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Background: Senior citizens, or individuals over 60 years, constitute 8.6% of India’s population. As a result of shifting family dynamics brought about by growing urbanization and globalization, these elderly populations are flocking to elder care centers. The objectives of this research are to ascertain the elderly’s self-reported chronic morbidities, disabilities, and the relationship between these factors with their quality of life (QOL). Methodologys: This cross-sectional study was conducted among 110 residents of old age homes in Mangalore block of Dakshina Kannada district. The data was collected using a semi-structured questionnaire consist of, Indian Disability Evaluation and assessment Scale and the World Health Organization Quality of life Brief Version (WHOQOL BREF) questionnaire and the data obtained was analyzed using SPSS version 24. Odd’s ratio was calculated, independent T test was used to compare the means across the groups and a ‘p’ value < 0.05 was considered as statistically significant. Results: In the current study 65.5% participants were female (N=72) and most of the study participants reported hypertension and musculoskeletal pain (41.8% & 36.7% respectively) as the major ailment they are seeking health care, followed by diabetes mellitus (20.0%), angina (12.3%), asthma (10.9%), COPD (6.4%) and heart attack (4.5%). There was a statistically significant association between age, male gender, and level of disability with quality of life. Age of the participant was found to be directly proportional to quality of life in 2 domains – psychological and social relationships. Male gender was found to be significantly associated with social relationships domain of quality of life. Conclusion: It was shown that there was no clinically significant correlation between chronic morbidities and any dimension of quality of life, suggesting that the frequency and quality of health examinations delivered in the care homes were sufficient, which must carry on in the subsequent years.

Objective: To investigate the impact of procyclical and countercyclical strategies on the performance of MSMEs in the context of the Covid-19 crisis. Methodology/approach: Quantitative sample, with 118 micro, small, and medium-sized companies in Minas Gerais, Brazil. Spearman's correlation analysis and multiple linear regression analysis were used. Main Results: In the period dominated by the pandemic (2020/2021), countercyclical strategies performed better than procyclical strategies. Theoretical/methodological contributions: Although the literature explores procyclical strategies, studies that associate the influence of procyclical and countercyclical strategies with organizational performance still need to be made available. This gap is even more evident when MSMEs in crisis contexts are considered. By associating still new dimensions, such as HR, marketing, and production, among others, this article helps to fill gaps associated with, even today, a lack of work that seeks integrated models capable of better understanding the impact that crises, such as COVID-19. Relevance/Originality: The article innovates by associating, in the context of the literature on the crisis, the two types of strategies (countercyclical and procyclical) in the elaboration and testing of an integrated analytical model composed of different variables, and capable of being used not only in new research as well as in the business context. Social/management contributions: By demonstrating that cuts in investments in marketing and other areas produce adverse effects on performance and that organizations benefit by keeping employees instead of firing them, this study sheds light on the relevance of countercyclical strategies, which still need to be explored.

Objetivo: Investigar o impacto de estratégias procíclicas e anticíclicas no desempenho de MPMEs no contexto da crise de Covid-19. Método/Abordagem: quantitativo, amostral, com 118 micro, pequenas e médias empresas de Minas Gerais, Brasil. Utilizou-se o aporte de análise da correlação de spearman e análise de regressão linear múltipla. Principais Resultados: no período dominado pela pandemia (2020/2021), as estratégias anticíclicas apresentaram desempenho superior àquelas que utilizam estratégias procíclicas. Contribuições teóricas/metodológicas: Embora a literatura explore as estratégias procíclicas, estudos que associam a influência de estratégias procíclicas e anticíclicas ao desempenho organizacional ainda são raros. Esta lacuna é ainda mais evidente quando são consideradas MPMEs em contextos de crise. Ao associar dimensões ainda novas, como recursos humanos, marketing e produção, entre outras, este artigo ajuda a preencher lacunas associadas, ainda hoje, à falta de trabalhos que busquem modelos integrados capazes de melhor compreender o impacto das crises, como o COVID-19. Relevância/Originalidade: o artigo inova ao associar, no contexto da literatura sobre crise, os dois tipos de estratégias (anticíclica e procíclica), na elaboração e teste de um modelo analítico integrado, composto de diferentes variáveis, e passível de ser utilizado não apenas em novas pesquisas como, também, no contexto empresarial. Contribuições sociais/de gestão: ao demonstrar que cortes de investimentos em marketing e outras áreas produzem efeitos adversos no desempenho, e que as organizações se beneficiam ao manter funcionários em vez de demiti-los, este estudo lança luz sobre a relevância de estratégias anticíclicas, que ainda precisam ser melhor exploradas.

Diante da necessidade de profissionalização da formação do professor de música, este artigo tem como objetivo refletir sobre as Pautas Didáticas, um conjunto de dispositivos de formação, resultado de pesquisa desenvolvida no âmbito do estágio de pós-doutorado. Tomando como eixo da formação a reflexão e a profissionalidade docente, entendida como aquilo que é específico para o desempenho da ação docente (comportamentos, atitudes, conhecimentos, habilidades, valores), foi desenvolvido um projeto no estágio supervisionado, no primeiro semestre de 2019. Para a etapa de Interação com a escola, as Pautas Didáticas tiveram foco no espaço escolar (estrutura, funcionamento e projeto pedagógico), na didática em sala de aula (gestão da classe e gestão dos aprendizados), na relação ética (valores, princípios, dilemas e tensões) e no reconhecimento dos aprendizados adquiridos (escrita reflexiva). Nos momentos de organização e socialização dos dados, foram disponibilizados aos licenciandos aportes teóricos e conceituas para subsidiar a análise de situações, dilemas e problematizações. Ao estimular a reflexividade, esses dispositivos caracterizam uma abordagem profissionalizante, uma vez que permitem identificar comportamentos, atitudes, escolhas metodológicas, formular pontos de vista, formalizar e refletir sobre elementos da prática docente observada, desenvolver postura crítica e ética diante de ações e escolhas pedagógicas, levantando pistas para a organização de propostas situadas de intervenção didática.

BACKGROUND: : Residual neuromuscular blockade (RNMB) is known to be associated with respiratory complications in the postoperative period after muscle relaxant usage. The authors hypothesized that RNMB causes reductions in pulmonary function test (PFT) parameters in the immediate postoperative period. METHODS: : An open-label prospective randomized cohort study was conducted comparing reductions in PFT parameters due to RNMB among different neuromuscular blocking agents. One hundred and fifty patients were randomized to receive vecuronium, atracurium, or rocuronium. After reversal of neuromuscular blockade and extubation, train-of-four ratio was measured every 5 min until the train-of-four ratio of 0.9 or greater was attained. PFTs were performed preoperatively and postoperatively when the patients were willing and fit. The train-of-four ratio, measured at PFT, was used to classify patients into 'RNMB absent' and 'RNMB present.' RNMB was defined as a train-of-four ratio less than 0.9. RESULTS: : Thirty-nine patients had RNMB at the time of performing PFT. There was no statistically significant difference in the postoperative reductions in PFT parameters in patients with RNMB among different neuromuscular blocking agents. Patients were regrouped as RNMB absent and RNMB present, irrespective of neuromuscular blocking agents. Postoperative PFT values for the RNMB-absent and RNMB-present groups were 62% and 49% of baseline forced vital capacity and 47% and 38% of baseline peak expiratory flow of the baseline, respectively. Postoperative forced vital capacity and peak expiratory flow values of RNMB-present patients were lower by 13% and 9% in absolute terms (P < 0.008) and 21% and 19% in relative terms, respectively, compared with RNMB-absent patients. CONCLUSION: : RNMB results in reductions in forced vital capacity and peak expiratory flow in the immediate postoperative period indicating impaired respiratory muscle function. [ABSTRACT FROM AUTHOR]

Este trabalho apresentou a experiência de construção e de planejamento da implementação do novo currículo de Graduação em Odontologia da Universidade Federal de Minas Gerais e descreveu o papel do Colegiado de Curso como dinamizador da participação dos docentes nas questões relativas ao ensino. O relato foi construído a partir dos registros, documentos e observações realizados pelas comissões do Colegiado. Descreveu-se a trajetória de construção do novo currículo, sua proposta e o contexto de mobilização dos docentes. O relato aponta a incorporação de instâncias consultivas com participação dos docentes; institucionalização de espaços coletivos de formação com apoio e articulação interinstitucional da Faculdade e da Universidade; ações de articulação interinstitucional e de institucionalização das condições para o trabalho docente. A gestão desses processos e parcerias tem levado o Colegiado a legitimar suas ações na Faculdade de Odontologia, constituindo-se um espaço representativo e responsável pela garantia da qualidade do ensino de graduação.

