Community Health Workers: Bridge to Pediatric Mental Health Equity.

We currently face a national crisis in youth mental health and well-being and significant child behavioral health inequities. Addressing social determinants is a primary approach to achieving health equity. Social determinants of mental health (SDoMH) impact every child across the mental health services continuum, with inequities driven by discrimination across social class, race, gender, sexual orientation, physical ability, national origin, intellectual or mental abilities, and other group categories and combinations of group categories. While clinician passion, ingenuity, and support for advancing SDoMH resources and social justice are crucial, navigating rapidly changing community resources and tailoring the strategies for individual patients can be daunting for clinical personnel who are already overwhelmed with clinical loads. We build upon Cotton and Shim's (2022) call to action for clinicians to meet SDoMH needs across the public health framework/pyramid. A complementary approach builds upon this traditional clinician-driven model to a community team model. It adds a new team member, the community health worker (CHW). CHWs bring deep community ties, community relationships, and trust to support family-driven priorities around unmet SDoMH needs. They help families navigate the evolving local resources, contacts, and processes to meet SDoMH needs as well as social change. We share community team examples across geographies (urban and rural), settings (clinics, schools, churches), and clinical service delivery (traditional in-person and telehealth) aimed at improving child biopsychosocial outcomes.

Enhancing Postmarketing Surveillance of Medical Products With Large Language Models.

Importance: The Sentinel System is a key component of the US Food and Drug Administration (FDA) postmarketing safety surveillance commitment and uses clinical health care data to conduct analyses to inform drug labeling and safety communications, FDA advisory committee meetings, and other regulatory decisions. However, observational data are frequently deemed insufficient for reliable evaluation of safety concerns owing to limitations in underlying data or methodology. Advances in large language models (LLMs) provide new opportunities to address some of these limitations. However, careful consideration is necessary for how and where LLMs can be effectively deployed for these purposes. Observations: LLMs may provide new avenues to support signal-identification activities to identify novel adverse event signals from narrative text of electronic health records. These algorithms may be used to support epidemiologic investigations examining the causal relationship between exposure to a medical product and an adverse event through development of probabilistic phenotyping of health outcomes of interest and extraction of information related to important confounding factors. LLMs may perform like traditional natural language processing tools by annotating text with controlled vocabularies with additional tailored training activities. LLMs offer opportunities for enhancing information extraction from adverse event reports, medical literature, and other biomedical knowledge sources. There are several challenges that must be considered when leveraging LLMs for postmarket surveillance. Prompt engineering is needed to ensure that LLM-extracted associations are accurate and specific. LLMs require extensive infrastructure to use, which many health care systems lack, and this can impact diversity, equity, and inclusion, and result in obscuring significant adverse event patterns in some populations. LLMs are known to generate nonfactual statements, which could lead to false positive signals and downstream evaluation activities by the FDA and other entities, incurring substantial cost. Conclusions and Relevance: LLMs represent a novel paradigm that may facilitate generation of information to support medical product postmarket surveillance activities that have not been possible. However, additional work is required to ensure LLMs can be used in a fair and equitable manner, minimize false positive findings, and support the necessary rigor of signal detection needed for regulatory activities.

Meeting Report: 2023 Muscular Dystrophy Association Summit on 'Safety and Challenges in Gene Therapy of Neuromuscular Diseases'.

 This meeting report summarizes the presentations and discussions held at the summit on Challenges in Gene Therapy hosted by the Muscular Dystrophy Association (MDA) in 2023. Topics covered include safety issues, mitigation strategies and practical considerations pertaining to the clinical translation of gene therapies for neuromuscular disease. The listing of actionable recommendations will assist in overall efforts in the field to achieve safe and efficacious translation of gene therapies for neuromuscular disease patients.

Hydroxyurea mobile directly observed therapy versus standard monitoring in patients with sickle cell anemia: a phase 2 randomized trial.

