ABSTRACT
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.
ABSTRACT
PURPOSE: Polygenic risk scores (PRSs) likely predict risk and prognosis of glaucoma. We compared the PRS performance for primary open-angle glaucoma (POAG), defined using International Classification of Diseases (ICD) codes vs manual medical record review. DESIGN: Retrospective cohort study. METHODS: We identified POAG cases in the Mount Sinai BioMe and Mass General Brigham (MGB) biobanks using ICD codes. We confirmed POAG based on optical coherence tomograms and visual fields. In a separate 5% sample, the absence of POAG was confirmed with intraocular pressure and cup-disc ratio criteria. We used genotype data and either self-reported glaucoma diagnoses or ICD-10 codes for glaucoma diagnoses from the UK Biobank and the lassosum method to compute a genome-wide POAG PRS. We compared the area under the curve (AUC) for POAG prediction based on ICD codes vs medical records. RESULTS: We reviewed 804 of 996 BioMe and 367 of 1006 MGB ICD-identified cases. In BioMe and MGB, respectively, positive predictive value was 53% and 55%; negative predictive value was 96% and 97%; sensitivity was 97% and 97%; and specificity was 44% and 53%. Adjusted PRS AUCs for POAG using ICD codes vs manual record review in BioMe were not statistically different (P ≥.21) by ancestry: 0.77 vs 0.75 for African, 0.80 vs 0.80 for Hispanic, and 0.81 vs 0.81 for European. Results were similar in MGB (P ≥.18): 0.72 vs 0.80 for African, 0.83 vs 0.86 for Hispanic, and 0.74 vs 0.73 for European. CONCLUSIONS: A POAG PRS performed similarly using either manual review or ICD codes in 2 electronic health record-linked biobanks; manual assessment of glaucoma status might not be necessary for some PRS studies. However, caution should be exercised when using ICD codes for glaucoma diagnosis given their low specificity (44%-53%) for manually confirmed cases of glaucoma.
ABSTRACT
Importance: The use of valve-in-valve (ViV) transcatheter aortic valve replacement (TAVR) has been rapidly expanding as an alternative treatment to redo surgical aortic valve replacement (SAVR) for failed bioprosthetic valves despite limited long-term data. Objective: To assess mortality and morbidity in patients undergoing intervention for failed bioprosthetic SAVR. Design, Setting, and Participants: This was a retrospective population-based cohort analysis conducted between January 1, 2015, and December 31, 2020, with a median (IQR) follow-up time of 2.3 (1.1-4.0) years. A total of 1771 patients with a history of bioprosthetic SAVR who underwent ViV-TAVR or redo SAVR in California, New York, and New Jersey were included. Data were obtained from the California Department of Health Care Access and Information, the New York Statewide Planning and Research Cooperative System, and the New Jersey Discharge Data Collection System. Exclusion criteria included undergoing TAVR or redo SAVR within 5 years from initial SAVR, as well as infective endocarditis, concomitant surgical procedures, and out-of-state residency. Propensity matching yielded 375 patient pairs. Data were analyzed from January to December 2023. Interventions: ViV-TAVR vs redo SAVR. Main Outcomes and Measurements: The primary outcome was all-cause mortality. Secondary outcomes were stroke, heart failure hospitalization, reoperation, major bleeding, acute kidney failure, new pacemaker insertion, and infective endocarditis. Results: From 2015 through 2020, the proportion of patients undergoing ViV-TAVR vs redo SAVR increased from 159 of 451 (35.3%) to 498 or 797 (62.5%). Of 1771 participants, 653 (36.9%) were female, and the mean (SD) age was 74.4 (11.3) years. Periprocedural mortality and stroke rates were similar between propensity-matched groups. The ViV-TAVR group had lower periprocedural rates of major bleeding (2.4% vs 5.1%; P = .05), acute kidney failure (1.3% vs 7.2%; P < .001), and new pacemaker implantations (3.5% vs 10.9%; P < .001). The 5-year all-cause mortality rate was 23.4% (95% CI, 15.7-34.1) in the ViV-TAVR group and 13.3% (95% CI, 9.2-18.9) in the redo SAVR group. In a landmark analysis, no difference in mortality was observed up to 2 years (hazard ratio, 1.03; 95% CI, 0.59-1.78), but after 2 years, ViV-TAVR was associated with higher mortality (hazard ratio, 2.97; 95% CI, 1.18-7.47) as well as with a higher incidence of heart failure hospitalization (hazard ratio, 3.81; 95% CI, 1.57-9.22). There were no differences in 5-year incidence of stroke, reoperation, major bleeding, or infective endocarditis. Conclusions and Relevance: Compared with redo SAVR, ViV-TAVR was associated with a lower incidence of periprocedural complications and a similar incidence of all-cause mortality through 2 years' follow-up. However, ViV-TAVR was associated with higher rates of late mortality and heart failure hospitalization. These findings may be influenced by residual confounding and require adjudication in a randomized clinical trial.
