Hepatitis B virus (HBV) infection disproportionately affects people with HIV (PWH) due to shared transmission routes. Data from the 1990s-2010s showed that 5-10% of PWH had chronic HBV in the United States. In the past decade, broader use of HBV-active and inactive antiretroviral therapy (ART), improved HBV vaccinations, and increasing intravenous drug use (IDU) may have changed the landscape of HBV infection in PWH and people without HIV (PWoH), but this has not been well studied. This study aimed to describe the prevalence of HIV/HBV coinfection among participants enrolled across 13 U.S. MACS/WIHS Combined Cohort Study (MWCCS) clinical research sites. Between 11/2020 and 3/2024, participants underwent serologic testing for HBV. We defined a positive result for HBsAg (surface antigen) as a current infection; negative HBsAg and positive anti-HBV core antibody (anti-HBc) as past infection; and both negative HBsAg and anti-HBc as never infection. We used the Chi-squared or Fisher’s exact test to compare categorical variables and the Kruskal-Wallis test for continuous variables among three HBV serogroups.Figure 1:Age group distribution of all participants stratified by Hepatitis B (HBV) serologic status Among 2130 participants, HIV seropositivity was associated with higher rates of current (PWH 3.1% vs. PWoH 1.7%) and prior HBV infection (PWH 28% vs. PWoH 23%, P=0.006) (Table 1). Current HBV infection was more common in men (3.9% in males and 1.7% in females) and those in the 40-59 age group (3.8% in the 40-49 age group and 2.8% in the 50-59 group) (Figure 1). Prior HBV infection was associated with higher rates of substance use, especially injection drug use, and having been infected with hepatitis C (Table 1B). Among PWH, current HBV infection was more common in men than women (4.7% vs. 1.7%, Table 2A). HIV suppression, CD4 count and nadir, and HBV-active ART use were similar among PWH across HBV categories (Table 2B). In PWH who never had HBV infection, 39% did not have immunity against HBV. The prevalence of HIV/HBV coinfection in this selected group of the MWCCS cohort is 3.1%, lower than previously reported in the 1990s-2010s. Male participants in the age group of 40-59 years are at higher risk for current HBV infection. Our study also highlights the need to screen for HBV immunity in people who never had HBV but are at risk for HBV infection. Jennifer C. Price, MD, PhD, AbbVie: Grant/Research Support|Gilead: Grant/Research Support|VIR: Grant/Research Support Maria L. Alcaide, MD, Gilead: Advisor/Consultant Valentina Stosor, MD, American Physician Institute: Honoraria|CDC: Grant/Research Support Bernard JC Macatangay, MD, Merck: Grant/Research Support

Background:This study aimed to examine the prevalence of hepatitis B virus (HBV) in people with HIV (PWH) undergoing contemporary antiretroviral therapy and people without HIV and to understand the risk factors in people with HIV/HBV coinfection. This retrospective cross-sectional study included 5238 participants with HIV or at risk for HIV acquisition across 13 US sites in the MACS/WIHS Combined Cohort Study (Multicenter AIDS Cohort Study / Women Interagency HIV Study) between January 2018 and December 2024. Methods:The primary outcome was the prevalence of HBV infection and HIV/HBV coinfection. We defined a positive HBsAg (surface antigen) as chronic HBV infection, a negative HBsAg and positive anti-HBV core antibody as recovered infection, and a negative HBsAg and negative anti-HBV core antibody as never infection. The prevalence of chronic and recovered HBV infection was described in different risk groups. Results:In this cohort, the overall prevalence of chronic HBV was 2.4%, and HIV/HBV coinfection was 3.0% among PWH. Current and prior HBV infection was more common in men, and the prevalence of prior HBV increased with age. As compared with the other 2 groups, PWH with chronic HBV infection had lower CD4+ T-cell counts (567 vs 651 and 689 cells/µL), CD4+ T-cell nadirs (210 vs 245 and 258 cells/µL), and HIV viral suppression rate (71.7% vs 82.3% and 83.7%). Among PWH who never had HBV infection, 40.6% lacked seroprotection against HBV. Conclusions:HBV is still prevalent in PWH. HBV coinfection was associated with lower CD4+ T-cell counts and viral suppression rate in PWH. The low seroprotection rate in those without HBV underscores the need for improved screening and immunization.

