Sex-specific associations between plasma interleukin-6 and depression in persons with and without HIV.

Background: Persons with HIV (PWH) have both more frequent depression and higher levels of plasma inflammatory biomarkers compared to persons without HIV (PWoH). Inflammation and depressive symptoms are linked, including in PWH; however, it is unclear whether these associations differ by HIV serostatus and biological sex. Methods: Six plasma inflammatory biomarkers were assessed using samples from PWH and PWoH who participated in six NIH-funded studies through the UCSD HIV Neurobehavioral Research Program (HNRP) from 2011 to 2019. Factor analysis was performed to identify intercorrelated groups of biomarkers. Factors and their components were then examined for relationships with Beck Depression Inventory-II (BDI-II) and modifying effects of sex or HIV serostatus using multivariable linear regression, adjusting for demographics, substance use diagnoses, and relevant co-morbidities. Results: Participants included 150 PWH (age = 48.3 ± 13.1 yr; 88% biologically male) and 138 PWoH (age = 46.3 ± 15.9; 56% male). Two inflammatory factors were identified: Factor 1 loaded on interleukin-6 (IL-6), C-reactive protein (CRP), and D-dimer; Factor 2 loaded on interleukin-8, chemokine C-C ligand 2 (CCL2), and chemokine C-X-C ligand 10 (CXCL10). Sex modified the effect of Factor 1 on BDI-II, with a more positive association for men than women (p = 0.04). No significant association between Factor 2 and BDI-II was found. Of the biomarkers in Factor 1, only IL-6 was significantly associated with BDI-II and was modified by sex (p = 0.003). In sex-stratified analysis, a positive association was found for men (ß = 5.42; 95% confidence interval = [1.32, 9.52]) but not women (ß = -3.88; 95% C.I. = [-11.02, 3.26]). No HIV-related interactions were detected. Interpretation: We identified a depression-associated inflammatory factor present in both PWH and PWoH, consistent with prior studies of PWH only. The association was driven by a correlation between IL-6 and depression exclusively in men, suggesting that the depression-inflammation link differs by sex. Future studies of depression etiology or treatment, including those on persons with HIV, should consider the impact of biological sex in both design and analysis.

Effects of clinical, comorbid, and social determinants of health on brain ageing in people with and without HIV: a retrospective case-control study.

BACKGROUND: Neuroimaging reveals structural brain changes linked with HIV infection and related neurocognitive disorders; however, group-level comparisons between people with HIV and people without HIV do not account for within-group heterogeneity. The aim of this study was to quantify the effects of comorbidities such as cardiovascular disease and adverse social determinants of health on brain ageing in people with HIV and people without HIV. METHODS: In this retrospective case-control study, people with HIV from Washington University in St Louis, MO, USA, and people without HIV identified through community organisations or the Research Participant Registry were clinically characterised and underwent 3-Tesla T1-weighted MRI between Dec 3, 2008, and Oct 4, 2022. Exclusion criteria were established by a combination of self-reports and medical records. DeepBrainNet, a publicly available machine learning algorithm, was applied to estimate brain-predicted age from MRI for people with HIV and people without HIV. The brain-age gap, defined as the difference between brain-predicted age and true chronological age, was modelled as a function of clinical, comorbid, and social factors by use of linear regression. Variables were first examined singly for associations with brain-age gap, then combined into multivariate models with best-subsets variable selection. FINDINGS: In people with HIV (mean age 44·8 years [SD 15·5]; 78% [296 of 379] male; 69% [260] Black; 78% [295] undetectable viral load), brain-age gap was associated with Framingham cardiovascular risk score (p=0·0034), detectable viral load (>50 copies per mL; p=0·0023), and hepatitis C co-infection (p=0·0065). After variable selection, the final model for people with HIV retained Framingham score, hepatitis C, and added unemployment (p=0·0015). Educational achievement assayed by reading proficiency was linked with reduced brain-age gap (p=0·016) for people without HIV but not for people with HIV, indicating a potential resilience factor. When people with HIV and people without HIV were modelled jointly, selection resulted in a model containing cardiovascular risk (p=0·0039), hepatitis C (p=0·037), Area Deprivation Index (p=0·033), and unemployment (p=0·00010). Male sex (p=0·078) and alcohol use history (p=0·090) were also included in the model but were not individually significant. INTERPRETATION: Our findings indicate that comorbid and social determinants of health are associated with brain ageing in people with HIV, alongside traditional HIV metrics such as viral load and CD4 cell count, suggesting the need for a broadened clinical perspective on healthy ageing with HIV, with additional focus on comorbidities, lifestyle changes, and social factors. FUNDING: National Institute of Mental Health, National Institute of Nursing Research, and National Institute of Drug Abuse.

