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Acute intoxication with cholinesterase inhibiting organophosphates (OP) can produce life-threatening cholinergic crisis and status epilepticus (SE). Survivors often develop long-term neurological consequences, including spontaneous recurrent seizures (SRS) and impaired cognition. Numerous studies implicate OP-induced neuroinflammation as a pathogenic mechanism contributing to these chronic sequelae; however, little is known about the inflammatory phenotype of innate immune cells in the brain following acute OP intoxication. Thus, the aim of this study was to characterize the natural history of microglial and astrocytic inflammatory phenotypes following acute intoxication with the OP, diisopropylfluorophosphate (DFP). Adult male and female Sprague-Dawley rats were administered a single dose of DFP (4 mg/kg, sc) followed by standard medical countermeasures. Within minutes, animals developed benzodiazepine-resistant SE as determined by monitoring seizures using a modified Racine scale. At 1, 3, 7, 14, and 28 d post-exposure (DPE), neuroinflammation was assessed using translocator protein (TSPO) positron emission tomography (PET) and magnetic resonance imaging (MRI). In both sexes, we observed consistently elevated radiotracer uptake across all examined brain regions and time points. A separate group of animals was euthanized at these same time points to collect tissues for immunohistochemical analyses. Colocalization of IBA-1, a marker for microglia, with iNOS or Arg1 was used to identify pro- and anti-inflammatory microglia, respectively; colocalization of GFAP, a marker for astrocytes, with C3 or S100A10, pro- and anti-inflammatory astrocytes, respectively. We observed shifts in the inflammatory profiles of microglia and astrocyte populations during the first month post-intoxication, largely in hyperintense inflammatory lesions in the piriform cortex and amygdala regions. In these areas, iNOS+ proinflammatory microglial cell density peaked at 3 and 7 DPE, while anti-inflammatory Arg1+ microglia cell density peaked at 14 DPE. Pro- and anti-inflammatory astrocytes emerged within 7 DPE, and roughly equal ratios of C3+ pro-inflammatory and S100A10+ anti-inflammatory astrocytes persisted at 28 DPE. In summary, microglia and astrocytes adopted mixed inflammatory phenotypes post-OP intoxication, which evolved over one month post exposure. These activated cell populations were most prominent in the piriform and amygdala areas and were more abundant in males compared to females. The temporal relationship between microglial and astrocytic responses suggests that initial microglial activity may influence delayed, persistent astrocytic responses. Further, our findings identify putative windows for inhibition of OP-induced neuroinflammatory responses in both sexes to evaluate the therapeutic benefit of anti-inflammation in this context.

ABSTRACTJustice-impacted persons may inconsistently access HIV testing. This cross-sectional secondary analysis investigates lifetime HIV testing prevalence among adults with prior histories of incarceration in Southern California, United States, participating in health-focused programming (n = 3 studies). Self-reported demographic and lifetime HIV testing data were collected between 2017-2023; descriptive analyses were conducted. Across the three samples, at least 74% of participants were male; Latino and African American individuals accounted for nearly two-thirds of participants. Lifetime HIV testing ranged from 72.8% to 84.2%. Males were significantly more likely than females to report never being tested in two samples and accounted for >95% of those never tested. No statistically significant differences in testing were observed by race/ethnicity. Single young adults (ages 18-26) were less likely than their partnered peers to report testing. HIV testing is critical for ensuring that individuals access prevention and treatment. HIV testing among justice-impacted adults in this study was higher than in the general population, potentially due to opt-out testing in correctional settings. Nevertheless, these findings underscore the importance of implementing targeted interventions to reduce structural (e.g., health insurance, access to self-testing kits) and social barriers (e.g., HIV stigma) to increase HIV testing among justice-impacted males and single young adults.

Effector secretion is crucial for root endophytes to establish and protect their ecological niche. We used time-resolved transcriptomics to monitor effector gene expression dynamics in two closely related Sebacinales, Serendipita indica and Serendipita vermifera, during symbiosis with three plant species, competition with the phytopathogenic fungus Bipolaris sorokiniana, and cooperation with root-associated bacteria. We observed increased effector gene expression in response to biotic interactions, particularly with plants, indicating their importance in host colonization. Some effectors responded to both plants and microbes, suggesting dual roles in intermicrobial competition and plant-microbe interactions. A subset of putative antimicrobial effectors, including a GH18-CBM5 chitinase, was induced exclusively by microbes. Functional analyses of this chitinase revealed its antimicrobial and plant-protective properties. We conclude that dynamic effector gene expression underpins the ability of Sebacinales to thrive in diverse ecological niches with a single fungal chitinase contributing substantially to niche defense.

Despite established efficacy for oral pre-exposure prophylaxis (PrEP) in reducing HIV incidence, multi-level barriers within the health system, clinics, and the processes that shape practice have hindered service delivery and subsequent population-level effects. We applied the Consolidated Framework for Implementation Research (CFIR) to assess the context of PrEP delivery for adolescent girls and young women (AGYW) in rural South Africa and identify the factors supporting and impeding PrEP implementation to develop strategies to improve PrEP delivery. Between 2021 and 2022, we conducted in-depth interviews with five young women with PrEP use experience and 11 healthcare providers as well as four key informant stakeholder interviews. Tailored interviews organized around the CFIR domains provided multiple perspectives on the inter-connected processes, gaps, and opportunities between health systems, clinics, communities, and PrEP services. Shifts in PrEP policies, funding pressures, and inconsistent communications from the National Department of Health spurred fragmented planning, engagement, execution, and monitoring of PrEP delivery processes within clinics already struggling to address multiple population health needs. Resulting challenges included: conflicting priorities within clinics and across NGO partners, unclear goals and targets, staffing and space constraints, and insufficient community engagement. Individual clinics' implementation climate and readiness to deliver PrEP varied in terms of operational plans and delivery models. Interviewees reported complexity of initiation procedures and support for PrEP maintenance, with opportunities to improve systems communications and processes to facilitate integrated services and more user-friendly experiences. Applying CFIR identified opportunities to strengthen PrEP delivery across levels within this complex service delivery setting.

Mononuclear phagocytes facilitate the dissemination of the obligate intracellular parasite Toxoplasma gondii. Here, we report how a set of secreted parasite effector proteins from dense granule organelles (GRA) orchestrates dendritic cell-like chemotactic and pro-inflammatory activation of parasitized macrophages. These effects enabled efficient dissemination of the type II T. gondii lineage, a highly prevalent genotype in humans. We identify novel functions for effectors GRA15 and GRA24 in promoting CCR7-mediated macrophage chemotaxis by acting on NF-κB and p38 mitogen-activated protein kinase signaling pathways, respectively, with contributions by GRA16/18 and counter-regulation by effector TEEGR. Furthermore, GRA28 boosted chromatin accessibility and GRA15/24/NF-κB-dependent transcription at the Ccr7 gene locus in primary macrophages. In vivo, adoptively transferred macrophages infected with wild-type T. gondii outcompeted macrophages infected with a GRA15/24 double mutant in migrating to secondary organs in mice. The data show that T. gondii, rather than being passively shuttled, actively promotes its dissemination by inducing a finely regulated pro-migratory state in parasitized human and murine phagocytes via co-operating polymorphic GRA effectors.ImportanceIntracellular pathogens can hijack the cellular functions of infected host cells to their advantage, for example, for intracellular survival and dissemination. However, how microbes orchestrate the hijacking of complex cellular processes, such as host cell migration, remains poorly understood. As such, the common parasite Toxoplasma gondii actively invades the immune cells of humans and other vertebrates and modifies their migratory properties. Here, we show that the concerted action of a number of secreted effector proteins from the parasite, principally GRA15 and GRA24, acts on host cell signaling pathways to activate chemotaxis. Furthermore, the protein effector GRA28 selectively acted on chromatin accessibility in the host cell nucleus to selectively boost host gene expression. The joint activities of GRA effectors culminated in pro-migratory signaling within the infected phagocyte. We provide a molecular framework delineating how T. gondii can orchestrate a complex biological phenotype, such as the migratory activation of phagocytes to boost dissemination.

