Selective depletion of HBV-infected hepatocytes by class A capsid assembly modulators requires high levels of intrahepatic HBV core protein.

Capsid assembly mediated by hepatitis B virus (HBV) core protein (HBc) is an essential part of the HBV replication cycle, which is the target for different classes of capsid assembly modulators (CAMs). While both CAM-A ("aberrant") and CAM-E ("empty") disrupt nucleocapsid assembly and reduce extracellular HBV DNA, CAM-As can also reduce extracellular HBV surface antigen (HBsAg) by triggering apoptosis of HBV-infected cells in preclinical mouse models. However, there have not been substantial HBsAg declines in chronic hepatitis B (CHB) patients treated with CAM-As to date. To investigate this disconnect, we characterized the antiviral activity of tool CAM compounds in HBV-infected primary human hepatocytes (PHHs), as well as in HBV-infected human liver chimeric mice and mice transduced with adeno-associated virus-HBV. Mechanistic studies in HBV-infected PHH revealed that CAM-A, but not CAM-E, induced a dose-dependent aggregation of HBc in the nucleus which is negatively regulated by the ubiquitin-binding protein p62. We confirmed that CAM-A, but not CAM-E, induced HBc-positive cell death in both mouse models via induction of apoptotic and inflammatory pathways and demonstrated that the degree of HBV-positive cell loss was positively correlated with intrahepatic HBc levels. Importantly, we determined that there is a significantly lower level of HBc per hepatocyte in CHB patient liver biopsies than in either of the HBV mouse models. Taken together, these data confirm that CAM-As have a unique secondary mechanism with the potential to kill HBc-positive hepatocytes. However, this secondary mechanism appears to require higher intrahepatic HBc levels than is typically observed in CHB patients, thereby limiting the therapeutic potential.

Repurposing mebendazole against triple-negative breast cancer CNS metastasis.

PURPOSE: Triple-negative breast cancer (TNBC) often metastasizes to the central nervous system (CNS) and has the highest propensity among breast cancer subtypes to develop leptomeningeal disease (LMD). LMD is a spread of cancer into leptomeningeal space that speeds up the disease progression and severely aggravates the prognosis. LMD has limited treatment options. We sought to test whether the common anti-helminthic drug mebendazole (MBZ) may be effective against murine TNBC LMD. METHODS: A small-molecule screen involving TNBC cell lines identified benzimidazoles as potential therapeutic agents for further study. In vitro migration assays were used to evaluate cell migration capacity and the effect of MBZ. For in vivo testing, CNS metastasis was introduced into BALB/c athymic nude mice through internal carotid artery injections of brain-tropic MDA-MB-231-BR or MCF7-BR cells. Tumor growth and spread was monitored by bioluminescence imaging and immunohistochemistry. MBZ was given orally at 50 and 100 mg/kg doses. MBZ bioavailability was assayed by mass spectrometry. RESULTS: Bioinformatic analysis and migration assays revealed higher migratory capacity of TNBC compared to other breast cancer subtypes. MBZ effectively slowed down migration of TNBC cell line MDA-MB-231 and its brain tropic derivative MDA-MB-231-BR. In animal studies, MBZ reduced leptomeningeal spread, and extended survival in brain metastasis model produced by MDA-MB-231-BR cells. MBZ did not have an effect in the non-migratory MCF7-BR model. CONCLUSIONS: We demonstrated that MBZ is a safe and effective oral agent in an animal model of TNBC CNS metastasis. Our findings are concordant with previous efforts involving MBZ and CNS pathology and support the drug's potential utility to slow down leptomeningeal spread.

The Role of Social Media in the Experiences of COVID-19 Among Long-Hauler Women: Qualitative Study.

