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In classic galactosemia (CG) patients, aldose reductase (AR) converts galactose to galactitol. In a phase 1/2, placebo-controlled study (NCT04117711), safety, pharmacokinetics (PK), and pharmacodynamics (PD) of govorestat were evaluated after single and multiple ascending doses (0.5-40 mg/kg) in healthy adults (n = 81) and CG patients (n = 14). Levels of govorestat in plasma and cerebrospinal fluid (CSF) and blood levels of galactitol, galactose, and galactose-1-phosphate (Gal-1p) were measured for population PK and PK/PD analyses. Govorestat was well tolerated. Adverse event frequency was comparable between placebo and govorestat. Govorestat PK displayed a 2-compartment model with sequential zero- and first-order absorption, and no effect of demographic factors. Multiple-dose PK of govorestat was linear in the 0.5-40 mg/kg range, and CSF levels increased dose dependently. Elimination half-life was â¼10 h. PK/PD modeling supported once-daily dosing. Change from baseline in galactitol was -15% ± 9% with placebo and -19% ± 10%, -46% ± 4%, and -51% ± 5% with govorestat 5, 20, and 40 mg/kg, respectively, thus was similar for 20 and 40 mg/kg. Govorestat did not affect galactose or Gal-1p levels. In conclusion, govorestat displayed a favorable safety, PK, and PD profile in humans, and reduced galactitol levels in the same magnitude (â¼50%) as in a rat model of CG that demonstrated an efficacy benefit on neurological, behavioral, and ocular outcomes.
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AIMS: To evaluate relationships between plasma concentrations of belantamab mafodotin, total monoclonal antibody, and its payload and changes in electrocardiogram (ECG) parameters in patients with relapsed or refractory multiple myeloma from the DREAMM-1 and DREAMM-2 studies. METHODS: Hysteresis plots and linear regression analyses of pharmacokinetic (PK) analyte (belantamab mafodotin, total monoclonal antibody, and cytotoxic cysteine-maleimidocaproyl monomethyl auristatin F payload) concentrations vs. time-matched ECG parameters (absolute/change from baseline in QT interval corrected for RR interval [QTc/ΔQTc] and QT interval corrected for heart rate by Fridericia's formula [QTcF/ΔQTcF]) were performed. Concentrations of PK analyte required for a 10-ms increase in QTc in DREAMM-2 were calculated via simulation, as was the probability of ΔQTc/ΔQTcF exceeding 10 ms for the expected Cmax of PK analyte concentrations associated with the doses (2.5 and 3.4 mg/kg) administered in DREAMM-2. RESULTS: Time-matched PK and ECG data from 290 patients (DREAMM-1, n = 73; DREAMM-2, n = 217) were analysed. Hysteresis plots did not clearly indicate any concentration-related prolongation in QTc or QTcF; regression analyses indicated a very small rate of increase in ΔQTc and ΔQTcF with increasing concentrations of PK analytes. Calculated concentrations of PK analyte required for a 10-ms prolongation in QTc were higher than the maximum analyte concentrations observed following treatment with belantamab mafodotin in DREAMM-2; the probability that each dose would prolong ΔQTc and ΔQTcF by >10 ms was 0 and <0.25%, respectively. CONCLUSION: This study of belantamab mafodotin and its payload did not provide evidence of QT prolongation in patients with relapsed or refractory multiple myeloma at clinically relevant doses.
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Background Few studies have examined patient experiences of the Patient Centred Medical Home (PCMH). This qualitative study explores the experiences of patients of an urban Aboriginal Community Controlled Health Service during its transition to a model of a PCMH. Methods Twenty-eight community members who were registered as patients of an urban Aboriginal Community Controlled Health Service were purposively recruited to participate in yarning interviews. Yarns were conducted using a guide containing open-ended questions in the same domains as those used in patient satisfaction surveys at the participating clinic. Data from yarns were analysed by Aboriginal and non-Indigenous researchers using thematic analysis. The interpretations of Aboriginal and Torres Strait Islander researchers were privileged in the analysis. Results Key themes highlighted the importance of relationships, connectedness, and personal growth and empowerment to community members' health and wellbeing, which they described as a journey of healing and recovery. Delays in implementing a process to empanel patients in a care team meant that most community members were unaware a PCMH had been implemented. However, community members commonly reported a more welcoming environment, more contact with the same doctor and more involvement of Aboriginal Health Workers in their care. Conclusions Aboriginal and Torres Strait Islander community members' narratives of their experiences bear evidence of the acceptability of a PCMH model for delivery in Aboriginal Community Controlled Health Services to improve relational care between patients and health staff. A patient-directed empanelment process has been implemented to better connect patients to their care team in the clinic, and the role of the Aboriginal Health Worker reshaped to strengthen connections between patients and their care team in and outside the clinic.
