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Abstract Background While people with substance use disorders, including people who inject drugs (PWID), experience increased risk for COVID-19 infection and adverse outcomes, COVID-19 vaccination rates among PWID are consistently lower than those observed in the general population. Offering COVID-19 vaccines at syringe services programs (SSPs) has been proposed as a critical strategy to increase vaccine uptake among this population. We explored the experiences of frontline staff at an SSP in Miami, Florida implementing onsite COVID-19 vaccines. Methods Between June and July 2022, we conducted in-depth semi-structured interviews with 17 staff members of an SSP in Miami, Florida. Data collection and codebook thematic analysis of transcribed interviews were guided by the Consolidated Framework for Implementation Research (CFIR). Results Facilitators and barriers of COVID-19 vaccine implementation at the SSP aligned with all major CFIR domains. Key facilitators included the SSP’s established partnership with the local health department for vaccine distribution, its existing funding sources which could be leveraged for vaccine-related expenses, consensus among staff about the need for new strategies to increase vaccine uptake among PWID, and PWID’s trust in the SSP. Major—but largely modifiable—barriers included lack of participant compensation, limited internal collaboration and communication regarding the vaccine initiative beyond implementation leads and innovation deliverers due to competing priorities and segmented roles and responsibilities, and insufficient involvement of the most participant-facing staff (i.e., the SSP’s peer navigators and outreach workers). Conclusions Implementing onsite COVID-19 vaccines was perceived as feasible and acceptable by frontline staff at the SSP, however contextual factors impeded optimal implementation. Multilevel strategies, such as participant compensation for vaccine completion and internal educational meetings with staff to improve vaccine implementation and reach, are required. As a trusted source of preventative services for PWID, SSPs are an underutilized venue for increasing vaccine uptake among this population, and findings from this study could inform the expansion of low-barrier vaccine services at SSPs nationwide.

Abstract Exogenous ketone supplements are a potential augmentation strategy for cognitive resilience during acute hypoxic exposure due to their capacity to attenuate the decline in oxygen (O2) availability, and by providing an alternative substrate for cerebral metabolism. Utilizing a single‐blind randomized crossover design, 16 male military personnel (age, 25.3 ± 2.4 year, body mass, 86.2 ± 9.3 kg) performed tests of cognitive performance at rest in three environments: room air (baseline), normoxia (20 min; 0 m; 20.9% O2) and hypoxia (20 min; 6096 m, 9.7% O2) using a reduced O2 breathing device (ROBD). (R)‐3‐Hydroxybutyl (R)‐3‐hydroxybutyrate (R‐BD R‐βHB) ketone monoester (KME; 650 mg/kg, split dose given at 30 min prior to each exposure) or taste‐matched placebo (PLA) was ingested prior to normoxia and hypoxic exposure. Blood R‐βHB and glucose concentrations, cognitive performance and O2 saturation (SpO2) were collected throughout. KME ingestion increased blood R‐βHB concentration, which was rapid and sustained (>4 mM 30 min post; P

Abstract Acute ingestion of exogenous ketone supplements in the form of a (R)‐3‐hydroxybutyl (R)‐3‐hydroxybutyrate (R‐BD R‐βHB) ketone monoester (KME) can attenuate declines in oxygen availability during hypoxic exposure and might impact cognitive performance at rest and in response to moderate‐intensity exercise. In a single‐blind randomized crossover design, 16 males performed assessments of cognitive performance before and during hypoxic exposure with moderate exercise [2 × 20 min weighted ruck (∼22 kg) at 3.2 km/h at 10% incline] in a normobaric altitude chamber (4572 m, 11.8% O2). The R‐BD R‐βHB KME (573 mg/kg) or a calorie‐ and taste‐matched placebo (∼50 g maltodextrin) were co‐ingested with 40 g of dextrose before exposure to hypoxia. The R‐βHB concentrations were rapidly elevated and sustained (>3 mM; P

Tissue-engineered nerve guidance conduits (NGCs) are an area of research interest and investment. Currently, two separate three-dimensional, filled NGCs have Food and Drug Administration approval in the management of nerve gaps up to 3 cm in length, with more on the horizon. Future NGC options will leverage increasingly intricate designs to mimic the natural biology and architecture of native nerve tissue. To enhance the development of next-generation NGCs, experimental protocols and models should be standardized. For the NGCs currently on the market, more clinical data and randomized comparative studies are needed.

Abstract Background Xylazine is an increasingly common adulterant in the North American unregulated drug supply that is associated with adverse health outcomes (e.g., skin infections, overdose). However, there are significant knowledge gaps regarding how xylazine was initially identified and how syringe services program (SSP) staff and clients (people who use drugs) responded to its emergence. Methods From June–July 2023, we conducted qualitative interviews with medical (e.g., clinicians) and frontline SSP staff (e.g., outreach workers) and adult clients with a history of injection drug use at a Miami-based SSP. Inductive memos identified emergent codes; thematic analysis involving team consensus established final themes. Results From interviews with SSP staff (n = 8) and clients (n = 17), xylazine emergence was identified at different times, in various ways. Initially, during summer 2022, clients identified a “tranquilizer-like substance” that worsened sedation and withdrawal and caused wounds. SSP medical staff later identified this adulterant as xylazine by treating new medical cases and through diverse information-sharing networks that included professional societies and news sources; however, frontline SSP staff and clients needed additional educational resources about xylazine and its side effects. With limited guidance on how to reduce harm from xylazine, SSP clients altered their drug consumption routes, reduced drug use, and relied on peers’ experiences with the drug supply to protect themselves. Some individuals also reported preferring xylazine-adulterated opioids and increasing their drug use, including the use of stimulants to avoid over sedation. Conclusions Xylazine’s emergence characterizes the current era of unprecedented shifts in the unregulated drug supply. We found that xylazine spurred important behavioral changes among people who use drugs (e.g., transitioning from injecting to smoking). Incorporating these experiences into early drug warning surveillance systems and scaling up drug-checking services and safer smoking supply distribution could help mitigate significant health harms caused by xylazine and other emergent adulterants.

Abstract Introduction People who use drugs (PWUD) are at increased risk for HIV infection. HIV self-testing (HIVST) is a promising method for identifying new infections, but optimal distribution strategies remain understudied. Methods To characterize PWUD by HIVST distribution strategy (peers vs. mail), we examined data from July 2022 to June 2023 collected from a real-world HIVST program led by the non-profit, Florida Harm Reduction Collective. We used descriptive statistics and Poisson regressions with robust error variance to compare those who received HIVST through peers or via mail by socio-demographics, Ending the HIV Epidemic (EHE) county designation, and HIV testing experience. Results Among 728 participants, 78% received HIVST from peers, 47% identified as cisgender female, 48% as heterosexual, and 45% as non-White; 66% resided in an EHE county, and 55% had no HIV testing experience. Compared to those who received an HIV self-test from peers, those who received tests via mail were less likely to be cisgender male (vs. cisgender female; prevalence ratio [PR] = 0.59, 95% confidence interval [CI]: 0.43, 0.81), non-Hispanic Black (vs. non-Hispanic White; PR = 0.57, 95% CI: 0.36, 0.89) or from EHE counties (vs. non-EHE counties; PR = 0.33, 95% CI: 0.25, 0.44). Those who received tests via mail were also more likely to identify their sexual orientation as “Other/Undisclosed” (vs. straight/heterosexual; PR = 2.00, 95% CI: 1.51, 2.66). Conclusion Our findings support the role of community-based HIVST distribution strategies in increasing HIV testing coverage among PWUD. Additional research could help inform the equitable reach of HIVST.

