Does ACE2 mediate the detrimental effect of exposures related to COVID‐19 risk: A Mendelian randomization investigation

alexandrossfakianakis shared this article with you from Inoreader Does ACE2 mediate the detrimental effect of exposures related to COVID‐19 risk: A Mendelian randomization investigation via Journal of Medical Virology Abstract Objectives Adiposity, smoking and lower socioeconomic position (SEP) increase COVID-19 risk whilst the association of vitamin D, blood pressure, and glycemic traits in COVID-19 risk were less clear. Whether angiotensin-converting enzyme 2 (ACE2), the key receptor for SARS-CoV-2, mediates these associations has not been investigated. We conducted a Mendelian randomization study to assess the role of these exposures in COVID-19 and mediation by ACE2. Methods We extracted genetic variants strongly related to various exposures (vitamin D, blood pressure, glycemic traits, smoking, adiposity and educational attainment (SEP proxy)), and ACE2 cis-variants from genome wide association studies (GWAS, n ranged from 28,204 to 3,037,499) and applied them to GWAS summary statistics of ACE2 (n=28,204) and COVID-19 (severe, hospitalized, and susceptibility, n≤2,942,817). We used inverse variance weighted as the main analyses, with MR-Egger and weighted median as sensitivit y analyses. Mediation analyses were performed based on product of coefficient method. Results Higher adiposity, lifetime smoking index, and lower educational attainment were consistently associated with higher risk of COVID-19 phenotypes whilst there was no strong evidence for an association of other exposures in COVID-19 risk. ACE2 partially mediates the detrimental effects of body mass index (ranged from 4.3% to 8.2%), waist-to-hip ratio (ranged from 11.2% to 16.8%) and lower educational attainment (ranged from 4.0% to 7.5%) in COVID-19 phenotypes whilst ACE2 did not mediate the detrimental effect of smoking. Conclusions We provided genetic evidence that reducing ACE2 could partly lower COVID-19 risk amongst people who were overweight/obese or of lower SEP. This article is protected by copyright. All rights reserved. View on Web

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A novel MAP3K20 mutation causing centronuclear myopathy-6 with fiber-type disproportion in a Pakistani family

alexandrossfakianakis shared this article with you from Inoreader A novel <i>MAP3K20</i> mutation causing centronuclear myopathy-6 with fiber-type disproportion in a Pakistani family via Journal of Human Genetics - Issue - nature.com science feeds View on Web

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FBXO6 regulates the anti‐viral immune‐responses via mediating alveolar macrophages survival

alexandrossfakianakis shared this article with you from Inoreader FBXO6 regulates the anti‐viral immune‐responses via mediating alveolar macrophages survival via Journal of Medical Virology Abstract Inducing early apoptosis in alveolar macrophages is one of the strategies influenza A virus (IAV) evolved to subvert host immunity. Correspondingly, the host mitochondrial protein nucleotide-binding oligomerization domain-like receptor (NLR)X1 is reported to interact with virus polymerase basic protein 1-frame 2 (PB1-F2) accessory protein to counteract virus induced apoptosis. Herein, we report that one of the F-box proteins, FBXO6, promotes proteasomal degradation of NLRX1, and thus facilitates IAV-induced alveolar macrophages apoptosis and modulates both macrophage survival and type I interferon (IFN) signaling. We observed that FBXO6-deficient mice infected with IAV exhibited decreased pulmonary viral replication, as well as alleviated inflammatory-associated pulmonary dysfunction and morbidity. Analysis of the lungs of IAV-infected mice revealed markedly reduced leukocyte recruitment but enhanced production of type I IFN in Fbxo6 -/- mice. Furthermore, increased type I IFN production and decreased viral replication were recapitulated in FBXO6 knockdown macrophages and was associated with reduced apoptosis. Through gain- and loss-of-function studies, we found lung resident macrophages but not bone marrow derived macrophages play the key role in the differences FBXO6 signaling pathway brings in the antiviral immune response. In further investigation, we identified that FBXO6 interacted with and promoted the proteasomal degradation of NLRX1. Together, our results demonstrate that FBXO6 negatively regulates immunity against IAV infection by enhancing the degradation of NLRX1 and thus impairs the survival of alveolar macrophages and antiviral immunity of the host. This article is protected by copyright. All rights reserved. View on Web