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Serviços de Saúde do Indígena , Havaiano Nativo ou Outro Ilhéu do Pacífico , Assistência Centrada no Paciente , Pesquisa Qualitativa , Humanos , Havaiano Nativo ou Outro Ilhéu do Pacífico/psicologia , Assistência Centrada no Paciente/métodos , Feminino , Masculino , Serviços de Saúde do Indígena/organização & administração , Adulto , Pessoa de Meia-Idade , Satisfação do Paciente , Entrevistas como Assunto , Serviços Urbanos de Saúde , Povos Aborígenes Australianos e Ilhéus do Estreito de TorresRESUMO
BACKGROUND: Autism spectrum disorder (hereafter referred to as autism) is characterised by difficulties with (i) social communication, social interaction, and (ii) restricted and repetitive interests and behaviours. Estimates of autism prevalence within the criminal justice system (CJS) vary considerably, but there is evidence to suggest that the condition can be missed or misidentified within this population. Autism has implications for an individual's journey through the CJS, from police questioning and engagement in court proceedings through to risk assessment, formulation, therapeutic approaches, engagement with support services, and long-term social and legal outcomes. METHODS: This consensus based on professional opinion with input from lived experience aims to provide general principles for consideration by United Kingdom (UK) CJS personnel when working with autistic individuals, focusing on autistic offenders and those suspected of offences. Principles may be transferable to countries beyond the UK. Multidisciplinary professionals and two service users were approached for their input to address the effective identification and support strategies for autistic individuals within the CJS. RESULTS: The authors provide a consensus statement including recommendations on the general principles of effective identification, and support strategies for autistic individuals across different levels of the CJS. CONCLUSION: Greater attention needs to be given to this population as they navigate the CJS.
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Transtorno do Espectro Autista , Transtorno Autístico , Humanos , Transtorno Autístico/diagnóstico , Transtorno Autístico/epidemiologia , Transtorno Autístico/terapia , Transtorno do Espectro Autista/diagnóstico , Transtorno do Espectro Autista/epidemiologia , Transtorno do Espectro Autista/terapia , Direito Penal , Comunicação , Reino Unido/epidemiologiaRESUMO
The in vitro oxygen microenvironment profoundly affects the capacity of cell cultures to model physiological and pathophysiological states. Cell culture is often considered to be hyperoxic, but pericellular oxygen levels, which are affected by oxygen diffusivity and consumption, are rarely reported. Here, we provide evidence that several cell types in culture actually experience local hypoxia, with important implications for cell metabolism and function. We focused initially on adipocytes, as adipose tissue hypoxia is frequently observed in obesity and precedes diminished adipocyte function. Under standard conditions, cultured adipocytes are highly glycolytic and exhibit a transcriptional profile indicative of physiological hypoxia. Increasing pericellular oxygen diverted glucose flux toward mitochondria, lowered HIF1α activity, and resulted in widespread transcriptional rewiring. Functionally, adipocytes increased adipokine secretion and sensitivity to insulin and lipolytic stimuli, recapitulating a healthier adipocyte model. The functional benefits of increasing pericellular oxygen were also observed in macrophages, hPSC-derived hepatocytes and cardiac organoids. Our findings demonstrate that oxygen is limiting in many terminally-differentiated cell types, and that considering pericellular oxygen improves the quality, reproducibility and translatability of culture models.