Mobile phone applications (MPAs) for substance use disorder (SUD) treatment are increasingly used by patients. Although pilot studies have shown promising results, multiple previous systematic reviews noted insufficient evidence for MPA use in SUD treatment—many of the previously published reviews evaluated different trials. Subsequently, we aimed to conduct an umbrella review of previously published reviews investigating the efficacy of MPAs for SUD treatment, excluding nicotine/tobacco because umbrella reviews have been done in this population and the nicotine/tobacco MPA approach often differs from SUD-focused MPAs. No previous reviews have included a statistical meta-analysis of clinical trials to quantify an estimated overall effect. Seven reviews met inclusion criteria, and 17 unique studies with available data were taken from those reviews for the meta-analysis. Overall, reviews reported a lack of evidence for recommending MPAs for SUD treatment. However, MPA-delivered recovery support services, cognitive behavioral therapy, and contingency management were identified across multiple reviews as having promising evidence for SUD treatment. Hedges g effect size for an MPA reduction in substance use–related outcomes relative to the control arm was insignificant (0.137; 95% CI, −0.056 to 0.330; P=.16). In subgroup analysis, contingency management (1.29; 95% CI, 1.088-1.482; τ2=0; k=2) and cognitive behavioral therapy (0.02; 95% CI, 0.001-0.030; τ2=0; k=2) were significant. Although contingency management’s effect was large, both trials were small (samples of 40 and 30). This review includes an adapted framework for the American Psychiatric Association’s MPA guidelines that clinicians can implement to review MPAs critically with patients.

Background Endovascular embolization can effectively treat spinal dural arteriovenous fistulas (SDAVFs). One factor limiting the success and durability of endovascular treatments is reliably casting and occluding the draining vein. We sought to compare the efficacies of n‐butyl‐2‐cyanoacrylate (nBCA) and Onyx in the treatment of SDAVFs. Methods We retrospectively analyzed patients with SDAVFs treated with endovascular embolization for whether a “durable cure” was achieved, defined as complete obliteration, clinical improvement, and sustained radiologic cure on follow‐up. We compared the outcomes of patients treated with Onyx to those treated with nBCA. Results A total of 40 embolizations for SDAVFs were performed in 38 patients. All patients were treated exclusively with liquid embolysates: Onyx alone (n = 22), nBCA alone (n = 16), or nBCA and Onyx combined (n = 2). For 45% (10/22) of patients treated with Onyx only, complete obliteration of the fistula with casting of the vein was not achieved. These patients were referred for microsurgical ligation. For all 16 patients treated with nBCA only, complete obliteration of the fistula was achieved. All 16 patients exhibited a durable cure compared with 11 of 22 patients (50%) in the Onyx‐only group (P = 0.002). Conclusion nBCA may be superior to Onyx for the embolization of SDAVFs. nBCA embolization is safe and effective for a subset of SDAVFs. Prospective studies comparing SDAVF treatment strategies are warranted.

Background: A prolonged repetitive transcranial magnetic stimulation (rTMS) treatment course could be beneficial for some patients experiencing major depressive episodes (MDE). We identified trajectories of rTMS response in depressive patients who received an extended rTMS treatment course and sought to determine which trajectories achieved the greatest benefit with a prolonged treatment course. Method: We applied group-based trajectory modeling to a naturalistic dataset of depressive patients receiving a prolonged course of sequential bilateral rTMS (up to 51 treatment sessions) to the dorsolateral prefrontal cortex. Trajectories of the PHQ-9 with extended treatment courses were characterized, and we explored the association between baseline clinical characteristics and group membership using multinomial logistic regression. Results: Among the 324 study participants, four trajectories were identified: “linear response, extended course” (N = 73; 22.5 %); “nonresponse” (N = 23; 7.1 %); “slowed response” (N = 159; 49.1 %); “rapid response, standard treatment length” (N = 69; 21.3 %). Only the “linear response, extended course” group showed considerable clinical improvement after receiving additional rTMS treatments. Greater baseline depressive symptoms were associated with linear response and non-response. Conclusion: Our results confirmed the distinctive response trajectories in depressive patients receiving rTMS and further highlighted that prolonged rTMS treatment courses may be beneficial for a subset of patients with higher initial symptom levels and linear early treatment response.

Abstract Background The wild pig (Sus scrofa) is an exotic species that has been present in the southeastern United States for centuries yet continues to expand into new areas dominated by bottomland and upland forests, the latter of which are less commonly associated with wild pigs. Here, we aimed to investigate wild pig movement and space use attributes typically used to guide wild pig management among multiple spatiotemporal scales. Our investigation focused on a newly invaded landscape dominated by bottomland and upland forests. Methods We examined (1) core and total space use using an autocorrelated kernel density estimator; (2) resource selection patterns and hot spots of space use in relation to various landscape features using step-selection analysis; and (3) daily and hourly differences in movement patterns between non-hunting and hunting seasons using generalized additive mixed models. Results Estimates of total space use among wild pigs (n = 9) were smaller at calculated core (1.2 ± 0.3 km2) and 90% (5.2 ± 1.5 km2) isopleths than estimates reported in other landscapes in the southeastern United States, suggesting that wild pigs were able to meet foraging, cover, and thermoregulatory needs within smaller areas. Generally, wild pigs selected areas closer to herbaceous, woody wetlands, fields, and perennial streams, creating corridors of use along these features. However, selection strength varied among individuals, reinforcing the generalist, adaptive nature of wild pigs. Wild pigs also showed a tendency to increase movement from fall to winter, possibly paralleling increases in hard mast availability. During this time, there were also increases in anthropogenic pressures (e.g. hunting), causing movements to become less diurnal as pressure increased. Conclusions Our work demonstrates that movement patterns by exotic generalists must be understood across individuals, the breadth of landscapes they can invade, and multiple spatiotemporal scales. This improved understanding will better inform management strategies focused on curbing emerging invasions in novel landscapes, while also protecting native natural resources.

Abstract Introduction Despite having a high risk of acquiring sexually transmitted infections, people who inject drugs (PWID) often do not receive recommended HPV screenings due to barriers to healthcare. Guideline-based cervical HPV screening and vaccination can prevent cervical cancer. Low-cost, low-barrier methods for cancer screening and prevention are important for vulnerable communities such as PWID. Methods We examined acceptability of HPV self-sampling at a syringe services program (SSP). Participants with a cervix (n = 49) participated in patient education followed by a survey to assess willingness to perform HPV self-sampling versus standard of care. Results 59% found self-sampling to be acceptable, citing privacy, ease, and quickness. Among those opting for HPV screening delivered by a provider (n = 16), participants cited concerns about adequate sampling (81%) and test accuracy (75%). Notably, only 18% of participants reported complete HPV vaccination. Conclusion Cervical HPV self-sampling was acceptable to PWID. SSP-based efforts to provide preventative health services could place tools for cancer screening into the hands of PWID, a need-to-reach community.

Abstract Background People who inject drugs (PWID) remain a high priority population under the federal Ending the HIV Epidemic initiative with 11% of new HIV infections attributable to injection drug use. There is a critical need for innovative, efficacious, scalable, and community-driven models of healthcare in non-stigmatizing settings for PWID. We seek to test a Comprehensive-TeleHarm Reduction (C-THR) intervention for HIV prevention services delivered via a syringe services program (SSP). Methods The CHARIOT trial is a hybrid type I effectiveness-implementation study using a parallel two-arm randomized controlled trial design. Participants (i.e., PWID; n = 350) will be recruited from a syringe services program (SSP) in Miami, Florida. Participants will be randomized to receive either C-THR or non-SSP clinic referral and patient navigation. The objectives are: (1) to determine if the C-THR intervention increases engagement in HIV prevention (i.e., HIV pre-exposure prophylaxis; PrEP or medications for opioid use disorder; MOUD) compared to non-SSP clinic referral and patient navigation, (2) to examine the long-term effectiveness and cost-effectiveness of the C-THR intervention, and (3) to assess the barriers and facilitators to implementation and sustainment of the C-THR intervention. The co-primary outcomes are PrEP or MOUD engagement across follow-up at 3, 6, 9 and 12 months. For PrEP, engagement is confirmed by tenofovir on dried blood spot or cabotegravir injection within the previous 8 weeks. For MOUD, engagement is defined as screening positive for norbuprenorphine or methadone on urine drug screen; or naltrexone or buprenorphine injection within the previous 4 weeks. Secondary outcomes include PrEP adherence, engagement in HCV treatment and sustained virologic response, and treatment of sexually transmitted infections. The short and long term cost-effectiveness analyses and mixed-methods implementation evaluation will provide compelling data on the sustainability and possible impact of C-THR on comprehensive HIV prevention delivered via SSPs. Discussion The CHARIOT trial will be the first to our knowledge to test the efficacy of an innovative, peer-led telehealth intervention with PWID at risk for HIV delivered via an SSP. This innovative healthcare model seeks to transform the way PWID access care by bypassing the traditional healthcare system, reducing multi-level barriers to care, and meeting PWID where they are. Trial Registration: ClinicalTrials.gov NCT05897099. Trial registry name: Comprehensive HIV and Harm Prevention Via Telehealth (CHARIOT). Registration date: 06/12/2023.

