OBJECTIVES:Sjogren's disease (SjD) shows a strong female predominance, but the contribution of age-related hormone changes to this sex bias remains uncertain. We investigated whether natural hormonal transitions across the lifespan align with variation in male and female prevalence of SjD. METHODS:Electronic health records from 101 856 SjD patients and 1.33 million controls were analysed. Sex-specific prevalence was compared with serum testosterone, oestradiol and SHBG levels. Population-level hormone distributions from the National Health and Nutrition Examination Survey (NHANES) were incorporated using imputation. Generalized linear models evaluated associations between hormone fluctuations and sex prevalence across age groups. RESULTS:Male prevalence among SjD patients peaked during early childhood (30.1% [95% CI: 26.2-34.1]), declining sharply in late puberty into adulthood (9.8% [95% CI: 9.5-10.2]) and rose again in older adults (13.5% [95% CI: 13.3-13.8]). These non-linear shifts paralleled age-dependent trajectories of testosterone and oestradiol. Hormone concentrations did not differ significantly between SjD patients and controls, indicating that physiological transitions, rather than abnormal levels, align with disease risk. CONCLUSION:Age-dependent hormonal changes correspond with evolving sex bias in SjD, challenging the static 9:1 female-to-male paradigm. These findings highlight the role of age-related hormonal dynamics in shaping autoimmune susceptibility.

Objective Sjögren's disease (SjD) is a chronic autoimmune disease with a complex etiology, where pathogens may influence disease development or progression. Although SjD is not communicable, environmental and endemic pathogen exposures may influence its onset or progression. This study assessed the prevalence and patterns of infectious diseases (IDs) in SjD compared to sicca symptom and autoimmune disease controls. Methods This retrospective, cross‐sectional study utilized 2015 to 2023 data from the University of Utah UHealth, analyzing 3,826 patients with SjD and age‐ and sex‐matched controls. ID diagnoses were classified using International Classification of Diseases, Tenth Revision (ICD‐10) codes, and odds ratios (ORs) were calculated to identify significant differences in ID prevalence between cases and control cohorts. Unique infections, reinfections, and temporal analyses were performed. Hierarchical cluster analysis identified common and unique patterns of ID diagnoses across different patient groups. Results Patients with SjD had an average of 5.30 ± 8.00 unique ID diagnoses compared to 4.86 ± 6.15 in controls (P < 0.001). Infections and reinfections were more frequent in SjD, particularly bacterial and fungal. Younger age at SjD diagnosis was associated with increased infections and reinfections. Anti‐SSA/Ro positivity correlated with higher infection and reinfection rates. One hundred thirty‐four ICD‐10 codes showed significant differences in prevalence (based on ORs), with increased bacterial (eg, Mycobacterium, Streptococcus spp.), viral (eg, herpesviruses, molluscum contagiosum), fungal (eg, Candida, Aspergillus), and parasitic (onchocerciasis) infections in SjD. ID profiles in SjD strongly aligned with systemic lupus erythematosus. Conclusion These findings suggest increased prevalence and recurrence of infections in SjD a potential role in disease onset and progression. Further studies are needed to clarify infection‐related mechanisms and identify therapeutic targets.

Dental students and practitioners may have an increased risk of COVID-19 infection due to frequent aerosol-generating procedures (AGP) and close patient contact. We examined the role of vaccination status, work role, and AGP frequency on positive SARS-CoV-2 PCR surveillance test using a Cox proportional hazards regression and weighted for dropout. A total of 410 dental health workers (200 students, 104 faculty, and 106 staff) had 8,270 screening tests performed between May 2020 and February 2022, with 158 positive tests; 60 (38%) occurred in January 2022. Omicron had a significant impact on vaccination effectiveness. Vaccine effectiveness within < 4 months was 91% (HR: 0.09,95% CI: 0.02-0.40) prior to Omicron, which decreased after its emergence. Work role was not associated with risk of positive test. Reported AGP frequency was also not associated with positive test risk; however, these analyses were limited to a subset of participants and should be considered exploratory. More than a third of all positive tests occurred during one month of Omicron. We found a high vaccine effectiveness prior to the Omicron surge, which decreased after the emergence of Omicron. Our results support encouraging dental healthcare workers (DCWs) to maintain up-to-date vaccination and continue engaging in preventive measures.

