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Primary care physicians played an important role in the global response during the COVID-19 pandemic, but with the absence of laboratory and diagnostics services, the move to telehealth and the focus on respiratory assessment, they faced increased uncertainty when making clinical decisions. This paper aims to examine the impact of the pandemic on decisions made by primary care physicians, as measured by referrals to chest X-ray and laboratory tests and by prescriptions of antibiotics. We conducted a retrospective study of all visits recorded with fever or cough, presenting to 209 community clinics in Southern Israel during the years 2018–2022. We describe changes in outcome rates across time and use multivariate generalised linear mixed effects model to compare the odds of referrals and prescriptions between periods, while accounting for gender, age, clinic sector, visit type, diagnosis, and season. In total, 609,823 visits to primary care physicians complied with the cohort definitions. Social restrictions were associated with a decline in all measured outcomes for primary care physician decisions, most prominently among ages 20-59, for throat culture referral during the first lockdown (OR = 0.46) and for cephalosporine prescription during the second lockdown (OR = 0.55). This trend persisted following the cancellation of the restrictions. Despite higher uncertainty during the COVID-19 social restrictions, the overall course of clinical decision-making processes was maintained, and was associated with a reduction in the use of auxiliary resources, which can improve the quality of patient care by lowering costs and supporting prevention of future antibiotics resistance. [ABSTRACT FROM AUTHOR]

(1) Background: COVID-19 presented many challenges to effective treatments, such as managing cardiovascular insufficiency while mitigating risks to healthcare providers. This study utilized NICaS, a non-invasive hemodynamic monitor that provides advanced data via whole-body impedance analysis. We investigated the associated trends in hemodynamic parameters obtained by the NICaS device and their correlation with in-hospital all-cause mortality during COVID-19 hospitalization in the intensive care unit. (2) Methods: Data from 29 patients with COVID-19 admitted to the intensive care unit and monitored with NICaS between April 2020 and February 2021 were analyzed retrospectively. (3) Results: Decreasing cardiac output and cardiac power were significantly associated with death. Total peripheral resistance was significantly increasing in non-survivors as was total body water percentage. Those admitted with a heart rate above 90 beats per minute had a significantly reduced survival. (4) Conclusions: Non-invasive hemodynamic monitoring via the NICaS device is simple and effective in evaluating critically ill patients with COVID-19 and may help guide clinical management via remote monitoring. Controlling tachycardia may help ensure adequate oxygen supply-demand ratio. A hint toward a beneficiary effect of a restrictive fluid balance may be observed. [ABSTRACT FROM AUTHOR]

A tiling array yields a series of abundance measurements across the genome using evenly spaced probes. These data can be used for detecting sequences that exhibit a particular behavior. Scanning window statistics are often employed for testing each probe while accounting for local correlation and smoothing noisy measurements. However, window testing may yield false probe discoveries around the sequences and false non-discoveries within the sequences, resulting in biased predicted intervals. We propose to avoid this problem by stipulating that a sequence of interest can appear at most once within a defined region, such as a gene; thus, only one window statistic is considered per region. This substantially reduces the number of tests and hence, is potentially more powerful. We compare this approach to a genome-wise scan that does not require pre-defined search regions, but considers clumps of adjacent probe discoveries. Simulations show that the gene-wise search maintains the nominal FDR level, while the genome-wise scan yields FDR that exceeds the nominal level for low interval effects, and achieves slightly less power. Using arrays to map introns in yeast, we identified 71% of the previously published introns, detected nine previously undiscovered introns, and observed no false intron discoveries by either method. [ABSTRACT FROM AUTHOR]

The multiplicity problem is evident in the simplest form of statistical analysis of gene expression data – the identification of differentially expressed genes. In more complex analysis, the problem is compounded by the multiplicity of hypotheses per gene. Thus, in some cases, it may be necessary to consider testing millions of hypotheses. We present three general approaches for addressing multiplicity in large research problems. (a) Use the scalability of false discovery rate (FDR) controlling procedures; (b) apply FDR-controlling procedures to a selected subset of hypotheses; (c) apply hierarchical FDR-controlling procedures. We also offer a general framework for ensuring reproducible results in complex research, where a researcher faces more than just one large research problem. We demonstrate these approaches by analyzing the results of a complex experiment involving the study of gene expression levels in different brain regions across multiple mouse strains. [ABSTRACT FROM AUTHOR]

