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Retinal ganglion cells (RGCs) are the sole output neurons that transmit visual information from the retina to the brain. Diverse insults and pathological states cause degeneration of RGC somas and axons leading to irreversible vision loss. A fundamental question is whether manipulation of a key regulator of RGC survival can protect RGCs from diverse insults and pathological states, and ultimately preserve vision. Here, we report that CaMKII-CREB signaling is compromised after excitotoxic injury to RGC somas or optic nerve injury to RGC axons, and reactivation of this pathway robustly protects RGCs from both injuries. CaMKII activity also promotes RGC survival in the normal retina. Further, reactivation of CaMKII protects RGCs in two glaucoma models where RGCs degenerate from elevated intraocular pressure or genetic deficiency. Last, CaMKII reactivation protects long-distance RGC axon projections in vivo and preserves visual function, from the retina to the visual cortex, and visually guided behavior.
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Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Citoproteção , Células Ganglionares da Retina/patologia , Visão Ocular , Animais , Axônios/efeitos dos fármacos , Axônios/patologia , Encéfalo/patologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Dependovirus/metabolismo , Modelos Animais de Doenças , Ativação Enzimática/efeitos dos fármacos , Glaucoma/genética , Glaucoma/patologia , Camundongos Endogâmicos C57BL , Neurotoxinas/toxicidade , Traumatismos do Nervo Óptico/patologia , Transdução de SinaisRESUMO
BACKGROUND & AIMS: Endoscopic assessment of ulcerative colitis (UC) typically reports only the maximum severity observed. Computer vision methods may better quantify mucosal injury detail, which varies among patients. METHODS: Endoscopic video from the UNIFI clinical trial (A Study to Evaluate the Safety and Efficacy of Ustekinumab Induction and Maintenance Therapy in Participants With Moderately to Severely Active Ulcerative Colitis) comparing ustekinumab and placebo for UC were processed in a computer vision analysis that spatially mapped Mayo Endoscopic Score (MES) to generate the Cumulative Disease Score (CDS). CDS was compared with the MES for differentiating ustekinumab vs placebo treatment response and agreement with symptomatic remission at week 44. Statistical power, effect, and estimated sample sizes for detecting endoscopic differences between treatments were calculated using both CDS and MES measures. Endoscopic video from a separate phase 2 clinical trial replication cohort was performed for validation of CDS performance. RESULTS: Among 748 induction and 348 maintenance patients, CDS was lower in ustekinumab vs placebo users at week 8 (141.9 vs 184.3; P < .0001) and week 44 (78.2 vs 151.5; P < .0001). CDS was correlated with the MES (P < .0001) and all clinical components of the partial Mayo score (P < .0001). Stratification by pretreatment CDS revealed ustekinumab was more effective than placebo (P < .0001) with increasing effect in severe vs mild disease (-85.0 vs -55.4; P < .0001). Compared with the MES, CDS was more sensitive to change, requiring 50% fewer participants to demonstrate endoscopic differences between ustekinumab and placebo (Hedges' g = 0.743 vs 0.460). CDS performance in the JAK-UC replication cohort was similar to UNIFI. CONCLUSIONS: As an automated and quantitative measure of global endoscopic disease severity, the CDS offers artificial intelligence enhancement of traditional MES capability to better evaluate UC in clinical trials and potentially practice.
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Colite Ulcerativa , Humanos , Inteligência Artificial , Colite Ulcerativa/diagnóstico , Colite Ulcerativa/tratamento farmacológico , Colonoscopia/métodos , Computadores , Indução de Remissão , Índice de Gravidade de Doença , Ustekinumab/efeitos adversosRESUMO
OBJECTIVE: We used a polygenic risk score (PRS) to identify high-risk groups for primary open-angle glaucoma (POAG) within population-based cohorts. DESIGN: Secondary analysis of four prospective population-based studies. PARTICIPANTS: We included four European-ancestry cohorts: the United States (US) based Nurses' Health Study (NHS), NHS2, and the Health Professionals Follow-up Study, and the Rotterdam Study (RS) in the Netherlands. The US cohorts included female nurses and male health professionals aged 55+ years. The RS included residents aged 45 years or older living in Rotterdam, the Netherlands. METHODS: PRS weights were estimated by applying the Lassosum method on imputed genotype and phenotype data from the UK-Biobank. This resulted in 144,020 variants, single nucleotide polymorphism (SNPs) and indels, with non-zero betas that we used to calculate a PRS in the target populations. Using multivariable Cox proportional hazard models, we estimated the relationship between the standardized PRS and relative risk for POAG. Additionally, POAG prediction was tested by calculating these models' concordance (Harrell's C-statistic). Finally, we assessed the association between PRS tertiles and glaucoma-related traits. MAIN OUTCOME MEASURES: The relative risk for POAG and Harrell's C-statistic (the equivalent of an area-under-the-curve for longitudinal models). RESULTS: Among 1,046 cases and 38,809⬠controls, the relative risk (95% confidence interval) for POAG for participants in the highest PRS quintile was 3.99 (3.08, 5.18) in the US cohorts, and 4.89 (2.93, 8.17) in the Rotterdam Study, compared with participants with median genetic risk (3rd quintile). In restricted cubic spline analyses, the relation between continuous PRS and POAG risk increased exponentially in the US and Rotterdam cohorts (Pspline<0.05). Combining age, sex, intraocular pressure >25 mmHg, and family history resulted in a meta-analyzed concordance of 0.75 (0.73, 0.75). Adding the PRS to this model improved the concordance to 0.82 (0.80, 0.84). In a meta-analysis of all cohorts, cases in the highest tertile had a larger cup-disc ratio at diagnosis, by 0.11 (0.07, 0.15), and a 2.07-fold increased risk of requiring glaucoma surgery (1.19, 3.60). CONCLUSIONS: Incorporating a PRS into a POAG predictive model improves identification concordance from 0.75 up to 0.82, supporting its potential for guiding more cost-effective screening strategies.