Purpose: In patients with end-stage heart failure who undergo left ventricular assist device (LVAD) implantation, higher pulmonary vascular resistance (PVR) is associated with higher right heart failure rates and ineligibility for heart transplant. Concomitant mitral regurgitation (MR) could potentially worsen pulmonary hemodynamics and lead to worse outcomes; however, its effects in this patient population have not been specifically examined., Methods: Using an institutional database spanning November 2003 to August 2017, we retrospectively identified patients with elevated PVR who underwent LVAD implantation. Patients were stratified by concurrent MR: moderate/severe (PVR + MR) vs. mild/none (PVR - MR). Cumulative incidence functions and Fine-Gray competing risk regression were performed to assess the effect of MR on heart transplant rates and overall survival during index LVAD support., Results: Of 644 LVAD recipients, 232 (171 HeartMate II, 59 HeartWare, 2 HeartMate III) had baseline PVR > 3 Woods units; of these, 124 (53%) were INTERMACS 1-2, and 133 (57%) had moderate/severe MR (≥ 3 +). Patients with PVR + MR had larger a baseline left ventricular end-diastolic diameter than patients with PVR - MR (87.9 ± 38.2 mm vs. 75.9 ± 38.0 mm; P = 0.02). Median clinical follow-up was 18.8 months (interquartile range: 4.7-36.4 months). Moderate/severe MR was associated with lower mortality rates during index LVAD support (adjusted hazard ratio 0.64, 95% CI 0.41-0.98; P = 0.045) and higher heart transplant rates (adjusted odds ratio 2.86, 95% CI 1.31-6.25; P = 0.009). No differences in stroke, gastrointestinal bleeding, or right heart failure rates were observed., Conclusions: Among LVAD recipients with elevated preoperative PVR, those with moderate/severe MR had better overall survival and higher transplant rates than those with mild/no MR. These hypothesis-generating findings could be explained by incremental LVAD benefits resulting from reduction of MR and better LV unloading in a subset of patients with larger ventricles at baseline. In patients with preoperative elevated PVR, MR severity may be a prognostic sign that can inform patient selection for end-stage heart failure therapy., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

We explored whether women undergo continuous-flow left ventricular assist device (CF-LVAD) implantation in later stages of heart failure (HF) than men, evidenced by worse preoperative right HF (RHF). We also compared two propensity models with and without preoperative RHF to assess its effect on outcomes. INTERMACS was queried from July 2008 to December 2017. Propensity model 1 matched men and women on age ≥50 years, HF etiology, body surface area, INTERMACS class, comorbidities, device strategy, temporary mechanical circulatory support, and device type. Model 2 included these variables plus LV end-diastolic diameter, right atrial pressure/pulmonary capillary wedge pressure, pulmonary artery pulsatility index, and right ventricular ejection fraction. The primary outcome was all-cause mortality. Secondary outcomes comprise RHF, rehospitalization, renal dysfunction, stroke, and device malfunction. In model 1, characteristics were comparable between 3,195 women and 3,195 men, except women more often had preoperative RHF and postoperative right VAD support and had worse 1 year and overall survival. In model 2, after propensity matching for additional risk factors for preoperative RHF, 1,119 women and 1,119 men had comparable post-LVAD implant RVAD use and survival. These findings suggest that women present more often with biventricular failure and after implantation have higher RHF and mortality rates., Competing Interests: There are no conflicts of interest for any of the authors., (Copyright © ASAIO 2024.)

Purpose: Stevens-Johnson syndrome (SJS) is characterised as an immuno-inflammatory condition with potentially blinding ocular sequelae. Therefore, we have investigated the ocular surface immune cell profile and correlated it with secreted tear molecular factors and clinical ocular sequelae in SJS patients., Methods: 21 patients (42 eyes) with chronic ocular SJS and 16 healthy controls (20 eyes) were included in the study. Severity, types of keratopathies and ocular surface (OS) manifestations were determined. OS wash samples from study subjects were used to determine the status of 13 immune cell subsets using flow cytometry. Levels of 42 secreted immuno-inflammatory factors were measured by flow cytometry-based multiplex ELISA in tear samples., Results: Neutrophils (Total, activated), neutrophils/NK cells ratio, neutrophils/T cells ratio were significantly (p < 0.05) elevated in SJS, while, proportions of T cells and NKT cells were significantly lower in SJS patients. Positive association between neutrophils and chronic ocular surface complication score (COCS) was observed, whereas, a negative association was noted between NK cells and COCS. Tear fluid levels of IL-6, IL-8, IL-18, IFNα/β/γ, TNFα, LIF, IL-8, HGF, sTNFR-I, NGAL, Granzyme, Perforins, MMP9/TIMP1 ratio were significantly higher in SJS. Loss of Limbal niche correlated significantly with immune profile and clinical sequelae. Increased neutrophils, decreased NK cells and specific set of altered secreted immuno-inflammatory mediators including bFGF, and IL-8 were observed in SJS patients with different types of keratopathies compared to those without keratopathy., Conclusion: Distinct ocular surface immune profile variations were observed to correlate with clinical stages of chronic ocular SJS. Our findings uncover novel mechanisms and potential for targeted therapy in chronic ocular SJS patients., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Vasoplegia after cardiac surgery is associated with adverse outcomes. However, the clinical effects of vasoplegia and the significance of its duration after continuous-flow left ventricular assist device (CF-LVAD) implantation are less known., Objectives: This study aimed to identify predictors of and outcomes from transient vs prolonged vasoplegia after CF-LVAD implantation., Methods: The study was a retrospective review of consecutive patients who underwent CF-LVAD implantation between January 1, 2005, and December 31, 2017. Vasoplegia was defined as the presence of all of the following: mean arterial pressure ≤65 mm Hg, vasopressor (epinephrine, norepinephrine, vasopressin, or dopamine) use for >6 hours within the first 24 hours postoperatively, cardiac index ≥2.2 L/min/m 2 and systemic vascular resistance <800 dyne/s/cm 5 , and vasodilatory shock not attributable to other causes. Prolonged vasoplegia was defined as that lasting 12 to 24 hours; transient vasoplegia was that lasting 6 to <12 hours. Patient characteristics, outcomes, and risk factors were analyzed., Results: Of the 600 patients who underwent CF-LVAD implantation during the study period, 182 (30.3%) developed vasoplegia. Mean patient age was similar between the vasoplegia and no-vasoplegia groups. Prolonged vasoplegia (n = 78; 13.0%), compared with transient vasoplegia (n = 104; 17.3%), was associated with greater 30-day mortality (16.7% vs 5.8%; P  = 0.02). Risk factors for prolonged vasoplegia included preoperative dialysis and elevated body mass index., Conclusions: Compared with vasoplegia overall, prolonged vasoplegia was associated with worse survival after CF-LVAD implantation. Treatment to avoid or minimize progression to prolonged vasoplegia may be warranted., Competing Interests: Dr Nair is a consultant for Abbott; and has received speaking fees from Abbott and Impulse Dynamics. Dr Frazier has received travel support from BiVACOR Inc. Dr Loor has received institutional grant support to Baylor College of Medicine from Abiomed, Transmedics, Abbott, and Maquet; and is a consultant for Abiomed & TransMedics, and is a scientific advisor for TransMedics. Dr Shafii has received institutional grant support to Baylor College of Medicine from Abbott and Evaheart, Inc. Dr Chatterjee has served on advisory boards for Edwards Lifesciences, La Jolla Pharmaceutical Company, Baxter Pharmaceuticals, and Eagle Pharmaceuticals, Inc. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Competing Interests: The authors have no conflicts of interest to declare.

Leber's hereditary optic neuropathy (LHON) is a mitochondrial hereditary disease in which visual loss affects complex 1 activity of the electron transport chain of mitochondria. It first manifests as painless dulling or blurry in one or even both eyes, and as it develops, sharpness and color perception are lost. In addition to primary mitochondrial DNA (mtDNA) mutations, there are also other environmental and epigenetic factors involved in the pathogenesis of LHON. One of the most common locations for deadly pathogenic mutations in humans is the human complex I accessory NDUFS4 subunit gene. The iron-sulfur clusters of the electron input domain were distorted in the absence of NDUFS4, which reduced complex I function and elevated the production of reactive oxygen species. Therefore, here, we studied the epigenetic alterations of NDUFS4 by focusing on histone activation and repressive markers. We isolated peripheral blood mononuclear cells (PBMCs) from LHON patients and healthy individuals and examined epigenetic modifications in ND4 mutant cells and control cells. Chromatin immunoprecipitation-qRT PCR (ChIP-qRT PCR) assays were performed to investigate the modifications of histones. In comparison to their controls, both LHON patients and ND4 mutant cells exhibited a significant enrichment in activation and repressive markers. This finding indicates that these modifications might mitigate the impact of LHON mutations on complex 1 and aid in elucidating the mechanism underlying the progression of LHON disease., (© 2024. The Author(s).)