Subject(s)
Bioprosthesis , Reoperation , Transcatheter Aortic Valve Replacement , Humans , Female , Male , Aged , Transcatheter Aortic Valve Replacement/methods , Retrospective Studies , Reoperation/statistics & numerical data , Aged, 80 and over , Heart Valve Prosthesis , Postoperative Complications/epidemiology , Prosthesis Failure , Aortic Valve/surgery , Aortic Valve Stenosis/surgery , Heart Valve Prosthesis Implantation/methodsABSTRACT
Electron bifurcation is an energy-conservation mechanism in which a single enzyme couples an exergonic reaction with an endergonic one. Heterotetrameric EtfABCX drives the reduction of low-potential ferredoxin (E°' â¼ -450 mV) by oxidation of the midpotential NADH (E°' = -320 mV) by simultaneously coupling the reaction to reduction of the high-potential menaquinone (E°' = -74 mV). Electron bifurcation occurs at the NADH-oxidizing bifurcating-flavin adenine dinucleotide (BF-FAD) in EtfA, which has extremely crossed half-potentials and passes the first, high-potential electron to an electron-transferring FAD and via two iron-sulfur clusters eventually to menaquinone. The low-potential electron on the BF-FAD semiquinone simultaneously reduces ferredoxin. We have expressed the genes encodingThermotoga maritimaEtfABCX in E. coli and purified the EtfABCX holoenzyme and the EtfAB subcomplex. The bifurcation activity of EtfABCX was demonstrated by using electron paramagnetic resonance (EPR) to follow accumulation of reduced ferredoxin. To elucidate structural factors that impart the bifurcating ability, EPR and NADH titrations monitored by visible spectroscopy and dye-linked enzyme assays have been employed to characterize four conserved residues, R38, P239, and V242 in EtfA and R140 in EtfB, in the immediate vicinity of the BF-FAD. The R38, P239, and V242 variants showed diminished but still significant bifurcation activity. Despite still being partially reduced by NADH, the R140 variant had no bifurcation activity, and electron transfer to its two [4Fe-4S] clusters was prevented. The role of R140 is discussed in terms of the bifurcation mechanism in EtfABCX and in the other three families of bifurcating enzymes.
