Publications

Sex differences in the immune response and in infectious disease susceptibility have been well described, although the mechanisms underlying these differences remain incompletely understood. We evaluated the frequency of cord blood CD4 T cell subsets in a highly malaria-exposed birth cohort of mother-infant pairs in Uganda by sex. We found that frequencies of cord blood regulatory T cell ([T] CD4CD25FoxP3CD127) differed by infant sex, with significantly lower frequencies of T in female than in male neonates ( = .006). When stratified by in utero malaria exposure status, this difference was observed in the exposed, but not in the unexposed infants.

Clinician burnout reduces the capacity for providers and health systems to deliver timely, high quality, patient-centered care and increases the risk that clinicians will leave practice. This is especially problematic in hospice and palliative care: patients are often frail, elderly, vulnerable, and complex; access to care is often outstripped by need; and demand for clinical experts will increase as palliative care further integrates into usual care. Efforts to mitigate and prevent burnout currently focus on individual clinicians. However, analysis of the problem of burnout should be expanded to include both individual- and systems-level factors as well as solutions; comprehensive interventions must address both. As a society, we hold organizations responsible for acting ethically, especially when it relates to deployment and protection of valuable and constrained resources. We should similarly hold organizations responsible for being ethical stewards of the resource of highly trained and talented clinicians through comprehensive programs to address burnout.

OBJECTIVE

To determine the merit of nailfold videocapillaroscopy (NVC) to detect meaningful microvascular changes over time in patients with systemic sclerosis (SSc) and whether these changes are associated with overall disease progression and organ involvements.

METHODS

A prospective cohort of 140 SSc patients was recruited over a 12-month period and was followed up on an annual basis for 3 years. Detailed NVC analysis was performed at inclusion and repeated annually. Disease progression and organ damage were defined according to validated definitions.

RESULTS

Significant NVC changes were detected in 72 SSc patients (51%) during the follow-up period. Patients with incident or increased number of giant capillaries were less at risk to develop new digital ulcers (DU) [hazard ratio (HR) = 0.53, 95% confidence interval (CI): 0.07-0.93]. Loss of capillaries over time was confirmed as a robust and independent marker of organ progression. The reduction of the number of capillaries was associated with overall disease progression (HR = 4.35, 95% CI: 1.87-10.12), occurrence of new DU (HR = 5.33, 95% CI: 1.69-16.71), lung vascular progression (HR = 18.53, 95% CI: 1.28-78.33), progression of skin fibrosis (HR = 4.22, 95% CI: 1.24-14.36), and worsening of the Medsger severity score (HR = 5.26, 95% CI: 1.78-15.52).

CONCLUSION

Significant NVC changes are observed in almost half of the patients with SSc during a follow-up of 3 years. Sequential NVC examinations have responsiveness to detect disease progression. Sequential NVC is confirmed of value to monitor SSc, as well as progressive loss of capillaries over time as a potential surrogate marker for disease progression.

Semantic heterogeneity (SH) is detrimental to data interoperability and integration in healthcare. Assessing SH is difficult, yet fundamental to addressing the problem. Using expert-based and data-driven methods we assessed SH among HIV-associated data elements (DEs). Using Clinicaltrials.gov, we identified and obtained eight data dictionaries, and created a DE inventory. We vectorized DEs by study, and developed a new method, String Metric-assisted Assessment of Semantic Heterogeneity (SMASH), to find DEs: similar in A and B, unique to A, and unique to B. An HIV expert assessed pairs for semantic equivalence. Heterogeneous DEs were either semantically-equivalent/syntactically-different (HIV-positive/HIV+/Seropositive), or syntactically-equivalent/semantically-different ("Partner" [sexual]/"Partner"[relationship]). Context of usage was considered. SMASH aided identification of SH. Of 1,175 DE from pairs, 1,048 (87%) were semantically heterogeneous and 127 (13%) were homogeneous. Most heterogeneous pairs (97%) were semantically-equivalent/syntactically-different. Expert-based and data-driven methods are complementary for assessing SH, especially among semantically-equivalent/syntactically-different DE. Similar expert-based/data-driven solutions are recommended for resolving SH.

BACKGROUND

People living in malaria endemic areas acquire protection from severe malaria quickly, but protection from clinical disease and control of parasitaemia is acquired only after many years of repeated infections. Antibodies play a central role in protection from clinical disease; however, protective antibodies are slow to develop. This study sought to investigate the influence of Plasmodium falciparum exposure on the acquisition of high-avidity antibodies to P. falciparum antigens, which may be associated with protection.