An unannounced balance loss during walking, i.e., balance perturbation, is a stressful event, which changes the activity of the sympathetic nervous system (SNS). We examined SNS response to unannounced balance perturbation during walking, simulating real-life condition of balance loss. We asked: do laboratory-induced unannounced balance losses during walking cause a sympathetic response, and—if so—does it habituate after a series of perturbations? Thirty-four young adults underwent a series of six successive unannounced balance perturbations while walking on a treadmill. Sympathetic activity was monitored continuously using electrodermal activity and compared before and immediately after each unannounced perturbation. All perturbations elicited a significant increase of electrodermal activity (P < 0.001), indicating a phasic increase in the sympathetic drive. The relative phasic increase of electrodermal activity caused by the first perturbation was significantly higher than the last perturbation (P < 0.05). Three different types of electrodermal activity behavior were observed: steady-level tonic SNS activity, increased SNS activity, and decreased SNS activity. Balance loss during walking triggers phasic SNS response, this response habituates after a series of unannounced balance perturbations. In addition, three distinct patterns of tonic sympathetic activity may imply variations in the ability of the SNS response to habituate across individuals. NEW & NOTEWORTHY: Up to date, the literature typically provides information about sympathetic nervous system activity and relatively static balance. We believe that exposing participants to a balance loss during walking, i.e., unexpected perturbation, provides a more ecologically valid situation to measure sympathetic nervous system response; this provides new and vital knowledge that can have a significant impact and understanding of how the SNS responds to a loss of balance in a real-life situation. [ABSTRACT FROM AUTHOR]

PURPOSE: Current guidelines for the management of metastatic non–small cell lung cancer (NSCLC) without driver mutations recommend checkpoint immunotherapy with PD-1/PD-L1 inhibitors, either alone or in combination with chemotherapy. This approach fails to account for individual patient variability and host immune factors and often results in less-than-ideal outcomes. To address the limitations of the current guidelines, we developed and subsequently blindly validated a machine learning algorithm using pretreatment plasma proteomic profiles for personalized treatment decisions. PATIENTS AND METHODS: We conducted a multicenter observational trial (ClinicalTrials.gov identifier: NCT04056247) of patients undergoing PD-1/PD-L1 inhibitor–based therapy (n = 540) and an additional patient cohort receiving chemotherapy (n = 85) who consented to pretreatment plasma and clinical data collection. Plasma proteome profiling was performed using SomaScan Assay v4.1. RESULTS: Our test demonstrates a strong association between model output and clinical benefit (CB) from PD-1/PD-L1 inhibitor–based treatments, evidenced by high concordance between predicted and observed CB (R 2 = 0.98, P <.001). The test categorizes patients as either PROphet-positive or PROphet-negative and further stratifies patient outcomes beyond PD-L1 expression levels. The test successfully differentiates between PROphet-negative patients exhibiting high tumor PD-L1 levels (≥50%) who have enhanced overall survival when treated with a combination of immunotherapy and chemotherapy compared with immunotherapy alone (hazard ratio [HR], 0.23 [95% CI, 0.1 to 0.51], P =.0003). By contrast, PROphet-positive patients show comparable outcomes when treated with immunotherapy alone or in combination with chemotherapy (HR, 0.78 [95% CI, 0.42 to 1.44], P =.424). CONCLUSION: Plasma proteome–based testing of individual patients, in combination with standard PD-L1 testing, distinguishes patient subsets with distinct differences in outcomes from PD-1/PD-L1 inhibitor–based therapies. These data suggest that this approach can improve the precision of first-line treatment for metastatic NSCLC. PROphet blood test supports first-line immunotherapy treatment decisions for patients with metastatic NSCLC. [ABSTRACT FROM AUTHOR]

