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Introduction: Tumor necrosis factor alpha (TNF-α) is an inflammatory cytokine implicated in pathological changes to the retinal pigment epithelium that are similar to changes in geographic atrophy (GA), an advanced form of age related macular degeneration (AMD). TNF-α also modulates expression of other cytokines including vascular endothelial growth factor (VEGF), leading to choroidal atrophy in models of AMD. The purpose of this study was to investigate systemic TNF-α and VEGF in patients with GA and intermediate AMD (iAMD) compared to controls without AMD. Methods: We examined plasma levels of TNF-α and VEGF in patients with GA, iAMD, and controls without AMD from the University of Colorado AMD registry (2014 to 2021). Cases and controls were characterized by multimodal imaging. TNF-α and VEGF were measured via multiplex immunoassay and data were analyzed using a non-parametric rank based linear regression model fit to plasma biomarkers. Results: There were 97 GA, 199 iAMD patients and 139 controls. TNF-α was significantly increased in GA (Median:9.9pg/ml, IQR:7.3-11.8) compared to iAMD (Median:7.4, IQR:5.3-9.1) and in both GA and iAMD compared to controls (Median:6.4, IQR:5.3-7.8), p<0.01 for all comparisons. VEGF was significantly increased in iAMD (Median:8.9, IQR:4.8-14.3) compared to controls (Median:7.7, IQR:4.6-11.1), p<0.01. There was a significant positive correlation between TNF-α and VEGF in GA (0.46, p<0.01), and iAMD (0.20, p=0.01) with no significant interaction between TNF-α and VEGF in any group. Discussion: These findings suggest TNF-α and VEGF may contribute to systemic inflammatory processes associated with iAMD and GA. TNF-α and VEGF may function as systemic biomarkers for disease development.
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BACKGROUND: Progressive, obstructive lung disease resulting from chronic infection and inflammation is the leading cause of morbidity and mortality in persons with cystic fibrosis (PWCF). Metabolomics and next -generation sequencing (NGS) of airway secretions can allow for better understanding of cystic fibrosis (CF) pathophysiology. In this study, global metabolomic profiling on bronchoalveolar lavage fluid (BALF) obtained from pediatric PWCF and disease controls (DCs) was performed and compared to lower airway microbiota, inflammation, and lung function. METHODS: BALF was collected from children undergoing flexible bronchoscopies for clinical indications. Metabolomic profiling was performed using a platform developed by Metabolon Inc. Total bacterial load (TBL) was measured using quantitative polymerase chain reaction (qPCR), and bacterial communities were characterized using 16S ribosomal RNA (rRNA) sequencing. Random Forest Analysis (RFA), principal component analysis (PCA), and hierarchical clustering analysis (HCA) were performed. RESULTS: One hundred ninety-five BALF samples were analyzed, 142 (73 %) from PWCF. Most metabolites (425/665) and summed categories (7/9) were significantly increased in PWCF. PCA of the metabolomic data revealed CF BALF exhibited more dispersed clustering compared to DC BALF. Higher metabolite concentrations correlated with increased inflammation, increased abundance of Staphylococcus, and decreased lung function. CONCLUSIONS: The lower airway metabolome of PWCF was defined by a complex expansion of metabolomic activity. These findings could be attributed to heightened inflammation in PWCF and aspects of the CF airway polymicrobial ecology. CF-specific metabolomic features are associated with the unique underlying biology of the CF airway.
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OBJECTIVES: To assess whether increasing levels of hospital stress-measured by intensive care unit (ICU) bed occupancy (primary), ventilators in use and emergency department (ED) overflow-were associated with decreasing COVID-19 ICU patient survival in Colorado ICUs during the pre-Delta, Delta and Omicron variant eras. DESIGN: A retrospective cohort study using discrete-time survival models, fit with generalised estimating equations. SETTING: 34 hospital systems in Colorado, USA, with the highest patient volume ICUs during the COVID-19 pandemic. PARTICIPANTS: 9196 non-paediatric SARS-CoV-2 patients in Colorado hospitals admitted once to an ICU between 1 August 2020 and 1 March 2022 and followed for 28 days. OUTCOME MEASURES: Death or discharge to hospice. RESULTS: For Delta-era COVID-19 ICU patients in Colorado, the odds of death were estimated to be 26% greater for patients exposed every day of their ICU admission to a facility experiencing its all-era 75th percentile ICU fullness or above, versus patients exposed for none of their days (OR: 1.26; 95% CI: 1.04 to 1.54; p=0.0102), adjusting for age, sex, length of ICU stay, vaccination status and hospital quality rating. For both Delta-era and Omicron-era patients, we also detected significantly increased mortality hazard associated with high ventilator utilisation rates and (in a subset of facilities) states of ED overflow. For pre-Delta-era patients, we estimated relatively null or even protective effects for the same fullness exposures, something which provides a meaningful contrast to previous studies that found increased hazards but were limited to pre-Delta study windows. CONCLUSIONS: Overall, and especially during the Delta era (when most Colorado facilities were at their fullest), increasing exposure to a fuller hospital was associated with an increasing mortality hazard for COVID-19 ICU patients.