Advances in antiretroviral therapy (ART) have made it possible for persons with human immunodeficiency virus (HIV) to live a lifespan approaching that of people without HIV, without progressing to AIDS or transmitting HIV to sexual partners or infants. There is, therefore, increasing emphasis on maintaining health throughout the lifespan. To receive optimal medical care and achieve desired outcomes, persons with HIV must be consistently engaged in care and able to access uninterrupted treatment, including ART. Comprehensive evidence-based HIV primary care guidance is, therefore, more important than ever. Creating a patient-centered, stigma-free care environment is essential for care engagement. Barriers to care must be decreased at the societal, health system, clinic, and individual levels. As the population ages and noncommunicable diseases arise, providing comprehensive health care for persons with HIV becomes increasingly complex, including management of multiple comorbidities and the associated challenges of polypharmacy, while also attending to HIV-specific health concerns. Clinicians must address issues specific to preventive health, including cancer screening, providing recommended vaccinations, as well as promoting sexual health, including sexually transmitted infection diagnosis, treatment, and prevention. Clinicians also must address issues for specific populations, including persons of childbearing potential, including during preconception and pregnancy; children; adolescents; and transgender and gender-diverse individuals. This guidance from an expert panel of the HIV Medicine Association of the Infectious Diseases Society of America updates the previous 2020 HIV Primary Care Guidance.

BackgroundCOVID-19 is associated with acute risk of major adverse cardiac events (MACE), including myocardial infarction, stroke, and mortality (all-cause). However, the duration and underlying determinants of heightened risk of cardiovascular disease and MACE post-COVID-19 are not known.MethodsData from the UK Biobank was used to identify COVID-19 cases (n=10 005) who were positive for polymerase chain reaction (PCR+)-based tests for SARS-CoV-2 infection (n=8062) or received hospital-based International Classification of Diseases version-10 (ICD-10) codes for COVID-19 (n=1943) between February 1, 2020 and December 31, 2020. Population controls (n=217 730) and propensity score-matched controls (n=38 860) were also drawn from the UK Biobank during the same period. Proportional hazard models were used to evaluate COVID-19 for association with long-term (>1000 days) risk of MACE and as a coronary artery disease risk equivalent. Additional analyses examined whether COVID-19 interacted with genetic determinants to affect the risk of MACE and its components.ResultsThe risk of MACE was elevated in COVID-19 cases at all levels of severity (HR, 2.09 [95% CI, 1.94-2.25]; P

BackgroundSerology (the detection of antibodies formed by the host against an infecting pathogen) is frequently used to assess current infections and past exposure to specific pathogens. However, the presence of cross-reactivity among host antibodies in serological data makes it challenging to interpret the patterns and draw reliable conclusions about the infecting pathogen or strain.Methodology/principal findingsIn our study, we use microscopic agglutination test (MAT) serological data from three host species [California sea lion (Zalophus californianus), island fox (Urocyon littoralis), and island spotted skunk (Spilogale gracilis)] with confirmed infections to assess differences in cross-reactivity by host species and diagnostic laboratory. All host species are known to be infected with the same serovar of Leptospira interrogans. We find that absolute and relative antibody titer magnitudes vary systematically across host species and diagnostic laboratories. Despite being infected by the same Leptospira serovar, three host species exhibit different cross-reactivity profiles to a 5-serovar diagnostic panel. We also observe that the cross-reactive antibody titer against a non-infecting serovar can remain detectable after the antibody titer against the infecting serovar declines below detectable levels.Conclusions/significanceCross-reactivity in serological data makes interpretation difficult and can lead to common pitfalls. Our results show that the highest antibody titer is not a reliable indicator of infecting serovar and highlight an intriguing role of host species in shaping reactivity patterns. On the other side, seronegativity against a given serovar does not rule out that serovar as the cause of infection. We show that titer magnitudes can be influenced by both host species and diagnostic laboratory, indicating that efforts to interpret absolute titers (e.g., as indicators of recent infection) must be calibrated to the system under study. Thus, we implore scientists and health officials using serological data for surveillance to interpret the data with caution.

Women living with HIV/AIDS (WLHA) encounter numerous challenges, such as stigma and gender disparities, that hinder their access to care, especially in patriarchal societies like Vietnam. We developed a hybrid intervention with online and offline (in-person) components to empower WLHA in Vietnam. The intervention was pilot tested with 91 WLHA in Hanoi. During baseline and 4-month, study investigators delivered two in-person sessions, one Zoom session, and 15 weeks of Zalo (social media platform) discussions to enhance positive coping strategies, treatment utilization and adherence, and engagement of support from family and peers. The participants continued their Zalo discussions from 4-month to 6-month without investigators' involvement. Intervention outcomes, including active coping and perceived barriers to care, were evaluated at baseline, 4-, and 6-month surveys. Mixed-effects regression models showed that the participants' active coping significantly increased from baseline (50.5 ± 9.4) to 4-month (53.8 ± 6.2; p = 0.0001), although there was a slight decrease at 6-month (52.8 ± 7.2), the change from 4-month to 6-month was not significantly significant (p = 0.3256). There was a significant reduction in participants' perceived barriers to care, from 19.8 ± 5.2 at baseline to 17.4 ± 5.2 at 4-month (p

In the United States, immigrant Latino men who have sex with men (ILMSM) are, compared to white MSM, disproportionately burdened by HIV and lack access to highly effective HIV prevention strategies, such as pre-exposure prophylaxis (PrEP). Qualitative research centered on exploring barriers that ILMSM experience in accessing PrEP and other sexual services is extremely limited, despite a high prevalence of HIV in this population. In this study, a purposive sample of ILMSM (n = 25) was recruited to participate in a semi-structured in-depth interview to identify the distinct barriers and facilitators ILMSM experience in accessing sexual health services given their complex intersectional identities of being an immigrant, Latino, and a sexual minority man. Using a thematic analysis approach, nine themes were generated from the data representing barriers and facilitators. Barriers included: (1) cost and a lack of health insurance, (2) complexity of PrEP assistance programs; (3) challenges related to the immigrant experience; (4) impact of gay stigma; and (5) communication challenges. Facilitators included: (1) improving affordability and accessibility of PrEP services; (2) receiving services from LGBT- or Latine LGBT-centered clinics; (3) receiving services from medical providers who are gay and/or Latino; and (4) providing targeted community outreach, education, and promotion of PrEP to ILMSM. While many of the barriers illuminated in the study were structural (e.g., cost and lack of health insurance), and not easy to overcome, the findings highlight a range of facilitators that can support access to PrEP and other sexual health services for ILMSM. Considering these findings, we suggest strategies that may enhance access to needed sexual health services among ILMSM.

Key HIV cure strategies involve reversing immune dysfunction and limiting the proliferation of infected T cells. We evaluate the safety of sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, in people with HIV (PWH) and study the impact of sirolimus on HIV-1 reservoir size and HIV-1-specific immunity in a single-arm study of 20 weeks of treatment in PWH on antiretroviral therapy (ART). Sirolimus treatment does not impact HIV-1-specific CD8 T cell responses but leads to a significant decrease in CD4+ T cell-associated HIV-1 DNA levels at 20 weeks of therapy in the primary efficacy population (n = 16; 31% decline, p = 0.008). This decline persists for at least 12 weeks following cessation of the study drug. Sirolimus treatment also leads to a significant reduction in CD4+ T cell cycling and PD-1 expression on CD8+ lymphocytes. These data suggest that homeostatic proliferation of infected cells, an important mechanism for HIV persistence, is an intriguing therapeutic target.

