Teixobactin kills bacteria by a two-pronged attack on the cell envelope.

Antibiotics that use novel mechanisms are needed to combat antimicrobial resistance1-3. Teixobactin4 represents a new class of antibiotics with a unique chemical scaffold and lack of detectable resistance. Teixobactin targets lipid II, a precursor of peptidoglycan5. Here we unravel the mechanism of teixobactin at the atomic level using a combination of solid-state NMR, microscopy, in vivo assays and molecular dynamics simulations. The unique enduracididine C-terminal headgroup of teixobactin specifically binds to the pyrophosphate-sugar moiety of lipid II, whereas the N terminus coordinates the pyrophosphate of another lipid II molecule. This configuration favours the formation of a ß-sheet of teixobactins bound to the target, creating a supramolecular fibrillar structure. Specific binding to the conserved pyrophosphate-sugar moiety accounts for the lack of resistance to teixobactin4. The supramolecular structure compromises membrane integrity. Atomic force microscopy and molecular dynamics simulations show that the supramolecular structure displaces phospholipids, thinning the membrane. The long hydrophobic tails of lipid II concentrated within the supramolecular structure apparently contribute to membrane disruption. Teixobactin hijacks lipid II to help destroy the membrane. Known membrane-acting antibiotics also damage human cells, producing undesirable side effects. Teixobactin damages only membranes that contain lipid II, which is absent in eukaryotes, elegantly resolving the toxicity problem. The two-pronged action against cell wall synthesis and cytoplasmic membrane produces a highly effective compound targeting the bacterial cell envelope. Structural knowledge of the mechanism of teixobactin will enable the rational design of improved drug candidates.

Celebrating the Birthday of AMPA Receptor Nanodomains: Illuminating the Nanoscale Organization of Excitatory Synapses with 10 Nanocandles.

A decade ago, in 2013, and over the course of 4 summer months, three separate observations were reported that each shed light independently on a new molecular organization that fundamentally reshaped our perception of excitatory synaptic transmission (Fukata et al., 2013; MacGillavry et al., 2013; Nair et al., 2013). This discovery unveiled an intricate arrangement of AMPA-type glutamate receptors and their principal scaffolding protein PSD-95, at synapses. This breakthrough was made possible, thanks to advanced super-resolution imaging techniques. It fundamentally changed our understanding of excitatory synaptic architecture and paved the way for a brand-new area of research. In this Progressions article, the primary investigators of the nanoscale organization of synapses have come together to chronicle the tale of their discovery. We recount the initial inquiry that prompted our research, the preceding studies that inspired our work, the technical obstacles that were encountered, and the breakthroughs that were made in the subsequent decade in the realm of nanoscale synaptic transmission. We review the new discoveries made possible by the democratization of super-resolution imaging techniques in the field of excitatory synaptic physiology and architecture, first by the extension to other glutamate receptors and to presynaptic proteins and then by the notion of trans-synaptic organization. After describing the organizational modifications occurring in various pathologies, we discuss briefly the latest technical developments made possible by super-resolution imaging and emerging concepts in synaptic physiology.

Centrosome-mediated microtubule remodeling during axon formation in human iPSC-derived neurons.

Axon formation critically relies on local microtubule remodeling and marks the first step in establishing neuronal polarity. However, the function of the microtubule-organizing centrosomes during the onset of axon formation is still under debate. Here, we demonstrate that centrosomes play an essential role in controlling axon formation in human-induced pluripotent stem cell (iPSC)-derived neurons. Depleting centrioles, the core components of centrosomes, in unpolarized human neuronal stem cells results in various axon developmental defects at later stages, including immature action potential firing, mislocalization of axonal microtubule-associated Trim46 proteins, suppressed expression of growth cone proteins, and affected growth cone morphologies. Live-cell imaging of microtubules reveals that centriole loss impairs axonal microtubule reorganization toward the unique parallel plus-end out microtubule bundles during early development. We propose that centrosomes mediate microtubule remodeling during early axon development in human iPSC-derived neurons, thereby laying the foundation for further axon development and function.

Weak tension accelerates hybridization and dehybridization of short oligonucleotides.