Abstract Alcohol use disorder (AUD) is the most prevalent substance use disorder worldwide. Acamprosate and naltrexone are anti-craving drugs used in AUD pharmacotherapy. However, molecular mechanisms underlying their anti-craving effect remain unclear. This study utilized a patient-derived induced pluripotent stem cell (iPSC)-based model system and anti-craving drugs that are used to treat AUD as “molecular probes” to identify possible mechanisms associated with alcohol craving. We examined the pathophysiology of craving and anti-craving drugs by performing functional genomics studies using iPSC-derived astrocytes and next-generation sequencing. Specifically, RNA sequencing performed using peripheral blood mononuclear cells from AUD patients with extreme values for alcohol craving intensity prior to treatment showed that inflammation-related pathways were highly associated with alcohol cravings. We then performed a genome-wide assessment of chromatin accessibility and gene expression profiles of induced iPSC-derived astrocytes in response to ethanol or anti-craving drugs. Those experiments identified drug-dependent epigenomic signatures, with IRF3 as the most significantly enriched motif in chromatin accessible regions. Furthermore, the activation of IRF3 was associated with ethanol-induced endoplasmic reticulum (ER) stress which could be attenuated by anti-craving drugs, suggesting that ER stress attenuation might be a target for anti-craving agents. In conclusion, we found that craving intensity was associated with alcohol consumption and treatment outcomes. Our functional genomic studies suggest possible relationships among craving, ER stress, IRF3 and the actions of anti-craving drugs.

Abstract Background Xylazine is an alpha-2 adrenergic receptor agonist that has emerged as a contaminant in the illicit drug supply of fentanyl. Xylazine use may be suspected in naloxone-resistant overdoses and atypical, chronic wounds in people who use drugs (PWUD). This case is unique because it is the first case to our knowledge describing wound care for a xylazine-induced wound with a confirmatory xylazine test strip (XTS) in the setting of a syringe services program (SSP) and in the state of Florida. Case presentation A 43-year-old woman with a past medical history of severe opioid use disorder and stimulant use disorder presented to a student-run clinic at a Miami SSP for wound care. She had multiple ulcerations diffusely over her bilateral forearms with surrounding erythema and warmth. Seven weeks later, she presented to clinic again for wound care because her wounds had progressed. At this visit, a XTS was used to confirm the presence of xylazine in her urine. Wound care management and harm reduction strategies employed at both visits were informed by best clinical judgement due to lack of formal guidelines at the time. Wound outcomes are unknown as the patient has not returned to clinic. Conclusions Many PWUD at highest risk for acute and chronic health consequences of xylazine-adulterated fentanyl do not have access to healthcare outside of low barrier clinics and SSPs due to lack of insurance or mistrust of the traditional healthcare system due to stigma. There is an urgent need for access to XTS for PWUD and clinical practice guidelines for the treatment of xylazine-related wounds in outpatient clinics.

Anthropogenic carbon emissions have resulted in drastic oceanic changes, including increased acidity, increased temperature, and decreased salinity. Anthropogenic carbon emissions have resulted in drastic oceanic changes, including increased acidity, increased temperature, and decreased salinity. Few studies have directly assessed the compounded impact of alterations to oceanic conditions on oyster physiology and the relation to the presence of V. parahaemolyticus. This project investigated the relationship between projected climate scenarios and their influence on both eastern oyster, Crassostrea virginica, and the aquatic bacteria, Vibrio parahaemolyticus. Specifically, we examined whether an increase in water temperature and/or decrease in salinity would impair oyster resistance to V. parahaemolyticus, a human food and waterborne pathogen. Using a culture-dependent approach, our data revealed that the alterations in environmental conditions did not significantly impact the numbers of V. parahaemolyticus numbers within oyster hemolymph or tissues. However, we did observe a dramatic increase in the total amount of bacteria and pathogenic native Vibrio species, Vibrio aestuarianus and Vibrio harveyi. Despite detecting V. parahaemolyticus in most tissues at 7 days post-challenge, oysters were able to reduce bacterial levels below our limit of detection by 28 days of exposure. Furthermore, in our second experimental trial exploring single vs. multiple inoculation of bacteria, we observed that oysters were either able to reduce total bacterial levels to pre-treatment burdens (i.e., below our limit of detection) or die. This study demonstrates that the synergistic effects of elevated temperature and decreased salinity do not inhibit oysters from preventing the long-term colonization of exogenous V. parahaemolyticus. However, our data do show these environmental stressors impact oyster physiology and the native microbiota. This can lead to the proliferation of opportunistic pathogens, which could have impacts on oyster population numbers and ecosystem and human health.

Evolutionary biology provides a unifying theory for testing hypotheses about the relationship between hormones and person perception. Person perception usually receives attention from the perspective of sexual selection. However, because person perception is one trait in a suite regulated by hormones, univariate approaches are insufficient. In this Perspectives article, quantitative genetics is presented as an important but underutilized framework for testing evolutionary hypotheses within this literature. We note tacit assumptions within the current literature on psychiatric genetics, which imperil the interpretation of findings thus far. As regulators of a diverse manifold of traits, hormones mediate tradeoffs among an array of functions. Hormonal pleiotropy also provides the basis of correlational selection, a process whereby selection on one trait in a hormone-mediated suite generates selection on the others. This architecture provides the basis for conflicts between sexual and natural selection within hormone-mediated suites. Due to its role in person perception, psychiatric disorders, and reproductive physiology, the sex hormone estrogen is highlighted as an exemplar here. The implications of this framework for the evolution of person perception are discussed. Empirical quantification of selection on traits within hormone-mediated suites remains an important gap in this literature with great potential to illuminate the fundamental nature of psychiatric disorders.

Abstract Bivalent molecules consisting of groups connected through bridging linkers often exhibit strong target binding and unique biological effects. However, developing bivalent inhibitors with the desired activity is challenging due to the dual motif architecture of these molecules and the variability that can be introduced through differing linker structures and geometries. We report a set of alternatively linked bivalent EGFR inhibitors that simultaneously occupy the ATP substrate and allosteric pockets. Crystal structures show that initial and redesigned linkers bridging a trisubstituted imidazole ATP-site inhibitor and dibenzodiazepinone allosteric-site inhibitor proved successful in spanning these sites. The re-engineered linker yielded a compound that exhibited significantly higher potency (~60 pM) against the drug-resistant EGFR L858R/T790M and L858R/T790M/C797S, which was superadditive as compared with the parent molecules. The enhanced potency is attributed to factors stemming from the linker connection to the allosteric-site group and informs strategies to engineer linkers in bivalent agent design.

Abstract Background Tele-harm reduction (THR) is a telehealth-enhanced, peer-led, harm reduction intervention delivered within a trusted syringe services program (SSP) venue. The primary goal of THR is to facilitate linkage to care and rapid, enduring virologic suppression among people who inject drugs (PWID) with HIV. An SSP in Miami, Florida, developed THR to circumvent pervasive stigma within the traditional healthcare system. Methods During intervention development, we conducted in-depth interviews with PWID with HIV (n = 25) to identify barriers and facilitators to care via THR. We employed a general inductive approach to transcripts guided by iterative readings of the raw data to derive the concepts, themes, and interpretations of the THR intervention. Results Of the 25 PWID interviewed, 15 were in HIV care and adherent to medication; 4 were in HIV care but non-adherent; and 6 were not in care. Themes that emerged from the qualitative analysis included the trust and confidence PWID have with SSP clinicians as opposed to professionals within the traditional healthcare system. Several barriers to treatment were reported among PWID, including perceived and actual discrimination by friends and family, negative internalized behaviors, denial of HIV status, and fear of engaging in care. Facilitators to HIV care included empathy and respect by SSP staff, flexibility of telehealth location, and an overall destigmatizing approach. Conclusion PWID identified barriers and facilitators to receipt of HIV care through the THR intervention. Interviews helped inform THR intervention development, centered on PWID in the destigmatizing environment of an SSP.