Sjogren′s Disease (SjD), like many autoimmune diseases, shows a strong female–to–male sex bias, raising the possibility of a hormone-mediated mechanism. However, specific hormonal drivers and the underlying mechanisms remain unclear. In this study, we analyze a electronic health record dataset containing >100,000 SjD patients, allowing for a comprehensive statistical investigation into sex bias and serum hormone levels associated with SjD susceptibility. Focusing on testosterone, estradiol, and sex hormone–binding globulin (SHBG), our analysis reveals an age–dependent trend in SjD's sex bias, with a substantially reduced female bias observed in pediatric cases. This finding, alongside statistical modeling, suggests that testosterone or estradiol may influence the sex disparity in SjD prevalence, with distinct effects at different life stages. Specifically, we observe a higher percentage of male SjD patients in early childhood (30.06%, [CI: 26.16–34.11]), declining sharply in late pubescence into adulthood (9.85% [CI: 9.51–10.16]), followed by a secondary steady increase in male prevalence among older adults (13.50% [CI: 13.25–13.76]). Our models indicate that these shifts in sex bias align with typical age–related hormonal changes rather than abnormal levels, suggesting that natural hormone fluctuations may play a significant role in modulating disease susceptibility. This research not only refines our understanding of SjD but also underscores the importance of hormone–level monitoring in future SjD studies and potential therapeutic strategies. Advanced studies are required to further clarify whether testosterone or estradiol is the primary mediator of these trends, promising new insights into hormone–linked pathways and autoimmune disease pathogenesis. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study did not receive any funding. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The University of Utah, Institutional Review Board gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced are available through request to TriNetX, LLC.

Hepatitis D virus (HDV) is a rare co-infection with hepatitis B virus. Currently, HDV is not a nationally notifiable disease in the United States. Only 55% of states and territories require HDV reporting, and most lack defined case definitions. Standardization of reporting requirements is crucial for monitoring HDV epidemiology.

BACKGROUND:This study assessed the epidemiology of hepatitis delta virus (HDV) within the University of Utah UHealth health care system (2000-2021). METHODS:Analysis of HDV/HBV testing, diagnostic codes, liver enzymes, and comorbidities was performed. RESULTS:Among the 1962 HBV patients, only 22.2% underwent HDV testing, revealing an 8.3% positivity rate for HDV coinfections. This study observed a consistent increase in HBV and HDV cases, with higher HDV detection rates linked to increased testing. Limited HDV testing and potential screening biases were evident. DISCUSSION:Improved HDV testing and surveillance are crucial for early detection and implementation of targeted therapies.

