacking PPIase activity prevented its capacity for disaggregation in vitro. Finally, we describe a unique structural property of CyP40 that may permit disaggregation to occur in an energy-independent manner. This study identifies a novel human protein disaggregase and, for the first time, demonstrates its capacity to dissolve intracellular amyloids.

Skeletal muscle-specific Cre recombinase expression, controlled by the human α-skeletal actin promoter, improves glucose tolerance in mice fed a high-fat diet.

AIMS/HYPOTHESIS: Cre-loxP systems are frequently used in mouse genetics as research tools for studying tissue-specific functions of numerous genes/proteins. However, the expression of Cre recombinase in a tissue-specific manner often produces undesirable changes in mouse biology that can confound data interpretation when using these tools to generate tissue-specific gene knockout mice. Our objective was to characterise the actions of Cre recombinase in skeletal muscle, and we anticipated that skeletal muscle-specific Cre recombinase expression driven by the human α-skeletal actin (HSA) promoter would influence glucose homeostasis. METHODS: Eight-week-old HSA-Cre expressing mice and their wild-type littermates were fed a low- or high-fat diet for 12 weeks. Glucose homeostasis (glucose/insulin tolerance testing) and whole-body energy metabolism (indirect calorimetry) were assessed. We also measured circulating insulin levels and the muscle expression of key regulators of energy metabolism. RESULTS: Whereas tamoxifen-treated HSA-Cre mice fed a low-fat diet exhibited no alterations in glucose homeostasis, we observed marked improvements in glucose tolerance in tamoxifen-treated, but not corn-oil-treated, HSA-Cre mice fed a high-fat diet vs their wild-type littermates. Moreover, Cre dissociation from heat shock protein 90 and translocation to the nucleus was only seen following tamoxifen treatment. These improvements in glucose tolerance were not due to improvements in insulin sensitivity/signalling or enhanced energy metabolism, but appeared to stem from increases in circulating insulin. CONCLUSIONS/INTERPRETATION: The intrinsic glycaemia phenotype in the HSA-Cre mouse necessitates the use of HSA-Cre controls, treated with tamoxifen, when using Cre-loxP models to investigate skeletal muscle-specific gene/protein function and glucose homeostasis.

The active Hsc70/tau complex can be exploited to enhance tau turnover without damaging microtubule dynamics.

The pathological accumulation of abnormally hyperphosphorylated and aggregated tau, a neuronal microtubule (MT)-associated protein that functions to maintain MT stability, is implicated in a number of hereditary and sporadic neurodegenerative diseases including frontotemporal dementia and Alzheimer's disease. Targeting tau for the treatment of these diseases is an area of intense interest and toward that end, modulation of cellular molecular chaperones is a potential therapeutic target. In particular, the constitutive Hsp70 isoform, Hsc70, seems highly interconnected with tau, preserving tau protein levels and synergizing with it to assemble MTs. But the relationship between tau and Hsc70, as well as the impact of this interaction in neurons and its therapeutic implications remain unknown. Using a human dominant negative Hsc70 that resembles isoform selective inhibition of this important chaperone, we found for the first time that Hsc70 activity is required to stimulate MT assembly in cells and brain. However, surprisingly, active Hsc70 also requires active tau to regulate MT assembly in vivo, suggesting that tau acts in some ways as a co-chaperone for Hsc70 to coordinate MT assembly. This was despite tau binding to Hsc70 as substrate, as determined biochemically. Moreover, we show that while chronic Hsc70 inhibition damaged MT dynamics, intermittent treatment with a small molecule Hsp70 inhibitor lowered tau in brain tissue without disrupting MT integrity. Thus, in tauopathies, where MT injury would be detrimental to neurons, the unique relationship of tau with the Hsc70 machinery can be exploited to deplete tau levels without damaging MT networks.

The Case for Assessing and Reporting on Facilitator Fidelity: Introducing the Fidelity of Implementation in Parenting Programs Guideline.