The hybridization and dehybridization of DNA subject to tension is relevant to fundamental genetic processes and to the design of DNA-based mechanobiology assays. While strong tension accelerates DNA melting and decelerates DNA annealing, the effects of tension weaker than 5 pN are less clear. In this study, we developed a DNA bow assay, which uses the bending rigidity of double-stranded DNA (dsDNA) to exert weak tension on a single-stranded DNA (ssDNA) target in the range of 2-6 pN. Combining this assay with single-molecule FRET, we measured the hybridization and dehybridization kinetics between a 15 nt ssDNA under tension and a 8-9 nt oligonucleotide, and found that both the hybridization and dehybridization rates monotonically increase with tension for various nucleotide sequences tested. These findings suggest that the nucleated duplex in its transition state is more extended than the pure dsDNA or ssDNA counterpart. Based on coarse-grained oxDNA simulations, we propose that this increased extension of the transition state is due to steric repulsion between the unpaired ssDNA segments in close proximity to one another. Using linear force-extension relations verified by simulations of short DNA segments, we derived analytical equations for force-to-rate conversion that are in good agreement with our measurements.

Characteristics of Received HIV Prevention Advocacy from Persons Living with HIV in Uganda, and Associations with HIV Testing and Condom Use Among Social Network Members.

Receiving peer advocacy has been shown to result in increased HIV protective behaviors, but little research has gone beyond assessment of the mere presence of advocacy to examine aspects of advocacy driving these effects. With baseline data from a controlled trial of an advocacy training intervention, we studied characteristics of HIV prevention advocacy received among 599 social network members of persons living with HIV in Uganda and the association of these characteristics with the social network members' recent HIV testing (past six months) and consistent condom use, as well as perceived influence of advocacy on these behaviors. Participants reported on receipt of advocacy specific to HIV testing and condom use, as well as on measures of advocacy content, tone of delivery, support for autonomous regulation, and perceived influence on behavior. Receiving HIV testing advocacy and condom use advocacy were associated with recent HIV testing [65.2% vs. 51.4%; OR (95% CI) = 1.77 (1.11-2.84)], and consistent condom use with main sex partner [19.3% vs. 10.0%; OR (95% CI) = 2.16 (1.12-4.13)], respectively, compared to not receiving advocacy. Among those who received condom advocacy, perceived influence of the advocacy was positively correlated with consistent condom use, regardless of type of sex partner; support of autonomous regulation was a correlate of consistent condom use with casual sex partners, while judgmental advocacy was a correlate of consistent condom use with serodiscordant main partners. Among those who received testing advocacy, HIV testing in the past 6 months was positively correlated with receipt of direct support for getting tested. In multiple regression analysis, perceived influence of both HIV testing and condom use advocacy were positively correlated with advocacy that included access information and support of autonomous regulation; confrontational advocacy and judgmental advocacy were independent positive correlates of perceived influence of testing and condom use advocacy, respectively. These findings support associations that suggest potential benefits of peer advocacy from PLWH on HIV testing and condom use among their social network members, and indicate that advocacy content, tone of delivery, and support of autonomous regulation advocacy may play an important role in the success of advocacy.

Concordance of HIV Prevention Advocacy Reports and its Associations with HIV Protective Behaviors.

Peer advocacy can promote HIV protective behaviors, but little is known about the concordance on prevention advocacy(PA) reports between people living with HIV(PLWH) and their social network members. We examined prevalence and correlates of such concordance, and its association with the targeted HIV protective behavior of the social network member. Data were analyzed from 193 PLWH(index participants) and their 599 social network members(alters). Kappa statistics measured concordance between index and alter reports of PA in the past 3 months. Logistic and multinomial regressions evaluated the relationship between advocacy concordance and alter condom use and HIV testing behavior and correlates of PA concordance. Advocacy concordance was observed in 0.3% of index-alter dyads for PrEP discussion, 9% for condom use, 18% for HIV testing, 26% for care engagement, and 49% for antiretroviral use discussions. Fewer indexes reported condom use(23.5% vs. 28.1%;[Formula: see text]=3.7, p=0.05) and HIV testing(30.5% vs. 50.5%; [Formula: see text]=25.3, p<0.001) PA occurring. Condom advocacy concordance was higher if the index and alter were romantic partners(OR=3.50; p=0.02), and lower if the index was 10 years younger than the alter(OR=0.23; p = 0.02). Alters had higher odds of using condoms with their main partner when both reported condom advocacy compared to dyads where neither reported advocacy(OR=3.90; p<0.001) and compared to dyads where only the index reported such advocacy(OR = 3.71; p=0.01). Age difference and relationship status impact advocacy agreement, and concordant perceptions of advocacy are linked to increased HIV protective behaviors. Alters' perceptions may be crucial for behavior change, informing strategies for improving advocacy.