Assessment of Dentist Participation in Public Insurance Programs for Children in the US.

Importance: Evaluating the availability of dentists to provide dental care services to children is important for identifying interventions for improving access. Objective: To assess dental care availability for children in the US by public insurance participation, rural-urban setting, and dentist taxonomy (general, pediatric, or specialized). Design, Setting, and Participants: This cross-sectional study analyzed the availability of dentists from matching 3 data sets: the 2020 National Plan and Provider Enumeration System, the 2019-2020 State Board of Dentistry information acquired from each state, and the 2019 InsureKidsNow.org database. Data on active dentists in most states (including the District of Columbia [combined hereinafter with states] and excluding Hawaii and Washington) were included in the analysis. The study was conducted from January 2019 to March 2022. Main Outcomes and Measures: The number and percentage of dentists participating in public insurance programs (Medicaid and/or Children's Health Insurance Program [CHIP]) were aggregated at the dental office and stratified by the rurality of their practice and taxonomy. State-level comparisons were derived between this study and reports from the Health Policy Institute of the American Dental Association, along with maps and summary statistics disseminated through a data portal and state reports. Results: Among 204 279 active dentists, participation in public insurance varied widely across states, especially for the states that manage the Medicaid and CHIP programs separately. Participation rates in Medicaid and CHIP varied substantially from those of the Health Policy Institute of the American Dental Association. Participation in Medicaid and CHIP was lowest among urban dentists (Medicaid, 26%; CHIP, 29%) and highest among rural dentists (Medicaid, 39%; CHIP, 40%), while urban dentists accounted for most of the dentist population (urban, 84%; rural, 5%). Similarly, participation in Medicaid and CHIP was substantially lower among general dentists (Medicaid, 28%; CHIP, 29%) vs pediatric dentists (57% in both programs), while each state's dentist population consisted of notably more general (84%) than pediatric (3%) dentists. Nearly half of the states revealed wide variations in Medicaid and CHIP participation between counties, ranging from no participation (21 states) to full participation (22 states). Conclusions and Relevance: The findings of this study suggest that disparities in the availability of dentists for pediatric dental care are extensive, particularly for Medicaid- and CHIP-insured children, those living in rural communities, and those receiving specialized care. Lack of dentist availability for Medicaid- and CHIP-insured children appears to deter access to receiving dental care.

The effect of a fennel seed extract on the STAT signaling and intestinal barrier function.

BACKGROUND: Foeniculum vulgare, F. vulgare, commonly known as fennel, is believed to be one of the world's oldest medicinal herbs and has been exploited by people for centuries as a nutritional aid for digestive disorders. In many southeast Asian countries, it is ingested as an after-meal snack, mukhvas, due to its breath-freshening and digestive aid properties. F. vulgare is used in some countries, such as Iran, as a complementary and alternative treatment for inflammatory bowel disease (IBD). METHODS: This study investigated the effects of fennel seed extract on intestinal epithelium barrier function and the Signal Transducer and Activator of Transcription (STAT) pathway. This pathway is active in inflammatory bowel disease. To study the protective effects of fennel seed extract in vitro, monolayers derived from the T84 colonic cell line were challenged with interferon-gamma (IFN-γ) and monitored with and without fennel seed extract. To complement our in vitro studies, the dextran sodium sulfate induced murine colitis model was employed to ascertain whether the protective effect of fennel seed extract can be recapitulated in vivo. RESULTS: Fennel seed extract was shown to exert a protective effect on transepithelial electrical resistance (TEER) in both T84 and murine models and showed increases in tight junction-associated mRNA in T84 cell monolayers. Both models demonstrated significant decreases in phosphorylated STAT1 (pSTAT1), indicating reduced activation of the STAT pathway. Additionally, mice treated with fennel seed showed significantly lower ulcer indices than control mice. CONCLUSIONS: We conclude barrier function of the gastrointestinal tract is improved by fennel seed extract, suggesting the potential utility of this agent as an alternative or adjunctive therapy in IBD.

Internet search patterns reveal clinical course of COVID-19 disease progression and pandemic spread across 32 countries.