Subject(s)
Ferredoxins , Thermotoga maritima , Ferredoxins/metabolism , NAD/metabolism , Electrons , Flavin-Adenine Dinucleotide/chemistry , Escherichia coli/genetics , Escherichia coli/metabolism , Vitamin K 2 , Bacteria/metabolism , Electron Transport , Oxidation-Reduction , Archaea/metabolismABSTRACT
Background Many Americans are informal caregivers providing unpaid care for their loved ones living with chronic conditions, such as dementia and heart failure. As the US population continues to age and live longer with more complex chronic conditions, informal caregivers play an increasingly important role in the care of older adults with functional impairment and multiple comorbidities. Caregivers face many challenges in managing the health of themselves and their loved ones, including physical, emotional, and financial burdens, which may potentially vary by race and ethnicity. Therefore, it is critical to develop culturally tailored solutions, such as smart technology, aimed at improving the quality of life of informal caregivers and care recipients from diverse backgrounds. Methods Data were collected from a convenient sample of 69 informal caregivers in Texas who were members or volunteers for either the International Buddhist Progress Society-Dallas (IBPS Dallas) or University of Texas Medical Branch (UTMB). Caregivers answered questions about their caregiving experiences, including the type of care they provided, challenges they faced, and lessons learned. Responses were stratified by race/ethnicity (White, Hispanic, or Asian American) to assess for potential cultural differences in caregiving experiences. A chi-squared test and one-way analysis of variance (ANOVA) were conducted. Results White, Hispanic, and Asian American caregivers all reported high non-medical related needs. White, Hispanic, and Asian American care recipients all had a high degree of neurological disease and functional impairment. White and Hispanic caregivers were also more likely to offer emotional support (p=0.007) and financial support (p=0.025) than Asian American caregivers. Asian American caregivers reported greater worry about the health-related knowledge of their family members (p=0.040) than White and Hispanic caregivers. Hispanic (18.8%) and Asian American caregivers (12.5%) reported the least knowledge of caregiving-related government policies than White caregivers (43.2%) (p=0.025). Hispanic (18.8%) and Asian American caregivers (18.8%) also reported the least knowledge of available support programs and services for care recipients (p=0.001). Conclusions White, Hispanic, and Asian American informal caregivers vary in their types of worries, care provided, and challenges faced. Our study found that Asian American caregivers reported greater worry about the health-related knowledge of their family members than White and Hispanic caregivers. White caregivers were better at navigating government resources and caregiver support programs than Hispanic and Asian American caregivers. While race and ethnicity are potential factors for these observed differences, several other factors may have played a role, including age, gender, income, education, patient diagnosis, and disease severity. Future research should consider these factors and evaluate a larger and more diverse sample for more definitive racial and ethnic comparisons. Understanding disparities in caregiving experiences is a critical initial step to developing culturally appropriate interventions to reduce caregiving burden and promote the health and well-being of both patients and their informal caregivers from diverse backgrounds.
ABSTRACT
INTRODUCTION: Aging is associated with significant alterations in physical, cognitive, and emotional functions, predisposing older adults to multimorbidity and functional dependence that necessitate assistance with the activity of daily living (ADL) and medical care from caregivers. With a substantial increase in the aging population comes a growing demand for caregivers, particularly informal caregivers who provide unpaid care to older adults with complex needs. However, they face substantial physical, emotional, and financial burdens as they balance caregiving with their family and job demands. AIM: This study aimed to explore key challenges faced by caregivers and the resources they need to address their caregiving burden. Additionally, we wanted to identify whether the number of years of caregiving is associated with their burden. These study findings will inform the design and development of our smartphone app which aims to alleviate the burden of diseases for older adults and the burden of caregiving for caregivers. METHODS: From October to December 2022, we invited 80 self-reported caregivers for an anonymous online survey. The caregivers were located in three cities (Galveston, Houston, and Dallas in Texas) and were affiliated with the International Buddhist Progress Society-Dallas (IBPS Dallas) and the University of Texas Medical Branch (UTMB) Osher Lifelong Learning Institute (OLLI). The collected data were subjected to content analysis through systematic examination for meaningful patterns, themes, and insights. Individual characteristics and caregiving experiences were divided by years of care: 0-4 vs. 5+ years to investigate whether the caregiving burden was affected by the duration of caregiving. RESULTS: The results showed several important insights, including gender dynamics and traditional norms, the advanced age of caregivers, and the prevalent health conditions they are managing. Caregivers' roles ranged from medical (insurance and medication assistance, etc.) at 63.8% to the provision of non-medical related resources (basic needs, utility, transportation, financial assistance, etc.) at 96.3%. Caregiving is also associated with some positive outcomes, such as changes in knowledge and skills (77.5%) with more confidence in ADL support tasks and a deepening of caregiver/care recipient dyad relationships (56.3%). Some faced challenges in navigating complex healthcare and social service systems and others experienced neglect and received inadequate support from the government-supported social services (33.8%). However, there is no significant variation between those with 0-4 and 5+ years of experience across all identified themes, suggesting that the burdens and resource needs of caregivers can manifest early on and are likely to persist beyond the five-year mark. CONCLUSION: Our findings reveal that the number of caregiving years does not significantly influence the types of caregiving burden experienced by caregivers or the resources they require. This indicates the need for providing long-term support to older adults with chronic conditions from the early stage, while also emphasizing the critical role of immediate assistance for caregivers to alleviate caregiving burden. A free-of-charge technology like our smartphone app has the potential to effectively reduce stress for caregivers, offering them support at any time and place. Future studies will focus on evaluating the outcomes of caregivers after utilizing our app.