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The intestinal epithelium exhibits a rapid and efficient regenerative response to injury. Emerging evidence supports a model where plasticity of differentiated cells, particularly those in the secretory lineages, contributes to epithelial regeneration upon ablation of injury-sensitive stem cells. However, such facultative stem cell activity is rare within secretory populations. Here, we ask whether specific functional properties predict facultative stem cell activity. We utilize in vivo labeling combined with ex vivo organoid formation assays to evaluate how cell age and autophagic state contribute to facultative stem cell activity within secretory lineages. Strikingly, we find that cell age (time elapsed since cell cycle exit) does not correlate with secretory cell plasticity. Instead, high autophagic vesicle content predicts plasticity and resistance to DNA damaging injury independently of cell lineage. Our findings indicate that autophagic status prior to injury serves as a lineage-agnostic marker for the prospective identification of facultative stem cells.
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Mucosa Intestinal , Células-Tronco , Estudos Prospectivos , Células-Tronco/metabolismo , Linhagem da Célula , Diferenciação Celular/genéticaRESUMO
INTRODUCTION: Ballistic injuries cause both a temporary and permanent cavitation event, making them far more destructive and complex than other penetrating trauma. We hypothesized that global injury scoring and physiologic parameters would fail to capture the lethality of gunshot wounds (GSW) compared to other penetrating mechanisms. METHODS: The 2019 American College of Surgeons Trauma Quality Programs participant use file was queried for the mortality rate for GSW and other penetrating mechanisms. A binomial logistic regression model ascertained the effects of sex, age, hypotension, tachycardia, mechanism, Glasgow Coma Scale, ISS, and volume of blood transfusion on the likelihood of mortality. Subgroup analyses examined isolated injuries by body regions. RESULTS: Among 95,458 cases (82% male), GSW comprised 46.4% of penetrating traumas. GSW was associated with longer hospital length of stay (4 [2-9] versus 3 [2-5] days), longer intensive care unit length of stay (3 [2-6] versus 2 [2-4] days), and more ventilator days (2 [1-4] versus 2 [1-3]) compared to stab wounds, all P < 0.001. The model determined that GSW was linked to increased odds of mortality compared to stab wounds (odds ratio 4.19, 95% confidence interval 3.55-4.93). GSW was an independent risk factor for acute kidney injury, acute respiratory distress syndrome, venous thromboembolism, sepsis, and surgical site infection. CONCLUSIONS: Injury scoring systems based on anatomical or physiological derangements fail to capture the lethality of GSW compared to other mechanisms of penetrating injury. Adjustments in risk stratification and reporting are necessary to reflect the proportion of GSW seen at each trauma center. Improved classification may help providers develop quality processes of care. This information may also help shape public discourse on this highly lethal mechanism.
