Identification of RTS,S/AS01 vaccine-induced humoral biomarkers predictive of protection against controlled human malaria infection.

BACKGROUNDThe mechanism(s) responsible for the efficacy of WHO-recommended malaria vaccine RTS,S/AS01 are not completely understood. We previously identified RTS,S vaccine-induced Plasmodium falciparum circumsporozoite protein-specific (PfCSP-specific) antibody measures associated with protection from controlled human malaria infection (CHMI). Here, we tested the protection-predicting capability of these measures in independent CHMI studies.METHODSVaccine-induced total serum antibody (immunoglobulins, Igs) and subclass antibody (IgG1 and IgG3) responses were measured by biolayer interferometry and the binding antibody multiplex assay, respectively. Immune responses were compared between protected and nonprotected vaccinees using univariate and multivariate logistic regression.RESULTSBlinded prediction analysis showed that 5 antibody binding measures, including magnitude-avidity composite of serum Ig specific for PfCSP, major NANP repeats and N-terminal junction, and PfCSP- and NANP-specific IgG1 subclass magnitude, had good prediction accuracy (area under the receiver operating characteristic curves [ROC AUC] > 0.7) in at least 1 trial. Furthermore, univariate analysis showed a significant association between these antibody measures and protection (odds ratios 2.6-3.1). Multivariate modeling of combined data from 3 RTS,S CHMI trials identified the combination of IgG1 NANP binding magnitude plus serum NANP and N-junction Ig binding magnitude-avidity composite as the best predictor of protection (95% confidence interval for ROC AUC 0.693-0.834).CONCLUSIONThese results reinforce our previous findings and provide a tool for predicting protection in future trials.TRIAL REGISTRATIONClinicalTrials.gov NCT03162614, NCT03824236, NCT01366534, and NCT01857869.FUNDINGThis study was supported by Bill & Melinda Gates Foundation's Global Health-Discovery Collaboratory grants (INV-008612 and INV-043419) to GDT.

The Causes and Consequences of Stigma among Individuals Involved in the Criminal Legal System: A Systematic Review.

The purpose of this study was to systematically review the types of stigmatized attributes that have been assessed and the causes and consequences of stigma for individuals involved in the criminal legal system. PubMed, GoogleScholar, and PsycInfo databases were searched to identify studies for inclusion through March 2021. Eligible studies were peer-reviewed, quantitative, and assessed stigma from the perspective of the person involved in the criminal legal system. 59 studies were included (total n=21,738), assessing stigma associated with criminal involvement, HIV, substance use, race/ethnicity, help-seeking, and others. Experiencing criminal involvement stigma was linked to poor well-being, but less so for racial/ethnic minorities. Experiencing racial/ethnic stigma was associated with recidivism risk, and substance use stigma was associated with substance use risk. Several stigmas intersected to impact treatment engagement and well-being. In conclusion, individuals involved in the criminal legal system experience many stigmatized statuses that impact their well-being, treatment adherence, community integration, and criminal behavior. Stigma must be addressed among individuals involved in the criminal legal system and the systems they interact with to reduce health inequity and recidivism risk.

Successful Delayed Amputated Split-Thickness Dermis Reattachment of a Fingertip Injury in the Home Setting without Sutures.

Presentation: This case reports details a fingertip amputation injury. The patient was vitally stable post-injury and blood loss was controlled with direct pressure. Diagnosis: The injury was inspected and found to involve the finger pulp and nailbed, without exposure of the terminal phalanx (Allen 2). Treatment: The avulsed tissue was initially placed in situ at the site of the injury. At day 3 the viable dermis from the avulsed tissue was dissected away and a split-thickness dermal graft was performed. The graft was held in place with antibacterial dressings. Epithelialisation was complete at two weeks, sensation returned to normal at five months and progress was tracked with interval photography. Overall there was an excellent cosmetic and functional outcome. Discussion: Split-thickness grafting of the dermis has been previously described, but there are no reports of this technique being applied to fingertip injuries. De-epithelialisation may enhance the likelihood of graft survival when compared to composite grafting techniques.

