Enhancing Protocols for Concussion Management in Professional Soccer Events.

AIM: Every year, there are an estimated 1.7 to 3.8 million sports-related traumatic brain injuries. A sports concussion results from an external force or a blow to the head or body, causing cranial encephalic trauma that can affect motor skills and brain function, producing varying symptoms related to an alteration in neurological functioning. Soccer poses a risk of concussions due to heading, where the player's head directly hits the ball to redirect or accelerate it. However, most concussions are caused by contact between players, such as head-to-head or head-to-elbow contact. This study analyzed the incidence of concussions or mild traumatic brain injuries in professional soccer during the "Copa America 2019" to understand the feasibility of soccer concussion protocols and propose evidence-based enhancements. METHODS: The data were previously collected by our first two authors, O. Pangrazio and F. Forriol, during the 46th edition of the "Copa America 2019," where the South American Football Confederation implemented the Concussion Fast Recognition Protocol to detect traumatic brain injuries. The descriptive basic data will help to raise awareness and motivate further research in this field. We have analyzed and correlated it with global data to provide a comprehensive review and tangible evidence of the population size where soccer protocols are typically applied, thus calculating incidence rates to measure it mathematically. RESULTS: Our study reveals that the incidence rate of concussions during the "Copa America 2019" was 5.3 per 1,000 athlete exposures, with a total of three concussions occurring among 567 players. Despite the effectiveness of current protocols in detecting concussions rapidly and accurately, the relatively low incidence rate at this level of professional competition poses a challenge to validating these protocols. These results indicate that while the protocols in place are efficient, the testing and validation of new tools and approaches would be more beneficial at different levels of play where the incidence rates of concussions are higher. In environments with a greater frequency of concussions, the robustness and reliability of these protocols can be more thoroughly evaluated, ensuring they provide optimal protection and care for athletes. CONCLUSION: The incidence of concussions is low in professional soccer tournaments. Protocols are necessary to protect players and educate sports professionals. However, their validation is difficult given the low incidence of concussions at this level of competition. Our proposed protocol helps unify a basic approach in the field and an advanced approach in any emergency department, providing better detection of concussions and improved outcomes for players. This protocol should be validated in populations with higher incidence rates to demonstrate its effectiveness.

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

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

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

Ocean weather, biological rates, and unexplained global ecological patterns.

As on land, oceans exhibit high temporal and spatial temperature variation. This "ocean weather" contributes to the physiological and ecological processes that ultimately determine the patterns of species distribution and abundance, yet is often unrecognized, especially in tropical oceans. Here, we tested the paradigm of temperature stability in shallow waters (<12.5 m) across different zones of latitude. We collated hundreds of in situ, high temporal-frequency ocean temperature time series globally to produce an intuitive measure of temperature variability, ranging in scale from quarter-diurnal to annual time spans. To estimate organismal sensitivity of ectotherms (i.e. microbes, algae, and animals whose body temperatures depend upon ocean temperature), we computed the corresponding range of biological rates (such as metabolic rate or photosynthesis) for each time span, assuming an exponential relationship. We found that subtropical regions had the broadest temperature ranges at time spans equal to or shorter than a month, while temperate and tropical systems both exhibited narrow (i.e. stable) short-term temperature range estimates. However, temperature-dependent biological rates in tropical regions displayed greater ranges than in temperate systems. Hence, our results suggest that tropical ectotherms may be relatively more sensitive to short-term thermal variability. We also highlight previously unexplained macroecological patterns that may be underpinned by short-term temperature variability.

The Education Crisis and the Allied Role of School-Based Mental Health Care.

The COVID-19 pandemic has had a profound impact on educational services, leading the World Bank, UNESCO, and UNICEF to jointly declare the "worst educational crisis on record."1 In the United States, standardized testing revealed large declines in reading and mathematics.1 Disadvantaged students have been disproportionately affected as the achievement gap widened for students from historically marginalized and low-income backgrounds.1 Experts predict a culminative exacerbation of these learning losses in the years ahead.1.

Rational protein engineering to enhance MHC-independent T cell receptors.