BACKGROUND: Sickle cell anemia (SCA) prevalence remains high in sub-Saharan Africa. Long-term treatment with hydroxyurea (HU) increases survival, however, poor adherence to treatment could limit effectiveness. Whilst HU treatment adherence is currently high, this might decrease over time. METHODS: We conducted a single-center, randomized, open-label, parallel group phase 2 controlled clinical trial to determine whether mobile Directly Observed Therapy (m-DOT) increases HU treatment adherence (NCT02844673). Eligible participants were adults with homozygous SCA. People on a chronic blood transfusion program, with hemoglobin (Hb) A levels greater than 20% of the total Hb, total Hb less than 4 g/dL, pregnant or HIV positive were excluded. After a 3-month pre-treatment period participants were randomized to either m-DOT or standard monitoring arm. All participants received smart mobile phones and were treated with HU (15 mg/kg) daily for three months. In the m-DOT arm, drug intake was video recorded on cell phone by the participant and the video sent to the study team. The primary objective was to evaluate the effect of m-DOT on adherence to HU treatment by medication possession ratio (MPR). RESULTS: Of the 86 participants randomized, 76 completed the trial (26.13 ± 6.97 years, 63.5 % female). Adherence was high (MPR > 95 %) in both groups, 29 (80.6 %) in m-DOT versus 37 (94.9 %) in the standard monitoring arm (P = 0.079). No HU treatment was withheld from participants due to safety concerns. CONCLUSIONS: m-DOT did not increase adherence to HU treatment. We recommend that further testing in larger trials with a longer follow up period be undertaken.

Sickle cell anemia (SCA) is an inherited blood disorder in which there is an abnormal protein inside red blood cells. This results in red blood cells becoming sickle shaped and more easily destroyed in the body. Long-term treatment with hydroxyurea can reduce the frequency of illness and hospitalization. However, often people do not manage to take their medication regularly when treatment is long-term. We therefore investigated whether people with SCA in sub-Saharan Africa are more likely to take hydroxyurea when they are remotely monitored than when they are not. Remote monitoring did not improve adherence. However, our study is small and was undertaken over a short time period when hydroxyurea had only recently become available to people with SCA. We propose further studies, to see if remote monitoring increases medication adherence in people with SCA in other scenarios.

The Royal Zoological Society of Scotland's Approach to Assessing and Promoting Animal Welfare in Collaboration with Universities.

Good zoos have four aims-to conserve species, educate the public, engage in research, and provide recreation-all of which can only be achieved when underpinned by high animal welfare standards. In this paper, we share the approach that The Royal Zoological Society of Scotland's (RZSS) Edinburgh Zoo and Highland Wildlife Park take to animal welfare. We highlight the role that animal welfare research, in collaboration with universities, has had in enabling the zoo to take an evidence-based approach to welfare and to put findings into practice. We share the collaborative process through which we developed and piloted the current animal welfare assessment tools, how they were validated, and how they were tested for reliability as part of a long-term collaboration between the Royal Zoological Society of Scotland and the University of Stirling: (1) the RZSS Welfare Assessment Tool, a 50-question animal welfare assessment adapted from the British and Irish Association of Zoos and Aquariums (BIAZA) Toolkit; and (2) the Stirling Toolkit, a package of evidence-based resources for behavioural-data collection. Our aim is to facilitate standardised, evidence-based approaches to assessing animal welfare which, when finalised, can be used collaboratively across zoos.

Postpartum Obesity Is Associated With Increases in Child Adiposity in Midchildhood in a Cohort of Black and Dominican Youth.

Background: Obesity disproportionately affects marginalized and low-income populations. Birth parent obesity from the prenatal period and childhood has been associated with child obesity. It is unknown whether prenatal or postnatal birth parent obesity has differential effects on subsequent changes in adiposity and metabolic health in children. Objectives: We evaluated how birth parent obesity 7 y after delivery was associated with child body composition changes and cardiometabolic health in midchildhood and further assessed the influence of the perinatal and postpartum period on associations. Methods: Black and Dominican pregnant individuals were enrolled, and dyads (n = 319) were followed up at child age 7 and 9 y. Measures included, height, weight, waist circumference (WC), and percent body fat (BF%). Multiple linear regression was used to relate postpartum weight status with child outcomes accounting for attrition, and a series of secondary analyses were conducted with additional adjustment for perinatal weight status, gestational weight gain (GWG), and/or long-term weight retention to evaluate how these factors influenced associations. Results: Almost one-quarter (23%) of birth parents and 24.1% children were classified with obesity at child age 7 y, while at 9 y, 30% of children had obesity. Birth parent obesity at child age 7 y was associated with greater changes, from ages 7 to 9 y, in child BMI z-score (ß: 0.13; 95% CI: 0.02, 0.24) and BF% (ß: 1.15; 95% CI: 0.22, 2.09) but not obesity at age 9 y. All observed associations crossed the null after additional adjustment for prenatal factors. Conclusions: Birth parent obesity at 7-y postpartum is associated with greater gains in child BMI z-score and BF% in midchildhood. These associations diminish after accounting for prenatal size, suggesting a lasting impact of the perinatal environment and that interventions supporting families from the prenatal period through childhood are needed.