Abstract Background People who use drugs (PWUD) experience elevated HIV risk and numerous barriers to facility-based HIV testing. HIV self-testing (HIVST) could circumvent many of those barriers and is acceptable among PWUD, yet HIVST implementation for PWUD is limited. Service providers’ perspectives on specific HIVST delivery strategies could help increase availability for PWUD. Methods From April–November 2021, we interviewed 16 health, harm reduction, and social service providers working with PWUD in San Diego, CA. Interviews and rapid thematic analysis explored perspectives on HIVST’s utility and appropriateness, as well as the feasibility of and anticipated challenges with specific HIVST delivery strategies, including peer or secondary distribution. Results Participants viewed HIV as a significant threat to PWUD health and confirmed the presence of numerous barriers to local facility-based HIV testing. Participants viewed HIVST as a promising and potentially empowering solution. Based on community familiarity with secondary distribution of harm reduction supplies (i.e., naloxone) and information, participants viewed secondary distribution of HIVST kits as an appropriate and feasible strategy for increasing the reach of HIVST, but also described potential barriers (e.g., engaging socially disconnected individuals, ensuring linkages to services following HIVST) and provided suggestions for alternative HIVST kit delivery models (e.g., harm reduction vending machines). Conclusions Service providers viewed secondary distribution of HIVST kits among PWUD as promising, appropriate, and feasible, yet specialized efforts may be needed to reach the most marginalized individuals and ensure consistent provision of educational information and referral supports that maximize the impact of this approach.

Abstract Background Population screening for risk of type 1 diabetes (T1D) has been proposed to identify those with islet autoimmunity (presence of islet autoantibodies). As islet autoantibodies can be transient, screening with a genetic risk score has been proposed as an entry into autoantibody testing. Methods Children were recruited from eight general pediatric and specialty clinics across Virginia with diverse community settings. Recruiters in each clinic obtained informed consent/assent, a medical history, and a saliva sample for DNA extraction in children with and without a history of T1D. A custom genotyping panel was used to define T1D genetic risk based upon associated SNPs in European- and African-genetic ancestry. Subjects at “high genetic risk” were offered a separate blood collection for screening four islet autoantibodies. A follow-up contact (email, mail, and telephone) in one half of the participants determined interest and occurrence of subsequent T1D. Results A total of 3818 children aged 2–16 years were recruited, with 14.2% (n = 542) having a “high genetic risk.” Of children with “high genetic risk” and without pre-existing T1D (n = 494), 7.0% (34/494) consented for autoantibody screening; 82.4% (28/34) who consented also completed the blood collection, and 7.1% (2/28) of them tested positive for multiple autoantibodies. Among children with pre-existing T1D (n = 91), 52% (n = 48) had a “high genetic risk.” In the sample of children with existing T1D, there was no relationship between genetic risk and age at T1D onset. A major factor in obtaining islet autoantibody testing was concern over SARS-CoV-2 exposure. Conclusions Minimally invasive saliva sampling implemented using a genetic risk score can identify children at genetic risk of T1D. Consent for autoantibody screening, however, was limited largely due to the SARS-CoV-2 pandemic and need for blood collection.

Abstract Despite increased Atlantic hurricane risk, projected trends in hurricane frequency in the warming climate are still highly uncertain, mainly due to short instrumental record that limits our understanding of hurricane activity and its relationship to climate. Here we extend the record to the last millennium using two independent estimates: a reconstruction from sedimentary paleohurricane records and a statistical model of hurricane activity using sea surface temperatures (SSTs). We find statistically significant agreement between the two estimates and the late 20th century hurricane frequency is within the range seen over the past millennium. Numerical simulations using a hurricane-permitting climate model suggest that hurricane activity was likely driven by endogenous climate variability and linked to anomalous SSTs of warm Atlantic and cold Pacific. Volcanic eruptions can induce peaks in hurricane activity, but such peaks would likely be too weak to be detected in the proxy record due to large endogenous variability.

Abstract Background Intermittent theta burst stimulation (iTBS), a novel form of repetitive transcranial magnetic stimulation (rTMS), can be administered in 1/10th of the time of standard rTMS (~ 3 min vs. 37.5 min) yet achieves similar outcomes in depression. The brief nature of the iTBS protocol allows for the administration of multiple iTBS sessions per day, thus reducing the overall course length to days rather than weeks. This study aims to compare the efficacy and tolerability of active versus sham iTBS using an accelerated regimen in patients with treatment-resistant depression (TRD). As a secondary objective, we aim to assess the safety, tolerability, and treatment response to open-label low-frequency right-sided (1 Hz) stimulation using an accelerated regimen in those who do not respond to the initial week of treatment. Methods Over three years, approximately 230 outpatients at the Centre for Addiction and Mental Health and University of British Columbia Hospital, meeting diagnostic criteria for unipolar MDD, will be recruited and randomized to a triple blind sham-controlled trial. Patients will receive five consecutive days of active or sham iTBS, administered eight times daily at 1-hour intervals, with each session delivering 600 pulses of iTBS. Those who have not achieved response by the week four follow-up visit will be offered a second course of treatment, regardless of whether they initially received active or sham stimulation. Discussion Broader implementation of conventional iTBS is limited by the logistical demands of the current standard course consisting of 4–6 weeks of daily treatment. If our proposed accelerated iTBS protocol enables patients to achieve remission more rapidly, this would offer major benefits in terms of cost and capacity as well as the time required to achieve clinical response. Trial registration ClinicalTrials.gov Identifier: NCT04255784.

AbstractBackground: At the start of the pandemic, relaxation of buprenorphine prescribing regulations created an opportunity to create new models of medications for opioid use disorder (MOUD) delivery and care. To expand and improve access to MOUD, we adapted and implemented the Tele-Harm Reduction (THR) intervention; a multicomponent, telehealth-based and peer-driven intervention to promote HIV viral suppression among people who inject drugs (PWID) accessing a syringe services program (SSP). This study examined buprenorphine initiation and retention among PWID with opioid use disorder who received the adapted THR intervention at the IDEA Miami SSP.Methods: A retrospective chart review of participants who received the THR intervention for MOUD was performed to examine the impact of telehealth on buprenorphine retention. Our primary outcome was three-month retention, defined as three consecutive months of buprenorphine dispensed from the pharmacy.Results: A total of 109 participants received the adapted THR intervention. Three-month retention rate on buprenorphine was 58.7%. Seeing a provider via telehealth at baseline or any follow up visit (aOR = 7.53, 95% CI: [2.36, 23.98]) and participants who had received an escalating dose of buprenorphine after baseline visit (aOR = 8.09, 95% CI: [1.83, 35.87]) had a higher adjusted odds of retention at three months. Participants who self-reported or tested positive for a stimulant (methamphetamine, amphetamine, or cocaine) at baseline had a lower adjusted odds of retention on buprenorphine at three months (aOR = 0.29, 95% CI: [0.09, 0.93]).Conclusions: Harm reduction settings can adapt dynamically to the needs of PWID in provision of critical lifesaving buprenorphine in a truly destigmatising approach. Our pilot suggests that an SSP may be an acceptable and feasible venue for delivery of THR to increase uptake of buprenorphine by PWID and promote retention in care.KEY MESSAGESThe Tele-Harm Reduction intervention can be adapted for initiating and retaining people who inject drugs with opioid use disorder on buprenorphine within a syringe services program settingUsing telehealth was associated with increased three-month buprenorphine retentionBaseline stimulant use was negatively associated with three-month buprenorphine retention