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Adipócitos , Diferenciação Celular , Oxigênio , Oxigênio/metabolismo , Adipócitos/metabolismo , Adipócitos/citologia , Humanos , Técnicas de Cultura de Células/métodos , Animais , Glicólise , Hepatócitos/metabolismo , Hipóxia Celular , Mitocôndrias/metabolismo , Camundongos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Células Cultivadas , Glucose/metabolismo , Macrófagos/metabolismoRESUMO
The heart is a metabolic "omnivore" and adjusts its energy source depending on the circulating metabolites. Human cardiac organoids, a three-dimensional in vitro model of the heart wall, are a useful tool to study cardiac physiology and pathology. However, cardiac tissue naturally experiences shear stress and nutrient fluctuations via blood flow in vivo, whilst in vitro models are conventionally cultivated in a static medium. This necessitates the regular refreshing of culture media, which creates acute cellular disturbances and large metabolic fluxes. To culture human cardiac organoids in a more physiological manner, we have developed a perfused bioreactor for cultures in a 96-well plate format. The designed bioreactor is easy to fabricate using a common culture plate and a 3D printer. Its open system allows for the use of traditional molecular biology techniques, prevents flow blockage issues, and provides easy access for sampling and cell assays. We hypothesized that a perfused culture would create more stable environment improving cardiac function and maturation. We found that lactate is rapidly produced by human cardiac organoids, resulting in large fluctuations in this metabolite under static culture. Despite this, neither medium perfusion in bioreactor culture nor lactate supplementation improved cardiac function or maturation. In fact, RNA sequencing revealed little change across the transcriptome. This demonstrates that cardiac organoids are robust in response to fluctuating environmental conditions under normal physiological conditions. Together, we provide a framework for establishing an easily accessible perfusion system that can be adapted to a range of miniaturized cell culture systems.
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BACKGROUND: Need-altruism (a preference to help people in need) and kin-altruism (a preference to help kin over non-kin) underlie two hypotheses for voluntary blood donation: (i) Need-altruism underlies motivations for volunteer blood donation and (ii) Black people express a stronger preference for kin-altruism, which is a potential barrier to donation. This paper tests these hypotheses and explores how need- and kin-altruism are associated with wider altruistic motivations, barriers, and strategies to encourage donation. METHODS: We assessed need- and kin-altruism, other mechanisms-of-altruism (e.g., reluctant-altruism), barriers, strategies to encourage donation, donor status, and willingness-to-donate across four groups based on ethnicity (Black; White), nationality (British; Nigerian), and country-of-residence: (i) Black-British people (n = 395), and Black-Nigerian people (ii) in the UK (n = 97) or (iii) across the rest of the world (n = 101), and (v) White-British people in the UK (n = 452). We also sampled a Black-Nigerian Expert group (n = 60). RESULTS: Need-altruism was higher in donors and associated with willingness-to-donate in non-donors. Levels of kin-altruism did not differ between Black and White people, but need-altruism was lower in Black-British people. Kin-altruism was associated with a preference for incentives, and need-altruism with a preference for recognition (e.g., a thank you) as well as an increased willingness-to-donate for Black non-donors. Need-altruism underlies a blood-donor-cooperative-phenotype. CONCLUSION: Need-altruism is central to blood donation, in particular recruitment. Lower need-altruism may be a specific barrier for Black-British people. Kin-altruism is important for Black non-donors. The blood donor cooperative phenotype deserves further consideration. Implications for blood services are discussed.
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Altruísmo , Doadores de Sangue , População Europeia , População da África Ocidental , Humanos , Motivação , População Negra , População BrancaRESUMO
OBJECTIVE: To compare long-term effectiveness of Standard (UV intensity: 3 mW/cm2, duration: 30 min) vs Accelerated (UV intensity: 9 mW/cm2, duration: 10 min) corneal cross-linking (CXL) for stabilising keratoconus. METHODS: Data for this observational study were captured through a web-based registry system from the routine clinical practice (15 sites across Australia, New Zealand and Italy). The outcomes were compared using mixed-effects regression models. A total of 100 eyes (75 patients) who had standard CXL and 76 eyes (66 patients) who had accelerated CXL, with a follow-up visit at five-year post-CXL were included. RESULTS: Both CXL protocols were effective and safe in stabilising keratoconus and improving outcomes. The adjusted mean changes (95% CI) in outcomes were better in standard CXL than in accelerated CXL [visual acuity gain, 10.2 (7.9-12.5) vs 4.9 (1.6-8.2) logMAR letters; pinhole visual acuity 5.7 (3.5-7.8) vs 0.2 (-2.2 to 2.5) logMAR letters; Kmax -1.8 (-4.3 to 0.6) vs 1.2 (-1.5 to 3.9)D; K2 -0.9 (-2.2 to 0.3) vs 0.1 (-1.3 to 1.6)D; MCT -3.0 (-13.7 to 7.7) vs -11.8 (-23.9 to 0.4) µm (p values for visual acuity, pinhole visual acuity, Kmax: <0.05; for K2 and MCT: >0.05)]. The frequency of adverse events at the 5-year follow-up visit was low in both groups [standard, 5 (5%; haze 3; scarring 1, epithelial defect 1) and accelerated 3 (3.9%; haze 2, scarring 1)]. CONCLUSIONS: Both standard and accelerated CXL were safe and effective procedures for stabilising keratoconus in the long term. The standard CXL resulted in greater improvements in visual acuity and keratometry.
