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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.

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.

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.

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.

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.

Many factors contribute to the ability of a microbial species to persist when encountering complexly contaminated environments including time of exposure, the nature and concentration of contaminants, availability of nutritional resources, and possession of a combination of appropriate molecular mechanisms needed for survival. Herein we sought to identify genes that are most important for survival of Gram-negative Enterobacteriaceae in contaminated groundwater environments containing high concentrations of nitrate and metals using the metal-tolerant Oak Ridge Reservation (ORR) isolate, Pantoea sp. MT58 (MT58). Survival fitness experiments in which a randomly barcoded transposon insertion (RB-TnSeq) library of MT58 was exposed directly to contaminated ORR groundwater samples from across a nitrate and mixed metal contamination plume were used to identify genes important for survival with increasing exposure times and concentrations of contaminants, and availability of a carbon source. Genes involved in controlling and using carbon, encoding transcriptional regulators, and related to Gram-negative outer membrane processes were among those found to be important for survival in contaminated ORR groundwater. A comparative genomics analysis of 75 Pantoea genus strains allowed us to further separate the survival determinants into core and non-core genes in the Pantoea pangenome, revealing insights into the survival of subsurface microorganisms during contaminant plume intrusion.

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.

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.

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

IntroductionThe COVID-19 pandemic profoundly affected the health and well-being of people globally. Some studies suggest individuals with overweight or obesity may have been more adversely impacted by pandemic restrictions. Additionally, military personnel may have been more vulnerable to stress during the pandemic because of job demands (e.g., work in close quarters). Our research group was conducting a randomized clinical trial of a weight management intervention in active duty military personnel with overweight or obesity when the COVID-19 pandemic struck. Thus, we collected additional pandemic-related data from participants enrolled during the COVID-19 pandemic and conducted exploratory analyses to understand how the pandemic affected their stress levels and perceived abilities to engage in health behaviors like exercise and healthy eating. The aims of this exploratory study were to: (1) assess associations between pandemic-related stress and health behaviors with body fat percentage (BF%) and psychological and physical health, and (2) explore how pandemic-related stress and health behaviors affected BF% during and after the intervention.Materials and methodsA total of 29 active duty Navy personnel (55% female, 69% White) were enrolled after the onset of pandemic restrictions and completed measures assessing pandemic-related stress and health behaviors as well as measures of general psychological and physical health before the intervention. BF% was collected at 5 timepoints, including baseline, during, and following the intervention. Bivariate correlations assessed associations at baseline. Linearmixed-effects longitudinal models explored how pandemic-related stress and health behaviors affected BF%. Post-hoc analyses evaluated the effects of pandemic factors on BF% at each timepoint.ResultsMost participants perceived of the pandemic as increasing stress and detracting from their abilities to engage in health behaviors (i.e., exercise and healthy eating). Higher pandemic stress was significantly associated with reporting exercise and healthy eating as more difficult, worse overall health, and more anxiety and general stress. Reporting exercise as harder during the pandemic also was associated with more psychological distress at baseline. A linearmixed- effects model controlling for age, sex, and number of intervention sessions attended revealed endorsing "exercise as harder" was associated with higher BF%. Post-hoc regression analyses revealed rating "exercise as harder" significantly predicted higher BF% 3 months post-intervention (B = 0.65, P = .01), whereas pandemic stress was not significantly associated with higher BF% at 3 month (B =0.14, P = .08) or 6 month (B = 0.21, P = .09) follow-up.ConclusionsAs expected, most participants perceived of the pandemic as heightening stress and interfering with engagement in health behaviors. It is possible that pandemic-related stress may have exacerbated weight gain-promoting behaviors and/or interfered with achievement of desired weight management outcomes. Outside the context of the pandemic, it may be beneficial for healthcare providers to screen individuals for stress and perceptions of ease of engagement in health behaviors before enrollment in a weight management intervention. Further, tailoring interventions to mitigate stress and promote perceptions of ease in engaging in health behaviors may promote better weight management outcomes.

BackgroundRising overdose deaths globally and increased social isolation during the coronavirus disease 2019 (COVID-19) pandemic may have disproportionately impacted people with human immunodeficiency virus (PWH) with substance use disorders (SUD). We examined trends in SUD risk among PWH before and after the COVID-19 shelter-in-place (SIP) mandate.MethodsData were collected between 2018 and 2022 among PWH enrolled across 8 US sites in the Centers for AIDS Research Network of Integrated Clinical Systems cohort. We evaluated changes in moderate/high SUD risk after SIP using interrupted time series analyses.ResultsThere were 7126 participants, including 21 741 SUD assessments. The median age was 51 (interquartile range, 39-58) years; 12% identified as Hispanic or Latino/Latina, 46% Black/African American, and 46% White. Moderate/high SUD risk increased continuously after the pandemic's onset, with 43% (95% confidence interval [CI], 40%-46%) endorsing moderate/high SUD risk post-SIP, compared to 24% (95% CI, 22%-26%) pre-SIP (P < .001). There were increases in the use of heroin, methamphetamine, and fentanyl, and decreases in prescription opioids and sedatives post-SIP. Further, there was a decrease in reported substance use treatment post-SIP compared to pre-SIP (P = .025).ConclusionsThe rising prevalence of SUD through late 2022 could be related to an increase in isolation and reduced access to substance use and HIV treatment caused by disruptions due to COVID-19. A renewed investment in integrated substance use treatment is vital to address the combined epidemics of substance use and HIV following the COVID-19 pandemic and to support resilience in the face of future disruptions.