Chimeric antigen receptor (CAR)-based therapies have pioneered synthetic cellular immunity but remain limited in their long-term efficacy. Emerging data suggest that dysregulated CAR-driven T cell activation causes T cell dysfunction and therapeutic failure. To re-engage the precision of the endogenous T cell response, we designed MHC-independent T cell receptors (miTCRs) by linking antibody variable domains to TCR constant chains. Using predictive modeling, we observed that this standard "cut and paste" approach to synthetic protein design resulted in myriad biochemical conflicts at the hybrid variable-constant domain interface. Through iterative modeling and sequence modifications we developed structure-enhanced miTCRs which significantly improved receptor-driven T cell function across multiple tumor models. We found that 41BB costimulation specifically prolonged miTCR T cell persistence and enabled improved leukemic control in vivo compared to classic CAR T cells. Collectively, we have identified core features of hybrid receptor structure responsible for regulating function.

Navigating phenylketonuria management to improve it in Latin America: a systematic literature review and applicability analysis.

Introduction: Phenylketonuria (PKU) is an autosomal recessive metabolic disorder resulting from phenylalanine hydroxylase deficiency, which impacts neurodevelopment. Lifelong low-phenylalanine diets and multidisciplinary care are pivotal for managing PKU. Latin American challenges in PKU care include diverse newborn screening programs, limited specialized healthcare, and resource scarcity. Methods: A systematic literature review was conducted (2010-2023) on PKU management following PRISMA guidelines. Inclusion criteria encompassed English/Spanish articles focusing on PKU management guidelines approved by an organization as well as articles focusing on PKU management in Latin America. After screening 127,276 results, 6 articles were included. Results: Six articles were analyzed, highlighting shared principles like multidisciplinary care, lifelong dietary adherence, personalized plans, and regular monitoring. Guides emphasized regional variations, breastfeeding complexities, and challenges for pregnant women with PKU. Discussion: Multidisciplinary care emerges as critical, incorporating physicians, psychologists, dietitians, nurses, and genetic counselors. Lifelong adherence to low-phenylalanine diets and personalized strategies for different life stages are emphasized. Challenges in Latin America include healthcare gaps, scarce resources, and reliance on international guidance. The importance of breastfeeding, preconception care, and comprehensive support for pregnant women with PKU is underscored. Conclusion: Collaborative efforts are essential to address PKU challenges in Latin America. Advocacy for awareness, specialized training, regional databases, and international collaborations can enhance diagnosis and management, ensuring a better quality of life for PKU individuals in the region. Embracing lessons from existing guides will contribute to improved PKU care and overall well-being.

Single-frame transmission and phase imaging using off-axis holography with undetected photons.

Imaging with undetected photons relies upon nonlinear interferometry to extract the spatial image from an infrared probe beam and reveal it in the interference pattern of an easier-to-detect visible beam. Typically, the transmission and phase images are extracted using phase-shifting techniques and combining interferograms from multiple frames. Here we show that off-axis digital holography enables reconstruction of both transmission and phase images at the infrared wavelength from a single interferogram, and hence a single frame, recorded in the visible. This eliminates the need for phase stepping and multiple acquisitions, thereby greatly reducing total measurement time for imaging with long acquisition times at low flux or enabling video-rate imaging at higher flux. With this single-frame acquisition technique, we are able to reconstruct transmission images of an object in the infrared beam with a signal-to-noise ratio of 3.680 ± 0.004 at 10 frames per second, and record a dynamic scene in the infrared beam at 33 frames per second.

Direct measurements of neurosteroid binding to specific sites on GABAA receptors.

