Genotype–phenotype correlation in contactin-associated protein-like 2 (CNTNAP-2) developmental disorder

Contactin-associated protein-like 2 (CNTNAP2) gene encodes for CASPR2, a presynaptic type 1 transmembrane protein, involved in cell–cell adhesion and synaptic interactions. Biallelic CNTNAP2 loss has been associated with “Pitt-Hopkins-like syndrome-1” (MIM#610042), while the pathogenic role of heterozygous variants remains controversial. We report 22 novel patients harboring mono- (n = 2) and bi-allelic (n = 20) CNTNAP2 variants and carried out a literature review to characterize the genotype–phenotype correlation. Patients (M:F 14:8) were aged between 3 and 19 years and affected by global developmental delay (GDD) (n = 21), moderate to profound intellectual disability (n = 17) and epilepsy (n = 21). Seizures mainly started in the first two years of life (median 22.5 months). Antiseizure medications were successful in controlling the seizures in about two-thirds of the patients. Autism spectrum disorder (ASD) and/or other neuropsychiatric comorbidities were present in nine patients (40.9%). Nonspecific midline brain anomalies were noted in most patients while focal signal abnormalities in the temporal lobes were noted in three subjects. Genotype–phenotype correlation was performed by also including 50 previously published patients (15 mono- and 35 bi-allelic variants). Overall, GDD (p < 0.0001), epilepsy (p < 0.0001), hyporeflexia (p = 0.012), ASD (p = 0.009), language impairment (p = 0.020) and severe cognitive impairment (p = 0.031) were significantly associated with the presence of biallelic versus monoallelic variants. We have defined the main features associated with biallelic CNTNAP2 variants, as severe cognitive impairment, epilepsy and behavioral abnormalities. We propose CASPR2-deficiency neurodevelopmental disorder as an exclusively recessive disease while the contribution of heterozygous variants is less likely to follow an autosomal dominant inheritance pattern

Positive airway pressure (PAP) treatment reduces glycated hemoglobin (HbA1c) levels in obstructive sleep apnea patients with concomitant weight loss: Longitudinal data from the ESADA

Patients with obstructive sleep apnea (OSA) are at increased risk of developing metabolic disease such as diabetes. The effects of positive airway pressure on glycemic control are contradictory. We therefore evaluated the change in glycated hemoglobin (HbA1c) in a large cohort of OSA patients after long-term treatment with positive airway pressure. HbA1c levels were assessed in a subsample of the European Sleep Apnea Database [n=1608] at baseline and at long-term follow up with positive airway pressure therapy (mean 378.9±423.0 days). In a regression analysis, treatment response was controlled for important confounders. Overall, HbA1c decreased from 5.98±1.01% to 5.93±0.98% (p=0.001). Patient subgroups with a more pronounced HbA1c response included patients with diabetes (−0.15±1.02, p=0.019), those with severe OSA baseline (−0.10±0.68, p=0.005), those with morbid obesity (−0.20±0.81, p&lt;0.001). The strongest HbA1c reduction was observed in patients with a concomitant weight reduction &gt;5 kilos (−0.38±0.99, p&lt;0.001). In robust regression analysis, severe OSA (p=0.038) and morbid obesity (p=0.005) at baseline, and weight reduction &gt;5 kilos (p&lt;0.001) during follow up were independently associated with a reduction of HbA1c following PAP treatment. In contrast, PAP treatment alone without weight reduction was not associated with significant Hb1Ac reduction. In conclusion, positive airway pressure therapy is associated with HbA1c reduction in patients with severe OSA, in morbidly obese patients. and most obviously in those with significant weight lost during the follow-up. Our study underlines the importance to combine positive airway pressure use with adjustments in lifestyle to substantially modify metabolic complications in OSA

Securing effective and equitable coverage of marine protected areas : the UK's progress towards achieving Convention on Biological Diversity commitments and lessons learned for the way forward

Current international agreements call for protecting 10% of marine and coastal waters by 2020, with the intention of increasing that target to 30% by 2030. With 24% of its territorial waters protected, the UK falls short of the new expected target. As well as quantitative targets, qualitative criteria have been internationally agreed for protected area designation, including minimum coverage values and characteristics that encompass effectively and equitably managed, ecologically representative and well-connected systems of protected areas and other effective area-based conservation measures, and integrated into the wider landscape and seascape. The legal framework supporting protected area designations at sea is summarized and explained for UK territorial waters. Efforts to date to achieve current marine protected area (MPA) targets are reviewed, with emphasis on how well the existing protected area portfolio captures the qualitative criteria. Examples are given of other effective conservation measures complementary to formalized MPAs, especially with regard to achieving and promoting qualitative criteria for biodiversity conservation, including appropriate recognition of and support for areas conserved by indigenous people, local communities and private entities. A precis on the governance of MPAs and other effective conservation measures in the UK and its overseas territories is presented. Whilst the UK has made exceptional progress with quantitative MPA coverage, it is still not clear whether designated areas offer effective protection. A UK-level strategy is in place to address this; and at site level, Lyme Bay MPA illustrates the benefits of addressing qualitative criteria. Illustrated by the UK example, an urgent call is made for ongoing and future marine in situ area-based conservation efforts to substantiate quantitative and qualitative considerations, and to ensure that MPA networks are ultimately fit for purpose