There is little information available on antibiotic resistance (ABR) within shrimp aquaculture environments. The aim of this study was to investigate the presence of antibiotic resistance genes (ARGs) in shrimp farming operations in Atacames, Ecuador. Water samples (n = 162) and shrimp samples (n = 54) were collected from three shrimp farming operations. Samples were cultured and a subset of isolates that grew in the presence of ceftriaxone, a third-generation cephalosporin, were analyzed using whole-genome sequencing (WGS). Among the sequenced isolates (n = 44), 73% of the isolates contained at least one ARG and the average number of ARGs per isolate was two, with a median of 3.5 ARGs. Antibiotic resistance genes that confer resistance to the β-lactam class of antibiotics were observed in 65% of the sequenced isolates from water (20/31) and 54% of the isolates from shrimp (7/13). We identified 61 different ARGs across the 44 sequenced isolates, which conferred resistance to nine antibiotic classes. Over half of all sequenced isolates (59%, n = 26) carried ARGs that confer resistance to more than one class of antibiotics. ARGs for certain antibiotic classes were more common, including beta-lactams (26 ARGs); aminoglycosides (11 ARGs); chloramphenicol (three ARGs); and trimethoprim (four ARGs). Sequenced isolates consisted of a diverse array of bacterial orders and species, including Escherichia coli (48%), Klebsiella pneumoniae (7%), Aeromonadales (7%), Pseudomonadales (16%), Enterobacter cloacae (2%), and Citrobacter freundii (2%). Many ARGs were shared across diverse species, underscoring the risk of horizontal gene transfer in these environments. This study indicated the widespread presence of extended-spectrum β-lactamase (ESBL) genes in shrimp aquaculture, including blaCTX-M, blaSHV, and blaTEM genes. Increased antibiotic resistance surveillance of shrimp farms and identification of aquaculture operation-level risk factors, such as antibiotic use, will likely be important for mitigating the spread of ARGs of clinical significance.

ObjectiveTo evaluate the feasibility and preliminary efficacy of Telehealth Behavioral Parent Training (T-BPT), a school telehealth group intervention for attention-deficit/hyperactivity disorder (ADHD) with a companion training program for school clinicians.MethodsT-BPT was developed in an iterative three-phase design in partnership with community stakeholders during the COVID-19 pandemic. School clinicians (N = 4) delivered T-BPT over 8 weeks to parents (N = 21, groups of 5-6 per school) of children (Grades 2-5) with ADHD while simultaneously receiving training and consultation from PhD-level study trainers. A single-arm open trial was used to assess feasibility, engagement, and preliminary efficacy.ResultsParents and school clinicians endorsed high feasibility, acceptability, and usability of T-BPT. Parent attendance was high (M = 94.6%) and a majority of parents (66.7%) attended all eight sessions. Preliminary outcomes indicate moderate to large reductions in parent-reported ADHD symptoms (ω2 = .36), functional and clinical global impairment (ω2s= .21 and .19, respectively), and distance learning challenges (ω2 = .22).ConclusionsResults were in line with in-person delivery, indicating promising feasibility of school telehealth BPT groups. This study also provided further support for the feasibility of the remote training model for school clinicians. Implications of the commonly endorsed barriers and benefits beyond COVID-19 and relevance to under resourced communities are also discussed.

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.

AbstractBabesiosis, caused by protozoan parasites of the genus Babesia, is an emerging tick-borne disease of significance for both human and animal health. Babesia parasites infect erythrocytes of vertebrate hosts where they develop and multiply rapidly to cause the pathological symptoms associated with the disease. The identification of new Babesia species underscores the ongoing risk of zoonotic pathogens capable of infecting humans, a concern amplified by anthropogenic activities and environmental changes. One such pathogen, Babesia MO1, previously implicated in severe cases of human babesiosis in the United States, was initially considered a subspecies of B. divergens, the predominant agent of human babesiosis in Europe. Here we report comparative multiomics analyses of B. divergens and B. MO1 that offer insight into their biology and evolution. Our analysis shows that despite their highly similar genomic sequences, substantial genetic and genomic divergence occurred throughout their evolution resulting in major differences in gene functions, expression and regulation, replication rates and susceptibility to antiparasitic drugs. Furthermore, both pathogens have evolved distinct classes of multigene families, crucial for their pathogenicity and adaptation to specific mammalian hosts. Leveraging genomic information for B. MO1, B. divergens, and other members of the Babesiidae family within Apicomplexa provides valuable insights into the evolution, diversity, and virulence of these parasites. This knowledge serves as a critical tool in preemptively addressing the emergence and rapid transmission of more virulent strains.