Patients with left ventricular assist devices (LVADs) receive anticoagulation to decrease the risk of thrombosis. Various circumstances require discontinuing anticoagulation in LVAD patients, but the risks entailed are not well defined. In a retrospective review of LVAD implantation procedures, we examined the effect of time off anticoagulation on thrombosis and mortality rates after implantation. An international normalized ratio ≤ 1.5 was used to screen for patients taken off anticoagulation. Patients were divided into three groups by the cumulative number of days off anticoagulation: no discontinuation, short-term discontinuation (< 30 days), and long-term discontinuation (≥ 30 days). Rates of ischemic stroke, pump thrombosis, and mortality were compared among groups. Of 245 patients who underwent LVAD implantation during the study, 70 (28.6%) were off anticoagulation during follow-up: 37 (15.1%) had short-term discontinuation (median, 11 days), and 33 (13.5%) had long-term discontinuation (median, 124 days). Patients with long-term discontinuation had a higher rate of ischemic stroke (adjusted hazard ratio 8.5, p = 0.001) and death (adjusted hazard ratio 3.9, p = 0.001). The three groups did not differ in pump thrombosis rate. We conclude that after LVAD implantation, discontinuing anticoagulation for ≥ 30 days is independently associated with an increased risk of ischemic stroke and death., (© 2022. The Japanese Society for Artificial Organs.)

Lack of retinoblastoma (Rb) protein causes aggressive intraocular retinal tumors in children. Recently, Rb tumors have been shown to have a distinctly altered metabolic phenotype, such as reduced expression of glycolytic pathway proteins alongside altered pyruvate and fatty acid levels. In this study, we demonstrate that loss of hexokinase 1(HK1) in tumor cells rewires their metabolism allowing enhanced oxidative phosphorylation-dependent energy production. We show that rescuing HK1 or retinoblastoma protein 1 (RB1) in these Rb cells reduced cancer hallmarks such as proliferation, invasion, and spheroid formation and increased their sensitivity to chemotherapy drugs. Induction of HK1 was accompanied by a metabolic shift of the cells to glycolysis and a reduction in mitochondrial mass. Cytoplasmic HK1 bound Liver Kinase B1 and phosphorylated AMP-activated kinase-α (AMPKα Thr172 ), thereby reducing mitochondria-dependent energy production. We validated these findings in tumor samples from Rb patients compared to age-matched healthy retinae. HK1 or RB1 expression in Rb-/- cells led to a reduction in their respiratory capacity and glycolytic proton flux. HK1 overexpression reduced tumor burden in an intraocular tumor xenograft model. AMPKα activation by AICAR also enhanced the tumoricidal effects of the chemotherapeutic drug topotecan in vivo. Therefore, enhancing HK1 or AMPKα activity can reprogram cancer metabolism and sensitize Rb tumors to lower doses of existing treatments, a potential therapeutic modality for Rb., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: To measure the levels of inflammatory factors in tear fluid of pre-term infants with and without retinopathy of prematurity (ROP)., Methods: The cross-sectional pilot study included 29 pre-term infants undergoing routine ROP screening. Pre-term infants were grouped as those without ROP (no ROP; n = 14) and with ROP (ROP; n = 15). Sterile Schirmer's strips were used to collect the tear fluid from pre-term infants. Inflammatory factors such as interleukin (IL)-6, IL-8, MCP1 (Monocyte Chemoattractant Protein 1; CCL2), RANTES (Regulated on Activation, Normal T Cell Expressed and Secreted; CCL5), and soluble L-selectin (sL-selectin) were measured by cytometric bead array using a flow cytometer., Results: Birth weight (BW) and gestation age (GA) were significantly (P < 0.05) lower in pre-term infants with ROP compared with those without ROP. Higher levels of RANTES (P < 0.05) and IL-8 (P = 0.09) were observed in the tear fluid of pre-term infants with ROP compared with those without ROP. Lower levels of tear fluid IL-6 (P = 0.14) and sL-selectin (P = 0.18) were measured in pre-term infants with ROP compared with those without ROP. IL-8 and RANTES were significantly (P < 0.05) higher in the tear fluid of pre-term infants with stage 3 ROP compared with those without ROP. Tear fluid RANTES level was observed to be inversely associated with GA and BW of pre-term infants with ROP and not in those without ROP. Furthermore, the area under the curve and odds ratio analysis demonstrated the relevance of RANTES/BW (AUC = 0.798; OR-7.2) and RANTES/MCP1 (AUC = 0.824; OR-6.8) ratios in ROP., Conclusions: Distinct changes were observed in the levels of tear inflammatory factors in ROP infants. The status of RANTES in ROP suggests its possible role in pathobiology and warrants further mechanistic studies to harness it in ROP screening and management., Competing Interests: None

Parkinson's disease (PD) is caused due to degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) which leads to the depletion of dopamine in the body. The lack of dopamine is mainly due to aggregation of misfolded α-synuclein which causes motor impairment in PD. Dopamine is also required for normal retinal function and the light-dark vision cycle. Misfolded α-synuclein present in inner retinal layers causes vision-associated problems in PD patients. Hence, individuals with PD also experience structural and functional changes in the retina. Mutation in LRRK2, PARK2, PARK7, PINK1, or SNCA genes and mitochondria dysfunction also play a role in the pathophysiology of PD. In this review, we discussed the different etiologies which lead to PD and future prospects of employing non-invasive techniques and retinal changes to diagnose the onset of PD earlier., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Deregulation of vascular endothelial growth factor (VEGF) levels leads to retinopathy of prematurity (ROP). Vitamin D (VIT-D) is known to regulate VEGF in an oxygen dependent manner. The purpose of this study was to correlate tear levels of VEGF and VIT-D with different ROP stages in preterm infants. In this prospective cross-sectional study, we enrolled 104 pre-term infants. They were grouped into: Group-1 (Classical ROP) and Group-2 (Aggressive ROP), which were further subdivided into Group-1A (progressing), Group-1B (regressing), Group-2A (pre-treatment), and Group-2B (post-treatment). Tear VEGF and VIT-D levels and their association with different ROP stages were assessed. Stage 1 and stage 2 had higher whereas stage 3 had lower VEGF levels in Group-1B compared to Group-1A. Stage 1 and stage 3 showed higher levels of VIT-D with no difference in stage 2 in Group-1B compared to Group-1A., Group-2B showed higher VEGF and lower VIT-D levels compared to Group-2A. Presence of a positive correlation at an early stage (stage 1) of ROP and a negative correlation at a more advanced stage (stage 3) of ROP with VIT-D and VEGF implies stage-specific distinct signaling crosstalk. These findings suggest that VIT-D supplementation may have the potential to modify the course and outcome of ROP., (© 2023. The Author(s).)

Background: Postoperative respiratory failure is a major complication that affects up to 10% of patients who undergo cardiac surgery and has a high in-hospital mortality rate. Few studies have investigated whether patients who require tracheostomy for postoperative respiratory failure after continuous-flow left ventricular assist device (CF-LVAD) implantation have worse survival outcomes than patients who do not., Objective: To identify risk factors for respiratory failure necessitating tracheostomy in CF-LVAD recipients and to compare survival outcomes between those who did and did not require tracheostomy., Methods: Consecutive patients who underwent primary CF-LVAD placement at a single institution between August 1, 2002, and December 31, 2019, were retrospectively reviewed. Propensity score matching accounted for baseline differences between the tracheostomy and nontracheostomy groups. Multivariate logistic regression was used to identify tracheostomy risk factors and 90-day survival; Kaplan-Meier analysis was used to assess midterm survival., Results: During the study period, 664 patients received a CF-LVAD; 106 (16.0%) underwent tracheostomy for respiratory failure. Propensity score matching produced 103 matched tracheostomy-nontracheostomy pairs. Patients who underwent tracheostomy were older (mean [SD] age, 57.9 [12.3] vs 54.6 [13.9] years; P = .02) and more likely to need preoperative mechanical circulatory support (61.3% vs 47.8%; P = .01) and preoperative intubation (27.4% vs 8.8%; P < .001); serum creatinine was higher in the tracheostomy group (mean [SD], 1.7 [1.0] vs 1.4 [0.6] mg/dL; P < .001), correlating with tracheostomy need (odds ratio, 1.76; 95% CI, 1.21-2.56; P = .003). Both before and after propensity matching, 30-day, 60-day, 90-day, and 1-year survival were worse in patients who underwent tracheostomy. Median follow-up was 0.8 years (range, 0.0-11.2 years). Three-year Kaplan-Meier survival was significantly worse for the tracheostomy group before (22.0% vs 61.0%; P < .001) and after (22.4% vs 48.3%; P < .001) matching., Conclusion: Given the substantially increased probability of death in patients who develop respiratory failure and need tracheostomy, those at high risk for respiratory failure should be carefully considered for CF-LVAD implantation. Comprehensive management to decrease respiratory failure before and after surgery is critical., (© 2023 by the Texas Heart® Institute, Houston.)

