Mitigating Racial And Ethnic Bias And Advancing Health Equity In Clinical Algorithms: A Scoping Review.

In August 2022 the Department of Health and Human Services (HHS) issued a notice of proposed rulemaking prohibiting covered entities, which include health care providers and health plans, from discriminating against individuals when using clinical algorithms in decision making. However, HHS did not provide specific guidelines on how covered entities should prevent discrimination. We conducted a scoping review of literature published during the period 2011-22 to identify health care applications, frameworks, reviews and perspectives, and assessment tools that identify and mitigate bias in clinical algorithms, with a specific focus on racial and ethnic bias. Our scoping review encompassed 109 articles comprising 45 empirical health care applications that included tools tested in health care settings, 16 frameworks, and 48 reviews and perspectives. We identified a wide range of technical, operational, and systemwide bias mitigation strategies for clinical algorithms, but there was no consensus in the literature on a single best practice that covered entities could employ to meet the HHS requirements. Future research should identify optimal bias mitigation methods for various scenarios, depending on factors such as patient population, clinical setting, algorithm design, and types of bias to be addressed.

Sex modifies the effect of genetic risk scores for polycystic ovary syndrome on metabolic phenotypes.

Females with polycystic ovary syndrome (PCOS), the most common endocrine disorder in women, have an increased risk of developing cardiometabolic disorders such as insulin resistance, obesity, and type 2 diabetes (T2D). While only diagnosable in females, males with a family history of PCOS can also exhibit a poor cardiometabolic profile. Therefore, we aimed to elucidate the role of sex in the cardiometabolic comorbidities observed in PCOS by conducting bidirectional genetic risk score analyses in both sexes. We first conducted a phenome-wide association study (PheWAS) using PCOS polygenic risk scores (PCOSPRS) to identify potential pleiotropic effects of PCOSPRS across 1,380 medical conditions recorded in the Vanderbilt University Medical Center electronic health record (EHR) database, in females and males. After adjusting for age and genetic ancestry, we found that European (EUR)-ancestry males with higher PCOSPRS were significantly more likely to develop hypertensive diseases than females at the same level of genetic risk. We performed the same analysis in an African (AFR)-ancestry population, but observed no significant associations, likely due to poor trans-ancestry performance of the PRS. Based on observed significant associations in the EUR-ancestry population, we then tested whether the PRS for comorbid conditions (e.g., T2D, body mass index (BMI), hypertension, etc.) also increased the odds of a PCOS diagnosis. Only BMIPRS and T2DPRS were significantly associated with a PCOS diagnosis in EUR-ancestry females. We then further adjusted the T2DPRS for measured BMI and BMIresidual (regressed on the BMIPRS and enriched for the environmental contribution to BMI). Results demonstrated that genetically regulated BMI primarily accounted for the relationship between T2DPRS and PCOS. Overall, our findings show that the genetic architecture of PCOS has distinct sex differences in associations with genetically correlated cardiometabolic traits. It is possible that the cardiometabolic comorbidities observed in PCOS are primarily explained by their shared genetic risk factors, which can be further influenced by biological variables including sex and BMI.

Similarities and Differences in the Acute-Phase Response to SARS-CoV-2 in Rhesus Macaques and African Green Monkeys.

Understanding SARS-CoV-2 immune pathology is critical for the development of effective vaccines and treatments. Here, we employed unbiased serial whole-blood transcriptome profiling by weighted gene network correlation analysis (WGCNA) at pre-specified timepoints of infection to understand SARS-CoV-2-related immune alterations in a cohort of rhesus macaques (RMs) and African green monkeys (AGMs) presenting with varying degrees of pulmonary pathology. We found that the bulk of transcriptional changes occurred at day 3 post-infection and normalized to pre-infection levels by 3 weeks. There was evidence of coordination of transcriptional networks in blood (defined by WGCNA) and the nasopharyngeal SARS-CoV-2 burden as well as the absolute monocyte count. Pathway analysis of gene modules revealed prominent regulation of type I and type II interferon stimulated genes (ISGs) in both RMs and AGMs, with the latter species exhibiting a greater breadth of ISG upregulation. Notably, pathways relating to neutrophil degranulation were enriched in blood of SARS-CoV-2 infected AGMs, but not RMs. Our results elude to hallmark similarities as well as differences in the RM and AGM acute response to SARS-CoV-2 infection, and may help guide the selection of particular NHP species in modeling aspects of COVID-19 disease outcome.