AbstractCompared with the general population, hematopoietic cell transplantation (HCT) survivors are at elevated risk for developing solid subsequent neoplasms (SNs). The Center for International Blood and Marrow Transplant Research (CIBMTR) is a key resource for quantifying solid SN incidence following HCT, but the completeness of SN ascertainment is uncertain. Within a cohort of 18 450 CIBMTR patients linked to the California Cancer Registry (CCR), we evaluated the completeness of solid SN data reported to the CIBMTR from 1991 to 2018 to understand the implications of using CIBMTR data alone or combined with CCR data to quantify the burden of solid SNs after HCT. We estimated the cumulative incidence of developing a solid SN, accounting for the competing risk of death. Within the cohort, solid SNs were reported among 724 patients; 15.6% of these patients had an SN reported by CIBMTR only, 36.9% by CCR only, and 47.5% by both. The corresponding cumulative incidence of developing a solid SN at 10 years following a first HCT was 4.0% (95% confidence interval [CI], 3.5-4.4) according to CIBMTR data only, 5.3% (95% CI, 4.9-5.9) according to CCR data only, and 6.3% (95% CI, 5.7-6.8) according to both sources combined. The patterns were similar for allogeneic and autologous HCT recipients. Linking detailed HCT information from CIBMTR with comprehensive SN data from cancer registries provides an opportunity to optimize SN ascertainment for informing follow-up care practices and evaluating risk factors in the growing population of HCT survivors.

Scrub typhus, a vector-borne bacterial infection, is an important but neglected disease globally. Accurately characterizing the burden is challenging because of nonspecific symptoms and limited diagnostics. Prior seroepidemiology studies have struggled to find consensus cutoffs that permit comparisons of estimates across contexts and time. In this study, we present a novel approach that does not require a cutoff and instead uses information about antibody kinetics after infection to estimate seroincidence. We use data from three cohorts of scrub typhus patients in Chiang Rai, Thailand, and Vellore, India, to characterize antibody kinetics after infection and two population serosurveys in the Kathmandu Valley, Nepal, and Tamil Nadu, India, to estimate seroincidence. The samples were tested for IgM and IgG responses to Orientia tsutsugamushi-derived recombinant 56-kDa antigen using commercial enzyme-linked immunosorbent assay kits. We used Bayesian hierarchical models to characterize antibody responses after scrub typhus infection and used the joint distributions of the peak antibody titers and decay rates to estimate population-level incidence rates in the cross-sectional serosurveys. Median responses persisted above an optical density (OD) of 1.8 for 23.6 months for IgG and an OD of 1 for 4.5 months for IgM. Among 18- to 29-year-olds, the seroincidence was 10 per 1,000 person-years (95% CI, 5-19) in Tamil Nadu, India, and 14 per 1,000 person-years (95% CI: 10-20) in the Kathmandu Valley, Nepal. When seroincidence was calculated with antibody decay ignored, the disease burden was underestimated by more than 50%. The approach can be deployed prospectively, coupled with existing serosurveys, or leverage banked samples to efficiently generate scrub typhus seroincidence estimates.

The first descriptions of "non-specific" killing of tumor cells by lymphocytes were reported in 1973, and subsequently, the mediators of the activity were named "natural killer" (NK) cells by Rolf Kiessling and colleagues at the Karolinska Institute in 1975. The activity was detected in mice, rats, and humans that had no prior exposure to the tumors, major histocompatibility complex (MHC) antigen matching of the effectors and tumor cells was not required, and the cells responsible were distinct from MHC-restricted, antigen-specific T cells. In the ensuing five decades, research by many labs has extended knowledge of NK cells beyond an in vitro curiosity to demonstrate their in vivo relevance in host defense against tumors and microbial pathogens and their role in regulation of the immune system. This brief Perspective highlights a timeline of a few selected advancements in NK cell biology from a personal perspective of being involved in this quest.

