Nevin Manimala

J Med Virol. 2023 Feb 10. doi: 10.1002/jmv.28570. Online ahead of print.

ABSTRACT

PURPOSE: COVID-19 may cause a dysregulation of the immune system and has complex relationships with multiple autoimmune diseases, including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). However, little is known about their common genetic architecture.

METHODS: Using the latest data from COVID-19 host genetics consortium and consortia on RA and SLE, we conducted a genome-wide cross-trait analysis to examine the shared genetic etiology between COVID-19 and RA/SLE and evaluated their causal associations using bi-directional Mendelian randomization.

RESULTS: The cross-trait meta-analysis identified 23, 28, and 10 shared genetic loci for severe COVID-19, COVID-19 hospitalization, and SARS-CoV-2 infection with RA, and 14, 17, and 7 shared loci with SLE, respectively. Co-localization analysis identified five causal variants in TYK2, IKZF3, PSORS1C1 and COG6 for COVID-19 with RA, and four in CRHR1, FUT2 and NXPE3 for COVID-19 with SLE, involved in immune function, angiogenesis and coagulation. Bi-directional Mendelian randomization analysis suggested RA is associated with a higher risk of COVID-19 hospitalization, and COVID-19 is not related to RA or SLE.

CONCLUSION: Our novel findings improved the understanding of the genetic aetiology shared by COVID-19, RA and SLE, and suggested an increased risk of COVID-19 hospitalization in people with higher genetic liability to RA. This article is protected by copyright. All rights reserved.

PMID:36762574 | DOI:10.1002/jmv.28570

Mol Inform. 2023 Feb 10:e2200198. doi: 10.1002/minf.202200198. Online ahead of print.

ABSTRACT

The main protease (M^pro ) is an essential enzyme for the life cycle of SARS-CoV-2 and a validated target for treatment of COVID-19 infection. Structure-based pharmacophore modeling combined with QSAR calculations were employed to identify new chemical scaffolds of M^pro inhibitors from natural products repository. Hundreds of pharmacophore models were manually built from their corresponding X-ray crystallographic structures. A pharmacophore model that was validated by receiver operating characteristic (ROC) curve analysis and selected using the statistically optimum QSAR equation was implemented as a 3D-search tool to mine AnalytiCon Discovery database of natural products. Captured hits that showed the highest predicted inhibitory activities were bioassayed. Three active M^pro inhibitors (pseurotin A, lactupicrin, and alpinetin) were successfully identified with IC₅₀ values in low micromolar range.

PMID:36762567 | DOI:10.1002/minf.202200198

Ann Surg. 2023 Feb 10. doi: 10.1097/SLA.0000000000005820. Online ahead of print.

ABSTRACT

OBJECTIVE: The aim of this study was to analyze overall survival of robotic-assisted lobectomy (RL), video-assisted thoracoscopic lobectomy (VATS) and open lobectomy (OL) performed by experienced thoracic surgeons across multiple institutions.

SUMMARY BACKGROUND DATA: Surgeons have increasingly adopted RL for resection of early-stage lung cancer. Comparative survival data following these approaches is largely from single-institution case series or administrative datasets.

METHODS: Retrospective data was collected from 21 institutions from 2013-2019. Consecutive cases performed for clinical stage IA-IIIA lung cancer were included. Induction therapy patients were excluded. The propensity-score method of inverse-probability of treatment weighting (IPTW) was used to balance baseline characteristics. Overall survival (OS) was estimated using the Kaplan-Meier method. Multivariable Cox proportional hazard models were used to evaluate association among OS and relevant risk factors.

RESULTS: A total of 2,789 RL, 2,661 VATS, and 1,196 OL cases were included. The unadjusted 5-year overall survival rate was highest for OL (84%) followed by RL (81%) and VATS (74%); P=0.008. Similar trends were also observed after IPTW adjustment (RL 81%; VATS 73%, OL 85%, P=0.001). Multivariable Cox regression analyses revealed that OL and RL were associated with significantly higher overall survival compared to VATS (OL vs. VATS: HR 0.64, P<0.001 and RL vs. VATS: HR 0.79; P=0.007).

CONCLUSIONS: Our finding from this large multicenter study suggests that patients undergoing RL and OL have statistically similar OS, while the VATS group was associated with shorter OS. Further studies with longer follow-up are necessary to help evaluate these observations.

PMID:36762564 | DOI:10.1097/SLA.0000000000005820

Circulation. 2023 Feb 10. doi: 10.1161/CIRCULATIONAHA.122.060687. Online ahead of print.

ABSTRACT

BACKGROUND: The benefit-risk profile of direct oral anticoagulants (DOACs) compared with warfarin, and between DOACs in patients with atrial fibrillation (AF) and chronic liver disease is unclear.

