Outcomes of patients who underwent treatment for anti‐HLA donor‐specific antibodies before receiving a haploidentical hematopoietic cell transplant

alexandrossfakianakis shared this article with you from Inoreader Outcomes of patients who underwent treatment for anti‐HLA donor‐specific antibodies before receiving a haploidentical hematopoietic cell transplant via Pediatric Blood & Cancer Abstract Pediatric and adolescent and young adult (AYA) patients who receive many blood product transfusions, such as individuals with sickle cell disease (SCD), severe aplastic anemia (SAA) or indolent hematologic malignancies, are at high risk for developing donor-specific antibodies (DSA). DSAs with mean fluorescence intensity (MFI) greater than 5000 have been associated with significant graft failure, but lower MFI values between 2000 and 5000 may result in poor graft function after hematopoietic cell transplant (HCT). Desensitization strategies have been developed to reduce the DSA burden in HCT recipients before graft infusion, but the experience with these strategies in the pediatric and AYA populations is not well described in the literature. Here, we describe our experience with successful desensitization by using a combination of treatment strategies in five pediatric and AYA patients, including a novel use of daratumumab in a young adult patient who had refractory DSAs and had s uffered serious side effects from conventional desensitization strategies. The presence of elevated DSAs in pediatric and AYA recipients of a human leukocyte antigen (HLA)-mismatched haploidentical HCT can be overcome by a multipronged treatment strategy. View on Web

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Therapeutic targeting of DNA damage repair pathways guided by homologous recombination deficiency scoring in ovarian cancers

alexandrossfakianakis shared this article with you from Inoreader Therapeutic targeting of DNA damage repair pathways guided by homologous recombination deficiency scoring in ovarian cancers via Fundamental & Clinical Pharmacology Abstract The susceptibility of cells to DNA damage and their DNA repair ability are crucial for cancer therapy. Homologous recombination is one of the major repairing mechanisms for DNA double-strand breaks. Approximately half of ovarian cancer (OvCa) cells harbor homologous recombination deficiency (HRD). Considering that HRD is a major hallmark of OvCas, scholars proposed HRD scoring to evaluate the HRD degree and guide the choice of therapeutic strategies for OvCas. In the last decade, synthetic lethal strategy by targeting poly (ADP-ribose) polymerase (PARP) in HR-deficient OvCas has attracted considerable attention in view of its favorable clinical effort. We therefore suggested that the uses of other DNA damage/repair-targeted drugs in HR-deficient OvCas might also offer better clinical outcome. Here, we reviewed the current small molecule compounds which targeted DNA damage/repair pathways, and discussed the HRD scoring system to guide their clinical uses. View on Web

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Two stage, hybrid endovascular and open surgical approach to treat difficult carotid body tumors

alexandrossfakianakis shared this article with you from Inoreader Two stage, hybrid endovascular and open surgical approach to treat difficult carotid body tumors via Head & Neck Abstract Objective Present the feasibility, applicability, clinical effectiveness, and results of complicated Shamblin II or III carotid body tumors treated with a two-stage hybrid surgical approach. Materials and Methods Retrospective, observational, cross-sectional, descriptive study of the successful treatment of 16 cases of difficult Shamblin II or III carotid body tumors, consisting of a two-stage surgical approach. We conducted a retrospective, observational, cross-sectional, descriptive study of a series of patients with complicated Shamblin II or III carotid body tumors, which we treated with a two-stage hybrid surgical procedure, in which we first placed a carotid endoprosthesis and 45 days later performed surgical resection of the tumor, following our originally published technique. This study was conducted from February, 2007 to November, 2019, in a third level care centre. Results We treated 16 patients with a mean age of 50.5 years. All resided at more than 2000 meters above sea level. In all 16 a complete resection was performed. The average duration of surgery was 103.9 min, the average intraoperative bleeding was 69 ml. There were three cases of neuropraxia. The ansa cervicalis nerve had to be sectioned in three cases and there was permanent upper laryngeal nerve injury in two cases. There were no permanent cerebrovascular injuries from placement of the endoprostheses. One patient developed transient cerebral ischaemia (TIA) with no long-term sequelae. There were two cases of asymptomatic late occlusion of the endoprostheses. The average initial volume of the tumors was 54.4 cc. The average tumor volume 35 days after implant of the endoprosthesis was 30.9 cc. Symptoms Presence of tumors in the neck in all cases and two cases of dysphagia. Conclusion This two-stage hybrid technique allowed for the complete resection of difficult Shamblin II or III carotid body tumors, with one case of TIA and two with permanent upper laryngeal nerve injuries and without mortality. View on Web