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Armas de Fogo , Ferimentos por Arma de Fogo , Ferimentos Penetrantes , Ferimentos Perfurantes , Humanos , Masculino , Feminino , Estudos Retrospectivos , Ferimentos Penetrantes/epidemiologia , Centros de Traumatologia , Escala de Gravidade do FerimentoRESUMO
INTRODUCTION: Relative to other hospitalized patients, trauma patients are younger with fewer comorbidities, but the incidence and outcomes of in-hospital cardiopulmonary arrest (IHCA) with cardiopulmonary resuscitation (CPR) in this population is unknown. Therefore, we aimed to investigate factors associated with survival in trauma patients after IHCA to test the hypothesis that compared to other hospitalized patients, trauma patients with IHCA have improved survival. METHODS: Retrospective review of the Trauma Quality Improvement Program database 2017 to 2019 for patients who had IHCA with CPR. Primary outcome was survival to hospital discharge. Secondary outcomes were in-hospital complications, hospital length of stay, intensive care unit length of stay, and ventilator days. Data were compared with univariate and multivariate analyses at P < 0.05. RESULTS: In 22,346,677 admitted trauma patients, 14,056 (0.6%) received CPR. Four thousand three hundred seventy-seven (31.1%) survived to discharge versus 26.4% in a national sample of all hospitalized patients (P < 0.001). In trauma patients, median age was 55 y, the majority were male (72.2%). Mortality was higher for females versus males (70.3% versus 68.3%, P = 0.026). Multivariate regression showed that older age 1.01 (95% confidence interval (CI) 1.01-1.02), Hispanic ethnicity 1.21 (95% CI 1.04-1.40), and penetrating trauma 1.51 (95% CI 1.32-1.72) were risk factors for mortality, while White race was a protective factor 0.36 (95% CI 0.14-0.89). CONCLUSIONS: This is the first study to show that the incidence of IHCA with CPR is approximately six in 1000 trauma admissions and 31% survive to hospital discharge, which is higher than other hospitalized patients. Age, gender, racial, and ethnic disparities also influence survival.
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Reanimação Cardiopulmonar , Parada Cardíaca , Mortalidade Hospitalar , Ferimentos e Lesões , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Retrospectivos , Parada Cardíaca/mortalidade , Parada Cardíaca/terapia , Parada Cardíaca/epidemiologia , Parada Cardíaca/etiologia , Adulto , Ferimentos e Lesões/mortalidade , Ferimentos e Lesões/complicações , Ferimentos e Lesões/terapia , Idoso , Reanimação Cardiopulmonar/estatística & dados numéricos , Adulto Jovem , Tempo de Internação/estatística & dados numéricos , Estados Unidos/epidemiologiaRESUMO
PURPOSE OF REVIEW: Telemedicine has an increasingly significant role in the fields of ophthalmology and glaucoma. This review covers recent advancements in the development and optimization of teleglaucoma techniques and applications. RECENT FINDINGS: Glaucoma monitoring and diagnosis via remote tonometry, perimetry, and fundus imaging have become a possibility based on recent developments. Many applications work in combination with smart devices, virtual reality, and artificial intelligence and have been tested in patient populations against conventional "reference-standard" measurement tools, demonstrating promising results. Of note, there is still much progress to be made in teleglaucoma and telemedicine at large, such as accessibility to internet, broadband, and smart devices, application affordability, and reimbursement for remote services. However, continued development and optimization of these applications suggest that the implementation of remote monitoring will be a mainstay for glaucoma patient care. SUMMARY: Especially since the beginning of the COVID-19 pandemic, remote patient care has taken on an important role in medicine and ophthalmology. Remote versions of tonometry, perimetry, and fundus imaging may allow for a more patient-centered and accessible future for glaucoma care.
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Glaucoma , Oftalmologia , Telemedicina , Humanos , Inteligência Artificial , Pandemias , Glaucoma/diagnóstico , Telemedicina/métodos , Tonometria Ocular , Oftalmologia/métodosRESUMO
Mitochondrial diseases comprise a heterogeneous group of genetically inherited disorders that cause failures in energetic and metabolic function. Boosting residual oxidative phosphorylation (OXPHOS) activity can partially correct these failures. Herein, using a high-throughput chemical screen, we identified the bromodomain inhibitor I-BET 525762A as one of the top hits that increases COX5a protein levels in complex I (CI) mutant cybrid cells. In parallel, bromodomain-containing protein 4 (BRD4), a target of I-BET 525762A, was identified using a genome-wide CRISPR screen to search for genes whose loss of function rescues death of CI-impaired cybrids grown under conditions requiring OXPHOS activity for survival. We show that I-BET525762A or loss of BRD4 remodeled the mitochondrial proteome to increase the levels and activity of OXPHOS protein complexes, leading to rescue of the bioenergetic defects and cell death caused by mutations or chemical inhibition of CI. These studies show that BRD4 inhibition may have therapeutic implications for the treatment of mitochondrial diseases.
