Clinical and genetic heterogeneity associated with retinal diseases makes stem-cell-based therapies an attractive strategy for personalized medicine. However, we have limited understanding of the ...timing of key events in the developing human retina, and in particular the factors critical for generating the unique architecture of the fovea and surrounding macula. Here we define three key epochs in the transcriptome dynamics of human retina from fetal day (D) 52 to 136. Coincident histological analyses confirmed the cellular basis of transcriptional changes and highlighted the dramatic acceleration of development in the fovea compared with peripheral retina. Human and mouse retinal transcriptomes show remarkable similarity in developmental stages, although morphogenesis was greatly expanded in humans. Integration of DNA accessibility data allowed us to reconstruct transcriptional networks controlling photoreceptor differentiation. Our studies provide insights into human retinal development and serve as a resource for molecular staging of human stem-cell-derived retinal organoids.
•Transcriptomes of developing human retina reveal compartmentalized neurogenesis•Fovea differentiation, including lamination, is complete long before nasal retina•Combined RNA-seq and DNase analysis reveals developmental regulatory networks•Provides a reference for molecular staging of retinal organoids from human stem cells
Hoshino et al. describe transcriptome dynamics and spatiotemporal analyses of developing human retina, demonstrating distinct periods of neurogenesis in the fovea versus nasal retina. Comparison with mouse retinal transcriptomes and integration with open chromatin datasets reveal evolutionary conservation of developmental regulatory networks and unique characteristics of human retinal differentiation.
Optoelectronic effects of sidewall passivation on micro-sized light-emitting diodes (µLEDs) using atomic-layer deposition (ALD) were investigated. Moreover, significant enhancements of the optical ...and electrical effects by using ALD were compared with conventional sidewall passivation method, namely plasma-enhanced chemical vapor deposition (PECVD). ALD yielded uniform light emission and the lowest amount of leakage current for all µLED sizes. The importance of sidewall passivation was also demonstrated by comparing leakage current and external quantum efficiency (EQE). The peak EQEs of 20 × 20 µm
µLEDs with ALD sidewall passivation and without sidewall passivation were 33% and 24%, respectively. The results from ALD sidewall passivation revealed that the size-dependent influences on peak EQE can be minimized by proper sidewall treatment.
Many retinal diseases lead to the loss of retinal neurons and cause visual impairment. The adult mammalian retina has little capacity for regeneration. By contrast, teleost fish functionally ...regenerate their retina following injury, and Müller glia (MG) are the source of regenerated neurons. The proneural transcription factor Ascl1 is upregulated in MG after retinal damage in zebrafish and is necessary for regeneration. Although Ascl1 is not expressed in mammalian MG after injury, forced expression of Ascl1 in mouse MG induces a neurogenic state in vitro and in vivo after NMDA (N-methyl-d-aspartate) damage in young mice. However, by postnatal day 16, mouse MG lose neurogenic capacity, despite Ascl1 overexpression. Loss of neurogenic capacity in mature MG is accompanied by reduced chromatin accessibility, suggesting that epigenetic factors limit regeneration. Here we show that MG-specific overexpression of Ascl1, together with a histone deacetylase inhibitor, enables adult mice to generate neurons from MG after retinal injury. The MG-derived neurons express markers of inner retinal neurons, synapse with host retinal neurons, and respond to light. Using an assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq), we show that the histone deacetylase inhibitor promotes accessibility at key gene loci in the MG, and allows more effective reprogramming. Our results thus provide a new approach for the treatment of blinding retinal diseases.
The developments of high performance InGaN based micro-light-emitting diodes (μLEDs) are discussed. We first review the early demonstrations of μLEDs and the state-of-the-art outstanding achievements ...on the emerging high-quality display and visible-light communication applications. Due to the miniature dimensions of μLEDs, the key understandings and the significant device advancements to achieve excellent energy efficiency are addressed. Lastly, two other critical challenges of μLEDs, namely full-color scheme and mass transfer technique, and their potential solutions are explored for future investigations.
Children and adolescents with attention-deficit/hyperactivity disorder (ADHD) are prone to sustaining trauma that requires emergency department (ED) admission. Methylphenidate (MPH) can reduce ADHD ...symptoms and may thus theoretically reduce the risk of trauma-related ED admission, but previous studies do not make this association clear. This study examines this association.
A total of 17 381 patients aged 6 to 19 years who received MPH prescriptions were identified by using the Clinical Data Analysis & Reporting System (2001-2013). Using a self-controlled case series study design, the relative incidence of trauma-related ED admissions was compared with periods of patient exposure and nonexposure to MPH.
Among 17 381 patients prescribed MPH, 4934 had at least 1 trauma-related ED admission. The rate of trauma-related ED admission was lower during exposed periods compared with nonexposed periods (incidence rate ratio IRR: 0.91 95% confidence interval (CI): 0.86-0.97). The findings were similar only when the incident trauma episode was assessed (IRR: 0.89 95% CI: 0.82-0.96). A similar protective association was found in both genders. In validation analysis using nontrauma-related ED admissions as a negative control outcome, no statistically significant association was found (IRR: 0.99 95% CI: 0.95-1.02). All sensitivity analyses demonstrated consistent results.
This study supports the hypothesis that MPH is associated with a reduced risk of trauma-related ED admission in children and adolescents. A similar protective association was found in both male and female patients. This protective association should be considered in clinical practice.
We aimed to evaluate and characterize the scale and relationships of emergency department (ED) visits and excess mortality associated with the early phase of the COVID-19 pandemic in the territory of ...Hong Kong.