Nfkbid Overexpression in Nonobese Diabetic Mice Elicits Complete Type 1 Diabetes Resistance in Part Associated with Enhanced Thymic Deletion of Pathogenic CD8 T Cells and Increased Numbers and Activity of Regulatory T Cells.

Type 1 diabetes (T1D) in both humans and NOD mice is caused by T cell-mediated autoimmune destruction of pancreatic ß cells. Increased frequency or activity of autoreactive T cells and failures of regulatory T cells (Tregs) to control these pathogenic effectors have both been implicated in T1D etiology. Due to the expression of MHC class I molecules on ß cells, CD8 T cells represent the ultimate effector population mediating T1D. Developing autoreactive CD8 T cells normally undergo extensive thymic negative selection, but this process is impaired in NOD mice and also likely T1D patients. Previous studies identified an allelic variant of Nfkbid, a NF-κB signal modulator, as a gene strongly contributing to defective thymic deletion of autoreactive CD8 T cells in NOD mice. These previous studies found ablation of Nfkbid in NOD mice using the clustered regularly interspaced short palindromic repeats system resulted in greater thymic deletion of pathogenic CD8 AI4 and NY8.3 TCR transgenic T cells but an unexpected acceleration of T1D onset. This acceleration was associated with reductions in the frequency of peripheral Tregs. In this article, we report transgenic overexpression of Nfkbid in NOD mice also paradoxically results in enhanced thymic deletion of autoreactive CD8 AI4 T cells. However, transgenic elevation of Nfkbid expression also increased the frequency and functional capacity of peripheral Tregs, in part contributing to the induction of complete T1D resistance. Thus, future identification of a pharmaceutical means to enhance Nfkbid expression might ultimately provide an effective T1D intervention approach.

Social pathways to care: how community-based network ties shape the health care response of individuals with mental health problems.

PURPOSE: Mental health research has powerfully documented inequities related to characteristics, such as ethnicity and gender. Yet how and where disparities like unmet need occur have been more elusive. Drawing from a now modest body of research that deployed the Network Episode Model (NEM), we examine how individuals create patterns of response to mental health problems, influenced by the culture and resources embedded in their social networks. METHODS: The Person-to-Person Health Interview Study (P2P; N ~ 2,700, 2018-2021) provides representative, community-based, NEM-tailored data. Both descriptive, latent class and multinomial regression analyses mark mental health care-seeking patterns, including individuals consulted and activities used, as well as the influence of the structure and cultural content of social networks. RESULTS: Latent class analysis detected five pathways with good fit statistics. The Networked General Care Path (37.0%) and The Kin General Care Path (14.5%) differ only in whether friends are activated in using the general care sector. The Networked Multi-Sector Care Path (32.5%) and The Saturated Path (12.6%) involve family, friends, and both general and specialty care with only the latter expanding consultation to coworkers and clergy. The Null Path (3.3%), or no contacts, is not used as perceived problem severity increases. Network size and strength are associated with the more complex pathways that activate ties, respectively. Trust in doctors is associated with pathways that include specialty providers but not others at work or church. Race, age, and rural residence have specific pathway effects, while gender has no significant impact. CONCLUSIONS: Social networks propel individuals with mental health problems into action. Tie strength and trust produce care responses that are fuller and more targeted. Considering the nature of homophily, results also suggest that majority status and college education are clearly implicated in networked pathways. Overall, findings support community-targeted rather than individually based efforts to increase service use.

Who has mental health problems? Comparing individual, social and psychiatric constructions of mental health.