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Ceratocone , Fotoquimioterapia , Humanos , Ceratocone/tratamento farmacológico , Crosslinking Corneano , Fármacos Fotossensibilizantes/uso terapêutico , Fotoquimioterapia/métodos , Riboflavina/uso terapêutico , Raios Ultravioleta , Cicatriz , Colágeno/uso terapêutico , Reagentes de Ligações Cruzadas/uso terapêutico , Sistema de Registros , Topografia da Córnea/métodos , SeguimentosRESUMO
STUDY OBJECTIVES: This study investigated the differences in melatonin circadian timing and output, sleep characteristics, and cognitive function in myopic and non-myopic (or emmetropic) children, aged 8-15 years. METHODS: Twenty-six myopes (refractive error [meanâ ±â standard error mean] -2.06â ±â 0.23 diopters) and 19 emmetropes (-0.06â ±â 0.04 diopters), aged 11.74â ±â 2.31 years were recruited. Circadian timing was assessed using salivary dim-light melatonin onset (DLMO), collected half-hourly for 7 hours, beginning 5 hours before and finishing 2 hours after individual average sleep onset in a sleep laboratory. Nocturnal melatonin output was assessed via aMT6s levels from urine voids collected from 05:30 pm to 8:00 am the following morning. Actigraphy-derived objective sleep timing were acquired for a week prior to the sleep laboratory visit. Cognitive assessments of sustained attention (using psychomotor vigilance task [PVT]) and working memory (using digit spans) were performed on the night of sleep laboratory. RESULTS: Myopic children (9:07 pmâ ±â 14 minutes) exhibited a DLMO phase-delay of 1 hour 8 minutes compared to emmetropes (7:59 pmâ ±â 13 minutes), pâ =â 0.002. aMT6s melatonin levels were significantly lower among myopes (18.70â ±â 2.38) than emmetropes (32.35â ±â 6.93, pâ =â 0.001). Myopes also exhibited significantly delayed sleep onset, delayed wake-up time, poor and reduced sleep, and more evening-type diurnal preference than emmetropes (all pâ <â 0.05). Finally, myopes showed a slower reaction time in the PVT (pâ <â 0.05), but not digit span tasks at night. CONCLUSIONS: These findings suggest a potential association between circadian rhythm dysfunction and myopia in children.
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Melatonina , Miopia , Criança , Humanos , Sono , Ritmo Circadiano , VigíliaRESUMO
Genomic regulation of cardiomyocyte differentiation is central to heart development and function. This study uses genetic loss-of-function human-induced pluripotent stem cell-derived cardiomyocytes to evaluate the genomic regulatory basis of the non-DNA-binding homeodomain protein HOPX. We show that HOPX interacts with and controls cardiac genes and enhancer networks associated with diverse aspects of heart development. Using perturbation studies in vitro, we define how upstream cell growth and proliferation control HOPX transcription to regulate cardiac gene programs. We then use cell, organoid, and zebrafish regeneration models to demonstrate that HOPX-regulated gene programs control cardiomyocyte function in development and disease. Collectively, this study mechanistically links cell signaling pathways as upstream regulators of HOPX transcription to control gene programs underpinning cardiomyocyte identity and function.