The proteasome is a proteolytic enzyme complex essential for protein homeostasis in mammalian cells and protozoan parasites like Trichomonas vaginalis (Tv), the cause of the most common, non-viral sexually transmitted disease. Tv and other protozoan 20S proteasomes have been validated as druggable targets for antimicrobials. However, low yields and purity of the native proteasome have hindered studies of the Tv 20S proteasome (Tv20S). We address this challenge by creating a recombinant protozoan proteasome by expressing all seven α and seven β subunits of Tv20S alongside the Ump-1 chaperone in insect cells. The recombinant Tv20S displays biochemical equivalence to its native counterpart, confirmed by various assays. Notably, the marizomib (MZB) inhibits all catalytic subunits of Tv20S, while the peptide inhibitor carmaphycin-17 (CP-17) specifically targets β2 and β5. Cryo-electron microscopy (cryo-EM) unveils the structures of Tv20S bound to MZB and CP-17 at 2.8 Å. These findings explain MZB's low specificity for Tv20S compared to the human proteasome and demonstrate CP-17's higher specificity. Overall, these data provide a structure-based strategy for the development of specific Tv20S inhibitors to treat trichomoniasis.

Despite their role as innate sentinels, macrophages can serve as cellular reservoirs of chikungunya virus (CHIKV), a highly-pathogenic arthropod-borne alphavirus that has caused large outbreaks among human populations. Here, with the use of viral chimeras and evolutionary selection analysis, we define CHIKV glycoproteins E1 and E2 as critical for virion production in THP-1 derived human macrophages. Through proteomic analysis and functional validation, we further identify signal peptidase complex subunit 3 (SPCS3) and eukaryotic translation initiation factor 3 subunit K (eIF3k) as E1-binding host proteins with anti-CHIKV activities. We find that E1 residue V220, which has undergone positive selection, is indispensable for CHIKV production in macrophages, as its mutation attenuates E1 interaction with the host restriction factors SPCS3 and eIF3k. Finally, we show that the antiviral activity of eIF3k is translation-independent, and that CHIKV infection promotes eIF3k translocation from the nucleus to the cytoplasm, where it associates with SPCS3. These functions of CHIKV glycoproteins late in the viral life cycle provide a new example of an intracellular evolutionary arms race with host restriction factors, as well as potential targets for therapeutic intervention.

The Phase 3 randomized controlled trial, TBTC Study 31/ACTG A5349 (NCT02410772) demonstrated that a 4-month rifapentine-moxifloxacin regimen for drug-susceptible pulmonary tuberculosis was safe and effective. The primary efficacy outcome was 12-month tuberculosis disease free survival, while the primary safety outcome was the proportion of grade 3 or higher adverse events during the treatment period. We conducted an analysis of demographic, clinical, microbiologic, radiographic, and pharmacokinetic data and identified risk factors for unfavorable outcomes and adverse events. Among participants receiving the rifapentine-moxifloxacin regimen, low rifapentine exposure is the strongest driver of tuberculosis-related unfavorable outcomes (HR 0.65 for every 100 µg∙h/mL increase, 95%CI 0.54-0.77). The only other risk factors identified are markers of higher baseline disease severity, namely Xpert MTB/RIF cycle threshold and extent of disease on baseline chest radiography (Xpert: HR 1.43 for every 3-cycle-threshold decrease, 95%CI 1.07-1.91; extensive disease: HR 2.02, 95%CI 1.07-3.82). From these risk factors, we developed a simple risk stratification to classify disease phenotypes as easier-, moderately-harder, or harder-to-treat TB. Notably, high rifapentine exposures are not associated with any predefined adverse safety outcomes. Our results suggest that the easier-to-treat subgroup may be eligible for further treatment shortening while the harder-to-treat subgroup may need higher doses or longer treatment.

BACKGROUND: An escape room is a cooperative game that has been adapted into medical education and major academic conferences. METHODS: We describe the design, development, and implementation of an educational ID-themed escape room activity entitled Out-BREAK! at an international conference, IDWeek 2023. An anonymous survey was conducted to collect demographic data, assess participant satisfaction with the escape room puzzles, and gauge participant interest in game-based learning. RESULTS: Thirty escape room sessions were held over 3 days and included 201 participants. Escape room survey respondents (n = 132) were younger and more likely to be trainees compared with in-person IDWeek attendants. Among 131 responses, all respondents enjoyed the experience and would recommend the escape room activity to friends. Survey respondents enjoyed the puzzle solving (93%), medical content (92%), and team building (79%) components. Only 35% of the respondents had ever previously participated in game-based learning; 95% thought the escape room was a valuable teaching method. Among the 72 survey respondents involved in medical education, almost all (90%) said they were interested in incorporating escape rooms into medical education. CONCLUSIONS: The Out-BREAK! escape room at IDWeek 2023 was successfully implemented and well received. Despite only a third of participants having prior experience with game-based learning, almost all respondents perceived the escape room to be an effective teaching method.

BackgroundPoor treatment outcomes among people with drug-resistant TB (DR-TB) are a major concern. Heteroresistance (presence of susceptible and resistant Mycobacterium tuberculosis in the same sample) has been identified in some people with TB, but its impact on treatment outcomes is unknown.MethodsWe used targeted deep sequencing to identify mutations associated with DR-TB and heteroresistance in culture samples of 624 people with DR-TB. We evaluated the association between heteroresistance and time to unfavorable treatment outcome using Cox proportional hazards regression.ResultsThe proportion of drug-resistant isolates with a known mutation conferring resistance was lower for streptomycin (45.2%) and second-line injectables (79.1%) than for fluoroquinolones (86.7%), isoniazid (93.2%) and rifampin (96.5%). Fifty-two (8.3%) had heteroresistance, and it was more common for fluoroquinolones (4.6%) than rifampin (2.2%), second-line injectables (1.4%), streptomycin (1.7%), or isoniazid (1.3%). There was no association between heteroresistance and time to unfavorable outcome among people with multidrug-resistant TB (adjusted hazard ratio [aHR] 1.74, 95% CI 0.39-7.72) or pre-extensively DR-TB (aHR 0.65, 95% CI 0.24-1.72).ConclusionsHeteroresistance was relatively common (8.3%) among people with DR-TB in the Philippines. However, we found insufficient evidence to demonstrate an impact on unfavorable treatment outcomes.

We present the first described case of bacteremia due to Butyricimonas paravirosa, a commensal gram-negative anaerobic bacterium identified by whole-genome sequencing in an elderly patient with acute terminal ileitis, who was successfully treated with ceftriaxone and metronidazole. We reviewed eleven previous cases of infection due to other Butyricimonas spp, which can cause a range of diseases but may be treated conservatively with a short antimicrobial course in the appropriate clinical setting. Additionally, while most Butyricimonas spp are susceptible to empiric anaerobic therapy, drug resistance has been reported in some cases.

BackgroundBefore SARS-CoV-2 vaccination availability, medical center employees were at high risk of COVID-19. However, risk factors for SARS-CoV-2 infection in medical center employees, both healthcare and non-healthcare workers, are poorly understood.MethodsFrom September-December 2020, free IgG antibody testing was offered to all employees at a large urban medical center. Participants were asked to complete a questionnaire on work and non-work related risk factors for COVID-19 infection.ResultsSARS-CoV-2 seropositivity was found in 4.7%. Seropositivity was associated with close contact with COVID-19 cases with or without the use of adequate personal protective equipment (PPE), (OR 3.1 [95% CI 1.4-6.9] and OR 4.7 [95% CI 2.0-11.0] respectively), never wearing a mask outside of work (OR 10.1 [95% CI 1.9-57]), and Native Hawaiian/Pacific Islander race (OR 6.3 95% CI (1.6-25)].ConclusionsAmong workers in a large urban medical center, SARS-CoV-2 seropositivity was associated with work-related COVID-19 close contacts and low mask use outside of work, suggesting that non-workplace close contacts are also relevant routes of COVID-19 spread among healthcare workers.

Long COVID is a chronic and often disabling illness with long-term consequences. Although progress has been made in the clinical characterization of long COVID, no approved treatments exist and disconnects between patients and researchers threaten to hinder future progress. Incorporating patients as active collaborators in long COVID research can bridge the gap and accelerate progress toward treatments and cures.