PURPOSE: The persistent gap between population indicators of poor mental health and the uptake of services raises questions about similarities and differences between social and medical/psychiatric constructions. Rarely do studies have assessments from different perspectives to examine whether and how lay individuals and professionals diverge. METHODS: Data from the Person-to-Person Health Interview Study (P2P), a representative U.S. state sample (N ~ 2700) are used to examine the overlap and correlates of three diverse perspectives-self-reported mental health, a self/other problem recognition, and the CAT-MH™ a validated, computer adaptive test for psychopathology screening. Descriptive and multinominal logit analyses compare the presence of mental health problems across stakeholders and their association with respondents' sociodemographic characteristics. RESULTS: Analyses reveal a set of socially constructed patterns. Two convergent patterns indicate whether there is (6.9%, The "Sick") or is not (64.6%, The "Well") a problem. The "Unmet Needers" (8.7%) indicates that neither respondents nor those around them recognize a problem identified by the screener. Two patterns indicate clinical need where either respondents (The "Self Deniers", 2.9%) or others (The "Network Deniers", 6.0%) do not. Patterns where the diagnostic indicator does not suggest a problem include The "Worried Well" (4.9%) where only the respondent does, The "Network Coerced" (4.6%) where only others do, and The "Prodromal" (1.4%) where both self and others do. Education, gender, race, and age are associated with social constructions of mental health problems. CONCLUSIONS: The implications of these results hold the potential to improve our understanding of unmet need, mental health literacy, stigma, and treatment resistance.

Correlates of HIV Prevention Advocacy by Persons Living with HIV in Kampala, Uganda: A Cross-sectional Evaluation of a Conceptual Model.

BACKGROUND: HIV prevention advocacy empowers persons living with HIV (PLWH) to act as advocates and encourage members of their social networks to engage in protective behaviors such as HIV testing, condom use, and antiretroviral therapy (ART) adherence. We examined correlates of HIV prevention advocacy among PLWH in Uganda. METHOD: A cross-sectional analysis was conducted with baseline data from 210 PLWH (70% female; mean age = 40 years) who enrolled in a trial of an HIV prevention advocacy training program in Kampala, Uganda. The baseline survey, which was completed prior to receipt of the intervention, included multiple measures of HIV prevention advocacy (general and specific to named social network members), as well as internalized HIV stigma, HIV disclosure, HIV knowledge, positive living (condom use; ART adherence), and self-efficacy for HIV prevention advocacy. RESULTS: Consistent with our hypotheses, HIV disclosure, HIV knowledge, consistent condom use, and HIV prevention advocacy self-efficacy were all positively correlated with at least one measure of HIV prevention advocacy, after controlling for the other constructs in multiple regression analysis. Internalized HIV stigma was positively correlated with advocacy in bivariate analysis only. CONCLUSION: These findings identify which characteristics of PLWH are associated with acting as change agents for others in their social network to engage in HIV protective behaviors.

VAP-SCRN1 interaction regulates dynamic endoplasmic reticulum remodeling and presynaptic function.

In neurons, the continuous and dynamic endoplasmic reticulum (ER) network extends throughout the axon, and its dysfunction causes various axonopathies. However, it remains largely unknown how ER integrity and remodeling modulate presynaptic function in mammalian neurons. Here, we demonstrated that ER membrane receptors VAPA and VAPB are involved in modulating the synaptic vesicle (SV) cycle. VAP interacts with secernin-1 (SCRN1) at the ER membrane via a single FFAT-like motif. Similar to VAP, loss of SCRN1 or SCRN1-VAP interactions resulted in impaired SV cycling. Consistently, SCRN1 or VAP depletion was accompanied by decreased action potential-evoked Ca2+ responses. Additionally, we found that VAP-SCRN1 interactions play an important role in maintaining ER continuity and dynamics, as well as presynaptic Ca2+ homeostasis. Based on these findings, we propose a model where the ER-localized VAP-SCRN1 interactions provide a novel control mechanism to tune ER remodeling and thereby modulate Ca2+ dynamics and SV cycling at presynaptic sites. These data provide new insights into the molecular mechanisms controlling ER structure and dynamics, and highlight the relevance of ER function for SV cycling.

Postpartum uptake of diabetes screening tests in women with gestational diabetes: The PANDORA study.