OBJECTIVE:To investigate SARS-CoV-2 viral shedding duration in autoimmune patients using B cell depleting (BCD) therapy or tumor necrosis factor inhibitors (TNFi) and immunocompetent comparators. METHODS:We conducted a matched cohort analysis among participants in POSITIVES, a prospective study enrolling outpatients with acute COVID-19 within five days of diagnosis. Anterior nasal swabs were self-collected thrice weekly over two weeks and then weekly until two negative polymerase chain reaction (PCR) results. We compared autoimmune cases on BCD or TNFi at baseline with immunocompetent comparators, matched using a propensity score based on age, sex, race and ethnicity, number of COVID-19 vaccinations, calendar time, and antiviral use. Survival methods with Cox proportional hazards modeling was used to compare the time to undetectable PCR. RESULTS:We enrolled 16 BCD users and 30 TNFi users, each matched to 33 and 53 immunocompetent comparators, respectively. The most common autoimmune disease was rheumatoid arthritis (31% among BCD and 53% among TNFi). About 60% used an antiviral, and the mean number of COVID-19 vaccinations was 4.3. At the time of infection, BCD users had significantly longer viral shedding duration than comparators (median 15 vs 7 days; hazard ratio [HR] 0.43, 95% confidence interval [CI] 0.22-0.86; P = 0.017). The median time to undetectable viral load was similar between TNFi users and comparators (10 vs 8 days; HR 0.77, 95% CI 0.48-1.23; P = 0.27). CONCLUSION:BCD users had eight days longer viral shedding duration than immunocompetent comparators; TNFi users and comparators had similar viral shedding duration. These findings inform clinical and public health strategies for autoimmune patients with COVID-19.

Lenacapavir (LEN) is a novel long-acting injectable antiretroviral therapy (ART) drug for heavily treatment-experienced (HTE) people with HIV (PWH). However, real-world data on its use and outcomes are limited. We describe early real-world experience with LEN among HTE PWH across five clinics in Chicago, IL and Pittsburgh, PA. We conducted a multi-center retrospective cohort study of HTE PWH who started LEN from November 13, 2020, through April 4, 2025. Demographic and clinical characteristics were collected, including previous ART regimens, HIV drug resistance mutations, HIV viral loads (VL), and self-reported adherence to optimized background regimen (OBR) after starting LEN. Forty-six individuals received at least one dose of LEN; most were cisgender men (61%), Black (72%), and had stable housing (87%) (Table 1). At initiation, their mean age was 52 years and on average had been living with HIV for 25 years. Extensive drug resistance was common: 34 had resistance to ≥2 NRTIs, 34 to ≥2 NNRTIs, 13 to ≥2 PIs, and 21 to ≥2 INSTIs; four showed resistance across all four drug classes. Among 23 individuals with viremia at LEN initiation (VL ≥200 c/mL), 91% achieved viral suppression during the observed period, with 70% doing so within the first 3 months (Figures 1 and 2). Two individuals remained unsuppressed after LEN due to self-reported OBR non-adherence. All individuals without viremia at initiation maintained viral suppression throughout follow-up. Before LEN, 30% had a genotypic susceptibility score indicating their regimen had fewer than two fully active agents; after initiation, all had regimens with at least two active agents (Table 2). Nearly all individuals (91%) remained on LEN through the observation period; median time on LEN was 373 days (IQR 123–576). Discontinuations (n=4) were due to OBR non-adherence, injection site reaction, hospice entry, or loss to follow-up. In this real-world cohort, LEN-based regimens resulted in high rates of virologic suppression among HTE PWH. Our findings support LEN as a promising salvage therapy when paired with an active OBR. As LEN use expands, targeted implementation strategies will be critical to address adherence challenges, manage side effects, and optimize sustained treatment success for HTE populations. Aniruddha Hazra, MD, Abbott Laboratories: Advisor/Consultant|Gilead Sciences, Inc: Advisor/Consultant|Gilead Sciences, Inc: Grant/Research Support|GSK/ViiV Healthcare: Advisor/Consultant