Update on Recommendations for Surveillance for Children with Predisposition to Hematopoietic Malignancy.

Children with certain germline gene variants have an increased risk of developing myelodysplastic syndrome (MDS) and other hematopoietic malignancies (HM), such as leukemias and lymphomas. Recent studies have identified an expanding number of these predisposition genes, with variants most prevalent in children with MDS but also found in other HM. For some hematopoietic malignancy predisposition (HMP) disorders, specifically those with a high risk of MDS, early intervention through hematopoietic stem cell transplantation (HSCT) can favorably impact overall survival, providing a rationale for rigorous surveillance. A multidisciplinary panel of experts at the 2023 AACR Childhood Cancer Predisposition Workshop reviewed the latest advances in the field and updated prior 2017 surveillance recommendations for children with HMP. In addition to general guidance for all children with HMP, which includes annual physical examination, education about the signs and symptoms of HM, consultation with experienced providers, and early assessment by an HSCT specialist, the panel provided specific recommendations for individuals with a higher risk of MDS based on the affected gene. These recommendations include periodic and comprehensive surveillance for individuals with those syndromes associated with higher risk of MDS, including serial bone marrow examinations to monitor for morphologic changes and deep sequencing for somatic changes in genes associated with HM progression. This approach enables close monitoring of disease evolution based on the individual's genetic profile. As more HMP-related genes are discovered and the disorders' natural histories are better defined, these personalized recommendations will serve as a foundation for future guidelines in managing these conditions.

Unraveling iron oxides as abiotic catalysts of organic phosphorus recycling in soil and sediment matrices.

In biogeochemical phosphorus cycling, iron oxide minerals are acknowledged as strong adsorbents of inorganic and organic phosphorus. Dephosphorylation of organic phosphorus is attributed only to biological processes, but iron oxides could also catalyze this reaction. Evidence of this abiotic catalysis has relied on monitoring products in solution, thereby ignoring iron oxides as both catalysts and adsorbents. Here we apply high-resolution mass spectrometry and X-ray absorption spectroscopy to characterize dissolved and particulate phosphorus species, respectively. In soil and sediment samples reacted with ribonucleotides, we uncover the abiotic production of particulate inorganic phosphate associated specifically with iron oxides. Reactions of various organic phosphorus compounds with the different minerals identified in the environmental samples reveal up to ten-fold greater catalytic reactivities with iron oxides than with silicate and aluminosilicate minerals. Importantly, accounting for inorganic phosphate both in solution and mineral-bound, the dephosphorylarion rates of iron oxides were within reported enzymatic rates in soils. Our findings thus imply a missing abiotic axiom for organic phosphorus mineralization in phosphorus cycling.

Two decades of network meta-analysis: Roadmap to their applications and challenges.

Recently, Ades and colleagues discussed the controversies and advancements in network meta-analysis (NMA) over the past two decades, discussing its reliability, assumptions, novel approaches, and provided some useful recommendations for the conduction of NMAs. The present discussion paper builds on the insights by Ades and colleagues, providing a roadmap for NMA applications, advancements in software and tools, and approaches designed to facilitate the assessment and interpretation of NMA findings. It also discusses the impact of NMA across disciplines, particularly for policymakers and guideline developers. Despite 20 years of NMA history, challenges remain in understanding and assessing assumptions, communicating and interpreting findings, and applying common approaches like network meta-regression and NMA involving non-randomized studies in readily available software. NMA has proven particularly valuable in clinical decision-making, which highlights the need for additional training and interdisciplinary collaboration of knowledge users, including patient engagement, to enhance its adoption and address real-world problems.

