Nevin Manimala

PLoS Pathog. 2021 Aug 17;17(8):e1009773. doi: 10.1371/journal.ppat.1009773. Online ahead of print.

ABSTRACT

More humans have died of tuberculosis (TB) than any other infectious disease and millions still die each year. Experts advocate for blood-based, serum protein biomarkers to help diagnose TB, which afflicts millions of people in high-burden countries. However, the protein biomarker pipeline is small. Here, we used the Diversity Outbred (DO) mouse population to address this gap, identifying five protein biomarker candidates. One protein biomarker, serum CXCL1, met the World Health Organization’s Targeted Product Profile for a triage test to diagnose active TB from latent M.tb infection (LTBI), non-TB lung disease, and normal sera in HIV-negative, adults from South Africa and Vietnam. To find the biomarker candidates, we quantified seven immune cytokines and four inflammatory proteins corresponding to highly expressed genes unique to progressor DO mice. Next, we applied statistical and machine learning methods to the data, i.e., 11 proteins in lungs from 453 infected and 29 non-infected mice. After searching all combinations of five algorithms and 239 protein subsets, validating, and testing the findings on independent data, two combinations accurately diagnosed progressor DO mice: Logistic Regression using MMP8; and Gradient Tree Boosting using a panel of 4: CXCL1, CXCL2, TNF, IL-10. Of those five protein biomarker candidates, two (MMP8 and CXCL1) were crucial for classifying DO mice; were above the limit of detection in most human serum samples; and had not been widely assessed for diagnostic performance in humans before. In patient sera, CXCL1 exceeded the triage diagnostic test criteria (>90% sensitivity; >70% specificity), while MMP8 did not. Using Area Under the Curve analyses, CXCL1 averaged 94.5% sensitivity and 88.8% specificity for active pulmonary TB (ATB) vs LTBI; 90.9% sensitivity and 71.4% specificity for ATB vs non-TB; and 100.0% sensitivity and 98.4% specificity for ATB vs normal sera. Our findings overall show that the DO mouse population can discover diagnostic-quality, serum protein biomarkers of human TB.

PMID:34403447 | DOI:10.1371/journal.ppat.1009773

PLoS One. 2021 Aug 17;16(8):e0256072. doi: 10.1371/journal.pone.0256072. eCollection 2021.

ABSTRACT

Knee and hip arthroplasty are common surgeries within an aging population. Some data has suggested that knee arthroplasty is more traumatic to the body than hip arthroplasty due to the increased complexity and load bearing nature of the joint. Here, we compare the stress of the two surgeries by measuring urinary neopterin and total neopterin as biomarkers of oxidative stress and inflammation. Urinary neopterin and total neopterin (neopterin + 7,8-dihydroneopterin) levels were analysed in 28 knee and 22 hip arthroplasty patients pre- and post-operatively to determine oxidative stress and inflammation levels. Total neopterin was 31.1% higher with knee arthroplasty (p<0.05). Urinary neopterin was 32.8% higher in the knee arthroplasty group versus hips. The increase in neopterin and total neopterin following a post-surgical decrease in levels was significant in both groups. Levels of neopterin and total neopterin were varied between patients, but all increased following surgery and subsided by day 28. The increased levels of urinary neopterin and total neopterin from knee arthroplasty indicate that knee osteoarthritis and arthroplasty is a more significant trauma to the body than hip osteoarthritis and arthroplasty surgery. This is also shown by faster inflammatory resolution following hip arthroplasty.

PMID:34403444 | DOI:10.1371/journal.pone.0256072

PLoS One. 2021 Aug 17;16(8):e0256139. doi: 10.1371/journal.pone.0256139. eCollection 2021.

