Aditi Bhargava

Maternal stressors during pregnancy are linked to adverse birth outcomes, but the biochemical pathways involved remain poorly defined. We previously reported that the human placenta buffers the fetus from several effects of maternal perceived stress in a cohort of term pregnancies. Here, using the same cohort and no additional participants, we analyze a broader steroid panel and, for the first time, a targeted bile acid metabolomic panel across four maternal–fetal compartments: maternal plasma, placental tissue, cord plasma, and maternal hair. Nulliparous women were recruited during the third trimester at UCSF Mission Bay Hospital; perceived stress was measured using the 10-item Perceived Stress Scale (PSS) and retained as a continuous variable for the primary analysis from 17 women. Of 212 analyte compartment pairs evaluated, 38 metabolites met a predefined detectability criterion and were tested for association with PSS and sociodemographic scores using Kendall’s tau b, with permutation p-values, bootstrap confidence intervals, and Benjamini–Hochberg correction for multiple comparisons. No association survived multiple testing corrections. In exploratory, uncorrected comparisons (p < 0.05), three metabolites were nominally lower in a cohort-derived, higher-PSS group: placental estrone (E1), cord plasma glycochenodeoxycholic acid (GCDCA), and maternal plasma ursodeoxycholic acid (UDCA). Nearly 47.1% of women had gestational diabetes; 20-hydroxyprogesterone (20-OH-PROG) in maternal plasma, dihydroprogesterone (DHP), and pregnenolone (PELN) in placental tissues were nominally decreased in women who developed gestational diabetes compared to women who did not develop gestational diabetes. Maternal hair was not a good compartment for detection of bile acid metabolites. Despite a wide range of perceived stress/sociodemographic scores and a substantial burden of maternal clinical comorbidities in this cohort, all pregnancies resulted in favorable neonatal outcomes at delivery. These findings support the hypothesis that the placenta functions as a buffering organ that protects the developing fetus against broad insults while remaining susceptible to more selective disruptions.

Introduction: Extrapulmonary tuberculosis (EPTB) is rising in India and carries higher case fatality than pulmonary tuberculosis (PTB). A Phase III trial of VPM1002 missed its primary composite endpoint, but secondary endpoints showed a stronger EPTB signal (vaccine efficacy 42·3%, 95% CI −9·1 to 69·4). We identified no published model resolving tuberculosis by disease type, nutritional and socioeconomic status, and dose event against a dynamic baseline. Methods: We built a deterministic model with 1,152 population compartments (72 strata by age, HIV status, body-mass index and socioeconomic status), calibrated to WHO India incidence and mortality for 2015–2024. Separate PTB and EPTB effectiveness posteriors, derived by Bayesian evidence synthesis of the trial’s per-protocol and modified intention-to-treat estimates, were propagated through 1,000 Monte Carlo iterations. Three doses were modeled at 10-year intervals assuming 3 or 10 years of protection. Economic analysis used societal and health-system perspectives with 3% discounting. Results: Posterior median effectiveness was higher against EPTB (42·9%, 95% credible interval [CrI] −5·6 to 69·1) than PTB (14·0%, −19·0 to 37·9). Per 1,000,000 targeted under 10-year protection, three doses averted 5,218 cases (95% uncertainty interval 153–10,157), 682 deaths (24–1,255) and 9,463 disability-adjusted life-years (DALYs; 328–17,404); under 3-year protection, 1,961 cases and 3,708 DALYs. EPTB accounted for about two-thirds of averted deaths and DALYs but about half of averted cases. Under 10-year protection, the first booster added 46% more cases and 34% more DALYs at an incremental benefit–cost ratio of 19·1 (initial dose 20·7); the second booster added 8% more cases and 4·5% more DALYs at 6·8. Median gross incremental cost-effectiveness ratios were US$329 (10-year) and US$832 (3-year) per DALY averted. Conclusion: Composite-endpoint models cannot show this dissociation. A booster a decade later was nearly as economically efficient but averted less disease. This is an adolescent and adult booster program, not a replacement for infant BCG. What is already known on this topic: TB vaccine modeling studies for India and other high burden settings have relied on aggregate single efficacy estimates that combine pulmonary and extrapulmonary disease into a single endpoint. Published models have evaluated vaccines against static programmatic baselines and a single course intervention, so the marginal value of revaccination has rarely been quantified. What this study adds: This 1,152 population compartment model tracks pulmonary and extrapulmonary TB as separate compartments with independently calibrated natural history and separately propagated Bayesian effectiveness posteriors. Vaccination history is preserved through disease treatment and recovery, so people infected after vaccination remain correctly identified as previously vaccinated and eligible for later doses; this becomes relevant only once boosting is modeled Extrapulmonary disease accounts for approximately 2/3 of averted deaths and DALYs against roughly half of averted cases, a dissociation that a composite endpoint model cannot provide. Seed-matched paired Monte Carlo makes each dose event’s marginal contribution directly estimable rather than inferential. How this study might affect research, practice or policy: Policy assessments anchored to composite endpoints, or assuming a single lifetime dose, may underestimate this vaccine’s population value. A single booster a decade after the initial dose is close to as economically efficient as the initial dose; a second booster is materially less so within a horizon to 2050. The framework is country- and candidate-agnostic and can be recalibrated for other high-burden settings and other vaccine candidates, including those evaluated in other Phase III trials. The schedule evaluated here is an adolescent and adult booster program and does not bear on infant BCG policy.