Stress, Behavior, and Immune Function.

Background From the original studies investigating the effects of adrenal gland secretion to modern high throughput multi-dimensional analyses, stress research has been a topic of scientific interest spanning just over a century. Summary The objective of this review is to provide historical context for influential discoveries, accidental findings, breakthroughs, and pre-clinical models in stress-related neuroimmune research. Furthermore, we summarize the culmination of these findings and present a current understanding of the stress pathways and their effects on the immune system and behavior. We focus on recent work demonstrating stress-induced immune changes within the brain and highlight studies investigating stress effects on microglia. Lastly, we conclude with potential areas for future investigation concerning microglia heterogeneity, bone marrow niches, and sex differences. Key Messages Stress is a phenomenon that ties together not only the central and peripheral nervous system, but the immune system as well. The cumulative effects of stress can enhance or suppress immune function, based on the intensity and duration of the stressor. These stress-induced immune alterations are associated with neurobiological changes, including structural remodeling of neurons and decreased neurogenesis, and these contribute to the development of behavioral and cognitive deficits. As such, research in this field has revealed important insights into neuroimmune communication as well as molecular and cellular mediators of complex behaviors relevant to psychiatric disorders.

Sidestream dark field video microscopy demonstrates shelf-stable blood products preserve the endothelial glycocalyx in a canine hemorrhagic shock model.

OBJECTIVE: To utilize sidestream dark field video microscopic technology to evaluate the endothelium in a canine hemorrhagic shock and resuscitation model. METHODS: 6 purpose-bred adult dogs were anesthetized, instrumented, and subjected to hemorrhagic shock from September 2021 through June 2022. Each dog was resuscitated with 5 resuscitation strategies in an experimental crossover design study: (1) lactated Ringer's solution (LRS) and hydroxyethyl starch (HES) solution; (2) canine chilled whole blood (CWB); (3) canine fresh frozen plasma (FFP) and packed RBCs (pRBC); (4) canine freeze-dried plasma (FDP) and hemoglobin-based oxygen carrier (HBOC); or (5) HBOC/FDP and canine lyophilized platelets. Sidestream dark field video microscopic evaluation was performed at 5 time points: commencement, after hemorrhage, after shock, after resuscitation (T135), and conclusion (T180). RESULTS: There was a significant difference between the perfused boundary region (PBR) measurements when comparing the LRS/HES resuscitation arm to the CWB and FFP/pRBC resuscitation arms at T180. A significant difference in PBR was appreciated in the LRS/HES arm at T135 and T180 compared to its baseline. No other significant differences in PBR were appreciated when resuscitation arms were compared longitudinally or to each other. CONCLUSIONS: Shelf-stable blood products preserved the endothelial glycocalyx similarly to CWB and pRBC/FFP as evaluated by sidestream dark field video microscopy. Lactated Ringer and HES solutions did not adequately preserve the endothelial glycocalyx compared to CWB and pRBC/FFP. CLINICAL RELEVANCE: Shelf-stable blood products are a viable option to preserve the endothelial glycocalyx when used during hemorrhagic resuscitation in dogs.

Advancing the chemotherapy of tuberculous meningitis: a consensus view.

Tuberculous meningitis causes death or disability in approximately 50% of affected individuals and kills approximately 78 200 adults every year. Antimicrobial treatment is based on regimens used for pulmonary tuberculosis, which overlooks important differences between lung and brain drug distributions. Tuberculous meningitis has a profound inflammatory component, yet only adjunctive corticosteroids have shown clear benefit. There is an active pipeline of new antitubercular drugs, and the advent of biological agents targeted at specific inflammatory pathways promises a new era of improved tuberculous meningitis treatment and outcomes. Yet, to date, tuberculous meningitis trials have been small, underpowered, heterogeneous, poorly generalisable, and have had little effect on policy and practice. Progress is slow, and a new approach is required. In this Personal View, a global consortium of tuberculous meningitis researchers articulate a coordinated, definitive way ahead via globally conducted clinical trials of novel drugs and regimens to advance treatment and improve outcomes for this life-threatening infection.