Background The Atlantic mackerel, Scomber scombrus (Linnaeus, 1758) is a commercially valuable migratory pelagic fish inhabiting the northern Atlantic Ocean and the Mediterranean Sea. Given its highly migratory behaviour for feeding and spawning, several studies have been conducted to assess differentiation among spawning components to better define management units, as well as to investigate possible adaptations to comprehend and predict recent range expansion northwards. Methods Here, a high-quality genome of S. scombrus was sequenced and annotated, as an increasing number of population genetic studies have proven the relevance of reference genomes to investigate genomic markers/regions potentially linked to differences at finer scale. Such reference genome was used to map Restriction-site-associated sequencing (RAD-seq) reads for SNP discovery and genotyping in more than 500 samples distributed along the species range. The resulting genotyping tables have been used to perform connectivity and adaptation analyses. Results The assembly of the reference genome for S. scombrus resulted in a high-quality genome of 741 Mb. Our population genetic results show that the Atlantic mackerel consist of three previously known genetically isolated units (Northwest Atlantic, Northeast Atlantic, Mediterranean), and provide no evidence for genetically distinct spawning components within the Northwest or Northeast Atlantic. Conclusions Therefore, our findings resolved previous uncertainties by confirming the absence of genetically isolated spawning components in each side of the northern Atlantic, thus rejecting homing behaviour and the need to redefine management boundaries in this species. In addition, no further genetic signs of ongoing adaptation were detected in this species.

Summary: Pain that persists beyond the time required for tissue healing and pain that arises in the absence of tissue injury, collectively referred to as nociplastic pain, are poorly understood phenomena mediated by plasticity within the central nervous system. The parabrachial nucleus (PBN) is a hub that relays aversive sensory information and appears to play a role in nociplasticity. Here, by preventing PBN Calca neurons from releasing neurotransmitters, we demonstrate that activation of Calca neurons is necessary for the manifestation and maintenance of chronic pain. Additionally, by directly stimulating Calca neurons, we demonstrate that Calca neuron activity is sufficient to drive nociplasticity. Aversive stimuli of multiple sensory modalities, such as exposure to nitroglycerin, cisplatin, or lithium chloride, can drive nociplasticity in a Calca-neuron-dependent manner. Aversive events drive nociplasticity in Calca neurons in the form of increased activity and excitability; however, neuroplasticity also appears to occur in downstream circuitry.

Commensal gut bacteria use oleate hydratase to release a spectrum of hydroxylated fatty acids using host-derived unsaturated fatty acids. These compounds are thought to attenuate the immune response, but the underlying signaling mechanism(s) remain to be established. The pathogen Staphylococcus aureus also expresses an oleate hydratase and 10-hydroxyoctadecanoic acid (h18:0) is the most abundant oleate hydratase metabolite found at Staphylococcal skin infection sites. Here, we show h18:0 stimulates the transcription of a set of lipid metabolism genes associated with the activation of peroxisome proliferator activated receptor (PPAR) in the RAW 264.7 macrophage cell line and mouse primary bone marrow-derived macrophages. Cell-based transcriptional reporter assays show h18:0 selectively activates PPARα. Radiolabeling experiments with bone marrow-derived macrophages show [1-14C]h18:0 is not incorporated into cellular lipids, but is degraded by β-oxidation, and mass spectrometry detected shortened fragments of h18:0 released into the media. The catabolism of h18:0 was >10-fold lower in bone marrow-derived macrophages isolated from Ppara−/− knockout mice, and we recover 74-fold fewer S. aureus cells from the skin infection site of Ppara−/− knockout mice compared to wildtype mice. These data identify PPARα as a target for oleate hydratase-derived hydroxy fatty acids and support the existence of an oleate hydratase-PPARα signaling axis that functions to suppress the innate immune response to S. aureus.

ABSTRACTLecanosticta acicola is the causal agent for brown spot needle blight that affects pine trees across the northern hemisphere. Based on marker genes and microsatellite data, two distinct lineages have been identified that were introduced into Europe on two separate occasions. Despite their overall distinct geographic distribution, they have been found to coexist in regions of northern Spain and France. Here, we present the first genome-wide study of Lecanosticta acicola, including assembly of the reference genome and a population genomics analysis of 70 natural isolates from northern Spain. We show that most of the isolates belong to the southern lineage but show signs of introgression with northern lineage isolates, indicating mating between the two lineages. We also identify phenotypic differences between the two lineages based on the activity profiles of 20 enzymes, with introgressed strains being more phenotypically similar to members of the southern lineage. In conclusion, we show undergoing genetic admixture between the two main lineages of L. acicola in a region of recent expansion.IMPORTANCELecanosticta acicola is a fungal pathogen causing severe defoliation, growth reduction, and even death in more than 70 conifer species. Despite the increasing incidence of this species, little is known about its population dynamics. Two divergent lineages have been described that have now been found together in regions of France and Spain, but it is unknown how these mixed populations evolve. Here we present the first reference genome for this important plant pathogenic fungi and use it to study the population genomics of 70 isolates from an affected forest in the north of Spain. We find signs of introgression between the two main lineages, indicating that active mating is occurring in this region which could propitiate the appearance of novel traits in this species. We also study the phenotypic differences across this population based on enzymatic activities on 20 compounds.

Breast cancer is a leading cause of cancer‐related deaths in women. Many genetic and behavioral risk factors can contribute to the initiation and progression of breast cancer, one being alcohol consumption. Numerous epidemiological studies have established a positive correlation between alcohol consumption and breast cancer; however, the molecular basis for this link remains ill defined. Elucidating ethanol‐induced changes to global transcriptional programming in breast cells is important to ultimately understand how alcohol and breast cancer are connected mechanistically. We investigated induced transcriptional changes in response to a short cellular exposure to moderate levels of alcohol. We treated the nontumorigenic breast cell line MCF10A and the tumorigenic breast cell lines MDA‐MB‐231 and MCF7, with ethanol for 6 h, and then captured the changes to ongoing transcription using 4‐thiouridine metabolic labeling followed by deep sequencing. Only the MCF10A cell line exhibited statistically significant changes in newly transcribed RNA in response to ethanol treatment. Further experiments revealed that some ethanol‐upregulated genes are sensitive to the dose of alcohol treatment, while others are not. Gene Ontology and biochemical pathway analyses revealed that ethanol‐upregulated genes in MCF10A cells are enriched in biological functions that could contribute to cancer development.

Abstract The CRISPR/Cas9 nuclease from Streptococcus pyogenes (SpCas9) can be used with single guide RNAs (sgRNAs) as a sequence-specific antimicrobial agent and as a genome-engineering tool. However, current bacterial sgRNA activity models struggle with accurate predictions and do not generalize well, possibly because the underlying datasets used to train the models do not accurately measure SpCas9/sgRNA activity and cannot distinguish on-target cleavage from toxicity. Here, we solve this problem by using a two-plasmid positive selection system to generate high-quality data that more accurately reports on SpCas9/sgRNA cleavage and that separates activity from toxicity. We develop a machine learning architecture (crisprHAL) that can be trained on existing datasets, that shows marked improvements in sgRNA activity prediction accuracy when transfer learning is used with small amounts of high-quality data, and that can generalize predictions to different bacteria. The crisprHAL model recapitulates known SpCas9/sgRNA-target DNA interactions and provides a pathway to a generalizable sgRNA bacterial activity prediction tool that will enable accurate antimicrobial and genome engineering applications.