METHODS: We conducted a new-user, retrospective cohort study of patients with AF and chronic liver disease who were enrolled in a large, US-based administrative database between January 1, 2011, and December 31, 2017. We assessed the effectiveness and safety of DOACs (as a class and individually) compared with warfarin, and between DOACs in patients with AF and chronic liver disease. The primary outcomes were hospitalization for ischemic stroke/systemic embolism and hospitalization for major bleeding. Inverse probability treatment weights were used to balance the treatment groups on measured confounders.

RESULTS: Overall, 10 209 participants were included, with 4421 (43.2%) on warfarin, 2721 (26.7%) apixaban, 2211 (21.7%) rivaroxaban, and 851 (8.3%) dabigatran. The incidence rates per 100 person-years for ischemic stroke/systemic embolism were 2.2, 1.4, 2.6, and 4.4 for DOACs as a class, apixaban, rivaroxaban, and warfarin, respectively. The incidence rates per 100 person-years for major bleeding were 7.9, 6.5, 9.1, and 15.0 for DOACs as a class, apixaban, rivaroxaban, and warfarin, respectively. After inverse probability treatment weights, the risk of hospitalization for ischemic stroke/systemic embolism was significantly lower between DOACs as a class (hazard ratio [HR], 0.64 [95% CI, 0.46-0.90]) or apixaban (HR, 0.40 [95% CI, 0.19-0.82]) compared with warfarin, but not significantly different between rivaroxaban versus warfarin (HR, 0.76 [95% CI, 0.47-1.21]) or rivaroxaban versus apixaban (HR, 1.73 [95% CI, 0.91-3.29]). Compared with warfarin, the risk of hospitalization for major bleeding was lower with DOACs as a class (HR, 0.69 [95% CI, 0.58-0.82]), apixaban (HR, 0.60 [95% CI, 0.46-0.78]), and rivaroxaban (HR, 0.79 [95% CI, 0.62-1.0]). However, the risk of hospitalization for major bleeding was higher for rivaroxaban versus apixaban (HR, 1.59 [95% CI, 1.18-2.14]).

CONCLUSION: Among patients with AF and chronic liver disease, DOACs as a class were associated with lower risks of hospitalization for ischemic stroke/systemic embolism and major bleeding versus warfarin. However, the incidence of clinical outcomes among patients with AF and chronic liver disease varied between individual DOACs and warfarin, and in head-to-head DOAC comparisons.

PMID:36762560 | DOI:10.1161/CIRCULATIONAHA.122.060687

Stroke. 2023 Feb 10. doi: 10.1161/STROKEAHA.122.040883. Online ahead of print.

ABSTRACT

BACKGROUND: Ischemic stroke (IS) is a highly heritable trait, and genome-wide association studies have identified several commonly occurring susceptibility risk loci for this condition. However, there are limited data on the contribution of rare genetic variation to IS.

METHODS: We conducted an exome-wide study using whole-exome sequencing data from 152 058 UK Biobank participants, including 1777 IS cases. We performed single-variant analyses for rare variants and gene-based analyses for loss-of-function and deleterious missense rare variants. We validated these results through (1) gene-based testing using summary statistics from MEGASTROKE-a genome-wide association study of IS that included 67 162 IS cases and 454 450 controls, (2) gene-based testing using individual-level data from 1706 IS survivors, including 142 recurrent IS cases, enrolled in the VISP trial (Vitamin Intervention for Stroke Prevention); and (3) gene-based testing against neuroimaging phenotypes related to cerebrovascular disease using summary-level data from 42 310 UK Biobank participants with available magnetic resonance imaging data.

RESULTS: In single-variant association analyses, none of the evaluated variants were associated with IS at genome-wide significance levels (P<5×10^-8). In the gene-based analysis focused on loss-of-function and deleterious missense variants, rare genetic variation at CYP2R1 was significantly associated with IS risk (P=2.6×10^-6), exceeding the Bonferroni-corrected threshold for 16 074 tests (P<3.1×10^-6). Validations analyses indicated that CYP2R1 was associated with IS risk in MEGASTROKE (gene-based test, P=0.003), with IS recurrence in the VISP trial (gene-based test, P=0.001) and with neuroimaging traits (white matter hyperintensity, mean diffusivity, and fractional anisotropy) in the UK Biobank neuroimaging study (all gene-based tests, P<0.05).

CONCLUSIONS: Because CYP2R1 plays an important role in vitamin D metabolism and existing observational evidence suggests an association between vitamin D levels and cerebrovascular disease, our results support a role of this pathway in the occurrence of IS.

PMID:36762557 | DOI:10.1161/STROKEAHA.122.040883

J Am Geriatr Soc. 2023 Feb 10. doi: 10.1111/jgs.18271. Online ahead of print.

