Atlantic water intrusion triggers rapid retreat and regime change at previously stable Greenland glacier.

Ice discharge from Greenland's marine-terminating glaciers contributes to half of all mass loss from the ice sheet, with numerous mechanisms proposed to explain their retreat. Here, we examine K.I.V Steenstrups Nordre Bræ ('Steenstrup') in Southeast Greenland, which, between 2018 and 2021, retreated ~7 km, thinned ~20%, doubled in discharge, and accelerated ~300%. This rate of change is unprecedented amongst Greenland's glaciers and now places Steenstrup in the top 10% of glaciers by contribution to ice-sheet-wide discharge. In contrast to expected behaviour from a shallow, grounded tidewater glacier, Steenstrup was insensitive to high surface temperatures that destabilised many regional glaciers in 2016, appearing instead to respond to a >2 °C anomaly in deeper Atlantic water (AW) in 2018. By 2021, a rigid proglacial mélange had developed alongside notable seasonal variability. Steenstrup's behaviour highlights that even long-term stable glaciers with high sills are vulnerable to sudden and rapid retreat from warm AW intrusion.

Uniparental disomy screen of Irish rare disorder cohort unmasks homozygous variants of clinical significance in the TMCO1 and PRKRA genes.

A uniparental disomy (UPD) screen using whole genome sequencing (WGS) data from 164 trios with rare disorders in the Irish population was performed to identify large runs of homozygosity of uniparental origin that may harbour deleterious recessive variants. Three instances of whole chromosome uniparental isodisomy (UPiD) were identified: one case of maternal isodisomy of chromosome 1 and two cases of paternal isodisomy of chromosome 2. We identified deleterious homozygous variants on isodisomic chromosomes in two probands: a novel p (Glu59ValfsTer20) variant in TMCO1, and a p (Pro222Leu) variant in PRKRA, respectively. The overall prevalence of whole chromosome UPiD in our cohort was 1 in 55 births, compared to 1 in ∼7,500 births in the general population, suggesting a higher frequency of UPiD in rare disease cohorts. As a distinct mechanism underlying homozygosity compared to biallelic inheritance, the identification of UPiD has important implications for family planning and cascade testing. Our study demonstrates that UPD screening may improve diagnostic yields by prioritising UPiD chromosomes during WGS analysis.

Correction to: Spectrum of movement disorders and neurotransmitter abnormalities in paediatric POLG disease.

Due to a typesetting error the wrong Table 2 was used. The correct Table 2 is shown here.

Spectrum of movement disorders and neurotransmitter abnormalities in paediatric POLG disease.

OBJECTIVES: To describe the spectrum of movement disorders and cerebrospinal fluid (CSF) neurotransmitter profiles in paediatric patients with POLG disease. METHODS: We identified children with genetically confirmed POLG disease, in whom CSF neurotransmitter analysis had been undertaken. Clinical data were collected retrospectively. CSF neurotransmitter levels were compared to both standardised age-related reference ranges and to non-POLG patients presenting with status epilepticus. RESULTS: Forty-one patients with POLG disease were identified. Almost 50% of the patients had documented evidence of a movement disorder, including non-epileptic myoclonus, choreoathetosis and ataxia. CSF neurotransmitter analysis was undertaken in 15 cases and abnormalities were seen in the majority (87%) of cases tested. In many patients, distinctive patterns were evident, including raised neopterin, homovanillic acid and 5-hydroxyindoleacetic acid levels. CONCLUSIONS: Children with POLG mutations can manifest with a wide spectrum of abnormal movements, which are often prominent features of the clinical syndrome. Underlying pathophysiology is probably multifactorial, and aberrant monoamine metabolism is likely to play a role.

Land Ice Freshwater Budget of the Arctic and North Atlantic Oceans: 1. Data, Methods, and Results.

