Bulletin of Computer Science and Electrical Engineering (BCSEE)
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Mycobacterium Abscessus Complex Infections Among Lung Transplant Recipients: A National Retrospective Cohort Study
No full textMycobacterium abscessus (MABS) is a non-tuberculous mycobacteria (NTM) known to cause life threatening disease involving the lung, skin and soft tissue, and disseminated disease in lung transplantation recipients (LTRs). Therefore, many centres consider the presence of MABS as a relative contraindication to lung transplantation (LT). The goal of this study was to assess the epidemiology and outcomes of MABS infection before and after LT in a pan-Canadian cohort.
We conducted a multicenter retrospective cohort study including all 4 LT centers in Canada. All LTRs transplanted between January 2006 and December 2016 with at least one respiratory sample positive for MABS complex prior to or post transplantation were included. Pulmonary disease was defined using the American Thoracic Society criteria for NTM lung infection. Follow up duration was 5 years after transplantation.
Among a cohort of 2230 LTRs across Canada, 15 patients (0.67%) had MABS infection prior to LT. Median age was 32 (range 17-58), 7/15 (47%) were female and the most common underlying disease was cystic fibrosis 11/15 (73%). Among patients with MABS infection pre-transplant, 80% (12/15) received treatment prior to transplant. Following LT, 53% (8/15) developed recurrent MABS infection (6 disease and 2 colonization). Five-year mortality among patients with pre-transplant MABS infection was 27% (4/15). Among patients with pre-transplant MABS infection, mortality was higher in those who had recurrence of MABS infection after transplant (50% vs 0%, 0.077), though this did not reach statistical significance. Microbiologic eradication prior to transplant occurred in 8/15 (72.7%) and was associated with decreased mortality (0% vs 57.1%, 0.026) and decreased risk of recurrence (12.5% vs 100%, 0.001). In addition to the 8 patients with recurrent disease, 12 patients developed de novo MABS infection after transplant of which 66.7% (8/12) had disease. Among the 14 patients with post-transplant disease, 5 year mortality was 50% (7/14), the majority of which was due to MABS infection (5/7, 71.4%).
MABS is an uncommon cause of infection among LTRs. Recurrence rate among those with pre-transplant infection is high and this may be associated with decreased survival. Survival among those with pre-transplant MABS infection was similar to contemporary cohorts of LTRs
The Evolution of Assessing Central Nervous System Complications in Human Immunodeficiency Virus: Where Do We Go From Here?
No full textIn this fifth decade of the human immunodeficiency virus (HIV) epidemic, central nervous system (CNS) complications including cognitive impairment and mental health remain a burden for people with HIV (PWH) on antiretroviral therapy. Despite the persistence of these complications, which often co-occur, the underlying pathophysiology remains elusive and consequently treatments remain limited. To continue to grow our understanding of the underlying mechanisms of CNS complications among PWH, there is a need to reexamine our current approaches, which are now more than 2 decades old. At the 2021 National Institutes of Health-sponsored meeting on Biotypes of CNS Complications in PWH, the Neurobehavioral Working Group addressed the following: (1) challenges inherent to determining CNS complications; (2) heterogeneity in CNS complications; and (3) problems and solutions for examining integrated biotypes. The review below provides a summary of the main points presented and discussed by the Neurobehavioral Working Group at the meeting
Evaluation and Recommendations for the Brazilian Version of safeMedicate: A Cross-Cultural Adaptation
No full textsafeMedicate was developed as an English-language web-based system designed to support learning and competence development in solving medication dosage problems. Our purpose was to identify the adaptations necessary to implement safeMedicate for use in Brazil, with an explorative, qualitative design using an adapted Participatory and Iterative Process Framework for Language Adaptation (PIPFLA) process and the Delphi technique with online focus groups. Focus group transcripts were analyzed using content analysis. The main themes were language, visual content, programing, data, and strength. safeMedicate was considered to be acceptable for use in Brazil. Participants perceived that it would be welcomed by faculty and students as a way to address current teaching and practice gaps. Cultural and political barriers should be identified and addressed when adapting material for use in different national contexts
GSDMD deficiency ameliorates hyperoxia-induced BPD and ROP in neonatal mice
No full textBronchopulmonary dysplasia (BPD) and retinopathy of prematurity (ROP) are among the most common morbidities affecting extremely premature infants who receive oxygen therapy. Many clinical studies indicate that BPD is associated with advanced ROP. However, the mechanistic link between hyperoxia, BPD, and ROP remains to be explored. Gasdermin D (GSDMD) is a key executor of inflammasome-induced pyroptosis and inflammation. Inhibition of GSDMD has been shown to attenuate hyperoxia-induced BPD and brain injury in neonatal mice. The objective of this study was to further define the mechanistic roles of GSDMD in the pathogenesis of hyperoxia-induced BPD and ROP in mouse models. Here we show that global GSDMD knockout (GSDMD-KO) protects against hyperoxia-induced BPD by reducing macrophage infiltration, improving alveolarization and vascular development, and decreasing cell death. In addition, GSDMD deficiency prevented hyperoxia-induced ROP by reducing vasoobliteration and neovascularization, improving thinning of multiple retinal tissue layers, and decreasing microglial activation. RNA sequencing analyses of lungs and retinas showed that similar genes, including those from inflammatory, cell death, tissue remodeling, and tissue and vascular developmental signaling pathways, were induced by hyperoxia and impacted by GSDMD-KO in both models. These data highlight the importance of GSDMD in the pathogenesis of BPD and ROP and suggest that targeting GSDMD may be beneficial in preventing and treating BPD and ROP in premature infants
Predictive Value of C-Peptide Measures for Clinical Outcomes of β-Cell Replacement Therapy in Type 1 Diabetes: Report From the Collaborative Islet Transplant Registry (CITR)
No full textTo determine C-peptide measures and levels associated with positive glycemic control outcomes following islet transplant (ITx) in type 1 diabetes.