Background:Lenacapavir (LEN), a first-in-class long-acting human immunodeficiency virus type 1 (HIV-1) capsid inhibitor, has demonstrated potent antiviral activity in heavily treatment-experienced (HTE) people with HIV (PWH) in clinical trials, but real-world data remain limited. We describe outcomes from 6 US HIV clinics using LEN-based regimens in a largely HTE cohort of PWH to assess virologic response, regimen potency, and tolerability. Methods:We conducted a multicenter retrospective cohort study of adults with HIV who initiated LEN between November 2020 and June 2025 at 6 clinics in Chicago, Illinois and Pittsburgh, Pennsylvania. Demographic, clinical, and genotypic data were abstracted from electronic health records. Virologic suppression was defined as HIV viral load <200 copies/mL. Stanford genotypic susceptibility scores (S-GSS) were calculated to assess regimen potency. Wilcoxon signed-rank tests compared antiretroviral therapy pill burden and regimen potency before and after LEN initiation. Results:Seventy PWH initiated LEN. Median follow-up was 12 months. At baseline, 18 (26%) PWH with available genotypes had multidrug-resistant HIV, and 54% had unsuppressed virus. Among 38 PWH with unsuppressed virus, 34 (89%) achieved viral suppression, and none of the PWH with suppressed HIV experienced rebound. LEN significantly improved regimen potency (P < .00005) and reduced daily pill burden from 2 tablets to 1 tablet (P < .00005). Injection site reactions occurred in 30% and led to discontinuation in 1 person. Conclusions:In this real-world cohort, LEN-based regimens achieved high rates of virologic suppression, improved regimen activity, and reduced pill burden with good tolerability. LEN represents a promising salvage therapy for PWH, warranting equitable and implementation-focused integration into HIV care.

Background:Nirmatrelvir-ritonavir (N-R) reduces morbidity and mortality from COVID-19 in high-risk individuals; however, N-R use has been associated with risk of SARS-CoV-2 virologic rebound. The mechanisms contributing to virologic rebound after N-R treatment are currently unknown. One plausible mechanism is that antiviral treatment may alter the development of immune responses to SARS-CoV-2 infection, thereby contributing to rebound after cessation of therapy. Methods:We profiled immune responses in a case-ascertained, longitudinal, prospective cohort of ambulatory individuals with COVID-19. Participants were grouped according to whether virological rebound occurred and whether they had received N-R treatment. We assessed antibody, T-cell, and innate responses. Results:We observed no differences in the binding or neutralizing antibody, T-cell, and innate immune responses between participants with virologic rebound compared to participants without virologic rebound. N-R use was associated with slightly weaker antibody responses overall, even after adjustment for immunosuppression. Conclusion:Virologic rebound after N-R treatment is likely driven by non-immune mechanisms. Funding:The project was supported by the National Institutes of Health (R01 AI 138801) and the Massachusetts Consortium on Pathogen Readiness. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.

Little is known about serological responses to MVA-BN (JYNNEOS) against mpox in elderly individuals with or without HIV. In this study, MVA-BN induced sustained IgG levels regardless of HIV status even up to one year. Birth before 1973 correlated with higher IgG. MVA-BN unvaccinated individuals with HIV had lower IgG than vaccinated.

In the ever-evolving arena of molecular biology, epigenetic modifications stand out as crucial determinants in the orchestration of cellular identity, function, and fate. This review analyzes the close relationship between epigenetics and tumor immunity, emphasizing the intricate interplay with the tumor microenvironment (TME). Rooted in the knowledge that the incidence of cancer correlates strongly with the biological and genetic age, we highlight DNA methylation as a cornerstone of the "epigenetic aging" process with close ties to tumorigenesis. The TME, with its diverse cellular and acellular constituents, is an active participant in tumor biology, further complicated by epigenetic alterations. These modifications, from DNA methylation to histone changes, not only shape the TME but are reciprocally influenced by it, reinforcing a cycle that propels malignancy. Through this exploration, we underline the importance of understanding this mutual relationship, as it holds significant implications for tumor growth, heterogeneity, and therapeutic resistance. Ultimately, this review illuminates the potential of harnessing epigenetic insights for innovative cancer therapeutic strategies, pointing towards a promising avenue for future cancer management.