Clinical and diagnostic features of central nervous system tuberculosis in Indian children - a descriptive study.

Background: Children with tuberculous meningitis (TBM) present with diagnostic challenges as they often have atypical clinical features. Objective: To describe the baseline characteristic features of children diagnosed with central nervous system (CNS) TB (TBM and tuberculoma). Design: Retrospective descriptive study. Methods: Children less than 12 years presenting with neurological signs and symptoms were assessed for a therapeutic TBM trial eligibility. The results of their clinical, laboratory, neuroimaging, cerebrospinal fluid evaluations were analysed for TBM diagnosis. Results: Of 600 children evaluated, 61(10%) had CNS tuberculosis; TBM 47, tuberculoma 14. 20(33%) had definite TBM. Mean age of children with TBM was 5 ± 3.4 years. Of 47, 13(28%), 21(45%) and 13(28%) had grade I, II, and III disease respectively. Abnormalities suggestive of TBM in MRI and computed tomography brain were observed in 76% (26/34) and 77% (24/31) respectively. Abnormal cerebrospinal fluid white blood cell count, protein and glucose were observed in 56% (24/43), 49% (22/45), 47% (21/45) respectively. Among 41 patients with TBM followed up until discharge, five died. Conclusion: Younger children with TBM have severe forms. Confirmatory results may not be available in all. A holistic approach to care including addressing complications of hydrocephalus and strokes is needed.

Clinical features, results of brain imaging and other tests in the cerebrospinal fluid among children diagnosed with tuberculous meningitis ­ descriptive study Why was the study done? What did the researchers do? Records of children aged between 6 months and 12 years who presented to the health care centre with signs and symptoms of central nervous system (CNS) disease and assessed for tuberculous meningitis (TBM) clinical trial eligibility were reviewed. The research team studied the signs and symptoms of the TBM, results of the CT/MRI brain scan and tests which were done in the cerebrospinal fluid (CSF) during hospitalization. What did the researchers find? Total number of children who presented to the health centre during the study period with CNS complaints and underwent lumbar puncture were 600. Among them 61 were diagnosed with CNS TB (47 had TBM and 14 had tuberculoma). Half of them were less than five years of age. Ten had neurological dysfunction. Fever, vomiting were the common complaints. Almost half of the children had vomiting, altered level of consciousness and seizures. Tests done in the CSF detected the bacteria causing TBM in half of the children. Abnormal cell counts or biochemical changes in the CSF specific to TBM were observed in half of the children. Abnormalities in CT/MRI imaging with features specific to the disease were observed in closer to three fourth of the children. What do the findings mean? Children with TBM often present late for care with severe forms and its complications. There would be diagnostic challenges as the symptoms were vague and might not present in a specific manner, specific tests in the CSF could be negative and if undiagnosed could lead to severe morbidity impacting the quality of life or death. Taking the overall picture of presenting complaints, results of CSF test and brain scan and with high degree of suspicion, TBM should be diagnosed early and managed appropriately.

In vivo confocal microscopic features of canine primary corneal squamous cell carcinoma.