ABSTRACT

Quantitative analysis of computed tomography (CT) radiomic features is an indirect measure of tumor heterogeneity, which has been associated with prognosis in human lung carcinoma. Canine lung tumors share similar features to human lung tumors and serve as a model in which to investigate the utility of radiomic features in differentiating tumor type and prognostication. The purpose of this study was to correlate first-order radiomic features from canine pulmonary tumors to histopathologic characteristics and outcome. Disease-free survival, overall survival time and tumor-specific survival were calculated as days from the date of CT scan. Sixty-seven tumors from 65 dogs were evaluated. Fifty-six tumors were classified as primary pulmonary adenocarcinomas and 11 were non-adenocarcinomas. All dogs were treated with surgical resection; 14 dogs received adjuvant chemotherapy. Second opinion histopathology in 63 tumors confirmed the histologic diagnosis in all dogs and further characterized 53 adenocarcinomas. The median overall survival time was longer (p = 0.004) for adenocarcinomas (339d) compared to non-adenocarcinomas (55d). There was wide variation in first-order radiomic statistics across tumors. Mean Hounsfield units (HU) ratio (p = 0.042) and median mean HU ratio (p = 0.042) were higher in adenocarcinomas than in non-adenocarcinomas. For dogs with adenocarcinoma, completeness of excision was associated with overall survival (p<0.001) while higher mitotic index (p = 0.007) and histologic score (p = 0.037) were associated with shorter disease-free survival. CT-derived tumor variables prognostic for outcome included volume, maximum axial diameter, and four radiomic features: integral total, integral total mean ratio, total HU, and max mean HU ratio. Tumor volume was also significantly associated with tumor invasion (p = 0.044). Further study of radiomic features in canine lung tumors is warranted as a method to non-invasively interrogate CT images for potential predictive and prognostic utility.

PMID:34403435 | DOI:10.1371/journal.pone.0256139

PLoS One. 2021 Aug 17;16(8):e0256307. doi: 10.1371/journal.pone.0256307. eCollection 2021.

ABSTRACT

To assess trends in life expectancy and the contribution of specific causes of death to Native American-White longevity gaps in the Four Corners states, we used death records from the National Center for Health Statistics and population estimates from the U.S. Census Bureau from 1999-2017 to generate period life tables and decompose racial gaps in life expectancy. Native American-White life expectancy gaps narrowed between 2001 and 2012 but widened thereafter, reaching 4.92 years among males and 2.06 years among females in 2015. The life expectancy disadvantage among Native American males was primarily attributable to motor vehicle accidents (0.96 years), liver disease (1.22 years), and diabetes (0.78 years). These causes of deaths were also primary contributors to the gap among females, forming three successive waves of mortality that occurred in young adulthood, midlife, and late adulthood, respectively, among Native American males and females. Interventions to reduce motor vehicle accidents in early adulthood, alcohol-related mortality in midlife, and diabetes complications at older ages could reduce Native American-White longevity disparities in the Four Corners states.

PMID:34403430 | DOI:10.1371/journal.pone.0256307

PLoS Negl Trop Dis. 2021 Aug 17;15(8):e0009670. doi: 10.1371/journal.pntd.0009670. Online ahead of print.

ABSTRACT

BACKGROUND: Fever with jaundice is a common symptom of some infectious diseases. In public health surveillance within the Democratic Republic of the Congo (DRC), yellow fever is the only recognized cause of fever with jaundice. However, only 5% of the surveillance cases are positive for yellow fever and thus indicate the involvement of other pathogens. Leptospira spp. are the causative agents of leptospirosis, a widespread bacterial zoonosis, a known cause of fever with jaundice. This study aimed to determine the seropositivity of anti-Leptospira antibodies among suspected yellow fever cases and map the geographical distribution of possible leptospirosis in the DRC.

METHODS: We conducted a retrospective study using 1,300 samples from yellow fever surveillance in the DRC from January 2017 to December 2018. Serum samples were screened for the presence of IgM against Leptospira spp. by a whole cell-based IgM ELISA (Patoc-IgM ELISA) at the Institut National de Recherche Biomedicale in Kinshasa (INRB) according to World Health Organization (WHO) guidance. Exploratory univariable and multivariable logistic regression analyses were undertaken to assess associations between socio-demographic factors and the presence of Leptospira IgM.

RESULTS: Of the 1,300 serum samples screened, 88 (7%) showed evidence of IgM against Leptospira spp. Most positive cases (34%) were young adult males in the 20-29-year group. There were statistically significant associations between having Leptospira IgM antibodies, age, sex, and living area. Observed positive cases were mostly located in urban settings, and the majority lived in the province of Kinshasa. There was a statistically significant association between seasonality and IgM Leptospira spp. positivity amongst those living in Kinshasa, where most of the positive cases occurred during the rainy season.

CONCLUSIONS: This study showed that leptospirosis is likely an overlooked cause of unexplained cases of fever with jaundice in the DRC and highlights the need to consider leptospirosis in the differential diagnosis of fever with jaundice, particularly in young adult males. Further studies are needed to identify animal reservoirs, associated risk factors, and the burden of human leptospirosis in the DRC.

