Brandeis University

The use of public health vending machines (PHVMs) is an emerging strategy implemented to mitigate drug-related harms via the dispensation of supplies like naloxone and sterile syringes from vending machines that have been documented to reduce transmission of blood borne viruses, support hygiene and basic personal health needs, and prevent overdose. To inform future applications of this technology and performed initially as part of a technical assistance request, we sought to examine PHVM adoption and implementation by conducting semi-structured interviews with 26 individuals from diverse roles and organizations/agencies across the United States in March 2023 about their experiences launching and optimizing PHVMs. We engaged in a secondary thematic analysis of the interview data using both deduction and induction. Using the interview guide as the frame, we broadly organized our findings into themes that are pertinent to consider prior to PHVM implementation ("Pre-implementation") and those that are relevant during implementation ("Implementation and maintenance"). Pre-implementation themes included (1) Motivating factors influencing implementation, (2) Intended PHVM uptake population, (3) Partnership cultivation, (4) Responsiveness to community needs and concerns, and (5) Factors influencing placement of PHVMs. Implementation and maintenance themes included: (1) Operational components of implementation and (2) Tracking consumer use of machines and supply flow. We found that PHVMs have emerged as versatile and central tools to expand and extend critical, life-saving supplies and services to PWUD and other groups within communities throughout the United States, especially to underserved and high-risk populations, such as people of color, young people, rural residents, individuals leaving incarceration, and veterans. We also found that the planning phases of implementation were shaped by local needs, funding opportunities, collaboration, and community engagement, with PHVM placement most often determined by feasibility and willingness of host sites, as well as the perceptions and needs of the community. Operational challenges included unanticipated costs related to maintenance and supply stocking of the PHVMs. Our findings elucidate the local, ground-up, and bold approaches and innovations undertaken by many organizations, agencies, and programs throughout the country in PHVM implementation. Policymakers and government officials should consider passing local ordinances or granting permissions in support of placing PHVMs and securing access to life saving materials.

Claims-based analyses can suffer from residual and unmeasured confounding due to factors that are poorly captured in claims. Some of these factors may be measured in other data sources, such as in structured fields of electronic health records (EHR), for example, laboratory test results, or in free-text physician notes. We conducted a proof-of-principle study to demonstrate a process for evaluating the potential risk of confounding-factors poorly captured in claims data but measurable in the EHR as part of drug safety surveillance activities. In future practical applications, this approach could be used along with other sensitivity analyses to evaluate potential residual confounding (e.g., E-values, negative controls). We used claims-EHR linked data from the Mass General Brigham site of the US Food and Drug Administration's (FDA) Sentinel Real World Evidence Data Enterprise. We extracted a cohort that was previously used in a prototypical Sentinel claims-based query that compared initiators of sacubitril-valsartan vs. angiotensin-converting enzyme inhibitors or angiotensin receptor blockers on the risk of angioedema. In this cohort, we used EHR data to characterize angioedema risk factors poorly captured in claims and observed that claims-based proxies balanced most risk factors that were measurable only in EHR data. While quantitative bias analysis methods can be used to adjust for residual confounding using external information on magnitude and direction of bias, this was deemed unnecessary for this example due to the observed balance achieved on risk factors for angioedema measured in the EHR. A robust linked EHR-claims data infrastructure is crucial for routine application of these methods to evaluate and mitigate residual confounding in drug safety surveillance studies.

Faithful DNA replication in Escherichia coli requires the DNA polymerase III holoenzyme (DNA pol III HE) and its clamp loader complex, which couples processive DNA synthesis with -clamp loading. The clamp loader accessory subunits and link single-stranded DNA-binding protein (SSB) to the replisome, stabilizing replication on SSB-coated templates through interactions with the SSB C-terminal tail. Chi has also been implicated in tolerance to the chain-terminating nucleoside analog azidothymidine (AZT), though whether this function depends on within DNA pol III HE or on its independent interaction with the YoaA helicase remains unclear. To address this, we engineered fusion proteins with flexible glycine-serine linkers to tether the two subunits while preserving folding and activity. Both fusions were biochemically competent, supporting ATP hydrolysis and clamp loading on SSB-coated DNA. In vivo, however, neither the -GS12- fusion nor expression of a operon restored AZT tolerance in ΔholC cells, whereas expression of alone was sufficient. Fusion expression impaired growth in both wild-type (WT) and ΔholC backgrounds, a phenotype alleviated by disrupting -SSB binding. These findings support a model in which must dynamically engage SSB and YoaA outside of the clamp loader to promote AZT tolerance, highlighting the importance of regulated -SSB interactions in genome maintenance.

Parents of children on the autism spectrum face challenging treatment-related decisions, often with limited knowledge about available options. Shared Decision Making (SDM), a process where clinicians, patients, and families collaborate to make decisions based on evidence and preferences, can assist parents in navigating these choices. However, little is known about the use of SDM interventions for autism-related parental decisions. A systematic and scoping review was conducted across four databases (PubMed, Embase, Web of Science, and PsycInfo), and grey literature in two clinical trial registries. Study selection was conducted in two phases: title and abstract screening and full-text screening. From 7,610 records identified, two studies were included from Australia and Italy, describing multicomponent SDM interventions for parents of young children (< 18 years) on the autism spectrum. Both interventions demonstrated improvements in SDM-related outcomes, including parents' knowledge of autism treatments (such as speech pathology services and Early Intensive Behavior Intervention) and parents' involvement in treatment discussions. This review reveals a critical gap in SDM intervention research for autism parental decision-making. Despite the critical role parents play in autism treatment decisions, evidence-based SDM interventions remain scarce. This finding is significant given the well-established benefits of SDM in other healthcare populations and underscores the urgent need to develop and rigorously evaluate SDM interventions tailored to autism care contexts that support parents in making informed decisions about their children's care.Systematic review registration: A protocol was registered on PROSPERO.