OBJECTIVE: To describe the in vivo confocal microscopy (IVCM) findings in dogs with primary corneal squamous cell carcinoma (SCC). ANIMALS: Eight dogs with primary corneal SCC. PROCEDURES: Dogs diagnosed with primary corneal SCC by histopathology were examined with a modified Heidelberg Retina tomograph and Rostock Cornea Module prior to surgical intervention. The findings from the IVCM examination were correlated with clinical details from ophthalmic examinations and diagnostic test results. RESULTS: Eight eyes from eight dogs with unilateral primary corneal SCC were examined. Corneal lesions were characterized with IVCM by abnormal epithelial cells that were polygonal and enlarged with marked morphological variability and anisocytosis within individual corneas. The abnormal cells displayed variable reflectivity, but most had highly reflective cellular borders and moderately reflective cytoplasm. Cells that were markedly and diffusely hyperreflective were also occasionally observed possibly representing keratinization and dyskeratosis. On IVCM, neoplastic cells were grouped into cords, clusters, and sheets, and nests of neoplastic cells often invaded the underlying corneal stroma. Keratin pearls were a frequent finding and appeared as circular whirls of neoplastic epithelial cells arranged around concentric layers of hyperreflective amorphous material within a dark cyst-like space. Abundant blood vessels and scattered leukocytes were present in all tumors. There was a high degree of morphologic agreement between IVCM analysis and histopathological findings in all cases. CONCLUSIONS: The distinguishing features of primary corneal SCC during IVCM examine were similar to those seen in histopathologic examination of tumor sections, including enlarged and pleomorphic squamous epithelial cells, anisocytosis, keratin pearl formation, and dense vascularization.

Safety and immunogenicity after a 30-month boost of a subtype C ALVAC-HIV (vCP2438) vaccine prime plus bivalent subtype C gp120/MF59 vaccine boost (HVTN 100): A phase 1-2 randomized double-blind placebo-controlled trial.

Induction of broad, durable immune responses is a challenge in HIV vaccine development. HVTN 100 Part A administered subtype C-containing ALVAC-HIV at months 0 and 1, and ALVAC-HIV with bivalent subtype C gp120/MF59 at months 3, 6 and 12. As IgG binding antibody and T-cell responses were similar or greater at month 12.5 vs. month 6.5, but waned by month 18, we investigated vaccine-elicited immune responses after a month 30 boost in this study, HVTN 100 Part B. From 13 September 2017 to 7 August 2018, a subgroup of vaccinees was randomized to receive intramuscular injections of ALVAC+gp120/MF59 (n = 32) or gp120/MF59 alone (n = 31) and a subgroup of placebo recipients was administered placebo (n = 7) at month 30. Primary outcomes were safety, IgG binding antibodies (bAbs) to vaccine-specific and V1V2 Env proteins and vaccine-specific CD4+ T cells at month 30.5. Secondary outcomes included neutralizing and antibody dependent cellular cytotoxicity functions and durability at months 30 and 36. Both vaccine groups had an acceptable safety profile. There were no statistically significant differences in the occurrence or level of IgG bAbs between the vaccine boost groups for any vaccine-specific or V1V2 antigens. IgG responses were higher to vaccine-matched gp120 than to V1V2. The booster vaccination restored the magnitude-breadth IgG bAb response to V1V2 antigens at month 30.5. However, it rapidly waned by month 36. CD4+ T-cell response rates to the 3 vaccine-matched Env antigens for the combined vaccine groups ranged from 37% at month 30, boosted to as high as 91% at month 30.5, and waned by month 36 to as low as 44%, with no significant differences between the vaccine boost groups. Because these responses waned after 6 months, additional strategies may be needed to maintain the durability of prime-boost vaccine regimens and to generate these or other immune responses that confer protection. Trial registration: South African National Clinical Trials Register (SANCTR number: DOH-27-0215-4796) and ClinicalTrials.gov (NCT02404311).

Impact of post-operative transoral robotic surgery hemorrhage on adjuvant treatment delays in patients with oropharyngeal squamous cell carcinoma.