We evaluated Collaborative Islet Transplant Registry (CITR) islet-alone recipients with pretransplant C-peptide <0.1 nmol/L and mean follow-up of 4.6 ± 1.1 years (n = 677). Receiver operating characteristic area under the curve (ROC-AUC) was used to evaluate the predictive value of fasting and stimulated glucose and C-peptide measures for seven primary outcomes: 1) absence of severe hypoglycemic events (ASHEs); 2) HbA1c <7.0%; 3) HbA1c <7.0% and ASHEs; 4) HbA1c ≤6.5%; 5) HbA1c ≤6.5% and ASHEs; 6) insulin independence; and 7) ASHEs, HbA1c ≤6.5%, and insulin independence (the optimal outcome). Measures with the highest ROC-AUC were selected for determination of optimal cut points.
Fasting C-peptide was highly predictive for ASHE (ROC-AUC 0.906; optimal cut point 0.070 nmol/L) and the optimal outcome (ROC-AUC 0.845; optimal cut point 0.33 nmol/L). Mixed-meal tolerance test (MMTT)-stimulated C-peptide-to-glucose ratio (CPGR) outperformed both fasting and stimulated C-peptide for all outcomes except ASHE. The optimal cut point for the optimal outcome was 0.12 nmol/mmol for MMTT-stimulated CPGR and 0.97 nmol/L for MMTT-stimulated C-peptide.
Fasting C-peptide reliably predicts ITx primary outcomes. MMTT-stimulated CPGR provides marginally better prediction for composite ITx outcomes, including insulin independence. In the absence of an MMTT, a fasting C-peptide ≥0.33 nmol/L is a reassuring measure of optimal islet graft function. C-peptide targets represent excellent and easily determinable means to predict glycemic control outcomes after ITx and should be considered as potential goals of β-cell replacement
Transcriptional programing of T cell metabolism by STAT family transcription factors
No full textT cells adapt their metabolism to meet the energetic and biosynthetic demands imposed by changes in location, behavior, and/or differentiation state. Many of these adaptations are controlled by cytokines. Traditionally, research on the metabolic properties of cytokines has focused on downstream signaling via the PI3K-AKT, mTOR, or ERK-MAPK pathways but recent studies indicate that JAK-STAT is also crucial. This review synthesizes current thinking on how JAK-STAT signaling influences T cell metabolism, focusing on adaptations necessary for the naive, effector, regulatory, memory, and resident-memory states. The overarching theme is that JAK-STAT has both direct and indirect effects. Direct regulation involves STATs localizing to and instructing expression of metabolism-related genes. Indirect regulation involves STATs instructing genes encoding upstream or regulatory factors, including cytokine receptors and other transcription factors, as well as non-canonical JAK-STAT activities. Cytokines impact a vast range of metabolic processes. Here, we focus on those that are most prominent in T cells; lipid, amino acid, and nucleotide synthesis for anabolic metabolism, glycolysis, glutaminolysis, oxidative phosphorylation, and fatty acid oxidation for catabolic metabolism. Ultimately, we advocate the idea that JAK-STAT is a key node in the complex network of signaling inputs and outputs which ensure that T cell metabolism meets lifestyle demands
Risk of endometrial cancer in asymptomatic postmenopausal women in relation to ultrasonographic endometrial thickness: A reply to unfounded concerns
No full textA DEFECT IN MITOCHONDRIAL COMPLEX III BUT NOT IN COMPLEXES I OR IV CAUSES EARLY BETA CELL DYSFUNCTION AND HYPERGLYCEMIA IN MICE
No full textMitochondrial metabolism and oxidative respiration are crucial for pancreatic beta-cell function and stimulus secretion coupling. Oxidative phosphorylation (OxPhos) produces ATP and other metabolites that potentiate insulin secretion. However, the contribution of individual OxPhos complexes to beta-cell function is unknown. We generated beta-cell-specific, inducible OxPhos complex knock-out (KO) mouse models to investigate the effects of disrupting complex I, complex III, or complex IV on beta-cell function. Although all KO models had similar mitochondrial respiratory defects, complex III caused early hyperglycemia, glucose intolerance, and loss of glucose-stimulated insulin secretion in vivo. However, ex vivo insulin secretion did not change. Complex I and IV KO models showed diabetic phenotypes much later. Mitochondrial Ca2+ responses to glucose stimulation 3 weeks after gene deletion ranged from not affected to severely disrupted, depending on the complex targeted, supporting the unique roles of each complex in beta-cell signaling. Mitochondrial antioxidant enzyme immunostaining increased in islets from complex III KO, but not from complex I or IV KO mice, indicating that severe diabetic phenotype in the complex III-deficient mice is causing alterations in cellular redox status. The present study highlights that defects in individual OxPhos complexes lead to different pathogenic outcomes.</p
