scholarly journals Large population study identifies drugs associated with reduced COVID-19 severity

2020 ◽  
Author(s):  
Ariel Israel ◽  
Alejandro A. Schäffer ◽  
Assi Cicurel ◽  
Ilan Feldhamer ◽  
Ameer Tal ◽  
...  
Keyword(s):  
Protective Effect ◽  
Population Study ◽  
Multiple Testing ◽  
Anatomical Therapeutic Chemical ◽  
Severe Disease ◽  
Large Population ◽  
P Value ◽  
Exact Test ◽  
Latex Gloves ◽  
Surgical Masks

AbstractBACKGROUNDIt may take months to years until drugs specifically designed to treat COVID-19 are available. Until then, it is crucial to identify whether existing medications could have a protective effect against severe disease. This is the objective of this large population study performed in Clalit Health Services (CHS), the largest healthcare provider in Israel.METHODSCHS centrally manages electronic health records (EHRs) including medication purchases for over 4.5 million members. Two case-control matched cohorts were assembled to assess systematically which drugs affected the risk of COVID-19 hospitalization: in both cohorts, case patients were hospitalized for COVID-19; matched control patients were taken from the general population in the first cohort, and non-hospitalized SARS-CoV-2 positive patients in the second cohort. For each medication anatomical-therapeutic-chemical (ATC) class acquired during the last month before the index-date, we computed the odds ratio (OR) for hospitalization, 95% confidence interval (CI), and the p-value, using Fisher’s exact test. False discovery rate was used to adjust for multiple testing.RESULTSSeveral drugs and pharmacy sold items were associated with significantly reduced odds for SARS-CoV-2 hospitalization, notably ubiquinone (OR=0.185, 95% CI [0.058,0.458], p<0.001), ezetimibe (OR=0.513, 95% CI [0.375,0.688], P<0.001), rosuvastatin (OR=0.746, 95% CI [0.645,0.858], p<0.001) and flecainide (OR=0.303, 95% CI [0.080,0.813], p<0.01). Additionally, acquisition of surgical masks, latex gloves and several ophthalmological products were associated with decreased risk for hospitalization.CONCLUSIONUbiquinone, ezetimibe and rosuvastatin, all related to the cholesterol synthesis pathway were associated with reduced hospitalization risk. These findings suggest a promising protective effect which should be further investigated.

scholarly journals Identification of drugs associated with reduced severity of COVID-19: A case-control study in a large population

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Ariel Israel ◽  
Alejandro A Schäffer ◽  
Assi Cicurel ◽  
Ilan Feldhamer ◽  
Ameer Tal ◽  
...  
Keyword(s):  
Protective Effect ◽  
Multiple Testing ◽  
Severe Disease ◽  
Large Population ◽  
Positive Control ◽  
Case Control ◽  
National Institutes Of Health ◽  
P Value ◽  
Exact Test ◽  
Control Study

Background: Until COVID-19 drugs specifically developed to treat COVID-19 become more widely accessible, it is crucial to identify whether existing medications have a protective effect against severe disease. Towards this objective, we conducted a large population study in Clalit Health Services (CHS), the largest healthcare provider in Israel, insuring over 4.7 million members. Methods: Two case-control matched cohorts were assembled to assess which medications, acquired in the last month, decreased the risk of COVID‑19 hospitalization. Case patients were adults aged 18-95 hospitalized for COVID-19. In the first cohort, five control patients, from the general population, were matched to each case (n=6202); in the second cohort, two non-hospitalized SARS-CoV-2 positive control patients were matched to each case (n=6919). The outcome measures for a medication were: odds ratio (OR) for hospitalization, 95% confidence interval (CI), and the p‑value, using Fisher's exact test. False discovery rate was used to adjust for multiple testing. Results: Medications associated with most significantly reduced odds for COVID-19 hospitalization include: ubiquinone (OR=0.185, 95% CI (0.058 to 0.458), p<0.001), ezetimibe (OR=0.488, 95% CI ((0.377 to 0.622)), p<0.001), rosuvastatin (OR=0.673, 95% CI (0.596 to 0.758), p<0.001), flecainide (OR=0.301, 95% CI (0.118 to 0.641), p<0.001), and vitamin D (OR=0.869, 95% CI (0.792 to 0.954), p<0.003). Remarkably, acquisition of artificial tears, eye care wipes, and several ophthalmological products were also associated with decreased risk for hospitalization. Conclusions: Ubiquinone, ezetimibe and rosuvastatin, all related to the cholesterol synthesis pathway were associated with reduced hospitalization risk. These findings point to a promising protective effect which should be further investigated in controlled, prospective studies. Funding: This research was supported in part by the Intramural Research Program of the National Institutes of Health, NCI.