ABSTRACT

BACKGROUND: We investigated potential differences between in-person cognitive testing and video telehealth administration of the Montreal Cognitive Assessment (MoCA). In addition to the MoCA, the Patient Health Questionnaire-8 (PHQ-8) and Generalized Anxiety Disorder-7 (GAD-7) were administered.

METHODS: MoCA scores from participants in the Emory Health Brain Study (EHBS) were contrasted based upon whether they were administered the MoCA in the standard face-to-face (F2F) assessment setting (n = 1205) or using a video telehealth administration (n = 491). All EHBS participants were self-reported to be cognitively normal.

RESULTS: MoCA scores did not differ across administration method (F2F MoCA = 26.6, SD = 2.4; telehealth MoCA = 26.5, SD = 2.4). The 95% confidence interval for difference in administration was small (CI = -0.16 to 0.34). When examining MoCA domain scores, administration differences were either associated with no statistically significant effect, or if present due to large sample sizes, were associated with small effects and differences <0.5 point. Telehealth patients reported slightly lower PHQ-8 scores (F2F PHQ-8 = 2.0, SD = 2.5; telehealth PHQ-8 = 1.6, SD = 2.1), although these scores are well within the normal range. No group difference in GAD-7 scores was present (F2F GAD-7 = 1.4, SD = 2.4; telehealth PHQ-8 = 1.4, SD = 2.4).

DISCUSSION: This report with its large sample size and between subject cohort provides complementary evidence to smaller test-retest studies, further supporting equivalence of MoCA telehealth testing to F2F MoCA administration. These findings provide additional reassurance that administration mode does not introduce systematic performance differences for MoCA test administration, thereby permitting telehealth MoCA testing to be applied confidently for both clinical and research applications.

PMID:36762513 | DOI:10.1111/jgs.18271

J Cardiovasc Surg (Torino). 2023 Feb 10. doi: 10.23736/S0021-9509.22.12491-2. Online ahead of print.

ABSTRACT

INTRODUCTION: The aim of this study was to perform a systematic review about the clinical and technical aspects of late open conversion for failed endovascular aortic repair (EVAR) of abdominal aortic aneurysms (AAA), and to investigate if the need for suprarenal aortic cross clamping, graft infection, urgent procedures, endoleaks and aortic rupture were associated with an increase of 30-days (perioperative) mortality.

EVIDENCE ACQUISITION: A literature search was conducted on PubMed using the words “open conversion endovascular” on December 29^th, 2021. Studies included randomized controlled trials, cohort studies, and case series of patients submitted to open conversion that were performed at least 1 month after the initial EVAR for AAA, reporting about 30-days mortality after surgery. A meta-analysis was performed to explore the association of suprarenal aortic cross clamping, graft infection, urgent procedures, endoleaks and aortic rupture with 30-days postoperative mortality using log odds ratios (ORs), with STATA/MP 17.0 (Stata Corp. 2021, LLC). Two-sided P values less than 0.05 were considered statistically significant.

EVIDENCE SYNTHESIS: The search retrieved 985 results on PubMed from 1994 to 2021. Among them, 40 papers were included in the study for the systematic review, and 5 of them for the meta-analysis. A total of 2297 patients from 1992 to 2020 were submitted to open conversion after a median of 40.4 months from the initial EVAR. Endoleak was the most frequent cause of open conversion (76.3%). Perioperative mortality was 23.5% for urgent and 5.3% for elective conversions. At meta-analysis, urgent procedures and aortic rupture were both associated with higher perioperative mortality (OR 5.27, 95% CI 2.90-9.57 and OR 5.61, 95% CI 3.09-10.19 respectively). Similarly, patients with infections and who needed suprarenal aortic clamping were at higher risk of 30-days postoperative death (OR 3.74, 95% CI 1.96-7.13) and OR 2.23, 95% CI 1.24-4.02), while the presence of a preoperative endoleaks was not associated with a higher 30-days mortality.

CONCLUSIONS: Late open conversion after EVAR of AAA is burdened by a perioperative mortality rate of 23.5% for urgent and 5.3% for elective cases. Urgent treatment, presence of aortic rupture or infection, and the need for suprarenal aortic cross clamping were associated with increased perioperative mortality, while the presence of an endoleak did not affect perioperative mortality.

PMID:36762507 | DOI:10.23736/S0021-9509.22.12491-2

Acta Anaesthesiol Scand. 2023 Feb 10. doi: 10.1111/aas.14212. Online ahead of print.

ABSTRACT

BACKGROUND: Emergence agitation is a common clinical condition in children. Symptoms pertaining to the spectrum of early postoperative negative behavior typically occur upon emergence from anesthesia. Clonidine is an effective adjunctive agent for the prevention of emergence agitation in children, but evidence in the smallest age groups is sparse We aim to investigate the efficacy and safety of an intraoperative bolus of intravenous clonidine for preventing emergence agitation in children 3-12 months of age.