The freshwater budget of the Arctic and sub-polar North Atlantic Oceans has been changing due, primarily, to increased river runoff, declining sea ice and enhanced melting of Arctic land ice. Since the mid-1990s this latter component has experienced a pronounced increase. We use a combination of satellite observations of glacier flow speed and regional climate modeling to reconstruct the land ice freshwater flux from the Greenland ice sheet and Arctic glaciers and ice caps for the period 1958-2016. The cumulative freshwater flux anomaly exceeded 6,300 ± 316 km3 by 2016. This is roughly twice the estimate of a previous analysis that did not include glaciers and ice caps outside of Greenland and which extended only to 2010. From 2010 onward, the total freshwater flux is about 1,300 km3/yr, equivalent to 0.04 Sv, which is roughly 40% of the estimated total runoff to the Arctic for the same time period. Not all of this flux will reach areas of deep convection or Arctic and Sub-Arctic seas. We note, however, that the largest freshwater flux anomalies, grouped by ocean basin, are located in Baffin Bay and Davis Strait. The land ice freshwater flux displays a strong seasonal cycle with summer time values typically around five times larger than the annual mean. This will be important for understanding the impact of these fluxes on fjord circulation, stratification, and the biogeochemistry of, and nutrient delivery to, coastal waters.

Droplet distribution and airborne bacteria in an experimental shower unit.

Although human exposure to water aerosols is common in residential showers, the droplet distribution patterns generated in showers are not well understood nor is the bacteria released during shower operation. In this study, a two-phase flow Particle Tracking Velocimetry (PTV) algorithm was successfully used to characterize the spatial spray pattern and velocity field in two experimental showers (one low-flow and one high-flow). In addition, the airborne bacteria present in the shower over nearly 5 months of controlled operation was determined for both showers. The results indicate that the droplet velocity out of the low-flow showerhead (which had fewer orifices) was significantly higher than that out of the high-flow showerhead resulting in a higher aerosol number concentration in the low-flow shower and more consistent wetting of the shower wall. Both showerheads generated droplets in the respirable range and genera of potential health concern were observed in the shower aerosols measured both prior to and following shower operation. The study provides one of the first visualizations of droplet spray patterns in residential showers and provides insight into the airborne bacteria present in showers.

Unexplained developmental delay/learning disability: guidelines for best practice protocol for first line assessment and genetic/metabolic/radiological investigations.

BACKGROUND: Investigation of patients, particularly children, with unexplained global developmental delay (GDD)/learning disability (LD) has been challenging due to a lack of clear guidance from specialised centres. Limited knowledge of rare diseases and a poor understanding of the purpose or limitations of appropriate investigations have been some of the principal reasons for this difficulty. AIMS: A guideline development group was formed to recommend on appropriate, first line metabolic, genetic and radiological investigations for children and adults with unexplained GDD/ID. METHODS AND RECOMMENDATIONS: A comprehensive literature search was conducted, evaluated and reviewed by the guideline committee and a best practice protocol for first line assessment and genetic, metabolic and radiological investigations was decided upon after considering diagnostic yield, practicality, treatability and costs. CONCLUSION: It is hoped that these recommendations will become national guidelines for the first line metabolic, genetic and radiological investigation of patients presenting with unexplained GDD/ID.

NAPB - a novel SNARE-associated protein for early-onset epileptic encephalopathy.

Next-generation sequencing has accelerated the identification of disease genes in many rare genetic disorders including early-onset epileptic encephalopathies (EOEEs). While many of these disorders are caused by neuronal channelopathies, the role of synaptic and related neuronal proteins are increasingly being described. Here, we report a 6-year-old girl with unexplained EOEE characterized by multifocal seizures and profound global developmental delay. Recessive inheritance was considered due to parental consanguinity and Irish Traveller descent. Exome sequencing was performed. Variant prioritization identified a homozygous nonsense variant in the N-ethylmaleimide-sensitive factor attachment protein, beta (NAPB) gene resulting in a premature stop codon and 46% loss of the protein. NAPB plays a role in soluble N-ethylmaleimide-sensitive fusion attachment protein receptor (SNARE)-complex dissociation and recycling (synaptic vesicle docking). Knockout mouse models of the murine ortholog Napb have been previously reported. These mice develop recurrent post-natal epileptic seizures in the absence of structural brain changes. The identification of a disease-causing variant in NAPB further recognizes the importance of the SNARE complex in the development of epilepsy and suggests that this gene should be considered in patients with unexplained EOEE.