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COVID-19 , Mortalidade Hospitalar , Unidades de Terapia Intensiva , SARS-CoV-2 , Humanos , COVID-19/mortalidade , COVID-19/epidemiologia , Colorado/epidemiologia , Estudos Retrospectivos , Unidades de Terapia Intensiva/estatística & dados numéricos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Ocupação de Leitos/estatística & dados numéricos , Adulto , Serviço Hospitalar de Emergência/estatística & dados numéricosRESUMO
OBJECTIVE: Determine the association between severe hypertensive disease of pregnancy (HDP) with moderate-severe bronchopulmonary dysplasia (BPD) in preterm infants (< 31 weeks' gestation). STUDY DESIGN: Preterm birth cohort study of 693 mother-infant dyads. Severe HDP was defined as severe preeclampsia, HELLP syndrome or eclampsia. The outcome was moderate-severe BPD classified at 36 weeks corrected gestational age, per the NICHD Consensus statement. RESULTS: 225 (32%) mothers developed severe HDP and 234 (34%) infants had moderate-severe BPD. There was an interaction between severe HDP and gestational age (p = 0.03). Infants born at < 25 weeks gestation to mothers with HDP had increased odds for moderate-severe BPD compared to infants of normotensive mothers delivering at the same gestational age. Infants born > 28 weeks to mothers with severe HDP had decreased odds for the outcome, though not statistically significant. CONCLUSIONS: Severe HDP has a differential effect on the development of moderate-severe BPD based on gestational age.
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Displasia Broncopulmonar , Idade Gestacional , Hipertensão Induzida pela Gravidez , Recém-Nascido Prematuro , Humanos , Displasia Broncopulmonar/complicações , Feminino , Gravidez , Recém-Nascido , Adulto , Índice de Gravidade de Doença , Fatores de Risco , Pré-Eclâmpsia , Masculino , Estudos de Coortes , Modelos LogísticosRESUMO
Antimicrobial resistant lower respiratory tract infections are an increasing public health threat and an important cause of global mortality. The lung microbiome can influence susceptibility of respiratory tract infections and represents an important reservoir for exchange of antimicrobial resistance genes. Studies of the gut microbiome have found an association between age and increasing antimicrobial resistance gene burden, however, corollary studies in the lung microbiome remain absent. We performed an observational study of children and adults with acute respiratory failure admitted to the intensive care unit. From tracheal aspirate RNA sequencing data, we evaluated age-related differences in detectable antimicrobial resistance gene expression in the lung microbiome. Using a multivariable logistic regression model, we find that detection of antimicrobial resistance gene expression was significantly higher in adults compared with children after adjusting for demographic and clinical characteristics. This association remained significant after additionally adjusting for lung bacterial microbiome characteristics, and when modeling age as a continuous variable. The proportion of adults expressing beta-lactam, aminoglycoside, and tetracycline antimicrobial resistance genes was higher compared to children. Together, these findings shape our understanding of the lung resistome in critically ill patients across the lifespan, which may have implications for clinical management and global public health.
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Microbiota , Infecções Respiratórias , Adulto , Criança , Humanos , Estado Terminal , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Microbiota/genética , Pulmão , Resistência Microbiana a Medicamentos/genética , Infecções Respiratórias/tratamento farmacológicoRESUMO
Pulmonary disease, lower respiratory tract infection, and pneumonia are the largest causes of morbidity and mortality in individuals with Down syndrome (DS), but whether pulmonary diagnoses in children with DS are common and occur independently of cardiac disease and pulmonary hypertension (PH) is unknown. Cardiopulmonary phenotypes were examined in a cohort of 1248 children with DS. Aptamer-based proteomic analysis of blood was performed in a subset (n = 120) of these children. By the age of 10 years, half of the patients in this cohort (n = 634, 50.8%) had co-occurring pulmonary diagnoses. That proteins and related pathways were distinct between children with pulmonary diagnoses and those with cardiac disease and/or PH may indicate that pulmonary diagnoses appear to occur independently of cardiac disease and PH. Heparin sulfate-glycosaminoglycandegradation, nicotinate metabolism, and elastic fiber formation were ranked highest in the group with pulmonary diagnoses.