Adolescent anxiety symptoms are a global concern, and studying their trends and influencing factors in China is essential due to unique cultural and social dynamics impacting mental health. This study presents a cross-temporal meta-analysis of research employing the GAD-7 to assess anxiety symptoms among Chinese adolescents. Systematic searches were conducted across databases including CNKI, Wanfang, VIP, Web of Science, PubMed, Scopus, ProQuest, and Wiley, resulting in the inclusion of 66 articles (67 studies) spanning data collection from 2016 to 2023. The findings revealed that: (1) Anxiety symptoms among Chinese adolescents showed a slight decrease from 2016 to 2020, which was not statistically significant, but then experienced a significant increase from 2021 to 2023. (2) Throughout the period, female adolescents had significantly higher increases in anxiety symptoms compared to males. Clinically anxious adolescents had a slightly more pronounced decline in anxiety symptoms from 2016 to 2020 compared to those with subclinical anxiety, but this difference was not significant from 2021 to 2023. (3) Social change factors including social connectedness, socioeconomic conditions, and social threats did not significantly impact adolescent anxiety symptoms in China from 2016 to 2020, and this pattern continued from 2021 to 2023. This research advances the understanding of the mechanisms driving adolescent anxiety symptoms in China and offers a foundation for targeted prevention and intervention strategies, emphasizing the importance of addressing emerging stressors in mental health policies.

Little is known about the serologic response elicited by the Modified Vaccinia Ankara-Bavarian Nordic (MVA-BN) vaccination (JYNNEOS) against mpox in elderly individuals with or without HIV. In this study, we measured levels of antibody against orthopoxvirus in selected participants (n = 114) with HIV or at risk for HIV acquisition from the Multicenter AIDS Cohort Study/Women's Interagency HIV Study Combined Cohort Study, who had no prior reported history of mpox. Participants reported MVA-BN vaccination history via questionnaires. The median age was 64 years, 24.6% were female, and 46% were HIV seropositive. Twenty out of 114 participants received at least 1 dose of MVA-BN. We found that MVA-BN induced sustained IgG levels regardless of HIV status, even up to 1 year. Birth before 1973 was correlated with higher IgG. MVA-BN-unvaccinated individuals with HIV had lower IgG than those without HIV. Although limited by small sample size, our study is among the first to assess anti-orthopoxvirus antibodies specifically in a vulnerable, older population and stratified by HIV status.

Antibiotic misuse has escalated globally, posing significant threats to public health. This rampant misuse not only fuels antibiotic resistance but also triggers the formation of anti-antibiotic antibodies, which may cause severe complications such as immune-mediated hemolytic anemia and compromise therapeutic efficacy. This review provides an in-depth analysis of this critical issue, evaluating both theoretical and clinical evidence regarding the emergence of these antibodies and elucidating their impact on clinical pharmacotherapy and severe complications, particularly in immune-mediated hemolytic anemia. Additionally, it underscores the growing challenge of antibiotic resistance and the pressing necessity for effective strategies to address this global health crisis.

Adipose tissue inflammation contributes to obesity-induced insulin resistance. However, increasing evidence shows that high BMI (obesity) is not an accurate predictor of poor metabolic health in individuals. The molecular mechanisms regulating the metabolically activated M1 macrophage phenotype in the adipose tissues leading to insulin resistance remain largely unknown. Although the Janus Kinase (Jak)/signal transducer and activator of transcription 3 (Stat3) signaling in myeloid cells are known to promote the M2 phenotype in tumors, we demonstrate here that the Jak2/Stat3 pathway amplifies M1-mediated adipose tissue inflammation and insulin resistance under metabolic challenges. Ablating Jak2 in the myeloid compartment reduces insulin resistance in obese mice, which is associated with a decrease in infiltration of adipose tissue macrophages (ATMs). We show that the adoptive transfer of Jak2-deficient myeloid cells improves insulin sensitivity in obese mice. Furthermore, the protection of obese mice with myeloid-specific Stat3 deficiency against insulin resistance is also associated with reduced tissue infiltration by macrophages. Jak2/Stat3 in the macrophage is required for the production of pro-inflammatory cytokines that promote M1 macrophage polarization in the adipose tissues of obese mice. Moreover, free fatty acids (FFAs) activate Stat3 in macrophages, leading to the induction of M1 cytokines. Silencing the myeloid cell Stat3 with an in vivo siRNA targeted delivery approach reduces metabolically activated pro-inflammatory ATMs, thereby alleviating obesity-induced insulin resistance. These results demonstrate Jak2/Stat3 in myeloid cells is required for obesity-induced insulin resistance and inflammation. Moreover, targeting Stat3 in myeloid cells may be a novel approach to ameliorate obesity-induced insulin resistance.