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Benzodiazepinas/farmacologia , Grupo dos Citocromos c/genética , Complexo I de Transporte de Elétrons/genética , Mitocôndrias/metabolismo , Proteínas Mitocondriais/genética , Proteínas Nucleares/genética , Fatores de Transcrição/genética , Proteínas de Ciclo Celular , Fusão Celular , Linhagem Celular , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Grupo dos Citocromos c/metabolismo , Complexo I de Transporte de Elétrons/deficiência , Complexo IV da Cadeia de Transporte de Elétrons , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Ensaios de Triagem em Larga Escala , Humanos , Metaboloma , Metabolômica , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Doenças Mitocondriais/tratamento farmacológico , Doenças Mitocondriais/genética , Doenças Mitocondriais/metabolismo , Doenças Mitocondriais/patologia , Proteínas Mitocondriais/metabolismo , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/metabolismo , Fosforilação Oxidativa/efeitos dos fármacos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Regiões Promotoras Genéticas , Ligação Proteica , Transdução de Sinais , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/metabolismoRESUMO
Optical Coherence Tomography (OCT) enables non-invasive imaging of the retina and is used to diagnose and manage ophthalmic diseases including glaucoma. We present the first large-scale genome-wide association study of inner retinal morphology using phenotypes derived from OCT images of 31,434 UK Biobank participants. We identify 46 loci associated with thickness of the retinal nerve fibre layer or ganglion cell inner plexiform layer. Only one of these loci has been associated with glaucoma, and despite its clear role as a biomarker for the disease, Mendelian randomisation does not support inner retinal thickness being on the same genetic causal pathway as glaucoma. We extracted overall retinal thickness at the fovea, representative of foveal hypoplasia, with which three of the 46 SNPs were associated. We additionally associate these three loci with visual acuity. In contrast to the Mendelian causes of severe foveal hypoplasia, our results suggest a spectrum of foveal hypoplasia, in part genetically determined, with consequences on visual function.
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Bancos de Espécimes Biológicos , Variação Genética , Fenótipo , Retina/metabolismo , Tomografia de Coerência Óptica , Feminino , Genótipo , Glaucoma/genética , Glaucoma/patologia , Cor de Cabelo/genética , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Controle de Qualidade , Retina/patologia , Reino Unido , Transtornos da Visão , Acuidade Visual/genéticaRESUMO
[This corrects the article DOI: 10.1371/journal.pgen.1009497.].
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Diabetic retinopathy (DR) is a common consequence in type 2 diabetes (T2D) and a leading cause of blindness in working-age adults. Yet, its genetic predisposition is largely unknown. Here, we examined the polygenic architecture underlying DR by deriving and assessing a genome-wide polygenic risk score (PRS) for DR. We evaluated the PRS in 6079 individuals with T2D of European, Hispanic, African and other ancestries from a large-scale multi-ethnic biobank. Main outcomes were PRS association with DR diagnosis, symptoms and complications, and time to diagnosis, and transferability to non-European ancestries. We observed that PRS was significantly associated with DR. A standard deviation increase in PRS was accompanied by an adjusted odds ratio (OR) of 1.12 [95% confidence interval (CI) 1.04-1.20; P = 0.001] for DR diagnosis. When stratified by ancestry, PRS was associated with the highest OR in European ancestry (OR = 1.22, 95% CI 1.02-1.41; P = 0.049), followed by African (OR = 1.15, 95% CI 1.03-1.28; P = 0.028) and Hispanic ancestries (OR = 1.10, 95% CI 1.00-1.10; P = 0.050). Individuals in the top PRS decile had a 1.8-fold elevated risk for DR versus the bottom decile (P = 0.002). Among individuals without DR diagnosis, the top PRS decile had more DR symptoms than the bottom decile (P = 0.008). The PRS was associated with retinal hemorrhage (OR = 1.44, 95% CI 1.03-2.02; P = 0.03) and earlier DR presentation (10% probability of DR by 4 years in the top PRS decile versus 8 years in the bottom decile). These results establish the significant polygenic underpinnings of DR and indicate the need for more diverse ancestries in biobanks to develop multi-ancestral PRS.
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Diabetes Mellitus Tipo 2/epidemiologia , Retinopatia Diabética/epidemiologia , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Adulto , Idoso , População Negra/genética , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patologia , Retinopatia Diabética/complicações , Retinopatia Diabética/genética , Retinopatia Diabética/patologia , Hispânico ou Latino/genética , Humanos , Pessoa de Meia-Idade , Herança Multifatorial/genética , Medição de Risco , Fatores de Risco , População Branca/genéticaRESUMO
The profound complexity of the intestinal mucosa demands a spatial approach to the study of gut transcriptomics. Although single-cell RNA sequencing has revolutionized our ability to survey the diverse cell types of the intestine, knowledge of cell type alone cannot fully describe the cells that make up the intestinal mucosa. During homeostasis and disease, dramatic gradients of oxygen, nutrients, extracellular matrix proteins, morphogens, and microbiota collectively dictate intestinal cell state, and only spatial techniques can articulate differences in cellular transcriptomes at this level. Spatial transcriptomic techniques assign transcriptomic data to precise regions in a tissue of interest. In recent years, these protocols have become increasingly accessible, and their application in the intestinal mucosa has exploded in popularity. In the gut, spatial transcriptomics typically involve the application of tissue sections to spatially barcoded RNA sequencing or laser capture microdissection followed by RNA sequencing. In combination with single-cell RNA sequencing, these spatial sequencing approaches allow for the construction of spatial transcriptional maps at pseudosingle-cell resolution. In this review, we describe the spatial transcriptomic technologies recently applied in the gut and the previously unattainable discoveries that they have produced.
