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PURPOSE: To estimate and compare cross-sectional scotopic versus mesopic macular sensitivity losses measured by microperimetry, and to report and compare the longitudinal rates of scotopic and mesopic macular sensitivity losses in ABCA4 gene associated Stargardt Disease (STGD1). DESIGN: Multicenter prospective cohort study. METHODS: PARTICIPANTS: 127 molecular confirmed STGD1 patients enrolled from 6 centers in the USA and Europe and followed every 6 months for up to 2 years. OBSERVATION PROCEDURES: The Nidek MP-1S device was used to measure macular sensitivities of the central 20° under mesopic and scotopic conditions. The mean deviations (MD) from normal for mesopic macular sensitivity for the fovea (within 2° eccentricity) and extrafovea (4°−10° eccentricity), and the MD for scotopic sensitivity for the extrafovea were calculated. Linear mixed effects models were used to estimate mesopic and scotopic changes. MAIN OUTCOME MEASURES: Baseline mesopic mean deviation (mMD) and scotopic MD (sMD) and rates of longitudinal changes in the mMDs and sMD. RESULTS: At baseline, all eyes had larger sMD, and the difference between extrafoveal sMD and mMD was 10.7 dB (p

We propose target date funds modified to exploit stock return predictability driven by the variance risk premium. The portfolio rule of these tactical target date funds (TTDFs) is extremely simplified relative to the optimal one, making it easy to implement and to communicate to investors. We show that saving for retirement in TTDFs generates economically large welfare gains, even after we introduce turnover restrictions and transaction costs, and after taking into account parameter uncertainty. This predictability also appears to be uncorrelated with individual household risk, suggesting that households are in a prime position to exploit it. This paper was accepted by Tomasz Piskorski, finance.

Chemogenetics enables precise, noninvasive, and reversible modulation of neural activity via the activation of engineered receptors that are pharmacologically selective to endogenous or exogenous ligands. With recent advances in therapeutic gene delivery, chemogenetics is poised to support novel interventions against neuropsychiatric diseases and disorders. To evaluate its translational potential, we performed a scoping review of applications of chemogenetics that led to the reversal of molecular and behavioral deficits in studies relevant to neuropsychiatric diseases and disorders. In this review, we present these findings and discuss the potential and challenges for using chemogenetics as a precision medicine-based neuromodulation strategy.

Non-human primate (NHP) models are essential for developing and translating new treatments that target neural circuit dysfunction underlying human psychopathology. As a proof-of-concept for treating neuropsychiatric disorders, we used a NHP model of pathological anxiety to investigate the feasibility of decreasing anxiety by chemogenetically (DREADDs [designer receptors exclusively activated by designer drugs]) reducing amygdala neuronal activity. Intraoperative MRI surgery was used to infect dorsal amygdala neurons with AAV5-hSyn-HA-hM4Di in young rhesus monkeys. Invivo microPET studies with [11C]-deschloroclozapine and postmortem autoradiography with [3H]-clozapine demonstrated selective hM4Di binding in the amygdala, and neuronal expression of hM4Di was confirmed with immunohistochemistry. Additionally, because of its high affinity for DREADDs, and its approved use in humans, we developed an individualized, low-dose clozapine administration strategy to induce DREADD-mediated amygdala inhibition. Compared to controls, clozapine selectively decreased anxiety-related freezing behavior in the human intruder paradigm in hM4Di-expressing monkeys, while coo vocalizations and locomotion were unaffected. These results are an important step in establishing chemogenetic strategies for patients with refractory neuropsychiatric disorders in which amygdala alterations are central to disease pathophysiology.

BACKGROUND: The U.K. 100,000 Genomes Project is in the process of investigating the role of genome sequencing in patients with undiagnosed rare diseases after usual care and the alignment of this research with health care implementation in the U.K. National Health Service. Other parts of this project focus on patients with cancer and infection.METHODS: We conducted a pilot study involving 4660 participants from 2183 families, among whom 161 disorders covering a broad spectrum of rare diseases were present. We collected data on clinical features with the use of Human Phenotype Ontology terms, undertook genome sequencing, applied automated variant prioritization on the basis of applied virtual gene panels and phenotypes, and identified novel pathogenic variants through research analysis.RESULTS: Diagnostic yields varied among family structures and were highest in family trios (both parents and a proband) and families with larger pedigrees. Diagnostic yields were much higher for disorders likely to have a monogenic cause (35%) than for disorders likely to have a complex cause (11%). Diagnostic yields for intellectual disability, hearing disorders, and vision disorders ranged from 40 to 55%. We made genetic diagnoses in 25% of the probands. A total of 14% of the diagnoses were made by means of the combination of research and automated approaches, which was critical for cases in which we found etiologic noncoding, structural, and mitochondrial genome variants and coding variants poorly covered by exome sequencing. Cohortwide burden testing across 57,000 genomes enabled the discovery of three new disease genes and 19 new associations. Of the genetic diagnoses that we made, 25% had immediate ramifications for clinical decision making for the patients or their relatives.CONCLUSIONS: Our pilot study of genome sequencing in a national health care system showed an increase in diagnostic yield across a range of rare diseases. (Funded by the National Institute for Health Research and others.).

Highlights • KCNV2-associated retinopathy is a slowly progressive disease with early retinal changes, which are predominantly symmetric between eyes. • Disease course can be unpredictable and may severely affect children and young adults. • Findings suggest a potential window for intervention until 40 years of age, albeit with variability between patients due to macular atrophy., Purpose To describe the detailed retinal phenotype of KCNV2-associated retinopathy. Study design Multicenter international retrospective case series. Methods Review of retinal imaging including fundus autofluorescence (FAF) and optical coherence tomography (OCT), including qualitative and quantitative analyses. Results Three distinct macular FAF features were identified: (1) centrally increased signal (n = 35, 41.7%), (2) decreased autofluorescence (n = 27, 31.1%), and (3) ring of increased signal (n = 37, 44.0%). Five distinct FAF groups were identified based on combinations of those features, with 23.5% of patients changing the FAF group over a mean (range) follow-up of 5.9 years (1.9-13.1 years). Qualitative assessment was performed by grading OCT into 5 grades: (1) continuous ellipsoid zone (EZ) (20.5%); (2) EZ disruption (26.1%); (3) EZ absence, without optical gap and with preserved retinal pigment epithelium complex (21.6%); (4) loss of EZ and a hyporeflective zone at the foveola (6.8%); and (5) outer retina and retinal pigment epithelium complex loss (25.0%). Eighty-six patients had scans available from both eyes, with 83 (96.5%) having the same grade in both eyes, and 36.1% changed OCT grade over a mean follow-up of 5.5 years. The annual rate of outer nuclear layer thickness change was similar for right and left eyes. Conclusions KCNV2-associated retinopathy is a slowly progressive disease with early retinal changes, which are predominantly symmetric between eyes. The identification of a single OCT or FAF measurement as an endpoint to determine progression that applies to all patients may be challenging, although outer nuclear layer thickness is a potential biomarker. Findings suggest a potential window for intervention until 40 years of age.

Introduction To assess inter-device agreement in optical coherence tomography-derived retinal thickness measurements in patients with known macular conditions between spectral-domain and swept-source optical coherence tomography (OCT). Methods Two hundred seventy-two subjects were included in the study. They consisted of 91 male (33.5%) and 181 female (66.5%) subjects, and 132 left (48.5%) and 140 right (51.5%) eyes. Each subject underwent spectral-domain OCT (SD-OCT, Spectralis, Heidelberg Engineering; RTVue XR Avanti XR HD, Optovue) and swept-source OCT (SS-OCT; DRI-OCT-1, Atlantis, Topcon) in a single imaging session performed by the same clinical trial-certified technician. The comparison of retinal thickness reproducibility between devices was performed using Bland-Altman analyses and across the entire data set using the intraclass correlation coefficient (ICC). Results The ICC of the retinal thickness measurements (95% confidence interval) made using all three OCT instruments was 0.81 (0.77-0.84). The mean difference in mean retinal thickness between Spectralis SD-OCT and Topcon SS-OCT was 59.1 μm (95% limit of agreement [LoA] -21.7 to 139.8 μm). The mean difference in mean retinal thickness between Optovue SD-OCT and Topcon SS-OCT was 21.8 μm (95% LoA -34.7 to 78.3 μm). Conclusions Retinal layer thickness measurements vary between SS-OCT and SD-OCT devices. We describe inter-device agreement in retinal thickness between SS-OCT and SD-OCT in patients with macular conditions. Clinicians should be aware of the differences in retinal thickness values when imaging patients using different OCT devices and should consider using the same OCT device model in order to monitor clinical change. Trial registration ClinicalTrials.gov Identifier (NCT02828215).