ABSTRACT
PURPOSE: To evaluate medical student perceptions of a novel ophthalmology resource delivered through facilitated workshops in the core clerkship curriculum. METHODS: We created www.2020sim.com, a free case-based learning (CBL) ophthalmology tool, adapted from NephSIM (www.nephsim.com). The tool was first piloted with the internal medicine (IM) residents. After confirming a need, we focused on undergraduate medical education (UME) by expanding the 20/20 SIM content and partnering with the neurology (pilot academic year [AY] 2020-2021) and pediatric clerkships (pilot AY 2021-2022) to deliver a facilitated one-hour ophthalmology workshop within each clerkship's didactic curriculum. We evaluated the tool using pre- and post-surveys and knowledge assessments. RESULTS: Of 80 IM residents, 33 (41.3%) completed the needs assessment. Of the 25 residents who attended the workshop, 23 (92.0%) completed the exit survey. IM residents reported discomfort in several ophthalmology domains (9 of 14 rated mean score < 3.0), confirming a need. Most (n = 21/23, 91.3%) rated the tool as good/excellent. Of 145 neurology clerkship students, 125 (86.2%) and at least 88 (60.7%) students completed the pre- and post-test/exit surveys, respectively. On average, participants highly rated the tool, perceiving 20/20 SIM to be relevant to their education [4.1 (0.8)]. Mean pre- to post-test knowledge scores increased from 7.5 to 8.5/10.0 points (p < 0.001). Of the 136 pediatric clerkship students, 67 (49.3%) and 51 (37.5%) completed the pre- and post-surveys, respectively. Respondents perceived increased comfort with ophthalmology topics after the facilitated workshop [3.8 (0.8)]. Mean pre- to post-test knowledge scores trended from 1.8 to 2.0/5.0 points (p = 0.30). Collectively, 20/139 (14.4%) of exit survey respondents visited www.2020sim.com within 1 month after the workshop. CONCLUSION: After identifying areas of greatest need with residents, we partnered with core clerkships to deliver cross-disciplinary ophthalmology content in UME. We found high engagement with 20/20 SIM, with trends toward increased knowledge.
Subject(s)
Clinical Clerkship , Education, Medical, Undergraduate , Ophthalmology , Students, Medical , Humans , Child , CurriculumABSTRACT
PHB granules are bacterial organelles that store excess carbohydrates in the form of water-insoluble polyhydroxybutyrate (PHB). The PHB polymerase, phasin (a small amphipathic protein), and active PHB synthesis are essential for the formation of mature PHB granules in Caulobacter crescentus. Granule formation was found to be initiated by the condensation of self-associating PHB polymerase-GFP into foci, closely followed by the recruitment and condensation of phasin-mCherry. Following the active synthesis of PHB and granule maturation, the polymerase dissociates from mature granules and the PHB depolymerase is recruited to the granule. The polymerase directly binds phasin in vitro through its intrinsically disordered N-terminal domain. Thus, granule biogenesis is initiated and controlled by the action of a PHB polymerase and an associated helper protein, phasin, that together synthesize the hydrophobic granule's content while forming the granules protein boundary.
ABSTRACT
Monoclonal antibody (mAb) production using non-human cells can introduce non-human glycan epitopes including terminal galactosyl-α1-3-galactose (α1-3-Gal) moieties. Cetuximab is a commercial mAb associated with causing anaphylaxis in some patients due to the binding of endogenous anti-α1-3-Gal IgE to the Fab (containing bi-α1-3-galactosylated glycans) but not to the Fc region (containing mono-α1-3-galactosylated glycans). Despite being low in abundance in typical commercial mAbs, the inherent sensitivity of cell culture conditions on glycosylation profiles, and the development of novel glycoengineering strategies, novel antibody-based modalities, and biosimilars by various manufacturers with varying procedures, necessitates a better understanding of the structural requirements for anti-α1-3-Gal IgE binding to the Fc region. Herein, we synthesized mAb glycoforms with varying degrees and regioisomers of α1-3-galactosylation and tested their binding to two commercial anti-α1-3-Gal human IgE antibodies derived from a human patient with allergies to red meat (comprising α1-3-Gal epitopes), as well as to the FcγRIIIA receptor. Our results demonstrate that unexpectedly, anti-α1-3-Gal human IgE antibodies can bind to Fc glycans, with bi-α1-3-galactosylation being the most important factor, highlighting that their presence in the Fc region may be considered as a potential critical quality attribute, particularly when using novel platforms in mAb-based biotherapeutics.