The sizeable body of evidence indicating that parenting programs have a positive impact on children and families highlights the potential public health benefits of their implementation on a large scale. Despite evidence and global attention, beyond the highly controlled delivery of parenting programs via randomized trials, little is known about program effectiveness or how to explain the poorer results commonly observed when implemented in community settings. Researchers, practitioners, and policymakers must work together to identify what is needed to spur adoption and sustainment of evidence-based parenting programs in real-world service systems and how to enhance program effectiveness when delivered via these systems. Collecting, analyzing, and using facilitator fidelity data is an important frontier through which researchers and practitioners can contribute. In this commentary, we outline the value of assessing facilitator fidelity and utilizing the data generated from these assessments; describe gaps in research, knowledge, and practice; and recommend directions for research and practice. In making recommendations, we describe a collaborative process to develop a preliminary guideline-the Fidelity of Implementation in Parenting Programs Guideline or FIPP-to use when reporting on facilitator fidelity. Readers are invited to complete an online survey to provide comments and feedback on the first draft of the guideline. Supplementary Information: The online version contains supplementary material available at 10.1007/s43477-023-00092-5.

A hybrid digital parenting programme to prevent abuse of adolescents in Tanzania: study protocol for a pragmatic cluster-randomised controlled trial.

BACKGROUND: Evidence-based parenting programmes have strong evidence in preventing and mitigating violence, but in-person programmes are challenging to deliver at scale. ParentApp is an open-source, offline-first app-based adaptation of the Parenting for Lifelong Health for Parents and Teens programme to promote playful and positive parenting, reduce risks for sexual violence victimisation, and prevent violence against adolescents. This study aims to evaluate the effectiveness and cost-effectiveness of ParentApp compared to an attention-control group. METHODS: This study is a two-arm pragmatic cluster-randomised controlled trial to test whether ParentApp reduces adolescent physical abuse, emotional abuse, and sexual violence risks and victimisation at 1 month and 12 months post-intervention. Caregivers of adolescents aged 10-17 years and their adolescent children (N = 2400 caregiver-adolescent dyads) will be recruited in urban and peri-urban communities in the Mwanza region of Tanzania. A total of 80 study clusters will be stratified and randomised (1:1) to the intervention group, who will receive ParentApp with support through a WhatsApp group, or to an attention-control group, who will receive a water, sanitation, and hygiene app. Quantitative data will be collected through outcomes questionnaires with caregivers and adolescents, administered at baseline, 4 months post-baseline, and 16 months post-baseline, as well as through routine implementation data and ParentApp engagement data. Qualitative data will be collected through individual interviews and focus groups with caregivers, adolescents, and implementing partner staff. DISCUSSION: App-based interventions have the potential to expand access to evidence-based parenting support, but currently lack rigorous evidence in low- and middle-income countries. This is the first known randomised control trial of a hybrid digital parenting programme to prevent the abuse of adolescents in low- and middle-income settings. TRIAL REGISTRATION: The trial was registered on the Open Science Framework on 14 March 2023, registration: OSF.IO/T9FXZ .

Quantitative differentiation of benign and misfolded glaucoma-causing myocilin variants on the basis of protein thermal stability.

Accurate predictions of the pathogenicity of mutations associated with genetic diseases are key to the success of precision medicine. Inherited missense mutations in the myocilin (MYOC) gene, within its olfactomedin (OLF) domain, constitute the strongest genetic link to primary open-angle glaucoma via a toxic gain of function, and thus MYOC is an attractive precision-medicine target. However, not all mutations in MYOC cause glaucoma, and common variants are expected to be neutral polymorphisms. The Genome Aggregation Database (gnomAD) lists ∼100 missense variants documented within OLF, all of which are relatively rare (allele frequency <0.001%) and nearly all are of unknown pathogenicity. To distinguish disease-causing OLF variants from benign OLF variants, we first characterized the most prevalent population-based variants using a suite of cellular and biophysical assays, and identified two variants with features of aggregation-prone familial disease variants. Next, we considered all available biochemical and clinical data to demonstrate that pathogenic and benign variants can be differentiated statistically based on a single metric: the thermal stability of OLF. Our results motivate genotyping MYOC in patients for clinical monitoring of this widespread, painless and irreversible ocular disease.

The Prevalence of Sexual Assault Among Higher Education Students: A Systematic Review With Meta-Analyses.