BACKGROUND: The extant literature suggests that women are more vulnerable to COVID-19 infection and at higher risk for developing long COVID. Due to pandemic mitigation recommendations, social media was relied upon for various aspects of daily life, likely with differences of usage between genders. OBJECTIVE: This study aimed to explore the role and functions of social media in the lives of long-hauler women. METHODS: Participants were purposively snowball-sampled from an online health promotion intervention for long-hauler women with COVID-19 from March to June 2021. During this time, one-on-one, semistructured interviews were conducted online until data saturation was agreed to have been achieved (ie, 15 interviews). Interview transcripts and field notes were analyzed using an emergent, inductive approach. RESULTS: In total, 15 women were enrolled. The main roles of social media included facilitating support group participation, experience sharing, interpersonal connections, and media consumption. Emergent themes demonstrated that participants rely on social media to fulfill needs of emotional support, social engagement, spirituality, health planning, information gathering, professional support, and recreationally for relaxation. As long-hauler women turn to social media to discuss symptom and health management as well as the intention to vaccinate, this study demonstrates both the associated benefits (ie, decreased isolation) and challenges (ie, misinformation, rumination, resentment, jealousy). CONCLUSIONS: The public health implications of these findings support the development of gender-tailored health promotion interventions that leverage the benefits of social media, while mitigating the negative impacts, for women with long COVID.

Electrolyte Dependence of Li+ Transport Mechanisms in Small Molecule Solvents from Classical Molecular Dynamics.

As demands on Li-ion battery performance increase, the need for electrolytes with high ionic conductivity and a high Li+ transference number (tLi) becomes crucial to boost power density. Unfortunately, tLi in liquid electrolytes is typically <0.5 due to Li+ migrating via a vehicular mechanism, whereby Li+ diffuses along with its solvation shell, making its diffusivity slower than the counteranion. Designing liquid electrolytes where the Li+ ion diffuses independently of its solvation shell is of significant interest to enhance the transference number. In this work, we elucidate how the properties of the solvent influence the Li+ transport mechanism. Using classical molecular dynamics simulations, we find that a vehicular mechanism can be increasingly preferred with a decreasing solvent viscosity and increasing interaction energy between the solvent and Li+. Thus, a weaker interaction energy can enhance tLi through a solvent-exchange mechanism, ultimately improving Li-ion battery performance. Finally, metadynamics simulations show that in electrolytes where a solvent-exchange mechanism is preferable, the energy barrier to changing the coordination environment of Li+ is much lower than in electrolytes where a vehicular mechanism dominates.

Measurement Instruments Assessing Multi-Faceted Stigma Regarding Sexual and Gender Minorities: A Systematic Review of Psychometric Properties.

Stigma against sexual and gender minorities (SGM) populations has serious negative health effects for SGM populations. Despite the growing need for accurate stigma measurement in SGM, there are insufficient valid measurement instruments. Moreover, the lack of consistency in construct usage makes comparisons across studies particularly challenging. A critical review and comparative evaluation of the psychometric properties of the various stigma measures for SGM is necessary to advance our understanding regarding stigma measurement against/among SGMs. Based on the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, a comprehensive search was conducted in 4 bibliographic databases (MEDLINE, PsycINFO, CINAHL, and Web of Science) for empirical articles published from 2010 to 2022 that evaluated the psychometrics properties of measurement instruments assessing stigma against SGMs. The screening, extraction, and scoring of the psychometric properties and methodological quality of selected instruments were performed by following the established standards and COSMIN (Consensus-based Standards for the selection of health Measurement Instruments) checklist, respectively. Of the 2031 studies identified, 19 studies were included that reported psychometric properties of 17 measurement instruments. All instruments, except two, were developed for SGMs (n = 15/17). Most instruments included men who have sex with men (MSM) or gay men (n = 11/15), whereas less than half of the instruments assessed stigma among SGM women (n = 6/15). Internal consistency (Cronbach's alpha) and content validity was reported for all instruments (n = 17); construct and structural validity was also reported for majority of the instruments (n = 15 and 10, respectively). However, test-retest reliability and criterion validity was reported for very few instruments (n = 5 each). Based on the COSMIN checklist, we identified the most psychometrically and methodologically robust instruments for each of the five stigma types: combined stigma, enacted stigma, internalized stigma, intersectional stigma, and perceived stigma. For each stigma type, except anticipated stigma, at least one instrument demonstrated strong promise for use in empirical research; however, the selection of instrument depends on the target population and context of the study. Findings indicated a growing use of instruments assessing multiple stigma types. Future studies need to develop intersectional stigma instruments that account for the multiple and intersecting social identities of SGMs. Additionally, most existing instruments would benefit from further psychometric testing, especially on test-retest reliability, criterion validity, adaptability to different LGBTQIA + populations and cultures.