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Síndrome de Down , Cardiopatias , Hipertensão Pulmonar , Criança , Humanos , Síndrome de Down/complicações , Síndrome de Down/diagnóstico , Proteômica , Coração , Hipertensão Pulmonar/diagnóstico , Cardiopatias/complicaçõesRESUMO
OBJECTIVES: Viral lower respiratory tract infection (vLRTI) contributes to substantial morbidity and mortality in children. Diagnosis is typically confirmed by reverse transcriptase polymerase chain reaction (RT-PCR) of nasopharyngeal specimens in hospitalized patients; however, it is unknown whether nasopharyngeal detection accurately reflects presence of virus in the lower respiratory tract (LRT). This study evaluates agreement between viral detection from nasopharyngeal specimens by RT-PCR compared with metagenomic next-generation RNA sequencing (RNA-Seq) from tracheal aspirates (TAs). DESIGN: This is an analysis of of a seven-center prospective cohort study. SETTING: Seven PICUs within academic children's hospitals in the United States. PATIENTS: Critically ill children (from 1 mo to 18 yr) who required mechanical ventilation via endotracheal tube for greater than or equal to 72 hours. INTERVENTIONS: We evaluated agreement in viral detection between paired upper and LRT samples. Results of clinical nasopharyngeal RT-PCR were compared with TA RNA-Seq. Positive and negative predictive agreement and Cohen's Kappa were used to assess agreement. MEASUREMENTS AND MAIN RESULTS: Of 295 subjects with paired testing available, 200 (68%) and 210 (71%) had positive viral testing by RT-PCR from nasopharyngeal and RNA-Seq from TA samples, respectively; 184 (62%) were positive by both nasopharyngeal RT-PCR and TA RNA-Seq for a virus, and 69 (23%) were negative by both methods. Nasopharyngeal RT-PCR detected the most abundant virus identified by RNA-Seq in 92.4% of subjects. Among the most frequent viruses detected, respiratory syncytial virus demonstrated the highest degree of concordance (κ = 0.89; 95% CI, 0.83-0.94), whereas rhinovirus/enterovirus demonstrated lower concordance (κ = 0.55; 95% CI, 0.44-0.66). Nasopharyngeal PCR was more likely to detect multiple viruses than TA RNA-Seq (54 [18.3%] vs 24 [8.1%], p ≤ 0.001). CONCLUSIONS: Viral nucleic acid detection in the upper versus LRT reveals good overall agreement, but concordance depends on the virus. Further studies are indicated to determine the utility of LRT sampling or the use of RNA-Seq to determine LRTI etiology.
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Estado Terminal , Infecções Respiratórias , Criança , Humanos , Lactente , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Estudos Prospectivos , Infecções Respiratórias/diagnóstico , Nasofaringe , Análise de Sequência de RNARESUMO
BACKGROUND: In singleton pregnancies, fetal sexual dimorphism has been observed in hypertensive disorders of pregnancy, particularly preeclampsia, a morbid syndrome that increases the risk of adult-onset cardiovascular disease for mothers and their offspring. However, few studies have explored the effect of fetal sex on hypertensive disorders of pregnancy among twin pregnancies. METHODS: We conducted a retrospective cohort study of 1032 twin pregnancies between 2011 and 2022 using data from a perinatal database that recruits participants from 3 hospitals in Houston, TX. We categorized pregnancies based on fetal sex pairings into female/female, male/male, and female/male. Pregnancies with female/female pairs were used as our reference group. Our primary outcomes included gestational hypertension, preeclampsia, superimposed preeclampsia, and preeclampsia subtyped by gestational age of delivery. A modified Poisson regression model with robust error variance was used to calculate the relative risk and 95% CI for the association between fetal sex pairs and hypertensive disorders of pregnancy. RESULTS: Adjusted models of female/male pairs were associated with preterm preeclampsia (relative risk, 2.01 [95% CI, 1.15-3.53]) relative to those with female/female pairs. No associations with other hypertensive disorders of pregnancy were observed among pregnancies with male/male pairs compared with those with female/female fetal sex pairs. CONCLUSIONS: We found some evidence of sexual dimorphism for preterm preeclampsia among female/male twin pairs. Additional research is needed to understand what biological mechanisms could explain these findings.