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Phase 1b study of carfilzomib with induction chemotherapy in pediatric relapsed/refractory acute lymphoblastic leukemia

alexandrossfakianakis shared this article with you from Inoreader Phase 1b study of carfilzomib with induction chemotherapy in pediatric relapsed/refractory acute lymphoblastic leukemia via Pediatric Blood & Cancer Abstract Background Acute lymphoblastic leukemia (ALL) is the most common cancer diagnosed in childhood. Survival for patients following relapse remains poor, and achieving complete remission (CR) after relapse is the first critical step to cure. Carfilzomib is a proteasome inhibitor with an acceptable safety profile and clinical activity in adults with multiple myeloma but has not been assessed in children. The primary objective of this phase 1b study was to assess the safety and tolerability of carfilzomib combined with vincristine, dexamethasone, asparaginase, and daunorubicin (VXLD) in children with relapsed and/or refractory ALL. Methods Patients aged 1–21 years (n = 24) received 4-week induction therapy with carfilzomib at dose levels of 27 mg/m2 (n = 3), 36 mg/m2 (n = 7), 45 mg/m2 (n = 4), and 56 mg/m2 (n = 10) in combination with VXLD. Patients achieving stable disease were offered further consolidation chemotherapy. Analyses were based on the safety evaluable population. Results Following dose escalation of carfilzomib, the recommended phase 2 carfilzomib dose was identified as 56 mg/m2. Grade ≥3 hematological adverse events were common (83%, 20/24 patients), and serious treatment-emergent adverse events occurred in 58% (14/24) of patients. At the end of induction, CR/CR with incomplete platelet recovery (CRp)/CR with incomplete blood count recovery (CRi) was identified in 50% of patients (n = 12/24). By the end of consolidation, cumulative CR/CRp/CRi was identified in 58% of patients (n = 14/24). Conclusion These data support the use of carfilzomib in pediatric patients with relapsed and/or refractory ALL. View on Web

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Length of Stay in Patients Undergoing Tracheoplasty: A NSQIP Study

alexandrossfakianakis shared this article with you from Inoreader Length of Stay in Patients Undergoing Tracheoplasty: A NSQIP Study via The Laryngoscope Background Prolonged length of stay (LOS) has been associated with increased morbidity and resource utilization in various surgical procedures. We aim to determine factors associated with increased hospital stay in patient undergoing tracheoplasty. Methods The 2012–2018 National Surgical Quality Improvement Program (NSQIP) database was queried for patients undergoing tracheoplasty. Patient LOS was the primary clinical outcome. A LOS >75th percentile was considered as prolonged and was utilized for bivariate analysis of demographic, comorbidity, and operative characteristics. LOS was utilized as a continuous variable for multivariate linear regression analysis. Results A total of 252 patients were queried. The majority of patients were female (67.5%), white (82.4%), and over the age of 65 (77.0%). Patients had a median LOS of 7 days with the 75th percentile cutoff being defined at 10 days. On bivariate analysis of associated comorbidities, patients with prolonged LOS were more commonly obese (72.4% vs. 53.1%, p = 0.009), diabetic (37.9% vs. 16.5%, p < 0.001), dyspneic (58.6% vs. 40.7%, p = 0.016), and had chronic steroid use (25.9% vs. 12.9%, p = 0.018). Multivariable logistic regression analysis demonstrated significant associations between prolonged LOS and both chronic obstructive pulmonary disorder (COPD) (OR: 3.43, p = 0.020) and chronic steroid use (OR: 3.81, p = 0.018). Conclusions This study elucidates factors associated with prolonged LOS in patients undergoing tracheoplasty. Patients with COPD and chronic steroid use were significantly associated with prolonged LOS. Level of Evidence 4 Laryngoscope, 2022 View on Web