Impact of enacted stigma on mental health, substance use, and HIV-related behaviors among sexual minority men in Zambia.

Sexual minority men (SMM) in Zambia face significant challenges including stigma, discrimination, and mental health issues, which further impact their HIV-related risk behaviors. This study aimed to investigate the associations between enacted stigma, substance abuse, HIV-related behaviors, and mental health (i.e., depression, anxiety, and post-traumatic stress disorder [PTSD] symptoms) among SMM in Zambia. SMM aged 18-35 years who reported having multiple and/or concurrent sexual partners or low and/or inconsistent condom use in the past three months were recruited from four districts in Zambia between February and November 2021. Participants completed an anonymous interviewer-administered survey. Key variables of interest were compared between participants with higher vs. lower levels of enacted stigma. Independent samples t-tests were used for continuous variables, and chi-squared tests were used for categorical variables. A total of 197 eligible SMM participated in the study (mean age = 24.41 years). Participants with a higher level of enacted stigma showed a higher level of anxiety symptoms (χ2 = 12.91, p ≤ .001), PTSD symptoms (χ2 = 7.13, p < .01), tobacco use (χ2 = 10.47, p < .01), cannabis use (χ2 = 5.90, p < .05), and a higher number of sexual partners (t = 1.99, p < .05) in the past three months. Stigma reduction interventions may help mitigate substance abuse, HIV-related behaviors, and adverse mental health outcomes among SMM in Zambia. Health care providers, especially psychiatric-mental health nurses, can incorporate strategies for recognizing and addressing stigma into their practice through training and integrate multiple resources to create an inclusive and non-judgmental environment for SMM to improve their well-being.

Stigmatizing clinical setting erodes physician-patient interaction quality for sexual minority men through perceived HIV stigma and HIV infection concerns in Zambia.

This study investigated whether perceived HIV stigma and HIV infection concerns among healthcare providers (HCPs) mediate the association between stigmatizing clinical setting and their interaction quality with sexual minority men (SMM) patients in Zambia. In 2021, a cross-sectional survey was conducted with 91 HCPs offering HIV-related services to SMM in Zambia. Path analysis was conducted to examine the potential mediation effect of "perceived HIV stigma" and "HIV infection concern" among HCPs in the association between "stigmatizing clinical setting" and their "interaction quality with SMM". Mediators i.e., "perceived HIV stigma" and "HIV infection concern" among HCPs, were associated positively with the stigmatizing clinical setting (ß = 0.329, p < .01, ß = 0.917, p < 0.01), and negatively with physician-patient interaction quality (ß = -0.167, p = 0.051; ß = -0.126, p < 0.05). Stigmatizing clinical setting had a significant and negative indirect effect on HCPs interaction quality with SMM through increased perceived HIV stigma (z = -1.966, p < 0.05) and increased HIV infection concern (z = -1.958, p = 0.050). To improve physician-patient interaction quality, stigma reduction interventions among HCPs, who serve SMM in Zambia, should target development of development of inclusive policies and the cultivation of cultural norms that are supportive and respectful to SMM, and protection of HCPs from enacted stigma due to offering care to SMM.

Repurposing mebendazole against triple-negative breast cancer leptomeningeal disease.