BackgroundMany adolescent and young adult (AYA) patients with breast cancer (BC) receive adjuvant therapy as initial treatment, with long-term bone marrow suppression as a potential complication, but no studies have evaluated the impact of race/ethnicity on the development of bone marrow suppression in AYA BC survivors.Patients and methodsFemale patients ages 15-39 years diagnosed with BC (2006-2018) and surviving ≥ 2 years were identified from the California Cancer Registry and linked to statewide hospitalization data. We estimated the cumulative incidence of developing late effects of bone marrow suppression, such as leukopenia, anemia, thrombocytopenia, bleeding, and infection/sepsis, during hospital discharge diagnoses present ≥ 2 years after diagnosis. We examined the impact of sociodemographic and clinical factors on late effects using multivariate Cox proportional hazards regression.ResultsOf 11,293 patients, 42.8% were non-Hispanic (nH) White, 28.8% Hispanic, 19.5% nH Asian/Pacific Islander, and 7.5% nH Black. In multivariable analyses, nH Blacks had the highest risk (versus nH Whites) of anemia [hazard ratio (HR) 1.72, 95% confidence interval (CI) 1.47-2.02], leukopenia (HR 1.56, CI 1.14-2.13), thrombocytopenia (HR 1.46, CI 1.08-1.99), major infection/sepsis (HR 1.64, CI 1.4-1.92), and bleeding (HR 1.89, CI 1.39-2.58). Hispanics had a higher risk of developing anemia (HR 1.17, CI 1.04-1.32), bleeding (HR 1.4, CI 1.12-1.76), and major infections/sepsis (HR 1.36, CI 1.21-1.52). Asian/Pacific Islanders had only a higher risk of developing bleeding (HR 1.33, CI 1.03-1.72). Patients from a low neighborhood socioeconomic status had a 20% higher risk of infection/sepsis (HR 1.21, CI 1.1-1.34), but there were no associations for the other late effects.ConclusionsWe identified that AYAs of nH Black, Hispanic, and Asian/Pacific Islander race/ethnicity are at an increased risk of several late effects after adjuvant therapy compared with nH White patients. From these data, providers can implement early/frequent screening of hematologic late effects in these high-risk survivors.

BackgroundAlthough vaccines are largely effective and safe, there is variability in post-vaccination experience regarding antibody response, side effects, and affective outcomes. Vaccine mindsets, specific beliefs about the vaccine, may be associated with post-vaccination experience. This is important since mindsets are malleable and may help decrease vaccine hesitancy and improve post-vaccination experience.MethodsIn a prospective study, we measured overall positive vaccine mindset and specific mindsets regarding efficacy, body response, and side effects. We tested whether vaccine mindsets before vaccination predicted neutralizing antibody response, side effects, vaccine-related stress, and affective outcomes (general stress, sadness, and happiness). Antibody response was assessed one month and six months after participants completed a SARS-CoV-2 vaccination series. Side effect experience and affective reactions were assessed daily on the vaccination day and the subsequent five days.ResultsThere was no significant association between the aggregate vaccine mindset score and neutralizing antibody response; however, people with a more positive vaccine mindset reported fewer side effects, less same-day vaccine-related anxiety, and improved affective outcomes after vaccination. In secondary analyses, when specific mindsets were explored, the mindset that vaccine side effects are a sign of treatment efficacy predicted higher antibodies, but not side effects experience and vaccine-related anxiety. Vaccine efficacy and body-response mindsets predicted fewer side effects, vaccine-related anxiety, and improved affective outcomes after vaccination.ConclusionThese findings underscore the potential of vaccine mindsets in enhancing the overall post-vaccination experience and, in some cases, increasing antibody response.

Abstract: Many herbivorous insect species exhibit phenotypic plasticity when using multiple hosts, which facilitates survival in heterogeneous host environments. Physiological host acclimation is an important part of it, yet the effects of host acclimation on insect feeding behaviour are not well studied, particularly for insect vectors of plant pathogens. We studied the combined effects of host acclimation and infection with a plant pathogenic symbiont on feeding behaviour of Bactericera cockerelli, an oligophagous psyllid widespread in both crop and natural habitats that feed primarily on Solanaceae and transmit an economically important plant pathogen, Candidatus Liberibacter solanacearum (CLso). We used a factorial design and the electrical penetration graphing technique to disentangle the effects of host acclimation, CLso infection and psyllid haplotype on the within‐plant feeding behaviour of B. cockerelli during conspecific and heterospecific host switches. This approach allows to connect phenotypic plasticity with the role of B. cockerelli as a vector by quantifying the frequency and duration of behaviours involved in CLso transmission. We found significant reductions in multiple metrics of B. cockerelli feeding efficiency, exacerbated by infection with CLso, which could lead to reduced transmission of this pathogen. Psyllid genotype was also important; the Central haplotype exhibited less dramatic changes in feeding efficiency than the Western haplotype during heterospecific host switches. Our study shows that host acclimation and heterospecific host switching directly alter feeding behaviours underlying pathogen transmission, and that the magnitude of feeding efficiency reductions depends on both host genotype and infection status.

Salmonella translocate to the gut epithelium via microfold cells lining the follicle-associated epithelium (FAE). How Salmonella localize to the FAE is not well characterized. Here we use live imaging and competitive assays between wild-type and chemotaxis-deficient mutants to show that Salmonella enterica serotype Typhimurium (S. Typhimurium) localize to the FAE independently of chemotaxis in an ex vivo mouse caecum infection model. Electrical recordings revealed polarized FAE with sustained outward current and small transepithelial potential, while the surrounding villus is depolarized with inward current and large transepithelial potential. The distinct electrical potentials attracted S. Typhimurium to the FAE while Escherichia coli (E. coli) localized to the villi, through a process called galvanotaxis. Chloride flux involving the cystic fibrosis transmembrane conductance regulator (CFTR) generated the ionic currents around the FAE. Pharmacological inhibition of CFTR decreased S. Typhimurium FAE localization but increased E. coli recruitment. Altogether, our findings demonstrate that bioelectric cues contribute to S. Typhimurium targeting of specific gut epithelial locations, with potential implications for other enteric bacterial infections.

PurposeLong COVID-19 syndrome occurs in 10-20 % of people after a confirmed/probable SARS-COV-2 infection; new symptoms begin within three months of COVID-19 diagnosis and last > 8 weeks. Little is known about risk factors for long COVID, particularly in older people who are at greater risk of COVID complications.MethodsData are from Women's Health Initiative (WHI) postmenopausal women who completed COVID surveys that included questions on whether they had ever been diagnosed with COVID and length and nature of symptoms. Long COVID was classified using standard consensus criteria. Using WHI demographic and health data collected at study enrollment (1993-98) through the present day, machine learning identified the top 20 risk factors for long COVID. These variables were tested in logistic regression models.ResultsOf n = 37,280 survey respondents, 1237 (mean age = 83 years) reported a positive COVID-19 test and 425 (30 %) reported long COVID. Symptoms included an array of neurological, cardio-pulmonary, musculoskeletal, and general fatigue, and malaise symptoms. Long COVID risk factors included weight loss, physical and mobility limitations, and specific heath conditions (e.g., history of heart valve procedure, rheumatoid arthritis).ConclusionsKnowledge of risk factors for long COVID may be the first step in understanding the etiology of this complex disease.

The presence of HIV in sequestered reservoirs is a central impediment to a functional cure, allowing HIV to persist despite life-long antiretroviral therapy (ART), and driving a variety of comorbid conditions. Our understanding of the latent HIV reservoir in the central nervous system is incomplete, because of difficulties in accessing human central nervous system tissues. Microglia contribute to HIV reservoirs, but the molecular phenotype of HIV-infected microglia is poorly understood. We leveraged the unique "Last Gift" rapid autopsy program, in which people with HIV are closely followed until days or even hours before death. Microglial populations were heterogeneous regarding their gene expression profiles but showed similar chromatin accessibility landscapes. Despite ART, we detected occasional microglia containing cell-associated HIV RNA and HIV DNA integrated into open regions of the host's genome (∼0.005%). Microglia with detectable HIV RNA showed an inflammatory phenotype. These results demonstrate a distinct myeloid cell reservoir in the brains of people with HIV despite suppressive ART. Strategies for curing HIV and neurocognitive impairment will need to consider the myeloid compartment to be successful.