Diabetic retinopathy (DR) is a leading cause of blindness in working-age adults and remains an important public health issue worldwide. Here we demonstrate that the expression of stimulator of interferon genes (STING) is increased in patients with DR and animal models of diabetic eye disease. STING has been previously shown to regulate cell senescence and inflammation, key contributors to the development and progression of DR. To investigate the mechanism whereby STING contributes to the pathogenesis of DR, diabetes was induced in STING-KO mice and STINGGT (loss-of-function mutation) mice, and molecular alterations and pathological changes in the retina were characterized. We report that retinal endothelial cell senescence, inflammation, and capillary degeneration were all inhibited in STING-KO diabetic mice; these observations were independently corroborated in STINGGT mice. These protective effects resulted from the reduction in TBK1, IRF3, and NF-κB phosphorylation in the absence of STING. Collectively, our results suggest that targeting STING may be an effective therapy for the early prevention and treatment of DR.

Heart failure (HF) is common in adult congenital heart disease (ACHD) patients; however, use of continuous-flow ventricular assist devices (CF-VADs) remains rare. We reviewed outcomes of patients with congenital heart disease greater than or equal to 18 years of age at the time of CF-VAD implant at the affiliated pediatric and adult institutions between 2006 and 2020. In total, 18 ACHD patients (15 with great anatomical complexity) received 21 CF-VADs. Six patients (median age 34 years) received seven percutaneous CF-VADs with a median duration of support of 20 days (3-44 days) with all patients survived to hospital discharge and two patients were bridged to durable CF-VADs. Fourteen patients (median age 38 years) received durable CF-VADs. Thirteen patients (93%) survived to hospital discharge and the median duration of support was 25.8 months (6.4-52.1 months). Estimated survival on durable CF-VAD at 1, 3, and 5 years was 84%, 72%, and 36%, respectively. Three patients were successfully bridged to transplantation. Device-related complications include cerebrovascular accident (n = 5), driveline infection (n = 3), device infection requiring chronic antibiotic therapy (n = 4), gastrointestinal bleeding (n = 6), and presumed pump thrombosis (n = 5). These results show percutaneous and durable CF-VADs can support ACHD patients with advanced HF., Competing Interests: Disclosure: C.R.B. reports financial relationship with Medtronic Inc. H.T. reports relationship with Abbott. O.H.F. reports financial relationships with Syncardia, Medtronic Inc., and Abbott. A.Q. reports financial relationships with Medtronic and Abiomed. I.A. serves as a consultant and proctor for Berlin Heart, Inc., Medtronic Inc., Jarvik Inc., BiVACOR Inc., and Sony-Olympus Medical Solutions Inc. A.C. reports financial relationships with Medtronic Inc. and Abbott. The remaining authors have no conflicts of interest to report., (Copyright © ASAIO 2022.)

A stem cell is a particular group of cells that has the extraordinary potential to convert within the body into particular cell types. They are used to regenerate tissues and cells in the body that have been damaged or destroyed by the disease. Stem cells come in three different varieties: adult stem cells, embryonic stem cells and induced pluripotent stem cells (iPSCs). Embryonic stem cells have a high chance of immune rejection and also have ethical dilemmas and iPSCs have genetic instability. Adult stem cells are difficult to analyze and extract for research since they are frequently insufficient in native tissues. However, mesenchymal stem cells (MSC) one of the categories of adult stem cells are stromal cells with a variety of potentials that can differentiate into a wide range of cell types. MSCs can be transplanted into a variety of people without worrying about rejection because they have demonstrated the ability to prevent an adverse reaction from the immune system. These transplants have powerful anti-inflammatory and immunosuppressive effects and greatly enhance the body's inherent healing capacity. While MSCs do not offer treatment for illnesses, the idea behind them is to enable the body to recover sufficiently for a protracted reduction in symptoms. In many cases, this is sufficient to significantly enhance the patient's well-being. Inspite of several advantages some potential long-term concerns connected to MSC therapy are maldifferentiation, immunosuppression and cancerous tumor growth. In this review, we will compare the mesenchymal stem cells with other stem cells with respect to the source of origin, their properties and therapeutic applications, and discuss the MSC's disadvantages., (Copyright © 2023 Elsevier GmbH. All rights reserved.)

Purpose: To study ocular surface signs, symptoms, and tear film composition following prophylactic thermal pulsation therapy (TPT) prior to refractive surgery, and to compare these outcomes with those who underwent TPT after refractive surgery., Methods: Patients with mild-to-moderate evaporative dry eye disease (DED) and/or meibomian gland dysfunction (MGD) undergoing refractive surgery were included. Group 1 patients received TPT (LipiFlow) prior to laser-assisted in situ keratomileusis (LASIK; n = 32, 64 eyes), and Group 2 patients received TPT three months after LASIK (n = 27, 52 eyes). Ocular Surface Disease Index (OSDI) score, Schirmer's test (ST1, ST2), Tear Breakup Time (TBUT), meibography, and tear fluid were obtained preoperatively and at three months postoperatively in Groups 1 and 2. Additional postoperative evaluation was performed three months after TPT in Group 2. Tear soluble factor profile was measured by multiplex enzyme-linked immunosorbent assay (ELISA) using flow cytometry., Results: Postoperative OSDI score was significantly lower and TBUT was significantly higher when compared with matched preoperative values of Group 1 participants. On the other hand, the postoperative OSDI score was significantly higher and TBUT significantly lower when compared with matched preoperative values of Group 2 participants. TPT significantly reduced the postoperative elevation in OSDI and significantly reduced the postoperative reduction in TBUT in Group 2 participants. Tear Matrix metalloproteinase-9/ Tissue inhibitor matrix metalloproteinase 1 (MMP-9/TIMP1) ratio was significantly higher, postoperatively, when compared with matched preoperative levels in Group 2. However, MMP9/TIMP1 ratio remained unaltered in Group 1 participants., Conclusion: TPT prior to refractive surgery improved postsurgical ocular surface signs and symptoms and reduced tear inflammatory factors, thereby suggesting the plausibility of reduced post-refractive surgery DED in patients., Competing Interests: None

Dry eye disease (DED) is a multifactorial chronic ocular surface inflammatory condition. Disease severity has been directly related to the immuno-inflammatory status of the ocular surface. Any perturbation in the orchestrated functional harmony between the ocular surface structural cells and immune cells, both resident and trafficking ones, can adversely affect ocular surface health. The diversity and contribution of ocular surface immune cells in DED have been of interest for over a couple of decades. As is true with any mucosal tissue, the ocular surface harbors a variety of immune cells of the innate-adaptive continuum and some of which are altered in DED. The current review curates and organizes the knowledge related to the ocular surface immune cell diversity in DED. Ten different major immune cell types and 21 immune cell subsets have been studied in the context of DED in human subjects and in animal models. The most pertinent observations are increased ocular surface proportions of neutrophils, dendritic cells, macrophages, and T cell subsets (CD4+; CD8+; Th17) along with a decrease in T regulatory cells. Some of these cells have demonstrated disease-causal association with ocular surface health parameters such as OSDI score, Schirmer's test-1, tear break-up time, and corneal staining. The review also summarizes various interventional strategies studied to modulate specific immune cell subsets and reduce DED severity. Further advancements would enable the use of ocular surface immune cell diversity, in patient stratification, i.e. DED-immunotypes, disease monitoring, and selective targeting to resolve the morbidity related to DED., Competing Interests: None

With changes in lifestyle, such as the increasing use of digital screens and rising demand for refractive surgery, dry eye disease has become increasingly prevalent in recent times. While we are equipped with a number of diagnostic modalities and a myriad of treatment forms, ranging from topical medication to procedural therapies, the condition remains an enigma in terms of varied patient satisfaction. An understanding of the molecular basis of a disease may open up new avenues in the customization of its treatment. We attempt to simplify this in the form of a stepwise protocol to incorporate biomarker assays in dry eye management., Competing Interests: None

A multi-MHz laser absorption sensor at 777.2 nm (12,863 c m -1 ) is developed for simultaneous sensing of (1)  O ( 5 S 0 ) number density, (2) electron number density, and (3) translational temperature at conditions relevant to high-speed entry conditions and molecular dissociation. This sensor leverages a bias tee circuit with a distributed feedback diode laser and an optimization of the laser current modulation waveform to enable temporal resolution of sub-microsecond kinetics at electronvolt temperatures. In shock-heated O 2 , the precision of the temperature measurement is tested at 5 MHz and is found to be within ±5 % from 6000 to 12,000 K at pressures from 0.1 to 1 atm. The present sensor is also demonstrated in a CO:Ar mixture, in parallel with a diagnostic for CO rovibrational temperature, providing an additional validation across 7500-9700 K during molecular dissociation. A demonstration of the electron number density measurement near 11,000 K is performed and compared to a simplified model of ionization. Finally, as an illustration of the utility of this high-speed diagnostic, the measurement of the heavy particle excitation rate of O ( 5 S 0 ) is extended beyond the temperatures available in the literature and is found to be well represented by k ( 3 P → 5 S 0 )=2.7×10 -14 T 0.5 exp ⁡(-1.428×10 4 / T ) c m 3 ⋅ s -1 from 5400 to 12,200 K.