Purpose: Triple-negative breast cancer (TNBC) is an aggressive subtype that often metastasizes to the brain. Leptomeningeal disease (LMD), a devastating brain metastasis common in TNBC, has limited treatment options. We sought to test whether the common anti-helminthic drug mebendazole (MBZ) may be effective against murine TNBC LMD. Methods: A small-molecule screen involving TNBC cell lines identified benzimidazoles as potential therapeutic agents for further study. In vitro migration assays were used to evaluate cell migration capacity and the effect of MBZ. For in vivo testing, LMD was introduced into BALB/c athymic nude mice through internal carotid artery injections of brain-tropic MDA-MB-231-BR or MCF7-BR cells. Tumor growth and spread was monitored by bioluminescence imaging. MBZ was given orally at 50 and 100 mg/kg doses. MBZ bioavailability was assayed by mass spectrometry. Results: Bioinformatic analysis and migration assays revealed higher migratory capacity of TNBC compared to other breast cancer subtypes. MBZ effectively slowed down migration of TNBC cell line MDA-MB-231 and its brain tropic derivative MDA-MB-231-BR. In animal studies, MBZ reduced tumor growth and extended survival in the LMD model produced by MDA-MB-231-BR cells. MBZ did not have an effect in the non-migratory MCF7-BR model. Conclusions: We demonstrated that MBZ is a safe and effective oral agent in an animal model of TNBC LMD. Our findings are concordant with previous efforts involving MBZ and central nervous system pathology and further support the drug's potential utility as an alternative therapeutic for TNBC LMD.

Physician-Patient Interaction Quality Mediates the Association Between HIV-Related Stigma and HIV-Prevention Behaviors Among Sexual Minority Men in Zambia.

HIV-related stigma is a major challenge to HIV prevention for sexual minority men (SMM) in Zambia, but little is known about the underlying mechanisms. This study aimed to investigate whether physician-patient interaction quality mediates the relationship between HIV-related stigma and HIV-prevention behaviors among SMM. Data were collected using a cross-sectional survey from 194 SMM (aged: mean = 24.08, SD = 4.27) across four districts in Zambia between February and November 2021. Participants were asked about their demographic characteristics, HIV-related stigma, SMM-related stigma, physician-patient interaction quality, HIV-testing intention, and use of pre-exposure prophylaxis (PrEP). Path analysis was used to test the mediation effect of physician-patient interaction quality in the associations of HIV-related stigma/SMM-related stigma with HIV-testing intention and current PrEP use. Higher self-reported physician-patient interaction quality was negatively associated with HIV-related stigma (ß = - 0.444, z = - 2.223, p < 0.05), and positively associated with HIV-testing intention (ß = 0.039, z = 5.121, p < 0.001) and current PrEP use (ß = 0.008, z = 2.723, p < 0.01). HIV-related stigma among SMM had a significant and negative indirect effect on HIV-testing intention (ß = - 0.017, z = - 2.006, p < 0.05), and current PrEP use (ß = - 0.004, z = - 2.009, p < 0.05) through physician-patient interaction quality. Contrary to our expectations, SMM-related stigma did not have a significant and negative indirect effect on HIV prevention behaviors through physician-patient interaction quality. Health interventions need to improve physician-patient interaction quality by offering healthcare provider training, targeting HIV-related stigma in healthcare settings, and devising inclusive healthcare policies to promote HIV prevention efforts.

Substance use, psychiatric symptoms, personal mastery, and social support among COVID-19 long haulers: A compensatory model.