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Células-Tronco Pluripotentes Induzidas , Miócitos Cardíacos , Animais , Humanos , Miócitos Cardíacos/metabolismo , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Peixe-Zebra/metabolismo , Diferenciação Celular/genética , Proliferação de CélulasRESUMO
The majority of children with developmental coordination disorder (DCD) struggle with static and dynamic balance, yet there is limited understanding of the underlying neuromechanical mechanisms that underpin poor balance control in these children. Eighteen children with DCD and seven typically developing (TD) children aged 7-10 years stood with eyes open on a moveable platform progressively translated antero-posteriorly through three frequencies (0.1, 0.25 and 0.5 Hz). Myoelectric activity of eight leg muscles, whole-body 3D kinematics and centre of pressure were recorded. At each frequency, postural data were divided into transition-state and steady-state cycles. Data were analyzed using a linear mixed model with follow-up Tukey's pairwise comparisons. At the slowest frequency, children with DCD behaved like age-matched TD controls. At the fastest frequency, children with DCD took a greater number of steps, had a greater centre of mass variability, had a greater centre of pressure area, and tended to activate their muscles earlier and for longer than TD children. Children with DCD did not alter their postural response following prolonged exposure to platform movement, however they made more, non-structured postural adjustments in the medio-lateral direction as task difficulty increased. At the faster oscillation frequencies, children with DCD adopted a different muscle recruitment strategy to TD children. Activating their muscles earlier and for longer may suggest that children with DCD attempt to predict and react to postural disturbances, however the resulting anticipatory muscle excitation patterns do not seem as finely tuned to the perturbation as those demonstrated by TD children. Future work should examine the impact of balance training interventions on the muscle recruitment strategies of children with DCD, to ensure optimal interventions can be prescribed.
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BACKGROUND: The patient-centred medical home (PCMH) is a model of team-based primary care that is patient-centred, coordinated, accessible, and focused on quality and safety. In response to substantial population growth and increasing demand on existing primary care services, the Institute for Urban Indigenous Health (IUIH) developed the IUIH System of Care-2 (ISoC2), based on an international Indigenous-led PCMH. ISoC2 was piloted at an urban Aboriginal and Torres Strait Islander Community-Controlled Health Service in South-East Queensland between 2019-2020, with further adaptations made to ensure its cultural and clinical relevance to local Aboriginal and Torres Strait Islander people. Little is known on the implementation and impact of PCMH in the Australian Indigenous primary care setting. Changes in implementation process measures and outcomes relating to engagement and quality-of-care are described here. METHODS: De-identified routinely collected data extracted from electronic health records for clients regularly attending the service were examined to assess pre-post implementation changes relevant to the study. Process measures included enrolment in PCMH team-based care, and outcome measures included engagement with the health service, continuity-of-care and clinical outcomes. RESULTS: The number of regular clients within the health service increased from 1,186 pre implementation to 1,606 post implementation; representing a small decrease as a proportion of the services' catchment population (38.5 to 37.6%). In clients assigned to a care team (60% by end 2020), care was more evenly distributed between providers, with an increased proportion of services provided by the Aboriginal and Torres Strait Islander Health Worker (16-17% versus 10-11%). Post-implementation, 41% of clients had continuity-of-care with their assigned care team, while total, preventive and chronic disease services were comparable pre- and post-implementation. Screening for absolute cardiovascular disease risk improved, although there were no changes in clinical outcomes. CONCLUSIONS: The increase in the number of regular clients assigned to a team and their even distribution of care among care team members provides empirical evidence that the service is transforming to a PCMH. Despite a complex transformation process compounded by the COVID-19 pandemic, levels of service delivery and quality remained relatively stable, with some improvements in risk factor screening.
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Povos Aborígenes Australianos e Ilhéus do Estreito de Torres , Assistência Centrada no Paciente , Humanos , Austrália/epidemiologia , Projetos PilotoRESUMO
Recent studies in non-human model systems have shown therapeutic potential of nucleoside-modified messenger RNA (modRNA) treatments for lysosomal storage diseases. Here, we assessed the efficacy of a modRNA treatment to restore the expression of the galactosidase alpha (GLA), which codes for α-Galactosidase A (α-GAL) enzyme, in a human cardiac model generated from induced pluripotent stem cells (iPSCs) derived from two individuals with Fabry disease. Consistent with the clinical phenotype, cardiomyocytes from iPSCs derived from Fabry-affected individuals showed accumulation of the glycosphingolipid Globotriaosylceramide (GB3), which is an α-galactosidase substrate. Furthermore, the Fabry cardiomyocytes displayed significant upregulation of lysosomal-associated proteins. Upon GLA modRNA treatment, a subset of lysosomal proteins were partially restored to wild-type levels, implying the rescue of the molecular phenotype associated with the Fabry genotype. Importantly, a significant reduction of GB3 levels was observed in GLA modRNA-treated cardiomyocytes, demonstrating that α-GAL enzymatic activity was restored. Together, our results validate the utility of iPSC-derived cardiomyocytes from affected individuals as a model to study disease processes in Fabry disease and the therapeutic potential of GLA modRNA treatment to reduce GB3 accumulation in the heart.