METHODS

Cross-sectional surveys were performed in children and adults at three sites in Uganda with varied P. falciparum transmission intensity (entomological inoculation rates; 3.8, 26.6, and 125 infectious bites per person per year). Sandwich ELISA was used to measure antibody responses to two P. falciparum merozoite surface antigens: merozoite surface protein 1-19 (MSP1-19) and apical membrane antigen 1 (AMA1). In individuals with detectable antibody levels, guanidine hydrochloride (GuHCl) was added to measure the relative avidity of antibody responses by ELISA.

RESULTS

Within a site, there were no significant differences in median antibody levels between the three age groups. Between sites, median antibody levels were generally higher in the higher transmission sites, with differences more apparent for AMA-1 and in ≥5 year group. Similarly, median avidity index (proportion of high avidity antibodies) showed no significant increase with increasing age but was significantly lower at sites of higher transmission amongst participants ≥5 years of age. Using 5 M GuHCl, the median avidity indices in the ≥5 year group at the highest and lowest transmission sites were 19.9 and 26.8, respectively (p = 0.0002) for MSP1-19 and 12.2 and 17.2 (p = 0.0007) for AMA1.

CONCLUSION

Avidity to two different P. falciparum antigens was lower in areas of high transmission intensity compared to areas with lower transmission. Appreciation of the mechanisms behind these findings as well as their clinical consequences will require additional investigation, ideally utilizing longitudinal data and investigation of a broader array of responses.

Hereditary cancer panels (HCPs), testing for multiple genes and syndromes, are rapidly transforming cancer risk assessment but are controversial and lack formal insurance coverage. We aimed to identify payers' perspectives on barriers to HCP coverage and opportunities to address them. Comprehensive cancer risk assessment is highly relevant to the Precision Medicine Initiative (PMI), and payers' considerations could inform PMI's efforts. We describe our findings and discuss them in the context of PMI priorities. We conducted semi-structured interviews with 11 major US payers, covering >160 million lives. We used the framework approach of qualitative research to design, conduct, and analyze interviews, and used simple frequencies to further describe findings. Barriers to HCP coverage included poor fit with coverage frameworks (100%); insufficient evidence (100%); departure from pedigree/family history-based testing toward genetic screening (91%); lacking rigor in the HCP hybrid research/clinical setting (82%); and patient transparency and involvement concerns (82%). Addressing barriers requires refining HCP-indicated populations (82%); developing evidence of actionability (82%) and pathogenicity/penetrance (64%); creating infrastructure and standards for informing and recontacting patients (45%); separating research from clinical use in the hybrid clinical-research setting (44%); and adjusting coverage frameworks (18%). Leveraging opportunities suggested by payers to address HCP coverage barriers is essential to ensure patients' access to evolving HCPs. Our findings inform 3 areas of the PMI: addressing insurance coverage to secure access to future PMI discoveries; incorporating payers' evidentiary requirements into PMI's research agenda; and leveraging payers' recommendations and experience to keep patients informed and involved.

The first goal of this study was to identify the most appropriate measure of cigarette smoking for identifying unique smoking trajectories among adolescents; the second goal was to describe the resulting trajectories and their characteristics. Using 15 annual waves of smoking data in the National Longitudinal Survey of Youth 1997 (NLSY97), we conducted an exploratory latent class growth analysis to determine the best of four outcome variables for yearly smoking (cigarettes per day on days smoked, days smoked per month, mean cigarettes per day, and total cigarettes per month) among individuals aged 12 to 30 (n = 8,791). Days smoked per month was the best outcome variable for identifying unique longitudinal trajectories of smoking and characteristics of these trajectories that could be used to target different types of smokers for prevention and cessation. Objective statistics were used to identify four trajectories in addition to never smokers (34.1%): experimenters (13.6%), quitters (8.1%), early established smokers (39.0%), and late escalators (5.2%). We identified a quitter and late escalator class not identified in the only other comparable latent class growth analysis. Logistic regressions were used to identify the characteristics of individuals in each trajectory. Compared with never smokers, all trajectories except late escalators were less likely to be black; experimenters were more likely to be out of school and unemployed and drink alcohol in adolescence; quitters were more likely to have a mother with a high school degree/GED or higher (versus none) and to use substances in adolescence and less likely to have ever married as a young adult; early established smokers were more likely to have a mother with a high school diploma or GED, be out of school and unemployed, not live with both parents, have used substances, be depressed, and have peers who smoked in adolescence and to have children as young adults and less likely to be Hispanic and to have ever married as young adults; and late escalators were more likely to be Hispanic, drink alcohol, and break rules in adolescence and less likely to have ever married as young adults. Because of the number of waves of data analyzed, this analysis provided a clearer temporal depiction of smoking behavior and more easily distinguishable smoking trajectories than previous analyses. Tobacco control interventions need to move beyond youth-focused approaches to reach all smokers.