The COVID-19 pandemic has uniquely impacted people living with HIV (PLWH) worldwide. The negative impacts on PLWH's mental health from fear of COVID-19 are labeled as "a double stress." The association between fear of COVID-19 and HIV (internalized) stigma has been found among PLWH. Studies that explore the relationships between fear of COVID-19 and physical health outcomes are few, especially among PLWH. In this study, we explored the relationship between fear of COVID-19 and physical health among PLWH and the mediated effects of HIV stigma, social support, and substance use. A cross-sectional online survey of PLWH (n = 201) from November 2021 to May 2022 was carried out in Shanghai, China. The data on socio-demographics, fear of COVID-19, physical health, HIV-related perceived stigma, social support, and substance use were gathered and analyzed by structure equation modeling (SEM). In SEM analysis, fear of COVID-19 showed a significant and indirect effect on physical health (β=-0.085) which was primarily mediated by HIV stigma. In SEM analysis, the final model had a good fit. Fear of COVID-19 showed a significant effect on HIV stigma (β = 0.223) with the majority being direct effects (β = 0.262) and a small indirect effect via substance use (β=-0.039). Furthermore, HIV stigma showed a significant effect on physical health (β=-0.382), the majority of which was direct (β=-0.340), and a small indirect effect via social support (β=-0.042). This is one of the first studies to explore how fear of contracting COVID-19 can affect PLWH's coping behaviors (e.g., using substances and obtaining social support) used to combat HIV stigma as well as to achieve better physical health in China.

IntroductionThe COVID-19 pandemic raised significant concerns about fitness to dive due to potential damage to the pulmonary and cardiovascular systems. Our group previously published guidelines (original and revised) for assessment of these divers. Here, we report a prospective, observational study to evaluate the utility of these guidelines.MethodsRecreational, commercial, and scientific divers with a history of COVID-19 were consented and enrolled. Subjects were evaluated according to the aforementioned guidelines and followed for any additional complications or diving related injuries.ResultsOne-hundred and twelve divers (56 male, 56 female, ages 19-68) were enrolled: 59 commercial, 30 scientific, 20 recreational, two unknown (not documented), one military. Cases were categorised according to two previous guidelines ('original' n = 23 and 'revised' n = 89): category 0 (n = 6), category 0.5 (n = 64), category 1 (n = 38), category 2 (n = 2), category 3 (n = 1), uncategorisable due to persistent symptoms (n = 1). One hundred divers (89.3%) were cleared to return to diving, four (3.6%) were unable to return to diving, four (3.6%) were able to return to diving with restrictions, and four (3.6%) did not complete testing. Regarding diving related complications, one diver had an episode of immersion pulmonary oedema one year later and one diver presented with decompression sickness and tested positive for COVID-19.ConclusionsMost divers who presented for evaluation were able to return to diving safely. Abnormalities were detected in a small percentage of divers that precluded them from being cleared to dive. Guidelines were easily implemented by a variety of clinicians.

Life-threatening thrombotic events and neurological symptoms are prevalent in COVID-19 and are persistent in patients with long COVID experiencing post-acute sequelae of SARS-CoV-2 infection1-4. Despite the clinical evidence1,5-7, the underlying mechanisms of coagulopathy in COVID-19 and its consequences in inflammation and neuropathology remain poorly understood and treatment options are insufficient. Fibrinogen, the central structural component of blood clots, is abundantly deposited in the lungs and brains of patients with COVID-19, correlates with disease severity and is a predictive biomarker for post-COVID-19 cognitive deficits1,5,8-10. Here we show that fibrin binds to the SARS-CoV-2 spike protein, forming proinflammatory blood clots that drive systemic thromboinflammation and neuropathology in COVID-19. Fibrin, acting through its inflammatory domain, is required for oxidative stress and macrophage activation in the lungs, whereas it suppresses natural killer cells, after SARS-CoV-2 infection. Fibrin promotes neuroinflammation and neuronal loss after infection, as well as innate immune activation in the brain and lungs independently of active infection. A monoclonal antibody targeting the inflammatory fibrin domain provides protection from microglial activation and neuronal injury, as well as from thromboinflammation in the lung after infection. Thus, fibrin drives inflammation and neuropathology in SARS-CoV-2 infection, and fibrin-targeting immunotherapy may represent a therapeutic intervention for patients with acute COVID-19 and long COVID.

Introduction: The U.S. Child and Adult Care Food Program (CACFP) provides tiered reimbursements for healthy foods for children at participating family childcare homes (FCCH). Higher tier 1 reimbursements are for providers who operate in low-income communities or who are themselves living on a low income. All FCCHs received a higher rate to address food insecurity during the COVID-19 pandemic. Methods: A survey was administered in the spring of 2023 to a randomly selected sample of licensed California FCCHs to assess the perceived impacts of the increased reimbursement on CACFP participation and anticipated challenges with reinstated tiered rates. A total of 518 surveys (261 tier 1, 257 tier 2) were analyzed using linear or logistic regression, adjusting for confounders. Results: Among tier 1 and tier 2 providers combined, over half reported lowering out-of-pocket spending for food (59%) and serving greater variety (55%) and quality (54%) of foods. Tier 2 providers reported experiencing more benefits (p < 0.05) and tended to be more likely to implement optional CACFP best practices (although not significantly different between tiers). Most FCCH providers found reimbursement rates were inadequate before (83%) the pandemic; this amount decreased to 54% post-pandemic for tier 1 and tier 2 providers combined. Conclusions: The temporary CACFP reimbursement positively impacted the perceived quality and variety of foods served to children, especially among tier 2 providers. Increased reimbursements for all FCCHs may ensure children have access to the healthy meals and snacks provided by the CACFP.

BackgroundSince January 2020, COVID-19 has affected more than 100 million people in the U.S. Previous studies on racial and ethnic disparities related to characteristics and outcomes of COVID-19 patients have been insightful. However, appropriate epidemiologic age-standardization of the disease burden and disparities for hospitalization data are lacking.ObjectiveTo identify and describe racial and ethnic disparities for primary COVID-19 hospitalizations in the U.S. in 2020.MethodsIn this nationally representative observational study, we use the National Inpatient Sample to quantify racial and ethnic disparities in COVID-19 hospitalizations. Descriptive statistics for patient characteristics, common comorbidities, age-standardized hospitalization rates, inpatient complications, and mortality among COVID-19 hospitalizations were contrasted by race and ethnicity.ResultsThere were 1,058,815 primary COVID-19 hospitalizations in 2020. Of those, 47.2% were female, with median age of 66 (IQR, 54, 77). Overall inpatient mortality rate was 11.1%. When compared to White patients, Black, Hispanic, and Native American patients had higher age-standardized hospitalization rate ratios of 2.42 (95% CI 2.40-2.43), 2.26 (2.25-2.28), and 2.51 (2.46-2.56), respectively. Non-White patients had increased age-adjusted rates for procedures and complications. Factors associated with inpatient mortality include age, male sex, Hispanic or Native American race or ethnicity, lower income, Medicaid, heart failure, arrhythmias, coagulopathy, and chronic liver disease.ConclusionsMarginalized populations in the U.S. had over twice the COVID-19 hospitalization rate relative to White patients. Age-adjusted mortality rates were highest for Black, Hispanic, and Native American patients. Careful consideration for vulnerable populations is encouraged during highly communicable respiratory pandemics.

Immunocompromised patients are prone to recurrent Campylobacter infections. We report a case of recurrent multi-drug resistant Campylobactor jejuni bloodstream infections in a Bruton's X-linked agammaglobulinemia patient with prolonged ertapenem treatment. The isolate from the fifth recurrence developed carbapenem resistance, which is associated with mutations in a porin gene porA, and promoter changes and duplication of chromosomal blaOXA-61 gene. Combination therapy using cefepime and doxycycline (later switched to moxifloxacin) cleared the infection.