PMID:34403427 | DOI:10.1371/journal.pntd.0009670

PLoS One. 2021 Aug 17;16(8):e0255223. doi: 10.1371/journal.pone.0255223. eCollection 2021.

ABSTRACT

Large-scale excavations conducted by Smithsonian Institution archaeologists and avocational archaeologists during the 1960s and 1970s at three sites in Seaside, Oregon, resulted in the recovery of a diverse range of material culture curated by multiple institutions. One site, known as Palmrose (35CLT47), provides compelling evidence for the presence of one of the earliest examples of a rectangular plank house along the Oregon Coast. Previous research suggests habitation of the Palmrose site occurred between 2340 cal BC to cal AD 640. However, recent research highlights significant chronometric hygiene concerns of previously reported radiocarbon dates for the Seaside area, calling into question broader regional chronologies. This paper presents a revised chronology for the Palmrose site based on 12 new accelerator mass spectrometry (AMS) radiocarbon dates of ancient cervid bones. I evaluate these new dates and previously reported radiocarbon dates from the site, applying chronometric hygiene assessments and Bayesian statistics to build a refined chronology for the Palmrose site. Calibration of the 12 AMS radiocarbon dates suggests an initial occupation range from 345-55 cal BC and a terminal occupation range from cal AD 225-340-. Bayesian modeling of the Palmrose sequence suggests initial occupation may have spanned from 195-50 cal BC and the terminal occupation from cal AD 210-255. Modeling suggests the maximum range of occupation may span from 580-55 cal BC to cal AD 210-300 based on the start and end boundary calculations. Bayesian modeling of radiocarbon dates directly associated with the plank house deposits suggests the plank house’s occupation may have spanned from 160-1 cal BC to cal AD 170-320. The new radiocarbon dates significantly constrain the Palmrose habitation and alter regional chronologies.

PMID:34403411 | DOI:10.1371/journal.pone.0255223

PLoS Genet. 2021 Aug 17;17(8):e1009728. doi: 10.1371/journal.pgen.1009728. Online ahead of print.

ABSTRACT

Dosage compensation equalizes X-linked expression between XY males and XX females. In male fruit flies, expression levels of the X-chromosome are increased approximately two-fold to compensate for their single X chromosome. In testis, dosage compensation is thought to cease during meiosis; however, the timing and degree of the resulting transcriptional suppression is difficult to separate from global meiotic downregulation of each chromosome. To address this, we analyzed testis single-cell RNA-sequencing (scRNA-seq) data from two Drosophila melanogaster strains. We found evidence that the X chromosome is equally transcriptionally active as autosomes in somatic and pre-meiotic cells, and less transcriptionally active than autosomes in meiotic and post-meiotic cells. In cells experiencing dosage compensation, close proximity to MSL (male-specific lethal) chromatin entry sites (CES) correlates with increased X chromosome transcription. We found low or undetectable levels of germline expression of most msl genes, mle, roX1 and roX2 via scRNA-seq and RNA-FISH, and no evidence of germline nuclear roX1/2 localization. Our results suggest that, although dosage compensation occurs in somatic and pre-meiotic germ cells in Drosophila testis, there might be non-canonical factors involved in the dosage compensation mechanism. The single-cell expression patterns and enrichment statistics of detected genes can be explored interactively in our database: https://zhao.labapps.rockefeller.edu/gene-expr/.

PMID:34403408 | DOI:10.1371/journal.pgen.1009728

Eur J Endocrinol. 2021 Aug 1:EJE-21-0552.R1. doi: 10.1530/EJE-21-0552. Online ahead of print.

ABSTRACT

OBJECTIVE: Polycystic ovary syndrome is diagnosed based on clinical signs, but its presentation is heterogeneous and potentially confounded by concurrent conditions, as obesity and insulin-resistance. MicroRNAs have recently emerged as putative pathophysiological and diagnostic factors in PCOS. However, no reliable miRNA-based method for molecular diagnosis of PCOS has been reported. The aim of this study was to develop a tool for accurate diagnosis of PCOS by targeted miRNA profiling of plasma samples, defined on the basis of unbiased biomarker-finding analyses and biostatistical-tools.