Atmospherically relevant core-shell aerosol studied using optical trapping and Mie scattering.

Solid core-liquid shell aerosols have been trapped in a counter-propagating optical trap confirming potential core-shell morphology in the atmosphere. Mie spectroscopy can be used to measure the core radius and film thickness to 0.5 and 1 nm precision respectively and to measure the wavelength dependent refractive indices of silica (core) and oleic acid (shell).

PLA2G6-associated neurodegeneration (PLAN): further expansion of the clinical, radiological and mutation spectrum associated with infantile and atypical childhood-onset disease.

Phospholipase A2 associated neurodegeneration (PLAN) is a major phenotype of autosomal recessive Neurodegeneration with Brain Iron Accumulation (NBIA). We describe the clinical phenotypes, neuroimaging features and PLA2G6 mutations in 5 children, of whom 4 presented with infantile neuroaxonal dystrophy (INAD). One other patient was diagnosed with the onset of PLAN in childhood, and our report highlights the diagnostic challenges associated with this atypical PLAN subtype. In this series, the neuroradiological relevance of classical PLAN features as well as apparent claval hypertrophy' is explored. Novel PLA2G6 mutations were identified in all patients. PLAN should be considered not only in patients presenting with a classic INAD phenotype but also in older patients presenting later in childhood with non-specific progressive neurological features including social communication difficulties, gait disturbance, dyspraxia, neuropsychiatric symptoms and extrapyramidal motor features.

Developmental changes in cerebral grey and white matter volume from infancy to adulthood.

In order to quantify human brain development in vivo, high resolution magnetic resonance images of 158 normal subjects from infancy to young adulthood were studied (age range 3 months-30 years, 71 males, 87 females). Data were analysed using algorithms based on voxel-based morphometry (VBM) (an objective whole brain processing technique) to generate global volume measures of whole brain, grey matter (GM) and white matter (GM). Gender-specific development of WM and GM volumes is characterised using a piecewise polynomial growth curve model to account for the non-linear nature of human brain development, implemented using Markov chain Monte Carlo simulation. The statistical method employed in this study proved to be successful and robust in the characterisation of brain development. The resulting growth curve parameter estimates lead to the following observations: total brain volume is demonstrated to undergo an initial rapid spurt. The total GM volume peaks during childhood and decreases thereafter, whereas total WM volume increases up to young adulthood. Relative to brain size, GM decreases and WM increases markedly over this age range in a non-linear manner, resulting in an increasing WM-to-GM ratio over much of the observed age range. In addition, significant gender differences are found. In general, brain volume and total white and grey matter volume are larger in males than in females, with a time-dependent difference over the age range studied. Over part of the observed age range females tend to have more GM volume relative to brain size and lower WM-to-GM ratio than males. The presented findings should be taken into account when investigating physiological and pathological changes during brain development.

Proteolytic bacteria in the lower digestive tract of poultry may affect avian influenza virus pathogenicity.

Proteolytic cleavage of hemagglutinin is required for cell entry by receptor-mediated endocytosis and plays a key role in pathogenicity of the influenza virus. Despite several studies describing relationships between bacterial proteases and influenza A viral activation in mammals, very little is known about the role of the normal bacterial flora of birds on hemagglutinin activation. We examined the indigenous intestinal microflora of 100 mixed-sex, 27-d-old Ross chickens from a commercial poultry facility for protease-secreting bacteria. Protease-secreting bacteria were isolated from 82 of 100 chickens with 50 birds exhibiting 2 or more protease-secreting bacterial species. A total of 20 protease-secreting bacterial species were identified: 17 gram-positive cocci, 2 gram-positive rods, and 1 gram-negative rod. Enterococcus faecalis, Enterococcus gallinarum, and Proteus mirabilis were the most frequently observed protease-secreting bacterial species. The presence of proteolytic bacteria in the intestinal tract of poultry in this study suggests the possibility of yet-to-be-described role(s) in cleavage of hemagglutinin that may alter the pathogenicity of avian influenza viruses.