BACKGROUND:HIV-1 infection is associated with accelerated aging. The senescence-associated secretory phenotype (SASP) includes biological and cytokine profiles that induce cellular senescence and inflammaging. In this study, we leveraged the Multicenter AIDS Cohort Study (MACS) to evaluate the role of SASP in aging, HIV-1 reservoir, and inflammation in people with HIV-1 (PWH) on long-term suppressive antiretroviral therapy (ART). METHODS:In this retrospective study, we included plasma and serum samples from 27 virally suppressed PWH and 10 people without HIV-1 (PWoH) collected in 2019 and 2023. SASP markers were quantified in the 2019 and 2023 samples. Plasma residual viremia, intact and defective proviral DNA were quantified in the 2019 samples. Correlations between SASP markers and HIV-1 reservoir were performed using the Spearman test, and the sparse partial least squares discrimination analysis was used to identify variables that distinguish HIV-1 serostatus. RESULTS:All study participants were male with a median age of 59 years. SASP markers did not show significant changes longitudinally in either group. We identified a set of markers that had moderate performance in distinguishing PWH and PWoH, including cytomegalovirus (CMV) serum antibody titer, matrix metalloproteinase 9 (MMP-9), growth/differentiation factor-15, Stanniocalcin-1 and SerpinE1. Among all the SASP markers, MMP-9 was significantly associated with intact HIV-1 proviral levels [ ρ  = 0.60, P  = 0.002, false detection rate (FDR) = 0.03]. CONCLUSION:In this cohort study, we revealed the relationship between SASP markers and HIV-1 persistence. Future interventions targeting the senescence pathways may impact HIV-1 persistence.

BACKGROUND:Perinatal depression is a major global public health problem, but the onset and progression of symptoms that give rise to perinatal depression are less clear in the scientific literature. METHODS:This study followed 1210 Chinese pregnant women who completed the Edinburgh Postnatal Depression Scale at five time points: 13, 24, and 37 weeks of gestation (G13, G24, G37), and 1 and 6 weeks postpartum (W1, W6). Cross-lagged panel networks were used to analyze and compare networks from first to second trimester (G13 → G24), second to third trimester (G24 → G37), and one week to six weeks postpartum (W1 → W6). RESULTS:Results showed that network structure did not differ significantly between the three networks, demonstrating continuity of depressive symptoms over the course of pregnancy and postpartum. Across the three periods, self-reported panic was identified as the symptom that had the largest influence on other symptoms at a following assessment, and self-reported worry was the symptom that was most strongly influenced by depressive symptoms at previous timepoints. Moreover, thoughts of self-harm showed a distinct feature where it could only trigger other symptoms in the postnatal, but not prenatal period. LIMITATIONS:Self-reported questionnaires used in this study may be susceptible to bias. Items of perinatal depressive symptoms included in the network analysis are also not exhaustive. CONCLUSIONS:Findings from this symptom-oriented psychopathology network shed light upon the developmental course of perinatal depressive symptoms, providing insights for tailored preventative intervention programs.

BACKGROUNDSARS-CoV-2 has evolved subvariants since the emergence of the Omicron variant in 2021. Whether these changes impact viral shedding and transmissibility is not known.METHODSPOSITIVES is a prospective longitudinal cohort of individuals with mild SARS-CoV-2 infection. Ambulatory, immunocompetent participants who did not receive antivirals self-administered 6 anterior nasal swabs over 15 days. Samples were analyzed by qPCR to quantify viral RNA, semiquantitative viral culture to detect shedding of replication-competent virus, and whole-genome sequencing to classify subvariants. Our predictor of interest was Omicron subvariants: BA.1x, BA.2x, BA.4/5x, XBB.x, and JN.x. Outcomes included RNA levels and duration of shedding replication-competent virus. We additionally explored whether symptoms are a valid marker for ending isolation.RESULTSThe median peak nasal SARS-CoV-2 RNA (6.0-6.3 log10 RNA copies/mL), median days to peak RNA (4-5 days), median days to undetectable viral RNA (12-14 days), and median days to negative viral culture (4-8 days) were similar across Omicron subvariants. Number and duration of symptoms were also similar. For all subvariants, a sizeable percentage (range 27.5%-56.0%) shed replication-competent virus after fever resolution and improvement of symptoms.CONCLUSIONDespite ongoing viral evolution, key aspects of viral dynamics of SARS-CoV-2 infection, including the duration of shedding replication-competent virus, have not substantially changed across Omicron subvariants. Replication-competent shedding of these subvariants is detected for a large proportion of people who meet criteria for ending isolation.FUNDINGNIH (U19 AI110818, R01 AI176287, K24 HL166024), the Massachusetts Consortium on Pathogen Readiness, and the Massachusetts General Hospital Department of Medicine.