BACKGROUND AND PURPOSE: Neurosteroids are allosteric modulators of GABAA currents, acting through several functional binding sites although their affinity and specificity for each site are unknown. The goal of this study was to measure steady-state binding affinities of various neurosteroids for specific sites on the GABAA receptor. EXPERIMENTAL APPROACH: Two methods were developed to measure neurosteroid binding affinity: (1) quenching of specific tryptophan residues in neurosteroid binding sites by the neurosteroid 17-methylketone group, and (2) FRET between MQ290 (an intrinsically fluorescent neurosteroid) and tryptophan residues in the binding sites. The assays were developed using ELIC-α1GABAAR, a chimeric receptor containing transmembrane domains of the α1-GABAA receptor. Tryptophan mutagenesis was used to identify specific interactions. KEY RESULTS: Allopregnanolone (3α-OH neurosteroid) was shown to bind at intersubunit and intrasubunit sites with equal affinity, whereas epi-allopregnanolone (3ß-OH neurosteroid) binds at the intrasubunit site. MQ290 formed a strong FRET pair with W246, acting as a site-specific probe for the intersubunit site. The affinity and site-specificity of several neurosteroid agonists and inverse agonists was measured using the MQ290 binding assay. The FRET assay distinguishes between competitive and allosteric inhibition of MQ290 binding and demonstrated an allosteric interaction between the two neurosteroid binding sites. CONCLUSIONS AND IMPLICATIONS: The affinity and specificity of neurosteroid binding to two sites in the ELIC-α1GABAAR were directly measured and an allosteric interaction between the sites was revealed. Adaptation of the MQ290 FRET assay to a plate-reader format will enable screening for high affinity agonists and antagonists for neurosteroid binding sites.

Tuning the Size of TiO2-Supported Co Nanoparticle Fischer-Tropsch Catalysts Using Mn Additions.

Modifying traditional Co/TiO2-based Fischer-Tropsch (FT) catalysts with Mn promoters induces a selectivity shift from long-chain paraffins toward commercially desirable alcohols and olefins. In this work, we use in situ gas cell scanning transmission electron microscopy (STEM) with energy-dispersive X-ray spectroscopy (EDS) elemental mapping, and near-ambient pressure X-ray photoelectron spectroscopy (NAP-XPS) to demonstrate how the elemental dispersion and chemical structure of the as-calcined materials evolve during the H2 activation heat treatment required for industrial CoMn/TiO2 FT catalysts. We find that Mn additions reduce both the mean Co particle diameter and the size distribution but that the Mn remains dispersed on the support after the activation step. Density functional theory calculations show that the slower surface diffusion of Mn is likely due to the lower number of energetically accessible sites for the Mn on the titania support and that favorable Co-Mn interactions likely cause greater dispersion and slower sintering of Co in the Mn-promoted catalyst. These mechanistic insights into how the introduction of Mn tunes the Co nanoparticle size can be applied to inform the design of future-supported nanoparticle catalysts for FT and other heterogeneous catalytic processes.

Health Care Discrimination and Care Avoidance Due to Patient-Clinician Identity Discordance Among Sexual and Gender Minority Adults.

Sexual and gender minority (SGM) adults experience poor health outcomes, in part due to frequent avoidance of necessary health care. Little is known, however, about factors contributing to patterns of health care utilization in this population. Using national data from the All of Us Research Program, this study evaluated the prevalence of care avoidance due to patient-clinician identity discordance (PCID) and its association with health care discrimination among SGM adults. Sexual minority (20.0% vs 9.4%; adjusted rate ratio [aRR] = 1.58; 95% CI, 1.49-1.67, P <0.001) and gender minority adults (34.4% vs 10.3%; aRR = 2.00; 95% CI, 1.79-2.21, P <0.001) were significantly more likely than their non-SGM counterparts to report care avoidance due to PCID. Exposure to health care discrimination was also more prevalent in this population and was dose-dependently associated with significantly higher rates of PCID-based care avoidance. Study findings highlight the importance of diversifying the health care workforce, expanding SGM-related clinical training, and preventing health care discrimination against SGM patients.

Interventions for Improving HIV Care Continuum Outcomes Among LGBTQ+ Youth in the United States: A Narrative Review.