AIMS: To determine rates and predictors of postpartum diabetes screening among Aboriginal and/or Torres Strait Islander and non-Indigenous women with gestational diabetes mellitus (GDM). METHODS: PANDORA is a prospective longitudinal cohort of women recruited in pregnancy. Postpartum diabetes screening rates at 12 weeks (75-g oral glucose tolerance test (OGTT)) and 6, 12 and 18 months (OGTT, glycated haemoglobin [HbA1C ] or fasting plasma glucose) were assessed for women with GDM (n = 712). Associations between antenatal factors and screening with any test (OGTT, HbA1C , fasting plasma glucose) by 6 months postpartum were examined using Cox proportional hazards regression. RESULTS: Postpartum screening rates with an OGTT by 12 weeks and 6 months postpartum were lower among Aboriginal and/or Torres Strait Islander women than non-Indigenous women (18% vs. 30% at 12 weeks, and 23% vs. 37% at 6 months, p < 0.001). Aboriginal and/or Torres Strait Islander women were more likely to have completed a 6-month HbA1C compared to non-Indigenous women (16% vs. 2%, p < 0.001). Screening by 6 months postpartum with any test was 41% for Aboriginal and/or Torres Strait Islander women and 45% for non-Indigenous women (p = 0.304). Characteristics associated with higher screening rates with any test by 6 months postpartum included, insulin use in pregnancy, first pregnancy, not smoking and lower BMI. CONCLUSIONS: Given very high rates of type 2 diabetes among Aboriginal and Torres Strait Islander women, early postpartum screening with the most feasible test should be prioritised to detect prediabetes and diabetes for intervention.

ORANGE: A CRISPR/Cas9-based genome editing toolbox for epitope tagging of endogenous proteins in neurons.

The correct subcellular distribution of proteins establishes the complex morphology and function of neurons. Fluorescence microscopy techniques are invaluable to investigate subcellular protein distribution, but they suffer from the limited ability to efficiently and reliably label endogenous proteins with fluorescent probes. We developed ORANGE: Open Resource for the Application of Neuronal Genome Editing, which mediates targeted genomic integration of epitope tags in rodent dissociated neuronal culture, in organotypic slices, and in vivo. ORANGE includes a knock-in library for in-depth investigation of endogenous protein distribution, viral vectors, and a detailed two-step cloning protocol to develop knock-ins for novel targets. Using ORANGE with (live-cell) superresolution microscopy, we revealed the dynamic nanoscale organization of endogenous neurotransmitter receptors and synaptic scaffolding proteins, as well as previously uncharacterized proteins. Finally, we developed a mechanism to create multiple knock-ins in neurons, mediating multiplex imaging of endogenous proteins. Thus, ORANGE enables quantification of expression, distribution, and dynamics for virtually any protein in neurons at nanoscale resolution.

Characteristics of Individuals Seen as Sources of Social Support in Populations at Increased Risk for HIV.

Access to social support from one's social network can serve as a protective factor against HIV infection; however, research exploring the availability of support in diverse populations that include high proportions of people at increased risk for HIV and the characteristics of network members associated with access to such support is limited. Multi-level dyadic analyses of social network data collected from women at risk for HIV and their network members reveal which individual and relationship characteristics of network members are associated with providing emotional, material, and/or health informational support. Results indicate that access to all three types of support was associated with a network member being a friend, a member of a participant's 'core' group, someone whose opinion matters to the respondent, and the respondent trusting them. These findings have implications for interventions designed to increase access to support among individuals at risk for HIV.

The lived experiences of rural HIV social workers.

HIV service providers are the primary implementers of HIV care services, but rural HIV service providers are under researched. We used an interpretative phenomenological analysis to explore rural HIV service providers' lived experiences of working in HIV care, who work in a rural region of a Midwestern state in the United States. From July to August 2019, 15 HIV service providers participated in a one-hour semi-structured telephone interview that elicited their experiences working in the rural HIV care continuum. Participants were tired of constantly educating and working to reduce HIV stigma; however, they received support from family and friends once they educated them about HIV. Participants felt they lacked control over systems and they developed emotional-based coping to address constant occupational stressors. Findings highlight the importance of resiliency and advocacy research and practice across ecological levels.

Identifying Sex Dimorphism in Peripheral Artery Disease with Platelet Mapping.