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Hipertensão Induzida pela Gravidez , Pré-Eclâmpsia , Nascimento Prematuro , Adulto , Feminino , Humanos , Recém-Nascido , Masculino , Gravidez , Pré-Eclâmpsia/epidemiologia , Resultado da Gravidez , Gravidez de Gêmeos , Estudos Retrospectivos , Caracteres SexuaisRESUMO
Purpose: To evaluate the reliability and reproducibility of visual function assessments for patients with macula-off rhegmatogenous retinal detachment (RRD). Methods: This prospective study included patients with unilateral macula-off RRD of <10-day duration successfully treated with a single, uncomplicated surgery at least 1 year following repair. Visual function assessments were performed at time of enrollment and 1 month later. Testing included Early Treatment Diabetic Retinopathy Study (ETDRS) best-corrected visual acuity (BCVA), low-luminance visual acuity (LLVA), low-contrast visual acuity (VA) 2.5% and 5%, contrast sensitivity assessment with Mars and Gabor patches, reading speed (acuity, speed, and critical print size), color vision testing (protan, deutan, and tritan), and microperimetry. Spectral-domain ocular coherence tomography (SD-OCT) was performed. Paired t-statistics were used to compare values between visits and between the study and fellow eyes. Results: Fourteen patients (9 male, 5 female) with a mean age of 69 years at time of surgery were evaluated. Correlation coefficients across the two visits were highest for ETDRS BCVA (0.97), tritan color vision testing (0.96), and low-contrast VA 5% (0.96), while the average t-statistic was largest for low-luminance deficit (4.2), ETDRS BCVA (4.1), and reading speed critical print size (3.7). ETDRS BCVA did not correlate with SD-OCT findings. Conclusions: ETDRS BCVA can be considered a highly reliable and reproducible outcome measure. LLVA, protan color discrimination, contrast sensitivity, and reading speed may be useful secondary outcome measures. Translational Relevance: This study provides guidance on the selection of visual function outcome measures for clinical trials of patients with macula-off RRD.
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Retinopatia Diabética , Macula Lutea , Descolamento Retiniano , Humanos , Feminino , Masculino , Idoso , Descolamento Retiniano/diagnóstico , Descolamento Retiniano/cirurgia , Reprodutibilidade dos Testes , Estudos Prospectivos , Testes Visuais , Macula Lutea/diagnóstico por imagem , Macula Lutea/cirurgiaRESUMO
PURPOSE: To characterize cataract surgery in people with dementia (PWD) using a cataract surgery outcomes database. METHODS: Demographics, medical and ocular history, surgical characteristics, and postoperative measures were analyzed for differences between PWD and non-PWD cohorts. Patient-level data were analyzed with Fisher's Exact Test, and eye-level data were analyzed with logistic regression using generalized estimating equations to account for correlation of eyes from the same individual. RESULTS: 507 eyes from 296 PWD were identified using appropriate ICD codes and cross-referenced to a cataract surgery outcomes database containing 12,949 eyes from 7,853 patients who underwent cataract phacoemulsification at a single center between January 2014 and October 2019. PWD were older (p < .001), had shorter duration cataract surgeries (p = .006), and were more likely to have mature cataract (p = .017). The rate of general anesthesia was higher in PWD (p = .005). There were no differences in complication rates between PWD and non-PWD cohorts. Both preoperative best corrected LogMAR distance visual acuity (CDVA) (p < .001) and postoperative CDVA (p < .001) were worse in PWD. CDVA significantly improved in both groups (p < .001); however, the average magnitude of improvement in CDVA was not significantly different between groups (p = .169). CONCLUSIONS: PWD present for cataract surgery at a later age and were more likely to have mature cataracts and general anesthesia, but did not have higher rates of complication, and showed significant improvement in CDVA following surgery. These findings should be encouraging to PWD undergoing counseling for cataract surgery, and for the potential for improved function in PWD.