We evaluated keratin 7 (K7) hepatocellular expression in 92 patients with common types of acute and chronic cholestatic diseases caused by bile duct obstruction/destruction or parenchymal lesions [acute hepatitis (n=20), mixed/pure cholestasis (n=16), primary biliary cholangitis-PBC (n=35), primary sclerosing cholangitis-PSC (n=10), vanishing bile duct syndrome (n=3), complete large bile duct obstruction due to space-occupying lesions (n=8)]. K7 immunohistochemical hepatocellular expression and ductular reaction (DR) were semi-quantitatively assessed. Results were correlated with liver enzyme serum levels, cholestasis type, histological features, hepatocellular Ki67 labelling index (LI) and HepPar1 expression. Hepatocellular K7 expression was detected in 87% (81/92) cases and in all cholestatic disease types with lowest incidence in pure/mixed cholestasis and highest in incomplete bile duct obstruction (iBDO), reaching 100% in PSC. K7-positive hepatocytes had low Ki67 LI (0-5%) retaining HepPar1 expression, irrespective of disease type. PSC cases had high K7 hepatocellular expression even with intact bile ducts, a feature that may aid differential diagnosis of cholestatic syndromes. K7 hepatocellular expression significantly correlated with cholestasis type, bile duct loss and fibrosis stage. It was higher in milder acute cholestatic hepatitis showing inverse correlation with hepatocyte proliferation and serum transaminase levels. In iBDO, younger age independently correlated with high K7 expression, while serum GGT levels showed a nearly significant correlation. Correlation with DR findings implied that K7-positive hepatocytes may result through metaplasia. In conclusion, K7 hepatocellular expression is a sensitive though non-specific marker of cholestasis. It may represent a cytoprotective reaction of resting hepatocytes in cholestasis of longer duration especially in younger patients.

AimTo describe the clinical and molecular features of a novel, autosomal dominant RDH12-retinopathy.MethodsRetrospective cross-sectional study. Twelve individuals from a four-generation British pedigree underwent ophthalmic examination, genotyping using next generation sequencing, including whole genome sequencing and multimodal retinal imaging including fundus photography, optical coherence tomography (OCT), autofluorescence imaging and adaptive optics (AO) scanning light ophthalmoscopy were performed. Visual electrophysiology was performed in a subset.ResultsEight family members were confirmed as affected by genotyping heterozygous for RDH12 c.763delG. Visual acuity ranged from −0.1 to 0.2 logMAR. Affected individuals had constricted visual fields. A parafoveal and peripapillary ring of hyper-autofluorescence was seen initially, and with progression the area of perifoveal hypo-autofluorescence increased to involve the parafoveal area. Mild retinal thinning was identified on OCT imaging with reduction in both foveal total retinal and outer nuclear layer thickness. Cone densities along the temporal meridian were reduced in affected individuals compared with normative values at all temporal eccentricities studied. One individual with incomplete penetrance, was identified as clinically affected primarily on the basis of AO imaging. Full-field electroretinography demonstrated a rod-cone pattern of dysfunction and large-field pattern electroretinography identified peripheral macular dysfunction.ConclusionsThis novel heterozygous variant RDH12 c.763delG is associated with a rod-cone dystrophy with variable expression. Determination of the degree of penetrance may depend on the modality employed to phenotypically characterise an individual. This rare and specific heterozygous (dominant) variant is predicted to result in a gain of function, that causes disease in a gene typically associated with biallelic (recessive) variants.

Purpose To investigate genetics, electrophysiology, and clinical course of KCNV2-associated retinopathy in a cohort of children and adults. Study design This was a multicenter international clinical cohort study. Methods Review of clinical notes and molecular genetic testing. Full-field electroretinography (ERG) recordings, incorporating the international standards, were reviewed and quantified and compared with age and recordings from control subjects. Results In total, 230 disease-associated alleles were identified from 117 patients, corresponding to 75 different KCNV2 variants, with 28 being novel. The mean age of onset was 3.9 years old. All patients were symptomatic before 12 years of age (range, 0-11 years). Decreased visual acuity was present in all patients, and 4 other symptoms were common: reduced color vision (78.6%), photophobia (53.5%), nyctalopia (43.6%), and nystagmus (38.6%). After a mean follow-up of 8.4 years, the mean best-corrected visual acuity (BCVA ± SD) decreased from 0.81 ± 0.27 to 0.90 ± 0.31 logarithm of minimal angle of resolution. Full-field ERGs showed pathognomonic waveform features. Quantitative assessment revealed a wide range of ERG amplitudes and peak times, with a mean rate of age-associated reduction indistinguishable from the control group. Mean amplitude reductions for the dark-adapted 0.01 ERG, dark-adapted 10 ERG a-wave, and LA 3.0 30 Hz and LA3 ERG b-waves were 55%, 21%, 48%, and 74%, respectively compared with control values. Peak times showed stability across 6 decades. Conclusion In KCNV2-associated retinopathy, full-field ERGs are diagnostic and consistent with largely stable peripheral retinal dysfunction. Report 1 highlights the severity of the clinical phenotype and established a large cohort of patients, emphasizing the unmet need for trials of novel therapeutics., Highlights • The current study established the largest and most characterized cohort of molecularly confirmed patients with KCNV2-associated retinopathy. • Report 1 highlights the genetic background, evidence of electroretinography stability over a broad age range, and the severe phenotype of the disease.

Ketamine, a racemic mixture of (S)-ketamine and (R)-ketamine enantiomers, has been used as an anesthetic, analgesic and more recently, as an antidepressant. However, ketamine has known abuse liability (the tendency of a drug to be used in non-medical situations due to its psychoactive effects), which raises concerns for its therapeutic use. (S)-ketamine was recently approved by the United States' FDA for treatment-resistant depression. Recent studies showed that (R)-ketamine has greater efficacy than (S)-ketamine in preclinical models of depression, but its clinical antidepressant efficacy has not been established. The behavioral effects of racemic ketamine have been studied extensively in preclinical models predictive of abuse liability in humans (self-administration and conditioned place preference [CPP]). In contrast, the behavioral effects of each enantiomer in these models are unknown. We show here that in the intravenous drug self-administration model, the gold standard procedure to assess potential abuse liability of drugs in humans, rats self-administered (S)-ketamine but not (R)-ketamine. Subanesthetic, antidepressant-like doses of (S)-ketamine, but not of (R)-ketamine, induced locomotor activity (in an opioid receptor-dependent manner), induced psychomotor sensitization, induced CPP in mice, and selectively increased metabolic activity and dopamine tone in medial prefrontal cortex (mPFC) of rats. Pharmacological screening across thousands of human proteins and at biological targets known to interact with ketamine yielded divergent binding and functional enantiomer profiles, including selective mu and kappa opioid receptor activation by (S)-ketamine in mPFC. Our results demonstrate divergence in the pharmacological, functional, and behavioral effects of ketamine enantiomers, and suggest that racemic ketamine's abuse liability in humans is primarily due to the pharmacological effects of its (S)-enantiomer.