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The influence of low insertion torque values on survival rate of immediately loaded dental implants: a systematic review and meta‐analysis

alexandrossfakianakis shared this article with you from Inoreader The influence of low insertion torque values on survival rate of immediately loaded dental implants: a systematic review and meta‐analysis via Journal of Clinical Periodontology Abstract Introduction The aim was to systematically evaluate the effect of low insertion torque values on the survival rate of immediately loaded dental implants. Methods The protocol was registered (PROSPERO ID CRD42020189499), with an electronic search performed in the PubMed, Embase, Web of Science and Cochrane Central Register of Controlled Trials until June 2022 in English and Spanish. Studies analysing the failure or survival rate of immediately loaded dental implants according to different insertion torque values were included. Results Five hundred seventy-three articles were assessed of eligibility, of which 7 articles, 4 randomised clinical trials (RTCs), 1 controlled clinical trial and 2 prospective case series studies, were included in the qualitative analysis. The RCTs were classified as low risk of bias, and the non-RCTs as moderate and serious risk of bias. The mean survival rate for implants with low insertion toque (≤35 Ncm) was 96% (p>0.001, 95% CI: 0.91–0.98), and that for implants with medium or high insertion torque (>35 Ncm) was 92% (p>0.001, 95% CI: 0.86–0.96) (IRR = 1.05, 95% CI: 0.79–1.39, p=0.175, I2=0.0%). Splinted implants with insertion torque >20 Ncm and single implants with insertion torque >35 Ncm had a higher survival rate than implants with lower insertion torque values (IRR = 1.05, 95% CI: 0.78–1.43, p=0.956, I2=0.0%, and IRR = 0.92, 95% CI: 0.48–1.75, p=0.799, I2=0.0%, respectively). Different in sertion torque values achieved equivalent outcomes. The mean follow-up was 24 months. Conclusion Low insertion torque values have no significant effect on survival rates of immediate loading implants at a mean follow-up of 24 months. View on Web

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Efficacy of access flap and pocket elimination procedures in the management of peri‐implantitis – a systematic review and meta‐analysis

alexandrossfakianakis shared this article with you from Inoreader Efficacy of access flap and pocket elimination procedures in the management of peri‐implantitis – a systematic review and meta‐analysis via Journal of Clinical Periodontology Abstract Objectives To evaluate the efficacy of access flap and pocket elimination procedures in the surgical treatment of peri-implantitis. Methods Systematic electronic searches (Central/Medline/Embase) up to March 2022 were conducted to identify prospective clinical studies evaluating surgical therapy (access flap or pocket elimination procedures) of peri-implantitis. Primary outcome measures were reduction of probing depth (PD) and bleeding on probing (BOP). Risk of bias was evaluated according to study design. Meta-analysis and meta-regression were performed. Results were expressed as standardized mean effect with 95% confidence intervals (CI). Results Evidence from studies directly comparing surgical with non-surgical therapy is lacking. Based on pre-post data originating from 13 prospective patient cohorts, pronounced reductions of PD (standardized mean effect: 2.2 mm; 95%CI 1.8, 2.7) and BOP% (27.0; 95%CI 19.8, 34.2) as well as MBL gain (0.2 mm; 95%CI -0.0, 0.5) were observed at evaluation time points ranging from 1 to 5 years. Wide prediction intervals suggested a high degree of heterogeneity. Reduction of mean PD increased by 0.7 mm (95%CI 0.5, 0.9) for every mm in increase of mean PD at baseline. During follow-up period ranging from 1 to 5 years, disease recurrence occurred frequently and implant loss was not uncommon. Conclusions Access flap and pocket elimination surgery are effective procedures in the management of peri-implantitis, although rates of disease recurrence during 5 years were high. Treatment outcomes were affected by baseline conditions. View on Web

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Phosphatase and tensin homolog determines inflammatory status by differentially regulating the expression of Akt1 and Akt2 in macrophage alternative polarization of periodontitis

alexandrossfakianakis shared this article with you from Inoreader Phosphatase and tensin homolog determines inflammatory status by differentially regulating the expression of Akt1 and Akt2 in macrophage alternative polarization of periodontitis via Journal of Clinical Periodontology Abstract Aims Macrophages are closely involved in periodontitis; however, the molecular mechanism by which macrophages influence periodontitis is not well understood. We investigated the effects of phosphatase and tensin homolog (PTEN) on macrophage polarization, the underlying mechanism, and the regulatory roles in periodontium regeneration. Materials and Methods PTEN expression in periodontitis macrophages was detected ex vivo. The effects of PTEN on macrophage polarization and the underlying mechanisms were investigated in vitro. We also analyzed the ability of PTEN inhibitors to repair periodontitis in vivo, in a ligature-induced mouse model of periodontitis. Results Macrophage PTEN expression in periodontitis patients was significantly higher than that of controls. PTEN inhibition in macrophages induced alternative macrophage polarization, whereas PTEN overexpression facilitated classical polarization. PTEN inhibition facilitated activation of Akt1 while inhibited expression of Akt2. Furthermore, Akt2 overexpression could rescue the effects of PTEN inhibition on NF-κB. Treatment with PTEN inhibitor significantly attenuated the local inflammatory status and prevented alveolar bone resorption in mouse model. Conclusions Our findings suggest that PTEN inhibition could induce alternative macrophage polarization by differentially regulating Akt1 and Akt2. This also changed a pro-inflammatory microenvironment to an anti-inflammatory environment, by subsequently regulating the expression of NF-κB, and thereby attenuated inflammatory alveolar bone resorption induced by ligature. View on Web