Maternal psychological stress during pregnancy is linked to adverse birth outcomes, but the biochemical pathways involved remain poorly defined. We previously reported that the human placenta buffers the fetus from several effects of maternal perceived stress in a cohort of term pregnancies. Here, we extend that cohort with a broader steroid panel and, for the first time, a targeted bile acid metabolomic panel across four maternal–fetal compartments: maternal plasma, placental tissue, cord blood, and maternal hair. Nulliparous women were recruited during the third trimester at UCSF Mission Bay Hospital and stratified into Low- and High-Perceived Stress Scale (PSS) groups using the 10-item PSS. Steroid and bile acid metabolites were quantified by UPLC–MS/MS and compared between groups using nonparametric methods. Most steroid and bile acid metabolites did not differ significantly between High-PSS and Low-PSS groups, consistent with a broadly preserved placental metabolic barrier. However, three metabolites were selectively reduced in the High-PSS group: placental estrone (E1), cord blood glycochenodeoxycholic acid (GCDCA), and maternal plasma ursodeoxycholic acid (UDCA) (all p < 0.05), while estradiol and estriol concentrations were unaffected. Maternal hair showed poor con-cordance with plasma and placental compartments, suggesting limited value as a non-invasive proxy for these analytes in this setting. These findings reinforce the concept that placental buffering of maternal stress is broadly selective rather than absolute and identify E1, GCDCA, and UDCA as candidate stress-sensitive metabolites for validation in larger, longitudinal cohorts.