Impact of CMV Reactivation, Treatment Approaches, and Immune Reconstitution in a Nonmyeloablative Tolerance Induction Protocol in Cynomolgus Macaques.

BACKGROUND: Cytomegalovirus (CMV) infection is a serious complication in immunosuppressed patients, specifically transplant recipients. Here, we describe the development and use of an assay to monitor the incidence and treatment of CMV viremia in a Cynomolgus macaque model of bone marrow transplantation (BMT) for tolerance induction. We address the correlation between the course of viremia and immune reconstitution. METHODS: Twenty-one animals received a nonmyeloablative conditioning regimen. Seven received cyclosporine A for 28 days and 14 received rapamycin. A CMV polymerase chain reaction assay was developed and run twice per week to monitor viremia. Nineteen recipients were CMV seropositive before BMT. Immune reconstitution was monitored through flow cytometry and CMV viremia was tracked via quantitative polymerase chain reaction. RESULTS: Recipients developed CMV viremia during the first month post-BMT. Two animals developed uncontrollable CMV disease. CMV reactivation occurred earlier in cyclosporine A-treated animals compared with those receiving rapamycin. Post-BMT, T-cell counts remained significantly lower compared with pretransplant levels until CMV reactivation, at which point they increased during the viremic phase and approached pretransplant levels 3 months post-BMT. Management of CMV required treatment before viremia reached 10 000 copies/mL; otherwise clinical symptoms were observed. High doses of ganciclovir resolved the viremia, which could subsequently be controlled with valganciclovir. CONCLUSIONS: We developed an assay to monitor CMV in Cynomolgus macaques. CMV reactivation occurred in 100% of seropositive animals in this model. Rapamycin delayed CMV reactivation and ganciclovir treatment was effective at high doses. As in humans, CD8 T cells proliferated during CMV viremia.

Rational design of original materials for the electrocatalytic hydrogenation reactions: concept, preparation, characterization, and theoretical analysis.

Original and versatile new materials for the electrocatalytic hydrogenation of organic compounds were designed. The materials consist of reticulated glassy carbon cathode electrodes in which the modified silica particles (average diameter 40-63 microm) were dynamically circulated. The modification of the silica surface is 2-fold. First, the silica is surface-modified using organic functions such as -OSi(CH3)2(CH2)3OCH2CH-(OH)(CH)2OH (SiO2-Diol), -OSi(CH3)2(CH2)7CH3 (SiO2-C8), and -OSi(CH3)2C6H5 (SiO2-Phenyl). Second, these silica particles were further modified by vapor phase deposition of nickel nanoaggregates (used as sites for hydrogen atoms and electric contacts with the electrode material), which does not destroy or alter the organic functionalization as demonstrated by thermogravimetric analysis-mass spectrometry and Raman, diffuse reflectance IR Fourier transform, and Auger electron spectroscopies. The new concept stems from relative adsorption and desorption properties of the organic molecules and their corresponding reduced products into the organic functionalization of the surface-modified silica. In this work, the electrocatalytic hydrogenation cyclohexanone was used to test the concept. The performances (amount of cyclohexanol vs time of generated electrolysis at constant current) are measured and compared for the various bonded organic functions of the silica surface listed above, along with the unmodified silica particles (but still containing nickel nanoaggregates) and the presence or absence of methanol in solution. The measurements of the adsorption isotherms of cyclohexanone, and the calculations of the interaction energies (MM3 force field) between the chemisorbed organic functions and the substrates, corroborate perfectly the electrocatalysis results.