In the pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, epithelial populations in the distal lung expressing Angiotensin-converting enzyme 2 (ACE2) are infrequent, and therefore, the model of viral expansion and immune cell engagement remains incompletely understood. Using human lungs to investigate early host-viral pathogenesis, we found that SARS-CoV-2 had a rapid and specific tropism for myeloid populations. Human alveolar macrophages (AMs) reliably expressed ACE2 allowing both spike-ACE2-dependent viral entry and infection. In contrast to Influenza A virus, SARS-CoV-2 infection of AMs was productive, amplifying viral titers. While AMs generated new viruses, the interferon responses to SARS-CoV-2 were muted, hiding the viral dissemination from specific antiviral immune responses. The reliable and veiled viral depot in myeloid cells in the very early phases of SARS-CoV-2 infection of human lungs enables viral expansion in the distal lung and potentially licenses subsequent immune pathologies.

People with HIV and comorbid substance use problems may be among those who benefit most from long-acting HIV antiretroviral treatment, but they are routinely excluded from Phase 3 clinical trials. Their inclusion would permit an examination of the clinical value of long-acting therapies for people with adherence problems and an exploration of syndemic interactions between HIV, mental health conditions, and substance use problems, which compound into a major challenge in the efforts to end the HIV epidemic.

BACKGROUND: Exposure to antiretrovirals at or early after HIV acquisition can suppress viral replication and blunt antibody (Ab) responses; a reduced HIV detectability could impact diagnosis and blood donation screening. METHODS: We used three antigen (Ag)/Ab assays and one nucleic acid test (NAT) to analyze samples collected in pre-exposure prophylaxis (PrEP) trials (iPrEx; Partners PrEP) before infection detection by Ab-only rapid diagnostic tests (RDTs), and in early antiretroviral treatment (ART) initiation studies (RV254; SIPP). RESULTS: Reactivity using NAT and Ag/Ab assays in samples collected up to 8 weeks prior to the first reactive RDT from 251 PrEP trials participants varied between 49-61% for active PrEP users and between 27-37% for placebo users. Among RV254 participants, reactivity in Ag/Ab assays was

BackgroundDespite national testing guidelines, rates of testing for HIV, sexually transmitted infections, and hepatitis C remain lower than recommended for men who have sex with men (MSM) in the US. To help address this, the TakeMeHome (TMH) program was started in March 2020 by a consortium of public health organizations and dating apps - Building Healthy Online Communities - to work with health departments to increase access to HIV testing for MSM on dating apps.MethodsUsers of participating dating apps were sent messages about opportunities for testing with self-collected specimens through TMH. Program users were eligible to receive test kits if they lived in a participating zip code and were aged at least 18. Users who were interested in testing could order kits to be mailed to them for lab-based testing of HIV, hepatitis C, chlamydia, gonorrhea, and/or syphilis, depending on risk and availability in their zip code. Orders were sent via application programming interface (API) to Molecular Testing Labs (MTL) for fulfillment; kits were provided at no cost to the program user. Within approximately 24 hours of order receipt, MTL mailed program users a kit with required collection supplies, directions, and a link to a video instruction for self-collection. Program users received an automated email after testing was complete with a link to access results through their online account. Individuals with positive results on any of the relevant tests were directed to additional information and supported with linkage to additional testing or treatment, depending on local protocols.ResultsThe positivity rate of specimens processed through TMH was 1.4% for HIV, 0.6% for hepatitis C, and 2.9% for all STIs combined. The per-person positivity rate was 15.3% across all STIs.Conclusions: The TakeMeHome program demonstrates that self-collected lab-processed testing is feasible and effective at identifying new HIV and STI cases.

BackgroundHepatitis-E virus (HEV), an etiologic agent of acute inflammatory liver disease, is a significant cause of morbidity and mortality in South Asia. HEV is considered endemic in Nepal; but data on population-level infection transmission is sparse.MethodsWe conducted a longitudinal serosurvey in central Nepal to assess HEV exposure. At each visit, capillary blood samples were collected and analyzed for the presence of anti-HEV IgG antibodies. The study took place between February 2019 and April 2021, with up to 4 visits per participant approximately 6 months apart.ResultsWe collected 2513 samples from 923 participants aged 0-25 years, finding a seroprevalence of 4.8% and a seroincidence rate of 10.9 per 1000 person-years. Young adults and individuals consuming surface water faced the highest incidence of infection. Geospatial analysis identified potential HEV clusters, suggesting a need for targeted interventions.SignificanceOur findings demonstrate that HEV is endemic in Nepal and that the risk of infection increases with age.