The clinical significance of an abnormal free light chain (FLC) test, performed due to unspecific complains in the absence of a known plasma cell dyscrasia (PCD) or lymphoproliferative disease (LPD), is not fully elucidated. We investigated the importance of an abnormal FLC ratio (FLC-R) in this setting. Patients registered in the Maccabi Healthcare Services database, tested for FLC during 2007–2023 without previously documented PCD/LPD or increased total protein (TP) level, were reviewed. Demographics, co-morbidities, and laboratory tests were recorded. FLC-R was defined as normal (0.26–1.65) or slightly (slAb 0.1–0.26/1.65–4), moderately (mAbn 0.1–0.05/4–8) and significantly abnormal (sigAb- < 0.05 or > 8). Factors associated with PCD/LPD and overall survival were identified. In total, 8,661 patients, 2,215 (25.6%) with abnormal FLC-R [2,090 (24.1%)-slAb, 65 (0.75%)-mAbn and 60 (0.7%)-sigAb], were analyzed. Almost none had anemia nor acute renal failure. 14% had concomitant increased immunoglobulins. Within a median follow-up of 52 months, 943 were diagnosed with PCD (816-MGUS, 127-MM/Amyloidosis/plasmacytoma) and 48 with LPD. Median time to PCD and LPD were 19 and 28 months. Multivariate analysis found slAb (HR = 1.8, CI95%:1.53–2.12, p < 0.001), mAbn (HR = 6.3, CI95%:4.16–9.53, p < 0.001), and sigAb FLC (HR = 10.4, CI95%:7.0–15.35, p < 0.001), to be associated with PCD/LPD diagnosis. Decreased IgG, increased IgA, and concomitant comorbidities predicted PCD, whereas increased IgM predicted LPD. Older age, male gender, anemia, decreased albumin, increased IgG and concomitant comorbidities, predicted shorter survival. Our large study emphasizes the independent clinical significance of abnormal FLC-R as a predictor of PCD/LPD diagnosis even in patients with normal TP level, promoting early detection of PCD/LPD. [ABSTRACT FROM AUTHOR]

PURPOSE: Current guidelines for the management of metastatic non–small cell lung cancer (NSCLC) without driver mutations recommend checkpoint immunotherapy with PD-1/PD-L1 inhibitors, either alone or in combination with chemotherapy. This approach fails to account for individual patient variability and host immune factors and often results in less-than-ideal outcomes. To address the limitations of the current guidelines, we developed and subsequently blindly validated a machine learning algorithm using pretreatment plasma proteomic profiles for personalized treatment decisions. PATIENTS AND METHODS: We conducted a multicenter observational trial (ClinicalTrials.gov identifier: NCT04056247) of patients undergoing PD-1/PD-L1 inhibitor–based therapy (n = 540) and an additional patient cohort receiving chemotherapy (n = 85) who consented to pretreatment plasma and clinical data collection. Plasma proteome profiling was performed using SomaScan Assay v4.1. RESULTS: Our test demonstrates a strong association between model output and clinical benefit (CB) from PD-1/PD-L1 inhibitor–based treatments, evidenced by high concordance between predicted and observed CB (R 2 = 0.98, P <.001). The test categorizes patients as either PROphet-positive or PROphet-negative and further stratifies patient outcomes beyond PD-L1 expression levels. The test successfully differentiates between PROphet-negative patients exhibiting high tumor PD-L1 levels (≥50%) who have enhanced overall survival when treated with a combination of immunotherapy and chemotherapy compared with immunotherapy alone (hazard ratio [HR], 0.23 [95% CI, 0.1 to 0.51], P =.0003). By contrast, PROphet-positive patients show comparable outcomes when treated with immunotherapy alone or in combination with chemotherapy (HR, 0.78 [95% CI, 0.42 to 1.44], P =.424). CONCLUSION: Plasma proteome–based testing of individual patients, in combination with standard PD-L1 testing, distinguishes patient subsets with distinct differences in outcomes from PD-1/PD-L1 inhibitor–based therapies. These data suggest that this approach can improve the precision of first-line treatment for metastatic NSCLC. PROphet blood test supports first-line immunotherapy treatment decisions for patients with metastatic NSCLC. [ABSTRACT FROM AUTHOR]