Landscape of KRASG12C, associated genomic alterations, and interrelation with immuno-oncology (IO) biomarkers.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3127-3127
Author(s):  
Mohamed E. Salem ◽  
Sherif El-Refai ◽  
Wei Sha ◽  
Axel Grothey ◽  
Alberto Puccini ◽  
...  
Keyword(s):  
Multiple Testing ◽  
Smoking Status ◽  
Unknown Origin ◽  
P Value ◽  
Cancer Type ◽  
Tumor Type ◽  
Genomic Alterations ◽  
Kras Mutations ◽  
Exact Test ◽  
Cancer Subtypes

3127 Background: Sotorasib has shown promising activity in cancer patients (pts) specifically harboring the KRASG12C mutation. Response rates vary significantly by tumor type, suggesting KRASG12C pathogenesis may be cancer-type-dependent. Methods: We retrospectively analyzed de-identified records of 79,004 pts with various cancer types that underwent Tempus xT and xF next generation sequencing assays. Fisher’s exact test was used to analyze the association between cancer subtypes and KRAS variants. Logistic regression was used to study co-mutations between KRASG12C and other oncogenes, as well as the association between KRAS variants and IO biomarkers. False discovery rate-adjusted P-value (FDR P) was used for multiple testing. Results: In total, 13,578 (17.4%) tumors harbored KRAS mutations, of which 1,632 were G12C; 750 KRAS wild-type (WT) tumors gained KRAS mutation on follow-up testing, with 79 harboring G12C. The most frequent KRAS variants across all cancers were G12D, G12V, G12C, and G13D (see Table). The distribution of KRAS variants significantly varied by cancer type, with G12C and G12D being the most prevalent in non-small cell lung (NSCLC) and colorectal (CRC) cancers, respectively. G12C was most prevalent in NSCLC (9%), appendiceal cancer (3.9%), CRC (3.2%), tumors of unknown origin (1.6%), and pancreatic cancer (1.3%). Compared to non-G12C, G12C was more frequently identified in females (56% vs. 51%, FDR P = 0.0005), smokers/prior smokers (85% vs. 56%, FDR P < 0.0001), and pts > 60 years of age (73% vs. 63%, FDR P = 0.0006). While no G12C tumors exhibited BRAFV600E co-mutations, BRAFnon-V600E co-mutations were seen in 3.1% of pts. Significant differences were observed in genomic alterations co-occurring with G12C compared to non-G12C (e.g., STK11 (20.6% vs 6%), KEAP1 (15.4% vs 4.6%), SMAD4 (7.2% vs 19%), and PDGFRA (5.8% vs 3%); FDR P < 0.0001). However, G12C and oncogene co-mutations were not significantly different between NSCLC and CRC, except for KEAP1 (FDR_ P = 0.04). Compared to non-G12C and WT, G12C tumors were associated with TMB-High and PD-L1 over expression but were less likely to have MSI-H status (FDR P < 0.0001; Table). Conclusions: Our data suggest that KRAS variants significantly differ by cancer type. Tumors harboring KRASG12C were significantly associated with high TMB and PD-L1 overexpression. KRASG12C mutation appeared to be associated with smoking status. These results may guide future therapeutic strategies.[Table: see text]

scholarly journals Genomic and Ancestral Variation Underlies the Severity of COVID-19 Clinical Manifestation in Individuals of European Descent

Life ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 921
Author(s):  
Priyanka Upadhyai ◽  
Gokul Suresh ◽  
Rahul Parit ◽  
Ranajit Das
Keyword(s):  
Multiple Testing ◽  
Cholesterol Metabolism ◽  
Wide Spectrum ◽  
Severe Disease ◽  
Control Group ◽  
P Value ◽  
European Descent ◽  
Genome Wide ◽  
A Genome ◽  
Asymptomatic Subjects