Engineered reverse hairpin constructs containing a partial C-heptad repeat (CHR) sequence followed by a short loop and full-length N-heptad repeat (NHR) were previously shown to form trimers in solution and to be nanomolar inhibitors of HIV-1 Env mediated fusion. Their target is the in situ gp41 fusion intermediate, and they have similar potency to other previously reported NHR trimers. However, their design implies that the NHR is partially covered by CHR, which would be expected to limit potency. An exposed hydrophobic pocket in the folded structure may be sufficient to confer the observed potency, or they may exist in a partially unfolded state exposing full length NHR. Here we examined their structure by crystallography, CD and fluorescence, establishing that the proteins are folded hairpins both in crystal form and in solution. We examined unfolding in the milieu of the fusion reaction by conducting experiments in the presence of a membrane mimetic solvent and by engineering a disulfide bond into the structure to prevent partial unfolding. We further examined the role of the hydrophobic pocket, using a hairpin-small molecule adduct that occluded the pocket, as confirmed by X-ray footprinting. The results demonstrated that the NHR region nominally covered by CHR in the engineered constructs and the hydrophobic pocket region that is exposed by design were both essential for nanomolar potency and that interaction with membrane is likely to play a role in promoting the required inhibitor structure. The design concepts can be applied to other Class 1 viral fusion proteins.

ImportanceMost research to understand postacute sequelae of SARS-CoV-2 infection (PASC), or long COVID, has focused on adults, with less known about this complex condition in children. Research is needed to characterize pediatric PASC to enable studies of underlying mechanisms that will guide future treatment.ObjectiveTo identify the most common prolonged symptoms experienced by children (aged 6 to 17 years) after SARS-CoV-2 infection, how these symptoms differ by age (school-age [6-11 years] vs adolescents [12-17 years]), how they cluster into distinct phenotypes, and what symptoms in combination could be used as an empirically derived index to assist researchers to study the likely presence of PASC.Design, setting, and participantsMulticenter longitudinal observational cohort study with participants recruited from more than 60 US health care and community settings between March 2022 and December 2023, including school-age children and adolescents with and without SARS-CoV-2 infection history.ExposureSARS-CoV-2 infection.Main outcomes and measuresPASC and 89 prolonged symptoms across 9 symptom domains.ResultsA total of 898 school-age children (751 with previous SARS-CoV-2 infection [referred to as infected] and 147 without [referred to as uninfected]; mean age, 8.6 years; 49% female; 11% were Black or African American, 34% were Hispanic, Latino, or Spanish, and 60% were White) and 4469 adolescents (3109 infected and 1360 uninfected; mean age, 14.8 years; 48% female; 13% were Black or African American, 21% were Hispanic, Latino, or Spanish, and 73% were White) were included. Median time between first infection and symptom survey was 506 days for school-age children and 556 days for adolescents. In models adjusted for sex and race and ethnicity, 14 symptoms in both school-age children and adolescents were more common in those with SARS-CoV-2 infection history compared with those without infection history, with 4 additional symptoms in school-age children only and 3 in adolescents only. These symptoms affected almost every organ system. Combinations of symptoms most associated with infection history were identified to form a PASC research index for each age group; these indices correlated with poorer overall health and quality of life. The index emphasizes neurocognitive, pain, and gastrointestinal symptoms in school-age children but change or loss in smell or taste, pain, and fatigue/malaise-related symptoms in adolescents. Clustering analyses identified 4 PASC symptom phenotypes in school-age children and 3 in adolescents.Conclusions and relevanceThis study developed research indices for characterizing PASC in children and adolescents. Symptom patterns were similar but distinguishable between the 2 groups, highlighting the importance of characterizing PASC separately for these age ranges.

BackgroundSmall incentives could improve engagement in HIV care. We evaluated the short-term and longer-term effects of financial incentives for visit attendance on viral suppression among adults initiating antiretroviral therapy (ART) in Tanzania.MethodsIn a type 1 hybrid effectiveness-implementation study, we randomised (1:1) 32 primary care HIV clinics in four Tanzanian regions to usual care (control group) or the intervention (usual care plus ≤6 monthly incentives [22 500 Tanzanian Shillings, about US$10, each], conditional on visit attendance). Adults (aged ≥18 years) initiating ART (

ABSTRACT : Introduction:: Gastrointestinal (GI) parasites are major health concerns in both humans and domestic animals. Livestock farming is one of the common livelihood practices in rural Nepal. The proximity at human and domestic animal interface increases the chances of dissemination of enteric parasites, especially those of zoonotic importance. This study was aimed at finding the parasite prevalence and risk factors in both humans and their domestic animals in Jirel community. Materials and Methods:: A field survey was conducted on the Jirel ethnic people and their domestic animals in Dolakha district, where a total of 152 fresh fecal samples from humans and domestic animals (cow, pigs, goats, chickens, ducks, and pigeons) were collected. The feces were examined by wet mounts and concentration techniques. A structured questionnaire survey was carried out among the local people and owners of the domestic animals to gather sociodemographic information, awareness, and hygienic practices in relation to parasite transmission Results:: The enteric parasite prevalence was found to be highest in goats (80.0%;12/15), followed by pigs (55.55%;5/9), cows (45.45%;6/11), chickens (11.7%;4/34), and humans (1.41%;1/71), while the fecal samples of ducks and pigeons did not contain any parasites. The only parasite identified in humans was Ascaris lumbricoides. Similarly, three genera of GI parasites (Eimeria sp., Strongyloides sp, and Trichuris sp.) from goats, two genera each from cow (Eimeria sp. and Strongyloides sp.), pigs (Entamoeba sp. and A. suum), and chickens (Eimeria sp. and Ascaridia galli), were detected Conclusions:: Based on the direct field observation, questionnaire survey and laboratory analysis, it is concluded that the Jirel community people are aware of health and hygiene; however, intervention measures are necessary to prevent parasitic infection in their domestic animals.