Non-invasive oxygen saturation (SpO2) is a central vital sign used to shape the management of COVID-19 patients. Yet, there have been no report quantitatively describing SpO2 dynamics and patterns in COVID-19 patients using continuous SpO2 recordings. We performed a retrospective observational analysis of the clinical information and 27 K hours of continuous SpO2 high-resolution (1 Hz) recordings of 367 critical and non-critical COVID-19 patients hospitalised at the Rambam Health Care Campus, Haifa, Israel. An absolute SpO2 threshold of 93% most efficiently discriminated between critical and non-critical patients, regardless of oxygen support. Oximetry-derived digital biomarker (OBMs) computed per 1 h monitoring window showed significant differences between groups, notably the cumulative time below 93% SpO2 (CT93). Patients with CT93 above 60% during the first hour of monitoring, were more likely to require oxygen support. Mechanical ventilation exhibited a strong effect on SpO2 dynamics by significantly reducing the frequency and depth of desaturations. OBMs related to periodicity and hypoxic burden were markedly affected, up to several hours before the initiation of the mechanical ventilation. In summary, OBMs, traditionally used in the field of sleep medicine research, are informative for continuous assessment of disease severity and response to respiratory support of hospitalised COVID-19 patients. In conclusion, OBMs may improve risk stratification and therapy management of critical care patients with respiratory impairment. [ABSTRACT FROM AUTHOR]

We describe here the development, verification and validation of the SLE-key ® rule-out test for a definitive rule-out of a diagnosis of systemic lupus erythematosus (SLE). The test uses the proprietary iCHIP ® micro-array technology platform (Fattal et al., 2010) to identify discriminating patterns of circulating autoantibodies among SLE patients compared with self-declared healthy individuals. Given the challenges associated with the diagnosis of SLE and the healthcare costs of delayed diagnosis and misdiagnosis, a definitive rule-out test can provide significant clinical benefits to patients and potentially major cost savings to healthcare systems. [ABSTRACT FROM AUTHOR]

Objective and Methods: This paper proposes an inegrative two-stage genome-wide search for pairwise epistasis on expression quantitative trait loci (eQTL). The traits are clustered into multi-trait complexes that account for correlations between them that may result from common epistasis effects. The search is done by first screening for epistatic regions and then using dense markers within the identified regions, resulting in substantial reduction in the number of tests for epistasis. The FDR is controlled using a hierarchical procedure that accounts for the search structure. Each combination of trait and marker-pair is tested using a model that accounts for both statistical and functional interpretations of epistasis and considers orthogonal effects, such that their contributions to heritability can be estimated individually. We examine the impact of using multi-trait complexes rather than single traits, and of using a hierarchical search for epistasis rather than skipping the initial screen for epistatic regions. We apply the proposed algorithm on Arabidopsis transcription data. Principal Findings: Both epistasis detection power and heritability contributed by epistasis increased when using multi-trait complexes rather than single traits. Epistatic effects common to the eQTLs included in the complexes have higher chance of being identified by analysis of multi-trait complexes, particularly when epistatic effects on individual traits are small. Compared to direct testing for all potential epistatic effects, the hierarchical search was substantially more powerful in detecting epistasis, while controlling the FDR at the desired level. Association in functional roles within genomic regions was observed, supporting an initial screen for epistatic QTLs. [ABSTRACT FROM AUTHOR]

Many types of tumors exhibit characteristic chromosomal losses or gains, as well as local amplifications and deletions. Within any given tumor type, sample specific amplifications and deletions are also observed. Typically, a region that is aberrant in more tumors, or whose copy number change is stronger, would be considered as a more promising candidate to be biologically relevant to cancer. We sought for an intuitive method to define such aberrations and prioritize them. We define V, the "volume" associated with an aberration, as the product of three factors: (a) fraction of patients with the aberration, (b) the aberration's length and (c) its amplitude. Our algorithm compares the values of V derived from the real data to a null distribution obtained by permutations, and yields the statistical significance (p-value) of the measured value of V. We detected genetic locations that were significantly aberrant, and combine them with chromosomal arm status (gain/loss) to create a succinct fingerprint of the tumor genome. This genomic fingerprint is used to visualize the tumors, highlighting events that are co-occurring or mutually exclusive. We apply the method on three different public array CGH datasets of Medulloblastoma and Neuroblastoma, and demonstrate its ability to detect chromosomal regions that were known to be altered in the tested cancer types, as well as to suggest new genomic locations to be tested. We identified a potential new subtype of Medulloblastoma, which is analogous to Neuroblastoma type 1. [ABSTRACT FROM AUTHOR]