BACKGROUND: Substance use has become a critical health concern during the COVID-19 pandemic, and emerging attention has been paid to people with the persistent symptoms of COVID-19 (COVID-19 long haulers) due to their high vulnerability. However, scant research has investigated their substance use and relevant psychosocial factors. The current study was to (1) examine substance use behaviors (i.e., legal drug use, illicit drug use, and non-medical use of prescription drugs); and (2) assessed their associations with psychiatric symptoms (i.e., depression, anxiety, and post-traumatic stress disorder) and psychosocial factors (i.e., personal mastery and social support) among COVID-19 long haulers. METHODS: In January-March 2022, 460 COVID-19 long haulers (50% female), with an average age of 32, completed online surveys regarding their demographics, substance use, psychiatric symptoms, and psychosocial factors. RESULTS: In the past three months, the most commonly used or non-medically used substances were tobacco (82%) for legal drugs, cocaine (53%) for illicit drugs, and prescription opioids (67%) for prescription drugs. Structural equation modeling suggested that psychiatric symptoms were positively associated with substance use behaviors (ßs = 0.38 to .68, ps < 0.001), while psychosocial factors were negatively associated with substance use behaviors (ßs = -0.61 to -0.43, ps < 0.001). CONCLUSION: Substance use is common in COVID-19 long haulers and psychiatric symptoms are the risk factors. Personal mastery and social support appear to offer protection offsetting the psychiatric influences. Substance use prevention and mental health services for COVID-19 long haulers should attend to personal mastery and social support.

Efficient Removal of Uranyl Ions Using PAMAM Dendrimer: Simulation and Experiment.

In this work, using atomistic molecular dynamics (MD) simulations and polymer-assisted ultrafiltration experiments, we explore the adsorption and removal of uranyl ions from aqueous solutions using poly(amidoamine) (PAMAM) dendrimers. The effects of uranyl ion concentration and the pH of the solution were examined for PAMAM dendrimers of generations 3, 4, and 5. Our simulation results show that PAMAM has a high adsorption capacity for the uranyl ions. The adsorption capacity increases with increasing concentration of uranyl ions for all 3 generations of PAMAM in agreement with experimental findings. We find that the number of uranyl ions bound to PAMAM is significantly higher in acidic solutions (pH < 3) as compared to neutral solutions (pH ∼ 7) for all uranyl ion concentrations. Additionally, we find an increase in the number of adsorbed uranyl ions to PAMAM with the increase in the dendrimer generation. This increase is due to the greater number of binding sites present for higher-generation PAMAM dendrimers. Our simulation study shows that nitrate ions form a solvation shell around uranyl ions, which allows them to bind to PAMAM binding sites, including the amide, amine, and carbonyl groups. In polymer-assisted ultrafiltration (PAUF) experiments, the removal percentage of uranyl ions by G3 PAMAM dendrimer increased from 36.3% to 42.6% as the metal ion concentration increased from 2.1 × 10-5 M to 10.5 × 10-5 M at a pH of 2. Our combined experiment and simulation study suggests that PAMAM is an effective adsorbent for removing uranyl ions from aqueous solutions.

Intrahepatic quantification of HBV antigens in chronic hepatitis B reveals heterogeneity and treatment-mediated reductions in HBV core-positive cells.