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Microbiota , Transcriptoma , Perfilação da Expressão Gênica , Intestinos , Mucosa IntestinalRESUMO
Calorie restriction can enhance the regenerative capacity of the injured intestinal epithelium. Among other metabolic changes, calorie restriction can activate the autophagy pathway. Although independent studies have attributed the regenerative benefit of calorie restriction to downregulation of mTORC1, it is not known whether autophagy itself is required for the regenerative benefit of calorie restriction. We used mouse and organoid models with autophagy gene deletion to evaluate the contribution of autophagy to intestinal epithelial regeneration following calorie restriction. In the absence of injury, mice with intestinal epithelial-specific deletion of autophagy gene Atg7 (Atg7ΔIEC) exhibit weight loss and histological changes similar to wild-type mice following calorie restriction. Conversely, calorie-restricted Atg7ΔIEC mice displayed a significant reduction in regenerative crypt foci after irradiation compared with calorie-restricted wild-type mice. Targeted analyses of tissue metabolites in calorie-restricted mice revealed an association between calorie restriction and reduced glycocholic acid (GCA) in wild-type mice but not in Atg7ΔIEC mice. To evaluate whether GCA can directly modulate epithelial stem cell self-renewal, we performed enteroid formation assays with or without GCA. Wild-type enteroids exhibited reduced enteroid formation efficiency in response to GCA treatment, suggesting that reduced availability of GCA during calorie restriction may be one mechanism by which calorie restriction favors epithelial regeneration in a manner dependent upon epithelial autophagy. Taken together, our data support the premise that intestinal epithelial Atg7 is required for the regenerative benefit of calorie restriction, due in part to its role in modulating luminal GCA with direct effects on epithelial stem cell self-renewal.NEW & NOTEWORTHY Calorie restriction is associated with enhanced intestinal regeneration after irradiation, but the requirement of autophagy for this process is not known. Our data support the premise that intestinal epithelial autophagy is required for the regenerative benefit of calorie restriction. We also report that luminal levels of primary bile acid glycocholic acid are modulated by epithelial cell autophagy during calorie restriction with direct effects on epithelial stem cell function.
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Restrição Calórica , Intestinos , Camundongos , Animais , Intestinos/fisiologia , Mucosa Intestinal/metabolismo , Células Epiteliais , Autofagia/genéticaRESUMO
PURPOSE: To assess the association between intakes of total alcohol and individual alcoholic beverages and the incidence of exfoliation glaucoma/glaucoma suspect (XFG/XFGS) status. DESIGN: Prospective cohort study. PARTICIPANTS: A total of 195 408 participants in the Nurses' Health Study (1980-2018), the Health Professionals Follow-up Study (1986-2018), and the Nurses' Health Study II (1991-2019) were followed biennially. Eligible participants at each 2-year risk period were ⧠40 years and free of XFG/XFGS status with available data on diet and ophthalmic examination findings. METHODS: Cumulatively averaged total (primary exposure) and individual alcoholic beverage (beer, wine, and liquor) intakes from validated dietary information every 2-4 years. MAIN OUTCOME MEASURES: Confirmed incident XFG/XFGS status using medical records. We used per-eye Cox proportional hazards models, accounting for intereye correlations, to estimate multivariate-adjusted relative risks (MVRRs) and 95% confidence intervals (CIs). RESULTS: During 6 877 823 eye-years of follow-up, 705 eyes with XFG/XFGS status were documented. Greater total alcohol consumption was associated significantly with higher XFG/XFGS status risk: the MVRR for XFG/XFGS status for cumulatively averaged alcohol consumption of â§15 g/day or more versus nondrinking was 1.55 (95% CI, 1.17-2.07; P = 0.02 for trend). Long- and short-term alcohol intake was associated significantly with XFG/XFGS status risk, with the strongest associations with cumulatively averaged alcohol intake as of 4 years before diagnosis (MVRR ≥ 15 g/day vs. nondrinking, 1.65; 95% CI, 1.25-2.18; P = 0.002 for trend). Compared with nondrinkers, consuming ⧠3.6 drinks of beer, wine, or liquor per week was associated with the following MVRRs for XFG/XFGS status: 1.26 (95% CI, 0.89-1.77; P = 0.40 for trend), 1.30 (95% CI, 1.00-1.68; P = 0.15 for trend), and 1.46 (95% CI, 1.15-1.85; P = 0.01 for trend), respectively. We did not observe interactions by age, latitude, residential tier, or intakes of folate or vitamin A (P > 0.40 for interaction); however, the association between alcohol and XFG/XFGS status was suggestively stronger for those without a family history of glaucoma (P = 0.10 for interaction). CONCLUSIONS: Long-term alcohol consumption was associated with a higher risk of XFG/XFGS status. Our findings provide further clues regarding the XFG/XFGS etiology.