Inherited retinal diseases (IRDs) are a clinically and genetically heterogeneous group of disorders characterised by photoreceptor degeneration or dysfunction. These disorders typically present with severe vision loss that can be progressive, with disease onset ranging from congenital to late adulthood. The advances in genetics, retinal imaging and molecular biology, have conspired to create the ideal environment for establishing treatments for IRDs, with the first approved gene therapy and the commencement of multiple clinical trials. The scope of this review is to familiarise clinicians and scientists with the current management and the prospects for novel therapies for: (1) macular dystrophies, (2) cone and cone-rod dystrophies, (3) cone dysfunction syndromes, (4) Leber congenital amaurosis, (5) rod-cone dystrophies, (6) rod dysfunction syndromes and (7) chorioretinal dystrophies. We also briefly summarise the investigated end points for the ongoing trials.

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the developed world. The identification of the central role of vascular endothelial growth factor (VEGF) in the pathogenesis of neovascular AMD and the introduction of anti-VEGF agents as gold-standard treatment, have drastically changed its prognosis—something yet to be seen in dry AMD. Several therapeutic avenues with a wide variability of targets are currently being investigated in dry AMD. The approaches being investigated to reduce the rate of disease progression include, (1) drugs with antioxidative properties, (2) inhibitors of the complement cascade, (3) neuroprotective agents, (4) visual cycle inhibitors, (5) gene therapy and (6) cell-based therapies. A number of early phase clinical trials have provided promising results, with many more ongoing and anticipated in the near future. In this review, we aim to provide an update of the interventional trials to date and future prospects for the treatment of dry AMD.

Purpose To present the detailed retinal phenotype of patients with Leber Congenital Amaurosis/Early-Onset Severe Retinal Dystrophy (LCA/EOSRD) caused by sequence variants in four genes, either not (n = 1) or very rarely (n = 3) previously associated with the disease. Methods Retrospective case series of LCA/EOSRD from four pedigrees. Chart review of clinical notes, multimodal retinal imaging, electrophysiology, and molecular genetic testing at a single tertiary referral center (Moorfields Eye Hospital, London, UK). Results The mean age of presentation was 3 months of age, with disease onset in the first year of life in all cases. Molecular genetic testing revealed the following disease-causing variants: PRPF8 (heterozygous c.5804G > A), PRPH2 (homozygous c.620_627delinsTA, novel variant), RP1 (homozygous c.4147_4151delGGATT, novel variant) and RPGR (heterozygous c.1894_1897delGACA). PRPF8, PRPH2, and RP1 variants have very rarely been reported, either as unique cases or case reports, with limited clinical data presented. RPGR variants have not previously been associated with LCA/EOSRD. Clinical history and detailed retinal imaging are presented. Conclusions The reported cases extend the phenotypic spectrum of PRPF8-, PRPH2-, RP1-, and RPGR-associated disease, and the genotypic spectrum of LCA/EOSRD. The study highlights the importance of retinal and functional phenotyping, and the importance of specific genetic diagnosis to potential future therapy.

Since the electric grid does not store electrical energy, the demand for electric power must be matched by the production almost instantaneously. The supply-demand balance imposes a severe constraint on the penetration of renewable energy sources – especially wind and solar – in the power production markets of all nations, because solar irradiance and wind energy are not available at all hours of the day and exhibit daily and seasonal variabilities. Using the hourly data of the electric power demand in the Electric Reliability Council of Texas, we calculate the implications of this constraint on the substitution of fossil fuel power plants with renewable energy sources. When the market penetration of renewables increases and the utilization of solar and wind energy sources expands to approximately 25%–30% of the annual electricity production, significant energy storage capacity is needed. Simulations of the entire electric grid are performed to determine the power ratings of the renewable sources and the necessary storage capacity to substitute part or all of the fossil fuel power capacity in Texas with renewable energy sources.

To compare audiometric outcomes and complication rates between primary and revision stapes surgical cases.Retrospective cohort study.Large single-institution database.Data on 809 patients (including 170 revisions) undergoing primary and revision stapes surgery were reviewed, with Pearson chi-square and multivariable logistic regression analysis performed.Rates of postoperative air-bone gap (ABG) closure to ≤10 dB were significantly worse in the revision group (40.2% vs 61.8%,Revision stapes surgery was found to have less predictable and inferior results as compared with primary cases.4 (retrospective observational research).

Objective To determine the contributing factors associated with major depressive disorder (MDD) in SLE patients and examine the association between disease-specific health-related quality of life [lupus quality of life (LupusQoL)] domains and MDD. Methods Depression was assessed by the patient health questionnaire (PHQ)-9, and scores ≥10 indicate MDD. Demographic data, LupusQoL domains, clinical and other features of the SLE patients were described and compared between MDD (PHQ-9 ≥10) and non-MDD (PHQ-9 Results Eighty-eight patients with SLE met eligibility criteria, with a mean (range) age of 48.6 (19–80), mostly female (80%) and with a mean disease duration of 13.2 years. Compared with the non-MDD group, patients with MDD (n = 32, 36%) were more likely to have the following SLE manifestations: mucocutaneous, vascular, ocular, pulmonary and musculoskeletal involvement. Self-rated health described as poor/fair was markedly associated with MDD (P Conclusion Predictors of MDD in SLE patients include higher scores in pain and global assessment, poor or fair self-reported health, and specific organ involvement. These findings may help clinicians to recognize and manage MDD promptly.

Purpose To determine the genetic background of sector retinitis pigmentosa (RP) natural history to better inform patient counseling. Design Retrospective case series. Methods Review of clinical notes, retinal imaging including color fundus photography (CFP), fundus autofluorescence (FAF), optical coherence tomography (OCT), electrophysiological assessment (ERG), and molecular genetic testing were performed in patients with sector RP from a single tertiary referral center. Main outcomes measured were demographic data, signs and symptoms, visual acuity, molecular genetics; and ERG, FAF, and OCT findings. Results Twenty-six molecularly confirmed patients from 23 different families were identified harboring likely disease-causing variants in 9 genes. The modes of inheritance were autosomal recessive (AR, n=6: USH1C, n=2; MYO7A, n=2; CDH3, n=1; EYS, n=1), X-linked (XL, n=4: PRPS1, n=1; RPGR, n=3), and autosomal dominant (AD, n=16: IMPDH1, n=3; RP1, n=3; RHO, n=10), with a mean age of disease onset of 38.5, 30.5, and 39.0 years old, respectively. Five of these genes have not previously been reported to cause sector RP (PRPS1, MYO7A, EYS, IMPDH1, and RP1). Inferior and nasal predilection was common across the different genotypes, and patients tended to maintain good central vision. Progression on serial FAF was observed in RPGR, MYO7A, CDH23, EYS, IMPDH1, RP1, and RHO-associated sector RP. Conclusions The genotypic spectrum of the disease is broader than previously reported. The longitudinal data provided will help to make accurate patient prognoses and counseling as well as inform patients' potential participation in the increasing numbers of trials of novel therapeutics and access to future treatments., Highlights • This is the largest series and longitudinal study in sector retinitis pigmentosa. • The genotypic spectrum of the disease is broader than previously reported. • The longitudinal data provided more accurate patient prognosis and counseling. • The study informed patients' potential participation in the increasing numbers of trials of novel therapeutics and access to future treatments.