The international epidemiology of Hepatitis Delta Virus (HDV) is challenging to accurately estimate due to limited active surveillance for this rare infectious disease. Prior HDV epidemiological studies have relied on meta-analysis of aggregated and static datasets. These limitations restrict the capacity to actively detect low-level and/or geographically dispersed changes in the incidence of HDV diagnoses. This study was designed to provide a resource to track and analyze the international HDV epidemiology. Datasets analyzed collectively consisted of >700,000 HBV and >9,000 HDV reported cases ranging between 1999-2020. Datasets mined from government publications were identified for Argentina, Australia, Austria, Brazil, Bulgaria, Canada, Finland, Germany, Macao, Netherlands, New Zealand, Norway, Sweden, Taiwan, Thailand, United Kingdom, and United States. Time series analyses, including Mann-Kendall (MK) trend test, Bayesian Information Criterion (BIC), and hierarchal clustering, were performed to characterize trends in the HDV timelines. An aggregated prevalence of 2,560 HDV/HBV100,000 cases (95% CI 180-4940) or 2.56% HDV/HBV cases was identified, ranging from 0.26% in Canada to 20% in the United States. Structural breaks in the timeline of HDV incidence were identified in 2002, 2012, and 2017, with a significant increase occurring between 2013-2017. Significant increasing trends in reported HDV and HBV cases were observed in 47% and 24% of datasets, respectively. Analyses of the HDV incidence timeline identified four distinct temporal clusters, including Cluster I (Macao, Taiwan), Cluster II (Argentina, Brazil, Germany, Thailand), Cluster III (Bulgaria, Netherlands, New Zealand, United Kingdom, United States) and Cluster IV (Australia, Austria, Canada, Finland, Norway, Sweden). Tracking of HDV and HBV cases on an international scale is essential in defining the global impact of viral hepatitis. Significant disruptions of HDV and HBV epidemiology have been identified. Increased surveillance of HDV is warranted to further define the etiology of the recent breakpoints in the international HDV incidence.

Astroviruses (AstVs) can cause of severe infection of the central nervous system (CNS) in immunocompromised individuals. Here, we identified a human AstV of the VA1 genotype, HAstV-NIH, as the cause of fatal encephalitis in an immunocompromised adult. We investigated the cells targeted by AstV, neurophysiological changes, and host responses by analyzing gene expression, protein expression, and cellular morphology in brain tissue from three cases of AstV neurologic disease (AstV-ND). We demonstrate that neurons are the principal cells targeted by AstV in the brain and that the cerebellum and brainstem have the highest burden of infection. Detection of VA1 AstV in interconnected brain structures such as thalamus, deep cerebellar nuclei, Purkinje cells, and pontine nuclei indicates that AstV may spread between connected neurons transsynaptically. We found transcriptional dysregulation of neural functions and disruption of both excitatory and inhibitory synaptic innervation of infected neurons. Importantly, transcriptional dysregulation of neural functions occurred in fatal cases, but not in a patient that survived AstV-ND. We show that the innate, but not adaptive immune response was transcriptionally driving host defense in the brain of immunocompromised patients with AstV-ND. Both transcriptome and molecular pathology studies showed that most of the cellular changes were associated with CNS-intrinsic cells involved in phagocytosis and injury repair (microglia, perivascular/parenchymal border macrophages, and astrocytes), but not CNS-extrinsic cells (T and B cells), suggesting an imbalance of innate and adaptive immune responses to AstV infection in the brain as a result of the underlying immunodeficiencies. These results show that VA1 AstV infection of the brain in immunocompromised humans is associated with imbalanced host defense responses, disruption of neuronal somatodendritic compartments and synapses and increased phagocytic cellular activity. Improved understanding of the response to viral infections of the human CNS may provide clues for how to manipulate these processes to improve outcomes.

Abstract Background Hepatitis Delta Virus (HDV) is a rare infectious disease that requires a helper virus (ex. Hepatitis B Virus (HBV)) for transmission. Worldwide, it is estimated that 12-72 million individuals are infected with HDV. Within the United States, an accurate measure of HDV prevalence is attenuated by limited testing and variable notifiable disease status. Recent reports have noted a significant shift in the international HDV epidemiology. This retrospective study was designed to further evaluate the prevalence and clinical features of HDV and HBV within the Utahn patient population. Methods Within University of Utah Health, patient demographics, diagnostic codes (ICD9, ICD10) for HBV and HDV, CPT test codes and lab results were evaluated from 2000-2020. Univariate and multivariate analyses were performed. Timeseries analyses, including Mann-Kendall (MK) trend test, Bayesian Information Criterion (BIC) and Autoregressive Integrated Moving Average (ARIMA) were performed to characterize trends in HDV and HBV prevalence. Results Between 2000-2020, 2878 HBV and 180 HDV patients were identified within the University of Utah Health system. The median age of the HBV and HDV patients was 45 years with 56% males and 42 years with 60% males, respectively. 10% of all HBV-tested patients were tested for HDV. The positivity rate of patients tested for HDV was 7%. Statistical analysis of race and ethnicity showed a significant difference in incidence and testing rates among the Utahn Asian population when compared against non-Asian populations. A significant increasing trend in the incidence of both HBV (MK=156, p=2.8e-6) and HDV (MK=83, p=0.01) was observed between 2000-2020. Within the timeframe analyzed, two structural breaks were observed for HDV/HBV incidence ratio. Conclusion Together, our analysis suggests a significant change in the incidence of HDV and, due to the global temporal trend observed, may be suggestive of a change in HDV transmission pattern. Active surveillance of HDV in the United States and worldwide is warranted to further define these observed changes in HDV incidence. Disclosures All Authors: No reported disclosures.

