Proteomic Characterization of Acute Kidney Injury in Patients Hospitalized with SARS-CoV2 Infection

Acute kidney injury (AKI) is a known complication of COVID-19 and is associated with an increased risk of in-hospital mortality. Unbiased proteomics using longitudinally collected biological specimens can lead to improved risk stratification and discover pathophysiological mechanisms. Using longitudinal measurements of ∼4000 plasma proteins in two cohorts of patients hospitalized with COVID-19, we discovered and validated markers of COVID-associated AKI (stage 2 or 3) and long-term kidney dysfunction. In the discovery cohort (N= 437), we identified 413 upregulated and 40 downregulated proteins associated with COVID-AKI (adjusted p <0.05). Of these, 62 proteins were validated in an external cohort (p <0.05, N =261). We demonstrate that COVID-AKI is associated with increased markers of tubular injury (NGAL) and myocardial injury. Using estimated glomerular filtration (eGFR) measurements taken after discharge, we also find that 25 of the 62 AKI-associated proteins are significantly associated with decreased post-discharge eGFR (adjusted p <0.05). Proteins most strongly associated with decreased post-discharge eGFR included desmocollin-2, trefoil factor 3, transmembrane emp24 domain-containing protein 10, and cystatin-C indicating tubular dysfunction and injury. Using longitudinal clinical and proteomic data, our results suggest that while both acute and long-term COVID-associated kidney dysfunction are associated with markers of tubular dysfunction, AKI is driven by a largely multifactorial process involving hemodynamic instability and myocardial damage.

Implementation of a lung cancer screening initiative in HIV-infected subjects

In this pilot program of low-dose computed tomography (LDCT) for the screening of lung cancer (LC) in a targeted population of people with HIV (PWH), its prevalence was 3.6%; the number needed to screen in order to detect one case of lung cancer was 28, clearly outweighing the risks associated with lung cancer screening. While data from additional cohorts with longitudinal measurements are needed, PWH are a target population for lung cancer screening with LDCT.

Longitudinal Profiling in Phenotypic Metric of Aging: Insights From the Baltimore Longitudinal Study of Aging

It remains challenging to quantify the pace of aging across lifespan due to lack of comprehensive longitudinal measurements across wide range of age. In Baltimore Longitudinal Study of Aging, we have measured the longitudinal trajectories of more than 30 phenotypes across four pre-identified domain - body composition, energy regulation, homeostatic mechanisms and neurodegeneration/neuroplasticity, among participants with age between 20+ and 90+. We implemented a two-stage approach to summarize the longitudinal trajectories of these phenotypes across four domains into a summarized score. We demonstrated that higher summarized score (denoting for slower longitudinal phenotypic decline) is associated with slower decline in both cognitive and physical functions, across different stages of adulthood. Our results imply that deep longitudinal profiling contains rich information and may potentially replace diseases as an early endpoint in trials targeting at aging. Further, understanding the underpinning of longitudinal phenotypic trajectories may provide clues to the biological mechanisms of aging.

Mapping the field of misinformation correction and its effects: A review of four decades of research

Why people still rely on misinformation after clear corrections is a major concern driving relevant research. Different fields, from psychology to marketing, have been seeking answers. Yet there remains no systematic review to integrate these theoretical and empirical insights. To fill the gap, this article reviewed 135 articles on misinformation correction and its effects written before 2020 to examine the knowledge generated in the field. Our findings indicate a consistent interest on this topic over the past four decades, and a sharp increase of relevant scholarly work in the last ten years. Nevertheless, most studies have been built upon psychological inquiries and quantitative methodologies. What is lacking includes longitudinal measurements of debunking effectiveness, theoretical insights beyond cognitive sciences, methodological contributions from qualitative approaches, and empirical evidence from non-western societies. With this analysis, we propose worthwhile focuses for future exploration.

Early-pregnancy prediction of risk for pre-eclampsia using maternal blood leptin/ceramide ratio: discovery and confirmation