The rapid evolution of viruses generates proteins that are essential for infectivity and replication but with unknown functions, due to extreme sequence divergence1. Here, using a database of 67,715 newly predicted protein structures from 4,463 eukaryotic viral species, we found that 62% of viral proteins are structurally distinct and lack homologues in the AlphaFold database2,3. Among the remaining 38% of viral proteins, many have non-viral structural analogues that revealed surprising similarities between human pathogens and their eukaryotic hosts. Structural comparisons suggested putative functions for up to 25% of unannotated viral proteins, including those with roles in the evasion of innate immunity. In particular, RNA ligase T-like phosphodiesterases were found to resemble phage-encoded proteins that hydrolyse the host immune-activating cyclic dinucleotides 3',3'- and 2',3'-cyclic GMP-AMP (cGAMP). Experimental analysis showed that RNA ligase T homologues encoded by avian poxviruses similarly hydrolyse cGAMP, showing that RNA ligase T-mediated targeting of cGAMP is an evolutionarily conserved mechanism of immune evasion that is present in both bacteriophage and eukaryotic viruses. Together, the viral protein structural database and analyses presented here afford new opportunities to identify mechanisms of virus-host interactions that are common across the virome.

The poxvirus-derived protein vCCI (viral CC chemokine inhibitor) binds almost all members of the CC chemokine family with nanomolar affinity, inhibiting their pro-inflammatory actions. Understanding the affinity and specificity of vCCI could lead to new anti-inflammatory therapeutics. CCL17, also known as TARC, is unusual among CC chemokines by having only micromolar binding to vCCI. We have used sequence analysis and molecular simulations to determine the cause of this weak binding, which identified several locations in CCL17 where mutations seemed likely to improve binding to vCCI. Based on the aforementioned analysis, we expressed and tested multiple mutants of CCL17. We found two single point mutants V44K and Q45R that increased binding affinity to vCCI by 2-3-fold and, in combination, further improved affinity by 7-fold. The CCL17 triple mutant G17R/V44K/Q45R yielded a Kd of 0.25 ± 0.13 μM, a 68-fold improvement in affinity compared to the complex with wild-type CCL17. A quadruple mutant G17R/V44K/Q45R/R57W showed high affinity (0.59 ± 0.09 μM) compared to the wild type but lower affinity than the triple mutant. This work demonstrates that sequence comparisons and molecular simulations can predict chemokine mutations that increase the level of binding to vCCI, an important first step in developing engineered chemokine inhibitors useful for anti-inflammatory therapy.

AimsWidespread use of immune checkpoint inhibitors (ICIs) for treatment of advanced malignancies led to an increase in number of immune-related adverse events such as ICI gastrointestinal (GI) injury (ICIGI). The resulting immune dysregulation of the GI mucosa is believed to predispose patients to viral infections. We characterised the histopathological features of ICIGI and the frequency of viral infections such as cytomegalovirus (CMV), adenovirus, and Epstein-Barr virus (EBV).MethodsSingle-centre retrospective study (2011-2020).Results81 GI biopsies from 31 patients with ICIGI (65% male (20/31), 35% female (11/31)) with advanced malignancies were reviewed. Most patients received ipilimumab and nivolumab (14/31, 45%), followed by pembrolizumab (9/31, 29%), ipilimumab (4/31, 13%), nivolumab (2/31, 6%) and combination of all three medications (2/31, 6%). Average regimen prior to incidence of diarrhea was three cycles. Evidence of colitis or erythema by endoscopy was present in 77% of cases, while 23% showed normal endoscopy. Histologically, the predominant ICIGI findings were active inflammation (84%), including cryptitis (77%), crypt abscesses (65%), lymphocytic colitis-like (LCL) pattern (61%), increase in epithelial apoptosis (74%) and/or surface injury (81%). Only one case showed diffuse CMV positivity (3%) with characteristic CMV viral cytopathic effects present on H&E stain and four cases were positive for rare EBV (13%). Adenovirus infection was not identified.ConclusionWhile our cohort is small, ICIGI generally demonstrates active inflammation including cryptitis and crypt abscesses in the colon, LCL pattern, and an increase in epithelial apoptosis. Upfront immunohistochemistry for viral infection without high-degree of clinical and histologic suspicion is not recommended.

BackgroundColorectal cancer (CRC) screening is underused, particularly among low-income and minoritized populations, for whom the coronavirus disease 2019 (COVID-19) pandemic has challenged progress in achieving equity.MethodsA hub-and-spoke model was used. The hub was a nonacademic organization and the spokes were three community health center (CHC) systems overseeing numerous clinic sites. Via a cluster-randomized trial design, nine clinic sites were randomized to intervention and 16 clinic sites were randomized to usual care. Patient-level interventions included invitation letters, mailed fecal immunochemical tests (FITs), and call/text-based reminders. Year 1 intervention impact, which took place during the COVID-19 pandemic, was assessed as the proportion completing screening among individuals not up to date at baseline, which compared intervention and nonintervention clinics accounting for intraclinic cluster variation; confidence intervals (CIs) around differences not including 0 were interpreted as statistically significant.ResultsAmong 26,736 patients who met eligibility criteria, approximately 58% were female, 55% were Hispanic individuals, and 44% were Spanish speaking. The proportion completing screening was 11.5 percentage points (ppts) (95% CI, 6.1-16.9 ppts) higher in intervention versus usual care clinics. Variation in differences between intervention and usual care clinics was observed by sex (12.6 ppts [95% CI, 7.2-18.0 ppts] for females; 8.8 ppts [95% CI, 4.7-13.9 ppts] for males) and by racial and ethnic group (13.8 ppts [95% CI, 7.0-20.6 ppts] for Hispanic individuals; 13.0 ppts [95% CI, 3.6-22.4 ppts] for Asian individuals; 11.3 ppts [95% CI, 5.8-16.8 ppts] for non-Hispanic White individuals; 6.1 ppts [95% CI, 0.8-10.4 ppts] for Black individuals).ConclusionsA regional mailed FIT intervention was effective for increasing CRC screening rates across CHC systems serving diverse, low-income populations.

Human papillomavirus (HPV) is the most common sexually transmitted infection on U.S. college campuses. Although HPV vaccination is recommended through age 26, current efforts to improve vaccination rates have predominantly focused on adolescents. Consequently, vaccine uptake remains suboptimal among young adults. This represents a significant missed opportunity, as young adults face the highest risk for new HPV infections. To contextualize the factors impacting decision-making process for this vulnerable population, this study reports key themes that emerged from in-depth interviews with participants (N = 30) who had completed an online intervention study for HPV vaccination among college students. Twelve (40%) of the interviewees vaccinated after exposure to the intervention. Findings centered around empowerment among young adults as the facilitator to get the HPV vaccine: key themes emerged were (1) convenience is critical and empowering; (2) adulthood identity, marked by a heightened sense of autonomy, accountability, and responsibility for self/future self and others, is empowering; (3) equal access to health care and preventive resources is empowering, especially for participants with low socioeconomic status; and (4) accurate knowledge provided in the intervention destigmatized HPV vaccination to empower young adults to make informed decisions. Digital interventions with messages highlighting a newly gained autonomy, future-oriented self and social responsibility, inclusive and accurate knowledge, and providing navigation to improve access may enhance HPV vaccination among young adults.

Phylogenetic and discrete-trait evolutionary inference depend heavily on an appropriate characterization of the underlying character substitution process. In this paper, we present random-effects substitution models that extend common continuous-time Markov chain models into a richer class of processes capable of capturing a wider variety of substitution dynamics. As these random-effects substitution models often require many more parameters than their usual counterparts, inference can be both statistically and computationally challenging. Thus, we also propose an efficient approach to compute an approximation to the gradient of the data likelihood with respect to all unknown substitution model parameters. We demonstrate that this approximate gradient enables scaling of sampling-based inference, namely Bayesian inference via Hamiltonian Monte Carlo, under random-effects substitution models across large trees and state-spaces. Applied to a dataset of 583 SARS-CoV-2 sequences, an HKY model with random-effects shows strong signals of nonreversibility in the substitution process, and posterior predictive model checks clearly show that it is a more adequate model than a reversible model. When analyzing the pattern of phylogeographic spread of 1441 influenza A virus (H3N2) sequences between 14 regions, a random-effects phylogeographic substitution model infers that air travel volume adequately predicts almost all dispersal rates. A random-effects state-dependent substitution model reveals no evidence for an effect of arboreality on the swimming mode in the tree frog subfamily Hylinae. Simulations reveal that random-effects substitution models can accommodate both negligible and radical departures from the underlying base substitution model. We show that our gradient-based inference approach is over an order of magnitude more time efficient than conventional approaches.