METHODS: A case-control PCOS cohort was cross-sectionally studied, including 170 women classified into four groups: non-PCOS/lean; non-PCOS/obese; PCOS/lean; and PCOS/obese women. High-throughput miRNA analyses were performed in plasma, using NanoString technology and a 800-human-miRNA panel, followed by targeted-qPCR validation. Statistics were applied to define optimal normalization methods, identify deregulated biomarker miRNAs and build classification algorithms, considering PCOS and obesity as major categories.

RESULTS: The geometric mean of circulating hsa-miR-103a-3p, hsa-miR-125a-5p and hsa-miR-1976, selected among 125 unchanged miRNAs, was defined as optimal reference for internal normalization (named mR3-method). Ten miRNAs were identified and validated after mR3-normalization as differentially expressed across the groups. Multinomial LASSO-Regression and decision-tree models were built to reliably discriminate PCOS vs. non-PCOS, either in obese or non-obese women, using subsets of these miRNAs as performers.

CONCLUSIONS: We define herein a robust method for molecular classification of PCOS, based on unbiased identification of miRNA biomarkers and decision-tree protocols. This method allows not only reliable diagnosis of non-obese women with PCOS, but also discrimination between PCOS and obesity.

PMID:34403358 | DOI:10.1530/EJE-21-0552

Eur J Endocrinol. 2021 Aug 1:EJE-21-0475.R2. doi: 10.1530/EJE-21-0475. Online ahead of print.

ABSTRACT

OBJECTIVE: The diagnosis of growth hormone deficiency (GHD) in children is not always straightforward because IGF-1 or GH stimulation tests may not be able to discriminate GHD from constitutional delay of growth and puberty (CDGP) or other causes of short stature.

DESIGN: Boys and girls, n=429, (0.7 – 16 years old) that attended our department for short stature, participated in this study. They were followed up for an average period of 9 years (4-15). At the end of follow up, a definitive diagnosis was assigned to each individual, and all the components of ternary complex (IGF-1, IGFBP-3, ALS and IGF-1/IGFBP-3 ratio) were evaluated as biomarkers for the respective diagnosis.

RESULTS: All components of ternary complex were tightly correlated with each other and positively related to age. IGF-1, IGFBP-3, ALS, and IGF-1/IGFBP-3 ratio differed significantly between GHD and normal groups. IGF-1 and ALS levels were lower in GHD compared to children with familial short stature, while IGF-1 and IGF-1/IGFBP-3 ratio was significantly lower in GHD compared to children with CDGP. IGF-1 and IGF-1/IGFBP-3 Receiver Operating Curves (ROC) cutoff points were unable to discriminate between GHD and normal or between GHD and CDGP groups.

CONCLUSION: Despite the tight correlation among all components of the ternary complex, each one shows a statistically significant diagnosis-dependent alteration. There is a superiority of IGF-1, ALS and IGF-1/IGFBP-3 ratio in the distinction between GHD and CDGP or GHD and normal groups but without usable discriminating power, making thus auxology the primary criterion of establishing the diagnosis.

PMID:34403357 | DOI:10.1530/EJE-21-0475

J Biopharm Stat. 2021 Aug 17:1-21. doi: 10.1080/10543406.2021.1918140. Online ahead of print.

ABSTRACT

The use of real-world data became more and more popular in the pharmaceutical industry. The impact of real-world evidence is now well emphasized by the regulatory authorities. Indeed, the analysis of this type of data can play a key role for treatment efficacy and safety. The aim of this work is to assess various methods and give guidance on the comparisons of drugs, mostly with respect to time-to-event data, in non-randomized studies with potentially confounding variables. For that purpose, several statistical methodologies are compared based on simulation studies. These methodologies belong to family classes of methods that are widely used for this type of problem: regression, matching, weighting and subclassification methods. The evaluation criteria used to compare methods performances are the relative bias, the mean square error, the coverage probability and the width of the confidence interval. In this paper, we consider different scenarios of dataset features in order to study the effect of the sample size, the number of covariates and the magnitude of the treatment effect on the statistical methodologies performances. These statistical analyses are conducted within a proportional hazard model framework. Furthermore, we highlight the advantage of using techniques to identify relevant covariates for time-to-event outcomes by comparing two variable selection methods under a frequentist and a Bayesian inference. Based on simulation results, recommendations on each of the family of methods are provided to guide decision making.

PMID:34403296 | DOI:10.1080/10543406.2021.1918140