An integrated strategy to identify COVID‐19 causal genes and characteristics represented by LRRC37A2

AlexandrosSfakianakis shared this article with you from Inoreader An integrated strategy to identify COVID‐19 causal genes and characteristics represented by LRRC37A2 via Journal of Medical Virology ABSTRACT Genome-wide association study (GWAS) could identify host genetic factors associated with coronavirus disease 2019 (COVID-19). The genes or functional DNA elements through which genetic factors affect COVID-19 remain uncharted. The expression quantitative trait locus (eQTL) provides a path to assess the correlation between genetic variations and gene expression. Here, we firstly annotated GWAS data to describe genetic effects, obtaining genome-wide mapped genes. Subsequently, the genetic mechanisms and characteristics of COVID-19 were investigated by an integrated strategy that included three GWAS-eQTL analysis approaches. It was found that 20 genes were significantly associated with immunity and neurological disorders, including prior and novel genes such as OAS3 and LRRC37A2. The findings were then replicated in single-cell datasets to explore the cell-specific expression of causal genes. Furthermore, associations between COVID-19 and neurological disorders were assessed as a cau sal relationship. Finally, the effects of causal protein-coding genes of COVID-19 were discussed using cell experiments. The results revealed some novel COVID-19-related genes to emphasize disease characteristics, offering a broader insight into the genetic architecture underlying the pathophysiology of COVID-19. This article is protected by copyright. All rights reserved. View on Web

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Monitoring of SARS‐CoV‐2 concentration and circulation of variants of concern in wastewater of Leuven, Belgium.

AlexandrosSfakianakis shared this article with you from Inoreader Monitoring of SARS‐CoV‐2 concentration and circulation of variants of concern in wastewater of Leuven, Belgium. via Journal of Medical Virology Abstract Background Wastewater surveillance plays an important role in the management of the COVID-19 pandemic all over the world. Using different wastewater collection points in Leuven, we wanted to investigate the use of wastewater surveillance as an early warning system for an uprise of infections, and as a tool to follow the circulation of specific variants of concern (VOC) in particular geographic areas. Methods Wastewater samples were collected from local neighborhood sewers and from a large regional wastewater treatment plant (WWTP) in the area of Leuven, Belgium. After virus concentration, SARS-CoV-2 RNA was quantified by RT-qPCR and normalized with the human fecal indicator pepper mild mottle virus (PMMoV). A combination of multiplex RT-qPCR assays was used to detect signature mutations of circulating VOCs. Fecal virus shedding of SARS-CoV-2 variants was measured in feces samples of hospitalized patients. Results In two residential sampling sites, a rise in wastewater SARS-CoV-2 concentration preceded peaks in positive cases. In the WWTP, viral load peaks were seen concomitant with the consecutive waves of positive cases caused by the original Wuhan SARS-CoV-2 strain and subsequent VOCs. During the Omicron BA.1 wave, the wastewater viral load increased to a lesser degree, even after normalization of SARS-CoV-2 concentration using PMMoV. This might be attributable to a lower level of fecal excretion of this variant. Circulation of SARS-CoV-2 VOCs Alpha, Delta, Omicron BA1/BA.2 and BA.4/BA.5 could be detected based on the presence of specific key mutations. The shift in variants was noticeable in the wastewater, with key mutations of two different variants being present simultaneously during the transition period. Conclusions Wastewater-based surveillance is a sensitive tool to monitor SARS-CoV-2 circulation levels and VOCs in larger regions. In times of reduced test capacity this can prove to be highly valuable. Differences in excretion levels of various SARS-CoV-2 variants should however be taken into account when using wastewater surveillance to monitor SARS-CoV-2 circulation levels in the population. This article is protected by copyright. All rights reserved. View on Web

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Pustular psoriasis in Malaysia: A review of the Malaysian Psoriasis Registry 2007 – 2018