Purpose To investigate the clinical course, genetic findings, and phenotypic spectrum of autosomal recessive bestrophinopathy (ARB) in a large cohort of children and adults. Design Retrospective case series. Participants Patients with a detailed clinical phenotype consistent with ARB, biallelic likely disease-causing sequence variants in the BEST1 gene, or both identified at a single tertiary referral center. Methods Review of case notes, retinal imaging (color fundus photography, fundus autofluorescence, OCT), electrophysiologic assessment, and molecular genetic testing. Main Outcome Measures Visual acuity (VA), retinal imaging, and electrophysiologic changes over time. Results Fifty-six eyes of 28 unrelated patients were included. Compound heterozygous variants were detected in most patients (19/27), with 6 alleles recurring in apparently unrelated individuals, the most common of which was c.422G→A, p.(Arg141His; n = 4 patients). Mean presenting VA was 0.52 ± 0.36 logarithm of the minimum angle of resolution (logMAR), and final VA was 0.81 ± 0.75 logMAR (P = 0.06). The mean rate of change in VA was 0.05 ± 0.13 logMAR/year. A significant change in VA was detected in patients with a follow-up of 5 years or more (n = 18) compared with patients with a follow-up of 5 years or less (n = 10; P = 0.001). Presence of subretinal fluid and vitelliform material were early findings in most patients, and this did not change substantially over time. A reduction in central retinal thickness was detected in most eyes (80.4%) over the course of follow-up. Many patients (10/26) showed evidence of generalized rod and cone system dysfunction. These patients were older (P < 0.001) and had worse VA (P = 0.02) than those with normal full-field electroretinography results. Conclusions Although patients with ARB are presumed to have no functioning bestrophin channels, significant phenotypic heterogeneity is evident. The clinical course is characterized by a progressive loss of vision with a slow rate of decline, providing a wide therapeutic window for anticipated future treatment strategies.

Rationale: Obstructive sleep apnea is recurrent upper airway obstruction caused by a loss of upper airway muscle tone during sleep. The main goal of our study was to determine if designer receptors exclusively activated by designer drugs (DREADD) could be used to activate the genioglossus muscle as a potential novel treatment strategy for sleep apnea. We have previously shown that the prototypical DREADD ligand clozapine-N-oxide increased pharyngeal diameter in mice expressing DREADD in the hypoglossal nucleus. However, the need for direct brainstem viral injections and clozapine-N-oxide toxicity diminished translational potential of this approach, and breathing during sleep was not examined.Objectives: Here, we took advantage of our model of sleep-disordered breathing in diet-induced obese mice, retrograde properties of the adeno-associated virus serotype 9 (AAV9) viral vector, and the novel DREADD ligand J60.Methods: We administered AAV9-hSyn-hM3(Gq)-mCherry or control AAV9 into the genioglossus muscle of diet-induced obese mice and examined the effect of J60 on genioglossus activity, pharyngeal patency, and breathing during sleep.Measurements and Main Results: Compared with control, J60 increased genioglossus tonic activity by greater than sixfold and tongue uptake of 2-deoxy-2-[18F]fluoro-d-glucose by 1.5-fold. J60 increased pharyngeal patency and relieved upper airway obstruction during non-REM sleep.Conclusions: We conclude that following intralingual administration of AAV9-DREADD, J60 can activate the genioglossus muscle and improve pharyngeal patency and breathing during sleep.

Purpose To describe the detailed phenotype, long-term clinical course, clinical variability, and genotype of patients with enhanced S-cone syndrome (ESCS). Design Retrospective case series. Participants Fifty-six patients with ESCS. Methods Clinical history, examination, imaging, and electrophysiologic findings of 56 patients (age range, 1–75 years) diagnosed with ESCS were reviewed. Diagnosis was established by molecular confirmation of disease-causing variants in the NR2E3 gene (n = 38) or by diagnostic full-field electroretinography findings (n = 18). Main Outcome Measures Age at onset of visual symptoms, best-corrected visual acuity (BCVA), quantitative age-related electrophysiologic decline, and imaging findings. Results Mean age at onset of visual symptoms was 4.0 years, and median age at presentation was 20.5 years, with mean follow-up interval being 6.1 years. Six patients were assessed once. Disease-causing variants in NR2E3 were identified in 38 patients. Mean BCVA of the better-seeing eye was 0.32 logarithm of the minimum angle of resolution (logMAR) at baseline and 0.39 logMAR at follow-up. In most eyes (76% [76/100]), BCVA remained stable, with a mean BCVA change of 0.07 logMAR during follow-up. Nyctalopia was the most common initial symptom, reported in 92.9% of patients (52/56). Clinical findings were highly variable and included foveomacular schisis (41.1% [26/56]), yellow-white dots (57.1% [32/56]), nummular pigmentation (85.7% [48/56]), torpedo-like lesions (10.7% [6/56]), and circumferential subretinal fibrosis (7.1% [4/56]). Macular and peripheral patterns of autofluorescence were classified as (1) minimal change, (2) hypoautofluorescent (mild diffuse, moderate speckled, moderate diffuse, or advanced), or (3) hyperautofluorescent flecks. One patient showed undetectable electroretinography findings; quantification of main electroretinography components in all other patients revealed amplitude and peak time variability but with pathognomonic electroretinography features. The main electroretinography components showed evidence of age-related worsening over 6.7 decades, at a rate indistinguishable from that seen in unaffected control participants. Eighteen sequence variants in NR2E3 were identified, including 4 novel missense changes. Conclusions Enhanced S-cone syndrome has a highly variable phenotype with relative clinical and imaging stability over time. Most electroretinography findings have pathognomonic features, but quantitative assessment reveals variability and a normal mean rate of age-related decline, consistent with largely nonprogressive peripheral retinal dysfunction.

OBJECTIVE Review surgical outcomes of stapedectomy for otosclerosis in patients with Meniere's disease. STUDY DESIGN Retrospective case review. SETTING Tertiary referral center. PATIENTS Patients with otosclerosis and Meniere's disease undergoing stapedectomy between 2010 and 2017. INTERVENTION Stapedectomy. MAIN OUTCOME MEASURES Pre- and postoperative hearing and complications. Hearing was measured by air conduction (AC) and bone conduction (BC) pure-tone frequency, pure-tone averages (PTA), air-bone gap (ABG), and word recognition scores (WRS). RESULTS Among 1,499 patients with otosclerosis, the incidence of concomitant Meniere's disease was 1.7%. Fifteen patients with otosclerosis and Meniere's disease underwent stapedectomy, 12 primary and three revisions. Mean AC PTA was 43 dB preoperatively, and 25 dB postoperatively (p = 0.0007), while the ABG improved on average from 20 to 5 dB (p = 0.0001). There was no significant difference in BC PTA or WRS postoperatively. Two patients experienced fluctuation of hearing in the postoperative period, one of which resolved with a course of steroids. The mean follow-up time was 41 months. CONCLUSIONS In patients with otosclerosis and Meniere's disease, stapedectomy provides excellent hearing outcomes in a majority of patients. As is characteristic of Meniere's disease, some patients will continue to experience fluctuating hearing postoperatively, which may progress to severe sensorineural hearing loss. Meniere's disease may not be an absolute contraindication to stapes surgery.

Objectives: To describe audiologic outcomes following hydroxyapatite bone cement fixation of stapedotomy prostheses. Methods: A retrospective case review at a tertiary neurotology referral center was performed of patients undergoing primary or revision stapedotomy between 2010 and 2017. Patients with hydroxyapatite bone cement fixation of stapes prostheses were assessed. Pre- and postoperative hearing was compared, consisting of air conduction (AC) and bone conduction (BC) pure-tone averages (PTA), air-bone gap (ABG), and word recognition scores (WRS). Short and long-term outcomes were assessed. Results: Forty-six patients with otosclerosis underwent stapedotomy with bone cement fixation: 21 primary cases and 25 revision cases, with an average follow-up time of 17 months. Mean AC PTA was 56 dB preoperatively, and 34 dB postoperatively ( P < .0001), while the ABG improved on average from 27 dB to 9 dB ( P < .0001). There was no significant difference in postoperative ABG between primary and revision stapes surgery (6 dB vs 10 dB, P = .07). These results persisted through long-term follow-up in a subgroup of patients with significantly longer follow-up time (mean 44 months). There was no significant change in BC PTA or word recognition scores. Three patients underwent subsequent revisions, one patient developed sensorineural hearing loss. Conclusion: Stapedotomy with bone cement fixation of the prosthesis provides excellent hearing outcomes in both primary and revision treatment of otosclerosis. Results are consistent and stable through long-term follow-up. The use of bone cement should be incorporated into the surgical armamentarium of the otologist for the prevention and treatment of loose-wire syndrome and incus necrosis.