Sexual assault among higher education students has detrimental impacts on the health and educational outcomes of survivors. This systematic review aims to describe and synthesize the available quantitative evidence on sexual assault prevalence among this population. We searched Medline, EMBASE, Global Health, PsycINFO, Web of Science, ERIC, and CINAHL for studies published in English, French, Italian, and Spanish from database inception to August 2020 (updated May 2022). We screened studies using prespecified inclusion criteria for the population and context (registered higher education students), condition (self-reported sexual assault), and study design (quantitative survey). The Joanna Briggs Institute Critical Appraisal Checklist was used to assess study quality. Prevalence estimates disaggregated by type of sexual assault, gender identity, and world region were meta-analyzed using a random-effects model and reported following PRISMA guidance. We identified 131 articles, from 21 different countries. The meta-analyzed prevalence of sexual assault was 17.5% for women, 7.8% for men, and 18.1% for transgender and gender diverse people. Four types of sexual assault were identified: rape, attempted rape, forced sexual touching, and coercive sex. Forced sexual touching was the most common act experienced. The African Region had the highest prevalence estimates for women's sexual assault, and the Western Pacific region had the highest prevalence estimates for men's sexual assault. Higher education institutions, especially those outside of the United States, should commit to the implementation of surveys to monitor sexual assault prevalence and dedicate increased resources to supporting student survivors of sexual assault.

Differences in Merkel Cell Carcinoma Presentation and Outcomes Among Racial and Ethnic Groups.

Importance: Racial and ethnic differences in skin cancer outcomes are understudied. Delineating these differences in Merkel cell carcinoma (MCC) is needed to better understand this rare disease. Objective: To determine how MCC presentation and outcomes differ across racial and ethnic groups. Design, Setting, and Participants: This retrospective cohort study included patients diagnosed with MCC and followed up from 2000 through 2018 in the 18 population-based cancer registries of the National Cancer Institute's Surveillance, Epidemiology, and End Results Program. Patients without follow-up data were excluded. Data analysis occurred from March 12 to November 30, 2022. Main Outcomes and Measures: A Cox proportional hazards regression was conducted to determine associations between demographic variables (race and ethnicity, age, sex, and income) and clinical variables (stage at diagnosis, primary site, and diagnosis year) with MCC-specific survival. Results: Of the 9557 patients with MCC identified (6758 [70.7%] aged ≥70 years; 6008 [62.9%] male), 222 (2.3%) were Asian American or Pacific Islander, 146 (1.5%) Black, 541 (5.7%) Hispanic, and 8590 (89.9%) White. Hispanic patients had improved MCC-specific survival compared with White patients (hazard ratio, 0.82; 95% CI, 0.67-0.99; P = .04). Black patients had the lowest MCC-specific survival, but it was not statistically different from White patients (hazard ratio, 1.19; 95% CI, 0.86-1.60; P = .28). Hispanic and Black patients were less likely to present with a primary site of the head and neck than White patients (183 of 541 [33.8%] Hispanic patients and 45 of 146 [30.8%] Black patients vs 3736 of 8590 [43.5%] White patients; P < .001 and P = .002, respectively). Black patients presented more often than White patients with advanced disease at diagnosis (59 of 146 [40.4%] vs 2510 of 8590 [29.2%]; P = .004). Conclusions and Relevance: In this cohort study, there were differences between racial and ethnic groups in observed MCC outcomes and disease characteristics. Further investigations are warranted into the findings that, compared with White patients, Hispanic patients with MCC had improved outcomes and Black patients did not have worse outcomes despite presenting with more advanced disease.

Benzothiazole Substitution Analogs of Rhodacyanine Hsp70 Inhibitors Modulate Tau Accumulation.

The accumulation and aggregation of the microtubule-associated protein tau (tau) into intracellular neuronal tangles are a hallmark of a range of progressive neurodegenerative tauopathies, including Alzheimer's disease (AD), frontotemporal dementia, Pick's disease, and progressive supranuclear palsy. The aberrant phosphorylation of tau is associated with tau aggregates in AD. Members of the heat shock protein 70 kDa (Hsp70) family of chaperones bind directly to tau and modulate tau clearance and aggregation. Small molecules that inhibit the Hsp70 family of chaperones have been shown to reduce the accumulation of tau, including phosphorylated tau. Here, eight analogs of the rhodacyanine inhibitor, JG-98, were synthesized and evaluated. Like JG-98, many of the compounds inhibited ATPase activity of the cytosolic heat shock cognate 70 protein (Hsc70) and reduced total, aggregated, and phosphorylated tau accumulation in cultured cells. Three compounds, representing divergent clogP values, were evaluated for in vivo blood-brain barrier penetration and tau reduction in an ex vivo brain slice model. AL69, the compound with the lowest clogP and the lowest membrane retention in a parallel artificial membrane permeability assay (PAMPA), reduced phosphorylated tau accumulation. Our results suggest that benzothiazole substitutions of JG-98 that increase hydrophilicity may increase the efficacy of these Hsp70 inhibitors to reduce phosphorylated tau.