The coronavirus disease (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is characterized by a wide spectrum of clinical phenotypes ranging from asymptomatic to symptomatic with mild or moderate presentation and severe disease. COVID-19 susceptibility, severity and recovery have demonstrated high variability worldwide. Variances in the host genetic architecture may underlie the inter-individual and population-scale differences in COVID-19 presentation. We performed a genome-wide association analysis employing the genotyping data from AncestryDNA for COVID-19 patients of European descent and used asymptomatic subjects as the control group. We identified 621 genetic variants that were significantly distinct between asymptomatic and acutely symptomatic COVID-19 patients (multiple-testing corrected p-value < 0.001). These variants were found to be associated with pathways governing host immunity, such as interferon, interleukin and cytokine signalling, and known COVID-19 comorbidities, such as obesity and cholesterol metabolism. Further, our ancestry analysis revealed that the asymptomatic COVID-19 patients possess discernibly higher proportions of the Ancestral North Eurasian (ANE) and Eastern Hunter-Gatherer (EHG) ancestry, which was introduced to Europe through Bell Beaker culture (Yamnaya related) and lower fractions of Western Hunter-Gatherer (WHG) ancestry, while severely symptomatic patients have higher fractions of WHG and lower ANE/EHG ancestral components, thereby delineating the likely ancestral differences between the two groups.

3042Gender differences in the prevalence of a normal IMT with increasing severity of carotid disease

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
M Matangi ◽  
M Cases ◽  
D Brouillard ◽  
D Armstrong ◽  
A Johri
Keyword(s):  
Carotid Plaque ◽  
Severe Disease ◽  
Plaque Burden ◽  
P Value ◽  
Plaque Score ◽  
Exact Test ◽  
Fisher's Exact Test ◽  
Plaque Area ◽  
Fisher’S Exact Test ◽  
Carotid Bulb

Abstract Background The ARIC group has shown that increasing IMT is only predictive of increased cardiovascular (CV) risk in males (M). Plaque is predictive of increased CV risk in both M and females (F). Purpose To determine the prevalence of a normal IMT (<1.00mm) in M and F with evidence of carotid plaque. Plaque score (PS) was used as a measure of severity of disease. Methods Our database was searched for patients with all the required data, IMT, PS and plaque area. IMT was measured with automatic edge detection software, PS was calculated using the Rotterdam method and plaque area was measured in the carotid bulb and ICA bilaterally. Only the first carotid study was used in the analysis. PS of 0–6 were used to estimate plaque severity. ANOVA and the Fisher's exact test were used to detect differences between groups. A p value of <0.05 was considered significant. Results There were 5981 patients, 3062 M and 2919 F with an average age of 62.1±11.3 years. Table I. indicates that with increasing PS, age, IMT and plaque area all increase, with a reciprocal decrease in the proportion of patients with a normal IMT. Of 3829 patients with carotid plaque 1355 (35.4%) had an IMT <1.00mm. There were clear gender differences with a much higher prevalence of a normal IMT in F with carotid plaque than M, 776 of 1772 (43.8%) versus 579 of 2057 (28.1%), p<0.0001, Fisher's exact test. This gender difference applies to most groups with increasing plaque burden except those with the most severe disease (PS “5–6”). Table 1 PS “0” PS “1” PS “2” PS “3” PS “4” PS “5–6” N 2152 896 1209 792 562 370 ANOVA Age 57.6±12.2 60.4±9.2 63.0±9.5 66.5±9.3 67.8±8.9 71.5±8.8 <0.0001 IMT 0.94±0.32 1.00±0.23 1.08±0.29 1.30±0.55 1.51±0.75 2.77±0.88 <0.0001 Plaque area 0 16.5±11.6 35.1±20.0 58.6±29.9 91.0±43.1 130.4±61.3 <0.0001 Males 1005 424 627 422 331 253 IMT <1.00mm 671 222 226 77 50 4 Percentage 66.8% 52.4% 36.0% 18.2% 15.1% 1.6% Females 1147 472 582 370 231 117 IMT <1.00mm 879 293 288 136 57 2 Percentage 76.6% 62.1% 49.5% 36.8% 24.6% 1.7% Fisher's test <0.0001 <0.005 <0.0001 <0.0001 <0.0001 NS PS = Carotid ÷ 6 segments, assigned “0” or “1” if plaque is absent or present. Conclusions Significantly more women with carotid plaque have a normal IMT. This may explain why IMT fails to be predictive of CV risk in women.