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Síndrome de Exfoliação , Glaucoma , Hipertensão Ocular , Humanos , Estados Unidos/epidemiologia , Síndrome de Exfoliação/epidemiologia , Síndrome de Exfoliação/etiologia , Seguimentos , Estudos Prospectivos , Fatores de Risco , Consumo de Bebidas Alcoólicas/efeitos adversos , Consumo de Bebidas Alcoólicas/epidemiologia , Glaucoma/diagnóstico , Glaucoma/epidemiologia , Glaucoma/etiologiaRESUMO
PURPOSE: We tested whether dietary modification (DM) altered the risk for incident primary open-angle glaucoma (POAG). DESIGN: Secondary analysis of a randomized intervention trial. PARTICIPANTS: We linked Medicare claims data to 45 203 women in the Women's Health Initiative Dietary Modification Trial, of which 23 776 participants were enrolled in fee-for-service Medicare Part B and had physician claims. METHODS: Women were randomized to follow either DM (a low-fat diet, with increased vegetable, fruit, and grain intake) or their usual diet without modification. Nine thousand three hundred forty women were randomized to the DM intervention, whereas 13 877 women were randomized to the control group. Our analyses were based on an intention-to-treat design, with a follow-up to the end of continuous Medicare coverage, death, or the last claims date (12/31/2018), whichever occurred first. Primary open-angle glaucoma was defined as the first claim with the International Classification of Diseases, Ninth or Tenth Revision, codes. Dietary data were assessed using a food frequency questionnaire. MAIN OUTCOME MEASURES: We used Cox proportional hazards models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for risk of POAG. Subgroup analyses were performed with P values for interaction. RESULTS: After exclusion of women with Medicare-derived glaucoma before randomization, the final analysis included 23 217 women (mean age, 64.4 ± 5.8 years). Baseline characteristics were balanced between the intervention and control groups. Primary open-angle glaucoma incidence was 11.1 per 1000 woman-years (mean follow-up, 11.6 ± 7.4 years; mean DM duration, 5.2 ± 3.2 years). We found no overall benefit of DM in reducing incident POAG (HR, 1.04; 95% CI, 0.96-1.12). Race and participant age did not modify this relation (P = 0.08 and P = 0.24 for interaction, respectively). In further analysis of baseline nutrient and food intake stratified by quartile groups, risk of open-angle glaucoma (OAG) in DM participants in the lowest quartile group for percentage calories (kilocalories) from total fat (33.8 or lower) was increased (HR, 1.22; 95% CI, 1.05-1.41; P = 0.007 for interaction). CONCLUSIONS: Analysis suggests that DM in participants in the lowest quartile group for percentage calories from total fat at baseline increased the risk of incident OAG among women regardless of age or race. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.
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Dieta com Restrição de Gorduras , Glaucoma de Ângulo Aberto , Humanos , Feminino , Idoso , Estados Unidos/epidemiologia , Pessoa de Meia-Idade , Fatores de Risco , Glaucoma de Ângulo Aberto/epidemiologia , Medicare , Incidência , SeguimentosRESUMO
PURPOSE: Genetic variants in regions that include the mitochondrial genes thioredoxin reductase 2 (TXNRD2) and malic enzyme 3 (ME3) are associated with primary open-angle glaucoma (POAG) in genome-wide association studies (GWASs). To assess their clinical impact, we investigated whether TXNRD2 and ME3 genetic risk scores (GRSs) are associated with specific glaucoma phenotypes. DESIGN: Cross-sectional study. PARTICIPANTS: A total of 2617 patients with POAG and 2634 control participants from the National Eye Institute Glaucoma Human Genetics Collaboration Hereditable Overall Operational Database (NEIGHBORHOOD) consortium. METHODS: All POAG-associated single nucleotide polymorphisms (SNPs) in the TXNRD2 and ME3 loci were identified using GWAS data (P < 0.05). Of these, 20 TXNRD2 and 24 ME3 SNPs were selected after adjusting for linkage disequilibrium. The correlation between SNP effect size and gene expression levels was investigated using the Gene-Tissue Expression database. Genetic risk scores were constructed for each individual using the unweighted sum of TXNRD2, ME3, and TXNRD2 + ME3 combined risk alleles. Age- and sex-adjusted odds ratios (ORs) for POAG diagnosis were calculated per decile for each GRS. Additionally, the clinical features of patients with POAG in the top 1%, 5%, and 10% of each GRS were compared with those in the bottom 1%, 5%, and 10%, respectively. MAIN OUTCOME MEASURES: Primary open-angle glaucoma OR per GRS decile, maximum treated intraocular pressure (IOP), and prevalence of paracentral visual field loss among patients with POAG with high versus low GRSs. RESULTS: A larger SNP effect size strongly correlated with higher TXNRD2 and lower ME3 expression levels (r = 0.95 and r = -0.97, respectively; P < 0.05 for both). Individuals in decile 10 of the TXNRD2 + ME3 GRS had the highest odds of POAG diagnosis (OR, 1.79 compared with decile 1; 95% confidence interval, 1.39-2.30; P < 0.001). Patients with POAG in the top 1% of the TXNRD2 GRS showed higher mean maximum treated IOP compared with the bottom 1% (19.9 mmHg vs. 15.6 mmHg; adjusted P = 0.03). Patients with POAG in the top 1% of the ME3 and TXNRD2 + ME3 GRS showed a higher prevalence of paracentral field loss than the bottom 1% (72.7% vs. 14.3% for ME3 GRS and 88.9% vs. 33.3% for TXNRD2+ME3 GRS; adjusted P = 0.03 for both). CONCLUSIONS: Patients with POAG with higher TXNRD2 and ME3 GRSs showed higher treated IOP and a greater prevalence of paracentral field loss. Functional studies exploring how these variants impact mitochondrial function in patients with glaucoma are warranted. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.