Subject(s)
Antibodies, Monoclonal , Biosimilar Pharmaceuticals , Humans , Antibodies, Monoclonal/chemistry , Epitopes , Galactose/chemistry , Polysaccharides/chemistry , Immunoglobulin EABSTRACT
Telomeres are environment-sensitive regulators of health and aging. Here,we present telomere DNA length analysis of two reef-building coral genera revealing that the long- and short-term water thermal regime is a key driver of between-colony variation across the Pacific Ocean. Notably, there are differences between the two studied genera. The telomere DNA lengths of the short-lived, more stress-sensitive Pocillopora spp. colonies were largely determined by seasonal temperature variation, whereas those of the long-lived, more stress-resistant Porites spp. colonies were insensitive to seasonal patterns, but rather influenced by past thermal anomalies. These results reveal marked differences in telomere DNA length regulation between two evolutionary distant coral genera exhibiting specific life-history traits. We propose that environmentally regulated mechanisms of telomere maintenance are linked to organismal performances, a matter of paramount importance considering the effects of climate change on health.
Subject(s)
Anthozoa , Animals , Anthozoa/genetics , Coral Reefs , Temperature , Seasons , DNA/geneticsABSTRACT
Environmental toxicant exposure, including air pollution, is increasing worldwide. However, toxicant exposures are not equitably distributed. Rather, low-income and minority communities bear the greatest burden, along with higher levels of psychosocial stress. Both air pollution and maternal stress during pregnancy have been linked to neurodevelopmental disorders such as autism, but biological mechanisms and targets for therapeutic intervention remain poorly understood. We demonstrate that combined prenatal exposure to air pollution (diesel exhaust particles, DEP) and maternal stress (MS) in mice induces social behavior deficits only in male offspring, in line with the male bias in autism. These behavioral deficits are accompanied by changes in microglial morphology and gene expression as well as decreased dopamine receptor expression and dopaminergic fiber input in the nucleus accumbens (NAc). Importantly, the gut-brain axis has been implicated in ASD, and both microglia and the dopamine system are sensitive to the composition of the gut microbiome. In line with this, we find that the composition of the gut microbiome and the structure of the intestinal epithelium are significantly shifted in DEP/MS-exposed males. Excitingly, both the DEP/MS-induced social deficits and microglial alterations in males are prevented by shifting the gut microbiome at birth via a cross-fostering procedure. However, while social deficits in DEP/MS males can be reversed by chemogenetic activation of dopamine neurons in the ventral tegmental area, modulation of the gut microbiome does not impact dopamine endpoints. These findings demonstrate male-specific changes in the gut-brain axis following DEP/MS and suggest that the gut microbiome is an important modulator of both social behavior and microglia.
Subject(s)
Dopamine , Microglia , Pregnancy , Female , Mice , Male , Animals , Microglia/metabolism , Dopamine/metabolism , Social Behavior , Vehicle Emissions , Dopaminergic NeuronsABSTRACT
Electron-bifurcating flavoproteins catalyze the tightly coupled reduction of high- and low-potential acceptors using a median-potential electron donor, and are invariably complex systems with multiple redox-active centers in two or more subunits. Methods are described that permit, in favorable cases, the deconvolution of spectral changes associated with reduction of specific centers, making it possible to dissect the overall process of electron bifurcation into individual, discrete steps.