OBJECTIVES: Transoral robotic surgery (TORS) for the treatment for oropharyngeal squamous cell carcinoma (SCC) carries a risk of post-operative hemorrhage. Increased time from surgery to completion of adjuvant therapy has been associated with decreased survival. Our objective was to assess for adjuvant treatments delays in patients with post-operative bleeding. Secondarily, to assess post-operative swallowing outcomes. MATERIALS AND METHODS: Retrospective chart review of all patients who underwent TORS from 2014 to 2021 at a tertiary care center. Patient demographics, adjuvant therapy course, treatment-related dysphagia outcomes, incidence and severity of post-operative bleeding were reviewed. RESULTS: 221 patients underwent TORS, 160 (72%) of which were recommended to undergo adjuvant treatment. 33 patients developed post-operative bleeding, of which 22 patients underwent at least partial radiation therapy (RT) where there was an average of 53.0 ± 12 days elapsed from surgery to the initiation of RT. In the control group, 124 completed at least partial adjuvant treatment and there was an average of 55.3 ± 23 days from surgery to start of adjuvant RT. Time to start of RT was not significantly different between the cohorts (p=0.47). 9.1% of patients with bleeding and 23.7% of those without bleeding started radiation therapy within 6 weeks. The odds ratio of requiring a feeding tube during treatment in patients with post-operative bleeding compared to those without was 1.3 (95% C.I. 0.54-3.13). CONCLUSION: Patients with post-operative bleeding following TORS with TAL were not found to have a significantly higher risk of treatment delays or dysphagia burden, independent of hemorrhage severity.

Long Term Outcomes of Magnetic Sphincter Augmentation: A comparative study to Nissen Fundoplication.

BACKGROUND: Magnetic sphincter augmentation (MSA) demonstrates improvement in GERD across multiple short-term studies. Long-term, single arm studies show durable outcomes, but there is limited comparative data to Nissen (NF). METHODS: We performed a retrospective propensity matched cohort study of patients with GERD undergoing MSA or NF between 2012 and 2018. Patients were matched on age, gender, BMI, size of hiatal hernia, length of Barrett's and motility in a 1-to-1 fashion. A total of 523 patients (177 MSA, 346 NF) underwent surgery and after matching 177 MSA and 177 NF were analyzed. RESULTS: At 1 year, GERD quality of life scores improved (22 to 5 MSA vs 24 to 5 NF, p=0.593). PPI use was 14% vs 5% (p=0.010). pH testing demonstrated improved DeMeester scores (42 to 21 vs 46 to 7, p<0.001). At 5 years, GERD quality of life scores were stable (5 to 5 vs 5 to 4, p=0.208). PPI use was 31% vs 26% (p=0.474). The incidence of endoscopic dilation was similar between MSA and NF (7% vs 10%, p=0.347). Reoperation rates were higher for MSA (10% vs 4%, p=0.022) and recurrent hiatal hernias were found in 18% vs 7% (p=0.007). Compared to NF, MSA undergoing complete dissection showed no difference in dilation (5% MSA vs 7% NF, p=0.527), reoperation (8% MSA vs 6% NF, p=0.684) or hernia recurrence (10% MSA vs 6% NF, p=0.432). CONCLUSIONS: MSA achieves similar improvements in quality of life and freedom from medical therapy compared to NF especially with complete hiatal repair.

A machine-learning based model for automated recommendation of individualized treatment of rifampicin-resistant tuberculosis.

BACKGROUND: Rifampicin resistant tuberculosis remains a global health problem with almost half a million new cases annually. In high-income countries patients empirically start a standardized treatment regimen, followed by an individualized regimen guided by drug susceptibility test (DST) results. In most settings, DST information is not available or is limited to isoniazid and fluoroquinolones. Whole genome sequencing could more accurately guide individualized treatment as the full drug resistance profile is obtained with a single test. Whole genome sequencing has not reached its full potential for patient care, in part due to the complexity of translating a resistance profile into the most effective individualized regimen. METHODS: We developed a treatment recommender clinical decision support system (CDSS) and an accompanying web application for user-friendly recommendation of the optimal individualized treatment regimen to a clinician. RESULTS: Following expert stakeholder meetings and literature review, nine drug features and 14 treatment regimen features were identified and quantified. Using machine learning, a model was developed to predict the optimal treatment regimen based on a training set of 3895 treatment regimen-expert feedback pairs. The acceptability of the treatment recommender CDSS was assessed as part of a clinical trial and in a routine care setting. Within the clinical trial setting, all patients received the CDSS recommended treatment. In 8 of 20 cases, the initial recommendation was recomputed because of stock out, clinical contra-indication or toxicity. In routine care setting, physicians rejected the treatment recommendation in 7 out of 15 cases because it deviated from the national TB treatment guidelines. A survey indicated that the treatment recommender CDSS is easy to use and useful in clinical practice but requires digital infrastructure support and training. CONCLUSIONS: Our findings suggest that global implementation of the novel treatment recommender CDSS holds the potential to improve treatment outcomes of patients with RR-TB, especially those with 'difficult-to-treat' forms of RR-TB.