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The vaginal microbiome includes diverse microbiota dominated by Lactobacillus [L.] spp. that protect against infections, modulate inflammation, and regulate vaginal homeostasis. Because it is challenging to incorporate vaginal microbiota into in vitro models, including organ-on-a-chip systems, we assessed microbial metabolites as reliable proxies in addition to traditional vaginal epithelial cultures (VECs). Human immortalized VECs cultured on transwells with an air-liquid interface generated stratified cell layers colonized by transplanted healthy microbiomes (L. jensenii- or L. crispatus-dominant) or a community representing bacterial vaginosis (BV). After 48-h, a qPCR array confirmed the expected donor community profiles. Pooled apical and basal supernatants were subjected to metabolomic analysis (untargeted mass spectrometry) followed by ingenuity pathways analysis (IPA). To determine the bacterial metabolites' ability to recreate the vaginal microenvironment in vitro, pooled bacteria-free metabolites were added to traditional VEC cultures. Cell morphology, viability, and cytokine production were assessed. IPA analysis of metabolites from colonized samples contained fatty acids, nucleic acids, and sugar acids that were associated with signaling networks that contribute to secondary metabolism, anti-fungal, and anti-inflammatory functions indicative of a healthy vaginal microbiome compared to sterile VEC transwell metabolites. Pooled metabolites did not affect cell morphology or induce cell death (â¼5.5%) of VEC cultures (n = 3) after 72-h. However, metabolites created an anti-inflammatory milieu by increasing IL-10 production (p = .06, T-test) and significantly suppressing pro-inflammatory IL-6 (p = .0001), IL-8 (p = .009), and TNFα (p = .0007) compared to naïve VEC cultures. BV VEC conditioned-medium did not affect cell morphology nor viability; however, it induced a pro-inflammatory environment by elevating levels of IL-6 (p = .023), IL-8 (p = .031), and TNFα (p = .021) when compared to L.-dominate microbiome-conditioned medium. VEC transwells provide a suitable ex vivo system to support the production of bacterial metabolites consistent with the vaginal milieu allowing subsequent in vitro studies with enhanced accuracy and utility.
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Microbiota , Vaginose Bacteriana , Feminino , Humanos , Lactobacillus/fisiologia , Fator de Necrose Tumoral alfa/metabolismo , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Vagina/microbiologia , Vaginose Bacteriana/microbiologia , Bactérias , Anti-InflamatóriosRESUMO
Antimicrobial resistant lower respiratory tract infections (LRTI) are an increasing public health threat, and an important cause of global mortality. The lung microbiome influences LRTI susceptibility and represents an important reservoir for exchange of antimicrobial resistance genes (ARGs). Studies of the gut microbiome have found an association between age and increasing antimicrobial resistance gene (ARG) burden, however corollary studies in the lung microbiome remain absent, despite the respiratory tract representing one of the most clinically significant sites for drug resistant infections. We performed a prospective, multicenter observational study of 261 children and 88 adults with acute respiratory failure, ranging in age from 31 days to ≥ 89 years, admitted to intensive care units in the United States. We performed RNA sequencing on tracheal aspirates collected within 72 hours of intubation, and evaluated age-related differences in detectable ARG expression in the lung microbiome as a primary outcome. Secondary outcomes included number and classes of ARGs detected, proportion of patients with an ARG class, and composition of the lung microbiome. Multivariable logistic regression models (adults vs children) or continuous age (years) were adjusted for sex, race/ethnicity, LRTI status, and days from intubation to specimen collection. Detection of ARGs was significantly higher in adults compared with children after adjusting for sex, race/ethnicity, LRTI diagnosis, and days from intubation to specimen collection (adjusted odds ratio (aOR): 2.16, 95% confidence interval (CI): 1.10-4.22). A greater proportion of adults compared with children had beta-lactam ARGs (31% (CI: 21-41%) vs 13% (CI: 10-18%)), aminoglycoside ARGs (20% (CI: 13-30%) vs 2% (CI: 0.6-4%)), and tetracycline ARGs (14% (CI: 7-23%) vs 3% (CI: 1-5%)). Adults ≥70 years old had the highest proportion of these three ARG classes. The total bacterial abundance of the lung microbiome increased with age, and microbiome alpha diversity varied with age. Taxonomic composition of the lung microbiome, measured by Bray Curtis dissimilarity index, differed between adults and children (p = 0.003). The association between age and increased ARG detection remained significant after additionally including lung microbiome total bacterial abundance and alpha diversity in the multivariable logistic regression model (aOR: 2.38, (CI: 1.25-4.54)). Furthermore, this association remained robust when modeling age as a continuous variable (aOR: 1.02, (CI: 1.01-1.03) per year of age). Taken together, our results demonstrate that age is an independent risk factor for ARG detection in the lower respiratory tract microbiome. These data shape our understanding of the lung resistome in critically ill patients across the lifespan, which may have implications for clinical management and global public health.