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Doença de Fabry , Células-Tronco Pluripotentes Induzidas , Humanos , Miócitos Cardíacos , RNA , Doença de Fabry/genética , Doença de Fabry/terapia , RNA MensageiroRESUMO
The cardiac endothelium influences ventricular chamber development by coordinating trabeculation and compaction. However, the endothelial-specific molecular mechanisms mediating this coordination are not fully understood. Here, we identify the Sox7 transcription factor as a critical cue instructing cardiac endothelium identity during ventricular chamber development. Endothelial-specific loss of Sox7 function in mice results in cardiac ventricular defects similar to non-compaction cardiomyopathy, with a change in the proportions of trabecular and compact cardiomyocytes in the mutant hearts. This phenotype is paralleled by abnormal coronary artery formation. Loss of Sox7 function disrupts the transcriptional regulation of the Notch pathway and connexins 37 and 40, which govern coronary arterial specification. Upon Sox7 endothelial-specific deletion, single-nuclei transcriptomics analysis identifies the depletion of a subset of Sox9/Gpc3-positive endocardial progenitor cells and an increase in erythro-myeloid cell lineages. Fate mapping analysis reveals that a subset of Sox7-null endothelial cells transdifferentiate into hematopoietic but not cardiomyocyte lineages. Our findings determine that Sox7 maintains cardiac endothelial cell identity, which is crucial to the cellular cross-talk that drives ventricular compaction and coronary artery development.
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Vasos Coronários , Células Endoteliais , Animais , Camundongos , Vasos Coronários/metabolismo , Células Endoteliais/metabolismo , Miócitos Cardíacos/metabolismo , Regulação da Expressão Gênica , Endotélio/metabolismo , Fatores de Transcrição SOXF/genética , Fatores de Transcrição SOXF/metabolismoRESUMO
Here, we provide a protocol for next-generation human cardiac organoid modeling containing markers of vascularized tissues. We describe steps for cardiac differentiation, harvesting cardiac cells, and generating vascularized human cardiac organoids. We then detail downstream analysis of functional parameters and fluorescence labeling of human cardiac organoids. This protocol is useful for high throughput disease modeling, drug discovery, and providing mechanistic insight into cell-cell and cell-matrix interactions. For complete details on the use and execution of this protocol, please refer to Voges et al.1 and Mills et al.2.
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Comunicação Celular , Organoides , Humanos , Diferenciação Celular , Descoberta de Drogas , CoraçãoRESUMO
Purpose: To elucidate a potential association between the apolipoprotein E (APOE) E4 allele and glaucoma prevalence in large cohorts. Design: A cross-sectional analysis of baseline and prospectively collected cohort data. Participants: UK Biobank (UKBB) participants of genetically determined European ancestry (n = 438 711). Replication analyses were performed using clinical and genotyping data collected from European participants recruited to the Canadian Longitudinal Study of Aging (CLSA; n = 18 199), the Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG; n = 1970), and the Blue Mountains Eye Study (BMES; n = 2440). Methods: Apolipoprotein E alleles and genotypes were determined, and their distributions were compared on the basis of glaucoma status. Similar analyses were performed using positive control outcomes associated with the APOE E4 allele (death, dementia, age-related macular degeneration) and negative control outcomes not associated with the APOE E4 allele (cataract, diabetic eye disease). Outcome phenotypes were also correlated with Alzheimer's dementia (AD), a clinical outcome highly associated with the APOE E4 allele. Main Outcome Measures: Results of APOE E4 genotype-phenotype comparisons were reported as odds ratios (ORs) with 95% confidence intervals (CIs). Replication analyses investigated APOE E4 associations in 2 replication cohorts (CLSA and ANZRAG/BMES). Results: The APOE E4 allele was inversely associated with glaucoma (OR, 0.96; 95% CI, 0.93-0.99; P = 0.016) and both negative controls (cataract: OR, 0.98; 95% CI, 0.96-0.99; P = 0.015; diabetic eye disease: OR, 0.92; 95% CI, 0.87-0.97; P = 0.003) in the UKBB cohort. A paradoxical positive association was observed between AD and both glaucoma (OR, 1.30; 95% CI, 1.08-1.54; P < 0.01) and cataract (OR, 1.15; 1.04-1.28; P = 0.018). No association between the APOE E4 allele and glaucoma was observed in either replication cohort (CLSA: OR, 1.03; 95% CI, 0.89-1.19; P = 0.66; ANZRAG/BMES: OR, 0.97; 95% CI, 0.84-1.12; P = 0.65). Conclusions: A small negative association observed between APOE E4 and glaucoma within the UKBB was not evident in either replication cohort and may represent an artifact of glaucoma underdiagnosis in APOE E4 carriers. Financial Disclosures: The author(s) have no proprietary or commercial interest in any materials discussed in this article.