Isolated Liner Revision for Total Knee Arthroplasty Instability: A Road That Should Remain Less Taken

2020 ◽  
Author(s):  
Jason D. Tegethoff ◽  
Rafael Walker-Santiago ◽  
William M. Ralston ◽  
James A. Keeney
Keyword(s):  
Total Knee Arthroplasty ◽  
Femoral Component ◽  
Knee Arthroplasty ◽  
Primary Total Knee Arthroplasty ◽  
P Value ◽  
Surgical Morbidity ◽  
Exact Test ◽  
Total Knee ◽  
Component Revision

AbstractIsolated polyethylene liner exchange (IPLE) is infrequently selected as a treatment approach for patients with primary total knee arthroplasty (TKA) prosthetic joint instability. Potential advantages of less immediate surgical morbidity, faster recovery, and lower procedural cost need to be measured against reoperation and re-revision risk. Few published studies have directly compared IPLE with combined tibial and femoral component revision to treat patients with primary TKA instability. After obtaining institutional review board (IRB) approval, we performed a retrospective comparison of 20 patients treated with IPLE and 126 patients treated with tibial and femoral component revisions at a single institution between 2011 and 2018. Patient demographic characteristics, medical comorbidities, time to initial revision TKA, and reoperation (90 days, <2 years, and >2 years) were assessed using paired Student's t-test or Fisher's exact test with a p-value <0.01 used to determine significance. Patients undergoing IPLE were more likely to undergo reoperation (60.0 vs. 17.5%, p = 0.001), component revision surgery (45.0 vs. 8.7%, p = 0.002), and component revision within 2 years (30.0 vs. 1.6%, p < 0.0001). Differences in 90-day reoperation (p = 0.14) and revision >2 years (p = 0.19) were not significant. Reoperation for instability (30.0 vs. 4.0%, p < 0.001) and infection (20.0 vs. 1.6%, p < 0.01) were both higher in the IPLE group. IPLE does not provide consistent benefits for patients undergoing TKA revision for instability. Considerations for lower immediate postoperative morbidity and cost need to be carefully measured against long-term consequences of reoperation, delayed component revision, and increased long-term costs of multiple surgical procedures. This is a level III, case–control study.

The Protective Effect of Metformin against Oxandrolone-Induced Infertility in Male Rats

2020 ◽  
Vol 26 ◽  
Author(s):  
Abdulqader Fadhil Abed ◽  
Yazun Bashir Jarrar ◽  
Hamzeh J Al-Ameer ◽  
Wajdy Al-Awaida ◽  
Su-Jun Lee
Keyword(s):  
Gene Expression ◽  
Male Infertility ◽  
Protective Effect ◽  
Histological Examination ◽  
Sperm Count ◽  
Serum Testosterone ◽  
Male Rats ◽  
P Value ◽  
Protective Effects ◽  
Rt Pcr

Background: Oxandrolone is a synthetic testosterone analogue that is widely used among bodybuilders and athletes. However, oxandrolone causes male infertility. Recently, it was found that metformin reduces the risk of infertility associated with diabetes mellitus. Aim: This study aimed to investigate the protective effects of metformin against oxandrolone-induced infertility in male rats. Methods: Rats continuously received one of four treatments (n=7) over 14 days: control DMSO administration, oxandrolone administration, metformin administration, or co-administration of oxandrolone and metformin. Doses were equivalent to those used for human treatment. Subsequently, testicular and blood samples were collected for morphological, biochemical, and histological examination. In addition, gene expression of the testosterone synthesizing enzyme CYP11A1 was analyzed in the testes using RT-PCR. Results: Oxandrolone administration induced male infertility by significantly reducing relative weights of testes by 48%, sperm count by 82%, and serum testosterone levels by 96% (ANOVA, P value < 0.05). In addition, histological examination determined that oxandrolone caused spermatogenic arrest which was associated with 2-fold downregulation of testicular CYP11A1 gene expression. However, co-administration of metformin with oxandrolone significantly ameliorated toxicological alterations induced by oxandrolone exposure (ANOVA, P value < 0.05). Conclusion: Metformin administration protected against oxandrolone-induced infertility in male rats. Further clinical studies are needed to confirm the protective effect of metformin against oxandrolone-induced infertility among athletes.