Amputation Triggers Long-Range Epidermal Permeability Changes in Evolutionarily Distant Regenerative Organisms.

Previous studies have reported that amputation invokes body-wide responses in regenerative organisms, but most have not examined the implications of these changes beyond the region of tissue regrowth. Specifically, long-range epidermal responses to amputation are largely uncharacterized, with research on amputation-induced epidermal responses in regenerative organisms traditionally being restricted to the wound site. Here, we investigate the effect of amputation on long-range epidermal permeability in two evolutionarily distant, regenerative organisms: axolotls and planarians. We find that amputation triggers a long-range increase in epidermal permeability in axolotls, accompanied by a long-range epidermal downregulation in MAPK signaling. Additionally, we provide functional evidence that pharmacologically inhibiting MAPK signaling in regenerating planarians increases long-range epidermal permeability. These findings advance our knowledge of body-wide changes due to amputation in regenerative organisms and warrant further study on whether epidermal permeability dysregulation in the context of amputation may lead to pathology in both regenerative and non-regenerative organisms.

Determinants of Poor Health among Workers in Criminal Justice, Community and Social Services, and Healthcare: Adverse Childhood Experiences, Workplace Trauma Exposure, and Gender Differences.

Adverse childhood experiences and workplace trauma exposure are associated with poor health. However, their differential impacts by gender are difficult to assess in studies of organizations with gender imbalances (e.g., law enforcement officers are more likely men whereas social workers are more likely women). Using a community-based participatory research framework, this study examines trauma exposure, mental and physical health, and substance use in an occupationally diverse sample (n = 391). Trauma exposure was high and associated with poor health. Even though women experienced more adversity, they were often more resilient than men. Implications for trauma-informed workplaces are discussed.

Use of Emergency Mental Health Dispatch Training by a 9-1-1 Medical Dispatcher Assisting a Caller Expressing Suicidal Intent: A Case Report.

A growing number of individuals with unmet mental health needs in the United States rely on emergency medical services during mental health crises, and 9-1-1 emergency medical dispatchers (EMD) are often a critical lifeline to help. Unfortunately, current industry-standard dispatching protocols and training required for EMD certification largely lack specificity for managing 9-1-1 calls related to mental health emergencies. The purpose of this report is to illustrate the value of additional targeted training for EMDs that enables them to more effectively assist callers struggling with mental illness or suicidal thoughts. We review a 9-1-1 call in which an EMD utilized specific strategies and language learned during a 3-day emergency mental health dispatch (EMHD) training course to assist a middle-aged male who was expressing suicidal intent with a firearm. Key principles and phrasing from the training were used successfully by the EMD to dissuade the caller from self-harm, and he was ultimately safely met by first responders on scene and transported for care. We also share post-call recollections and reactions from the EMD to demonstrate how in addition to reducing risks for callers and their families, EMHD training has the potential to reduce on-scene risks for field responders and may increase confidence and mitigate negative stress responses in EMDs. Emergency medical services systems in the United States should continue to explore enhanced training and protocols to improve care for 9-1-1 callers experiencing mental health crises.

Pseudomonas aeruginosa population dynamics in a vancomycin-induced murine model of gastrointestinal carriage.