AlexandrosSfakianakis shared this article with you from Inoreader Pustular psoriasis in Malaysia: A review of the Malaysian Psoriasis Registry 2007 – 2018 via Wiley: Experimental Dermatology: Table of Contents Abstract Background Pustular psoriasis (PP) is an uncommon subtype of psoriasis with distinct genetic features and clinical phenotypes. Patients with PP tend to experience frequent flares and significant morbidity. This study aims to determine the clinical characteristics, comorbidities and treatment of PP patients in Malaysia. Methods This was a cross-sectional study of patients with PP notified to the Malaysian Psoriasis Registry (MPR) between January 2007 to December 2018. Results Of 21,735 psoriasis patients, 148 (0.7%) had pustular psoriasis. Of these, 93 (62.8%) were diagnosed with generalized pustular psoriasis (GPP) and 55 (37.2%) with localized PP (LPP). The mean age for pustular psoriasis onset was 31.71 ± 18.33 years with a male to female ratio of 1:2.1. Patients with PP were more likely to have dyslipidemia (23.6% vs 16.5%, p=0.022), severe disease [Body surface area >10 and/or Dermatology Life Quality Index (DLQI) >10] (64.8% vs 50%, p=0.003) and require systemic therapy (51.4% vs 13.9%, p<0.001) compared to non-PP patients. Patients with PP also suffered greater impairment to their quality of life (DLQI>10, 48.9% vs 40.3%, p=0.046), had more days off school/work (2.06 ± 6.09 vs 0.5 ± 4.91, p=0.004) and a higher mean number of hospitalizations (0.31 ± 0.95 vs 0.05 ± 1.22, p=0.001) in 6 months compared to non-PP patients. Conclusion Overall, 0.7% of psoriasis patients in the MPR had pustular psoriasis. Patients with PP had a higher rate of dyslipidaemia, severe disease, greater impairment of quality of life, and systemic therapy usage compared to other psoriasis subtypes. View on Web

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Nuclear membrane irregularity in high‐grade urothelial carcinoma cells can be measured by using circularity and solidity as morphometric shape definitions in digital image analysis of urinary tract cytology specimens

AlexandrosSfakianakis shared this article with you from Inoreader Nuclear membrane irregularity in high‐grade urothelial carcinoma cells can be measured by using circularity and solidity as morphometric shape definitions in digital image analysis of urinary tract cytology specimens via Cancer Cytopathology Abstract Background The Paris System for Reporting Urine Cytology defines objective (elevated nuclear/cytoplasmic ratio ≥0.7) and subjective (nuclear membrane irregularity, hyperchromicity, and coarse chromatin) cytomorphologic criteria to identify conventional high-grade urothelial carcinoma (HGUC) cells. Digital image analysis allows quantitative and objective measurement of these subjective criteria. In this study, digital image analysis was used to quantitate nuclear membrane irregularity in HGUC cells. Methods Whole-slide images of HGUC urine specimens were acquired, and HGUC nuclei were manually annotated using the open-source bioimage analysis software QuPath. Custom scripts were used to calculate nuclear morphometrics and perform downstream analysis. Results In total, 1395 HGUC cell nuclei were annotated across 24 HGUC specimens (48.1 ± 6.0 nuclei per case) using both pixel-level and smooth annotation approaches. Nuclear membrane irregularity was estimated by calculating nuclear circularity and solidity. Annotating at pixel-level resolution artifactually increases nuclear membrane perimeter, thus smoothing is necessary to better approximate a pathologist's assessment of nuclear membrane irregularity. After smoothing, nuclear circularity and solidity discriminate between HGUC cell nuclei with visually apparent differences in nuclear membrane irregularity. Conclusions Nuclear membrane irregularity defined by The Paris System for Reporting Urine Cytology is inherently subjective. This study identifies nuclear morphometrics that visually correlate with nuclear membrane irregularity. HGUC specimens show intercase variation in nuclear morphometrics, with some nuclei appearing remarkably regular while others show marked irregularity. A small population of irregular nuclei generates most of the intracase variation in nuclear morphometrics. These results highlight nuclear membrane irregularity as an important, but not definitive, cytomorphologic criterion in HGUC diagnosis. View on Web

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Primary tumor resection improves survival of gastrointestinal neuroendocrine carcinoma patients with nonresected liver metastases

AlexandrosSfakianakis shared this article with you from Inoreader Primary tumor resection improves survival of gastrointestinal neuroendocrine carcinoma patients with nonresected liver metastases via Wiley: Journal of Surgical Oncology: Table of Contents Abstract Background The role of primary tumor resection (PTR) in the survival of gastrointestinal neuroendocrine carcinoma (GI-NEC) patients with liver metastases only remains poorly defined. Therefore, we investigated the impact of PTR on the survival of GI-NEC patients with nonresected liver metastases. Methods GI-NEC patients with a liver-confined metastatic disease diagnosed between 2016 and 2018 were identified in the National Cancer Database. Multiple imputations by chained equations were used to account for missing data, and the inverse probability of treatment weighting (IPTW) method was used to eliminate selection bias. Overall survival (OS) was compared by adjusted Kaplan–Meier curves and log-rank test with IPTW. Results A total of 767 GI-NEC patients with nonresected liver metastases were identified. Among all patients, 177 (23.1%) received PTR and had a significantly favorable OS before (median: 43.6 months [interquartile range, IQR, 10.3–64.4] vs. 8.8 months [IQR, 2.1–23.1], p < 0.001 in log-rank test) and after (median: 25.7 months [IQR, 10.0–64.4] vs. 9.3 months [IQR, 2.2–26.4], p < 0.001 in IPTW-adjusted log-rank test) the IPTW adjustment. Additionally, this survival advantage persisted in an adjusted Cox model (IPTW adjusted hazard ratio = 0.431, 95% confidence interval: 0.332–0.560; p < 0.001). The improved survival persisted in subgroups stratified by primary tumor site, tumor grade, and N stage, even in the complete cohort (excluding patients with missing data). Conclusions PTR led to improved survival for GI-NEC patients with nonresected liver metastases regardless of primary tumor site, tumor grade, and N stage. However, the decision for PTR should be made on an individualized basis following multidisciplinary evaluation. View on Web