AbstractHepatitis delta virus (HDV) has been detected in the minor salivary gland (MSG) tissue of Sjogren’s Syndrome (SjS) patients in the absence of an HBV co-infection. HDV antigen expression was previously shown to trigger an SjS-like phenotype in vivo, demonstrating a cause-and-effect association. We hypothesize that if HDV regulates SjS development, then HDV profiles may correlate with disease manifestations. This retrospective study characterized HDV in a cohort of 48 SjS MSG between 2014-2021. Analyses of HDV antigen (HDAg) expression, including cell type and subcellular localization,in situhybridization of HDV RNA, and comparative analyses with associated SjS and viral hepatitis clinical features were conducted. HDAg was detected in MSG acinar, ductal, and adipose cells. HDAg localized with nuclei and mitochondria. HDV genomic RNA localized to the nucleus. A significant negative correlation was noted between HDAg intensity and focal lymphocytic inflammation. No significant associations were detected between MSG-localized HDAg and liver enzymes, or an evident HBV co-infection. This study has identified a non-hepatic reservoir for chronic HDV persistence in SjS-affected MSG and a unique mitochondrial localization for HDV antigen. Detection of non-hepatic HDV-mediated disease in the absence of an evident current or past HBV co-infection warrants further investigation.

Hepatitis delta virus (HDV) has been detected in the minor salivary gland (MSG) tissue of Sjogren’s Syndrome (SjS) patients in the absence of an HBV co-infection. HDV antigen expression was previously shown to trigger an SjS-like phenotype in vivo, demonstrating a cause-and-effect association. We hypothesize that if HDV regulates SjS development, then HDV profiles may correlate with disease manifestations. This retrospective study characterized HDV in a cohort of 48 SjS MSG between 2014-2021. Analyses of HDV antigen (HDAg) expression, including cell type and subcellular localization, in situ hybridization of HDV RNA, and comparative analyses with associated SjS and viral hepatitis clinical features were conducted. HDAg was detected in MSG acinar, ductal, and adipose cells. HDAg localized with nuclei and mitochondria. HDV genomic RNA localized to the nucleus. A significant negative correlation was noted between HDAg intensity and focal lymphocytic inflammation. No significant associations were detected between MSG-localized HDAg and liver enzymes, or an evident HBV co-infection. This study has identified a non-hepatic reservoir for chronic HDV persistence in SjS-affected MSG and a unique mitochondrial localization for HDV antigen. Detection of non-hepatic HDV-mediated disease in the absence of an evident current or past HBV co-infection warrants further investigation.### Competing Interest StatementThe authors have declared no competing interest.