Lesbian, gay, bisexual, transgender, queer, and all sexually and gender diverse (LGBTQ+) youth with HIV face multiple barriers to progression along the HIV care continuum. We searched PubMed, PsycInfo, clinicaltrials.gov, and the Adolescent Medicine Trials Network for HIV/AIDS Interventions for interventions focused on improving linkage to care, retention in care, adherence to antiretroviral therapy, or viral suppression (VS) among LGBTQ+ youth with HIV in the United States. Included studies were published in English between January 1, 2017 and December 31, 2022, took place in the United States, and had samples with a minimum age of 12 years, a median or mean age of 24 years or less, and with ≥50% reporting an LGBTQ+ identity. Our search identified 11 interventions that met our criteria, of which only three were designed and tailored exclusively for LGBTQ+ populations. Interventions used a variety of modalities, including remote electronic delivery, in-person delivery, or both. Interventions most commonly aimed to enhance self-efficacy, HIV health knowledge, and medication self-management to facilitate improvements in HIV care continuum outcomes. Only two interventions showed statistically significant improvements in VS. More interventions tailored for LGBTQ+ youth are needed to end the HIV epidemic in the United States.

Immunometabolic Blood Biomarkers of Developmental Trajectories of Depressive Symptoms: Findings From the ALSPAC Birth Cohort.

Studies of longitudinal trends of depressive symptoms in young people could provide insight into aetiologic mechanism, heterogeneity and origin of common cardiometabolic comorbidities for depression. Depression is associated with immunological and metabolic alterations, but immunometabolic characteristics of developmental trajectories of depressive symptoms remain unclear. Using depressive symptoms scores measured on 10 occasions between ages 10 and 25 years in the Avon Longitudinal Study of Parents and Children (n=7302), we identified four distinct trajectories: low-stable (70% of the sample), adolescent-limited (13%), adulthood-onset (10%) and adolescent-persistent (7%). We examined associations of these trajectories with: i) anthropometric, cardiometabolic and psychiatric phenotypes using multivariable regression (n=1709-3410); ii) 67 blood immunological proteins and 57 metabolomic features using empirical Bayes moderated linear models (n=2059 and n=2240 respectively); and iii) 28 blood cell counts and biochemical measures using multivariable regression (n=2256). Relative to the low-stable group, risk of depression and anxiety in adulthood was higher for all other groups, especially in the adolescent-persistent (ORdepression=22.80, 95% CI 15.25-34.37; ORGAD=19.32, 95% CI 12.86-29.22) and adulthood-onset (ORdepression=7.68, 95% CI 5.31-11.17; ORGAD=5.39, 95% CI 3.65-7.94) groups. The three depression-related trajectories vary in their immunometabolic profile, with evidence of little or no alterations in the adolescent-limited group. The adulthood-onset group shows widespread classical immunometabolic changes (e.g., increased immune cell counts and insulin resistance), while the adolescent-persistent group is characterised by higher BMI both in childhood and adulthood with few other immunometabolic changes. These findings point to distinct mechanisms and intervention opportunities for adverse cardiometabolic profile in different groups of young people with depression.

Persistent enrichment of multidrug-resistant Klebsiella in oral and nasal communities during long-term starvation.

BACKGROUND: The human oral and nasal cavities can act as reservoirs for opportunistic pathogens capable of causing acute infection. These microbes asymptomatically colonize the human oral and nasal cavities which facilitates transmission within human populations via the environment, and they routinely possess clinically significant antibiotic resistance genes. Among these opportunistic pathogens, the Klebsiella genus stands out as a notable example, with its members frequently linked to nosocomial infections and multidrug resistance. As with many colonizing opportunistic pathogens, the essential transmission factors influencing the spread of Klebsiella species among both healthy and diseased individuals remain unclear. RESULTS: Here, we explored a possible explanation by investigating the ability of oral and nasal Klebsiella species to outcompete their native microbial community members under in vitro starvation conditions, which could be analogous to external hospital environments or the microenvironment of mechanical ventilators. When K. pneumoniae and K. aerogenes were present within a healthy human oral or nasal sample, the bacterial community composition shifted dramatically under starvation conditions and typically became enriched in Klebsiella species. Furthermore, introducing K. pneumoniae exogenously into a native microbial community lacking K. pneumoniae, even at low inoculum, led to repeated enrichment under starvation. Precise monitoring of K. pneumoniae within these communities undergoing starvation indicated rapid initial growth and prolonged viability compared to other members of the microbiome. K. pneumoniae strains isolated from healthy individuals' oral and nasal cavities also exhibited resistance to multiple classes of antibiotics and were genetically similar to clinical and gut isolates. In addition, we found that in the absence of Klebsiella species, other understudied opportunistic pathogens, such as Peptostreptococcus, increased in relative abundance under starvation conditions. CONCLUSIONS: Our findings establish an environmental and microbiome community circumstance that allows for the enrichment of Klebsiella species and other opportunistic pathogens. Klebsiella's enrichment may hinge on its ability to quickly outgrow other members of the microbiome. The ability to outcompete other commensal bacteria and to persist under harsh environmental conditions could be an important factor that contributes to enhanced transmission in both commensal and pathogenic contexts. Video Abstract.