New horizons in clinical practice guidelines for use with older people.

Globally, more people are living into advanced old age, with age-associated frailty, disability and multimorbidity. Achieving equity for all ages necessitates adapting healthcare systems. Clinical practice guidelines (CPGs) have an important place in adapting evidence-based medicine and clinical care to reflect these changing needs. CPGs can facilitate better and more systematic care for older people. But they can also present a challenge to patient-centred care and shared decision-making when clinical and/or socioeconomic heterogeneity or personal priorities are not reflected in recommendations or in their application. Indeed, evidence is often lacking to enable this variability to be reflected in guidance. Evidence is more likely to be lacking about some sections of the population. Many older adults are at the intersection of many factors associated with exclusion from traditional clinical evidence sources with higher incidence of multimorbidity and disability compounded by poorer healthcare access and ultimately worse outcomes. We describe these challenges and illustrate how they can adversely affect CPG scope, the evidence available and its summation, the content of CPG recommendations and their patient-centred implementation. In all of this, we take older adults as our focus, but much of what we say will be applicable to other marginalised groups. Then, using the established process of formulating a CPG as a framework, we consider how these challenges can be mitigated, with particular attention to applicability and implementation. We consider why CPG recommendations on the same clinical areas may be inconsistent and describe approaches to ensuring that CPGs remain up to date.

Reduced nicotine in cigarettes in a marketplace with alternative nicotine systems: randomized clinical trial.

Background: Reducing cigarette addictiveness has the potential to avert millions of yearly tobacco-related deaths worldwide. Substantially reducing nicotine in cigarettes decreases cigarette consumption, but no large clinical trial has determined the effects of reduced-nicotine cigarettes when other nicotine-containing products are available. The aim of this study was to examine the effects of reduced-nicotine cigarettes in the context of the availability of alternative nicotine delivery systems. Methods: In a U.S. six-site, open-label, parallel-arm study, smokers were randomized for twelve weeks to an experimental marketplace containing cigarettes with either 0.4 mg or 15.8 mg nicotine per gram of tobacco; all had access to non-combusted alternative nicotine delivery systems (e.g., e-cigarettes; medicinal nicotine). Group differences in the primary outcomes (cigarettes per day, number of smoke-free days) were examined using linear and negative binomial regression, respectively (Trial Registration: NCT03272685). Findings: Among 438 randomized participants (mean [standard deviation (SD), range] age, 44.5 [11.9, 20-73] years, 225 [51.4%] women, 282 [64.4%] White and 339 [77.4%] trial completers), those in the 0.4 mg vs. 15.8 mg nicotine cigarette condition experienced significantly lower cigarettes per day at the end of intervention (mean [SD], 7.05 [7.88] vs. 12.95 [9.07], adjusted mean difference, -6.21 [95% CI, -7.66 to -4.75], P < 0.0001) and greater smoke-free days during intervention (mean [SD], 18.59 [27.97] vs. 5.06 [13.77], adjusted rate ratio, 4.25 [95% CI, 2.58-6.98], P < 0.0001). Interpretation: A reduced-nicotine cigarette standard in the context of access to other non-combusted nicotine products has the potential to benefit public health. Funding: U.S. NIH/FDA U54DA03165.

Comparative analysis of injury identification using KABCO and ISS in linked North Carolina trauma registry and crash data.

OBJECTIVE: The purpose of this study was to examine differences between police-reported injury severity and trauma registry data among persons with linked records in North Carolina and quantify the degree of alignment. METHODS: We analyzed linked North Carolina trauma registry and motor vehicle crash data from 2018. Injury severity identification was assessed using police-reported 5-point scale KABCO from crash data and Injury Severity Score (ISS) from trauma records. The analysis was stratified by age, sex/gender, race, ethnicity, and road users type to examine differences across groups. We calculated sensitivity, specificity, positive predictive values, and negative predictive values between police-reported injury severity and trauma registry data using ISS as the gold standard. RESULTS: A higher proportion of patients were classified as suspected minor injuries (39.0%) compared to moderate injuries in trauma registry (25.1%). Police-reported crash data underreported injury severity when compared to trauma registry data. Police-reported KABCO had a higher degree of specificity when classifying minor injuries (79.3%) but substantially underestimated seriously injured patients, with a sensitivity of 49.9%. These findings were also consistent when stratified by subpopulations. CONCLUSION: Hospital-based motor vehicle crash data are a main source of injury severity identification for road safety. Police-reported data were relatively accurate for minor injuries but not seriously injured patients. Understanding the characteristics of each data source both separately and linked will be critical for problem identification and program development to move toward a safe transportation system for all road users.