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Impact of Exercise and Detraining on Signs of Puberty and Selected Inflammatory Markers in Girls with Precocious Puberty

AlexandrosSfakianakis shared this article with you from Inoreader Impact of Exercise and Detraining on Signs of Puberty and Selected Inflammatory Markers in Girls with Precocious Puberty via Medicine & Science in Sports & Exercise - Published Ahead-of-Print Purpose We examined the effects of aerobic exercise and detraining on adiponectin, resistin, tumor necrosis factor alpha (TNF-α), white blood cell, and pubertal signs (uterine length, ovarian volume, luteinizing hormone (LH), and follicle-stimulating hormone (FSH)) in girls with central precocious puberty (CPP). Methods Thirty girls with CPP (aged 7-9) were randomly divided into CPP and CPP + Exercise (EX) groups. 15 Healthy age-matched girls without precocious puberty participated for comparison with CPP. Subjects in the CPP + Ex group attended 12 weeks of aerobic exercise protocol three sessions a week. In the baseline, after completing the exercise protocol and after 4 weeks of detraining, all the parameters were measured. In the CPP and healthy groups, all the parameters were measured in all three stages. To measure adiponectin, resistin, and TNF-α, the ELISA method was used. LH and FSH were measured by electrochemiluminescence immunoassay. WBC counts were analyzed by an automated blood cell counter. Analysis of Variance with repeated measures test was used to analyze the results. Results CPP girls have lower adiponectin (P = 0.01) and higher TNF-α levels (P = 0.001) than healthy girls. In the CPP + EX group, after 12 weeks, body weight and fat mass decreased, adiponectin increased significantly (P = 0.02). Resistin (P = 0.02), TNF-α (P = 0.02), neutrophils (P = 0.01), and signs of puberty significantly (P View on Web

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LRRK2 Quantification in Cerebrospinal Fluid of Patients with Parkinson's Disease and Atypical Parkinsonian Syndromes

AlexandrosSfakianakis shared this article with you from Inoreader LRRK2 Quantification in Cerebrospinal Fluid of Patients with Parkinson's Disease and Atypical Parkinsonian Syndromes via Movement Disorders Abstract Background The alteration of leucine-rich repeat kinase 2 (LRRK2) kinase activity is thought to be involved in Parkinson's disease (PD) pathogenesis beyond familiar cases, and LRRK2 inhibitors are currently under investigation. Preliminary data suggest a relationship between LRRK2 alteration and cognitive impairment in PD. Objective To investigate cerebrospinal fluid (CSF) LRRK2 levels in PD and other parkinsonian disorders, also correlating them with cognitive impairment. Methods In this study, we retrospectively investigated by means of a novel highly sensitive immunoassay the levels of total and phosphorylated (pS1292) LRRK2 in CSF of cognitively unimpaired PD (n = 55), PD with mild cognitive impairment (n = 49), PD with dementia (n = 18), dementia with Lewy bodies (n = 12), atypical parkinsonian syndromes (n = 35), and neurological controls (n = 30). Results Total and pS1292 LRRK2 levels were significantly higher in PD with dementia with respect to PD with mild cognitive impairment and PD, and also showed a correlation with cognitive performances. Conclusions The tested immunoassay may represent a reliable method for assessing CSF LRRK2 levels. The results appear to confirm an association of LRRK2 alteration with cognitive impairment in PD. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. View on Web

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LRRK2 Inhibition by BIIB122 in Healthy Participants and Patients with Parkinson's Disease