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Autonomous artificial intelligence (AI) promises to increase healthcare productivity, but real-world evidence is lacking. We developed a clinic productivity model to generate testable hypotheses and study design for a preregistered cluster-randomized clinical trial, in which we tested the hypothesis that a previously validated US FDA-authorized AI for diabetic eye exams increases clinic productivity (number of completed care encounters per hour per specialist physician) among patients with diabetes. Here we report that 105 clinic days are cluster randomized to either intervention (using AI diagnosis; 51 days; 494 patients) or control (not using AI diagnosis; 54 days; 499 patients). The prespecified primary endpoint is met: AI leads to 40% higher productivity (1.59 encounters/hour, 95% confidence interval [CI]: 1.37-1.80) than control (1.14 encounters/hour, 95% CI: 1.02-1.25), p < 0.00; the secondary endpoint (productivity in all patients) is also met. Autonomous AI increases healthcare system productivity, which could potentially increase access and reduce health disparities. ClinicalTrials.gov NCT05182580.
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BACKGROUND: Tobramycin inhalation solution (TIS) and chronic azithromycin (AZ) have known clinical benefits for children with CF, likely due to antimicrobial and anti-inflammatory activity. The effects of chronic AZ in combination with TIS on the airway microbiome have not been extensively investigated. Oropharyngeal swab samples were collected in the OPTIMIZE multicenter, randomized, placebo-controlled trial examining the addition of AZ to TIS in 198 children with CF and early P. aeruginosa infection. Bacterial small subunit rRNA gene community profiles were determined. The effects of TIS and AZ were assessed on oropharyngeal microbial diversity and composition to uncover whether effects on the bacterial community may be a mechanism of action related to the observed changes in clinical outcomes. RESULTS: Substantial changes in bacterial communities (total bacterial load, diversity and relative abundance of specific taxa) were observed by week 3 of TIS treatment for both the AZ and placebo groups. On average, these shifts were due to changes in non-traditional CF taxa that were not sustained at the later study visits (weeks 13 and 26). Bacterial community measures did not differ between the AZ and placebo groups. CONCLUSIONS: This study provides further evidence that the mechanism for AZ's effect on clinical outcomes is not due solely to action on airway microbial composition.
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Fibrose Cística , Microbiota , Infecções por Pseudomonas , Humanos , Criança , Azitromicina/farmacologia , Azitromicina/uso terapêutico , Infecções por Pseudomonas/tratamento farmacológico , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Fibrose Cística/complicações , Fibrose Cística/tratamento farmacológico , Fibrose Cística/microbiologia , Administração por Inalação , Pseudomonas aeruginosa/genética , Tobramicina/farmacologia , Bactérias/genética , Microbiota/genéticaRESUMO
Purpose: Chronic local inflammation underlies the pathogenesis of age-related macular degeneration (AMD) causing damage to the neurosensory retina. However, there is minimal research on systemic cell-mediated inflammation in AMD. Interleukin-4 (IL-4) is an immunoregulatory cytokine with an important role in modulating inflammation in chronic immune mediated disease. The purpose of this study was to: (1) investigate the role of systemic IL-4 in patients with intermediate AMD (iAMD) and in geographic atrophy (GA), an advanced form of AMD, compared to controls without AMD, and (2) determine if IL-4 levels are moderated by sex. Methods: We examined plasma levels of IL-4 in patients with iAMD, GA, and controls without AMD included in the University of Colorado AMD registry (August 2014 to June 2021). Cases and controls were defined by multimodal imaging. IL-4 was measured by multiplex immunoassay. Data were analyzed using a nonparametric rank based linear regression model fit to IL-4. Results: There were 199 patients with iAMD, 97 patients with GA, and 139 controls, with a percentage of female patients 61%, 55%, and 66%, respectively. We demonstrated significantly higher median IL-4 levels in GA (35.3; interquartile range [IQR] = 22.8-50.5) compared to iAMD (6.1; IQR = 2.2-11.3, P < 0.01) and controls (10.7; IQR = 5.0-16.8, P < 0.01). There were no significant differences in levels of IL-4 for cases and controls when stratified by sex. Conclusions: These findings demonstrate a systemic immunological difference between iAMD and GA, indicating IL-4 may be a systemic biomarker for GA development. Translational Relevance: The plasma biomarker IL-4 is significantly elevated in patients with GA.