Risk and Protective Factors for Men's Sexual Violence Against Women at Higher Education Institutions: A Systematic and Meta-Analytic Review of the Longitudinal Evidence.

Sexual violence among higher education institution (HEI) students is a growing public health concern. To date, there is little evidence on how to effectively prevent sexual violence among this demographic. This study is the first systematic review to meta-analyze all available evidence for risk and protective factors of sexual violence perpetrated by men at HEIs. We searched four electronic databases and multiple gray literature sources. We screened studies using prespecified selection criteria for the sample (HEI students who identify as men), outcome (sexual violence perpetration against peers), and study design (quantitative and longitudinal). Longitudinal studies provide the most rigorous available evidence on risk and protective factors. We identified 16 studies and meta-analyzed eight different risk factors: alcohol consumption, hostility toward women, delinquency, fraternity membership, history of sexual violence perpetration, rape myth acceptance, age at first sex, and peer approval of sexual violence. We deemed included studies to have a varied risk of bias and the overall quality of evidence to range from moderate to high. History of sexual violence perpetration (perpetration prior to entering an HEI) emerged as the strongest predictor of sexual violence perpetration at HEIs, complicating the notion that HEI environments themselves foster a culture of sexual violence. Peer support for sexual violence predicted perpetration while individual rape-supporting beliefs did not. Our findings suggest that interventions targeting peer norms (e.g., bystander interventions) and early sexual violence prevention and consent interventions for high school and elementary school students could be effective in reducing and preventing sexual violence at HEIs.

Challenges documenting racial disparities in Merkel cell carcinoma.

Merkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine skin cancer that predominantly impacts White patients. Overall incidence and the proportion of minority patients with MCC are both rising. In the more common skin cancer, melanoma, racial disparities are well-documented in stage at presentation and patient survival. Whether racial and ethnic disparities exist in MCC remains unclear. The study of MCC disparities is hampered by limitations in data registries, including SEER and NCDB, and an evolving natural history due to the advent of immunotherapy. Published MCC immunotherapy clinical trials consistently reported the racial diversity among enrolled subjects but failed to include patients' ethnicities. Efforts to improve data capture in cancer registries and create multi-institutional clinical databases will allow for more effective study of racial and ethnic disparities in rare cancers like MCC. Such studies are needed to advance policies promoting equity in care.

Measures of Facilitator Competent Adherence Used in Parenting Programs and Their Psychometric Properties: A Systematic Review.

Implementation fidelity is a critical component of intervention science, which aims to understand how interventions unfold in practice to improve outcomes. A key element of fidelity is facilitator competent adherence-the extent to which a program is delivered as prescribed with the specified level of quality. We conducted a two-part systematic review examining these aspects in parenting programs aiming to reduce child behavior problems and maltreatment. Part One reviews measures of facilitator competent adherence and Part Two examines the psychometric properties of the observational measures found. Searches identified 9153 articles from electronic databases, citation tracking, and expert input. After screening using pre-specified criteria, 156 (Part One) and 41 (Part Two) articles remained. In Part One, measure, facilitator, and intervention characteristics were extracted and synthesized from 65 measures. Most measures were observational, used by facilitators and researchers, and employed Likert-scale ratings. In Part Two, evidence on the reliability (internal consistency, inter-rater, intra-rater, test-retest) and validity (content, construct, convergent/divergent, criterion) of 30 observational measures identified from Part One was synthesized and evaluated. An adapted COSMIN checklist was used to assess study and measure quality. We found most studies to be of reasonably high quality. This is the first review to summarize and critically appraise measures of facilitator competent adherence used in the parenting program literature and establish their psychometric properties. The findings underscore the need to advance research on measures of facilitator competent adherence; reliable, valid, and high-quality implementation measures allow for evidence-based decisions regarding the delivery and scale-up of parenting programs. PROSPERO Registration Number: CRD42020167872.