Effective public health response to novel pandemics relies on accurate and timely surveillance of pandemic spread, as well as characterization of the clinical course of the disease in affected individuals. We sought to determine whether Internet search patterns can be useful for tracking COVID-19 spread, and whether these data could also be useful in understanding the clinical progression of the disease in 32 countries across six continents. Temporal correlation analyses were conducted to characterize the relationships between a range of COVID-19 symptom-specific search terms and reported COVID-19 cases and deaths for each country from January 1 through April 20, 2020. Increases in COVID-19 symptom-related searches preceded increases in reported COVID-19 cases and deaths by an average of 18.53 days (95% CI 15.98-21.08) and 22.16 days (20.33-23.99), respectively. Cross-country ensemble averaging was used to derive average temporal profiles for each search term, which were combined to create a search-data-based view of the clinical course of disease progression. Internet search patterns revealed a clear temporal pattern of disease progression for COVID-19: Initial symptoms of fever, dry cough, sore throat and chills were followed by shortness of breath an average of 5.22 days (3.30-7.14) after initial symptom onset, matching the clinical course reported in the medical literature. This study shows that Internet search data can be useful for characterizing the detailed clinical course of a disease. These data are available in real-time at population scale, providing important benefits as a complementary resource for tracking pandemics, especially before widespread laboratory testing is available.

Cause-specific effects of radiotherapy and lymphadenectomy in stage I-II endometrial cancer: a population-based study.

BACKGROUND: Radiotherapy and lymphadenectomy have been associated with improved survival in population-based studies of endometrial cancer, which is in contrast with findings from randomized trials and meta-analyses. The primary study aim was to estimate the cause-specific effects of adjuvant radiotherapy and lymphadenectomy on competing causes of mortality. METHODS: We analyzed Surveillance, Epidemiology, and End Results (SEER) data from 1988 to 2006. The sample comprised 58172 patients with stage I and II endometrial adenocarcinoma. Patients were risk stratified by stage, grade, and age. Cumulative incidences and cause-specific hazards of competing causes of mortality were estimated according to treatment. All statistical tests were two-sided. RESULTS: Pelvic radiotherapy was associated with statistically significantly increased endometrial cancer mortality (hazard ratio [HR] = 1.66; 95% confidence interval [CI] = 1.52 to 1.82) in all stage I and II patients and decreased noncancer mortality in intermediate and high-risk stage I and II patients (HR = 0.82; 95% CI = 0.77 to 0.89). Lymphadenectomy was associated with increased endometrial cancer mortality in stage I patients (HR = 1.27; 95% CI = 1.16 to 1.39), decreased endometrial cancer mortality in stage II patients (HR = 0.61; 95% CI = 0.52 to 0.72), and decreased noncancer mortality in both stage I and II patients (HR = 0.84; 95% CI = 0.80 to 0.88). Effects of radiotherapy and lymphadenectomy on second cancer mortality varied according to risk strata. CONCLUSIONS: Radiotherapy and lymphadenectomy are associated with statistically significantly reduced noncancer mortality in stage I and II endometrial cancer. The improved overall survival associated with these treatments reported from SEER studies is largely attributable to their selective application in healthier patients rather than their effects on endometrial cancer.

Inhibition of phosphodiesterase-4 decreases ethanol intake in mice.

RATIONALE: Cyclic AMP (cAMP)-protein kinase A signaling has been implicated in the regulation of ethanol consumption. Phosphodiesterase-4 (PDE4) specifically hydrolyzes cAMP and plays a critical role in controlling intracellular cAMP levels in the brain. However, the role of PDE4 in ethanol consumption remains unknown. OBJECTIVE: The objective of this study is to examine whether PDE4 was involved in regulating ethanol intake. METHODS: The two-bottle choice paradigm was used to assess intake of ethanol, sucrose, and quinine in C57BL/6J mice treated with the selective PDE4 inhibitor rolipram or Ro 20-1724; locomotor activity was also monitored using the open-field test in mice treated with rolipram. RESULTS: Administration (i.p.) of either rolipram (0.25 and 0.5 mg/kg) or Ro 20-1724 (10 mg/kg) reduced ethanol intake and preference by 60-80%, but did not alter total fluid intake. In contrast, rolipram even at the higher dose of 0.5 mg/kg was not able to affect intake of sucrose or quinine, alcohol-induced sedation, or blood ethanol elimination. At 0.5 mg/kg, rolipram did decrease locomotor activity, but the effect only lasted for approximately 40 min, which did not likely affect behavior of ethanol drinking. CONCLUSIONS: These results suggest that PDE4 is a novel target for drugs that reduce ethanol intake; PDE4 inhibitors may be used for treatment of alcohol dependence.