Partial wrapping of single-stranded DNA by replication protein A and modulation through phosphorylation.

Single-stranded DNA (ssDNA) intermediates which emerge during DNA metabolic processes are shielded by replication protein A (RPA). RPA binds to ssDNA and acts as a gatekeeper to direct the ssDNA towards downstream DNA metabolic pathways with exceptional specificity. Understanding the mechanistic basis for such RPA-dependent functional specificity requires knowledge of the structural conformation of ssDNA when RPA-bound. Previous studies suggested a stretching of ssDNA by RPA. However, structural investigations uncovered a partial wrapping of ssDNA around RPA. Therefore, to reconcile the models, in this study, we measured the end-to-end distances of free ssDNA and RPA-ssDNA complexes using single-molecule FRET and double electron-electron resonance (DEER) spectroscopy and found only a small systematic increase in the end-to-end distance of ssDNA upon RPA binding. This change does not align with a linear stretching model but rather supports partial wrapping of ssDNA around the contour of DNA binding domains of RPA. Furthermore, we reveal how phosphorylation at the key Ser-384 site in the RPA70 subunit provides access to the wrapped ssDNA by remodeling the DNA-binding domains. These findings establish a precise structural model for RPA-bound ssDNA, providing valuable insights into how RPA facilitates the remodeling of ssDNA for subsequent downstream processes.

Nanosized Chevrel phases for dendrite-free zinc-ion based energy storage: unraveling the phase transformations.

The nanoscale form of the Chevrel phase, Mo6S8, is demonstrated to be a highly efficient zinc-free anode in aqueous zinc ion hybrid supercapacitors (ZIHSCs). The unique morphological characteristics of the material when its dimensions approach the nanoscale result in fast zinc intercalation kinetics that surpass the ion transport rate reported for some of the most promising materials, such as TiS2 and TiSe2. In situ Raman spectroscopy, post-mortem X-ray diffraction, Hard X-ray photoelectron spectroscopy, and density functional theory (DFT) calculations were combined to understand the overall mechanism of the zinc ion (de)intercalation process. The previously unknown formation of the sulfur-deficient Zn2.9Mo15S19 (Zn1.6Mo6S7.6) phase is identified, leading to a re-evaluation of the mechanism of the (de)intercalation process. A full cell comprised of an activated carbon (YEC-8A) positive electrode delivers a cell capacity of 38 mA h g-1 and an energy density of 43.8 W h kg-1 at a specific current density of 0.2 A g-1. The excellent cycling stability of the device is demonstrated for up to 8000 cycles at 3 A g-1 with a coulombic efficiency close to 100%. Post-mortem microscopic studies reveal the absence of dendrite formation at the nanosized Mo6S8 anode, in stark contrast to the state-of-the-art zinc electrode.

Nutritional perspectives in female soccer: a scoping review.