Background: COVID-19 vaccine hesitancy has been widely studied using closed-ended survey instruments, yet the nuanced motivations underlying refusal remain poorly characterised. We aimed to identify and categorise the specific concerns driving COVID-19 vaccine refusal by analysing free-text survey responses from a global cohort using large language model (LLM) classification.Methods: The PROVES (Participant Responses on Vaccination and Evolving Skepticism) study was a cross-sectional, self-reported online survey conducted between Sept 3, 2022, and April 16, 2024. Participants aged 18 years or older with working English proficiency were recruited via exponential non-discriminative snowball sampling through university listservs, physician offices, and social media platforms across 95 countries. The primary outcome was the categorisation of free-text reasons for COVID-19 vaccine refusal. The Mistral LLM, integrated via the ollama Python library, was used to classify 7254 free-form responses from 3756 unvaccinated individuals into seven predefined thematic subcategories. Demographic characteristics were compared between vaccinated and unvaccinated groups using two-tailed t-tests and Mann-Whitney U tests.Findings: 7541 individuals participated, of whom 6916 provided sufficient data for subgroup analysis. 80·07% of participants were unvaccinated. The most frequently cited reason for refusal was safety concerns regarding mRNA technology, including characterisation of vaccines as "experimental" or "gene therapy" (3033 of 7254 responses [41·8%]). Institutional mistrust of pharmaceutical companies and government was the second most common reason (1354 [18·7%]), followed by autonomy and freedom of choice (691 [9·5%]), natural immunity from prior infection (317 [4·4%]), perceived lack of need (90 [1·2%]), prior vaccine injury or allergy (52 [0·7%]), and pregnancy-related concerns (25 [0·3%]). Despite high educational attainment across the cohort (≥87% held a college degree), hesitancy remained pronounced. Notably, only two of 7541 participants reported receiving no vaccines since childhood, suggesting that the overwhelming majority of COVID-19 vaccine-hesitant individuals were not broadly opposed to vaccination.Interpretation: In this self-selected, predominantly vaccine-hesitant cohort, COVID-19 vaccine refusal was driven primarily by specific technical concerns about mRNA vaccine safety and deep institutional mistrust rather than by general anti-vaccination ideology or low educational attainment. These findings suggest that public health strategies emphasising transparent communication about vaccine technology and acknowledging legitimate safety concerns may be more effective than enforcement-based approaches in addressing COVID-19 vaccine hesitancy. However, the non-probability sampling method and the heavily vaccine-hesitant composition of this cohort limit the generalisability of these findings to the broader population.

The contribution of pre-existing conditions to severe versus mild postacute sequelae (PASC) of SARS-CoV-2 in the population is lacking. Here, we evaluated reproductive and other PASC side-by-side in unvaccinated and vaccinated individuals after 1st SARS-CoV-2 infection. In an online global survey of 7,541 individuals from 95 countries, high grade fever (> 102˚F)/ hospitalization after a first SARS-CoV-2 infection were more likely to be reported by vaccinated males than unvaccinated males (13.64% vs. 8.34%; p = 0.0483; HR = 1.63 [95% CI: 1.008, 2.65]). Women reported experiencing more frequent PASC than men. More women than men reported vaccine-associated adverse events (AEs) after the 1st dose (60.85% vs 48.79%, p < 0.01). Vaccine-associated hospitalization was reported by 6.24% SARS-CoV-2 naïve respondents versus 1.06% of unvaccinated after 1st SARS-CoV-2 infection. Pre-existing thyroid disease, osteoporosis, and autoimmune disorders were more prevalent in women, whereas more men reported back problems, elevated cholesterol, and hypertension; several pre-existing conditions posed ≥ 2.0 relative risk of developing severe vs mild COVID-19. Individuals aged < 55 years had an absolute risk of 6.01%, whereas individuals ≥ 55 years had an absolute risk of 11.69% of getting severe vs mild COVID-19 disease. Vaccinated women reported significantly greater menstrual cycle-associated reproductive PASC compared to unvaccinated women. Vaccinated men reported hormonal changes and sexual dysfunction as reproductive PASC compared to unvaccinated men. A detailed and thorough follow-up is needed to better understand if pre-existing health conditions and/or vaccine-associated AEs exacerbated COVID-19 sequelae.