Background & Aims: Patterns of liver HBV antigen expression have been described but not quantified at single-cell resolution. We applied quantitative techniques to liver biopsies from individuals with chronic hepatitis B and evaluated sampling heterogeneity, effects of disease stage, and nucleos(t)ide (NUC) treatment, and correlations between liver and peripheral viral biomarkers. Methods: Hepatocytes positive for HBV core and HBsAg were quantified using a novel four-plex immunofluorescence assay and image analysis. Biopsies were analysed from HBeAg-positive (n = 39) and HBeAg-negative (n = 75) participants before and after NUC treatment. To evaluate sampling effects, duplicate biopsies collected at the same time point were compared. Serum or plasma samples were evaluated for levels of HBV DNA, HBsAg, hepatitis B core-related antigen (HBcrAg), and HBV RNA. Results: Diffusely distributed individual HBV core+ cells and foci of HBsAg+ cells were the most common staining patterns. Hepatocytes positive for both HBV core and HBsAg were rare. Paired biopsies revealed large local variation in HBV staining within participants, which was confirmed in a large liver resection. NUC treatment was associated with a >100-fold lower median frequency of HBV core+ cells in HBeAg-positive and HBeAg-negative participants, whereas reductions in HBsAg+ cells were not statistically significant. The frequency of HBV core+ hepatocytes was lower in HBeAg-negative participants than in HBeAg-positive participants at all time points evaluated. Total HBV+ hepatocyte burden correlated with HBcrAg, HBV DNA, and HBV RNA only in baseline HBeAg-positive samples. Conclusions: Reductions in HBV core+ hepatocytes were associated with HBeAg-negative status and NUC treatment. Variation in HBV positivity within individual livers was extensive. Correlations between the liver and the periphery were found only between biomarkers likely indicative of cccDNA (HBV core+ and HBcrAg, HBV DNA, and RNA). Impact and Implications: HBV infects liver hepatocyte cells, and its genome can exist in two forms that express different sets of viral proteins: a circular genome called cccDNA that can express all viral proteins, including the HBV core and HBsAg proteins, or a linear fragment that inserts into the host genome typically to express HBsAg, but not HBV core. We used new techniques to determine the percentage of hepatocytes expressing the HBV core and HBsAg proteins in a large set of liver biopsies. We find that abundance and patterns of expression differ across patient groups and even within a single liver and that NUC treatment greatly reduces the number of core-expressing hepatocytes.

Interaortocaval Lymph Node Metastasis in Gall Bladder Cancer: Is It Regional Node or Metastatic Disease?

BACKGROUND AND OBJECTIVES: Interaortocaval or para-aortic lymph node (IACLN) metastasis in gall bladder cancer (GBC) is usually a contraindication to curative resection with a prognosis similar to liver or peritoneal metastases. However, few authors have reported survival similar to regional lymph node (RLN) positive disease after curative resection in these patients. This study aims to analyse the role of curative surgery in such cases. METHODS: Data of all patients operated for GBC from 2012 to 2019 was retrieved. Survival of the IACLN- and RLN-positive patients was compared and factors associated with recurrence and survival were analysed. RESULTS: Patients were divided in RLN-positive (n = 47) and IACLN-positive (n = 17) group. At a median follow-up of 19.7 months, median disease-free survival (18 vs 13 months) and median overall survival (27 vs 20 months) were inferior (p = 0.06) in IACLN group. But it was higher than the patients who received only palliative therapy (median OS, 14 months). Lack of adjuvant therapy was a significant factor for disease recurrence. CONCLUSION: Selected cases of GBC with IACLN metastases can achieve meaningful survival after curative resection and adjuvant therapy. Survival was inferior to RLN-positive cases but it was higher than the patients who received only palliative chemotherapy. This concept needs further evaluation in a prospective study with larger number of patients.

Artificial Intelligence-Based Chatbots for Promoting Health Behavioral Changes: Systematic Review.

BACKGROUND: Artificial intelligence (AI)-based chatbots can offer personalized, engaging, and on-demand health promotion interventions. OBJECTIVE: The aim of this systematic review was to evaluate the feasibility, efficacy, and intervention characteristics of AI chatbots for promoting health behavior change. METHODS: A comprehensive search was conducted in 7 bibliographic databases (PubMed, IEEE Xplore, ACM Digital Library, PsycINFO, Web of Science, Embase, and JMIR publications) for empirical articles published from 1980 to 2022 that evaluated the feasibility or efficacy of AI chatbots for behavior change. The screening, extraction, and analysis of the identified articles were performed by following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. RESULTS: Of the 15 included studies, several demonstrated the high efficacy of AI chatbots in promoting healthy lifestyles (n=6, 40%), smoking cessation (n=4, 27%), treatment or medication adherence (n=2, 13%), and reduction in substance misuse (n=1, 7%). However, there were mixed results regarding feasibility, acceptability, and usability. Selected behavior change theories and expert consultation were used to develop the behavior change strategies of AI chatbots, including goal setting, monitoring, real-time reinforcement or feedback, and on-demand support. Real-time user-chatbot interaction data, such as user preferences and behavioral performance, were collected on the chatbot platform to identify ways of providing personalized services. The AI chatbots demonstrated potential for scalability by deployment through accessible devices and platforms (eg, smartphones and Facebook Messenger). The participants also reported that AI chatbots offered a nonjudgmental space for communicating sensitive information. However, the reported results need to be interpreted with caution because of the moderate to high risk of internal validity, insufficient description of AI techniques, and limitation for generalizability. CONCLUSIONS: AI chatbots have demonstrated the efficacy of health behavior change interventions among large and diverse populations; however, future studies need to adopt robust randomized control trials to establish definitive conclusions.