METHODS: This is a randomized, placebo-controlled, double-blind trial. We will enroll 320 patients aged 3-12 months who have been scheduled for general anesthesia maintained with sevoflurane and opioid. The randomization is parallel and stratified by age group, sex, and site. The investigational medicinal product will be administered intravenously approximately 20 minutes before the anticipated end of the surgical procedure. The intervention is clonidine 3 mcg/kg and placebo is isotonic saline in a corresponding volume.

RESULTS: The primary outcome is the incidence of emergence agitation as assessed on the Watcha scale i.e., any Watcha score > 2 during participants’ stay in the post-anesthetic care unit. Secondary outcomes are the proportion of participants with postoperative pain, with postoperative nausea and vomiting, and a composite safety outcome. Statistical analysis will be conducted according to the Statistical Analysis Plan with the intention-to-treat population for our primary analyses.

CONCLUSION: The PREVENT AGITATION II trial will contribute valuable knowledge on efficacy for the prevention of emergence agitation and safety in infants.

TRIAL REGISTRATION: EudraCT number: 2020-005409-26, clinicaltrials.gov: NCT05091242.

PMID:36762465 | DOI:10.1111/aas.14212

Colorectal Dis. 2023 Feb 10. doi: 10.1111/codi.16512. Online ahead of print.

ABSTRACT

AIM: The study aimed to compare five-year overall survival in a national cohort of patients undergoing curative abdominal resection for colon cancer by minimally invasive surgery (MIS) or open (OPEN) technique.

METHODS: All patients diagnosed between 2010 and 2016 in Sweden with pathological UICC stage I-III colon cancer localized in the cecum, ascending colon, hepatic flexure or sigmoid colon, and those who underwent curative right sided hemicolectomy, sigmoid resection or high anterior resection by MIS or OPEN were included. Patients were identified in the Swedish Colorectal Cancer Registry from which all data was retrieved. The analyses were performed as intention-to-treat and the relationship between surgical technique (MIS or OPEN) and overall mortality within five years was analysed. For the primary research question a non-inferiority hypothesis was assumed with a statistical power of 90%, a one-side type I error of 2.5%, and a non-inferiority margin of 2%. For the secondary analyses, multilevel survival regression models with the patients matched by propensity scores were employed, adjusted for patient- and tumuor-related variables.

RESULTS: A total of 11605 pathological UICC cancer stage I-III patients were included with 3297 MIS (28.4%) and 8308 OPEN (71.6%) and were followed until December 31, 2020. The primary analysis demonstrated superiority for MIS compared to OPEN. The multilevel survival regression analyses confirmed that five-year overall survival was higher in MIS with a hazard ratio (HR) of 0.874 (95% confidence interval (CI): 0.791-0.965), and if excluding pT4, outcome was similar, with a HR of 0.847 (95% CI: 0.756-0.948).

CONCLUSION: This observational study demonstrated that MIS was favourable to OPEN with regard to five-year overall survival. These results support the use of laparoscopic colon cancer surgery in routine practise.

PMID:36762443 | DOI:10.1111/codi.16512

Subst Use Misuse. 2023 Feb 10:1-9. doi: 10.1080/10826084.2023.2177960. Online ahead of print.

ABSTRACT

Background: Prominent theories suggest that individuals with co-occurring traumatic stress symptoms (TSS) and substance use (SU) may be less responsive to SU treatment compared to those with SU only. However, empirical findings in adult samples are mixed, and there has been limited work among adolescents. This study assesses the association between TSS and SU treatment outcomes among trauma-exposed adolescents, using statistical methods to reduce potential confounding from important factors such as baseline SU severity. Method: 2,963 adolescents with lifetime history of victimization received evidence-based SU treatment in outpatient community settings. At baseline, 3- and 6-months, youth were assessed using the Global Appraisal of Individual Needs Traumatic Stress Scale and the Substance Frequency Scale. Propensity score weighting was used to mitigate potential confounding due to baseline differences in sociodemographic characteristics and SU across youth with varying levels of TSS. Results: Propensity score weighting successfully balanced baseline differences in sociodemographic factors and baseline SU across youth. Among all youth, mean SU was lower at both 3- and 6- month follow-up relative to baseline, indicating declining use. After adjusting for potential confounders, we observed no statistically significant relationship between TSS and SU at either 3- or 6-month follow-up. Conclusions: Based on this investigation, conducted among a large sample of trauma-exposed youth receiving evidence-based outpatient SU treatment, baseline TSS do not appear to be negatively associated with SU treatment outcomes. However, future research should examine whether youth with TSS achieve better outcomes through integrative treatment for both SU and TSS.

PMID:36762441 | DOI:10.1080/10826084.2023.2177960