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PURPOSE: To assess the association between a glaucoma polygenic risk score (PRS) and treatment outcomes in primary open-angle glaucoma. DESIGN: Prospective, observational cohort study. PARTICIPANTS: Participants from the Progression Risk of Glaucoma: Relevant SNPs with Significant Association Study were divided into a cohort with suspect glaucoma who were treatment naive at enrollment and one with early manifest and suspect glaucoma receiving treatment at enrollment. METHODS: A per-allele weighted glaucoma PRS was calculated for 1107 participants. Multivariable mixed-effects Cox proportional regression analysis assessed the association between PRS and time to commencement of intraocular pressure (IOP)-lowering therapy in 416 patients with suspect glaucoma who were treatment naive at study enrollment. Secondary analysis evaluated the association between PRS and escalation of IOP-lowering therapy among 691 patients with suspect and early manifest glaucoma who were receiving IOP-lowering therapy at enrollment. MAIN OUTCOME MEASURES: Commencement or escalation of IOP-lowering therapy. RESULTS: A higher PRS was associated with a greater risk of commencing IOP-lowering therapy within 5 years (hazard ratio [HR], 1.45 per 1 standard deviation [/SD]; 95% confidence interval [CI], 1.27-1.62; P < 0.001). Participants in the upper population-based quintile showed a 3.3 times greater risk of commencing therapy by 5 years than those in the lowest quintile (HR, 3.30; 95% CI, 1.63-6,70; P < 0.001) and a 5.4 times greater risk of commencing IOP-lowering therapy by 2 years than the those in the lowest quintile (HR, 5.45; 95% CI, 2.08-14.25; P < 0.001). A higher PRS was associated with a greater risk of treatment escalation among patients receiving treatment at enrollment (HR, 1.19/SD; 95% CI, 1.09-1.31; P < 0.001). In combined analysis of all participants, participants in the top population-based quintile were at 2.3 times greater risk of requiring initiation or escalation of IOP-lowering therapy than those in the lowest quintile (HR, 2.33; 95% CI, 1.75-3.01; P < 0.001). CONCLUSIONS: This study demonstrated novel associations between glaucoma polygenic risk and risk of commencement or escalation of IOP-lowering therapy, building on previous work highlighting the potential clinical usefulness of genetic risk stratification in glaucoma. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.
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Glaucoma de Ângulo Aberto , Glaucoma , Hipertensão Ocular , Humanos , Glaucoma de Ângulo Aberto/tratamento farmacológico , Glaucoma de Ângulo Aberto/genética , Estudos Prospectivos , Pressão Intraocular , Hipertensão Ocular/tratamento farmacológicoRESUMO
Crosstalk between cardiac cells is critical for heart performance. Here we show that vascular cells within human cardiac organoids (hCOs) enhance their maturation, force of contraction, and utility in disease modeling. Herein we optimize our protocol to generate vascular populations in addition to epicardial, fibroblast, and cardiomyocyte cells that self-organize into in-vivo-like structures in hCOs. We identify mechanisms of communication between endothelial cells, pericytes, fibroblasts, and cardiomyocytes that ultimately contribute to cardiac organoid maturation. In particular, (1) endothelial-derived LAMA5 regulates expression of mature sarcomeric proteins and contractility, and (2) paracrine platelet-derived growth factor receptor ß (PDGFRß) signaling from vascular cells upregulates matrix deposition to augment hCO contractile force. Finally, we demonstrate that vascular cells determine the magnitude of diastolic dysfunction caused by inflammatory factors and identify a paracrine role of endothelin driving dysfunction. Together this study highlights the importance and role of vascular cells in organoid models.