In dry age-related macular degeneration (AMD), LCN2 (lipocalin 2) is upregulated. Whereas LCN2 has been implicated in AMD pathogenesis, the mechanism remains unknown. Here, we report that in retinal pigmented epithelial (RPE) cells, LCN2 regulates macroautophagy/autophagy, in addition to maintaining iron homeostasis. LCN2 binds to ATG4B to form an LCN2-ATG4B-LC3-II complex, thereby regulating ATG4B activity and LC3-II lipidation. Thus, increased LCN2 reduced autophagy flux. Moreover, RPE cells from cryba1 KO, as well as sting1 KO and Sting1 Gt mutant mice (models with abnormal iron chelation), showed decreased autophagy flux and increased LCN2, indicative of CGAS- and STING1-mediated inflammasome activation. Live cell imaging of RPE cells with elevated LCN2 also showed a correlation between inflammasome activation and increased fluorescence intensity of the Liperfluo dye, indicative of oxidative stress-induced ferroptosis. Interestingly, both in human AMD patients and in mouse models with a dry AMD-like phenotype ( cryba1 cKO and KO), the LCN2 homodimer variant is increased significantly compared to the monomer. Sub-retinal injection of the LCN2 homodimer secreted by RPE cells into NOD-SCID mice leads to retinal degeneration. In addition, we generated an LCN2 monoclonal antibody that neutralizes both the monomer and homodimer variants and rescued autophagy and ferroptosis activities in cryba1 cKO mice. Furthermore, the antibody rescued retinal function in cryba1 cKO mice as assessed by electroretinography. Here, we identify a molecular pathway whereby increased LCN2 elicits pathophysiology in the RPE, cells known to drive dry AMD pathology, thus providing a possible therapeutic strategy for a disease with no current treatment options. Abbreviations: ACTB: actin, beta; Ad-GFP: adenovirus-green fluorescent protein; Ad-LCN2: adenovirus-lipocalin 2; Ad-LCN2-GFP: adenovirus-LCN2-green fluorescent protein; LCN2AKT2: AKT serine/threonine kinase 2; AMBRA1: autophagy and beclin 1 regulator 1; AMD: age-related macular degeneration; ARPE19: adult retinal pigment epithelial cell line-19; Asp278: aspartate 278; ATG4B: autophagy related 4B cysteine peptidase; ATG4C: autophagy related 4C cysteine peptidase; ATG7: autophagy related 7; ATG9B: autophagy related 9B; BLOC-1: biogenesis of lysosomal organelles complex 1; BLOC1S1: biogenesis of lysosomal organelles complex 1 subunit 1; C57BL/6J: C57 black 6J; CGAS: cyclic GMP-AMP synthase; ChQ: chloroquine; cKO: conditional knockout; Cys74: cysteine 74; Dab2: DAB adaptor protein 2; Def: deferoxamine; DHE: dihydroethidium; DMSO: dimethyl sulfoxide; ERG: electroretinography; FAC: ferric ammonium citrate; Fe 2+ : ferrous; FTH1: ferritin heavy chain 1; GPX: glutathione peroxidase; GST: glutathione S-transferase; H 2 O 2 : hydrogen peroxide; His280: histidine 280; IFNL/IFNλ: interferon lambda; IL1B/IL-1β: interleukin 1 beta; IS: Inner segment; ITGB1/integrin β1: integrin subunit beta 1; KO: knockout; LC3-GST: microtubule associated protein 1 light chain 3-GST; C-terminal fusion; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; LCN2: lipocalin 2; mAb: monoclonal antibody; MDA: malondialdehyde; MMP9: matrix metallopeptidase 9; NLRP3: NLR family pyrin domain containing 3; NOD-SCID: nonobese diabetic-severe combined immunodeficiency; OS: outer segment; PBS: phosphate-buffered saline; PMEL/PMEL17: premelanosome protein; RFP: red fluorescent protein; rLCN2: recombinant LCN2; ROS: reactive oxygen species; RPE SM: retinal pigmented epithelium spent medium; RPE: retinal pigment epithelium; RSL3: RAS-selective lethal; scRNAseq: single-cell ribonucleic acid sequencing; SD-OCT: spectral domain optical coherence tomography; shRNA: small hairpin ribonucleic acid; SM: spent medium; SOD1: superoxide dismutase 1; SQSTM1/p62: sequestosome 1; STAT1: signal transducer and activator of transcription 1; STING1: stimulator of interferon response cGAMP interactor 1; TYR: tyrosinase; VCL: vinculin; WT: wild type.

Introduction: Colchicine acts upstream in the cytokines cascade by inhibiting the nod-like receptor protein 3 (NLRP3) inflammasome while interleukin 6 (IL-6) receptor antagonists, such as tocilizumab, block the end result of the cytokines cascade. Hence, adding colchicine to tocilizumab with the aim of blocking the early and end products of the cytokines cascade, might reduce the risk of developing cytokine storm., Methods and Analysis: We aim to conduct an open-label randomized controlled trial to evaluate the efficacy and safety of adding colchicine to tocilizumab among patients with severe COVID-19 pneumonia to reduce the rate of invasive mechanical ventilation and mortality. We will include patients with severe COVID-19 pneumonia who received tocilizumab according to our local guidelines. Enrolled patients will be then randomized in 1:1 to colchicine versus no colchicine. Patients will be followed up for 30 days. The primary outcome is the rate of invasive mechanical ventilation and will be determined using Cox proportional hazard model., Discussion: Given colchicine's ease of use, low cost, good safety profile, and having different anti-inflammatory mechanism of action than other IL-6 blockade, colchicine might serve as a potential anti-inflammatory agent among patients with severe COVID-19 pneumonia. This study will provide valuable insights on the use of colchicine in severe COVID-19 when added to IL-6 antagonists., Ethics and Dissemination: The Medical Research Center and Institutional Review Board at Hamad Medical Corporation in Qatar approved the study protocol (MRC-01-21-299). Results of the analysis will be submitted for publication in a peer-reviewed journal., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objectives: Non-small cell lung cancer (NSCLC) accounts for 75-85% of all lung cancer diagnoses. This meta-analysis sought to estimate the overall survival (OS) of NSCLC based on randomized control trials which had compared docetaxel with kinase inhibitors, antineoplastic agents, and monoclonal antibodies as second-line chemotherapy for advanced NSCLC., Methods: We selected 18 randomized control trials which used docetaxel as the standard treatment arm, while kinase inhibitors, antineoplastic agents, and monoclonal antibodies constituted the experimental arm. The methodological quality of the trial was classified according to the Modified Jadad score. Several steps were taken to reduce publication bias. A forest plot was used to graphically summarize the meta-analysis., Results: The Hedge's g value of antineoplastic agents was 0.11 (95% CI: -0.03-0.26), while for kinase inhibitors was 0.04 (95% CI: -0.10-0.17) and monoclonal antibodies was 0.05 (95% CI: -0.02-0.13). Forest plot showed a clear though only slightly higher overall survival using docetaxel compared to those of the antineoplastic agents, kinase inhibitors, and monoclonal antibodies, due to the existence of moderate heterogeneity and lower impact., Conclusions: Overall, the patients in these studies who were in the standard (docetaxel) treatment arm had slightly better OS than those in the intervention treatment arm. As per the results, docetaxel was more effective in the second-line treatment of advanced NSCLC than antineoplastic agents, monoclonal antibodies, and kinase inhibitors. We infer that docetaxel-based second-line therapy for patients with advanced NSCLC is supported by our meta-analysis., (The OMJ is Published Bimonthly and Copyrighted 2022 by the OMSB.)