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Atrofia Geográfica , Degeneração Macular , Humanos , Feminino , Interleucina-4 , Angiofluoresceinografia/métodos , Degeneração Macular/diagnóstico , Biomarcadores , InflamaçãoRESUMO
OBJECTIVE: To synthesise exercise therapy intervention data investigating patient rating outcomes for the management of tendinopathy. DESIGN: A systematic review and meta-analysis of randomized controlled trials investigating exercise therapy interventions and reporting patient rating outcomes. SETTING: Any setting in any country listed as very high on the human development index. PARTICIPANTS: People with a diagnosis of any tendinopathy of any severity or duration. INTERVENTIONS: Exercise therapy for the management of tendinopathy comprising five different therapy classes: 1) resistance; 2) plyometric; 3) vibration; 4) flexibility, and 5) movement pattern retraining modalities, were considered for inclusion. MAIN OUTCOME MEASURES: Outcomes measuring patient rating of condition, including patient satisfaction and Global Rating of Change (GROC). RESULTS: From a total of 124 exercise therapy studies, 34 (Achilles: 41%, rotator cuff: 32%, patellar: 15%, elbow: 9% and gluteal: 3%) provided sufficient information to be meta-analysed. The data were obtained across 48 treatment arms and 1246 participants. The pooled estimate for proportion of satisfaction was 0.63 [95%CrI: 0.53-0.73], and the pooled estimate for percentage of maximum GROC was 53 [95%CrI: 38-69%]. The proportion of patients reporting positive satisfaction and perception of change increased with longer follow-up periods from treatment onset. CONCLUSION: Patient satisfaction and GROC appear similar and are ranked moderately high demonstrating that patients generally perceive exercise therapies positively. Further research including greater consistency in measurement tools is required to explore and where possible, identify patient- and exercise-related moderating factors that can be used to improve person-centred care. SYSTEMATIC REVIEW REGISTRATION NUMBER: PROSPERO ID=CRD42020168187 CONTRIBUTION OF PAPER.
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Tendinopatia , Humanos , Tendinopatia/terapia , Terapia por Exercício , Modalidades de Fisioterapia , Manguito Rotador , Satisfação do PacienteRESUMO
BACKGROUND: Repository corticotrophin injection (RCI, Acthar Gel) and intravenous methylprednisolone (IVMP) improve the rate but not the extent of visual recovery following acute optic neuritis. RCI has adrenal-stimulating and melanocortin receptor-stimulating properties that may endow it with unique anti-inflammatory properties relative to IVMP. METHODS: Individuals with acute optic neuritis of less than 2 weeks duration were prospectively enrolled and randomized 1:1 to receive either RCI or IVMP. Peripapillary retinal nerve fiber layer (pRNFL) and ganglion cell plus inner plexiform layer thickness (GC + IPL) were serially evaluated by OCT. In addition, patient-reported outcomes (PROs) for changes in fatigue, mood, visual function, depression, and quality of life (QOL) were measured, and high and low contrast visual acuity were recorded. RESULTS: Thirty-seven subjects were enrolled (19 RCI; 18 IVMP); the average time from symptom to treatment was 8.8 days. At 6 months, there was no difference in the primary outcome: loss of average pRNFL thickness in the affected eye (RCI vs IVMP: -13.1 vs -11.7 µm, P = 0.88) 6 months after randomization. Additional outcomes also showed no difference between treatment groups: 6-month attenuation of GC + IPL thickness (RCI vs IVMP: -13.8 vs -12.0 µm, P = 0.58) and frequency of pRNFL swelling at 1 month (RCI vs IVMP: 63% vs 72%, P = 0.73) and 3 months (RCI vs IVMP: 26% vs 31%, P = 0.99). Both treatments resulted in improvement in visual function and PROs. CONCLUSIONS: Treatment of acute optic neuritis with RCI or IVMP produced no clinically meaningful differences in optic nerve structure or visual function.
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Metilprednisolona , Neurite Óptica , Humanos , Metilprednisolona/uso terapêutico , Qualidade de Vida , Neuroproteção , Estudos Prospectivos , Neurite Óptica/diagnóstico , Neurite Óptica/tratamento farmacológico , Hormônio Adrenocorticotrópico , Tomografia de Coerência Óptica/métodosRESUMO
BACKGROUND: Changes in upper airway microbiota may impact early disease manifestations in infants with cystic fibrosis (CF). To investigate early airway microbiota, the microbiota present in the oropharynx of CF infants over the first year of life was assessed along with the relationships between microbiota and growth, antibiotic use and other clinical variables. METHODS: Oropharyngeal (OP) swabs were collected longitudinally between 1 and 12 months of age from infants diagnosed with CF by newborn screen and enrolled in the Baby Observational and Nutrition Study (BONUS). DNA extraction was performed after enzymatic digestion of OP swabs. Total bacterial load was determined by qPCR and community composition assessed using 16S rRNA gene analysis (V1/V2 region). Changes in diversity with age were evaluated using mixed models with cubic B-splines. Associations between clinical variables and bacterial taxa were determined using a canonical correlation analysis. RESULTS: 1,052 OP swabs collected from 205 infants with CF were analyzed. Most infants (77%) received at least one course of antibiotics during the study and 131 OP swabs were collected while the infant was prescribed an antibiotic. Alpha diversity increased with age and was only marginally impacted by antibiotic use. Community composition was most highly correlated with age and was only moderately correlated with antibiotic exposure, feeding method and weight z-scores. Relative abundance of Streptococcus decreased while Neisseria and other taxa increased over the first year. CONCLUSIONS: Age was more influential on the oropharyngeal microbiota of infants with CF than clinical variables including antibiotics in the first year of life.