Subject(s)
Electrons , Flavoproteins , Oxidation-Reduction , Catalysis , Electron TransportABSTRACT
Environmental toxicant exposure, including air pollution, is increasing worldwide. However, toxicant exposures are not equitably distributed. Rather, low-income and minority communities bear the greatest burden, along with higher levels of psychosocial stress. Both air pollution and maternal stress during pregnancy have been linked to neurodevelopmental disorders such as autism, but biological mechanisms and targets for therapeutic intervention remain poorly understood. We demonstrate that combined prenatal exposure to air pollution (diesel exhaust particles, DEP) and maternal stress (MS) in mice induces social behavior deficits only in male offspring, in line with the male bias in autism. These behavioral deficits are accompanied by changes in microglial morphology and gene expression as well as decreased dopamine receptor expression and dopaminergic fiber input in the nucleus accumbens (NAc). Importantly, the gut-brain axis has been implicated in ASD, and both microglia and the dopamine system are sensitive to the composition of the gut microbiome. In line with this, we find that the composition of the gut microbiome and the structure of the intestinal epithelium are significantly shifted in DEP/MS-exposed males. Excitingly, both the DEP/MS-induced social deficits and microglial alterations in males are prevented by shifting the gut microbiome at birth via a cross-fostering procedure. However, while social deficits in DEP/MS males can be reversed by chemogenetic activation of dopamine neurons in the ventral tegmental area, modulation of the gut microbiome does not impact dopamine endpoints. These findings demonstrate male-specific changes in the gut-brain axis following DEP/MS and suggest that the gut microbiome is an important modulator of both social behavior and microglia.
ABSTRACT
Purpose: The purpose of this study was to describe the genetic relationship between smoking and glaucoma. Methods: We used summary-level genetic data for smoking initiation, smoking intensity (cigarettes per day [CPD]), intraocular pressure (IOP), vertical cup-disc ratio, and open-angle glaucoma (OAG) to estimate global genetic correlations (rg) and perform two-sample Mendelian randomization (MR) experiments that explored relations between traits. Finally, we examined associations between smoking genetic risk scores (GRS) and smoking traits with measured IOP and OAG in Rotterdam Study participants. Results: We identified weak inverse rg between smoking- and glaucoma-related traits that were insignificant after Bonferroni correction. However, MR analysis revealed that genetically predicted smoking initiation was associated with lower IOP (-0.18 mm Hg per SD, 95% confidence interval [CI] = -0.30 to -0.06, P = 0.003). Furthermore, genetically predicted smoking intensity was associated with decreased OAG risk (odds ratio [OR] = 0.74 per SD, 95% CI = 0.61 to 0.90, P = 0.002). In the Rotterdam Study, the smoking initiation GRS was associated with lower IOP (-0.09 mm Hg per SD, 95% CI = -0.17 to -0.01, P = 0.04) and lower odds of OAG (OR = 0.84 per SD, 95% CI = 0.73 to 0.98, P = 0.02) in multivariable-adjusted analyses. In contrast, neither smoking history nor CPD was associated with IOP (P ≥ 0.38) or OAG (P ≥ 0.54). Associations between the smoking intensity GRS and glaucoma traits were null (P ≥ 0.13). Conclusions: MR experiments and GRS generated from Rotterdam Study participants support an inverse relationship between smoking and glaucoma. Translational Relevance: Understanding the genetic drivers of the inverse relationship between smoking and glaucoma could yield new insights into glaucoma pathophysiology.
