G-formula for observational studies under stratified interference, with application to bed net use on malaria.

Assessing population-level effects of vaccines and other infectious disease prevention measures is important to the field of public health. In infectious disease studies, one person's treatment may affect another individual's outcome, that is, there may be interference between units. For example, the use of bed nets to prevent malaria by one individual may have an indirect effect on other individuals living in close proximity. In some settings, individuals may form groups or clusters where interference only occurs within groups, that is, there is partial interference. Inverse probability weighted estimators have previously been developed for observational studies with partial interference. Unfortunately, these estimators are not well suited for studies with large clusters. Therefore, in this paper, the parametric g-formula is extended to allow for partial interference. G-formula estimators are proposed for overall effects, effects when treated, and effects when untreated. The proposed estimators can accommodate large clusters and do not suffer from the g-null paradox that may occur in the absence of interference. The large sample properties of the proposed estimators are derived assuming no unmeasured confounders and that the partial interference takes a particular form (referred to as 'weak stratified interference'). Simulation studies are presented demonstrating the finite-sample performance of the proposed estimators. The Demographic and Health Survey from the Democratic Republic of the Congo is then analyzed using the proposed g-formula estimators to assess the effects of bed net use on malaria.

Longitudinal Dynamics of Intact HIV Proviral DNA and Outgrowth Virus Frequencies in a Cohort of Individuals Receiving Antiretroviral Therapy.

BACKGROUND: The replication-competent human immunodeficiency virus (HIV) reservoir is the major barrier to cure. The quantitative viral outgrowth assay (QVOA), the gold-standard method to quantify replication-competent HIV, is resource intensive, which limits its application in large clinical trials. The intact proviral DNA assay (IPDA) requires minimal cell input relative to QVOA and quantifies both defective and intact proviral HIV DNA, the latter potentially serving as a surrogate marker for replication-competent provirus. However, there are limited cross-sectional and longitudinal data on the relationship between IPDA and QVOA measurements. METHODS: QVOA and IPDA measurements were performed on 156 resting CD4 T-cell (rCD4) samples from 83 antiretroviral therapy-suppressed HIV-positive participants. Longitudinal QVOA and IPDA measurements were performed on rCD4 from 29 of these participants. RESULTS: Frequencies of intact, defective, and total proviruses were positively associated with frequencies of replication-competent HIV. Longitudinally, decreases in intact proviral frequencies were strikingly similar to that of replication-competent virus in most participants. In contrast, defective proviral DNA frequencies appeared relatively stable over time in most individuals. CONCLUSIONS: Changes in frequencies of IPDA-derived intact proviral DNA and replication-competent HIV measured by QVOA are similar. IPDA is a promising high-throughput approach to estimate changes in the frequency of the replication-competent reservoir.

Long-term Complications of Ebola Virus Disease: Prevalence and Predictors of Major Symptoms and the Role of Inflammation.

BACKGROUND: Cohort studies have reported a high prevalence of musculoskeletal, neurologic, auditory, and visual complications among Ebola virus disease (EVD) survivors. However, little is known about the host- and disease-related predictors of these symptoms and their etiological mechanisms. METHODS: The presence and patterns of 8 cardinal symptoms that are most commonly reported following EVD survival were assessed in the 326 EVD survivors who participated in the ongoing longitudinal Liberian EVD Survivor Study. At quarterly study visits, symptoms that developed since acute EVD were recorded and blood was collected for biomarkers of inflammation and immune activation. RESULTS: At baseline (mean 408 days from acute EVD), 75.5% of survivors reported at least 1 new cardinal symptom since surviving EVD, which in 85.8% was rated as highly interfering with life. Two or more incident symptoms were reported by 61.0% of survivors, with pairings of joint pain, headache, or fatigue the most frequent. Women were significantly more likely than men to report headache, while older age was significantly associated with musculoskeletal and visual symptoms. In analyses adjusted for multiple comparisons, no statistically significant association was found between any symptom and 26 markers of inflammation and immune activation. Symptom frequency remained largely unchanged during study follow-up. CONCLUSIONS: Post-EVD complications occur in a majority of survivors and remain present more than 4 years after acute infection. An association between markers of inflammation and immune activation and individual symptoms was not found, suggesting an alternative etiology for persistent post-EVD symptomatology.

Estimands and inference in cluster-randomized vaccine trials.