ABSTRACT The incidence of infections of the central nervous system (CNS) in humans is increasing due to emergence and reemergence of pathogens and an increase in the number of immunocompromised patients. Many viruses are opportunists and can invade the CNS if the immune response of the host is impaired. Here we investigate neuropathogenesis of a rare CNS infection in immunocompromised patients caused by astrovirus and show that it shares many features with another opportunistic infection of the CNS caused by human immunodeficiency virus. We show that astrovirus infects CNS neurons with a major impact on the brainstem. In the setting of impaired peripheral adaptive immunity, host responses in the astrovirus infected brain are skewed to the innate immune response with exuberant activation of microglia and macrophages. Astrovirus infection of neurons and responses by phagocytic cells lead to disrupted synaptic integrity, loss of afferent innervation related to infected neurons, and global impairment of both excitatory and inhibitory neurotransmission. The response employed in the CNS against opportunistic viruses, such as astrovirus and HIV, may be a common compensatory defense mechanism which inadvertently leads to loss of neural functions due to the host’s exuberant innate immune response to pathogens when adaptive immunity is impaired.

Abstract Background Dental practitioners and students of dentistry are potentially at increased risk of COVID-19 infection due to frequent usage of aerosol-generating procedures. To mitigate risk to patients and providers, the University of Utah School of Dentistry began regular surveillance PCR testing of its patient-facing faculty, staff, and students in May 2020. Methods Surveillance testing occurred every other week for non-vaccinated individuals and continued through February 2022. After May 2021, fully vaccinated individuals were tested monthly and encouraged to seek additional testing if symptoms or an exposure occurred. We assessed risk of positive test among faculty, student, and staff groups through a Cox proportional hazards regression, accounting for multiple events and time-dependent variables with the Andersen-Gill model. To account for inconsistent testing after vaccination, time was examined as number of tests rather than calendar time. Results In total, 410 participants were followed during the observation period, with an average of 22 (SD 10.0, RNG 1-50) tests per person. A total of 9,452 tests were performed. There were 158 positive tests, with 60 (38%) occurring in January 2022 alone. When analyzed by themselves, staff and student groups were significantly more likely to test positive (HR 1.98, 95% CI 1.15-3.42; HR 2.16, 95% CI 1.29-3.63 respectively) compared to faculty. However, once additional covariates were accounted for, the relationship was no longer significant (Staff: HR 2.15, 95% CI 0.92-5.05; Students: HR 2.38, 95% CI 0.88-6.40). Risk of COVID-19 within Dental School Hazard Ratios for testing positive for COVID-19 among different groups within the dental school. Vaccination is accounted for as time since last vaccine, with separate categories for one dose, and 2 or more doses combined. Time examined as test number. Conclusion More than a third of all positive tests during the 22-month study occurred during one month of the Omicron wave. This sudden increase in positive tests was not observed in previous surges, and demonstrates the intensity of the Omicron wave. Additionally, we did not find a significant difference between patient-facing groups who had different work exposures. While this may be due to effective preventative measures, within the dental setting we do not see evidence that work role and resulting exposures increase risk. Disclosures All Authors: No reported disclosures.

ABSTRACT Background & Aims The international incidence of Hepatitis Delta Virus (HDV) is challenging to accurately estimate due to limited testing and lack of active surveillance for this rare infectious disease. These limitations prevent the detection of low-level and/or geographically dispersed changes in the incidence of HDV diagnoses. A study was designed to enable international active tracking and analyses of HDV epidemiology by aggregating international HDV and Hepatitis B Virus (HBV) diagnoses datasets. Methods Publicly accessible datasets containing yearly incidence for HDV and HBV diagnoses were mined from government publications for Argentina, Australia, Austria, Brazil, Bulgaria, Canada, Finland, Germany, Macao, Netherlands, New Zealand, Norway, Sweden, Taiwan, Thailand, United Kingdom, and United States. The Bayesian Information Criterion (BIC) was used to determine the best-fitting breakpoint model for the number of breakpoints and the break dates identified using the determined model. Results Aggregated analysis of these HDV and HBV datasets spanning 1999-2020 identified structural breaks in the timeline of HDV incidence in 2002, 2012, and 2017. A significant increase in the international HDV incidence, relative to reported HBV diagnoses, occurred in 2013-2017. Secondary analysis identified four distinct temporal clusters of HDV incidence, including Cluster I (Macao, Taiwan), Cluster II (Argentina, Brazil, Germany, Thailand), Cluster III (Bulgaria, Netherlands, New Zealand, United Kingdom, United States), and Cluster IV (Australia, Austria, Canada, Finland, Norway, Sweden). Conclusion Re-evaluation of the testing paradigm for HDV in HBV-positive patients and an active surveillance status of HDV are warranted to define the etiology of the structural breaks in HDV incidence timelines.