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Células Endoteliais , Miócitos Cardíacos , Humanos , Miócitos Cardíacos/metabolismo , Pericitos/metabolismo , Transdução de Sinais , Organoides/metabolismoRESUMO
Purpose: To assess the association between physical activity and spectral-domain optical coherence tomography (SD-OCT)-measured rates of macular thinning in an adult population with primary open-angle glaucoma. Methods: The correlation between accelerometer-measured physical activity and rates of macular ganglion cell-inner plexiform layer (GCIPL) thinning was measured in 735 eyes from 388 participants of the Progression Risk of Glaucoma: RElevant SNPs with Significant Association (PROGRESSA) study. The association between accelerometer-measured physical activity and cross-sectional SD-OCT macular thickness was then assessed in 8862 eyes from 6152 participants available for analysis in the UK Biobank who had SD-OCT, ophthalmic, comorbidity, and demographic data. Results: Greater physical activity was associated with slower rates of macular GCIPL thinning in the PROGRESSA study (beta = 0.07 µm/y/SD; 95% confidence interval [CI], 0.03-0.13; P = 0.003) after adjustment for ophthalmic, demographic and systemic predictors of macular thinning. This association persisted in subanalyses of participants characterized as glaucoma suspects (beta = 0.09 µm/y/SD; 95% CI, 0.03-0.15; P = 0.005). Participants in the upper tertile (greater than 10,524 steps/d) exhibited a 0.22-µm/y slower rate of macular GCIPL thinning than participants in the lower tertile (fewer than 6925 steps/d): -0.40 ± 0.46 µm/y versus -0.62 ± 0.55 µm/y (P = 0.003). Both time spent doing moderate/vigorous activity and mean daily active calories were positively correlated with rate of macular GCIPL thinning (moderate/vigorous activity: beta = 0.06 µm/y/SD; 95% CI, 0.01-0.105; P = 0.018; active calories: beta = 0.06 µm/y/SD; 95% CI, 0.006-0.114; P = 0.032). Analysis among 8862 eyes from the UK Biobank revealed a positive association between physical activity and cross-sectional total macular thickness (beta = 0.8 µm/SD; 95% CI, 0.47-1.14; P < 0.001). Conclusions: These results highlight the potential neuroprotective benefits of exercise on the human retina.
Assuntos
Glaucoma de Ângulo Aberto , Glaucoma , Adulto , Humanos , Estudos Transversais , Retina , Exercício FísicoRESUMO
PURPOSE: The objective of this study was to compare the effectiveness and safety of short versus standard riboflavin induction times in cross-linking (CXL) for keratoconus. METHODS: A retrospective comparative study was conducted with data from the Save Sight Keratoconus Registry. Inclusion criteria were epithelium-off technique, standard UVA CXL protocol (3 mW/cm 2 for 30 minutes), riboflavin induction for 15 minutes (short) or 30 minutes (standard), and 1 year of follow-up data after CXL. Outcome measures included changes in best-corrected visual acuity (BCVA), keratometry in the steepest meridian (K2), maximum keratometry (Kmax), thinnest pachymetry (TCT), and adverse events. Analysis was conducted using mixed-effects regression models adjusted for age, sex, visual acuity, keratometry, pachymetry, practice, and eye laterality. RESULTS: Two hundred eighty eyes (237 patients; mean, 27.3 ± 10.5 years old; 30% female) were included. The riboflavin induction time was short in 102 eyes (82 patients) and standard in 178 eyes (155 patients). The baseline characteristics (sex, mean age, BCVA, keratometry, and pachymetry [TCT]) were similar between the groups. At the 1-year follow-up visit, no statistically significant differences were observed in flattening in K2 and improvement in BCVA. Greater Kmax flattening [-1.5 diopters (D) vs. -0.5D, P = 0.031] and a greater proportion of >2% increase in TCT (23.5 vs. 11.3, P = 0.034) and haze (29 vs. 15, P = 0.005) were observed with short riboflavin induction. CONCLUSIONS: Short and standard riboflavin induction times achieved similar degrees of flattening in K2 and improvement in vision. Greater improvements in Kmax and TCT were seen with short riboflavin times; however, this group had higher rates of haze.