Insect herbivores frequently cospeciate with symbionts that enable them to survive on nutritionally unbalanced diets. While ancient symbiont gain and loss events have been pivotal for insect diversification and feeding niche specialization, evidence of recent events is scarce. We examine the recent loss of nutritional symbionts (in as little as 1 MY) in sap-feeding Pariaconus, an endemic Hawaiian insect genus that has undergone adaptive radiation, evolving various galling and free-living ecologies on a single host-plant species, Metrosideros polymorpha within the last ∼5 MY. Using 16S rRNA sequencing, we investigated the bacterial microbiomes of 19 Pariaconus species and identified distinct symbiont profiles associated with specific host-plant ecologies. Phylogenetic analyses and metagenomic reconstructions revealed significant differences in microbial diversity and functions among psyllids with different host-plant ecologies. Within a few millions of years, Pariaconus species convergently evolved the closed-gall habit twice. This shift to enclosed galls coincided with the loss of the Morganella-like symbiont that provides the essential amino acid arginine to free-living and open-gall sister species. After the Pariaconus lineage left Kauai and colonized younger islands, both open- and closed-gall species lost the Dickeya-like symbiont. This symbiont is crucial for synthesizing essential amino acids (phenylalanine, tyrosine, and lysine) as well as B vitamins in free-living species. The recurrent loss of these symbionts in galling species reinforces evidence that galls are nutrient sinks and, combined with the rapidity of the evolutionary timeline, highlights the dynamic role of insect-symbiont relationships during the diversification of feeding ecologies. We propose new Candidatus names for the novel Morganella-like and Dickeya-like symbionts.

Infectious keratitis is a leading cause of corneal blindness worldwide with little information known about causative etiologies in Malawi, Africa. This area is resource-limited with ophthalmologist and microbiology services. The Department of Ophthalmology at the Kamuzu College of Health Sciences in Blantyre, Malawi, is a participating site of an international corneal ulcer consortium, capriCORN (Comprehensive Analysis of Pathogens, Resistomes, and Inflammatory-markers in the CORNea). In this study, 50 patients with corneal ulcers were swabbed for pathogen identification using RNA-sequencing. Corneal trauma was reported in 41% and 19% of the patients worked in agriculture. A pathogen was identified in 58% of the cases. Fungal pathogens predominated, followed by viruses and bacteria. Aspergillus, Fusarium, HSV-1, and Gardnerella were the most common pathogens detected. 50% of patients reported treatment with an antibiotic before presentation. Pathogens unusual for infectious keratitis, such as Subramaniula asteroids, Aureobasidium pullulans, and Gardnerella vaginalis, were also detected.

Hepatitis C virus (HCV), the most common blood-borne infection, disproportionately affects people experiencing homelessness (PEH); however, HCV interventions tailored for PEH are scarce. This study utilized a community-based participatory approach to assess perceptions of HCV treatment experiences among HCV-positive PEH, and homeless service providers (HSP) to develop and tailor the "I am HCV Free" intervention which integrates primary, secondary, and tertiary care to attain and maintain HCV cure. Four focus groups were conducted with PEH (N = 30, Mage = 51.76, standard deviation 11.49, range 22-69) and HSPs (n = 10) in Central City East (Skid Row) in Los Angeles, California. An iterative, thematic approach was used to ensure the trustworthiness of the data. Barriers and facilitators emerged from the data which have the potential to impact initiating HCV treatment and completion across the HCV care continuum. Understanding and addressing barriers and strengthening facilitators to HCV treatment will aid in HCV treatment completion and cure for PEH.

Mosquito-borne diseases affect hundreds of millions of people annually and disproportionately impact the developing world1,2. One mosquito species, Aedes aegypti, is a primary vector of viruses that cause dengue, yellow fever and Zika. The attraction of Ae. aegypti female mosquitos to humans requires integrating multiple cues, including CO2 from breath, organic odours from skin and visual cues, all sensed at mid and long ranges, and other cues sensed at very close range3-6. Here we identify a cue that Ae. aegypti use as part of their sensory arsenal to find humans. We demonstrate that Ae. aegypti sense the infrared (IR) radiation emanating from their targets and use this information in combination with other cues for highly effective mid-range navigation. Detection of thermal IR requires the heat-activated channel TRPA1, which is expressed in neurons at the tip of the antenna. Two opsins are co-expressed with TRPA1 in these neurons and promote the detection of lower IR intensities. We propose that radiant energy causes local heating at the end of the antenna, thereby activating temperature-sensitive receptors in thermosensory neurons. The realization that thermal IR radiation is an outstanding mid-range directional cue expands our understanding as to how mosquitoes are exquisitely effective in locating hosts.

BackgroundPublic health crises, such as the COVID-19 pandemic, have prompted a need for health agencies to improve their disease preparedness strategies, informing their communities of new information and promoting preventive behaviors to help curb the spread of the virus.MethodsWe ran unsupervised machine learning and emotion analysis, validated with manual coding, on posts of health agencies (N = 1588) and their associated public comments (N = 7813) during a crucial initial period of the COVID-19 pandemic (January 2020 to February 2021) among nine different counties with a higher proportion of vaccine-hesitant communities in Northern California. In addition, we explored differences in concerns and expressed emotions by two key group-level factors, county-level COVID-19 death rate and political party affiliation.ResultsWe consistently find that while health agencies primarily disseminated information about COVID-19 and the vaccine, they failed to address the concerns of their communities as expressed in public comment sections. Topics among public audiences focused on concerns with the COVID-19 vaccine safety and rollout, state mandates, flu vaccination, and frustration with politicians, and they expressed more positive and more negative emotions than health agencies. Further, there were several differences in primary topics and emotions expressed among public audiences by county-level COVID-19 death rate and political party affiliation.ConclusionWhile this research serves as a case study, findings indicate how local health agencies, and their audiences, discuss their perceptions and concerns regarding the COVID-19 pandemic and may inform health communication researchers and practitioners on how to prepare and manage for emerging health crises.

COVID-19 is associated with increased risk for cognitive decline but very little is known regarding the neural mechanisms of this risk. We enrolled 49 adults (55% female, mean age = 30.7 ± 8.7), 25 with and 24 without a history of COVID-19 infection. We administered standardized tests of cognitive function and acquired brain connectivity data using MRI. The COVID-19 group demonstrated significantly lower cognitive function (W = 475, p

IntroductionPeople living with HIV have high rates of hypertension. Integrated HIV and hypertension care with aligned multi-month dispensing of medications (MMD) could decrease the burden of care for individuals and health systems. We sought to describe hypertension control and evaluate its association with different durations of MMD among Malawian adults receiving integrated care with aligned dispensing of antiretroviral therapy (ART) and antihypertensive medication.MethodsWe conducted a cross-sectional survey and retrospective chart review of adults (≥18 years) receiving integrated HIV and hypertension care on medications for both conditions for at least 1 year, with aligned MMD at seven clinics in Malawi. Data were collected from July 2021 to April 2022 and included socio-demographics, clinical characteristics, antihypertensive medications and up to the three most recent blood pressure measurements. Bivariate analyses were used to characterize associations with hypertension control. Uncontrolled hypertension was defined as ≥2 measurements ≥140 and/or ≥90 mmHg. Chart reviews were conducted for a random subset of participants with uncontrolled hypertension to describe antihypertensive medication adjustments in the prior year.ResultsWe surveyed 459 adults receiving integrated care with aligned dispensing (58% female; median age 54 years). Individuals most commonly received a 3-month aligned dispensing of ART and antihypertensive medications (63%), followed by every 6 months (16%) and every 4 months (15%). Hypertension control was assessed in 359 respondents, of whom only 23% had controlled hypertension; 90% of individuals in this group reported high adherence to blood pressure medications (0-1 missed days/week). Control was more common among those with longer aligned medication dispensing intervals (20% among those with 1- to 3-month dispensing vs. 28% with 4-month dispensing vs. 40% with 6-month dispensing, p = 0.011). Chart reviews were conducted for 147 individuals with uncontrolled hypertension. Most had high self-reported adherence to blood pressure medications (89% missing 0-1 days/week); however, only 10% had their antihypertensive medication regimen changed in the prior year.ConclusionsUncontrolled hypertension was common among Malawian adults receiving integrated care with aligned MMD and was associated with shorter refill intervals and few antihypertensive medication escalations. Integrated care with aligned MMD is promising, but further work is needed to understand how to optimize hypertension outcomes.