Mapping the hepatic immune landscape identifies monocytic macrophages as key drivers of steatohepatitis and cholangiopathy progression.

BACKGROUND AND AIMS: The progression of chronic liver diseases towards liver cirrhosis is accompanied by drastic tissue changes. This study combines elaborate transcriptomic and histological methods aiming at spatially resolving the hepatic immune microenvironment in NAFLD (including NASH, primary sclerosing cholangitis, primary biliary cholangitis, and severe alcoholic hepatitis). APPROACH AND RESULTS: Human liver samples were subjected to RNA-sequencing (n=225) and imaging cytometry (n=99) across 3 independent patient cohorts. Liver samples from alcoholic hepatitis and primary biliary cholangitis patients were used for comparison. Myeloid populations were further characterized in corresponding mouse models. Imaging, clinical, and phenotypical data were combined for multidimensional analysis. NAFLD/NASH and primary sclerosing cholangitis disease stages were associated with loss of parenchymal areas, increased ductular cell accumulation, and infiltration of immune cells. NASH patients predominantly exhibited myeloid cell accumulation, whereas primary sclerosing cholangitis patients additionally had pronounced lymphoid cell responses. Correlating to disease stage, both etiologies displayed intense IBA1 + CD16 low CD163 low macrophage aggregation in nonparenchymal areas, with a distinct spatial proximity to ductular cells. Mouse models revealed that disease-associated IBA1 + hepatic macrophages originated from bone marrow-derived monocytes. Using an unbiased, machine learning-based algorithm, IBA1 in combination with hepatocyte and ductular cell immunostaining-predicted advanced cirrhosis in human NASH, primary sclerosing cholangitis, and alcoholic hepatitis. CONCLUSIONS: Loss of hepatocytes and increased ductular reaction are tightly associated with monocyte-derived macrophage accumulation and represent the most prominent common immunological feature revealing the progression of NAFLD, primary sclerosing cholangitis, primary biliary cholangitis, and alcoholic hepatitis, suggesting IBA1 + CD163 low macrophages are key pathogenic drivers of human liver disease progression across diverse etiologies.

A rare case of peritoneal metastases from oropharyngeal squamous cell carcinoma in a young male after completion of chemoradiotherapy.

ABSTRACT: Distant metastases are frequent in head and neck squamous cell carcinomas (HNSCC), but they are limited to some organs like lungs, bone, mediastinum, liver and brain. Peritoneal metastases (PMs) from HNSCC are extremely rare. A 28-year-old chronic smoker and alcoholic was diagnosed with squamous cell carcinoma of oropharynx. Patient was admitted and was given six cycles of concurrent chemo and radiotherapy (CCRT) and was discharged. Two months later, he presented with abdominal pain and lump. Contrast-enhanced CT revealed ascites, peritoneal implants and subcutaneous deposit which were proved to be metastases by histopathology. The present case is the seventh reported case of PM from HNSCC. • Patients of HNSCC shall be screened for distant metastases. • Differential diagnosis of HNSCC needs consideration when encountered with peritoneal metastases. • Research is required to understand the basis of PM in HNSCC while on CCRT to suggest management modifications.

Substance use, psychiatric symptoms, personal mastery, and social support among COVID-19 long haulers: A compensatory model.