The influence of gut microbiome, metabolites, omics, hormones, and stress on general and mental health is increasingly being recognized. Ancient cultures recognized the importance of diet and gut health on the overall health of an individual. Western science and modern scientific methods are beginning to unravel the foundations and mechanisms behind some of the ancient beliefs and customs. The gut microbiome, an organ itself, is now thought to influence almost all other organs, ranging from the brain to the reproductive systems. Gut microbiome, metabolites, hormones, and biological sex also influence a myriad of health conditions that range from mental health disorders, obesity, gastrointestinal disorders, and cardiovascular diseases to reproductive health. Here, we review the history and current understanding of the gut–brain axis bidirectional talk in various mental health disorders with special emphasis on anxiety and depressive disorders, whose prevalence has increased by over 50% in the past three decades with COVID-19 pandemic being the biggest risk factor in the last few years. The vagal nerve is an important contributor to this bidirectional talk, but other pathways also contribute, and most remain understudied. Probiotics containing Lactobacillus and Bifidobacterium species seem to have the most impact on improvement in mental health symptoms, but the challenge appears to be maintaining sustained levels, especially since neither Lactobacillus nor Bifidobacterium can permanently colonize the gut. Ancient endogenous retroviral DNA in the human genome is also linked to several psychiatric disorders, including depression. These discoveries reveal the complex and intricately intertwined nature of gut health with mental health disorders.

Posttraumatic stress disorder (PTSD) can develop after trauma exposure. Some studies report that women develop PTSD at twice the rate of men, despite greater trauma exposure in men. Lipids and their metabolites (lipidome) regulate a myriad of key biological processes and pathways such as membrane integrity, oxidative stress, and neuroinflammation in the brain by maintaining neuronal connectivity and homeostasis. In this study, we analyzed the lipidome of 40 adults with PTSD and 40 trauma-exposed non-PTSD individuals (n = 20/sex/condition; 19–39 years old). Plasma samples were analyzed for lipidomics using Quadrupole Time-of-Flight (QToF) mass spectrometry. Additionally, ~ 90 measures were collected, on sleep, and mental and physical health indices. Poorer sleep quality was associated with greater PTSD severity in both sexes. The lipidomics analysis identified a total of 348 quantifiable known lipid metabolites and 1951 lipid metabolites that are yet unknown; known metabolites were part of 13 lipid subclasses. After adjusting for BMI and sleep quality, in women with PTSD, only one lipid subclass, phosphatidylethanolamine (PE) was altered, whereas, in men with PTSD, 9 out of 13 subclasses were altered compared to non-PTSD women and men, respectively. Severe PTSD was associated with 22% and 5% of altered lipid metabolites in men and women, respectively. Of the changed metabolites, only 0.5% measures (2 PEs and cholesterol) were common between women and men with PTSD. Several sphingomyelins, PEs, ceramides, and triglycerides were increased in men with severe PTSD. The correlations between triglycerides and ceramide metabolites with cholesterol metabolites and systolic blood pressure were dependent upon sex and PTSD status. Alterations in triglycerides and ceramides are linked with cardiac health and metabolic function in humans. Thus, disturbed sleep and higher body mass may have contributed to changes in the lipidome found in PTSD.

Posttraumatic stress disorder (PTSD) can develop after trauma exposure. Some studies report that women develop PTSD at twice the rate of men, despite greater trauma exposure in men. Lipids and their metabolites (lipidome) regulate a myriad of key biological processes and pathways such as membrane integrity, oxidative stress, and neuroinflammation in the brain by maintaining neuronal connectivity and homeostasis. In this study, we analyzed the lipidome of 40 individuals with PTSD and 40 trauma-exposed non-PTSD individuals. Plasma samples were analyzed for lipidomics using Quadrupole Time-of-Flight (QToF) mass spectrometry. Additionally, ∼ 90 measures were collected, on sleep, mental and physical health indices. Sleep quality worsened as PTSD severity increased in both sexes. The lipidomics analysis identified a total of 348 quantifiable known lipid metabolites and 1951 lipid metabolites that are yet unknown; known metabolites were part of 13 classes of lipids. After adjusting for sleep quality, in women with PTSD, only one lipid subclass, phosphatidylethanolamine (PE) was altered, whereas, in men with PTSD, 9 out of 13 subclasses were altered compared to non-PTSD women and men, respectively. Severe PTSD was associated with 22% and 5% of altered lipid metabolites in men and women, respectively. Of the changed metabolites, only 0.5% measures (2 PEs and cholesterol) were common between women and men with PTSD. Several sphingomyelins, PEs, ceramides, and triglycerides were increased in men with severe PTSD. The triglycerides and ceramide metabolites that were most highly increased were correlated with cholesterol metabolites and systolic blood pressure in men but not always in women with PTSD. Alterations in triglycerides and ceramides are linked with cardiac health and metabolic function in humans. Thus, disturbed sleep and higher weight may have contributed to changes in the lipidome found in PTSD.