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Gliovascular alterations in sporadic and familial Alzheimer's disease: APOE3 Christchurch homozygote glioprotection

alexandrossfakianakis shared this article with you from Inoreader Gliovascular alterations in sporadic and familial Alzheimer's disease: APOE3 Christchurch homozygote glioprotection via Brain Pathology The human frontal cortex of SAD, FAD, and APOEch is characterized by specific astrocyte phenotypes which define the integrity of Gliovascular unit. ApoE3ch mutation in an E280A carrier might be related to the promotion of astrocytic and gliovascular homeostatisis despite the massive load of Aβ. This study provides new insights into the potential relevance of the gliovascular unit in the development and protection of AD. Abstract In response to brain insults, astrocytes become reactive, promoting protection and tissue repair. However, astroglial reactivity is typical of brain pathologies, including Alzheimer's disease (AD). Considering the heterogeneity of the reactive response, the role of astrocytes in the course of different forms of AD has been underestimated. Colombia has the largest human group known to have familial AD (FAD). This group carries the autosomal dominant and fully penetrant mutation E280A in PSEN1, which causes early-onset AD. Recently, our group identified an E280A carrier who did not develop FAD. The individual was homozygous for the Christchurch mutation R136S in APOE3 (APOEch). Remarkably, APOE is the main genetic risk factor for developing sporadic AD (SAD) and most of cerebral ApoE is produced by astroglia. Here, we characterized astrocyte properties related to reactivity, glutamate homeostasis, and structural integrity of the gliovascular unit (GVU), as factors that could underlie the pathogenesis or protection of AD. Specifically, through histological and 3D microscopy analyses of postmortem samples, we briefly describe the histopathology and cytoarchitecture of the frontal cortex of SAD, FAD, and APOEch, and demonstrate that, while astrodegeneration and vascular deterioration are prominent in SAD, FAD is characterized by hyperreactive-like glia, and APOEch displays the mildest astrocytic and vascular alterations despite having the highest burden of Aβ. Notably, astroglial, gliovascular, and vascular disturbances, as well as brain cell death, correlate with the specific astrocytic phenotypes identified in each condition. This study provides new insights into the potential relevance of the gliovasculature in the development and protection of AD. To our knowledge, this is the first study assessing the components of the GVU in human samples of SAD, FAD, and APOEch. View on Web

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Use of Cold-Stored Whole Blood is Associated With Improved Mortality in Hemostatic Resuscitation of Major Bleeding: A Multicenter Study

alexandrossfakianakis shared this article with you from Inoreader Use of Cold-Stored Whole Blood is Associated With Improved Mortality in Hemostatic Resuscitation of Major Bleeding: A Multicenter Study via Annals of Surgery - Most Popular Articles Objective: The aim of this study was to identify a mortality benefit with the use of whole blood (WB) as part of the resuscitation of bleeding trauma patients. Background: Blood component therapy (BCT) is the current standard for resuscitating trauma patients, with WB emerging as the blood product of choice. We hypothesized that the use of WB versus BCT alone would result in decreased mortality. Methods: We performed a 14-center, prospective observational study of trauma patients who received WB versus BCT during their resuscitation. We applied a generalized linear mixed-effects model with a random effect and controlled for age, sex, mechanism of injury (MOI), and injury severity score. All patients who received blood as part of their initial resuscitation were included. Primary outcome was mortality and secondary outcomes included acute kidney injury, deep vein thrombosis/pulmonary embolism, pulmonary complications, and bleeding complications. Results: A total of 1623 [WB: 1180 (74%), BCT: 443(27%)] patients who sustained penetrating (53%) or blunt (47%) injury were included. Patients who received WB had a higher shock index (0.98 vs 0.83), more comorbidities, and more blunt MOI (all P View on Web