Increasing utilization of medications that treat opioid use disorders (MOUD) remains an essential strategy to curb the opioid crisis nationwide, especially among rural areas where access can present challenges. Washington State expanded access to MOUD through its opioid treatment networks (OTN), which provide low-barrier access to MOUD in non-traditional settings with an emphasis on buprenorphine and rural locations. We examined changes in buprenorphine utilization between Medicaid beneficiaries who initiated treatment at OTNs compared to individuals outside OTN facilities and by rural-urban residence. We used comparative time-series analyses to examine longitudinal patterns of buprenorphine utilization among a sample (n = 93,401) of age 18 to 64 Washington State Medicaid beneficiaries diagnosed with OUD between 2019 and 2022. Monthly aggregated rates of buprenorphine utilization, stratified by OTN versus non-OTN and rural-urban residence, were calculated for analysis. Between 2019 and 2022, rates of buprenorphine utilization were significantly higher among Medicaid beneficiaries initiating treatment at OTNs compared to beneficiaries treated at non-OTN facilities regardless of rural-urban status. Furthermore, utilization was most prevalent among rural OTNs (β = 25.5, SE = 1.91, p < 0.001, 95% CI 21.7, 29.2). Despite increases in OUD prevalence, buprenorphine rates remained consistent during the study period, except for a decrease within micropolitan OTNs. Washington's OTN provides an example of one strategy that may support greater prescribing of buprenorphine and help mitigate the opioid crisis in small town/rural areas. Except among micropolitan areas, OTNs were able to keep pace in buprenorphine utilization despite demand from increased OUD prevalence.

IntroductionParental mental illness is a major public health issue across the globe with well-known intergenerational impacts on children. There is a wide body of evidence supporting the effectiveness of a range of interventions supporting families, however, their implementation has rarely been sustained across public health systems. Systemic change is an important part of workforce development and known to be crucial to embed and sustain practice, policy and structural initiatives in services for families. While much is known about the barriers to implementing family focused approaches within organizations and systems, less is known about how systems change occurs and what supports systems change to improve outcomes for families.MethodsThis study uses a Delphi method, with 103 experts from 17 countries participating to identify systems change factors from their own experience and to build consensus about key strategies required across the globe to support systems change in health, education, social welfare and mental health services.ResultsThe findings identify that systems change can be defined as any workforce, policy, legislation or other mental health promotion strategy that collectively contributes to improving outcomes for parents with mental illness, their children and their families. A systems approach to improve outcomes for families where a parent has a mental illness requires partnerships and collaboration between services and sectors affecting families (mental health, welfare, primary health, education, social care, public health), social and health policy development, and families themselves. Success in system change requires a focus on change at all levels of the system for momentum building, leadership support, the use of relevant data and reporting mechanisms, establishing practice competency and collaborative care, and being able to reflect and adapt to changing conditions and structural barriers.DiscussionA focus on system change for supporting families where a parent has a mental illness appears to require the combination of many strategies and factors, with international approaches to knowledge sharing imperative to support implementing, resourcing and sustaining change.

For a pair $(G,\mathcal{P})$ consisting of a group and finite collection of subgroups, we introduce a simplicial $G$-complex $\mathcal{K}(G,\mathcal{P})$ called the coset intersection complex. We prove that the quasi-isometry type and the homotopy type of $\mathcal{K}(G,\mathcal{P})$ are quasi-isometric invariants of the group pair $(G,\mathcal{P})$. Classical properties of $\mathcal{P}$ in $G$ correspond to topological or geometric properties of $\mathcal{K}(G,\mathcal{P})$, such as having finite height, having finite width, being almost malnormal, admiting a malnormal core, or having thickness of order one. As applications, we obtain that a number of algebraic properties of $\mathcal{P}$ in $G$ are quasi-isometry invariants of the pair $(G,\mathcal{P})$. For a certain class of right-angled Artin groups and their maximal parabolic subgroups, we show that the complex $\mathcal{K}(G,\mathcal{P})$ is quasi-isometric to the Extension graph; in particular, it is quasi-isometric to a tree.

Double-strand break (DSB) repair is highly mutagenic compared to normal replication. In budding yeast, repair of an HO (homothallism) endonuclease-induced DSB at the mating-type α locus (MATα) can be repaired by using an ectopic heterochromatic HMR::Kl-URA3 donor, producing MAT::Kl-URA3. Among MAT::Kl-Ura3- mutations arising during repair, 50% are base-pair substitutions. 30% are 1-bp indels in short homonucleotide runs, with -1 strongly favored over +1, whereas during replication, spontaneous -1 and +1 events are equal. Microhomology-bounded, repair-associated intragenic deletions (IDs) are recovered 12 times more frequently than tandem duplications (TDs). These data suggest a picture of the structure of the repair replication fork: IDs and TDs occur within the open structure of a migrating D-loop, where the 3' end of a partly copied new DNA strand can dissociate and anneal with a single-stranded region of microhomology either within ~80 bp ahead or ~40 bp behind the 3' end. Approximately ~10% of repair-associated mutations are interchromosomal template switches (ICTS), even though the Kluyveromyces lactis URA3 sequence in HMR is only 72% identical (homeologous) with Saccharomyces cerevisiae ura3-52. ICTS events begin and end at regions of short (~7.5 bp) microhomology; however, ICTS events are constrained to the middle of the copied sequence. Whereas microhomology usage in intragenic deletions is not influenced by adjacent homeology, we show that extensive pairing of adjacent homeology plays a critical role in ICTS. Thus, although by convention, structural variants are characterized by the precise base pairs at their junction, microhomology-mediated template switching actually requires alignment of extensive adjacent homeology.