OBJECTIVE Facial function is a key outcome in surgery of the cerebellopontine angle (CPA). This study describes the natural history of facial weakness after CPA surgery. STUDY DESIGN AND SETTING Retrospective study of two tertiary centers. PATIENTS AND INTERVENTION Patients undergoing surgery for CPA tumors from 2003 to 2017 with preoperatively normal facial function and without subsequent surgical or adjuvant therapy. MAIN OUTCOME MEASURE Serial facial nerve examinations using the House-Brackmann (HB) scale. RESULTS Of 301 patients examined, 149 (49.5%) had facial weakness postoperatively and 74.5% of these occurred within 24 hours. Of patients with HB-1 function within 24 hours after surgery, 95.3% had HB-1 function and 100% had HB-3 or better function at last follow-up. Of patients with HB-4 or worse function within 24 hours after surgery, 22.6% ultimately achieved HB-1 function and 83.9% ultimately achieved HB-3 or better function. By 180 days postoperatively, 83.7% of patients' facial function had stabilized. At last follow-up, 3.0% of patients had facial function poorer than HB-3, which was associated with subtotal resections (12.9% vs. 4.4% for near total and 0.6% for gross total resections, p = 0.002), aspirin use (10.6% vs. 1.6%, p = 0.001), larger tumors (p

The recent emergence of Internet-of-Things (IoT) technologies in mission-critical applications in the maritime industry has led to the introduction of the Internet-of-Ships (IoS) paradigm. IoS is a novel application domain of IoT that refers to the network of smart interconnected maritime objects, which can be any physical device or infrastructure associated with a ship, a port, or the transportation itself, with the goal of significantly boosting the shipping industry toward improved safety, efficiency, and environmental sustainability. In this article, we provide a comprehensive survey of the IoS paradigm, its architecture, its key elements, and its main characteristics. Furthermore, we review the state of the art for its emerging applications, including safety enhancements, route planning and optimization, collaborative decision making, automatic fault detection and preemptive maintenance, cargo tracking, environmental monitoring, energy-efficient operations, and automatic berthing. Finally, the presented open challenges and future opportunities for research in the areas of satellite communications, security, privacy, maritime data collection, data management, and analytics, provide a road map toward optimized maritime operations and autonomous shipping.

We introduce an interatomic potential for hexagonal boron nitride (hBN) based on the Gaussian approximation potential (GAP) machine learning methodology. The potential is based on a training set of configurations collected from density functional theory (DFT) simulations and is capable of treating bulk and multilayer hBN as well as nanotubes of arbitrary chirality. The developed force field faithfully reproduces the potential energy surface predicted by DFT while improving the efficiency by several orders of magnitude. We test our potential by comparing formation energies, geometrical properties, phonon dispersion spectra, and mechanical properties with respect to benchmark DFT calculations and experiments. In addition, we use our model and a recently developed graphene-GAP to analyze and compare thermally and mechanically induced rippling in large scale two-dimensional (2D) hBN and graphene. Both materials show almost identical scaling behavior with an exponent of η ≈ 0.85 for the height fluctuations agreeing well with the theory of flexible membranes. On the basis of its lower resistance to bending, however, hBN experiences slightly larger out-of-plane deviations both at zero and finite applied external strain. Upon compression, a phase transition from incoherent ripple motion to soliton-ripples is observed for both materials. Our potential is freely available online at [http://www.libatoms.org].

Using data from Project GATE (Growing America Through Entrepreneurship), an experimental-design entrepreneurship training program, I show that white nascent entrepreneurs were more likely than blac...

To describe the clinical, electrophysiological, and molecular features of an unusual macula-predominant retinopathy in two unrelated probands with biallelic variants in RDH12. Retrospective case se...

Mean sensitivity (MS) derived from a standard test grid using microperimetry is a sensitive outcome measure in clinical trials investigating new treatments for degenerative retinal diseases. This study hypothesizes that the functional decline is faster at the edge of the dense scotoma (eMS) than by using the overall MS.Multicenter, international, prospective cohort study: ProgStar Study.Stargardt disease type 1 patients (carrying at least 1 mutation in the ABCA4 gene) were followed over 12 months using microperimetry with a Humphrey 10-2 test grid. Customized software was developed to automatically define and selectively follow the test points directly adjacent to the dense scotoma points and to calculate their mean sensitivity (eMS).Among 361 eyes (185 patients), the mean age was 32.9 ± 15.1 years old. At baseline, MS was 10.4 ± 5.2 dB (n = 361), and the eMS was 9.3 ± 3.3 dB (n = 335). The yearly progression rate of MS (1.5 ± 2.1 dB/year) was significantly lower (β = -1.33; P.001) than that for eMS (2.9 ± 2.9 dB/year). There were no differences between progression rates using automated grading and those using manual grading (β = .09; P = .461).In Stargardt disease type 1, macular sensitivity declines significantly faster at the edge of the dense scotoma than in the overall test grid. An automated, time-efficient approach for extracting and grading eMS is possible and appears valid. Thus, eMS offers a valuable tool and sensitive outcome parameter with which to follow Stargardt patients in clinical trials, allowing clinical trial designs with shorter duration and/or smaller cohorts.

Purpose To describe the clinical and electrophysiological features of adult-onset macular dystrophy, due to novel combinations of CDHR1 alleles, and compare the associated phenotypes with previous reports. Methods The clinical records of patients with macular dystrophy and biallelic variants in CDHR1 were reviewed. Data analysed included best corrected visual acuity (BCVA), fundus images: autofluorescence (AF) and optical coherence tomography (OCT); full field electroretinography (ERG) and pattern ERG (PERG). Results Seven patients from six pedigrees were ascertained. One patient was homozygous for a known synonymous variant p.(Pro261=), four were compound heterozygous for the p.(Pro261=) variant and a novel allele of CDHR1: p.(Gly188Ser), p.(Met1?), or p.(Val458Asp); one patient was compound heterozygous for two previously unreported variants: c.297+1G>T in trans with p.(Pro735Thr). The range of BCVA at the last clinic review was (6/5–6/60). Autofluorescence showed macular flecks of increased AF in mild cases and patches of reduced AF in severe cases. The OCT showed attenuation of the ellipsoid zone (EZ) in mild cases and loss of the EZ and the outer nuclear layer in severe cases; one patient had subfoveal hyporeflective region between the EZ and the retinal pigment epithelium. The full field ERG was normal or borderline subnormal in all cases, and the PERG was subnormal in mild cases or undetectable in severe cases. Conclusions This report corroborates previous observations that genotypes distinct from those causing pan-retinal dystrophy can cause a milder phenotype, predominantly affecting the macula, and expands the spectrum of these genotypes. The findings in this cohort suggest a potential macular susceptibility to mild perturbations of the photoreceptor cadherin.

Oliver McFarlane syndrome (OMS) is a rare autosomal recessive disorder characterised by pigmentary chorioretinal atrophy with no previous reports of choroidal neovascularisation (CNV).We describe the history, findings of clinical examination, retinal imaging and electrodiagnostic studies, and the treatment of a patient with CNV secondary to OMS.CNV secondary to OMS was diagnosed in a ten-year-old white female who presented with reduced visual acuity and a macular haemorrhage in her right eye. CNV was confirmed on optical coherence tomography. She was initially treated with a single injection of intravitreal bevacizumab and 2 years later with an injection of intravitreal ranibizumab for a recurrence. Although macular scarring secondary to the CNV was observed, her vision has stabilised and she continues to be closely monitored.We report the first case of CNV secondary to OMS and its successful treatment with intravitreal anti-vascular endothelial growth factor injections.