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Efficacy of Imaging Methods in the Detection and Diagnosis of Cerebrospinal Fluid Rhinorrhea

alexandrossfakianakis shared this article with you from Inoreader Efficacy of Imaging Methods in the Detection and Diagnosis of Cerebrospinal Fluid Rhinorrhea via The Laryngoscope We assess the diagnostic efficacy of various imaging methods in patients with suspected cerebrospinal fluid (CSF) rhinorrhea. This network meta-analysis demonstrates that intrathecal gadolinium-magnetic resonance cisternography is the most useful diagnostic method to detect CSF rhinorrhea. Objective To assess the diagnostic efficacy of various imaging methods in patients with suspected cerebrospinal fluid (CSF) rhinorrhea. Data Sources The PubMed, EMBASE, SCOPUS, Web of Science, Cochrane Trials, and Google Scholar databases were searched up to December 2021. Review Methods Diagnostic accuracy was compared among seven radiological methods: computed tomography (CT), CT cisternography (CTC), magnetic resonance imaging (MRI), magnetic resonance cisternography (MRC), CT + MRI, radionuclide cisternography, and intrathecal gadolinium (Gd)-MRC. Sensitivity, specificity, and accuracy were used as outcomes of the analysis. Both a traditional pairwise meta-analysis and a network meta-analysis were performed. Results Twenty-three trials were included in the analysis. The results of a network meta-analysis performed on a network consisting of seven diagnostic methods showed that all imaging modalities had greater diagnostic accuracy than CT, with the exception of CTC, which had lower sensitivity. Only intrathecal Gd-MRC was significantly superior to other imaging methods with regard to sensitivity and accuracy. Gd-MRC also showed the greatest surface under the cumulative ranking curve values for all of the outcomes (sensitivity: 0.9200; specificity: 0.8364; accuracy: 0.8920). Conclusion This network meta-analysis demonstrates that intrathecal Gd-MRC is the most useful diagnostic method to detect CSF rhinorrhea. Laryngoscope, 2022 View on Web

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Anti‐SARS‐CoV‐2 Activity of Targeted Kinase Inhibitors: Repurposing Clinically Available Drugs for COVID‐19 Therapy

alexandrossfakianakis shared this article with you from Inoreader Anti‐SARS‐CoV‐2 Activity of Targeted Kinase Inhibitors: Repurposing Clinically Available Drugs for COVID‐19 Therapy via Journal of Medical Virology Abstract Purpose Coronavirus disease 2019 (COVID-19) remains a major public health concern, and vaccine unavailability, hesitancy, or failure underscore the need for discovery of efficacious antiviral drug therapies. Numerous approved drugs target protein kinases associated with viral life cycle and symptoms of infection. Repurposing of kinase inhibitors is appealing as they have been vetted for safety and are more accessible for COVID-19 treatment. However, an understanding of drug mechanism is needed to improve our understanding of the factors involved in pathogenesis. Methods We tested the in vitro activity of three kinase inhibitors against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), including inhibitors of AXL kinase, a host cell factor that contributes to successful SARS-CoV-2 infection. Using multiple cell-based assays and approaches, gilteritinib, nintedanib, and imatinib were thoroughly evaluated for activity against SARS-CoV-2 varian ts. Results Each drug exhibited antiviral activity, but with stark differences in potency, suggesting differences in host dependency for kinase targets. Importantly, for gilteritinib, the amount of compound needed to achieve 90% infection inhibition, at least in part involving blockade of spike protein-mediated viral entry and at concentrations not inducing phospholipidosis (PLD), approached a clinically achievable concentration. Knockout of AXL, a target of gilteritinib and nintedanib, impaired SARS-CoV-2 variant infectivity, supporting a role for AXL in SARS-CoV-2 infection and supporting further investigation of drug-mediated AXL inhibition as a COVID-19 treatment. Conclusions This work supports further evaluation of AXL-targeting kinase inhibitors as potential antiviral agents and treatments for COVID-19. Additional mechanistic studies are needed to determine underlying differences in virus response. This article is protected by copyright. All r ights reserved. View on Web

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Prevention of the Occupational Silicosis Epidemic

alexandrossfakianakis shared this article with you from Inoreader Prevention of the Occupational Silicosis Epidemic in Australia: What Do Those Who Assess Workplace Health Risk Think Should Be Done Now? via Annals of Work Exposures and Health Advance Access Abstract An Australian National Dust Disease Taskforce was established to address the re-emergence of occupational lung disease, in particular silicosis. Exposure to respirable crystalline silica (RCS) occurs in various industries in Australia. We asked occupational hygienists about their practical experiences and perspectives on RCS exposure and regulatory action. A total of 105 members of the Australian Institute of Occupational Hygienists completed an anonymous questionnaire, which addressed individual characteristics, experience, perceived level of employer awareness, effectiveness of current regulation, and recommendations for improvement, across three main industrial sectors. Based on professional experience, 71% were concerned about the potential for RCS over-exposure. Barriers to adequate exposure control included lack of management commitment and financial resources. The employment of specialist occupational hygiene inspectors was considered to b e the most effective regulatory strategy. Given the large number of exposed workers in the construction industry, with only a moderate awareness, there is the potential for significant cost shifting of the burden of occupational lung disease from employers on to individuals and the public health system. A nationally consistent approach to RCS exposure control across all industrial sectors is now recommended, with an increased focus on measuring and controlling exposure. View on Web