BACKGROUND:Membrane (m) CD58 is a co-stimulatory ligand that binds to CD2, and the CD2-(m) CD58 axis participates in lymphocyte activation. In addition to mCD58, a soluble form of CD58 (sCD58) has been reported in human serum, urine, and in vitro cell culture supernatants. The role of sCD58 in the tumor immune microenvironment of pancreatic ductal adenocarcinoma (PDAC) is currently unknown. METHODS:The expression and prognostic role of CD58 in PDAC tissues were analyzed using various public databases. Then, the phenomenon of expressional separation of CD58 in PDAC cells induced by macrophages was observed by flow cytometry and ELISA, where the decrease of mCD58 on the membrane surface is accompanied by the increase of sCD58 in the supernatant. The molecular mechanisms of the expressional separation of CD58 were further explored by focusing on the TGF-β signaling pathway. The effects of expressional separation of CD58 on the immune activity and killing ability of T/NK cells for PDAC were determined in co-culture models. Furthermore, subcutaneous tumor-bearing models, lung metastasis models, and intraperitoneal dissemination models were used to confirm the in vitro data. Finally, the diagnostic and prognostic roles of serum sCD58 were determined by using 561 samples from PDAC patients, benign pancreatic disease patients, and healthy controls. RESULTS:Elevated CD58 expression in PDAC tissues was associated with worse clinical outcomes. After co-culture with PDAC cells, macrophages adopted an M2 phenotype, characterized by a high expression level of TGF-β. Co-cultured macrophages could induce the expressional separation of CD58 in PDAC cells. Activation of the TGF-β/Smad2/3 pathway markedly promoted this separation, and pathway inhibition largely blocked it. In vitro and in vivo assays revealed that mCD58 engaged CD2 on T/NK cells, facilitated their activation, enhanced their cytotoxicity, and stimulated the release of the anti-tumoral cytokines IFN-γ and TNF-α. Conversely, local high concentrations of sCD58 accumulation in PDAC tissues interfered with the CD2-CD58 axis by competitively binding CD2, inhibited the activation of T/NK cells, reduced T/NK cytotoxicity, and the secretion of IFN-γ and TNF-α. Furthermore, serum sCD58 levels were higher in the PDAC patients than in the healthy controls or patients with benign pancreatic diseases. sCD58 improved the diagnostic and prognostic power of CA199 in PDAC patients. A combined model incorporating CA199, TGF-β1, and sCD58 yielded an AUC (area under the curve) value of 0.946 for overall diagnosis. In the CA199 negative cohort, the combined model of TGF-β and sCD58 achieved an AUC of 0.955. CONCLUSIONS:This study uncovers a novel vicious crosstalk among macrophages, T/NK cells, and PDAC cells within the tumor microenvironment. Macrophages drive the expressional separation of CD58 via the TGF-β/Smad2/3 signaling pathway. This shift suppresses T/NK-cell activity, allows tumor cells to evade immune killing, and accelerates PDAC progression. In addition, serum sCD58 emerges as a promising diagnostic and prognostic biomarker for PDAC.