BackgroundHIV testing rates among South African men lag behind rates for women and national targets. Community-based HIV self-screening (HIVSS) distribution and follow-up by community health workers (CHWs) is a scalable option to increase testing coverage, diagnosis, and treatment initiation. We provided HIVSS and assisted linkage to care to men not recently tested (within the past 12 months) residing in high-HIV-burden areas of Johannesburg.MethodsCHWs distributed HIVSS in 6 clinic catchment areas. Follow-up to encourage confirmatory testing and antiretroviral therapy initiation was conducted through personal support (PS) or an automated short message service (SMS) follow-up and linkage system in 3 clinic areas each. Using a quasi-experimental pre-post design, we compared differences in the proportion of men testing in the clinic catchment areas during the HIVSS campaign (June-August 2019) to the 3 months prior (March-May 2019) and compared treatment initiations by assisted linkage strategy.ResultsAmong 4793 participants accepting HIVSS, 62% had never tested. Among 3993 participants with follow-up data, 90.6% reported using their HIVSS kit. Testing coverage among men increased by 156%, from under 4% when only clinic-based HIV testing services were available to 9.5% when HIVSS and HIV testing services were available (z = -11.6; P < 0.01). Reported test use was higher for men followed through PS (99% vs. 68% in SMS); however, significantly more men reported reactive self-test results in the SMS group compared with PS (6.4% vs. 2.0%), resulting in more antiretroviral therapy initiations in the SMS group compared with PS (23 vs. 9; P < 0.01).ConclusionsCHW HIVSS distribution significantly increases testing among men. While PS enabled personalized follow-up, reporting differences indicate SMS is more acceptable and better aligned with expectations of privacy associated with HIVSS.

Science is humanity's best insurance against threats from nature, but it is a fragile enterprise that must be nourished and protected. The preponderance of scientific evidence indicates a natural origin for SARS-CoV-2. Yet, the theory that SARS-CoV-2 was engineered in and escaped from a lab dominates media attention, even in the absence of strong evidence. We discuss how the resulting anti-science movement puts the research community, scientific research, and pandemic preparedness at risk.

ObjectivePeople with HIV (PWH) are at greater risk of developing lung diseases even when they are antiretroviral therapy (ART)-adherent and virally suppressed. The most common pulmonary function abnormality in PWH is that of impaired diffusing capacity of the lungs for carbon monoxide (DL CO ), which is an independent risk factor for increased mortality in PWH. Earlier work has identified several plasma biomarkers of inflammation and immune activation to be associated with decreased DL CO . However, the underpinning molecular mechanisms of HIV-associated impaired DL CO are largely unknown.DesignCross-sectional pilot study with PWH with normal DL CO (values greater than or equal to the lower limit of normal, DL CO  ≥ LLN, N = 9) or abnormal DL CO (DL CO

Language barriers are major obstacles that Asian American immigrants face when accessing health care in the USA. This study was conducted to explore the impact of language barriers and facilitators on the health care of Asian Americans. Qualitative, in-depth interviews and quantitative surveys were conducted with 69 Asian Americans (Chinese, Filipino, Japanese, Malaysian, Indonesian, Vietnamese, and mixed Asian backgrounds) living with HIV (AALWH) in three urban areas (New York, San Francisco, and Los Angeles) in 2013 and from 2017 to 2020. The quantitative data indicate that language ability is negatively associated with stigma. Major themes emerged related to communication, including the impact of language barriers on HIV care and the positive impact of language facilitators-family members/friends, case managers, or interpreters-who can communicate with healthcare providers in the AALWH's native language. Language barriers negatively impact access to HIV-related services and thus result in decreased adherence to antiretroviral therapy, increased unmet healthcare needs, and increased HIV-related stigma. Language facilitators enhanced the connection between AALWH and the healthcare system by facilitating their engagement with health care providers. Language barriers experienced by AALWH not only impact their healthcare decisions and treatment choices but also increase levels of external stigma which may influence the process of acculturation to the host country. Language facilitators and barriers to health services for AALWH represent a target for future interventions in this population.