AlexandrosSfakianakis shared this article with you from Inoreader LRRK2 Inhibition by BIIB122 in Healthy Participants and Patients with Parkinson's Disease via Movement Disorders Abstract Background Leucine-rich repeat kinase 2 (LRRK2) inhibition is a promising therapeutic approach for the treatment of Parkinson's disease (PD). Objective The aim of this study was to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of the potent, selective, CNS-penetrant LRRK2 inhibitor BIIB122 (DNL151) in healthy participants and patients with PD. Methods Two randomized, double-blind, placebo-controlled studies were completed. The phase 1 study (DNLI-C-0001) evaluated single and multiple doses of BIIB122 for up to 28 days in healthy participants. The phase 1b study (DNLI-C-0003) evaluated BIIB122 for 28 days in patients with mild to moderate PD. The primary objectives were to investigate the safety, tolerability, and plasma pharmacokinetics of BIIB122. Pharmacodynamic outcomes included peripheral and central target inhibition and lysosomal pathway engagement biomarkers. Results A total of 186/184 healthy participants (146/145 BIIB122, 40/39 placebo) and 36/36 patients (26/26 BIIB122, 10/10 placebo) were randomized/treated in the phase 1 and phase 1b studies, respectively. In both studies, BIIB122 was generally well tolerated; no serious adverse events were reported, and the majority of treatment-emergent adverse events were mild. BIIB122 cerebrospinal fluid/unbound plasma concentration ratio was ~1 (range, 0.7–1.8). Dose-dependent median reductions from baseline were observed in whole-blood phosphorylated serine 935 LRRK2 (≤98%), peripheral blood mononuclear cell phosphorylated threonine 73 pRab10 (≤93%), cerebrospinal fluid total LRRK2 (≤50%), and urine bis (monoacylglycerol) phosphate (≤74%). Conclusions At generally safe and well-tolerated doses, BIIB122 achieved substantial peripheral LRRK2 kinase inhibition and modulation of lysosomal pathways downstream of LRRK2, with evidence of CNS distribution and target inhibition. These studies support continued investigation of LRRK2 inhibition with BIIB122 for the treatment of PD. © 2023 Denali Therapeutics Inc and The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. View on Web

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Spermidine reduced neuropathic pain in chronic constriction injury‐induced peripheral neuropathy in rats

AlexandrosSfakianakis shared this article with you from Inoreader Spermidine reduced neuropathic pain in chronic constriction injury‐induced peripheral neuropathy in rats via Fundamental & Clinical Pharmacology Abstract Neuropathic pain is one of the most critical types of chronic pain despite the increasing advances in medical science. Spermidine (SPD) is a natural polyamine that has wide roles in several cellular processes inducing autophagy and reducing oxidative stress. This study aimed to investigate the effects of SPD on oxidative stress markers and pain threshold in the neuropathic rat model of chronic constriction injury (CCI) model. Eighteen adult male rats were divided into 3 groups: sham, CCI and CCI+ SPD. After induction of neuropathy via CCI model in the CCI and CCI+SPD groups, SPD (1 mg/kg/day, orally) was administered to the CCI+SPD group for 3 weeks. The behavioral tests (von Frey, hot plate) were done 4 times during the experiment. At the end of the study, electrophysiological tests, the H & E staining, and oxidative stress assay of the prefrontal cortex (PFC), spinal cord, and sciatic nerve were performed. The threshold of pain in hot plate and von Frey tests was significant ly lower in the CCI group than the sham group, which was reversed by SPD treatment in the CCI+ SPD group. In addition, nerve conduction was considerably lower in the CCI group than in the sham and CCI+SPD groups (P<0.01, P< 0.05, respectively). The CCI group showed neuronal degeneration and fibrosis in the different tissues in the H & E assay; elevated tissues level of nitrite, decreased levels of SOD, GPx, and catalase were also observed. However, SPD treatment modulated the pathological changes and oxidative stress biomarkers. In conclusion, SPD showed beneficial effects in decreasing neuropathic pains. SPD treatment reduced oxidative stress, improved histopathological changes and behavioral tests in the CCI-induced neuropathic pain in in vivo model. View on Web

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Xenogeneic collagen matrix versus connective tissue graft for soft tissue augmentation at immediately placed implants: a prospective clinical trial

AlexandrosSfakianakis shared this article with you from Inoreader Xenogeneic collagen matrix versus connective tissue graft for soft tissue augmentation at immediately placed implants: a prospective clinical trial via International Journal of Oral and Maxillofacial Surgery via MedWorm.com The advantages of immediate implant placement for patients include a reduced number of surgical procedures and a shorter overall treatment time. Disadvantages include a higher risk of aesthetic complications. The aim of this study was to compare xenogeneic collagen matrix (XCM) versus a subepithelial connective tissue graft (SCTG) used for soft tissue augmentation in combination with immediate implant placement without provisionalization. Forty-eight patients requiring a single implant-supported rehabilitation were selected and assigned to one of two surgical procedures: immediate implant with SCTG (SCTG group) or immediate implant with XCM (XCM group). (Source: International Journal of Oral and Maxillofacial Surgery) View on Web

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