Perioperative neurocognitive disorder (PND) is a long-term perioperative complication that affects elderly surgical patients. As the aging population continues to grow, the prevention and treatment of PND have become important issues to address. Research has shown that ulinastatin significantly reduces the incidence of PND in elderly patients undergoing various types of surgery, including spinal and abdominal surgeries. However, the underlying mechanisms of this effect remain unclear. Transient receptor potential melastatin 4 (TRPM4) is a Ca2 + -activated, monovalent cation channel associated with many neurological diseases. In the present study, we aimed to investigate the relationship between ulinastatin and TRPM4 in PND and to determine its underlying mechanism. Forty eighteen-month-old male Sprague‒Dawley rats were randomly divided into four groups: the sham group, surgery group (internal fixation of tibial fracture), ulinastatin group (ulinastatin + surgery), and 9-phenanthrol group (TRPM4 channel inhibitor 9-phenanthrol + surgery). The neurocognitive function of the rats was detected using the Y-maze and new object recognition (NOR) tests. We used WB, qPCR, and IF to detect the expression levels of TRPM4 in different groups of rats. We also detected the degree of apoptosis in rat hippocampal cells. Surgery under inhaled sevoflurane anesthesia induced cognitive impairments and elevated the expression of TRPM4 in the hippocampus. Downregulation of TRPM4 expression by ulinastatin or 9-phenanthrol alleviated cognitive impairments after anesthesia and surgery. Furthermore, ulinastatin treatment decreased the level of apoptosis in the hippocampus. Ulinastatin downregulates TRPM4 expression and apoptosis to mitigate cognitive dysfunction in aged perioperative neurocognitive disorder rats, and ulinastatin is a promising neuroprotectant against PND.

Background/Objectives: Despite the lifting of the COVID-19 public health emergency, SARS-CoV-2 infections continue to be recorded worldwide. The continued prevalence of infection has been attributed to the ability of the virus to evade host immune responses, including neutralizing antibody-derived immunity. The vast majority of antibody escape mutations has been associated with the S1 subunit of the spike protein. The other region of the spike, the S2 subunit, is the most conserved region amongst coronaviruses. We hypothesized that S2-specific antibody levels are modest in vaccinated and SARS-CoV-2-infected patients, resulting in suboptimal neutralization of distant coronaviruses. Methods: Here, we analyzed S1- and S2-specific antibody levels in SARS-CoV-2-infected individuals, including a mixed cohort of those with and without immunosuppression and prior vaccination. Results: We found that S2-specific antibody responses were generally lower than S1-specific antibody responses. Intriguingly, Omicron-S1-specific antibody levels were higher than Wuhan-S1-specific antibody levels despite all vaccinated participants having received Wuhan-spike-based immunogens. This emphasizes the importance of the infecting variant and vaccine immunogen in the production of spike-targeting antibodies and associated hybrid immunity. Although S1-specific antibody levels were generally higher than their S2-specific counterparts, the correlation between neutralization and binding antibody levels was mostly higher in S2- compared with S1-specific responses. Conclusions: We conclude that S2-based immunogens are suitable for the induction of antibody-based immunity against novel SARS-CoV-2 variants but also against more distant coronaviruses, which would support a better protection for the immunocompromised as well as other vulnerable populations.

Background The association between low-frequency human immunodeficiency virus type 1 (HIV-1) drug resistance mutations (DRMs) and treatment failure (TF) is controversial. We explore this association using next-generation sequencing (NGS) methods that accurately sample low-frequency DRMs.Methods We enrolled women with HIV-1 in Malawi who were either antiretroviral therapy (ART) naive (cohort A), had ART failure (cohort B), or had discontinued ART (cohort C). At entry, cohorts A and C began a nonnucleoside reverse transcriptase inhibitor-based regimen and cohort B started a protease inhibitor-based regimen. We used Primer ID MiSeq to identify regimen-relevant DRMs in entry and TF plasma samples, and a Cox proportional hazards model to calculate hazard ratios (HRs) for entry DRMs. Low-frequency DRMs were defined as <= 20%.Results We sequenced 360 participants. Cohort B and C participants were more likely to have TF than cohort A participants. The presence of K103N at entry significantly increased TF risk among A and C participants at both high and low frequency, with HRs of 3.12 (95% confidence interval [CI], 1.58-6.18) and 2.38 (95% CI, 1.00-5.67), respectively. At TF, 45% of participants showed selection of DRMs while in the remaining participants there was an apparent lack of selective pressure from ART.Conclusions Using accurate NGS for DRM detection may benefit an additional 10% of patients by identifying low-frequency K103N mutations. Carrying the drug resistance mutation K103N at either low or high frequency when starting a nonnucleoside reverse transcriptase inhibitor antiretroviral therapy regimen increases treatment failure risk.