Abstract Introduction The expanded capacity of syringe services programs (SSPs) in the USA to integrate telehealth services was largely related to flexibility of buprenorphine prescription in response to the COVID-19 pandemic. SSPs demonstrated the potential of using telehealth to reach participants with both medical and non-medical services. The present study examines the implementation of medical and non-medical telehealth-based health services in 2020 at SSPs in the USA and organizational characteristics associated with adopting specific telehealth services. Methods We administered a cross-sectional survey among all known SSPs operating in the USA as of 2021. The two primary study outcomes were (1) implementation of medical telehealth and (2) implementation of non-medical telehealth in 2020. Medical services included HIV counseling/care, hepatitis C virus (HCV) counseling/care, and buprenorphine. Non-medical services included wellbeing/check-ins, overdose prevention training, health navigation, harm reduction and psychological counseling. Bivariate and multivariable mixed effects logistic regression models were used to directly estimate the odds ratio associated with organizational characteristics on the implementation of telehealth-based health services. Results Thirty percent of programs (n = 290) reported implementing telehealth-based health services. In multivariable logistic regression models, community-based organization SSPs had higher odds of implementing medical (aOR = 4.69, 95% CI [1.96, 11.19]) and non-medical (aOR = 2.18, 95% CI [1.10, 4.31]) health services compared to public health department SSPs. SSPs that received governmental funding had higher odds of implementing medical services via telehealth (aOR = 2.45, 95% CI [1.35, 4.47]) compared to programs without governmental funding. Conclusion Community-based organization SSPs and those with government funding had the highest odds of telehealth implementation in response to the COVID-19 Public Health Emergency. Federal, state, and local governments must increase funding for low-barrier venues like SSPs to support telehealth implementation to serve the needs of people who use drugs.

Abstract The electrochemical nitrate reduction reaction (NO3RR) has the potential for distributed water treatment and renewable chemical synthesis. Cu is an active monometallic electrocatalyst for the NO3RR in acidic and alkaline electrolytes, where activity is limited by the reduction of adsorbed nitrate to nitrite. Oxygen‐vacancy forming metal‐oxide supports provide sites for N‐O bond activation in thermal reduction, impacting product distribution as well. Here we compare the electrochemical NO3RR activity of Cu deposited on two metal‐oxide supports (cerium dioxide [Cu/CeO2‐δ] and fluorine‐doped tin dioxide [Cu/FTO]) to a Cu foil benchmark. Considering activity in phosphate‐buffered neutral media, nitrate and adsorbed hydrogen compete for surface sites under NO3RR conditions. The less‐cathodic overpotential on Cu/CeO2‐δ compared to Cu/FTO is attributed to stronger nitrate adsorption, similar to thermal nitrate reduction. Utilization of CeO2‐δ as an electrocatalyst support slightly shifting product distribution toward more oxidized products, either by enhancing nitrate affinity or by a more dynamic process involving the formation and healing of oxygen vacancies (𝑣O••). These results suggest supporting catalysts on metal oxides may enhance activity by promoting the adsorption of anionic reactants on cathodic electrocatalysts.

Neurons throughout the brain modulate their firing rate lawfully in response to sensory input. Theories of neural computation posit that these modulations reflect the outcome of a constrained optimization in which neurons aim to robustly and efficiently represent sensory information. Our understanding of how this optimization varies across different areas in the brain, however, is still in its infancy. Here, we show that neural sensory responses transform along the dorsal stream of the visual system in a manner consistent with a transition from optimizing for information preservation towards optimizing for perceptual discrimination. Focusing on the representation of binocular disparities-the slight differences in the retinal images of the two eyes-we re-analyze measurements characterizing neuronal tuning curves in brain areas V1, V2, and MT (middle temporal) in the macaque monkey. We compare these to measurements of the statistics of binocular disparity typically encountered during natural behaviors using a Fisher Information framework. The differences in tuning curve characteristics across areas are consistent with a shift in optimization goals: V1 and V2 population-level responses are more consistent with maximizing the information encoded about naturally occurring binocular disparities, while MT responses shift towards maximizing the ability to support disparity discrimination. We find that a change towards tuning curves preferring larger disparities is a key driver of this shift. These results provide new insight into previously-identified differences between disparity-selective areas of cortex and suggest these differences play an important role in supporting visually-guided behavior. Our findings emphasize the need to consider not just information preservation and neural resources, but also relevance to behavior, when assessing the optimality of neural codes.

Background: We aimed to report the preliminary xylazine prevalence among people who inject drugs (PWID) treated at a student-run free clinic in Miami, FL, USA and to identify characteristics associated with screening positive for xylazine. Methods: A retrospective chart review of 59 patients presenting to a syringe services program (SSP) clinic in was conducted between April 27th and August 17th, 2023. We measured presence of xylazine with rapid visual immunoassay strips on patient urine samples. Results: Xylazine was present in 55.9 % (33/59) of urine samples including 2 without detected opioids. Xylazine presence was significantly associated with unsheltered homelessness (p = 0.018), presence of wound(s) (p = 0.008), and testing positive for hepatitis C antibody (p = 0.014), fentanyl (p = 0.005) and MDMA (p = 0.002). Conclusions: A high prevalence of xylazine in the Southeastern United States furthers evidence of the geographical spread of xylazine and rapidly evolving illicit drug supply. Widespread xylazine screening is urgently needed to inform people who inject drugs and to studyinterventions to minimize harms associated with xylazine.

The purpose of this study was to determine whether retention of a post-pyloric Dobhoff tube (DHT) in position to serve as a visual guide through the pylorus during gastrojejunostomy (GJ) tube placement results in a reduction in fluoroscopy time, procedure time, and estimated radiation dose. A retrospective study evaluated patients who underwent GJ tube placement or gastric to GJ conversion from January 1, 2017, to April 1, 2021. Demographic and procedural data were collected, and results were evaluated using descriptive statistics and hypothesis testing through an unpaired Student’s t-test. Of the 71 GJ tube placements included for analysis, 12 patients underwent placement with a post-pyloric DHT in position, and 59 patients underwent placement without a post-pyloric DHT in position. The mean fluoroscopy time and estimated radiation dose were significantly reduced in patients who underwent GJ tube placement with a post-pyloric DHT in position compared with those without (7.08 min vs. 11.02 min, P = 0.004; 123.12 mGy vs. 255.19 mGy, P = 0.015, respectively). The mean total procedure time was also reduced in patients who underwent GJ tube placement with a post-pyloric DHT in position compared with those who had no post-pyloric DHT, but this finding lacked statistical significance (18.55 min vs. 23.15 min; P = 0.09). Post-pyloric DHT retention can be utilized during GJ tube placement to reduce radiation exposure to both the patient and interventionalist.

Abstract Rucksack marches (‘rucks’) are strenuous, military‐relevant exercises that may benefit from pre‐event fuelling. The purpose of this investigation was to explore whether acute ingestion of carbohydrate‐ or lipid‐based nutritional bars before rucking can elicit unique advantages that augment exercise performance. Recreationally active and healthy males (n = 29) were randomized and counterbalanced to consume 1000 kcal derived from a novel, energy‐dense (percentage energy from carbohydrate/fat/protein: 5/83/12) ketogenic bar (KB), or isocaloric high‐carbohydrate bars (CB; 61/23/16) 3 h before a time‐to‐exhaustion (TTE) ruck. Conditions were separated by a 1‐week washout. The rucksack weight was standardized to 30% of bodyweight. Steady‐state treadmill pace was set at 3.2 km/h (0.89 m/s) and 14% grade. TTE was the primary outcome; respiratory exchange ratio (RER), capillary ketones (R‐β‐hydroxybutyrate), glucose and lactate, plus subjective thirst/hunger were the secondary outcomes. Mean TTE was similar between conditions (KB: 55 ± 25 vs. CB: 54 ± 22 min; P = 0.687). The RER and substrate oxidation rates revealed greater fat and carbohydrate oxidation after the KB and CB, respectively (all P

Abstract Introduction An estimated 39,010 Indiana residents were diagnosed with cancer in 2021. To address the cancer burden, Project ECHO (Extension Community Healthcare Outcomes) was launched in 2019 in Indiana to build specialty healthcare capacity among non‐specialists. Due to positive outcomes from the pilot year, the Cancer Prevention, Screening, and Survivorship ECHO was implemented for a second year. The purpose of this study was to measure the participation and regional impact of this ECHO. Methods ECHO sessions occurred twice monthly from October 2020 to October 2021. Changes were implemented in response to feedback from the pilot year, including making the curriculum more practical for learners and adding accreditation opportunities. Participant information and feedback was extracted from electronic surveys for review. Results There were 24 ECHO sessions with 213 unique participants, increased from 140 unique participants in the pilot year. An average of 23.5 individuals attended each session, increased from 15.5 individuals per session. Enrolled participants served in a diverse set of roles and represented 247 zip codes, 30 Indiana counties, and 32 states across the United States, each of which increased from the pilot year. Discussion In this second year, this ECHO expanded to reach more participants with increased attendance and a more diverse distribution of roles within healthcare, which may be attributed to feedback‐driven curriculum design. Cancer care is multi‐disciplinary, with health educators, nurses, and administrators, each acting within the cancer care continuum. As a result, this ECHO has been adapted to serve an increasingly broad distribution of professionals. Conclusion The second year of the Cancer Prevention, Screening, and Survivorship ECHO displayed increased overall enrollment and participation, greater diversity among participant roles, and a wider reach across Indiana and the United States.

