Blood counts in children with Down syndrome

alexandrossfakianakis shared this article with you from Inoreader Blood counts in children with Down syndrome via Pediatric Blood & Cancer Abstract Background Children with Down syndrome (DS) are more likely to have hematologic and immunologic abnormalities compared to their typically developing peers, but normal ranges have not been defined. The goal of this study was to create references for complete blood counts (CBCs) in patients with DS. Methods A retrospective investigation of 355 (male = 196, 55.2%; mean age = 6.49 years, SD = 5.07) healthy pediatric patients with DS who received a CBC between 2011 and 2017 as part of their medical care at a single, large, pediatric teaching hospital. Control data on 770 healthy patients without DS were included. Descriptive statistics were performed on demographic and clinical characteristics. Kruskal–Wallis H tests, nested analysis-of-variance tests, and t-tests were run to determine the significant associations. Results Age-related normative curves for healthy children with DS outlining 2.5th, 25th, 50th, 75th, and 97.5th percentiles are provided for total white blood count, hemoglobin concentration, hematocrit, mean corpuscular volume, and platelet, absolute neutrophil, absolute lymphocyte, eosinophil, monocyte, and basophil counts. Statistical differences were found between children with and without DS receiving care at the same hospital based on matched age/sex groups. Conclusions This study demonstrates that patients with DS have different reference ranges for multiple blood counts compared to those without DS, creating a new resource for pediatricians to refer to when evaluating CBCs in this population. View on Web

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Vaccine‐induced binding and neutralizing antibodies against Omicron 6 months after a homologous BNT162b2 booster

alexandrossfakianakis shared this article with you from Inoreader Vaccine‐induced binding and neutralizing antibodies against Omicron 6 months after a homologous BNT162b2 booster via Journal of Medical Virology Abstract Introduction Evidence about the long-term persistence of the booster-mediated immunity against Omicron is mandatory for pandemic management and deployment of vaccination strategies. Methods A total of 155 healthcare professionals (104 COVID-19 naive and 51 with a history of SARS-COV-2 infection) received a homologous BNT162b2 booster. Binding antibodies against the spike protein and neutralizing antibodies against Omicron were measured at several time points before and up to 6 months after the booster. Geometric mean titers of measured antibodies were correlated to vaccine efficacy against symptomatic disease. Results Compared to the highest response, a significant 10.2 and 11.5-fold decrease in neutralizing titers was observed after 6 months in participants with and without history of SARS-CoV-2 infection. A corresponding 2.5 and 2.9-fold decrease in binding antibodies was observed. The estimated T1/2 of neutralizing antibodies in pa rticipants with and without history of SARS-CoV-2 infection was 42 (95%CI, 25–137) and 36 days (95%CI, 25–65). Estimated T1/2 were longer for binding antibodies: 168 (95%CI, 116–303) and 139 days (95%CI, 113–180), respectively. Both binding and neutralizing antibodies were strongly correlated to vaccine efficacy (r = 0.83 and 0.89). However, binding and neutralizing antibodies were modestly correlated, and a high proportion of subjects (36.7%) with high binding antibody titers (i.e. > 8,434 BAU/mL) did not have neutralizing activity. Conclusion A considerable decay of the humoral response was observed 6 months after the booster, and was strongly correlated with vaccine efficacy. Our study also shows that commercial assays available in clinical laboratories might require adaptation to better predict neutralization in the Omicron era. This article is protected by copyright. All rights reserved. View on Web

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Longitudinal Effects of Base of Tongue Concurrent Chemoradiation Therapy in a Pre‐Clinical Model

alexandrossfakianakis shared this article with you from Inoreader Longitudinal Effects of Base of Tongue Concurrent Chemoradiation Therapy in a Pre‐Clinical Model via The Laryngoscope We present a clinically relevant animal model quantifying the effects of concurrent chemoradiation therapy (CCRT) on tongue strength and elasticity over time. This study demonstrates an increasing difference in tongue strength over time between control animals and those exposed to CCRT. Tongue elasticity was not significantly affected by CCRT, suggesting that changes in strength may not be caused by fibrosis during the time period studied. Background/Objectives Base of tongue (BOT) dysfunction is common following oropharyngeal concurrent chemoradiation therapy (CCRT). We present a clinically relevant animal model quantifying the effects of CCRT on tongue strength and elasticity over time. Methods Fifty-three male and 53 female Sprague–Dawley rats were randomized to control or experimental groups. Experimental animals received cisplatin, 5-fluorouracil, and 5 fractions of 7 Gy directed to the BOT. Controls received no intervention. At 2 weeks, 5 months, or 10 months after CCRT, animals underwent non-survival surgery to measure twitch and tetanic tongue strength, which were analyzed using multivariate linear mixed effects models. Tongue displacement, a surrogate for tongue elasticity, was also determined via stress–strain testing and analyzed via a multivariate linear mixed effects model. Results Reporting the combined results of both sexes, the estimated experimental group mean peak twitch forces became more divergent over time compared to controls, being 8.3% lower than controls at 2 weeks post-CCRT, 15.7% lower at 5 months, and 31.6% lower at 10 months. Estimated experimental group mean peak tetanic forces followed a similar course and were 2.9% lower than controls at 2 weeks post CCRT, 20.7% lower at 5 months, and 27.0% lower at 10 months. Stress–strain testing did not find CCRT to have a significant effect on tongue displacement across experimental timepoints. Conclusions This study demonstrates an increasing difference in tongue strength over time between controls and animals exposed to CCRT. Tongue elasticity was not significantly affected by CCRT, suggesting that changes in strength may not be caused by fibrosis. Level of Evidence NA Laryngoscope, 2022 View on Web

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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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