ObjectivesUnhealthy diets and inadequate exercise are associated with chronic health conditions and excess mortality. Older African Americans do not meet dietary and exercise guidelines, and this may have worsened during the COVID-19 pandemic due to individual and environmental factors, including food insecurity. Studies evaluating these dynamics are essential for developing interventions. This narrative details a study protocol and data collection experiences during the pandemic.MethodsParticipants > 55 years African American old completed detailed food frequency, exercise, and food access questionnaires between October 2020 and July 2021. Observations of the study administrators (authors of this manuscript) for the duration of the study are presented. Details on the study design and reflections on the opportunities, challenges, and lessons learned are summarized. Future manuscripts will report data analysis of study findings.ResultsA total of 123 older African American adults participated in the study, and 118 (70% female) completed all three questionnaires. More than 50% of the participants had at least two primary chronic conditions. About 85% were fully vaccinated against COVID-19. Applying community-based participatory approaches, leveraging partnerships, and exercising flexibility approaches were pivotal to successfully implementing the study protocol.ConclusionsDespite challenges related to the COVID-19 pandemic, detailed data on older African American adults' diet and exercise habits were obtained. Our study design and experiences will benefit future researchers. More importantly, results from our study will inform interventions and policies aimed at minimizing consequences associated with poor diet and exercise habits during the pandemic among this vulnerable population.

Across sub-Saharan Africa, men are less likely to know their HIV status than women, leading to later treatment initiation. Little is known about how experiences with general health services affect men's use of HIV testing. We used data from a 2019 community-representative survey of men in Malawi to understand frequency and cause of men's negative health service experiences (defined as men reporting they "would not recommend" a facility) and their association with future HIV testing. We conducted univariable and multivariable logistic regressions to determine which aspects of health facility visits were associated with would-not-recommend experiences and to determine if would-not-recommend experiences 12-24 months prior to the survey were associated with HIV testing in the 12 months prior to the survey. Among 1,098 men eligible for HIV testing in the 12 months prior to the survey, median age was 34 years; 9% of men reported at least one would-not-recommend experience, which did not differ by sociodemographics, gender norm beliefs, or HIV stigma beliefs. The factors most strongly associated with would-not-recommend experiences were cost (aOR 5.8, 95%CI 2.9-11.4), cleanliness (aOR 4.2, 95%CI 1.8-9.9), medicine availability (aOR 3.3, 95%CI 1.7-6.4), and wait times (aOR 2.7, 95%CI 1.5-5.0). Reporting a would-not-recommend experience 12-24 months ago was associated with a 59% decrease in likelihood of testing for HIV in the last 12 months (aOR 0.41; 95% CI:0.17-0.96). Dissatisfaction with general health services was strongly associated with reduced HIV testing. Coverage of high-priority screening services like HIV testing may benefit from improving overall health system quality.

Background and aimsSecond-generation direct-acting antivirals (2G DAA) to cure HCV have led to dramatic clinical improvements. HCV-associated hepatocellular carcinoma (HCC), however, remains common. Impaired immune tumor surveillance may play a role in HCC development. Our cohort evaluated the effects of innate immune types and clinical variables on outcomes including HCC.MethodsParticipants underwent full HLA class I/KIR typing and long-term HCV follow-up.ResultsA total of 353 HCV+ participants were followed for a mean of 7 years. Cirrhosis: 25% at baseline, developed in 12% during follow-up. 158 participants received 2G DAA therapy. HCC developed without HCV therapy in 20 subjects, 24 HCC after HCV therapy, and 10 of these after 2G DAA. Two predictors of HCC among 2G DAA-treated patients: cirrhosis (OR, 10.0, p = 0.002) and HLA/KIR profiles predicting weak natural killer (NK) cell-mediated immunity (NK cell complementation groups 6, 9, 11, 12, OR of 5.1, p = 0.02). Without 2G DAA therapy: cirrhosis was the main clinical predictor of HCC (OR, 30.8, p < 0.0001), and weak NK-cell-mediated immunity did not predict HCC.ConclusionCirrhosis is the main risk state predisposing to HCC, but weak NK-cell-mediated immunity may predispose to post-2G DAA HCC more than intermediate or strong NK-cell-mediated immunity.

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.

The obligate intracellular parasite Toxoplasma gondii causes life-threatening toxoplasmosis to immunocompromised individuals. The pathogenesis of Toxoplasma relies on its swift dissemination to the central nervous system through a 'Trojan Horse' mechanism using infected leukocytes as carriers. Previous work found TgWIP, a protein secreted from Toxoplasma, played a role in altering the actin cytoskeleton and promoting cell migration in infected dendritic cells (DCs). However, the mechanism behind these changes was unknown. Here, we report that TgWIP harbors two SH2-binding motifs that interact with tyrosine phosphatases Shp1 and Shp2, leading to phosphatase activation. DCs infected with Toxoplasma exhibited hypermigration, accompanying enhanced F-actin stress fibers and increased membrane protrusions such as filopodia and pseudopodia. By contrast, these phenotypes were abrogated in DCs infected with Toxoplasma expressing a mutant TgWIP lacking the SH2-binding motifs. We further demonstrated that the Rho-associated kinase (Rock) is involved in the induction of these phenotypes, in a TgWIP-Shp1/2 dependent manner. Collectively, the data uncover a molecular mechanism by which TgWIP modulates the migration dynamics of infected DCs in vitro.