Synthesis of the large pore aluminophosphate STA-1 and its application as a catalyst for the Beckmann rearrangement of cyclohexanone oxime.

The preparation of stable large pore aluminophosphate (AlPO) zeotypes offers materials for applications in adsorption and catalysis. Here we report the synthesis of the pure AlPO with the SAO topology type (AlPO STA-1) using N,N'-diethylbicyclo[2.2.2]oct-7-ene-2,3:5,6-dipyrrolidine (DEBOP) as the organic structure directing agent in the presence of fluoride. The AlPO STA-1 can be rendered microporous (pore volume 0.36 cm3 g-1) via calcination and the calcined form remains stable in the presence of moisture. The structure of the dehydrated form has been established by Rietveld refinement (tetragonal P4̄n2, a = 13.74317(10) Å, c = 21.8131(5) Å, V = 4119.94(16) Å3). Multinuclear 27Al and 31P MAS NMR, together with 2D COSY and CASTEP NMR calculations, enables resolution and assignment of the signals from all crystallographically distinct Al and P framework sites. Structural elucidation of the as-prepared aluminophosphate-fluoride is more challenging, because of the presence of partially protonated OSDA molecules in the 3D-connected channel system and in particular because the fluoride ions coordinate with positional disorder to some of the Al atoms to give 5-fold as well as tetrahedrally-coordinated framework Al species. These are postulated to occupy Al-F-Al bridging sites, where they are responsible for distortion of the framework [P4̄n2, a = 13.3148(9) Å, c = 22.0655(20) Å, V = 3911.9(7) Å3]. Calcination and removal of fluoride ions and OSDAs allows the framework to expand to its relaxed configuration. The SAO topology type aluminophosphate can also be synthesised with small amounts of Si and Ge in the framework, and these SAPO and GeAPO STA-1 materials are also stable to template removal. IR spectroscopy with CO as a probe at 123 K indicates all have weak-to-mild acidity, increasing in the order AlPO < GeAPO < SAPO. These STA-1 materials have been investigated for their activity in the Beckmann rearrangement of cyclohexanone oxime to ε-caprolactam at 598 K: while all are active, the AlPO form is favoured due to its high selectivity and slow deactivation, both of which are a consequence of its very weak acid strength, which is nevertheless sufficient to catalyse the reaction.

Development and usability testing of an online support tool to identify models and frameworks to inform implementation.

BACKGROUND: Theories, models and frameworks (TMFs) are useful when implementing, evaluating and sustaining healthcare evidence-based interventions. Yet it can be challenging to identify an appropriate TMF for an implementation project. We developed and tested the usability of an online tool to help individuals who are doing or supporting implementation practice activities to identify appropriate models and/or frameworks to inform their work. METHODS: We used methods guided by models and evidence on implementation science and user-centered design. Phases of tool development included applying findings from a scoping review of TMFs and interviews with 24 researchers/implementers on barriers and facilitators to identifying and selecting TMFs. Based on interview findings, we categorized the TMFs by aim, stage of implementation, and target level of change to inform the tool's algorithm. We then conducted interviews with 10 end-users to test the usability of the prototype tool and administered the System Usability Scale (SUS). Usability issues were addressed and incorporated into the tool. RESULTS: We developed Find TMF, an online tool consisting of 3-4 questions about the user's implementation project. The tool's algorithm matches key characteristics of the user's project (aim, stage, target change level) with characteristics of different TMFs and presents a list of candidate models/frameworks. Ten individuals from Canada or Australia participated in usability testing (mean SUS score 84.5, standard deviation 11.4). Overall, participants found the tool to be simple, easy to use and visually appealing with a useful output of candidate models/frameworks to consider for an implementation project. Users wanted additional instruction and guidance on what to expect from the tool and how to use the information in the output table. Tool improvements included incorporating an overview figure outlining the tool steps and output, displaying the tool questions on a single page, and clarifying the available functions of the results page, including adding direct links to the glossary and to complementary tools. CONCLUSIONS: Find TMF is an easy-to-use online tool that may benefit individuals who support implementation practice activities by making the vast number of models and frameworks more accessible, while also supporting a consistent approach to identifying and selecting relevant TMFs.