Pseudomonas aeruginosa is a common nosocomial pathogen and a major cause of morbidity and mortality in hospitalized patients. Multiple reports highlight that P. aeruginosa gastrointestinal colonization may precede systemic infections by this pathogen. Gaining a deeper insight into the dynamics of P. aeruginosa gastrointestinal carriage is an essential step in managing gastrointestinal colonization and could contribute to preventing bacterial transmission and progression to systemic infection. Here, we present a clinically relevant mouse model relying on parenteral vancomycin pretreatment and a single orogastric gavage of a controlled dose of P. aeruginosa. Robust carriage was observed with multiple clinical isolates, and carriage persisted for up to 60 days. Histological and microbiological examination of mice indicated that this model indeed represented carriage and not infection. We then used a barcoded P. aeruginosa library along with the sequence tag-based analysis of microbial populations (STAMPR) analytic pipeline to quantify bacterial population dynamics and bottlenecks during the establishment of the gastrointestinal carriage. Analysis indicated that most of the P. aeruginosa population was rapidly eliminated in the stomach, but the few bacteria that moved to the small intestine and the caecum expanded significantly. Hence, the stomach constitutes a significant barrier against gastrointestinal carriage of P. aeruginosa, which may have clinical implications for hospitalized patients.

Lipid and glucose profiles in pregnant women with HIV on tenofovir-based antiretroviral therapy.

OBJECTIVE: Tenofovir alafenamide (TAF)-based antiretroviral therapy (ART) regimens have been associated with adverse changes in lipid and glucose profiles compared with tenofovir disoproxil fumarate (TDF)-based ART, but data in pregnancy is limited. We evaluated metabolic markers in pregnant women with HIV after starting TAF- vs TDF-based ART. METHODS: We analyzed data within the IMPAACT 2010/VESTED trial, which demonstrated better pregnancy outcomes in pregnant women randomized to initiate TAF/Emtricitabine/Dolutegravir (TAF/FTC+DTG; n=217) or TDF/FTC+DTG (n=215). We measured non-fasting plasma concentrations of glucose, total-cholesterol, low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C), lipoprotein (a), and triglycerides from samples collected eight weeks after enrollment. We employed linear regression models to estimate by-arm mean differences. RESULTS: 219 participants enrolled in the DTG arms in Zimbabwe and Uganda: 109 in the TAF/FTC+DTG and 110 in the TDF/FTC+DTG arms. At study entry, mean gestational age was 22.6 weeks, median HIV-1 RNA was 711 copies/mL, and mean age was 25.8 years. By eight weeks, mean total cholesterol was 12 mg/dL higher in women randomized to TAF/FTC+DTG versus TDF/FTC+DTG (95% CI 3.8, 21.1). Pregnant women in the TAF/FTC+DTG arm had higher mean LDL-C (7.1 mg/dL, 95% CI 0.2, 14.0), triglycerides (12.3 mg/dL, 95% CI 1.8, 22.7), lipoprotein (a) (7.3 mg/dL, 95% CI 1.1, 13.6), and lower mean HDL-C (2.8 mg/dL, 95% CI 0.1, 5.6) compared to the TDF/FTC+DTG arm. CONCLUSION: Pregnant women randomized to start TAF/FTC+DTG had higher lipids than those randomized to TDF/FTC+DTG within eight weeks of ART initiation. However, lipid levels were within normal reference ranges.

Immune correlates analysis of the Imbokodo (HVTN 705/HPX2008) efficacy trial of a mosaic HIV-1 vaccine regimen evaluated in Southern African people assigned female sex at birth: a two-phase case-control study.

