Loss of Function of RIMS2 Causes a Syndromic Congenital Cone-Rod Synaptic Disease with Neurodevelopmental and Pancreatic Involvement.

Congenital cone-rod synaptic disorder (CRSD), also known as incomplete congenital stationary night blindness (iCSNB), is a non-progressive inherited retinal disease (IRD) characterized by night blindness, photophobia, and nystagmus, and distinctive electroretinographic features. Here, we report bi-allelic RIMS2 variants in seven CRSD-affected individuals from four unrelated families. Apart from CRSD, neurodevelopmental disease was observed in all affected individuals, and abnormal glucose homeostasis was observed in the eldest affected individual. RIMS2 regulates synaptic membrane exocytosis. Data mining of human adult bulk and single-cell retinal transcriptional datasets revealed predominant expression in rod photoreceptors, and immunostaining demonstrated RIMS2 localization in the human retinal outer plexiform layer, Purkinje cells, and pancreatic islets. Additionally, nonsense variants were shown to result in truncated RIMS2 and decreased insulin secretion in mammalian cells. The identification of a syndromic stationary congenital IRD has a major impact on the differential diagnosis of syndromic congenital IRD, which has previously been exclusively linked with degenerative IRD.

Circadian variability of the initial Glasgow Coma Scale score in traumatic brain injury patients.

INTRODUCTION: The Glasgow Coma Scale (GCS) score is the primary method of assessing consciousness after traumatic brain injury (TBI), and the clinical standard for classifying TBI severity. There is scant literature discerning the influence of circadian rhythms or emergency department (ED) arrival hour on this important clinical tool. METHODS: Retrospective cohort analysis of adult patients suffering blunt TBI using the National Sample Program of the National Trauma Data Bank, years 2003-2006. ED arrival GCS score was characterized by midday (10 a.m.-4 p.m.) and midnight (12 a.m.-6 a.m.) cohorts (N=24548). Proportions and standard errors are reported for descriptive data. Multivariable regressions using odds ratios (OR), mean differences (B), and their associated 95% confidence intervals [CI] were performed to assess associations between ED arrival hour and GCS score. Statistical significance was assessed at p<0.05. RESULTS: Patients were 42.48±0.13-years-old and 69.5% male. GCS score was 12.68±0.13 (77.2% mild, 5.2% moderate, 17.6% severe-TBI). Overall, patients were injured primarily via motor vehicle accidents (52.2%) and falls (24.2%), and 85.7% were admitted to hospital (33.5% ICU). Injury severity score did not differ between day and nighttime admissions.Nighttime admissions associated with decreased systemic comorbidities (p<0.001) and increased likelihood of alcohol abuse and drug intoxication (p<0.001). GCS score demonstrated circadian rhythmicity with peak at 12 p.m. (13.03±0.08) and nadir at 4am (12.12±0.12). Midnight patients demonstrated lower GCS (12 a.m.-6 a.m.: 12.23±0.04; 10 a.m.-4 p.m.: 12.95±0.03, p<0.001). Multivariable regression adjusted for demographic and injury factors confirmed that midnight-hours independently associated with decreased GCS (B=-0.29 [-0.40, -0.19]).In patients who did not die in ED or go directly to surgery (N=21862), midnight-hours (multivariable OR 1.73 [1.30-2.31]) associated with increased likelihood of ICU admission; increasing GCS score (per-unit OR 0.82 [0.80-0.83]) associated with decreased odds. Notably, the interaction factor ED GCS score*ED arrival hour independently demonstrated OR 0.96 [0.94-0.98], suggesting that the influence of GCS score on ICU admission odds is less important at night than during the day. CONCLUSIONS: Nighttime TBI patients present with decreased GCS scores and are admitted to ICU at higher rates, yet have fewer prior comorbidities and similar systemic injuries. The interaction between nighttime hours and decreased GCS score on ICU admissions has important implications for clinical assessment/triage.

Light-induced changes of the circadian clock of humans: increasing duration is more effective than increasing light intensity.

STUDY OBJECTIVES: To evaluate the effect of increasing the intensity and/or duration of exposure on light-induced changes in the timing of the circadian clock of humans. DESIGN: Multifactorial randomized controlled trial, between and within subject design SETTING: General Clinical Research Center (GCRC) of an academic medical center PARTICIPANTS: 56 healthy young subjects (20-40 years of age) INTERVENTIONS: Research subjects were admitted for 2 independent stays of 4 nights/3 days for treatment with bright or dim-light (randomized order) at a time known to induce phase delays in circadian timing. The intensity and duration of the bright light were determined by random assignment to one of 9 treatment conditions (duration of 1, 2, or 3 hours at 2000, 4000, or 8000 lux). MEASUREMENTS AND RESULTS: Treatment-induced changes in the dim light melatonin onset (DLMO) and dim light melatonin offset (DLMOff) were measured from blood samples collected every 20-30 min throughout baseline and post-treatment nights. Comparison by multi-factor analysis of variance (ANOVA) of light-induced changes in the time of the circadian melatonin rhythm for the 9 conditions revealed that changing the duration of the light exposure from 1 to 3 h increased the magnitude of light-induced delays. In contrast, increasing from moderate (2,000 lux) to high (8,000 lux) intensity light did not alter the magnitude of phase delays of the circadian melatonin rhythm. CONCLUSIONS: Results from the present study suggest that for phototherapy of circadian rhythm sleep disorders in humans, a longer period of moderate intensity light may be more effective than a shorter exposure period of high intensity light.