Danon disease (DD) is a rare X-linked disorder caused by pathogenic variants in LAMP2. DD primarily manifests as a severe cardiomyopathy. An early diagnosis is crucial for patient survival. The aim of the study was to determine the usefulness of ocular examination for identification of DD.Detailed ocular examination in 10 patients with DD (3 males, 7 females) and a 45-year-old asymptomatic female somatic mosaic carrier of a LAMP2 disease-causing variant.All patients with manifest cardiomyopathy had pigmentary retinopathy with altered autofluorescence and diffuse visual field loss. Best corrected visual acuity (BCVA) was decreased (0.63) in 8 (40%) out of 20 eyes. The severity of retinal pathology increased with age, resulting in marked cone-rod involvement overtime. Spectral-domain optical coherence tomography in younger patients revealed focal loss of photoreceptors, disruption and deposition at the retinal pigment epithelium/Bruch's membrane layer (corresponding to areas of marked increased autofluorescence), and hyperreflective foci in the outer nuclear layer. Cystoid macular oedema was seen in one eye. In the asymptomatic female with somatic mosaicism, the BCVA was 1.0 bilaterally. An abnormal autofluorescence pattern in the left eye was present; while full-field electroretinography was normal.Detailed ocular examination may represent a sensitive and quick screening tool for the identification of carriers of LAMP2 pathogenic variants, even in somatic mosaicism. Hence, further investigation should be undertaken in all patients with pigmentary retinal dystrophy as it may be a sign of a life-threatening disease.

Objective The objective of this study was to assess the strategic changes implemented in the departmental mission to continue safe delivery of otolaryngology care and to support the broader institutional mission during the COVID-19 pandemic response. Study Design Retrospective assessment was performed to the response and management strategy developed to transform the clinical and academic enterprise. Setting Large urban tertiary care referral center. Results The departmental structure was reorganized along new clinical teams to effectively meet the system directives for provision of otolaryngology care and support for inpatient cases of COVID-19. A surge deployment schedule was developed to assist frontline colleagues with clinical support as needed. Outpatient otolaryngology was consolidated across the system with conversion of the majority of visits to telehealth. Operative procedures were prioritized to ensure throughput for emergent and time-critical urgent procedures. A tracheostomy protocol was developed to guide management of emergent and elective airways. Educational and research efforts were redirected to focus on otolaryngology care in the clinical context of the COVID-19 crisis. Conclusion Emergence of the COVID-19 global health crisis has challenged delivery of otolaryngology care in an unparalleled manner. The concerns for preserving health of the workforce while ethically addressing patient career needs in a timely manner has created significant dilemmas. A proactive, thoughtful approach that reorganizes the overall departmental effort through provider and staff engagement can facilitate the ability to meet the needs of otolaryngology patients and to support the greater institutional mission to combat the pandemic.

KCNV2 -associated retinopathy or “cone dystrophy with supernormal rod responses” is an autosomal recessive cone-rod dystrophy with pathognomonic ERG findings. This gene encodes Kv8.2, a voltage-gated potassium channel subunit that acts as a modulator by shifting the activation range of the K+ channels in photoreceptor inner segments. Currently, no treatment is available for the condition. However, there is a lack of prospective long-term data in large molecularly confirmed cohorts, which is a prerequisite for accurate patient counselling/prognostication, to identify an optimal window for intervention and outcome measures, and ultimately to design future therapy trials. Herein we provide a detailed review of the clinical features, retinal imaging, electrophysiology and psychophysical studies, molecular genetics, and briefly discuss future prospects for therapy trials.

Waardenburg syndrome type I (WS-I) is a rare autosomal-dominant auditory-pigmentary disorder with limited reports in the Ophthalmic literature.We describe the history, clinical findings and detailed retinal imaging (ultra-widefield fundus images, fundus autofluorescence and optical coherence tomography) from a patient with WS-I.Our patient had a history of white forelock and congenital hearing loss. Ophthalmic examination demonstrated iris heterochromia and highly asymmetric choroidal hypopigmentation, with generalised fundus hyperautofluorescence. Similarly, the patient's mother demonstrated highly asymmetric fundus hypopigmentation. Genetic testing confirmed a pathogenic PAX3 nonsense variant.Our report demonstrates that highly asymmetric choroidal hypopigmentation is within the clinical spectrum of WS-I.OCT: Optical coherence tomography; WS-I: Waardenburg syndrome type 1.

Since 2012, the Besrour Centre for Global Family Medicine at the College of Family Physician of Canada has brought together its partners from the Americas annually, to reflect on the evolution of Family Medicine on the continent since Alma-Ata, and to look forward to future challenges. Family doctors are but one element of a strong health system. Family Medicine provides key ingredients to respond to population health needs especially as countries move through the epidemiological transition to face larger burdens of chronic disease and multimorbidity. In this paper, we provide a high-level overview of the state of Family Medicine on the continent. We then analyze trends in the education of family physicians to face this changing landscape, including the emphasis on the leader role of future family physicians. Postgraduate programs in Family Medicine in the Americas are placing increasing emphasis on teaching collaborative care in view of creating truly interdisciplinary health teams for the benefit of patients. Resumo Desde 2012, o Centro Besrour de Medicina Global de Família, na Faculdade de Medicina de Família do Canadá, reúne seus parceiros das Américas anualmente para refletir sobre a evolução da Medicina de Família no continente desde Alma-Ata e para os desafios futuros. Os médicos de família são apenas um elemento de um forte sistema de saúde. A Medicina de Família fornece ingredientes-chave para responder às necessidades de saúde da população, especialmente à medida em que os países passam pela transição epidemiológica para enfrentar um fardo maior de doenças crônicas e de multimorbidade. Neste artigo, fornecemos uma visão geral de alto nível do estado da Medicina de Família no continente. Em seguida, analisamos as tendências na educação dos médicos de família para enfrentar esse cenário em mudança, incluindo a ênfase no papel de líder dos futuros médicos de família. Os programas de pós-graduação em Medicina de Família nas Américas estão enfatizando cada vez mais o ensino do cuidado colaborativo, a fim de criar equipes de saúde verdadeiramente interdisciplinares para o benefício dos pacientes.

Visual hallucinations are common in older people and are especially associated with ophthalmological and neurological disorders, including dementia and Parkinson’s disease. Uncertainties remain whether there is a single underlying mechanism for visual hallucinations or they have different disease-dependent causes. However, irrespective of mechanism, visual hallucinations are difficult to treat. The National Institute for Health Research (NIHR) funded a research programme to investigate visual hallucinations in the key and high burden areas of eye disease, dementia and Parkinson’s disease, culminating in a workshop to develop a unified framework for their clinical management. Here we summarise the evidence base, current practice and consensus guidelines that emerged from the workshop.Irrespective of clinical condition, case ascertainment strategies are required to overcome reporting stigma. Once hallucinations are identified, physical, cognitive and ophthalmological health should be reviewed, with education and self-help techniques provided. Not all hallucinations require intervention but for those that are clinically significant, current evidence supports pharmacological modification of cholinergic, GABAergic, serotonergic or dopaminergic systems, or reduction of cortical excitability. A broad treatment perspective is needed, including carer support. Despite their frequency and clinical significance, there is a paucity of randomised, placebo-controlled clinical trial evidence where the primary outcome is an improvement in visual hallucinations. Key areas for future research include the development of valid and reliable assessment tools for use in mechanistic studies and clinical trials, transdiagnostic studies of shared and distinct mechanisms and when and how to treat visual hallucinations.

PurposeThis research paper uses a novel methodological approach to investigate the spillover effects among the key sectors of the US economy.Design/methodology/approachThe paper links the US sectors via a node theoretic scheme based on a general equilibrium framework, whereas it estimates the general equilibrium equation as a Global Vector Autoregressive process, taking into consideration the potential existence of dominant units.FindingsBased on our findings, the dominant sector in the US economy, for the period 1992–2015, is the sector of information technology, finance and communications, a fact that gives credence to the view that the US economy is a service-driven economy. In addition, the US economy seems to benefit by the increased labour mobility across knowledge-intensive sectors, thus avoiding the ‘employment trap’ which in turn enabled the US economy to overcome the financial crisis of 2007.Originality/valueFirstly, the paper models by means of a network approach which is based on a general equilibrium framework, the linkages between the US sectors while treating the sector of information, technology, communications and finance as dominant, as dictated by its degree of centrality in the network structure. Secondly, the paper offers a robustness analysis regarding both the existence and the identification of dominant sectors (nodes) in the US economy. Thirdly, the paper studies a wide period, namely 1992–2015, fully capturing the recent global recession, while acknowledging the impact of the global crisis through the introduction of the relevant exogenous dummy variables; Lastly and most importantly, it is the first study to apply the GVAR approach in a network general equilibrium framework at the sectoral level.