Background: Substance use has become a critical health concern during the COVID-19 pandemic, and emerging attention has been paid to people with the persistent symptoms of COVID-19 (COVID-19 long haulers) due to their high vulnerability. However, scant research has investigated their substance use and relevant psychosocial factors. The current study was to (1) examine substance use behaviors (i.e., legal drug use, illicit drug use, and non-medical use of prescription drugs); and (2) assessed their associations with psychiatric symptoms (i.e., depression, anxiety, and post-traumatic stress disorder) and psychosocial factors (i.e., personal mastery and social support) among COVID-19 long haulers. Methods: In January - March 2022, 460 COVID-19 long haulers (50% female), with an average age of 32, completed online surveys regarding their demographics, substance use, psychiatric symptoms, and psychosocial factors. Results: In the past three months, the most commonly used or non-medically used substances were tobacco (82%) for legal drugs, cocaine (53%) for illicit drugs, and prescription opioids (67%) for prescription drugs. Structural equation modeling suggested that psychiatric symptoms were positively associated with substance use behaviors ( ß s = .38 to .68, p s < .001), while psychosocial factors were negatively associated with substance use behaviors ( ß s = -.61 to -.43, p s < .001). Conclusion: Substance use is common in COVID-19 long haulers and psychiatric symptoms are the risk factors. Personal mastery and social support appear to offer protection offsetting the psychiatric influences. Substance use prevention and mental health services for COVID-19 long haulers should attend to personal mastery and social support.

Resilience resources and coping strategies of COVID-19 female long haulers: A qualitative study.

Background: Female long haulers deal with persistent post-acute COVID-19 symptoms that have serious health implications. This study aimed to identify resilience resources at multiple socio-ecological levels for female long haulers and describe how resilience resources affect their responses to long COVID. Methods: Purposive sampling was adopted to recruit participants through social media from April to June 2021 followed by 15 semi-structured interviews. An inductive analytical approach was adopted to categorize themes by open and axial coding that were verified by peer review. Results: Female long haulers relied on resources at various socio-ecological levels to foster their resilience in response to long COVID. At the individual level, they utilized cognitive and emotional resources to increase knowledge, learn new skills, set goals, and manage emotions; behavioral resources (e.g., internal motivation and executive functioning) to perform physical, creative, and recreational activities, and adopt healthier eating habits; and spiritual resources to perform spiritual rituals and connect with God. At the social level, the support from existing relationships and/or online social support groups enhanced their social identity and provided material and informational resources. At the health systems level, the guidance from counselors and physicians and availability of clinics, medicines, and health equipment assisted them in symptom management and medication adherence. Conclusion: The resilience of female long haulers can be enhanced through (1) offering financial and health-related resources, (2) developing online social-support groups, (3) counseling and care service training for healthcare professionals, and (4) implementing more psychosocial interventions by labor organizations.

Molecular Rectifiers with a Very High Rectification Ratio Enabled by Oxidative Damage in Double-Stranded DNA.

In this work, we report a novel strategy to construct highly efficient molecular diodes using oxidatively damaged DNA molecules. Being exposed to several endogenous and exogenous events, DNA suffers from constant oxidative damage, leading to the oxidation of guanine to 8-oxoguanine (8oxoG). Here, we study the charge migration properties of native and oxidatively damaged DNA using a multiscale multiconfigurational methodology comprising molecular dynamics, density functional theory, and kinetic Monte Carlo simulations. We perform a comprehensive study to understand the effect of different concentrations and locations of 8oxoG in a dsDNA sequence on its charge-transport properties and find tunable rectifier properties having potential applications in molecular electronics such as molecular switches and molecular rectifiers. We also discover the negative differential resistance properties of the fully oxidized Drew-Dickerson sequence. The presence of 8oxoG guanine leads to the trapping of charge, thus operating as a charge sink, which reveals how oxidized guanine saves the rest of the genome from further oxidative damage.