BACKGROUND: The purpose of the review was to evaluate the literature exploring nutritional habits and practices in female soccer players. METHODS: The PRISMA-ScR Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews were followed. Searches of Web of Science, PubMed and Scopus databases were conducted for studies exploring the nutritional habits and practices of female soccer players. RESULTS: A total of 72 studies were included in the scoping review. Studies on female soccer players mainly focused on daily energy expenditure, daily energy and macronutrient intake and hydration status. A negative energy balance was consistent across studies, and the ingestion of CHO appears below the current recommendations. Female soccer players are predominately in negative energy balance, which may indicate that they are at risk of low energy availability. A high use of nutritional supplements is apparent in female soccer, whilst a large proportion of players commence training dehydrated. CONCLUSIONS: The current findings have implications for practitioners relating to the planning, management, monitoring, and implementation of nutritional intake and training and competition schedules.

COVID-19: Medical education from the point of view of medical students using the participatory Delphi method.

BACKGROUND: The COVID-19 pandemic has prompted a transformation of medical training. Although there were obvious medical education and social interaction challenges, e-learning presented some advantages, which may have generated medical curricula innovation and adjustments to novel technological methodologies. This study aims to generate consensuses among medical students regarding medical education provided during the pandemic in the resource-limited context of a Global South university. METHODS: The implementation of a participatory Delphi method included a recruitment campaign, training, constitution of Delphi panels and questions, and development of the Delphi exercises. Students from the second to the sixth year of medicine of a university in Quito, Ecuador, constituted two Delphi panels, developed questions about the education received during the pandemic, and answered them over 3.5 rounds. FINDINGS: Twenty-two medical students participated in the Delphi exercises about their perception of medical education during the COVID-19 pandemic. The analysis consisted of a total of 22 Delphi questions divided into five distinct categories: adaptations and innovations, curriculum and assessment changes, virtual clinical practice, time management, and mental health. The authors established high, medium, and low consensuses for analysis. CONCLUSIONS: Consensuses were reached based on students' academic year and focused on the changes in lecture delivery, the usage of new technologies, patient care skills, the impact of the educational routine, and the mental health of the COVID-19 pandemic. The way the pandemic affected medical education in the Global South set the stage for the need for a comprehensive review of tools, skills, and curricula for students from culturally diverse backgrounds. This study offers a highly replicable methodology to generate consensuses and introduce students to academic research.

Identification of kinase inhibitors as potential host-directed therapies for intracellular bacteria.

The emergence of antimicrobial resistance has created an urgent need for alternative treatments against bacterial pathogens. Here, we investigated kinase inhibitors as potential host-directed therapies (HDTs) against intracellular bacteria, specifically Salmonella Typhimurium (Stm) and Mycobacterium tuberculosis (Mtb). We screened 827 ATP-competitive kinase inhibitors with known target profiles from two Published Kinase Inhibitor Sets (PKIS1 and PKIS2) using intracellular infection models for Stm and Mtb, based on human cell lines and primary macrophages. Additionally, the in vivo safety and efficacy of the compounds were assessed using zebrafish embryo infection models. Our screen identified 11 hit compounds for Stm and 17 hit compounds for Mtb that were effective against intracellular bacteria and non-toxic for host cells. Further experiments were conducted to prioritize Stm hit compounds that were able to clear the intracellular infection in primary human macrophages. From these, two structurally related Stm hit compounds, GSK1379738A and GSK1379760A, exhibited significant activity against Stm in infected zebrafish embryos. In addition, we identified compounds that were active against intracellular Mtb, including morpholino-imidazo/triazolo-pyrimidinones that target PIK3CB, as well as 2-aminobenzimidazoles targeting ABL1. Overall, this study provided insights into kinase targets acting at the host-pathogen interface and identified several kinase inhibitors as potential HDTs.

Exploration of weekly variation in naloxone possession and carriage among people who use opioids in New York City before, during, and after the COVID-19 pandemic.