Background Dry mouth currently affects roughly 20% of the population and is a condition characterized by chronic hyposalivation and/or subjective reports of xerostomia. Low saliva flow can be indicative of other undiagnosed diseases, such as primary Sjogren’s syndrome, and may contribute to difficulty chewing, increased caries susceptibility and infection. The passive drool test (PDT) is the primary method used to evaluate patients for hyposalivation but it is time-consuming and inconvenient. New methodology is needed to facilitate increased testing for hyposalivation in the dental clinic. The aim of this study was to evaluate an alternative method to measure salivary flow in dental offices. Methods In this study, we tested a new biomedical device, the BokaFlo™, to measure salivary flow in subjects in comparison to the current PDT standard. Participants completed an oral health questionnaire and saliva flow was evaluated by the PDT and the BokaFlo™ system. Results Saliva flow as measured by the BokaFlo™ positively correlated with the saliva flow measured by the PDT methodology (r = 0.22, p < 0.05). The device predicted low saliva flow in subjects with a sensitivity of 0.76 and specificity of 0.84 for subjects with hyposalivation, defined as a saliva flow rate of ≤ 0.1 ml/min. A significant negative correlation between the total oral health questionnaire score and the likelihood of participant exhibiting low salivary flow was observed (r = − 0.31, p < 0.006). Conclusion The BokaFlo™ was effectively able to measure low saliva flow correlating with the PDT methodology and may provide more efficient testing of saliva flow in the dental office.

Background.A significant increase in the yearly incidence of hepatitis delta virus (HDV) diagnosis in hepatitis B virus (HBV) patient populations has been identified through analysis of global infectious disease datasets.Currently, HDV is classified as a non-notifiable infectious disease in many countries around the world.Kuschner et al. reported over 90% of HBV-positive patients are not being tested for HDV (2015).Together, the non-notifiable status of HDV and the noncompliance in testing potential HDV carriers presents a significant barrier in active surveillance of changes in the incidence of HDV.Therefore, a study was designed to evaluate the global incidence of HDV using datamining approaches.Methods.Datasets containing yearly HDV and HBV incidence were utilized in this study including the National Health and Nutritional Examination Survey (NHANES) datasets and 14 additional datasets obtained through data-mining of global infectious disease datasets.These global datasets of reported yearly HDV and HBV diagnoses and demographic data ranging between 1999 and 2016 were analyzed.Results.Epidemiological analysis of infectious disease datasets from 15 countries identified a significant increase in the incidence of HDV relative to HBV-positive patients starting in 2011.Within the United States, analysis of NHANES datasets identified an increase in the incidence of HDV diagnosis among HBV-positive individuals from 5% in 1999-2010 to 58% in 2016.Comparative analysis of the yearly reported incidence of HDV and HBV in 14 additional countries identified a significant increase in the incidence of HDV in the same time period.Modeling of the collective spatiotemporal profile of the increase in HDV incidence is suggestive of a shared common intermittent exposure pattern of infection.The fastest growing demographic in the HDV-positive populations is in patients greater than 65 years of age.Conclusion.Our analysis identified a significant increase in the incidence of HDV diagnoses spanning three continents starting in 2011 and may be suggestive of an alteration in HDV transmission pattern.Active surveillance of HDV in the United States and worldwide is warranted to further define these observed changes in HDV incidence.