Cluster-randomized trials are often conducted to assess vaccine effects. Defining estimands of interest before conducting a trial is integral to the alignment between a study's objectives and the data to be collected and analyzed. This paper considers estimands and estimators for overall, indirect, and total vaccine effects in trials, where clusters of individuals are randomized to vaccine or control. The scenario is considered where individuals self-select whether to participate in the trial, and the outcome of interest is measured on all individuals in each cluster. Unlike the overall, indirect, and total effects, the direct effect of vaccination is shown in general not to be estimable without further assumptions, such as no unmeasured confounding. An illustrative example motivated by a cluster-randomized typhoid vaccine trial is provided.

Predictors of Non-Rhinogenic Facial Pain or Pressure in Otolaryngology Clinic.

OBJECTIVES: Identify demographic and clinical characteristics that may help differentiate non-rhinogenic facial pain or pressure (NRFP) from sinusitis. STUDY DESIGN: Retrospective single-institution study. SETTING: Tertiary Care Center Rhinology Clinic. METHODS: All patients presenting with a complaint of facial pain or pressure over a 3-year period were included. Patients were categorized into either NRFP or sinusitis groups based on computed tomography imaging and nasal endoscopy. Data pertaining to demographics, history, and SNOT-22 questionnaire domains were compared via univariate analysis as well as logistic regression with backwards variable selection. RESULTS: A total of 296 patients met inclusion criteria, of which 128 had NRFP and 168 had sinusitis. A significantly greater percentage of patients in the NRFP group were women of childbearing age (40.6% vs 28.0%, P = .02). Backwards variable selection resulted in a model with four variables predicting a diagnosis of NRFP-female sex (odds ratio [OR] = 2.998, P < .0001), no history of prior sinonasal surgery (OR = 0.340 for history vs no history, P < .01), low nasal domain score (OR = 0.551, P < .0001), and high ear/facial domain score (OR = 1.453, P < .01). CONCLUSION: Accurately identifying patients with NRFP at initial presentation based on history would help direct patients to the appropriate care pathway and prevent ineffective treatments such as antibiotics and sinus procedures. Our findings suggest that the suspicion for NRFP should be higher in women of child-bearing age as well as patients with greater ear/facial symptoms or lesser nasal symptoms.

Predictive Factors in Identifying Pediatric Patients at Risk of Diagnostically Limited Videofluoroscopic Swallow Studies.

Objective: Videofluoroscopic swallow studies (VFSS) are highly effective in characterizing pediatric dysphagia, but they are time- and resource-intensive, and necessitate the use of radiation. Identifying patients unlikely to benefit from VFSS is crucial to improving patient safety and resource allocation. The purpose of this study was to assess whether the ability of a patient to consume at least 0.5 oz by mouth is a reliable indicator of their ability to produce a diagnostically useful VFSS. Study Design: Retrospective chart review. Methods: Clinical data of pediatric patients aged 0 to 18 years, who underwent VFSS at a tertiary academic medical center from 2014 to 2021 were analyzed. Results: Regardless of whether due to mechanical dysphagia or oral aversion, an inability to consume at least 0.5 oz of any texture by mouth at home was not found to be associated with nondiagnostic VFSS. Age was found to have an effect on VFSS utility with toddlers having higher odds of nondiagnostic VFSS compared to children and adolescents. Overall, there was no significant interaction between the ability to take at least 0.5 oz and age group. Gastrointestinal (GI) and neuromuscular comorbidities were also associated with clinically useful swallow studies. Conclusions and Relevance: Clinicians should consider several factors, including age, at-home intake by mouth, and comorbidities such as neuromuscular and GI disorders, as they decide whether to order a VFSS.

Intergenerational response to the endocrine disruptor vinclozolin is influenced by maternal genotype and crossing scheme.

In utero exposure to vinclozolin (VIN), an antiandrogenic fungicide, is linked to multigenerational phenotypic and epigenetic effects. Mechanisms remain unclear. We assessed the role of antiandrogenic activity and DNA sequence context by comparing effects of VIN vs. M2 (metabolite with greater antiandrogenic activity) and wild-type C57BL/6 (B6) mice vs. mice carrying mutations at the previously reported VIN-responsive H19/Igf2 locus. First generation offspring from VIN-treated 8nrCG mutant dams exhibited increased body weight and decreased sperm ICR methylation. Second generation pups sired by affected males exhibited decreased neonatal body weight but only when dam was unexposed. Offspring from M2 treatments, B6 dams, 8nrCG sires or additional mutant lines were not similarly affected. Therefore, pup response to VIN over two generations detected here was an 8nrCG-specific maternal effect, independent of antiandrogenic activity. These findings demonstrate that maternal effects and crossing scheme play a major role in multigenerational response to in utero exposures.