Background Sub-Saharan Africans exhibit a higher frequency of chronic kidney disease (CKD) than other populations. In this study, we sought to determine the frequency of apolipoprotein L1 (APOL1) genotypes in hypertension-attributed CKD in Kinshasa, Democratic Republic of the Congo. Methods We performed a case–control study identifying 162 subjects: 79 with hypertension-attributed CKD and 83 controls living in Kinshasa who were genotyped for APOL1 risk variants between July 2013 and November 2016. We selected control subjects from the general population and matched them with the cases according to age. Logistic regression analysis was used to examine the relationship between APOL1 high-risk genotypes and CKD. Results The frequencies of the APOL1 G1 and G2 alleles were 19.1 and 7.1%, respectively. The number of individuals with the G1 and G2 risk alleles was significantly higher in the CKD group (12.7%) than in the control group (2.4%), particularly in individuals with end-stage kidney disease (14.3%). Subjects carrying two risk alleles was strongly and independently associated with hypertension-attributed nephropathy, with an adjusted odds ratio of 7.7 (95% confidence interval 1.5–39.7; P = 0.014). The high-risk APOL1 genotypes were G1/G1 and G1/G2, whereas G2/G2 was not found in the study population. Conclusions The results of this study demonstrate the association of high-risk APOL1 genotypes with kidney disease in Kinshasa. The absence of G2/G2 may be consistent with powerful selective sweeps induced by Trypanosoma brucei gambiense infection. In contrast, the presence of APOL1 G2/G2 among individuals of African ancestry in the USA may indicate relaxation of natural selection in a trypanosome-free environment. [ABSTRACT FROM AUTHOR]

Increased levels of bone marrow adipose tissue (BMAT) are negatively associated with skeletal health and hematopoiesis. BMAT is known to increase with age; however, the effect of long-term weight loss on BMAT is still unknown. In this study, we examined BMAT response to lifestyle-induced weight loss in 138 participants (mean age 48 y; mean body mass index 31 kg/m2), who participated in the CENTRAL-MRI trial. Participants were randomized for dietary intervention of low-fat or low-carb, with or without physical activity. Magnetic resonance imaging (MRI) was used to quantify BMAT and other fat depots at baseline, six and eighteen months of intervention. Blood biomarkers were also measured at the same time points. At baseline, the L3 vertebrae BMAT is positively associated with age, HDL cholesterol, HbA1c and adiponectin; but not with other fat depots or other metabolic markers tested. Following six months of dietary intervention, the L3 BMAT declined by an average of 3.1 %, followed by a return to baseline after eighteen months (p < 0.001 and p = 0.189 compared to baseline, respectively). The decrease of BMAT during the first six months was associated with a decrease in waist circumference, cholesterol, proximal-femur BMAT, and superficial subcutaneous adipose tissue (SAT), as well as with younger age. Nevertheless, BMAT changes did not correlate with changes in other fat depots. We conclude that physiological weight loss can transiently reduce BMAT in adults, and this effect is more prominent in younger adults. Our findings suggest that BMAT storage and dynamics are largely independent of other fat depots or cardio-metabolic risk markers, highlighting its unique functions. • L3 vertebrae BMAT decreased following six months diet-induced weight loss. • BMAT regained to baseline levels following 18 months of diet and physical activity. • MRI quantification of BMAT shows associations with age and with metabolic markers. • The change of L3 BMAT correlates with femur BMAT, but not with other fat depots. [ABSTRACT FROM AUTHOR]