This article provides a contemporary review and a new perspective on the role of neprilysin inhibition in heart failure (HF) in the context of recent clinical trials and addresses potential mechanisms and unanswered questions in certain HF patient populations. Neprilysin is an endopeptidase that cleaves a variety of peptides such as natriuretic peptides, bradykinin, adrenomedullin, substance P, angiotensin I and II, and endothelin. It has a broad role in cardiovascular, renal, pulmonary, gastrointestinal, endocrine, and neurologic functions. The combined angiotensin receptor and neprilysin inhibitor (ARNi) has been developed with an intent to increase vasodilatory natriuretic peptides and prevent counterregulatory activation of the angiotensin system. ARNi therapy is very effective in reducing the risks of death and hospitalization for HF in patients with HF and New York Heart Association functional class II to III symptoms, but studies failed to show any benefits with ARNi when compared with angiotensin-converting enzyme inhibitors or angiotensin receptor blocker in patients with advanced HF with reduced ejection fraction or in patients following myocardial infarction with left ventricular dysfunction but without HF. These raise the questions about whether the enzymatic breakdown of natriuretic peptides may not be a very effective solution in advanced HF patients when there is downstream blunting of the response to natriuretic peptides or among post-myocardial infarction patients in the absence of HF when there may not be a need for increased natriuretic peptide availability. Furthermore, there is a need for additional studies to determine the long-term effects of ARNi on albuminuria, obesity, glycemic control and lipid profile, blood pressure, and cognitive function in patients with HF., Competing Interests: Dr Bozkurt has served as a consultant for Bayer and scPharmaceuticals; is on the Clinical Events Committee for the Guide-HF Trial by Abbott Pharmaceuticals;and is on the Data Safety Monitoring Board for Anthem Trial by Liva Nova Pharmaceuticals. Dr Misra has served as a site primary investigator for PIONEER HF, PARAGON-HF, and PARAGLIDE-HF studies. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Aim: The aim of this study was to evaluate outcome of management of odontogenic keratocyst (OKC) using gas combination cryotherapy (GCC). GCC is a treatment modality where cyst enucleation is followed by applying an adjuvant agent, a spray containing propane, butane and isobutene gas onto the bony bed., Materials and Methods: This was a prospective interventional study which included patients with radiographic and histopathologic evidence of OKC. All patients underwent enucleation of the cysts followed by spraying of the bony cavity with "ENDOFROST ™"(commercially available agent for GCC). Patients were periodically reviewed and the presence of wound dehiscence, infection and neurosensory deficit was noted. After 15 months, a CBCT was taken to assess the amount of bone formation, the presence of any pathologic fracture or recurrence. Comparison of the preoperative and the postoperative size of the defect was also assessed., Results: A total of 10 patients were included in the study of which only 2 presented with neurosensory deficit in the post-op period. One patient of the two patients recovered completely within 12 months, while the other recovered within 15 months. There was no evidence of any patient developing infection, wound dehiscence, recurrence or pathologic fracture., Conclusion: The results of the study show that enucleation followed by GCC is a safe, effective and low-cost therapy for the management of OKC., Competing Interests: Conflict of interestThe authors declare that they have no conflict of interest., (© The Association of Oral and Maxillofacial Surgeons of India 2021.)

Background: Optic neuropathy has become a new typical syndromic multi-system disease that leads to optic atrophy. This review discusses potential treatments and advances of Leber's hereditary optic neuropathy (LHON), a sporadic genetic disorder. LHON is caused due to slight mutations in mitochondria leading to mitochondrial dysfunction, causing vision loss. There are no current significant treatments that have been proven to work for LHON., Methods: However, extensive review was carried out on capable studies that have shown potential treatment sensory systems and are being evaluated currently. Some of these studies are in clinical trials, whereas other ones are still being planned. Here, we focus more on treatment based on mesenchymal stem cells-mediated mitochondrial transfer via various techniques. We discuss different mitochondrial transfer modes and possible ways to understand the mitochondria transfer technique's phenotypic characteristics., Conclusion: It is clearly understood that transfer of healthy mitochondria from MSC to target cell would regulate the range of reactive oxygen species and ATP'S, which are majorly responsible for mutation upon irregulating. Therefore, mitochondrial transfer is suggested and discussed in this review with various aspects. The graphical abstract represents different means of mitochondrial transport like (a) Tunnelling nanotubules, (b) Extracellular vesicles, (c) Cell fusion and (d) Gap junctions. In (a) Tunnelling nanotubules, the signalling pathways TNF- α/TNF αip2 and NFkB/TNF αep2 are responsible for forming tunnels. Also, Miro protein acts as cargo for the transport of mitochondria with myosin's help in the presence of RhoGTPases [35]. In (b) Extracellular vesicles, the RhoA ARF6 contributes to Actin/Cytoskeletal rearrangement leading to the shedding of microvesicles. Coming to (c) Cell fusion when there is a high amount of ATP, the cells tend to fuse when in close proximity leading to the transfer of mitochondria via EFF-1/HAP2 [48]. In (d) Gap Junctions, Connexin43 is responsible for the intracellular channel in the presence of more ATP [86]., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Purpose of Review: In this review, we discuss the mechanisms of action of sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and the purported protective effects for mitigating heart failure (HF)-related outcomes., Recent Findings: Major randomized clinical trials have demonstrated the cardiovascular safety and efficacy of SGLT-2i among patients without known HF and those with established HF with reduced ejection fraction or preserved ejection fraction (HFrEF and HFpEF respectively). Recent HF guidelines have incorporated SGLT-2i in HF treatment algorithms. SGLT-2i have emerged as a novel treatment for both prevention of HF and reduction of cardiovascular morbidity and mortality among patients with existing HFrEF or HFpEF., (© 2022. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Purpose: Contact lens-induced discomfort (CLD) remains a primary factor in discontinuation or prevention of contact lens wear. Thus, we investigated the role of ocular surface immune cells in subjects with CLD., Methods: Habitual contact lens (CL) wearers with CLD (n = 19; 38 eyes) and without CLD (n = 21; 42 eyes) as determined by the Contact Lens Dry Eye Questionnaire-8 was included in a trial. Enrolled subjects used either of the two types of CL (designated as CL-A or CL-D). Ocular surface cells from the bulbar conjunctiva were obtained by impression cytology. The collected cells were phenotyped using fluorochrome-conjugated antibodies specific for leukocytes (CD45+), neutrophils (CD66b+,High,Low), macrophages (CD163+), T cells (CD3+CD4+, CD3+CD8+), natural killer (NK) cells (CD56+, High, Low), natural killer T (NKT) cells (CD3+CD56+), and gamma delta T (γδT) cells (CD3+γδTCR+) by flow cytometry. Further, corneal dendritic cell density (cDCD) was also determined using in vivo confocal microscopy., Results: Significantly higher proportions of CD45+ cells were observed in subjects with CLD compared to those without CLD. The percentages of CD66bTotal,Low, CD163+, pan T cells, CD4+T cells, CD8+T cells, CD56Total,High,Low (NK) cells, and NKT cells, as well as the CD4/CD8 ratio, were significantly higher in CLD subjects. The proportion of T cells (CD4, CD8, CD4/CD8 ratio, NKT cells) and macrophages exhibited a direct association with discomfort score. The percentages of CD45+, CD66bTotal,Low, CD163+, CD3+, CD56Total,High,Low, and NKT cells and cDCD were significantly higher in CLD subjects wearing CL-D. The percentages of CD66bHigh, CD4+T cells, CD8+T cells, NKT cells, and CD4/CD8 ratio were significantly higher in CLD subjects wearing CL-A., Conclusions: Increased proportions of ocular surface immune cells are observed in CLD, and the lens type could impact the immune cells associated with CLD., Translational Relevance: The association between the proportion of altered ocular surface immune cell subsets and contact lens-induced discomfort underpins the importance of considering immune-related aspects during contact lens development and in the clinical management of ocular surface pain.

Retinoblastoma (Rb) is a pediatric intraocular malignancy that is proposed to originate from maturing cone cell precursors in the developing retina. The molecular mechanisms underlying the biological and clinical behaviors are important to understand in order to improve the management of advanced-stage tumors. While the genetic causes of Rb are known, an integrated understanding of the gene expression and metabolic processes in tumors of human eyes is deficient. By integrating transcriptomic profiling from tumor tissues and metabolomics from tumorous eye vitreous humor samples (with healthy, age-matched pediatric retinae and vitreous samples as controls), we uncover unique functional associations between genes and metabolites. We found distinct gene expression patterns between clinically advanced and non-advanced Rb. Global metabolomic analysis of the vitreous humor of the same Rb eyes revealed distinctly altered metabolites, indicating how tumor metabolism has diverged from healthy pediatric retina. Several key enzymes that are related to cellular energy production, such as hexokinase 1, were found to be reduced in a manner corresponding to altered metabolites; notably, a reduction in pyruvate levels. Similarly, E2F2 was the most significantly elevated E2F family member in our cohort that is part of the cell cycle regulatory circuit. Ectopic expression of the wild-type RB1 gene in the Rb-null Y79 and WERI-Rb1 cells rescued hexokinase 1 expression, while E2F2 levels were repressed. In an additional set of Rb tumor samples and pediatric healthy controls, we further validated differences in the expression of HK1 and E2F2. Through an integrated omics analysis of the transcriptomics and metabolomics of Rb, we uncovered a significantly altered tumor-specific metabolic circuit that reduces its dependence on glycolytic pathways and is governed by Rb1 and HK1.

Prolonged daily face mask wearing over several months might affect health of the ocular surface and is reported to be associated with complaints of discomfort and dry-eye-like symptoms. We studied the ocular surface clinical parameters, tear soluble factors and immune cell proportions in ophthalmologists practicing within similar environmental conditions ( n = 17) at two time points: pre-face-mask period (Pre-FM; end of 2019) and post-face-mask-wearing period (Post-FM; during 2020 COVID-19 pandemic), with continuous (~8 h/day) mask wear. A significant increase in ocular surface disease index (OSDI) scores without changes in tear breakup time (TBUT), Schirmer's test 1 (ST1) and objective scatter index (OSI) was observed Post-FM. Tear soluble factors (increased-IL-1β, IL-33, IFNβ, NGF, BDNF, LIF and TSLP; decreased-IL-12, IL-13, HGF and VEGF-A) and mucins (MUC5AC) were significantly altered Post-FM. Ex vivo, human donor and corneoscleral explant cultures under elevated CO 2 stress revealed that the molecular profile, particularly mucin expression, was similar to the Post-FM tear molecular profile, suggesting hypercapnia is a potential contributor to ocular surface discomfort. Among the immune cell subsets determined from ocular surface wash samples, significantly higher proportions of leukocytes and natural killer T cells were observed in Post-FM compared to Pre-FM. Therefore, it is important to note that the clinical parameters, tear film quality, tear molecular factors and immune cells profile observed in prolonged mask-wear-associated ocular surface discomfort were distinct from dry eye disease or other common ocular surface conditions. These observations are important for differential diagnosis as well as selection of appropriate ocular surface treatment in such subjects.