Elevated body mass index (BMI) is a risk factor for surgical complications, but data in acoustic neuroma surgery are conflicting and limited to small single-institution studies. This work evaluates associations between BMI and complications in surgery for acoustic neuroma (AN).Retrospective review.Two tertiary otology referral institutions.Patients undergoing surgery for AN. Univariate and multivariate analysis of association between BMI and complications was performed using two-tailedBMI ranged from 18.0 kg/mThe largest series to date investigating BMI in acoustic surgery is presented. Elevated BMI is strongly associated with CSF leak and need for revision surgery but not with other complications. Obese or overweight patients undergoing acoustic neuroma resection should be counseled of their increased risk of CSF leak.

To date, there has been a global lack of data regarding the prevalence of conditions falling under the Inherited Retinal Diseases (IRD) classification, the impact on the individuals and families affected, and the cost burden to economies. The absence of an international patient registry, and equitable access to genetic testing, compounds this matter. The resulting incomplete knowledge of the impact of IRDs hinders the development and commissioning of clinical services, provision of treatments, and planning and implementation of clinical trials. Thus, there is a need for stronger evidence to support value for money to regulatory bodies for treatments approved, and progressing through clinical trials. To ensure a strategic approach to future research and service provision, it is necessary to learn more about the IRD landscape. This review highlights two recent cost-of-illness reports on the socio-economic impact of 10 IRDs in the Republic of Ireland (ROI) and the United Kingdom (UK), which demonstrate the comprehensive impact of IRDs on individuals affected, their families, friends and society. Total costs attributable to IRDs in the ROI were estimated to be £42.6 million in 2019, comprising economic (£28.8 million) and wellbeing costs (£13.8 million). Wellbeing costs were estimated using the World Health Organization (WHO) burden of disease methodology, a non-financial approach, where pain, suffering and premature mortality are measured in terms of disability-adjusted-life-years (DALYs). In the UK, wellbeing costs attributable to IRDs were £196.1 million, and economic costs were £327.2 million amounting to £523.3 million total costs in 2019. Accounting for over one-third of total costs, the wellbeing burden of persons affected by IRDs should be emphasized and factored into reimbursement processes for therapies and care pathways. This targeted review presents the most current and relevant data on IRD prevalence in the ROI and the UK, and the impacts (financial and non-financial) of IRDs in terms of diagnosis, wellbeing, employment, formal and informal care, health system costs, deadweight losses and issues surrounding payers and reimbursement. This review demonstrates IRD patients and their families have common issues including, the need for timely equitable access to genetic testing and counselling, equality in accessing employment, and a revision of the assessment process for reimbursement of therapies currently focused on the cost-of-illness to the healthcare system. This review reveals that IRD patients do not frequently engage the healthcare system and as such suggests a cost-of-illness model from a societal perspective may be a better format.

Purpose To determine the reliability and repeatability of quantitative evaluation of areas of decreased autofluorescence (DAF) from fundus autofluorescence (FAF) images and track disease progression in children with Stargardt disease (STGD1), and to investigate clinical and genotype correlations, disease symmetry, and intrafamilial variability. Design Prospective cohort study. Methods Children and adults with molecularly confirmed STGD1 (n = 90) underwent longitudinal FAF imaging with subsequent semiautomated measurement of the area of DAF and calculation of the annual rate of progression. The age of disease onset was recorded for all subjects, as well as the electroretinography (ERG) group at baseline (n = 86). Patients were grouped for analysis based on the age at baseline and age of onset, into children (n = 56), adults with childhood-onset STGD1 (n = 15), and adults with adult-onset (n = 19). Fifty FAF images were selected randomly and analyzed by 2 observers to evaluate repeatability and reproducibility. Differences between groups, interocular symmetry, genotype–phenotype correlations, and intrafamilial variability were also investigated both for baseline measurements as well as progression rates. We measured visual acuity, molecular genetics, ERG group, FAF metrics, and their correlations. Results The mean age of onset ± SD was 9.6 ± 3.4 years for childhood-onset (n = 71) and 28.3 ± 7.8 years for adult-onset STGD1 (n = 19). The intra- and interobserver reliability of DAF quantification was excellent (intraclass correlation coefficients 0.995 and 0.987, respectively). DAF area was symmetric between eyes and the mean rate of progression (SD) was 0.69 (0.72), 0.78 (0.48), and 0.40 (0.36) mm2/year for children, adults with childhood-onset, and adults with adult-onset disease, respectively. Patients belonging to a group 3 ERG phenotype (generalized cone and rod dysfunction) had a significantly greater progression rate. Limited intrafamilial variability was observed. Conclusions This is the first large prospective study of FAF in a cohort of molecularly confirmed children with STGD1. DAF area quantification was highly reliable and may thereby serve as a robust structural endpoint. A high rate of progression was observed in childhood-onset disease, making this subtype of STGD1 ideally suited to be considered for prioritization in clinical trials., Highlights • First large prospective study of fundus autofluorescence in a cohort of molecularly confirmed children with STGD1. • Fundus autofluorescence is a robust structural outcome measure in children with Stargardt disease. • A high rate of progression was observed in childhood-onset disease, making this subtype of STGD1 ideally suited to be considered for prioritization in clinical trials.

Konstantinos Kostikas,1 Theodoros I Vassilakopoulos,2,3 Nikos Tzanakis,4 Athanasios K Konstantinidis,1 Epameinondas N Kosmas,5 Spyros Papiris,6 Paschalis Steiropoulos,7 Effrosyni D Manali,6 Stylianos A Michaelides8,†, Grigorios Daskos9 1Respiratory Medicine Department, University Hospital of Ioannina, Ioannina, Greece; 2Pulmonary and Critical Care Medicine, Medical School, National and Kapodistrian University of Athens, Athens, Greece; 3Third Department of Critical Care Medicine, Evgenideio Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece; 4Department of Respiratory Medicine, University Hospital of Heraklion, Medical School, University of Crete, Crete, Greece; 5Department of Pulmonary Medicine, Metropolitan Hospital, Athens, Greece; 6Second Pulmonary Medicine Department, General University Hospital “Attikon”, Medical School, National and Kapodistrian University of Athens, Athens, Greece; 7Pulmonology Clinic Medical School, Democritus University of Thrace/University General Hospital, Alexandroupolis, Greece; 8Department of Occupational Lung Disease and Tuberculosis, “Sismanogleio-Amalia Fleming” General Hospital, Athens, Greece; 9MENARINI HELLAS, Athens, Greece†Stylianos A Michaelides passed away on September 14, 2019Correspondence: Konstantinos KostikasRespiratory Medicine Department, University of Ioannina School of Medicine, Leoforos Stavrou Niarchou, Ioannina 45500, GreeceTel +30-2651007536Email ktkostikas@gmail.comPurpose: This multicenter, prospective, observational study aimed to supplement real-world evidence on the effects of aclidinium bromide on the quality of life (QoL), symptoms, and activity impairment of patients with COPD.Patients and Methods: Eligible patients were ≥ 40 years of age, newly initiated on aclidinium bromide as monotherapy or add-on therapy according to the product’s approved label. Patient-reported COPD assessment test (CAT), the severity of symptoms and their impact on daily activities, and the features of the Genuair® inhaler device were assessed at enrollment and at 12 weeks post-treatment onset.Results: Between 13 March 2015 and 29 January 2016, 285 eligible consenting patients (76.3% males; median age: 69.0 years; 26.0% newlydiagnosed with COPD) were enrolled by 15 hospital-based respiratory medicine specialists in Greece. Aclidinium bromide was initiated as add-on therapy to other inhaled maintenance medications in 73.1% of evaluable patients. The median (interquartile range [IQR]) baseline CAT score decreased from 14.0 (9.0– 20.0) to 10.0 (6.0– 15.0) points (p< 0.001) after 12 weeks of treatment, with 76.5% of the patients achieving a ≥ 2-point decrease. The severity of night-time and early-morning symptoms, assessed using a 5-point Likert-type scale, decreased from a median (IQR) of 1.0 (0.0– 2.0) to 0.0 (0.0– 1.0), and from 2.0 (1.0– 2.0) to 1.0 (1.0– 2.0), respectively (p< 0.001 for both). In patients with paired data, the prevalence of at least moderate night-time symptoms, early-morning symptoms, and daily activity impairment decreased from 28.2% to 19.1%, from 63.6% to 34.2%, and from 59.5% to 38.7%, respectively (p< 0.001 for all). Inhaler device features were assessed as “very good”/“good” by more than 90% of the patients. The adverse drug reaction rate was 1.4%.Conclusion: The study provides real-world evidence on the beneficial effects of aclidinium bromide on the patients’ QoL, symptom severity, and daily activity impairment, which are complemented by a favorable safety profile and high patient satisfaction with the inhaler device.Keywords: aclidinium, chronic obstructive pulmonary disease, COPD assessment test, daily activities, quality of life, symptoms