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The T‐shaped FST pharyngoplasty step‐by‐step closure technique

alexandrossfakianakis shared this article with you from Inoreader The T‐shaped FST pharyngoplasty step‐by‐step closure technique via Head & Neck Abstract Pharyngocutaneous fistula is one of the most common and serious complications associated with total laryngectomy. Numerous studies tried to evaluate causative and predisposing factors associated with this complication, but data are considerably variable and there is still no international consensus. Incidence rate varies considerably between studies, with reported rates from 3% to 65%. This 4K video presents our T-shaped four-step technique (FST) for closing the pharyngeal mucosa after total laryngectomy in a step-by-step manner. All sutures were performed by braided absorbable 3/0 26 mm 1/2c (Vicryl plus 3.0; Ethicon, Somerville, NJ, USA). Recordings were performed using a Karl Storz 4K 3D VITOM® exoscope (Karl Storz SE & Co. KG, Tuttlingen, Germany). We have been described this technique through a high-definition video, showing each step, and tips from the authors. Our T-shaped pharyngoplasty closure technique can be divided into four steps: 1. "Key Stitches"; 2. "A rea Refinement Stitches"; 3. "Modified Connell Suture"; 4. "Modified Purse String Suture." Our T-shaped FST closure technique proved to be an effective and reproducible method, which we feel could be the preferred choice for primary pharyngoplasty closure. View on Web

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Effectiveness of root canal treatment for vital pulps compared with necrotic pulps in the presence or absence of signs of periradicular pathosis: a systematic review and meta‐analysis

alexandrossfakianakis shared this article with you from Inoreader Effectiveness of root canal treatment for vital pulps compared with necrotic pulps in the presence or absence of signs of periradicular pathosis: a systematic review and meta‐analysis via International Endodontic Journal Abstract Background Pre-operative pulpal status may influence the outcomes of root canal treatment (RCTx) according to various measures used. Objectives To compare effectiveness of RCTx of teeth with a vital pulp versus a necrotic pulp using a range of clinical and patient-related outcomes, for the development of S3-Level clinical practice guidelines. Methods A search was conducted in the PubMed-MEDLINE, Scopus, EMBASE, Google scholar databases and available repositories, followed by hand searches, until 29 March 2022. Clinical studies published in English language comparing the stipulated outcomes of RCTx of teeth with vital versus necrotic pulp were included. The Newcastle-Ottawa Scale was adapted to assess study quality. Effects of pulpal status were estimated and expressed as risk ratio (RR) using fixed- and random-effect meta-analyses. The quality of evidence was assessed through the Grading of Recommendations Assessment, Development, and Evaluation tool. Results Twenty-eight studies published between 1961 and 2021 were included. Five studies have investigated the 'tooth survival' outcome, four reported pulpal status was not a significant predictor, consistent with meta-analysis finding (RR: 1.00; 95% CI: 1.00, 1.00; n=3). Seven studies reported pulpal status had no significant influence on post-operative pain, regardless of duration after treatment. Sixteen studies have analysed 'periapical health', eleven revealed pulpal status had no significant influence. Meta-analyses revealed the influence was not significant if pre-operative periapical radiolucency was absent (RR: 0.95; 95% CI: 0.90, 1.00; n=9) but significant if it was present (RR: 1.12; 95% CI: 1.05, 1.19; n=11). Most studies were classified as 'some concerns' (n=16) to 'low' (n=10) risk of bias (RoB). Discussion Evidence is limited and only available for three outcomes when comparing the effectiveness of RCTx in permanent teeth with vital pulp versus pulp necrosis. Nevertheless, the quality of available evidence was moderate to high. The 'periapical health' data heterogeneity could be explained by pre-operative radiolucency, thus RCTx was found more effective for prevention than resolution of apical periodontitis. Conclusions There was no significant difference in the 'tooth survival', 'post-operative pain' and 'evidence of apical radiolucency' outcomes of RCTx in teeth with vital or necrotic pulps. View on Web

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