Neuro-ophthalmological and Ophthalmological Findings in Joubert Syndrome

Background: Joubert syndrome (JS) belongs to the ciliopathies and is a mostly autosomal recessively inherited disease (in the case of OFD1 mutations, JS is an X-linked trait). It is characterised by midbrain-hindbrain malformations with developmental delay, hypotonia and ataxia and a broad spectrum of other facultative findings. The aim of our study was to examine the ophthalmological and neuro-ophthalmological features of JS in our patients and to compare our findings to those of other studies. Methods: In a retrospective study we evaluated the ophthalmological and neuro-ophthalmological findings of 9 consecutive patients who met the diagnostic criteria of JS. Results: All patients had abnormalities of ocular motility, 4/9 used head thrusts to shift gaze (oculomotor apraxia OMA). In 6/8 patients, the optokinetic reflex (OKN) was absent. Furthermore, 8/9 children showed nystagmus, mostly see-saw nystagmus. Manifest strabismus was found in 8/9 while 3/9 had a retinopathy with either abnormal ERG and/or fundus appearance with or without visual impairment. Chorioretinal colobomata were present in 5/9 cases. Two patients showed a unilateral congenital ptosis, one a facial nerve paresis. Conclusions: The early neuro-ophthalmological findings in JS are not pathognonomic, but may lead to the diagnosis of JS. The syndrome should be suspected in patients with nystagmus, especially see-saw nystagmus, and abnormal OKN and/or OMA, and/or colobomata of the fundus, and further paediatric examinations should be initiated

A process for identifying national solutions to challenges faced in developing countries in reporting to environmental conventions : Insight from the facilitating national reporting to the rio conventions project

Almost all countries in the world are party to the Rio Conventions. This entails a number of responsibilities, including reporting periodically on aspects of environmental health and national implementation of the convention. These reports can cover hundreds of pages, so completing reports is often a significant undertaking. Since countries can be party to numerous Multilateral Environmental Agreements (MEAs), they may have several such reports to prepare at any one time, often using similar information. This article shares insights from a project that piloted nationally-driven, integrated approaches to reporting to the Rio Conventions and developed flexible methods for enhancing the national reporting process, in a way that is relevant for a particular country. The project found that a focus on collaborative institutional arrangements and building capacity as a nation, rather than as a series of departments, could enhance this reporting process. These lessons can inform decisions of United Nations agencies, MEA secretariats, Country Parties to these MEAs and the wider sustainability community to reduce the reporting burden and increase the synergistic implementation of environmental conventions

Study of crack initiation and crack propagation of short fiber reinforced polyamide

This paper is about a study of the crack initiation and the crack propagation of short fibre reinforced polyamides following from cyclic loading. The crack initiation and propagation was investigated macroscopic by camera and microscopic by computer tomography

Strabologic and neuro-ophthamologic aspects of childhood cancer

Pediatric oncology has achieved major progress by continuous optimization of diagnostic and therapeutic approaches. In the interdisciplinary team, the ophthalmologist plays an important role. In the field of strabismus and neuro-ophthalmology clinical symptoms as strabismus, visual loss, anisocoria, visual field defects, and involuntary eye movements may be key indicators of childhood cancer. The appropriate diagnostic workup as well as the diagnostic and therapeutic steps during the course of the disease are important often requiring individually tailored approaches

Decannulation/Weaning Potential and Success in Home Intensive Care

Background: The number of patients receiving home long-term ventilation has risen considerably in recent decades owing to medical advancements. Experts believe that the potential for ventilator weaning or tracheostoma removal is currently insufficiently exploited. Objective: The objective of this study was to investigate the characteristics, prognosis, and decannulation/weaning potential of patients under home intensive care. Methods: In this retrospective analysis of 607 patients on home intensive care, decannulation/weaning status and survival were documented for a 2-year period after initial assessment. At the time of hospital discharge, when clinicians had deemed the weaning process concluded, an independent expert noninvasively assessed the long-term decannulation/weaning. Comparative analyses based on specific criteria, such as ventilation and decannulation/weaning status, age, and underlying diseases, were performed. Potential predictors of survival were identified via multivariable logistic regression. Results: Eighteen percent of patients were decannulated/weaned within 2 years after hospital discharge and had better mean survival than patients not decannulated/weaned (552 vs. 420 days, p < 0.001). More than half of these patients were identified to have decannulation/weaning potential based on the assessment of the independent expert. Patients with neuromuscular and neurological diseases had the best survival (546 and 501 days), patients with postsurgical conditions and cardiological diseases the worst (346 and 323 days). Underlying disease and decannulation/weaning status were significant predictors of 2-year survival. Conclusion: Successful decannulation/weaning of patients on long-term home intensive care is associated with better survival. Even in the absence of decannulation/weaning potential at the time of hospital discharge, patients may develop decannulation/weaning potential over time, which should therefore be assessed repeatedly