A mixed methods evaluation of the large-scale implementation of a school- and community-based parenting program to reduce violence against children in Tanzania: a study protocol.

BACKGROUND: Despite the rapid dissemination of parenting programs aiming to reduce and prevent violence against children (VAC) worldwide, there is limited knowledge about and evidence of the implementation of these programs at scale. This study addresses this gap by assessing the quality of delivery and impact of an evidence-based parenting program for parents/caregivers and their adolescent girls aged 9 to 14-Parenting for Lifelong Health Teens (PLH-Teens), known locally as Furaha Teens-on reducing VAC at scale in Tanzania. The study will explore participating family and staff perspectives on program implementation and examine factors associated with implementation and how implementation quality is associated with intervention outcomes when the program is delivered to approximately 50,000 parent-child dyads (N = 100,000) in schools and community centers across eight districts of Tanzania. METHODS: This mixed-methods study will answer the following research questions: (1) what is the implementation quality and fidelity of PLH-Teens at scale in Tanzania; (2) what factors are associated with the quality of delivery and implementation fidelity of PLH-Teens; (3) how are implementation quality and fidelity associated with intervention outcomes; (4) what are participant and implementing staff perspectives on the acceptability, appropriateness, feasibility, benefits, and challenges of delivering PLH-Teens in their schools and communities; (5) what is the impact of PLH-Teens on VAC and participant well-being; and (6) how much does it cost to deliver PLH-Teens at scale? Qualitative and quantitative data will be collected directly from implementers, parents/caregivers, and adolescents using pre-post questionnaires, observational assessments, cost surveys, focus groups, and interviews. Qualitative data will be analyzed thematically with the aid of NVIVO software. Quantitative data will be cleaned and analyzed using methods such as correlation, regression, and structural equation models using Stata and R. COREQ and TREND guidelines will be used, where appropriate. DISCUSSION: Findings will provide vital insights into some of the factors related to quality implementation at scale. Lessons learned regarding the implementation of PLH-Teens at scale will be applied in Tanzania, and also in the delivery of PLH parenting programs globally.

Rationale and design of the preserved versus reduced ejection fraction biomarker registry and precision medicine database for ambulatory patients with heart failure (PREFER-HF) study.

INTRODUCTION: Patients with heart failure (HF) are classically categorised by left ventricular ejection fraction (LVEF). Efforts to predict outcomes and response to specific therapy among LVEF-based groups may be suboptimal, in part due to the underlying heterogeneity within clinical HF phenotypes. A multidimensional characterisation of ambulatory patients with and without HF across LVEF groups is needed to better understand and manage patients with HF in a more precise manner. METHODS AND ANALYSIS: To date, the first cohort of 1313 out of total planned 3000 patients with and without HF has been enroled in this single-centre, longitudinal observational cohort study. Baseline and 1-year follow-up blood samples and clinical characteristics, the presence and duration of comorbidities, serial laboratory, echocardiographic data and images and therapy information will be obtained. HF diagnosis, aetiology of disease, symptom onset and clinical outcomes at 1 and 5 years will be adjudicated by a team of clinicians. Clinical outcomes of interest include all-cause mortality, cardiovascular mortality, all-cause hospitalisation, cardiovascular hospitalisation, HF hospitalisation, right-sided HF and acute kidney injury. Results from the Preserved versus Reduced Ejection Fraction Biomarker Registry and Precision Medicine Database for Ambulatory Patients with Heart Failure (PREFER-HF) trial will examine longitudinal clinical characteristics, proteomic, metabolomic, genomic and imaging data to better understand HF phenotypes, with the ultimate goal of improving precision medicine and clinical outcomes for patients with HF. ETHICS AND DISSEMINATION: Information gathered in this research will be published in peer-reviewed journals. Written informed consent for PREFER-HF was obtained from all participants. All study procedures were approved by the Mass General Brigham Institutional Review Board in Boston, Massachusetts and performed in accordance with the Declaration of Helsinki (Protocol Number: 2016P000339). TRIAL REGISTRATION NUMBER: PREFER-HF ClinicalTrials.gov identifier: NCT03480633.