Subject(s)
Glaucoma, Open-Angle , Humans , Glaucoma, Open-Angle/epidemiology , Glaucoma, Open-Angle/genetics , Intraocular Pressure/genetics , Tonometry, Ocular , Risk Factors , Smoking/adverse effects , Smoking/epidemiology , Smoking/geneticsSubject(s)
Clinical Clerkship , Students, Medical , Humans , Inpatients , Personnel Staffing and Scheduling , StudentsABSTRACT
BACKGROUND: To describe outcomes and compare the effectiveness of stereotactic body radiotherapy (SBRT) versus 3-dimensional conformal radiotherapy (3DCRT) or intensity-modulated radiotherapy (IMRT) in patients with stage IIA lymph node-negative (N0) non-small cell lung cancer (NSCLC) tumors > 5 cm. METHODS: We used the SEER-Medicare database (2005-2015) to identify patients > 65 years with stage IIA (AJCC TNM7) N0 NSCLC > 5 cm tumors who were treated with SBRT, IMRT, and 3DCRT. We used propensity score methods with inverse probability weighting to compare lung cancer-specific survival (LCSS), overall survival (OS), and toxicity. RESULTS: Of 584 patients, 88 (15%), 140 (24%), and 356 (61%) underwent SBRT, IMRT, and 3DCRT, respectively. The SBRT group was older (P = .004), had more comorbidities (P = .02), smaller tumors (P = .03), and more adenocarcinomas (P < .0001). We found a trend towards higher median unadjusted OS with SBRT compared to IMRT and 3DCRT (19 vs. 13 and 14 months, respectively, P = .37). In our propensity score-adjusted analyses, SBRT was significantly associated with better OS and LCSS compared to IMRT (HROS: 0.78, 95% CI: 0.68-0.89, HRLCSS: 0.70, 95% CI: 0.60-0.81) and 3DCRT (HROS: 0.81, 95% CI: 0.72-0.93, HRLCSS: 0.80, 95% CI: 0.68-0.93). SBRT-treated patients also had lower overall adjusted complication rates compared to IMRT (OR: 0.74, 95% CI: 0.55-0.99) and 3DCRT (OR: 0.53, 95% CI: 0.40-0.71). CONCLUSION: For patients with NSCLC tumors > 5 cm, SBRT trends towards fewer toxicities and improved survival compared to other forms of radiotherapy. Our findings support SBRT as an appropriate treatment strategy for older patients with larger inoperable NSCLC tumors.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Radiosurgery , Radiotherapy, Conformal , Radiotherapy, Intensity-Modulated , United States/epidemiology , Humans , Aged , Carcinoma, Non-Small-Cell Lung/pathology , Radiotherapy, Intensity-Modulated/methods , Lung Neoplasms/pathology , Treatment Outcome , Medicare , Radiotherapy, Conformal/methodsABSTRACT
PURPOSE: To examine the associations of alcohol consumption with glaucoma and related traits, to assess whether a genetic predisposition to glaucoma modified these associations, and to perform Mendelian randomization (MR) experiments to probe causal effects. 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 intraocular pressure (IOP) (n = 109 097), OCT-derived macular inner retinal layer thickness measures (n = 46 236) and glaucoma status (n = 173 407). METHODS: Participants were categorized according to self-reported drinking behaviors. Quantitative estimates of alcohol intake were derived from touchscreen questionnaires and food composition tables. We performed a 2-step analysis, first comparing categories of alcohol consumption (never, infrequent, regular, and former drinkers) before assessing for a dose-response effect in regular drinkers only. Multivariable linear, logistic, and restricted cubic spline regression, adjusted for key sociodemographic, medical, anthropometric, and lifestyle factors, were used to examine associations. We assessed whether any association was modified by a multitrait glaucoma polygenic risk score. The inverse-variance weighted method was used for the main MR analyses. MAIN OUTCOME MEASURES: Intraocular pressure, macular retinal nerve fiber layer (mRNFL) thickness, macular ganglion cell-inner plexiform layer (mGCIPL) thickness, and prevalent glaucoma. RESULTS: Compared with infrequent drinkers, regular drinkers had higher IOP (+0.17 mmHg; P < 0.001) and thinner mGCIPL (-0.17 µm; P = 0.049), whereas former drinkers had a higher prevalence of glaucoma (odds ratio, 1.53; P = 0.002). In regular drinkers, alcohol intake was adversely associated with all outcomes in a dose-dependent manner (all P < 0.001). Restricted cubic spline regression analyses suggested nonlinear associations, with apparent threshold effects at approximately 50 g (â¼6 UK or 4 US alcoholic units)/week for mRNFL and mGCIPL thickness. Significantly stronger alcohol-IOP associations were observed in participants at higher genetic susceptibility to glaucoma (Pinteraction < 0.001). Mendelian randomization analyses provided evidence for a causal association with mGCIPL thickness. CONCLUSIONS: Alcohol intake was consistently and adversely associated with glaucoma and related traits, and at levels below current United Kingdom (< 112 g/week) and United States (women, < 98 g/week; men, < 196 g/week) guidelines. Although we cannot infer causality definitively, these results will be of interest to people with or at risk of glaucoma and their advising physicians. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.