ObjectiveThis study aimed to develop a blood test for the prediction of pre-eclampsia (PE) early in gestation. We hypothesised that the longitudinal measurements of circulating adipokines and sphingolipids in maternal serum over the course of pregnancy could identify novel prognostic biomarkers that are predictive of impending event of PE early in gestation.Study designRetrospective discovery and longitudinal confirmation.SettingMaternity units from two US hospitals.ParticipantsSix previously published studies of placental tissue (78 PE and 95 non-PE) were compiled for genomic discovery, maternal sera from 15 women (7 non-PE and 8 PE) enrolled at ProMedDx were used for sphingolipidomic discovery, and maternal sera from 40 women (20 non-PE and 20 PE) enrolled at Stanford University were used for longitudinal observation.Outcome measuresBiomarker candidates from discovery were longitudinally confirmed and compared in parallel to the ratio of placental growth factor (PlGF) and soluble fms-like tyrosine kinase (sFlt-1) using the same cohort. The datasets were generated by enzyme-linked immunosorbent and liquid chromatography-tandem mass spectrometric assays.ResultsOur discovery integrating genomic and sphingolipidomic analysis identified leptin (Lep) and ceramide (Cer) (d18:1/25:0) as novel biomarkers for early gestational assessment of PE. Our longitudinal observation revealed a marked elevation of Lep/Cer (d18:1/25:0) ratio in maternal serum at a median of 23 weeks’ gestation among women with impending PE as compared with women with uncomplicated pregnancy. The Lep/Cer (d18:1/25:0) ratio significantly outperformed the established sFlt-1/PlGF ratio in predicting impending event of PE with superior sensitivity (85% vs 20%) and area under curve (0.92 vs 0.52) from 5 to 25 weeks of gestation.ConclusionsOur study demonstrated the longitudinal measurement of maternal Lep/Cer (d18:1/25:0) ratio allows the non-invasive assessment of PE to identify pregnancy at high risk in early gestation, outperforming the established sFlt-1/PlGF ratio test.

Host methylation predicts SARS-CoV-2 infection and clinical outcome

Background Since the onset of the SARS-CoV-2 pandemic, most clinical testing has focused on RT-PCR1. Host epigenome manipulation post coronavirus infection2–4 suggests that DNA methylation signatures may differentiate patients with SARS-CoV-2 infection from uninfected individuals, and help predict COVID-19 disease severity, even at initial presentation. Methods We customized Illumina’s Infinium MethylationEPIC array to enhance immune response detection and profiled peripheral blood samples from 164 COVID-19 patients with longitudinal measurements of disease severity and 296 patient controls. Results Epigenome-wide association analysis revealed 13,033 genome-wide significant methylation sites for case-vs-control status. Genes and pathways involved in interferon signaling and viral response were significantly enriched among differentially methylated sites. We observe highly significant associations at genes previously reported in genetic association studies (e.g.IRF7, OAS1). Using machine learning techniques, models built using sparse regression yielded highly predictive findings: cross-validated best fit AUC was 93.6% for case-vs-control status, and 79.1%, 80.8%, and 84.4% for hospitalization, ICU admission, and progression to death, respectively. Conclusions In summary, the strong COVID-19-specific epigenetic signature in peripheral blood driven by key immune-related pathways related to infection status, disease severity, and clinical deterioration provides insights useful for diagnosis and prognosis of patients with viral infections.

Linking functional and molecular mechanisms of host resilience to malaria infection

It remains challenging to understand why some hosts suffer severe illnesses, while others are unscathed by the same infection. We fitted a mathematical model to longitudinal measurements of parasite and red blood cell density in murine hosts from diverse genetic backgrounds to identify aspects of within-host interactions that explain variation in host resilience and survival during acute malaria infection. Among eight mouse strains that collectively span 90% of the common genetic diversity of laboratory mice, we found that high host mortality was associated with either weak parasite clearance, or a strong, yet imprecise response that inadvertently removes uninfected cells in excess. Subsequent cross-sectional cytokine assays revealed that the two distinct functional mechanisms of poor survival were underpinned by low expression of either pro- or anti-inflammatory cytokines, respectively. By combining mathematical modelling and molecular immunology assays, our study uncovered proximate mechanisms of diverse infection outcomes across multiple host strains and biological scales.

Blood leukocyte count as a systemic inflammatory biomarker associated with a more rapid spirometric decline in a large cohort of iron and steel industry workers

Objective Iron and steel industry workers are exposed to high levels of inhalable dust particles that contain various elements, including metals, and cause occupational lung diseases. We aim to assess the relationship between occupational dust exposure, systemic inflammation, and spirometric decline in a cohort of Chinese iron and steel workers. Methods We studied 7513 workers who participated in a Health Surveillance program at Wugang Institute for Occupational Health between 2008 and 2017. Time-weighted exposure intensity (TWEI) of dust was quantified based on self-reported dust exposure history, the experience of occupational hygienists, and historical data of dust exposure for workers with certain job titles. A linear mixed-effects model was used for association analyses. Results The average annual change of lung function was − 50.78 ml/year in forced expiratory volume in 1 s (FEV1) and − 34.36 ml/year in forced vital capacity (FVC) in males, and − 39.06 ml/year in FEV1 and − 26.66 ml/year in FVC in females. Higher TWEI prior to baseline was associated with lower longitudinal measurements of FEV1 and FVC but not with their decline rates. Higher WBC and its differential at baseline were associated with lower longitudinal measurements and a more rapid decline of FEV1 and FVC in a dose-dependent monotonically increasing manner. Moreover, the increase of WBC and its differential post-baseline was also associated with a more rapid decline of FEV1 and FVC. Conclusions Our findings support the important role of systemic inflammation in affecting the temporal change of lung function in iron and steel industry workers.