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<0.001). The strongest HbA1c reduction was observed in patients with a concomitant weight reduction >5 kilos (−0.38±0.99, p<0.001). In robust regression analysis, severe OSA (p=0.038) and morbid obesity (p=0.005) at baseline, and weight reduction >5 kilos (p<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

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

Biallelic null variants in PNPLA8 cause microcephaly by reducing the number of basal radial glia.

Patatin-like phospholipase domain-containing lipase 8 (PNPLA8), one of the calcium-independent phospholipase A2 enzymes, is involved in various physiological processes through the maintenance of membrane phospholipids. Biallelic variants in PNPLA8 have been associated with a range of paediatric neurodegenerative disorders. However, the phenotypic spectrum, genotype-phenotype correlations and the underlying mechanisms are poorly understood. Here, we newly identified 14 individuals from 12 unrelated families with biallelic ultra-rare variants in PNPLA8 presenting with a wide phenotypic spectrum of clinical features. Analysis of the clinical features of current and previously reported individuals (25 affected individuals across 20 families) showed that PNPLA8-related neurological diseases manifest as a continuum ranging from variable developmental and/or degenerative epileptic-dyskinetic encephalopathy to childhood-onset neurodegeneration. We found that complete loss of PNPLA8 was associated with the more profound end of the spectrum, with congenital microcephaly. Using cerebral organoids generated from human induced pluripotent stem cells, we found that loss of PNPLA8 led to developmental defects by reducing the number of basal radial glial cells and upper-layer neurons. Spatial transcriptomics revealed that loss of PNPLA8 altered the fate specification of apical radial glial cells, as reflected by the enrichment of gene sets related to the cell cycle, basal radial glial cells and neural differentiation. Neural progenitor cells lacking PNPLA8 showed a reduced amount of lysophosphatidic acid, lysophosphatidylethanolamine and phosphatidic acid. The reduced number of basal radial glial cells in patient-derived cerebral organoids was rescued, in part, by the addition of lysophosphatidic acid. Our data suggest that PNPLA8 is crucial to meet phospholipid synthetic needs and to produce abundant basal radial glial cells in human brain development

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

Different Prevalences of Pneumological Disease Patterns in Outpatient and Inpatient Care

Background Evaluating the focus of treatment in pneumological inpatient and outpatient care is of special interest due to its impact on physician, patient and research. This work describes differences and commonalities in the focus of treatment of current pneumological inpatient and outpatient care and discusses their impact on patient, physician and research. Methods This study compares the inpatient and outpatient sector based on the prevalence of ICD codes of a pneumological specialist clinic (5.211 cases of 2016) and the most prevalent ICD-10 codes of pneumology practices in the third quarter 2016, published by the Association of Statutory Health Insurance Physicians North Rhine (Kassenarztliche Vereinigung Nordrhein, 142.431 cases). Results Whereas the proportion of many pneumological disease patterns treated in physicians' practices and hospitals is similar, the relative frequencies of specific diseases differ considerably between the two. Treatment of allergic conditions such as allergic rhinopathy and bronchial asthma is mostly done on an outpatient basis while respiratory insufficiency and lung carcinoma constitute domains of pneumological inpatient care. Conclusion Despite many commonalities in the focus of treatment in pneumological inpatient and outpatient care, there are also substantial differences between the two. These affect medical training, the conduct of clinical studies, and in particular, patient care. In order to maintain a high level of medical care in all areas of pneumology a close exchange between inpatient and outpatient sector seems crucial. In the end, the availability of medical expertise across both sectors will benefit all: physicians, patients and medical science