ABSTRACT
Mucosal-associated Invariant T (MAIT) cells are an innate-like T cell subset that recognize a broad array of microbial pathogens, including respiratory pathogens. Here we investigate the transcriptional profile of MAIT cells localized to the human lung, and postulate that MAIT cells may play a role in maintaining homeostasis at this mucosal barrier. Using the MR1/5-OP-RU tetramer, we identified MAIT cells and non-MAIT CD8+ T cells in lung tissue not suitable for transplant from human donors. We used RNA-sequencing of MAIT cells compared to non-MAIT CD8+ T cells to define the transcriptome of MAIT cells in the human lung. We show that, as a population, lung MAIT cells are polycytotoxic, secrete the directly antimicrobial molecule IL-26, express genes associated with persistence, and selectively express cytokine and chemokine- related molecules distinct from other lung-resident CD8+ T cells, such as interferon-γ- and IL-12- receptors. These data highlight MAIT cells' predisposition to rapid pro-inflammatory cytokine responsiveness and antimicrobial mechanisms in human lung tissue, concordant with findings of blood-derived counterparts, and support a function for MAIT cells as early sensors in the defense of respiratory barrier function.
Subject(s)
Anti-Infective Agents , Mucosal-Associated Invariant T Cells , Anti-Bacterial Agents , CD8-Positive T-Lymphocytes , Cytokines , Humans , LungABSTRACT
Persister cells are responsible for relapses of infections common in cystic fibrosis and chronic suppurative otitis media (CSOM). Yet, there are no Food and Drug Administration (FDA) approved antibiotics to eradicate persister cells. Frustratingly, the global preclinical bacterial pipeline does not contain antibacterial agents targeting persister cells. Therefore, we report a nontraditional antimicrobial chemotherapy strategy based on gold nanoclusters adjuvant to eradicate persister cells by existing antibiotics belonging to that different class. Compared to killing with antibiotics alone, combining antibiotics and AuNC@CPP sterilizes persister cells and biofilms. Enhanced killing of up to 4 orders of magnitude in a validated mouse model of CSOM with Pseudomonas aeruginosa infection was observed when combining antibiotics and AuNC@CPP, informing a potential approach to improve the treatment of CSOM. We established that the mechanism of action of AuNC@CPP is due to disruption of the proton gradient and membrane hyperpolarization. The method presented here could compensate for the lack of new antibiotics to combat persister cells. This method could also benefit the current effort to slow resistance development because AuNC@CPP abolished the emergence of drug-resistant strains induced by antibiotics.
Subject(s)
Anti-Bacterial Agents , Pseudomonas aeruginosa , Animals , Anti-Bacterial Agents/pharmacology , Biofilms , Gold/pharmacology , Mice , Microbial Sensitivity TestsABSTRACT
Introduction: Mycosis fungoides (MF), the most prevalent form of cutaneous T-cell lymphoma (CTCL), has been associated with a variety of environmental and occupational exposures. Flame-retardant clothing (FRC), in contrast to flame-resistant clothing, is chemically treated and may constitute a previously unrecognized occupational hazard. Objectives: To report an association between FRC and MF. Methods: After encountering several young male patients whose onset of MF coincided with the occupational use of FRC and occupation as fire fighters, we did a retrospective search. Additional biopsy proven MF patients with use of FRC were identified by the EPIC electronic medical record using the search terms "CTCL, mycosis fungoides, flame, and flame-retardant." Results: Eight MF patients, all males, ranging in age from 31 years to 64 years (median age, 35 years) with exposure to FRC were identified. MF remission was noted in three patients who discontinued FRC use and in one patient who used a cotton undershirt barrier, while disease persistence was noted in one patient who continued to use FRC. Conclusions: FRC appears to be associated with development of MF through chronic antigen stimulation. Use of FRC is an occupational hazard for fire fighters. Any patient whose MF coincides with use of FRC should avoid further exposure through avoidance or switching to clothing made from inherently flame-resistant fibers.