HPV Prevalence and its Association with Perinatal Outcomes among Singleton Mothers: Analysis of Pregnancy Risk Assessment and Monitoring System (PRAMS) Data, 2004-2011

2019 ◽  
Vol 15 (2) ◽  
pp. 143-149 ◽  
Author(s):  
Harpriya Kaur ◽  
Delf Schmidt-Grimminger ◽  
Baojiang Chen ◽  
K.M. Monirul Islam ◽  
Steven W. Remmenga ◽  
...  
Keyword(s):  
Birth Weight ◽  
Low Birth Weight ◽  
Pregnant Women ◽  
Monitoring System ◽  
Large Population ◽  
Perinatal Outcomes ◽  
Hpv Infection ◽  
Adverse Outcomes ◽  
P Value ◽  
Pregnancy Risk

Background: Pregnancy may increase the risk of Human Papillomavirus (HPV) infection because of pregnancy induced immune suppression. The objective of this study was to use a large population-based dataset to estimate the prevalence of HPV infection and its association with adverse outcomes among pregnant women. Methods: We analyzed Pregnancy Risk Monitoring System data from 2004-2011 (N=26,085) to estimate the self-reported HPV infection. Survey logistic procedures were used to examine the relationship between HPV infection and adverse perinatal outcomes. Results: Approximately 1.4% of women were estimated to have HPV infection during their pregnancy. The prevalence of adverse outcomes in this sample was preterm birth (8.4%), preeclampsia (7.5%), low birth weight (6.3%) and premature rupture of membranes (2.8%). Compared to women without HPV infection, HPV infection positive women were much more likely to have had other infections such as chlamydia (9.23% vs. 2.12%, p-value <.0001), Group B Strep (21.7% vs. 10.04%, p-value <.0001), and herpes (7.17% vs. 1.07%, p-value <.0001). After adjusting for other risk factors including other infections, HPV infection was significantly associated with low birth weight (OR: 1.94, 95% CI: 1.14-3.30). Conclusion: The study indicated a potential association between HPV infection and low birth weight. Because pregnant women with HPV infection are at higher risk of other infections, future research may focus on the roles of co-infection in the development of adverse perinatal effects.

Classifying depression using blood biomarkers: A large population study

2021 ◽  
Author(s):  
Ziqiang Lin ◽  
Wayne R. Lawrence ◽  
Yanhong Huang ◽  
Qiaoxuan Lin ◽  
Yanhui Gao
Keyword(s):  
Population Study ◽  
Large Population ◽  
Blood Biomarkers

scholarly journals Synergistic effect of genetic polymorphisms in TLR6 and TLR10 genes on the risk of pulmonary tuberculosis in a Moldavian population

2021 ◽  
pp. 175342592110299
Author(s):  
Alexander Varzari ◽  
Igor V. Deyneko ◽  
Elena Tudor ◽  
Harald Grallert ◽  
Thomas Illig
Keyword(s):  
Pulmonary Tuberculosis ◽  
Interaction Analysis ◽  
P Value ◽  
Fisher Exact Test ◽  
Snp Analysis ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Exact Test ◽  
Pulmonary Tb ◽  
The Republic

Polymorphisms in genes that control immune function and regulation may influence susceptibility to pulmonary tuberculosis (TB). In this study, 14 polymorphisms in 12 key genes involved in the immune response ( VDR, MR1, TLR1, TLR2, TLR10, SLC11A1, IL1B, IL10, IFNG, TNF, IRAK1, and FOXP3) were tested for their association with pulmonary TB in 271 patients with TB and 251 community-matched controls from the Republic of Moldova. In addition, gene–gene interactions involved in TB susceptibility were analyzed for a total of 43 genetic loci. Single nucleotide polymorphism (SNP) analysis revealed a nominal association between TNF rs1800629 and pulmonary TB (Fisher exact test P = 0.01843). In the pairwise interaction analysis, the combination of the genotypes TLR6 rs5743810 GA and TLR10 rs11096957 GT was significantly associated with an increased genetic risk of pulmonary TB (OR = 2.48, 95% CI = 1.62–3.85; Fisher exact test P value = 1.5 × 10−5, significant after Bonferroni correction). In conclusion, the TLR6 rs5743810 and TLR10 rs11096957 two-locus interaction confers a significantly higher risk for pulmonary TB; due to its high frequency in the population, this SNP combination may serve as a novel biomarker for predicting TB susceptibility.

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