Intercalation of protons in 2D materials plays a major role for several applications in energy storage and conversion. Here, the authors show that protons intercalated in Ti3C2Tx MXene interlayer during electrochemical cycling have a different hydration structure than protons in bulk water.

Neuropeptide Y targets the Y1 receptor (Y1) in the spinal dorsal horn (DH) to produce endogenous and exogenous analgesia. DH interneurons that express Y1 (Y1-INs; encoded by Npy1r) are necessary and sufficient for neuropathic hypersensitivity after peripheral nerve injury. However, as Y1-INs are heterogenous in composition in terms of morphology, neurophysiological characteristics, and gene expression, we hypothesized that a more precisely defined subpopulation mediates neuropathic hypersensitivity. Using fluorescence in situ hybridization, we found that Y1-INs segregate into 3 largely nonoverlapping subpopulations defined by the coexpression of Npy1r with gastrin-releasing peptide (Grp/Npy1r), neuropeptide FF (Npff/Npy1r), and cholecystokinin (Cck/Npy1r) in the superficial DH of mice, nonhuman primates, and humans. Next, we analyzed the functional significance of Grp/Npy1r, Npff/Npy1r, and Cck/Npy1r INs to neuropathic pain using a mouse model of peripheral nerve injury. We found that chemogenetic inhibition of Npff/Npy1r-INs did not change the behavioral signs of neuropathic pain. Further, inhibition of Y1-INs with an intrathecal Y1 agonist, [Leu31, Pro34]-NPY, reduced neuropathic hypersensitivity in mice with conditional deletion of Npy1r from CCK-INs and NPFF-INs but not from GRP-INs. We conclude that Grp/Npy1r-INs are conserved in higher order mammalian species and represent a promising and precise pharmacotherapeutic target for the treatment of neuropathic pain.

Anxiety disorder is characterized by excessive fear or avoidance of perceived threats that can be persistent and debilitating. Diet is a modifiable risk factor that may contribute to the pathogenesis or treatment of anxiety, depending on diet quality. Although the biological mechanisms by which food, specific nutrients, and nutraceuticals impact mental health are not completely understood, implicated pathways include inflammation, oxidative stress, brain plasticity effects, mitochondrial dysfunction, and neurotransmitter metabolism. Essential dietary trace minerals such as zinc, copper, iron, and selenium are critical components for numerous biological proteins and may have a role in these proposed mechanisms related to brain health and anxiety. This narrative review examines the influence of essential trace elements zinc, copper, iron, and selenium on anxiety symptoms based on the latest peer-reviewed scientific evidence. Current research indicates that deficiencies in zinc, iron, and selenium are associated with anxiety, while copper overload may impact anxiety to a greater degree than copper deficiency. Further investigation is needed to understand the specific neurobiological mechanisms involved. Overall, the collective findings demonstrate the importance of optimizing trace mineral homeostasis for the mitigation of anxiety disorders and preservation of mental health.

Abstract Background Naloxone is a medication that can quickly reverse an opioid overdose. Syringe service programs (SSPs) are community-based prevention programs that provide a range of evidence-based interventions in the USA, including naloxone distribution. Attributes of SSPs make them ideal settings for naloxone distribution—they have staff and delivery models that are designed to reach people who use drugs where they are. We assessed which outer and inner setting factors of SSPs were associated with naloxone distribution in the USA. Methods We surveyed SSPs in the USA known to the North American Syringe Exchange Network in 2019. Using the exploration, preparation, implementation and maintenance framework, we assessed inner and outer contextual factors associated with naloxone distribution among SSPs (n = 263 or 77% of SSPs). We utilized negative binomial regression to assess which factors were associated with the number of naloxone doses distributed and people receiving naloxone. Results SSPs reported distributing 710,232 naloxone doses to 230,506 people in the prior year. Regarding outer setting, SSPs located in areas with high levels of community support had a higher level of naloxone distribution (aIRR = 3.07; 95% confidence interval (CI): 2.09–4.51; p

Abstract Background The resurgence of HIV outbreaks and rising prevalence among people who inject drugs (PWID) remain exigent obstacles to Ending the HIV Epidemic in the USA. Adapting a low threshold, comprehensive treatment model for PWID with HIV can leverage syringe services programs (SSPs) to increase availability and accessibility of antiretrovirals (ART), medications for opioid use disorder (MOUD), and hepatitis C cure. We developed Tele-Harm Reduction, a telehealth-enhanced, harm reduction intervention delivered within an SSP venue. Methods The T-SHARP trial is an open-label, multi-site, randomized controlled superiority trial with two parallel treatment arms. Participants (n=240) recruited from SSPs in Miami, Ft. Lauderdale, and Tampa, Florida, who are PWID with uncontrolled HIV (i.e., HIV RNA>200) will be randomized to Tele-Harm Reduction or off-site linkage to HIV care. The primary objective is to compare the efficacy of Tele-Harm Reduction for initiation of ART at SSPs vs. off-site linkage to an HIV clinic with respect to viral suppression across follow-up (suppression at 3, 6, and 12 months post randomization). Participants with HIV RNA

Abstract Background Hospitalizations for severe injection drug use-related infections (SIRIs) are characterized by high costs, frequent patient-directed discharge, and high readmission rates. Beyond the health system impacts, these admissions can be traumatizing to people who inject drugs (PWID), who often receive inadequate treatment for their substance use disorders (SUD). The Jackson SIRI team was developed as an integrated infectious disease/SUD treatment intervention for patients hospitalized at a public safety-net hospital in Miami, Florida in 2020. We conducted a qualitative study to identify patient- and clinician-level perceived implementation barriers and facilitators to the SIRI team intervention. Methods Participants were patients with history of SIRIs (n = 7) and healthcare clinicians (n = 8) at one implementing hospital (Jackson Memorial Hospital). Semi-structured qualitative interviews were performed with a guide created using the Consolidated Framework for Implementation Research (CFIR). Interviews were transcribed, double coded, and categorized by study team members using CFIR constructs. Results Implementation barriers to the SIRI team intervention identified by participants included: (1) complexity of the SIRI team intervention; (2) lack of resources for PWID experiencing homelessness, financial insecurity, and uninsured status; (3) clinician-level stigma and lack of knowledge around addiction and medications for opioid use disorder (OUD); and (4) concerns about underinvestment in the intervention. Implementation facilitators of the intervention included: (1) a non-judgmental, harm reduction-oriented approach; (2) the team’s advocacy for PWID as a means of institutional culture change; (3) provision of close post-hospital follow-up that is often inaccessible for PWID; (4) strong communication with patients and their hospital physicians; and (5) addressing diverse needs such as housing, insurance, and psychological wellbeing. Conclusion Integration of infectious disease and SUD treatment is a promising approach to managing patients with SIRIs. Implementation success depends on institutional buy-in, holistic care beyond the medical domain, and an ethos rooted in harm reduction across multilevel (inner and outer) implementation contexts.