BACKGROUND: Clinical outcomes in women with peripheral artery disease (PAD) after revascularization procedures are worse compared to men, yet there is little in the existing literature as why this may be the case. Platelet Mapping is an emerging point-of-care viscoelastic technology that measures the comprehensive properties of a blood clot, including fibrin-platelet interactions. This prospective observational study aimed to characterize the clinical and Platelet Mapping profiles of female and male patients undergoing lower extremity revascularization, and to correlate Platelet Mapping distribution to thrombotic potential. METHODS: All patients with a diagnosis of PAD undergoing named vessel open or endovascular revascularization to re-establish inflow, outflow, or both, during December 2020 and January 2022 were prospectively included. Patients were followed clinically for thrombosis for up to 1 year. Platelet Mapping assays were performed in 3 clinical phases: preoperative, postoperative inpatient, and postoperative outpatient. Inferential analysis between female and male patient was performed. The quartile distribution of Platelet Mapping metrics associated with thrombosis was used to infer to thrombotic potential. RESULTS: One hundred seven patients were enrolled, of which 37 (34.6%) were female. Female patients had significantly lower rates of uncontrolled diabetes (2.7% vs. 18.6%), hypertension requiring combination therapy (37.8% vs. 58.6%), chronic kidney disease (27.0% vs. 51.4%), coronary artery disease (29.7% vs. 57.1%), and myocardial infarction (16.2% vs. 35.7%) (all P < 0.05). Platelet reactivity was significantly higher in female patients with greater platelet aggregation (75.9 ± 23.3 vs. 63.5 ± 28.8) and lower platelet inhibition (23.8 ± 23.4 vs. 36.8 ± 28.9) (all P < 0.01). This trend was consistent over time when stratified by the postoperative inpatient and postoperative outpatient clinical phases. There was no statistically discernible difference in the use of antiplatelet therapy between groups, yet female patients continued to exhibit greater platelet reactivity when analyzed by the type of pharmacologic regimen (platelet aggregation on mono-antiplatelet therapy: 80.6 ± 21.0 in women versus 69.4 ± 25.0 in men; platelet aggregation on dual antiplatelet therapy: 67.9 ± 23.8 in women versus 44.8 ± 31.8 in men) (all P < 0.01). Twenty-one patients experienced postoperative graft/stent thrombosis within the study period. In relation to the overall study population, patients with thrombosis had Platelet Mapping metrics above the 50th percentile of overall platelet aggregation distribution. CONCLUSIONS: There is a growing appreciation for the differences in etiology, disease progression, and outcomes of cardiovascular conditions as they relate to sex. In this cohort, traditional cardiovascular risk factors were in lower prevalence in female patients. Platelet reactivity was found to be higher across clinical phases and antiplatelet regimens. High platelet reactivity was also associated with an increased incidence of thrombosis after lower extremity revascularization. These hypothesis-generating findings provide the basis for further exploration of sex-specific coagulation profiling in PAD patients.

Effects of a peer advocacy intervention on cervical cancer screening among social network members: results of a randomized controlled trial in Uganda.

Cervical cancer (CC) is the most common cancer among women in Uganda, yet lifetime CC screening is as low as 5%. Training women who have screened for CC to engage in peer advocacy could increase uptake of CC screening in social networks. We conducted a randomized controlled trial of a peer-facilitated, manualized, 7-session group intervention to train women to engage in CC prevention advocacy. Forty women recently screened for CC (index participants) enrolled and were assigned to receive the intervention (n = 20) or wait-list control (n = 20). Each index was asked to recruit up to three female social network members (alters) who had not been screened for CC (n = 103 enrolled alters). All index and alter participants were assessed at baseline and month-6 follow-up. All but one (n = 39; 98%) index and 98 (95%) alter participants completed the month 6 assessment. In multivariate regression models controlling for baseline outcome measures and demographic covariates, intervention alters were more likely to have been screened for CC at month 6 [67% vs. 16%; adjusted OR (95% CI) = 12.13 (4.07, 36.16)], compared to control alters. Data also revealed significant increased engagement in CC prevention advocacy, among both index and alter participants in the intervention group at month 6, compared to the control group. The intervention was highly effective in increasing CC screening uptake among social network members, and engagement in CC prevention advocacy among not only intervention recipients, but also targets of advocacy, suggesting the potential for wide dissemination of CC knowledge.Trial Registration. NIH Clinical Trial Registry NCT04960748 ( clinicaltrials.gov ).

Comparing professional communities: Opioid prescriber networks and Public Health Preparedness Districts.