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Fibrose Cística , Microbiota , Recém-Nascido , Lactente , Humanos , Fibrose Cística/tratamento farmacológico , RNA Ribossômico 16S/genética , RNA Ribossômico 16S/análise , Traqueia , Antibacterianos/uso terapêuticoRESUMO
BACKGROUNDLower respiratory tract infection (LRTI) is a leading cause of death in children worldwide. LRTI diagnosis is challenging because noninfectious respiratory illnesses appear clinically similar and because existing microbiologic tests are often falsely negative or detect incidentally carried microbes, resulting in antimicrobial overuse and adverse outcomes. Lower airway metagenomics has the potential to detect host and microbial signatures of LRTI. Whether it can be applied at scale and in a pediatric population to enable improved diagnosis and treatment remains unclear.METHODSWe used tracheal aspirate RNA-Seq to profile host gene expression and respiratory microbiota in 261 children with acute respiratory failure. We developed a gene expression classifier for LRTI by training on patients with an established diagnosis of LRTI (n = 117) or of noninfectious respiratory failure (n = 50). We then developed a classifier that integrates the host LRTI probability, abundance of respiratory viruses, and dominance in the lung microbiome of bacteria/fungi considered pathogenic by a rules-based algorithm.RESULTSThe host classifier achieved a median AUC of 0.967 by cross-validation, driven by activation markers of T cells, alveolar macrophages, and the interferon response. The integrated classifier achieved a median AUC of 0.986 and increased the confidence of patient classifications. When applied to patients with an uncertain diagnosis (n = 94), the integrated classifier indicated LRTI in 52% of cases and nominated likely causal pathogens in 98% of those.CONCLUSIONLower airway metagenomics enables accurate LRTI diagnosis and pathogen identification in a heterogeneous cohort of critically ill children through integration of host, pathogen, and microbiome features.FUNDINGSupport for this study was provided by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Heart, Lung, and Blood Institute (UG1HD083171, 1R01HL124103, UG1HD049983, UG01HD049934, UG1HD083170, UG1HD050096, UG1HD63108, UG1HD083116, UG1HD083166, UG1HD049981, K23HL138461, and 5R01HL155418) as well as by the Chan Zuckerberg Biohub.
Assuntos
Microbiota , Infecções Respiratórias , Humanos , Criança , Metagenômica , Estado Terminal , Infecções Respiratórias/diagnóstico , Infecções Respiratórias/microbiologia , PulmãoRESUMO
Introduction: Airway infection and inflammation lead to the progression of obstructive lung disease in persons with cystic fibrosis (PWCF). However, cystic fibrosis (CF) fungal communities, known drivers of CF pathophysiology, remain poorly understood due to the shortcomings of traditional fungal culture. Our objective was to apply a novel small subunit rRNA gene (SSU-rRNA) sequencing approach to characterize the lower airway mycobiome in children with and without CF. Methods: Bronchoalveolar lavage fluid (BALF) samples and relevant clinical data were collected from pediatric PWCF and disease control (DC) subjects. Total fungal load (TFL) was measured using quantitative PCR, and SSU-rRNA sequencing was used for mycobiome characterization. Results were compared across groups, and Morisita-Horn clustering was performed. Results: 161 (84%) of the BALF samples collected had sufficient load for SSU-rRNA sequencing, with amplification being more common in PWCF. BALF from PWCF had increased TFL and increased neutrophilic inflammation compared to DC subjects. PWCF exhibited increased abundance of Aspergillus and Candida, while Malassezia, Cladosporium, and Pleosporales were prevalent in both groups. CF and DC samples showed no clear differences in clustering when compared to each other or to negative controls. SSU-rRNA sequencing was used to profile the mycobiome in pediatric PWCF and DC subjects. Notable differences were observed between the groups, including the abundance of Aspergillus and Candida. Discussion: Fungal DNA detected in the airway could represent a combination of pathogenic fungi and environmental exposure (e.g., dust) to fungus indicative of a common background signature. Next steps will require comparisons to airway bacterial communities.