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Estudo de Associação Genômica Ampla , Glaucoma de Ângulo Aberto , Humanos , Glaucoma de Ângulo Aberto/diagnóstico , Glaucoma de Ângulo Aberto/genética , Predisposição Genética para Doença , Estudos Transversais , Fenótipo , Pressão Intraocular , Fatores de Risco , Tiorredoxina Redutase 2/genéticaRESUMO
PURPOSE: To examine the association of physical activity (PA) with glaucoma and related traits, to assess whether genetic predisposition to glaucoma modified these associations, and to probe causal relationships using Mendelian randomization (MR). DESIGN: Cross-sectional observational and gene-environment interaction analyses in the UK Biobank. Two-sample MR experiments using summary statistics from large genetic consortia. PARTICIPANTS: UK Biobank participants with data on self-reported or accelerometer-derived PA and intraocular pressure (IOP; n = 94 206 and n = 27 777, respectively), macular inner retinal OCT measurements (n = 36 274 and n = 9991, respectively), and glaucoma status (n = 86 803 and n = 23 556, respectively). METHODS: We evaluated multivariable-adjusted associations of self-reported (International Physical Activity Questionnaire) and accelerometer-derived PA with IOP and macular inner retinal OCT parameters using linear regression and with glaucoma status using logistic regression. For all outcomes, we examined gene-PA interactions using a polygenic risk score (PRS) that combined the effects of 2673 genetic variants associated with glaucoma. MAIN OUTCOME MEASURES: Intraocular pressure, macular retinal nerve fiber layer (mRNFL) thickness, macular ganglion cell-inner plexiform layer (mGCIPL) thickness, and glaucoma status. RESULTS: In multivariable-adjusted regression models, we found no association of PA level or time spent in PA with glaucoma status. Higher overall levels and greater time spent in higher levels of both self-reported and accelerometer-derived PA were associated positively with thicker mGCIPL (P < 0.001 for trend for each). Compared with the lowest quartile of PA, participants in the highest quartiles of accelerometer-derived moderate- and vigorous-intensity PA showed a thicker mGCIPL by +0.57 µm (P < 0.001) and +0.42 µm (P = 0.005). No association was found with mRNFL thickness. High overall level of self-reported PA was associated with a modestly higher IOP of +0.08 mmHg (P = 0.01), but this was not replicated in the accelerometry data. No associations were modified by a glaucoma PRS, and MR analyses did not support a causal relationship between PA and any glaucoma-related outcome. CONCLUSIONS: Higher overall PA level and greater time spent in moderate and vigorous PA were not associated with glaucoma status but were associated with thicker mGCIPL. Associations with IOP were modest and inconsistent. Despite the well-documented acute reduction in IOP after PA, we found no evidence that high levels of habitual PA are associated with glaucoma status or IOP in the general population. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
Assuntos
Glaucoma , Macula Lutea , Humanos , Bancos de Espécimes Biológicos , Estudos Transversais , Glaucoma/genética , Pressão Intraocular , Células Ganglionares da Retina , Tomografia de Coerência Óptica , Reino Unido/epidemiologia , Análise da Randomização MendelianaRESUMO
BACKGROUND: Low-dose spiral computed tomography (LDCT) may not lead to a clear treatment path when small to intermediate-sized lung nodules are identified. We have combined flow cytometry and machine learning to develop a sputum-based test (CyPath Lung) that can assist physicians in decision-making in such cases. METHODS: Single cell suspensions prepared from induced sputum samples collected over three consecutive days were labeled with a viability dye to exclude dead cells, antibodies to distinguish cell types, and a porphyrin to label cancer-associated cells. The labeled cell suspension was run on a flow cytometer and the data collected. An analysis pipeline combining automated flow cytometry data processing with machine learning was developed to distinguish cancer from non-cancer samples from 150 patients at high risk of whom 28 had lung cancer. Flow data and patient features were evaluated to identify predictors of lung cancer. Random training and test sets were chosen to evaluate predictive variables iteratively until a robust model was identified. The final model was tested on a second, independent group of 32 samples, including six samples from patients diagnosed with lung cancer. RESULTS: Automated analysis combined with machine learning resulted in a predictive model that achieved an area under the ROC curve (AUC) of 0.89 (95% CI 0.83-0.89). The sensitivity and specificity were 82% and 88%, respectively, and the negative and positive predictive values 96% and 61%, respectively. Importantly, the test was 92% sensitive and 87% specific in cases when nodules were < 20 mm (AUC of 0.94; 95% CI 0.89-0.99). Testing of the model on an independent second set of samples showed an AUC of 0.85 (95% CI 0.71-0.98) with an 83% sensitivity, 77% specificity, 95% negative predictive value and 45% positive predictive value. The model is robust to differences in sample processing and disease state. CONCLUSION: CyPath Lung correctly classifies samples as cancer or non-cancer with high accuracy, including from participants at different disease stages and with nodules < 20 mm in diameter. This test is intended for use after lung cancer screening to improve early-stage lung cancer diagnosis. Trial registration ClinicalTrials.gov ID: NCT03457415; March 7, 2018.