Cerebellar leukoencephalopathy: most likely histiocytosis-related.

BACKGROUND: Histiocytosis, both Langerhans and non-Langerhans cell type, can be associated with cerebellar white matter abnormalities, thought to be paraneoplastic. The associated clinical picture consists of ataxia, spasticity, and cognitive decline. Hormonal dysfunction is frequent. MRI shows cerebellar white matter abnormalities, as well as brainstem and basal ganglia abnormalities. This so-called "neurodegenerative syndrome" may occur years before or during manifest histiocytosis and also years after cure. We discovered similar MRI abnormalities in 13 patients and wondered whether they could have the same syndrome. METHODS: We reviewed the clinical and laboratory information of these 13 patients and evaluated their brain MRIs. Seven patients underwent spinal cord MRI. RESULTS: All patients were isolated cases; 10 were male. They had signs of cerebellar and pyramidal dysfunction, behavioral problems, and cognitive decline. MRI showed abnormalities of the cerebellar white matter, brainstem, basal ganglia, and, to a lesser extent, cerebral white matter. Three patients had spinal cord lesions. Three patients had laboratory evidence of hormonal dysfunction. No evidence was found of an underlying metabolic defect. In two patients biopsy of nodular brain lesions revealed histiocytic infiltrates. CONCLUSIONS: Considering the striking clinical and MRI similarities between our patients and the patients with this neurodegenerative syndrome in the context of proven histiocytosis, it is likely that they share the same paraneoplastic syndrome, although we cannot exclude a genetic disorder with certainty. The fact that we found histiocytic lesions in two patients substantiates our conclusion. Patients with cerebellar white matter abnormalities should be monitored for histiocytosis.

Sensory-motor polyneuropathy occurring in variant maple syrup urine disease.

Maple syrup urine disease (MSUD; OMIM 248600) results from an inherited deficiency of the branched-chain ketoacid dehydrogenase (BCKD) complex. Approximately 20% of patients with BCKD deficiency are non-classic variants of MSUD with differing clinical severity. Outcomes for this cohort are generally favourable; episodes of metabolic decompensation do not appear to correlate with adverse events if acute management is promptly provided. A case of predominantly axonal sensory-motor neuropathy following metabolic decompensation which persisted for a number of months is presented in an adolescent girl with variant (intermediate type) MSUD. EMG and nerve conduction studies suggested a pre-existent asymptomatic chronic neuropathy, exacerbated by the acute decompensation. Peak leucine concentration at decompensation was 1083 µmol/L. The patient had laboratory signs of secondary mitochondrial respiratory chain dysfunction at presentation. She had been on a moderate dose of thiamine prior to decompensation; thiamine and pyridoxine blood concentrations were normal. This, to our knowledge, is the first report of a neuropathy presenting in a patient with a decompensation of variant MSUD. We propose that this presentation resembles the intermittent neuropathy observed in pyruvate dehydrogenase deficiency and may reflect secondary inhibition of pyruvate dehydrogenase activity by MSUD metabolites.

Further delineation of Pitt-Hopkins syndrome: phenotypic and genotypic description of 16 novel patients.

BACKGROUND: Haploinsufficiency of the gene encoding for transcription factor 4 (TCF4) was recently identified as the underlying cause of Pitt-Hopkins syndrome (PTHS), an underdiagnosed mental-retardation syndrome characterised by a distinct facial gestalt, breathing anomalies and severe mental retardation. METHODS: TCF4 mutational analysis was performed in 117 patients with PTHS-like features. RESULTS: In total, 16 novel mutations were identified. All of these proven patients were severely mentally retarded and showed a distinct facial gestalt. In addition, 56% had breathing anomalies, 56% had microcephaly, 38% had seizures and 44% had MRI anomalies. CONCLUSION: This study provides further evidence of the mutational and clinical spectrum of PTHS and confirms its important role in the differential diagnosis of severe mental retardation.