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The development and initial validation of self‐report measures of ICD‐11 depressive episode and generalized anxiety disorder: The International Depression Questionnaire (IDQ) and the International Anxiety Questionnaire (IAQ)

alexandrossfakianakis shared this article with you from Inoreader The development and initial validation of self‐report measures of ICD‐11 depressive episode and generalized anxiety disorder: The International Depression Questionnaire (IDQ) and the International Anxiety Questionnaire (IAQ) via Journal of Clinical Psychology Abstract Background The new International Classification of Diseases came into effect in 2022 (ICD-11; World Health Organization, 2022) and included updated descriptions and diagnostic rules for "Depressive Episode" and "Generalized Anxiety Disorder." No self-report measures align with these disorders so this study reports the development and initial validation of the "International Depression Questionnaire" (IDQ) and "International Anxiety Questionnaire" (IAQ). Methods Items were developed that aligned to the ICD-11 descriptions and their performance was assessed using data from a community sample (N = 2058) that was representative of the United Kingdom adult population. Results Item response theory models indicated that the two scales were unidimensional, and the items performed well in terms of difficulty and discrimination. Estimates of internal reliability were high. Based on ICD-11 derived diagnostic algorithms, 7.4% met requirements for ICD-11 Depressive Episode and 7.1% for Generalized Anxiety Disorder. Conclusions The IDQ and the IAQ are short, easy to use, self-report measures aligned to the new and updated ICD-11 diagnostic descriptions. This study provides initial evidence that the scales produce scores that are reliable and valid. View on Web

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Bone vitality and vascularization of mandibular and maxillary bone grafts in maxillary sinus floor elevation: A retrospective cohort study

alexandrossfakianakis shared this article with you from Inoreader Bone vitality and vascularization of mandibular and maxillary bone grafts in maxillary sinus floor elevation: A retrospective cohort study via Clinical Implant Dentistry and Related Research Abstract Objectives Mandibular retromolar (predominantly cortical) and maxillary tuberosity (predominantly cancellous) bone grafts are used in patients undergoing maxillary sinus floor elevation (MSFE) for dental implant placement. The aim of this retrospective cohort study was to investigate whether differences exist in bone formation and vascularization after grafting with either bone source in patients undergoing MSFE. Methods Fifteen patients undergoing MSFE were treated with retromolar (n = 9) or tuberosity (n = 6) bone grafts. Biopsies were taken 4 months postoperatively prior to dental implant placement, and histomorphometrically analyzed to quantify bone and osteoid area, number of total, apoptotic, and receptor activator of nuclear factor-κB ligand (RANKL)-positive osteocytes, small and large-sized blood vessels, and osteoclasts. The grafted area was divided in three regions (caudal-cranial): RI, RII, and RIII. Results Bone volume was 40% (RII, RIII) higher and osteoid volume 10% (RII) lower in retromolar compared to tuberosity-grafted areas. Total osteocyte number and number of RANKL-positive osteocytes were 23% (RII) and 90% (RI, RII) lower, but osteoclast number was higher (retromolar: 12, tuberosity: 0) in retromolar-grafted areas. The total number of blood vessels was 80% (RI) to 60% (RIII) lower, while the percentage of large-sized blood vessels was 86% (RI) to 25% (RIII) higher in retromolar-grafted areas. Number of osteocyte lacunae and apoptotic osteocytes were similar in both bone grafts used. Conclusions Compared to the retromolar bone, tuberosity bone showed increased bone vitality and vascularization in patients undergoing MSFE, likely due to faster bone remodeling or earlier start of new bone formation. Therefore, tuberosity bone grafts might perform better in enhancing bone regeneration. View on Web

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