Various ocular surface conditions such as dry eye disease can present with severe discomfort and pain. However, it is clinically challenging to establish etiology and prescribe correct treatment in patients who have a lot of discordance between symptoms and signs. To understand the basis of such discordance, we stratified subjects with ocular surface pain based on concordance between the severity of signs and symptoms and evaluated corneal structural features and tear molecular factors. All subjects underwent slit lamp examination, dry eye evaluation, and ocular surface disease index (OSDI) scoring. Subjects were stratified into group 1—without symptoms or clinical signs; group 2—without symptoms but with signs; group 3—with similar severity of symptoms and signs; and group 4—with symptom severity greater than that of the signs. Laser scanning in vivo confocal microscopy (IVCM) and tear fluid analysis for soluble factors by multiplex ELISA was performed for all subjects. Patients with a higher grade of symptoms and signs showed increased corneal dendritic cell (cDC) density (p < 0.05) which was more pronounced in subjects with discordance between the symptoms and signs (group 4). A significantly higher proportion of microneuroma-like structures and cDC were observed in group 4. IL-17A levels were significantly elevated in the tears of subjects with more discomfort. Our results demonstrate that corneal IVCM and the measurement of tear film factors can help clinicians improve diagnosis and treatment choice. Stratifying patients with ocular surface discomfort on the basis of discordance between symptoms and clinical signs may help identify patients who need additional adjunctive targeted therapy to resolve their condition.

Background Stenotrophomonas maltophilia  is a rapidly emerging nosocomial pathogen with intrinsic or acquired resistance mechanisms to several antibiotic classes. It can cause life-threatening opportunistic pneumonia, particularly among hospitalized patients. Incidence of infections by  S. maltophilia  has been reported as 0.07-0.4% of hospital discharges, but its mortality is 20 -60%. This is the first study from Qatar indexing the clinical and epidemiological characteristics and antibiotic susceptibility of  S. maltophilia. Materials and methods This retrospective descriptive epidemiological study was conducted in 6 tertiary care hospitals under Hamad Medical Corporation in Doha, Qatar, analyzing inpatient respiratory isolates of  S. maltophilia  during 2016-17. Out-patients, children below 14 years, and non-respiratory samples except blood cultures in patients with pneumonia were excluded. Clinical records were reviewed to identify possible risk factors. Infection and colonization were identified using the Centers for Disease Control and Prevention (CDC) algorithm for clinically defined pneumonia and statistically analyzed using the chi-square test and Pearson's correlation. Results S. maltophilia  was isolated from 2.07% (317/15312) of all respiratory samples received in the microbiology lab during our study period. Three hundred seventeen patients studied had a mean age of 60 ± 20 years, and 68% were men. Most of the isolates were from sputum (179), followed by tracheal aspirate (82) and bronchoscopy (42). Fourteen blood culture samples from patients diagnosed with pneumonia were also included. 67% were hospitalized for more than two weeks, 39.1% were on mechanical ventilators, and 88% had received a broad-spectrum antibiotic before the event. 29.1% were deemed to have an infection and 70.9% colonization. Incidence of infection in those with Charlson's Co-morbidity Index (CCI) ≥ 3 was 36.5% compared to 24.2% in those with CCI < 3 (Relative Risk (RR)=1.52; 95% CI: 1.04,2.18; p=0.01). Patients with recent chemotherapy, immunosuppressant, or steroid use had a significantly higher infection risk than those without (69.2% v/s 23.3% RR=2.96; 95% CI:2.2,3.9; p<0.005). The most common symptoms in patients with infection were fever (96%) and expectoration (61.9%). The most common radiological finding was lobar consolidation (71.6%). Mean CRP and procalcitonin were 106.5±15.5 mg/l and 12.3 ± 14 ng/ml. Overall mortality was 16.3%. Patients on mechanical ventilator with IBMP-10 score ≥ 2 had 22.8% mortality compared to 5.7% in those with score < 2 (RR=3.9;95%CI:0.9,16.6; p<0.015). As per The US Clinical and Laboratory Standards Institute (CSLI) breakpoint values, Trimethoprim-Sulfamethoxazole (TMP-SMX) showed the highest sensitivity (97.8%), followed by levofloxacin (71.6%). 0.3% of samples were pan-drug resistant. Conclusions S. maltophilia  is a frequent nosocomial colonizer, but it can cause nosocomial pneumonia in almost one-third of cases, specifically in immunocompromised and patients with CCI ≥ 3 with a high risk of mortality due to ventilator-associated pneumonia (VAP) in those with IBMP-10 ≥ 2. Prolonged hospital stay is a risk factor for colonization by  S. maltophilia,  while recent chemotherapy, immunosuppressant, or steroid use are risk factors for hospital-acquired pneumonia due to  S. maltophilia.  TMP-SMX and levofloxacin are the only reliable agents for monotherapy of respiratory infections due to S. maltophilia in Qatar., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Nair et al.)

Left ventricular assist devices (LVADs) are increasingly used as destination therapy or as a bridge to future cardiac transplant in patients with end-stage heart failure. Extracorporeal membrane oxygenation (ECMO) can be used to bridge patients in cardiogenic shock or with decompensated heart failure to durable mechanical circulatory support. We assessed outcomes in patients in critical cardiogenic shock (Interagency Registry for Mechanically Assisted Circulatory Support [INTERMACS] profile 1) who underwent implantation of a continuous-flow (CF)-LVAD, with or without preoperative ECMO bridging. For this retrospective study, we selected INTERMACS profile 1 patients who underwent CF-LVAD implantation at our institution between Sep 1, 2004 and Nov 30, 2018. Of 768 patients identified, 133 (17.3%) were INTERMACS profile 1; 26 (19.5%) received preoperative ECMO support, and 107 (80.5%) did not. Postimplantation outcomes were compared between the ECMO and no-ECMO groups. No significant differences were found in 30-day mortality (15.4 vs. 15.9%, P = 0.95) or survival at 1 year (53.8 vs. 60.9%, P = 0.51). Three patients who received ECMO before CF-LVAD implantation subsequently underwent cardiac transplant. In the ECMO group, the lactate level 1 day after ECMO initiation was lower in survivors than nonsurvivors (2.7 ± 2.2 vs. 7.4 ± 4.2 mmol/L, P = 0.02; area under the curve = 0.85, P = 0.01) after CF-LVAD implantation. Bridging with ECMO to CF-LVAD implantation in carefully selected INTERMACS profile 1 patients (those who are at the highest risk for critical cardiogenic shock and for whom palliation may be the only other option) produced acceptable postoperative outcomes.Field of research: Artificial lung/ECMO., (© 2021. The Japanese Society for Artificial Organs.)

Objectives: Dialysis is considered a contraindication to continuous-flow left ventricular assist device (CF-LVAD) implantation. We evaluated clinical outcomes and survival in carefully selected, low-risk patients with renal failure who required dialysis before CF-LVAD implantation., Methods: We extracted medical record data of patients who underwent CF-LVAD placement at our centre between 1 January 2006 and 31 August 2017, with 2 clinical scenarios: those who required long-term (>14 days) dialysis and those who required short-term (≤14 days) dialysis immediately before implantation. Demographic, clinical and intraoperative characteristics and survival outcomes were assessed., Results: Of 621 patients who underwent CF-LVAD implantation during the study period, 31 underwent dialysis beforehand. Of these, 17 required long-term dialysis (13 haemodialysis, 4 peritoneal dialysis), and 14 underwent short-term haemodialysis. Compared with the long-term dialysis patients, the short-term dialysis patients were more likely to be Interagency Registry for Mechanically Assisted Circulatory Support profile 1-2 (92.9% vs 70.6%; P < 0.001), to have needed preoperative mechanical circulatory support (78.6% vs 70.6%; P < 0.01) and to have higher in-hospital mortality (85.7% vs 29.4%; P = 0.01). Patients stable on long-term dialysis had acceptable overall survival and markedly better 6-month and 1-year survival than those with short-term dialysis before implantation (64.7% vs 14.3% and 58.8% vs 7.1%, respectively; P < 0.001)., Conclusions: Carefully selected patients who are stable on long-term dialysis have acceptable survival rates after CF-LVAD implantation. Patients with acute renal failure had much poorer outcomes than those with chronic end-stage renal disease., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.)