We conducted a territory-wide, retrospective cohort study to compare ED visits and the related impact of the COVID-19 pandemic on mortality. All ED visits at 18 public acute hospitals in Hong Kong between January 1 and August 31 of 2019 (n=1,426,259) and 2020 (n=1,035,562) were included. The primary outcome was all-cause mortality in the 28 days following an ED visit. The secondary outcomes were weekly number of ED visits and diagnosis-specific mortality.
ED visits decreased by 27.4%, from 1,426,259 in 2019 to 1,035,562 in 2020. Overall period mortality increased from 28,686 (2.0%) in 2019 to 29,737 (2.9%) in 2020. The adjusted odds ratio for 28-day, all-cause mortality in the pandemic period of 2020 relative to 2019 was 1.26 (95% confidence interval 1.24 to 1.28). Both sexes, age more than 45 years, all triage categories, all social classes, all ED visit periods, epilepsy (odds ratio 1.58, 95% confidence interval 1.20 to 2.07), lower respiratory tract infection, and airway disease had higher adjusted ORs for all-cause mortality.
A significant reduction in ED visits in the first 8 months of the COVID-19 pandemic was associated with an increase in deaths certified in the ED. The government must make provisions to encourage patients with alarming symptoms, mental health conditions, and comorbidities to seek timely emergency care, regardless of the pandemic.
The aim of candidate universal influenza vaccines is to provide broad protection against influenza A and B viruses. Studies have demonstrated that broadly reactive antibodies require Fc-Fc gamma ...receptor interactions for optimal protection; however, the innate effector cells responsible for mediating this protection remain largely unknown. Here, we examine the roles of alveolar macrophages, natural killer cells, and neutrophils in antibody-mediated protection. We demonstrate that alveolar macrophages play a dominant role in conferring protection provided by both broadly neutralizing and non-neutralizing antibodies in mice. Our data also reveal the potential mechanisms by which alveolar macrophages mediate protection in vivo, namely antibody-induced inflammation and antibody-dependent cellular phagocytosis. This study highlights the importance of innate effector cells in establishing a broad-spectrum antiviral state, as well as providing a better understanding of how multiple arms of the immune system cooperate to achieve an optimal antiviral response following influenza virus infection or immunization.Broadly reactive antibodies that recognize influenza A virus HA can be protective, but the mechanism is not completely understood. Here, He et al. show that the inflammatory response and phagocytosis mediated by the interaction between protective antibodies and macrophages are essential for protection.
New treatments have improved outcomes for patients with relapsed chronic lymphocytic leukemia (CLL), but complete remissions remain uncommon. Venetoclax has a distinct mechanism of action; it targets ...BCL2, a protein central to the survival of CLL cells.
We conducted a phase 1 dose-escalation study of daily oral venetoclax in patients with relapsed or refractory CLL or small lymphocytic lymphoma (SLL) to assess safety, pharmacokinetic profile, and efficacy. In the dose-escalation phase, 56 patients received active treatment in one of eight dose groups that ranged from 150 to 1200 mg per day. In an expansion cohort, 60 additional patients were treated with a weekly stepwise ramp-up in doses as high as 400 mg per day.
The majority of the study patients had received multiple previous treatments, and 89% had poor prognostic clinical or genetic features. Venetoclax was active at all dose levels. Clinical tumor lysis syndrome occurred in 3 of 56 patients in the dose-escalation cohort, with one death. After adjustments to the dose-escalation schedule, clinical tumor lysis syndrome did not occur in any of the 60 patients in the expansion cohort. Other toxic effects included mild diarrhea (in 52% of the patients), upper respiratory tract infection (in 48%), nausea (in 47%), and grade 3 or 4 neutropenia (in 41%). A maximum tolerated dose was not identified. Among the 116 patients who received venetoclax, 92 (79%) had a response. Response rates ranged from 71 to 79% among patients in subgroups with an adverse prognosis, including those with resistance to fludarabine, those with chromosome 17p deletions (deletion 17p CLL), and those with unmutated IGHV. Complete remissions occurred in 20% of the patients, including 5% who had no minimal residual disease on flow cytometry. The 15-month progression-free survival estimate for the 400-mg dose groups was 69%.
Selective targeting of BCL2 with venetoclax had a manageable safety profile and induced substantial responses in patients with relapsed CLL or SLL, including those with poor prognostic features. (Funded by AbbVie and Genentech; ClinicalTrials.gov number, NCT01328626.).
Quantification of injury burden is vital for injury prevention, as it provides a guide for setting policies and priorities. This study generated a set of Hong Kong specific disability weights (DWs) ...derived from patient experiences and hospital records. Patients were recruited from the Accident and Emergency Department (AED) of three major trauma centers in Hong Kong between September 2014 and December 2015 and subsequently interviewed with a focus on health-related quality of life at most three times over a 12-month period. These patient-reported data were then used for estimation of DWs. The burden of injury was determined using the mortality and inpatient data from 2001 to 2012 and then compared with those reported in the UK Burden of Injury (UKBOI) and global burden of diseases (GBD) studies. There were 22,856 mortality cases and 817,953 morbidity cases caused by injuries, in total contributing to 1,027,641 disability-adjusted life years (DALYs) in the 12-year study timeframe. Estimates for DALYs per 100,000 in Hong Kong amounted to 1192, compared with 2924 in UKBOI and 3459 in GBD. Our findings support the use of multiple data sources including patient-reported data and hospital records for estimation of injury burden.
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