BACKGROUND: Naloxone is critical for reversing opioid-related overdoses. However, there is a dearth of research examining how naloxone possession and carriage are impacted by time-varying individual and social determinants, and if this differed during the height of the COVID-related mitigation measures (e.g., shutdowns). METHODS: We utilized weekly ecological momentary assessments (EMA) to measure factors associated with naloxone possession and carriage among 40 people who use illicit opioids in New York City, for 24 months. Descriptive statistics were used to explore the frequency of weeks with consistent naloxone possession and carriage. Mixed effects binary and multivariable logistic regression was used to test for the impact of time-varying EMA- and baseline-level factors on each outcome. RESULTS: Approximately 70% of weekly EMAs were associated with consistent naloxone possession or carriage. In multivariable models, compared to during the height of the COVID-related shutdowns (March 12, 2020-May 19, 2021), the time before was associated with lower odds of consistent possession (Odds Ratio (OR) = 0.05, 95% Confidence Interval (CI) = 0.01-0.15) and consistent carriage (OR = 0.06, CI = 0.01-0.25). Additionally, being female (OR = 11.15, CI = 2.85-43.42), being White versus being Black or Hispanic/Latinx (OR = 8.05, CI = 1.96-33.06), and lifetime overdose (OR = 1.96, CI = 1.16-19.80) were associated with higher odds of consistent possession. Recent opioid injection (OR = 3.66, CI = 1.34-9.94), being female (OR = 7.91, CI = 3.91-8.23), and being White (OR = 5.77, CI = 1.35-24.55) were associated with higher odds of consistent carriage. Not wanting to be perceived as a drug user was reported in nearly one third (29.0%; 190/656) of EMAs where inconsistent possession was reported. CONCLUSIONS: Our findings paint a relatively positive picture of possession and carriage during COVID-related shutdowns, particularly among white and female participants, and highlight the importance of capturing time-varying factors to understand naloxone-related behavior. To curb growing disparities, outreach to equip Black and Hispanic/Latinx people with naloxone is needed as well as interventions to reduce stigma as a barrier to naloxone engagement.

Barriers to, and Facilitators of, Checking Drugs for Adulterants in the Era of Fentanyl and Xylazine: Qualitative Study.

BACKGROUND: Overdose deaths continue to reach new records in New York City and nationwide, largely driven by adulterants such as fentanyl and xylazine in the illicit drug supply. Unknowingly consuming adulterated substances dramatically increases risks of overdose and other health problems, especially when individuals consume multiple adulterants and are exposed to a combination of drugs they did not intend to take. Although test strips and more sophisticated devices enable people to check drugs for adulterants including fentanyl and xylazine prior to consumption and are often available free of charge, many people who use drugs decline to use them. OBJECTIVE: We sought to better understand why people in the New York City area do or do not check drugs before use. We plan to use study findings to inform the development of technology-based interventions to encourage consistent drug checking. METHODS: In summer 2023, team members who have experience working with people who use drugs conducted 22 semistructured qualitative interviews with a convenience sample of people who reported illicit drug use within the past 90 days. An interview guide examined participants' knowledge of and experience with adulterants including fentanyl, xylazine, and benzodiazepines; using drug testing strips; and whether they had ever received harm reduction services. All interviews were audio recorded, transcribed, and analyzed for emerging themes. RESULTS: Most participants lacked knowledge of adulterants, and only a few reported regularly checking drugs. Reasons for not checking included lacking convenient access to test supplies, or a place to check samples out of the public's view, as well as time considerations. Some participants also reported a strong belief that they were not at risk from fentanyl, xylazine, or other adulterants because they exclusively used cocaine or crack, or that they were confident the people they bought drugs from would not sell them adulterated substances. Those who did report testing their drugs described positive interactions with harm reduction agency staff. CONCLUSIONS: New forms of outreach are needed not only to increase people's knowledge of adulterated substances and awareness of the increasing risks they pose but also to encourage people who use drugs to regularly check their substances prior to use. This includes new intervention messages that highlight the importance of drug checking in the context of a rapidly changing and volatile drug supply. This messaging can potentially help normalize drug checking as an easily enacted behavior that benefits public health. To increase effectiveness, messages can be developed with, and outreach can be conducted by, trusted community members including people who use drugs and, potentially, people who sell drugs. Pairing this messaging with access to no-cost drug-checking supplies and equipment may help address the ongoing spiral of increased overdose deaths nationwide.