The impact of different strategies for modeling associations between medications at low doses and health outcomes: a simulation study and practical application to postpartum opioid use.

Pharmacoepidemiological studies commonly examine the association between drug dose and adverse health outcomes. In situations where no safe dose exists, the choice of modeling strategy can lead to identification of an apparent safe low dose range in the presence of a non-linear relationship or due to the modeling strategy forcing a linear relationship through a dose of 0. We conducted a simulation study to assess the performance of several regression approaches to model the drug dose-response curve at low doses in a setting where no safe range exists, including the use of a (1) linear dose term, (2) categorical dose term, and (3) natural cubic spline terms. Additionally, we introduce and apply an expansion of prior work related to modeling dose-response curves at low and infrequently used doses in the setting of no safe dose ("spike-at-zero" and "slab-and-spline"). Furthermore, we demonstrate and empirically assess the use of these regression strategies in a practical scenario examining the association between the dose of the initial postpartum opioid prescribed after vaginal delivery and the subsequent total dose of opioids prescribed in the entire postpartum period among a cohort of opioid-naïve women with a vaginal delivery enrolled in a State Medicaid program (2007-2014).

Chromatin-associated cohesin turns over extensively and forms new cohesive linkages in Drosophila oocytes during meiotic prophase.

In dividing cells, accurate chromosome segregation depends on sister chromatid cohesion, protein linkages that are established during DNA replication. Faithful chromosome segregation in oocytes requires that cohesion, first established in S phase, remain intact for days to decades, depending on the organism. Premature loss of meiotic cohesion in oocytes leads to the production of aneuploid gametes and contributes to the increased incidence of meiotic segregation errors as women age (maternal age effect). The prevailing model is that cohesive linkages do not turn over in mammalian oocytes. However, we have previously reported that cohesion-related defects arise in Drosophila oocytes when individual cohesin subunits or cohesin regulators are knocked down after meiotic S phase. Here, we use two strategies to express a tagged cohesin subunit exclusively during mid-prophase in Drosophila oocytes and demonstrate that newly expressed cohesin is used to form de novo linkages after meiotic S phase. Cohesin along the arms of oocyte chromosomes appears to completely turn over within a 2-day window during prophase, whereas replacement is less extensive at centromeres. Unlike S-phase cohesion establishment, the formation of new cohesive linkages during meiotic prophase does not require acetylation of conserved lysines within the Smc3 head. Our findings indicate that maintenance of cohesion between S phase and chromosome segregation in Drosophila oocytes requires an active cohesion rejuvenation program that generates new cohesive linkages during meiotic prophase.

Shape change in the saddle region of the equine back during trot and walk.

Equine back pain is prevalent among ridden horses and is often attributed to poor saddle fit. An alternative explanation is that saddle fits are technically good but fit to the wrong configuration. Saddles are fit for the standing horse, but much of the time ridden is instead spent locomoting when the back experiences the greatest peak forces. We used an array of cameras to reconstruct the surface of the back and its movement during trot, walk and standing for five horses. We verified the setup's accuracy by reconstructing a laser-scanned life-sized model horse. Our reconstructions demonstrate that saddles sit within a large, relatively low-mobile region of the back. However, saddles do sit adjacent to the highly mobile withers, which demands care in positioning and design around this important region. Critically, we identified that saddle curvature between standing and moving horses is substantially different, where trotting and walking horses have flatter backs than their standing configurations. Saddles designed around the locomoting configuration of horses may improve horse welfare by being better fit and decreasing the focal pressures applied by saddles.