Significance Understanding complex materials, in particular those with solid–liquid interfaces, such as water on surfaces or under confinement, is a key challenge for technological and scientific progress. Although established simulation approaches have been able to provide important atomistic insight, ab initio techniques struggle with the required time and length scales, while force field methods can often be limited in terms of their accuracy. Here we show how these limitations can be overcome in a simple and automated machine learning procedure to provide accurate models of interactions at the ab initio level, as illustrated for a variety of complex aqueous systems. These developments open up the prospect of the straightforward exploration of many technologically relevant systems by molecular simulations., Simulation techniques based on accurate and efficient representations of potential energy surfaces are urgently needed for the understanding of complex systems such as solid–liquid interfaces. Here we present a machine learning framework that enables the efficient development and validation of models for complex aqueous systems. Instead of trying to deliver a globally optimal machine learning potential, we propose to develop models applicable to specific thermodynamic state points in a simple and user-friendly process. After an initial ab initio simulation, a machine learning potential is constructed with minimum human effort through a data-driven active learning protocol. Such models can afterward be applied in exhaustive simulations to provide reliable answers for the scientific question at hand or to systematically explore the thermal performance of ab initio methods. We showcase this methodology on a diverse set of aqueous systems comprising bulk water with different ions in solution, water on a titanium dioxide surface, and water confined in nanotubes and between molybdenum disulfide sheets. Highlighting the accuracy of our approach with respect to the underlying ab initio reference, the resulting models are evaluated in detail with an automated validation protocol that includes structural and dynamical properties and the precision of the force prediction of the models. Finally, we demonstrate the capabilities of our approach for the description of water on the rutile titanium dioxide (110) surface to analyze the structure and mobility of water on this surface. Such machine learning models provide a straightforward and uncomplicated but accurate extension of simulation time and length scales for complex systems.

Security vulnerabilities make the Internet of Things (IoT) systems open to online attacks that threaten both their operation and user privacy. Among the many protocols governing IoT operation, MQTT has seen wide adoption, but comes with rudimentary security support. Specifically, while the MQTT standard strongly recommends that servers (brokers) offer Transport Layer Security (TLS), it is mainly concerned with the message transmission protocol, leaving to implementers the responsibility for providing appropriate security features. However, well-known solutions for Web Security (OAuth2) exist, which may benefit MQTT. This paper presents systematic implementation efforts and practical experimentation to evaluate the feasibility of one such approach, namely the MQTT-TLS profile for the Authentication and Authorization in Constrained Environments (ACE), recently specified by the IETF. Our implementation includes the functionality for (1) the Authorization Server (AS), to handle client registration, authorization policies, and Access Tokens; (2) the MQTT broker, to enforce authentication in both MQTT versions 3.1.1 and 5. Together, these enable ACE-MQTT clients to use (3) OAuth2-based authentication and authorization via Proof of Possession tokens. We make the source-code of our ACE-MQTT implementation publicly available, and evaluate it against plain MQTT systems in realistic settings with different computation constraints. To assess the cost of security, we measure the CPU, memory, network usage, and energy consumption. The results obtained confirm that the ACE requirements match the capabilities of moderately constrained devices, hence providing an affordable mechanism to secure MQTT systems.

In this chapter the general factors affecting the equilibrium and stability of arid regions are discussed, with particular focus given to rainfall, the primary factor influencing the continuity and development of these environments. Unfortunately, the scarcity or complete lack of rain gauges in such areas complicates the collection of sufficient rainfall data. Consequently, systematic steps are proposed toward the development of alternative analyses of the spatiotemporal distribution of rainfall in arid regions. The foremost approach is the incorporation of remote sensing data, along with the appropriate classifiers, into the indirect evaluation of rainfall. For the purpose of assessing the suitability of the proposed methods, a detailed study on rainfall in the eastern side of the Gulf of Suez in Egypt is presented.

Background This case series reports the performance of a next‐generation sequencing (NGS) panel of 176 retinal genes (NGS 176) in patients with inherited retinal disease (IRD). Methods Subjects are patients who underwent genetic testing between 1 August 2016 and 1 January 2018 at Moorfields Eye Hospital, London, UK. Panel‐based genetic testing was performed unless a specific gene (e.g., RS1) or small group of genes (e.g., ABCA4, PRPH2) were suspected. If a novel variant was identified, a further comment on their predicted pathogenicity and evolutionary conservation was offered and segregation studies performed. The main outcome measure is the likelihood of obtaining a genetic diagnosis using NGS 176. Results 488 patients were included. A molecular diagnosis was obtained for 59.4% of patients. Younger patients were more likely to receive a molecular diagnosis; with 92% of children under the age of 6 years receiving a conclusive result. There was a change in their initially assigned inheritance pattern in 8.4% of patients following genetic testing. Selected IRD diagnoses (e.g., achromatopsia, congenital stationary night blindness) were associated with high diagnostic yields. Conclusion This study confirms that NGS 176 is a useful first‐tier genetic test for most IRD patients. Age and initial clinical diagnosis were strongly associated with diagnostic yield., A retrospective study of 488 patients with inherited retinal dystrophy confirms that NGS 176 is a useful first tier genetic test, achieving a molecular diagnosis in 59.4% of those tested. Age and initial clinical diagnosis were strongly associated with diagnostic yield.

Objective Stapes surgery for otosclerosis occasionally requires revision due to recurrent or persistent conductive hearing loss (CHL). This study examines outcomes after revision stapes surgery. Study design Retrospective review. Setting Single tertiary neurotology center. Methods Patients undergoing revision stapes surgery for otosclerosis from 2008 to 2017 were reviewed. Postoperative air-bone gaps (ABGs) were the primary outcome measure. Results During the study period, 150 patients underwent revision stapes surgery. One hundred patients (67%) had gradually progressive recurrent CHL; 16 (11%), sudden recurrent CHL; 13 (9%), persistent CHL; and 21 (14%), no CHL. For 129 patients with CHL, the mean ABG improved from 23.7 to 9.3 dB (P .05). Four patients (2.7%) developed sensorineural hearing loss after revision, defined as an increase in bone conduction pure tone average ≥15 dB, all of whom had previous replacement of a malpositioned prosthesis. Conclusions Revision stapes surgery confers significant improvement in hearing for patients with persistent and recurrent CHL, although patients with persistent CHL after initial surgery see less improvement with revision.