Problem opioid use and opioid-related drug overdoses remain a major public health concern despite attempts to reduce and monitor opioid prescriptions and increase access to office-based opioid treatment. Current provider-focused interventions are implemented at the federal, state, regional, and local levels but have not slowed the epidemic. Certain targeted interventions aimed at opioid prescribers rely on populations defined along geographic, political, or administrative boundaries; however, those boundaries may not align well with actual provider-patient communities or with the geographic distribution of high-risk opioid use. Instead of relying exclusively on commonly used geographic and administrative boundaries, we suggest augmenting existing strategies with a social network-based approach to identify communities (or clusters) of providers that prescribe to the same set of patients as another mechanism for targeting certain interventions. To test this approach, we analyze 1 year of prescription data from a commercially insured population in the state of Indiana. The composition of inferred clusters is compared to Indiana's Public Health Preparedness Districts (PHPDs). We find that in some cases the correspondence between provider networks and PHPDs is very high, while in other cases the overlap is low. This has implications for whether an intervention is reaching its intended provider targets efficiently and effectively. Assessing the best intervention targeting strategy for a particular outcome could facilitate more effective interventions to tackle the ongoing opioid use epidemic.

GDM care re-imagined: Maternal and neonatal outcomes following a major model of care change for gestational diabetes mellitus at a large metropolitan hospital.

BACKGROUND: The rapidly rising prevalence of gestational diabetes mellitus (GDM) poses major challenges to the efficient, timely and sustainable provision of diabetes care. AIM: To assess whether the implementation of a novel, digital model of care would provide improved efficiency without compromising clinical outcomes in a cohort of women with GDM. METHODS: A digital model of care was developed, implemented and evaluated using a prospective pre-post study design in 2020-21 at a quaternary centre. We introduced six culturally and linguistically tailored educational videos, home delivery of equipment and prescriptions, and a smartphone app-to-clinician portal for glycaemic review and management. Outcomes were prospectively recorded by an electronic medical record. Associations between model of care and maternal and neonatal characteristics and birth outcomes were examined for all women and separately by treatment received (diet, metformin, insulin). RESULTS: Comparing pre-implementation (n = 598) and post-implementation (n = 337) groups, maternal (onset, mode of birth) and neonatal (birthweight, large for gestational age (LGA), nursery admission) clinical outcomes confirmed that the novel model of care was similar to standard, traditional care. Minor birthweight variation was noted when separated by treatment type (diet, metformin, insulin). CONCLUSION: This pragmatic service redesign demonstrates reassuring clinical outcomes in a culturally diverse GDM cohort. Despite the lack of randomisation, this intervention has potential generalisability for GDM care and important key learnings for service redesign in the digital era.

Gestational diabetes mellitus care re-imagined - A cost-minimisation analysis: Cost savings from a tertiary hospital, using a novel, digital-based gestational diabetes management model.

BACKGROUND: Diagnosis of gestational diabetes mellitus (GDM) in a pregnancy has a significant impact on health service resources and represents a substantial financial and time impost on women. AIM: To describe a cost-minimisation analysis conducted following the demonstration of clinically equivalent care of women using a novel, digital model for GDM management, compared with conventional care. MATERIALS AND METHODS: A pre-implementation model of care was compared with the post-implementation model of care which included systematic development and delivery of education videos, use of the Commonwealth Scientific and Industrial Research Organisation 'M♡THer' smart phone app/portal and a dramatically reduced schedule of visits. The Mater Mothers' Hospital Brisbane cares for approximately 1200 women with GDM per annum, on which the cost estimates were based. Service costs were estimated using the resource method, where resource volumes and costs were gathered from experts within the health service. Patient costs were estimated using results from a short survey completed by a cohort of the study population. RESULTS: Health service costs showed a modest saving of AU$17 441.78 (US$12 158.92) in the intervention group over a 12-month period. Cost savings for the woman were estimated at $566.56 (US$394.96) per patient after accounting for lost wages, childcare expenses, and travel expenses avoided. This reduction led to an overall saving of $679 872 (US$473 948.82) for the cohort of 1200 women, primarily due to the reduction in face-to-face visits. CONCLUSION: Re-imagining GDM patient care by introducing a novel, digital-based GDM model of care has substantial positive cost implications for patients.