Inflammatory factors have been considered to contribute to keratoconus (KC) pathogenesis. This study aims to determine the immune cells subsets and soluble inflammatory factor profile on the ocular surface of KC patients. 32 KC subjects (51 eyes) across different grades of severity and 15 healthy controls (23 eyes) were included in the study. Keratometry and pachymetry measurements were recorded. Ocular surface immune cells (collected by ocular surface wash) immunophenotyped using flow cytometry include leukocytes, neutrophils, macrophages, natural killer (NK) cells, pan-T cells, gamma delta T (γδT) cells and NKT cells. Tear fluid collected using Schirmer's strip was used to measure 50 soluble factors by multiplex ELISA. Proportions of activated neutrophils, NK cells and γδT cells were significantly increased in KC patients. Significantly higher levels of tear fluid IL-1β, IL-6, LIF, IL-17A, TNFα, IFNα/β/γ, EPO, TGFβ1, PDGF-BB, sVCAM, sL-selectin, granzyme-B, perforin, MMP2, sFasL and IgE, along with significantly lower levels of IL-1α and IL-9 were observed in KC patients. Alterations observed in few of the immuno-inflammatory parameters correlated with grades of disease, allergy, eye rubbing and keratometry or pachymetry measurements. The observation implies a distinct immuno-inflammatory component in KC pathogenesis and its potential as an additional therapeutic target in KC management., (© 2021. The Author(s).)

Purpose: Aberrant inflammation and immune dysregulation are known pathogenic contributors in dry eye disease (DED). Aim of the study was to determine the proportions of immune cell subsets on the ocular surface (OS) of DED patients., Methods: 15 healthy controls (22 eyes) and 48 DED subjects (36 eyes with evaporative DED - EDED; 60 eyes with aqueous deficient DED - ADED) were included in the study. Tear break up time (TBUT), Schirmer's test 1 (ST1), corneal staining (CS) and ocular surface disease index (OSDI) scoring were recorded. OS wash was used to collect immune cells on the OS of study subjects. The cells immunophenotyped using flow cytometry include leukocytes, neutrophils, macrophages, natural killer-NK cells and T cell subsets (CD4; CD8; double positive-DP; gamma delta-γδ and NK T cells)., Results: Significantly higher proportions of leukocytes, neutrophils, CD4 T cells, CD8 T cells, DP T cells and CD4/CD8 T cells ratio were observed in EDED and/or ADED patients. Significantly higher proportions of neutrophils and lower proportions of NK cells were observed in ADED subjects with corneal staining compared to those without and controls. Neutrophils/NK cells ratio was significantly higher in EDED and ADED subjects compared to controls. Correlation analysis revealed pathological relationships between proportions of leukocytes, neutrophils, CD4 T cells and Neutrophil/NK cells ratio with DED clinical parameters., Conclusion: OS immune cell subset proportion changes in DED patients were associated with DED types and severity. The data suggests the potential for a new generation of therapies targeting immune cells on the ocular surface., (Copyright © 2021. Published by Elsevier Inc.)

There is ongoing debate as to whether cardiac complications of coronavirus disease-2019 (COVID-19) result from myocardial viral infection or are secondary to systemic inflammation and/or thrombosis. We provide evidence that cardiomyocytes are infected in patients with COVID-19 myocarditis and are susceptible to severe acute respiratory syndrome coronavirus 2. We establish an engineered heart tissue model of COVID-19 myocardial pathology, define mechanisms of viral pathogenesis, and demonstrate that cardiomyocyte severe acute respiratory syndrome coronavirus 2 infection results in contractile deficits, cytokine production, sarcomere disassembly, and cell death. These findings implicate direct infection of cardiomyocytes in the pathogenesis of COVID-19 myocardial pathology and provides a model system to study this emerging disease., Competing Interests: Supported by the National Institutes of Health (R01 HL141086 to Dr. M.J. Greenberg; R01 HL138466, and R01 HL139714 to Dr. Lavine; 75N93019C00062, and R01 AI127828 to Dr. Diamond); Burroughs Welcome Fund (1014782 to Dr. Lavine); Defense Advanced Research Project Agency (HR001117S0019 to Dr. Diamond); the March of Dimes Foundation (FY18-BOC-430198 to Dr. M.J. Greenberg.); Foundation of Barnes-Jewish Hospital (8038–88 to Dr. Lavine.); and Children’s Discovery Institute of Washington University and St. Louis Children’s Hospital (CH-II-2017–628 to Dr. Lavine; PM-LI-2019-829 to Drs. Lavine and M.J. Greenberg.). Imaging was performed in the Washington University Center for Cellular Imaging (WUCCI) which is funded, in part by the Children’s Discovery Institute of Washington University and St. Louis Children’s Hospital (CDI-CORE-2015-505, CDI-CORE-2019-813) and the Foundation for Barnes-Jewish Hospital (3770). Dr. Diamond is a consultant for Inbios, Eli Lilly, Vir Biotechnology, NGM Biopharmaceuticals; is a member of the Scientific Advisory Board of Moderna; and has received funding and unrelated sponsored research agreements from Moderna, Vir Biotechnology, and Emergent BioSolutions. Dr. Lavine is a member of the Medtronic: DT-PAS/APOGEE trial advisory board; and has received funding and unrelated sponsored research agreements from Amgen. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2021 The Authors.)

Purpose: To determine the status of proangiogenic factors in the tear fluid of preterm infants with and without retinopathy of prematurity (ROP)., Methods: Preterm infants (n = 36) undergoing routine ROP screening included in the prospective study were categorized as No-ROP (n = 13, no ROP at any visits), ROP (if ROP was present at first visit; n = 18), or No-ROP to ROP (no disease at first visit, but developed ROP subsequently; n = 5). Infants with ROP were also grouped as progressing (n = 7) and regressing (n = 16) based on ROP evolution between the first and subsequent visits. Schirmer's strips were used to collect tear fluid and proangiogenic factors (VEGF, angiogenin, soluble vascular cell adhesion molecule, and fractalkine) levels (in picograms per milliliter) in tear fluid were measured by multiplex ELISA., Results: Lower levels of VEGF (135 ± 69; mean ± standard deviation) and higher levels of angiogenin (6568 ± 4975) were observed in infants with ROP compared with infants without ROP (172.5 ± 54.0; 4139 ± 3909) at the first visit. Significantly lower levels of VEGF were observed in the No-ROP to ROP group compared with the No-ROP and ROP groups. The VEGF and angiogenin levels at the first visit were significantly lower in infants with ROP with progressing disease. Angiogenin levels negatively correlated with birth weight and gestational age in ROP. The area under the curve (AUC) and odds ratio (OR) analysis demonstrated that angiogenin/birth weight (AUC = 0.776; OR, 8.6); angiogenin/gestational age (AUC = 0.706; OR, 7.3) and Angiogenin/VEGF (AUC = 0.806; OR, 14.3) ratios were able to differentiated preterm infants with and without ROP., Conclusions: The association between angiogenin and ROP suggests its possible role in ROP. The ratio of angiogenin level with birth weight, gestational age, and/or VEGF could serve as a potential noninvasive screening biomarker for ROP.

COVID-19 has surfaced as a multi-organ disease predominantly affecting the respiratory system. Detection of the viral RNA through reverse transcriptase-PCR (RT-PCR) from a nasopharyngeal or throat sample is the preferred method of diagnosis. Recent evidence has suggested that COVID-19 patients can shed the SARS-CoV-2 for several weeks. Herein, we report six cases of COVID-19 who had persistently positive SARS-CoV-2 on repeat RT-PCR testing reaching up to 9 weeks. The spectrum of cases described ranges from asymptomatic infection to severe COVID-19 pneumonia. A full understanding of the virus's transmission dynamics needs further research. Prolonged viral shedding currently has unclear implications on the management and isolation decisions-the role of the cycle threshold (Ct) value in guiding therapeutic decisions is yet to be clarified. More data on the relationship between Ct values and viral cultivation are needed, especially in patients with prolonged viral shedding, to understand the virus's viability and infectivity.

βA3/A1-crystallin, a lens protein that is also expressed in astrocytes, is produced as βA3 and βA1-crystallin isoforms by leaky ribosomal scanning. In a previous human proteome high-throughput array, we found that βA3/A1-crystallin interacts with protein tyrosine phosphatase 1B (PTP1B), a key regulator of glucose metabolism. This prompted us to explore possible roles of βA3/A1-crystallin in metabolism of retinal astrocytes. We found that βA1-crystallin acts as an uncompetitive inhibitor of PTP1B, but βA3-crystallin does not. Loss of βA1-crystallin in astrocytes triggers metabolic abnormalities and inflammation. In CRISPR/cas9 gene-edited βA1-knockdown (KD) mice, but not in βA3-knockout (KO) mice, the streptozotocin (STZ)-induced diabetic retinopathy (DR)-like phenotype is exacerbated. Here, we have identified βA1-crystallin as a regulator of PTP1B; loss of this regulation may be a new mechanism by which astrocytes contribute to DR. Interestingly, proliferative diabetic retinopathy (PDR) patients showed reduced βA1-crystallin and higher levels of PTP1B in the vitreous humor.