BACKGROUND: The HVTN 705 Imbokodo trial of 2636 people without HIV and assigned female sex at birth, conducted in southern Africa, evaluated a heterologous HIV-1 vaccine regimen: mosaic adenovirus 26-based vaccine (Ad26.Mos4.HIV) at Months 0, 3, 6, 12 and alum-adjuvanted clade C gp140 at Months 6, 12. Per-protocol vaccine efficacy (VE) against HIV-1 diagnosis from seven to 24 months was 14.1% (95% CI: -22.0% to 39.5%). Immune correlates analysis was performed for markers selected based on prior evidence in efficacy trials and/or nonhuman primate models. METHODS: Humoral and cellular immune response markers at Month 7 were evaluated as immune correlates of risk and of protection in a breakthrough case-control cohort (n = 52 cases, 246 non-cases). Primary markers were IgG binding to vaccine-strain gp140, IgG3 binding to diverse Env antigens (IgG3 Env breadth), IgG3 binding to diverse V1V2 antigens (IgG3 V1V2 breadth), antibody-dependent phagocytosis against the vaccine-strain gp140, Env-specific CD4+ and CD8+ T-cell responses, and multi-epitope functions. FINDINGS: No immune markers were statistically significant correlates of risk. IgG3 V1V2 breadth trended toward an inverse association: hazard ratio 0.70 (95% CI: 0.36 to 1.35; p = 0.29) per 10-fold increase and 0.51 (95% CI: 0.21 to 1.24; p = 0.14) in a Cox model with all primary markers. The VE estimate was 11.8% (95% CI: -17.9% to 34.0%) at all IgG3 V1V2 breadth values below 667 weighted geometric mean net MFI; just above this value, the VE estimate sharply increased to 62.6% (95% CI: -17.9% to 89.6%), and further increased to 80.9% (95% CI: -17.9% to 99.5%) at 1471 MFI, the 95th percentile of the marker distribution. Mediation analysis yielded a VE of 35.7% (95% CI: 15.0% to 51.3%) attributable to the vaccine's impact on this marker. INTERPRETATION: The trend in association of greater IgG3 V1V2 antibody breadth with lower likelihood of HIV acquisition is consistent with the identification of antibodies against V1V2 as immune correlates in three other HIV vaccine efficacy trials and suggests that a greater emphasis should be placed on studying this region in the HIV-1 envelope as a vaccine immunogen. FUNDING: National Institute of Allergy and Infectious Diseases and Janssen Vaccines & Prevention BV.

The Relation of Health Anxiety to Treatment Utilization Among Patients with Substance Use Disorders: The Moderating Role of Racial/Ethnic Background.

Background: Although health anxiety is broadly related to the overutilization of healthcare, limited research has examined this relation among individuals with substance use disorders (SUDs), or the extent to which racial/ethnic differences influence this relationship. Objectives: The purpose of the current study is to examine the moderating role of racial/ethnic minoritized background in the relationship between health anxiety and treatment utilization among individuals with SUDs. In the present study, patients with SUDs receiving residential treatment in Mississippi (N=118; 62% racial/ethnic minoritized status, 35.6% White) completed a measure of health anxiety and answered questions about past mental health, physical health, and substance use treatment. Regression models examined whether racial/ethnic minoritized status (White vs. racial/ethnic minoritized status) moderated the relation of health anxiety to treatment utilization among patients with SUDs. Treatment utilization was examined by asking whether participants had seen a doctor or mental health provider, engaged in substance use treatment, or alcohol treatment prior to their current treatment (dichotomous), as well as the number of times they had engaged in each treatment (physical health, mental health, substance use, and alcohol treatment) in the past year (continuous). Results: Results revealed that the facets of health anxiety involving concerns about pain and disease phobia were positively associated with treatment utilization, but only among racial/ethnic minoritized participants, with concerns about pain positively associated with self-reported physical health treatment utilization (OR=0.70, 95% CI=0.50; 0.97) and disease phobia positively associated with past mental health (B = 0.36, p = 0.023) and alcohol use treatment (B=-0.23, p=.009). Conversely, disease phobia was related to less prior alcohol use treatment among White participants (B=-0.23, p=.009). Conclusions: Overall, among patients in residential treatment for SUDs, racial/ethnic minoritized participants with SUDs reported more health anxiety compared to white participants, and certain facets of health anxiety (i.e., concerns about pain and worry about severe illness) were linked to heightened treatment utilization among racial/ethnic minoritized individuals.