Study objectiveMost long coronavirus disease (long COVID) studies rely on traditional surveillance methods that miss underserved populations who use emergency departments (EDs) as their primary health care source. In medically underserved ED populations, we sought to determine (1) whether there are gaps in awareness and self-declared understanding about long COVID illness, and (2) the prevalence, impact on school/work attendance, and receipt of care for long COVID symptoms.MethodsThis study was a cross-sectional, convenience sample survey study of adult patients at 11 geographically representative US EDs from December 2022 to October 2023. Awareness and self-declared understanding about long COVID illness were measured. Prevalence, impact on school/work attendance, and receipt of care for long COVID symptoms were also assessed.ResultsOf 1,618 eligible patients, 1455 (89.9%) agreed to participate, including 33.4% African Americans and 30.9% Latino/a. Of the patients, 17.1% lacked primary care. In total, 33.2% had persistent COVID-19 symptoms lasting >1 month, and 20.3% had symptoms >3 months. Moreover, 49.8% with long COVID symptoms missed work/school because of symptoms; 30.3% of all participants and 33.5% of participants who had long COVID symptoms had prior awareness and self-declared understanding of long COVID. Characteristics associated with poor understanding of long COVID were African American race (adjusted odds ratio [aOR] 3.68, 95% confidence interval [CI] 2.66 to 5.09) and Latino/a ethnicity (aOR 3.16, 95% CI 2.15 to 4.64). Participants lacking primary care were less likely to have received long COVID care (24.6% versus 51.2%; difference 26.6%; 95% CI 13.7% to 36.9%).ConclusionsDespite high prevalence and impact on school/work attendance of long COVID symptoms, most of this ED population had limited awareness and self-declared understanding of long COVID, and many had not received care. EDs should consider the development of protocols for diagnosis, education, and treatment of long COVID illness.

BackgroundIt is unknown if early COVID-19 monoclonal antibody (mAb) therapy can reduce risk of Long COVID. The mAbs amubarvimab/romlusevimab were previously demonstrated to reduce risk of hospitalization/death by 79%. This study assessed the impact of amubarvimab/romlusevimab on late outcomes, including Long COVID.MethodsNon-hospitalized high-risk adults within 10 days of COVID-19 symptom onset enrolled in a randomized, double-blind, placebo-controlled phase 2/3 trial of amubarvimab/romlusevimab for COVID-19 treatment. Late symptoms, assessed using a participant-completed symptom diary, were a pre-specified exploratory endpoint. The primary outcome for this analysis was the composite of Long COVID by participant self-report (presence of COVID-19 symptoms as recorded in the diary at week 36) or hospitalization or death by week 36. Inverse probability weighting (IPW) was used to address incomplete outcome ascertainment, giving weighted risk ratios (wRR) comparing amubarvimab/romlusevimab to placebo.FindingsParticipants received amubarvimab/romlusevimab (n = 390) or placebo (n = 390) between January and July 2021. Median age was 49 years, 52% were female, 18% Black/African American, 49% Hispanic/Latino, and 9% COVID-19-vaccinated at entry. At week 36, 103 (13%) had incomplete outcome ascertainment, and 66 (17%) on amubarvimab/romlusevimab and 92 (24%) on placebo met the primary outcome (wRR = 0.70, 95% confidence interval (CI) 0.53-0.93). The difference was driven by fewer hospitalizations/deaths with amubarvimab/romlusevimab (4%) than placebo (13%). Among 652 participants with available diary responses, 53 (16%) on amubarvimab/romlusevimab and 44 (14%) on placebo reported presence of Long COVID.InterpretationAmubarvimab/romlusevimab treatment, while highly effective in preventing hospitalizations/deaths, did not reduce risk of Long COVID. Additional interventions are needed to prevent Long COVID.FundingNational Institute of Allergy and Infectious Diseases of the National Institutes of Health. Amubarvimab and romlusevimab supplied by Brii Biosciences.

Human African trypanosomiasis, or sleeping sickness, is a neglected tropical disease caused by Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense and is invariably fatal unless treated. Current therapies present limitations in their application, parasite resistance, or require further clinical investigation for wider use. Our work, informed by previous findings, presents novel 4-[4-(4-methylpiperazin-1-yl)phenyl]-6-arylpyrimidine derivatives with promising antitrypanosomal activity. In particular, 32 exhibits an in vitro EC50 value of 0.5 µM against Trypanosoma brucei rhodesiense, and analogues 29, 30 and 33 show antitrypanosomal activities in the

Candida parapsilosis is known to cause severe and persistent outbreaks in clinical settings. Patients infected with multidrug-resistant C. parapsilosis (MDR Cp) isolates were identified in a large Turkish hospital from 2017-2020. We subsequently identified three additional patients infected with MDR Cp isolates in 2022 from the same hospital and two echinocandin-resistant (ECR) isolates from a single patient in another hospital. The increasing number of MDR and ECR isolates contradicts the general principle that the severe fitness cost associated with these phenotypes could prevent their dominance in clinical settings. Here, we employed a multidimensional approach to systematically assess the fitness costs of MDR and ECR C. parapsilosis isolates. Whole-genome sequencing revealed a novel MDR genotype infecting two patients in 2022. Despite severe in vitro defects, the levels and tolerances of the biofilms of our ECR and MDR isolates were generally comparable to those of susceptible wild-type isolates. Surprisingly, the MDR and ECR isolates showed major alterations in their cell wall components, and some of the MDR isolates consistently displayed increased tolerance to the fungicidal activities of primary human neutrophils and were more immunoevasive during exposure to primary human macrophages. Our systemic infection mouse model showed that MDR and ECR C. parapsilosis isolates had comparable fungal burden in most organs relative to susceptible isolates. Overall, we observed a notable increase in the genotypic diversity and frequency of MDR isolates and identified MDR and ECR isolates potentially capable of causing persistent outbreaks in the future.

Infectious diseases exploit niches that are often spatially defined as urban and/or rural. Yet spatial research on infectious diseases often fails to define "urban" and "rural" and how these contexts might influence their epidemiology. We use dengue fever, thought to be mostly an urban disease with rural foci, as a device to explore local definitions of urban and rural spaces and the impact of these spaces on dengue risk in the provinfine urban and rural locales. Interviews conducted from 2019 to 2021 with 71 residents and 23 health personce of Esmeraldas, Ecuador. Ecuador, like many countries, only uses population size and administrative function to denel found that they identified the availability of basic services, extent of their control over their environment, and presence of underbrush and weeds (known in Ecuador as monte and maleza and conceptualized in this paper as natural disorder) as important links to their conceptions of space and dengue risk. This broader conceptualization of space articulated by local residents and professionals reflects a more sophisticated approach to characterizing dengue risk than using categories of urban and rural employed by the national census and government. Rather than this dichotomous category of space, dengue fever can be better framed for health interventions in terms of specific environmental features and assemblages of high-risk spaces. An understanding of how community members perceive risk enhances our ability to collaborate with them to develop optimal mitigation strategies.