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Neoplasias Pulmonares , Humanos , Detecção Precoce de Câncer/métodos , Citometria de Fluxo , Pulmão , Neoplasias Pulmonares/diagnóstico por imagem , Aprendizado de Máquina , EscarroRESUMO
Asthma, rhinitis, and atopic dermatitis (AD) are interrelated clinical phenotypes that partly overlap in the human interactome. The concept of "one-airway-one-disease," coined over 20 years ago, is a simplistic approach of the links between upper- and lower-airway allergic diseases. With new data, it is time to reassess the concept. This article reviews (i) the clinical observations that led to Allergic Rhinitis and its Impact on Asthma (ARIA), (ii) new insights into polysensitization and multimorbidity, (iii) advances in mHealth for novel phenotype definitions, (iv) confirmation in canonical epidemiologic studies, (v) genomic findings, (vi) treatment approaches, and (vii) novel concepts on the onset of rhinitis and multimorbidity. One recent concept, bringing together upper- and lower-airway allergic diseases with skin, gut, and neuropsychiatric multimorbidities, is the "Epithelial Barrier Hypothesis." This review determined that the "one-airway-one-disease" concept does not always hold true and that several phenotypes of disease can be defined. These phenotypes include an extreme "allergic" (asthma) phenotype combining asthma, rhinitis, and conjunctivitis. Rhinitis alone and rhinitis and asthma multimorbidity represent two distinct diseases with the following differences: (i) genomic and transcriptomic background (Toll-Like Receptors and IL-17 for rhinitis alone as a local disease; IL-33 and IL-5 for allergic and non-allergic multimorbidity as a systemic disease), (ii) allergen sensitization patterns (mono- or pauci-sensitization versus polysensitization), (iii) severity of symptoms, and (iv) treatment response. In conclusion, rhinitis alone (local disease) and rhinitis with asthma multimorbidity (systemic disease) should be considered as two distinct diseases, possibly modulated by the microbiome, and may be a model for understanding the epidemics of chronic and autoimmune diseases.
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Asma , Rinite Alérgica , Rinite , Humanos , Rinite/diagnóstico , Rinite/epidemiologia , Rinite/complicações , Asma/diagnóstico , Asma/epidemiologia , Asma/etiologia , Rinite Alérgica/complicações , Alérgenos , MultimorbidadeRESUMO
Characterized by optic nerve atrophy due to retinal ganglion cell (RGC) death, glaucoma is the leading cause of irreversible blindness worldwide. Of the major risk factors for glaucoma (age, ocular hypertension, and genetics), only elevated intraocular pressure (IOP) is modifiable, which is largely regulated by aqueous humor outflow through the trabecular meshwork. Glucocorticoids such as dexamethasone have long been known to elevate IOP and lead to glaucoma. However, several recent studies have reported that steroid hormone estrogen levels inversely correlate with glaucoma risk, and that variants in estrogen signaling genes have been associated with glaucoma. As a result, estrogen dysregulation may contribute to glaucoma pathogenesis, and estrogen signaling may protect against glaucoma. The mechanism for estrogen-related protection against glaucoma is not completely understood but likely involves both regulation of IOP homeostasis and neuroprotection of RGCs. Based upon its known activities, estrogen signaling may promote IOP homeostasis by affecting extracellular matrix turnover, focal adhesion assembly, actin stress fiber formation, mechanosensation, and nitric oxide production. In addition, estrogen receptors in the RGCs may mediate neuroprotective functions. As a result, the estrogen signaling pathway may offer a therapeutic target for both IOP control and neuroprotection. This review examines the evidence for a relationship between estrogen and IOP and explores the possible mechanisms by which estrogen maintains IOP homeostasis.