Radiogenomic profiling of prostate tumors prior to external beam radiotherapy converges on a transcriptomic signature of TGF-β activity driving tumor recurrence
No full textBackground: Patients with localized prostate cancer have historically been assigned to clinical risk groups based on local disease extent, serum prostate specific antigen (PSA), and tumor grade. Clinical risk grouping is used to determine the intensity of treatment with external beam radiotherapy (EBRT) and androgen deprivation therapy (ADT), yet a substantial proportion of patients with intermediate and high risk localized prostate cancer will develop biochemical recurrence (BCR) and require salvage therapy. Prospective identification of patients destined to experience BCR would allow treatment intensification or selection of alternative therapeutic strategies. Methods: Twenty-nine individuals with intermediate or high risk prostate cancer were prospectively recruited to a clinical trial designed to profile the molecular and imaging features of prostate cancer in patients undergoing EBRT and ADT. Whole transcriptome cDNA microarray and whole exome sequencing was performed on pretreatment targeted biopsy of prostate tumors (n=60). All patients underwent pretreatment and 6-month post EBRT multiparametric MRI (mpMRI), and were followed with serial PSA to assess presence or absence of BCR. Genes differentially expressed in the tumor of patients with and without BCR were investigated using pathways analysis tools and were similarly explored in alternative datasets. Differential gene expression and predicted pathway activation were evaluated in relation to tumor response on mpMRI and tumor genomic profile. A novel TGF-β gene signature was developed in the discovery dataset and applied to a validation dataset. Findings: Baseline MRI lesion volume and PTEN/TP53 status in prostate tumor biopsies correlated with the activation state of TGF-β signaling measured using pathway analysis. All three measures correlated with the risk of BCR after definitive RT. A prostate cancer-specific TGF-β signature discriminated between patients that experienced BCR vs. those that did not. The signature retained prognostic utility in an independent cohort. Interpretation: TGF-β activity is a dominant feature of intermediate-to-unfavorable risk prostate tumors prone to biochemical failure after EBRT with ADT. TGF-β activity may serve as a prognostic biomarker independent of existing risk factors and clinical decision-making criteria. Funding: This research was supported by the Prostate Cancer Foundation, the Department of Defense Congressionally Directed Medical Research Program, National Cancer Institute, and the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research
Layer 5a Corticostriatal Projection Neurons are Selectively Vulnerable in Huntington's Disease
No full textThe properties of the cell types that are most vulnerable in the Huntington's disease (HD) cortex, the nature of somatic CAG expansion of
in these cells, and their importance in CNS circuitry have not been delineated. Here we have employed serial fluorescence activated nuclear sorting (sFANS), deep molecular profiling, and single nucleus RNA sequencing (snRNAseq) to demonstrate that layer 5a pyramidal neurons are selectively vulnerable in primary motor cortex and other cortical areas. Extensive somatic
-CAG expansion occurs in vulnerable layer 5a pyramidal cells, and in Betz cells, layer 6a, layer 6b neurons that are not lost in HD. Retrograde tracing experiments in the macaque brain identify the vulnerable layer 5a neurons as corticostriatal pyramidal cells. Our data establish that
-CAG expansion is not sufficient for cell loss in the cerebral cortex of HD, and suggest that cortico-striatal disconnection in early-stage HD patients may play an important role in neurodegeneration