BackgroundSocial care integration refers to the incorporation of activities into health systems that assist patients with health-related social needs (HRSNs) that negatively impact the health outcomes of their patients, such as food insecurity or homelessness. Social care integration initiatives are becoming more common. The COVID-19 pandemic strained health systems while simultaneously increasing levels of unmet social needs.ObjectiveTo describe the effects of the COVID-19 pandemic on established social care delivery in a primary care setting.DesignWe used qualitative semi-structured interviews of stakeholders to assess barriers and facilitators to social care delivery in the primary care setting during the COVID-19 health emergency. Data was analyzed using a hybrid inductive/deductive thematic analysis approach with both the Consolidated Framework for Implementation Research (CFIR) and the Screen-Navigate-Connect-Address-Evaluate model of social care integration.SettingTwo safety-net, hospital-based primary care clinics with established screening for food insecurity, homelessness, and legal needs.ParticipantsSix physicians, six nurses, six members of the social work team (clinical social workers and medical case workers), six community health workers, and six patients (total N = 30) completed interviews.ResultsFour major themes were identified. (1) A strained workforce experienced challenges confronting increased levels of HRSNs. (2) Vulnerable populations experienced a disproportionate negative impact in coping with effects of the COVID-19 pandemic on HRSNs. (3) COVID-19 protections compounded social isolation but did not extinguish the sense of community. (4) Fluctuations in the social service landscape led to variable experiences.ConclusionsThe COVID-19 pandemic disrupted established social care delivery in a primary care setting. Many of the lessons learned about challenges to social care delivery when health systems are strained are important considerations that can inform efforts to expand social care delivery.

Bacteriophage ϕ6 is a segmented dsRNA virus with a lipid envelope, which are unusual traits in bacterial viruses but common in eukaryotic viruses. This uniqueness allowed ϕ6 and its Pseudomonad hosts to serve as a molecular model for RNA genetics, mutation, replication, packaging, and reassortment in both bacterial and eukaryotic viruses. However, an additional uniqueness of ϕ6, created by its high mutation rate, was its use as an experimental system to study key questions such as the evolution of sex (segment reassortment), host-pathogen interactions, mutational load, rates of adaptation, genetic and phenotypic complexity, and game theory.

Covid-19 led to a dramatic change in the academic library work environment, with many workers shifting to a hybrid work schedule once they returned to in person work. The authors describe the impact of this schedule shift through the novel use of the socio-ecological model. The socio-ecological model looks at the impact of choices through varying circles or levels. The authors discuss the individual, interpersonal, community, and societal levels of impact that the switch to hybrid work had within their context and discuss their role as unit leaders and the decisions made to address these varying impacts.

The prevalence of "long COVID" is just one of the conundrums highlighting how little we know about the lung's response to viral infection, particularly to syndromecoronavirus-2 (SARS-CoV-2), for which the lung is the point of entry. We used an in vitro human lung system to enable a prospective, unbiased, sequential single-cell level analysis of pulmonary cell responses to infection by multiple SARS-CoV-2 strains. Starting with human induced pluripotent stem cells and emulating lung organogenesis, we generated and infected three-dimensional, multi-cell-type-containing lung organoids (LOs) and gained several unexpected insights. First, SARS-CoV-2 tropism is much broader than previously believed: Many lung cell types are infectable, if not through a canonical receptor-mediated route (e.g., via Angiotensin-converting encyme 2(ACE2)) then via a noncanonical "backdoor" route (via macropinocytosis, a form of endocytosis). Food and Drug Administration (FDA)-approved endocytosis blockers can abrogate such entry, suggesting adjunctive therapies. Regardless of the route of entry, the virus triggers a lung-autonomous, pulmonary epithelial cell-intrinsic, innate immune response involving interferons and cytokine/chemokine production in the absence of hematopoietic derivatives. The virus can spread rapidly throughout human LOs resulting in mitochondrial apoptosis mediated by the prosurvival protein Bcl-xL. This host cytopathic response to the virus may help explain persistent inflammatory signatures in a dysfunctional pulmonary environment of long COVID. The host response to the virus is, in significant part, dependent on pulmonary Surfactant Protein-B, which plays an unanticipated role in signal transduction, viral resistance, dampening of systemic inflammatory cytokine production, and minimizing apoptosis. Exogenous surfactant, in fact, can be broadly therapeutic.