Abstract Large-scale single-cell ‘omics profiling is being used to define a complete catalogue of brain cell types, something that traditional methods struggle with due to the diversity and complexity of the brain. But this poses a problem: How do we organise such a catalogue - providing a standard way to refer to the cell types discovered, linking their classification and properties to supporting data? Cell ontologies provide a partial solution to these problems, but no existing ontology schemas support the definition of cell types by direct reference to supporting data, classification of cell types using classifications derived directly from data, or links from cell types to marker sets along with confidence scores. Here we describe a generally applicable schema that solves these problems and its application in a semi-automated pipeline to build a data-linked extension to the Cell Ontology representing cell types in the Primary Motor Cortex of humans, mice and marmosets. The methods and resulting ontology are designed to be scalable and applicable to similar whole-brain atlases currently in preparation.

Abstract Introduction A recent surge in HIV outbreaks, driven by the opioid and stimulant use crises, has destabilized our progress toward targets set forth by Ending the HIV Epidemic: A Plan for America for the high-priority community of people who inject drugs (PWID), particularly Black PWID. Methods In order to ascertain the acceptability and feasibility of using a mobile syringe services program (SSP) for comprehensive HIV prevention via PrEP and medications for opioid use disorder (MOUD), our mixed methods approach included a quantitative assessment and semi-structured qualitative interviews with Black PWID (n = 30) in Miami-Dade County who were actively engaged in mobile syringe services. Results Participants felt that delivery of MOUD and PrEP at a mobile SSP would be both feasible and acceptable, helping to address transportation, cost, and stigma barriers common within traditional healthcare settings. Participants preferred staff who are compassionate and nonjudgmental and have lived experience. Conclusions A mobile harm reduction setting could be an effective venue for delivering comprehensive HIV prevention services to Black PWID, a community that experiences significant barriers to care via marginalization and racism in a fragmented healthcare system.

Background People who inject drugs (PWID) are at an amplified vulnerability for experiencing a multitude of harms related to their substance use, including viral (e.g. HIV, Hepatitis C) and bacterial infections (e.g. endocarditis). Implementation of evidence-based interventions, such as syringe services programs (SSPs), remains imperative, particularly in locations at an increased risk of HIV outbreaks. This study aims to identify communities in Florida that are high-priority locations for SSP implementation by examining state-level data related to the substance use and overdose crises.Methods State-level surveillance data were aggregated at the ZIP Code Tabulation Area (ZCTA) (n = 983) for 2017. We used confirmed cases of acute HCV infection as a proxy of injection drug use. Least Absolute Selection and Shrinkage Operator (LASSO) regression was used to develop a machine learning model to identify significant indicators of acute HCV infection and high-priority areas for SSP implementation due to their increased vulnerability to an HIV outbreak.Results The final model retained three variables of importance: (1) the number of drug-associated skin and soft tissue infection hospitalizations, (2) the number of chronic HCV infections in people aged 18–39, and 3) the number of drug-associated endocarditis hospitalizations. High-priority SSP implementation locations were identified in both urban and rural communities outside of current Ending the HIV Epidemic counties.Conclusion SSPs are long researched, safe, and effective evidence-based programs that offer a variety of services that reduce disease transmission and assist with combating the overdose crisis. Opportunities to increase services in needed regions across the state now exist in Florida as supported by the expansion of the Infectious Disease Elimination Act of 2019. This study provides details where potential areas of concern may be and highlights regions where future evidence-based harm reduction programs, such as SSPs, would be useful to reduce opioid overdoses and disease transmission among PWID.Key messagesThe rate of acute HCV in Florida in 2017 was 1.9 per 100,000, nearly twice the national average.Serious injection related infections among PWID are significant indicators of acute HCV infection.High-priority SSP implementation locations in Florida were identified in both urban and rural communities, including those outside of current Ending the HIV Epidemic counties.

Abstract The collapse of the Maya civilization in the late 1st/early 2nd millennium CE has been attributed to multiple internal and external causes including overpopulation, increased warfare, and environmental deterioration. Yet the role hurricanes may have played in the fracturing of Maya socio-political networks, site abandonment, and cultural reconfiguration remains unexplored. Here we present a 2200 yearlong hurricane record developed from sediment recovered from a flooded cenote on the northeastern Yucatan peninsula. The sediment archive contains fine grain autogenic carbonate interspersed with anomalous deposits of coarse carbonate material that we interpret as evidence of local hurricane activity. This interpretation is supported by the correlation between the multi-decadal distribution of recent coarse beds and the temporal distribution of modern regional landfalling storms. In total, this record allows us to reconstruct the variable hurricane conditions impacting the northern lowland Maya during the Late Preclassic, Classic, and Postclassic Periods. Strikingly, persistent above-average hurricane frequency between ~ 700 and 1450 CE encompasses the Maya Terminal Classic Phase, the declines of Chichén Itza, Cobá, and subsequent rise and fall of the Mayapán Confederacy. This suggests that hurricanes may have posed an additional environmental stressor necessary of consideration when examining the Postclassic transformation of northern Maya polities.

Abstract Background Despite the proven efficacy of medications for opioid use disorder (MOUD) and recent reduction in barriers to prescribers, numerous obstacles exist for patients seeking MOUD. Prior studies have used telephone surveys to investigate pharmacy-related barriers to MOUD. We applied this methodology to evaluate inpatient and outpatient pharmacy barriers to MOUD in South Florida. Methods Randomly selected pharmacies in South Florida (Miami-Dade, Broward, and Palm Beach Counties) were called using a standardized script with a “secret shopper” approach until 200 successful surveys had been completed. The primary outcome was the availability of any buprenorphine products. Second, a list of all 48 acute care hospitals within the aforementioned counties was compiled, and hospitals were contacted by telephone using a second structured script. Results A total of 1374 outpatient pharmacies and 48 inpatient pharmacies were identified. 378 randomly selected outpatient pharmacies were contacted to accrue 200 successful calls (53% success rate). All 48 inpatient pharmacies were contacted to successfully complete 25 inpatient surveys (52%). Of the 200 outpatient pharmacies contacted, 38% had any buprenorphine available. There was a significant difference in buprenorphine availability by county, with Miami-Dade having the least availability and Palm Beach having the most availability (27% vs. 47%, respectively; p = 0.04). Of the 38% with buprenorphine available, 82% had a sufficient supply for a two-week prescription of buprenorphine 8 mg twice daily. Of the pharmacies that did not have buprenorphine, 55% would be willing to order with a median estimated time to receive an order of 2 days (IQR 1.25–3 days). Of the 25 surveyed inpatient pharmacies, 88% reported having buprenorphine on inpatient formulary, and 55% of hospitals had at least one restriction on ordering of buprenorphine beyond federal regulations. Conclusions The results of this study highlight significant pharmacy-related barriers to comprehensive OUD treatment across the healthcare system including both acute care hospital pharmacies and outpatient community pharmacies. Despite efforts to increase the number of MOUD providers, there still remain downstream obstacles to MOUD access.

IntroductionUnderstanding the reasons for the wide variation in health care spending among patients with schizophrenia may benefit the development of interventions aimed at improving patient outcomes and health care spending efficiency. The aim of our study was to determine factors associated with high health care spending in the patient population. MethodsA serial cross­sectional study used the administrative health records of residents of Alberta, Canada between 1 January 2008 and 31 December 2017 and provincial costing methodologies to calculate total health care spending and sector­specific costs. Factors that modified the odds of being a high cost (i.e. 95th percentile or higher) patient with schizophrenia were estimated using generalized estimating equations. ResultsThis study captured 242 818 person­years of observations among 38 177 unique patients with schizophrenia. Increased odds of being a high­cost patient were associated with younger age (18–29 years), male sex, unstable housing status and requiring care from multiple medical specialties. The strongest estimated associations between high cost status and comorbidity were for metastatic cancer (OR = 2.26) and cirrhosis (OR = 2.07). In contrast, polypharmacy was associated with a decreased odds of being high cost compared with untreated patients. ConclusionFactors associated with being a high­cost patient are the result of complex interactions between individual, structural and treatment­related factors. Efforts to improve patient outcomes and address rising health care costs must consider the value of allocating resources towards early detection and support of patients with schizophrenia along with the prevention/management of comorbidity.