COVID-19-associated intensive care unit (ICU) admissions were recognized as critical health issues that contributed to morbidity and mortality in SARS-CoV-2-infected patients. Severe symptoms in COVID-19 patients are often accompanied by cytokine release syndrome. Here, we analyzed publicly available data from the Yale IMPACT cohort to address immunological misfiring and sex differences in early COVID-19 patients. In 2020, SARS-CoV-2 was considered far more pathogenic and lethal than other circulating respiratory viruses, and the inclusion of SARS-CoV-2 negative patients in IMPACT cohorts confounds many findings. We ascertained the impact of several important biological variables such as days from symptom onset (DFSO); pre-existing risk factors, including obesity; and early COVID-19 treatments on significantly changed immunological measures in ICU-admitted COVID-19 patients that survived versus those that did not. Deceased patients had 19 unique measures that were not shared with ICU patients including increased granzyme-B-producing GzB⁺CD8⁺ T cells and interferon-γ. Male COVID-19 patients in ICU experienced many more changes in immunological and clinical measures than female ICU patients (25% vs. ~16%, respectively). A total of 13/124 measures including CCL5, CCL17, IL-18, IFNα2, Fractalkine, classical monocytes, T cells, and CD4Temra exhibited significant sex differences in female vs. male COVID-19 patients. A total of nine measures including IL-21, CCL5, and CD4Temra differed significantly between female and male healthy controls. Immunosuppressed patients experienced the most decreases in CD4Temra and CD8Tem cell numbers. None of the early COVID-19 treatments were effective in reducing levels of IL-6, a major component of the cytokine storm. Obesity (BMI >30) was the most impactful risk factor for COVID-19-related deaths and worst clinical outcomes. Our analysis highlights the contribution of biological sex, risk factors, and early treatments with respect to COVID-19-related ICU admission and progression to morbidity and mortality.

Summary: Introduction: Men reportedly experience more severe disease and adverse outcomes from COVID-19, including death. Women report more adverse events (AEs) after vaccination in general. While few studies have addressed sex-specific risk factors or molecular mechanisms behind COVID-19, none have examined sex differences in the response to COVID-19 vaccination. Methods: We searched AE reporting databases to find sex differences specific to COVID-19 vaccines. We analyzed public datasets to identify baseline sex differences in gene expression across cell types and time points, and sex differences in the response to the second BNT162b2 mRNA vaccine dose. Results: Sex differences in AE rates for mRNA vaccines equaled those for other non-mRNA vaccines. T cells and monocytes showed the greatest number of sexually dimorphic genes. Platelet counts in the study population differed significantly before vaccination (3.6% in females vs 1.8% in males) but not after the second BNT162b2 dose (7.2% vs 7.3%). There were no notable sex differences in the expression of key genes induced by the second dose after exclusion of platelets. BNT162b2 dose 2-specific APOBEC3A ^high monocytes and the dose 2-induced gene signature persisted for longer in women. Glucocorticoid-responsive TSC22D3, CEBPB/D and DDIT4 were specifically induced in females; the voltage-gated potassium channel regulatory subunit KCNE3 was specifically induced in males. Conclusions: This sexual dimorphism in both X-linked and autosomal gene transcriptome in PBMCs after mRNA COVID-19 vaccination might explain fatigue, autoimmune, and neurological AEs reported after vaccination at different rates in women and men.