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How should we think of the preferences of citizens? Whereas self-optimal policy is relatively straightforward to produce, socially optimal policy often requires a more detailed examination. In this paper, we identify an issue that has received far too little attention in welfarist modelling of public policy, which we name the "hidden assumptions" problem. Hidden assumptions can be deceptive because they are not expressed explicitly and the social planner (e.g. a policy maker, a regulator, a legislator) may not give them the critical attention they need. We argue that ethical expertise has a direct role to play in public discourse because it is hard to adopt a position on major issues like public health policy or healthcare prioritisation without making contentious assumptions about population ethics. We then postulate that ethicists are best situated to critically evaluate these hidden assumptions, and can therefore play a vital role in public policy debates., Forthcoming in Ethics & Bioethics

Background The low FODMAP diet (LFD) is effective in managing irritable bowel syndrome (IBS) in the short term. This study assessed the long-term effect of the LFD on symptoms, nutritional composition and socialising. Methods Patients with IBS who received dietetic-led LFD advice were approached at long term follow up (>6 months post LFD advice) from six centres across the United Kingdom. Participants completed questionnaires assessing gastrointestinal symptoms, adherence, nutritional intake, dietary acceptability and food related quality of life (QOL). Results 205 participants completed the study, with a mean follow up of 44 months (3.7 years). Adequate symptom relief was noted in 60% of individuals at long term follow up, with 76% being on the personalisation phase of the LFD (pLFD). Mean nutritional intake did not differ between individuals on the pLFD versus habitual diet, with no difference in fructan intake (2.9 g/d vs 2.9 g/d, p = 0.96). The majority (80%) of individuals on the pLFD consumed specific ‘free-from’ products at the long term, with the purchase of gluten or wheat free products being the commonest (68%). Conclusion The majority of patients follow the pLFD in the long term, with a large proportion purchasing gluten or wheat free products to manage their symptoms.

Bosch-Boonstra-Schaaf Optic Atrophy Syndrome (BBSOAS) is an autosomal dominant neurodevelopmental disorder caused by loss-of-function variants in NR2F1 and characterized by visual impairment, developmental delay, and intellectual disability. Here we report 18 new cases, provide additional clinical information for 9 previously reported individuals, and review an additional 27 published cases to present a total of 54 patients. Among these are 22 individuals with point mutations or in-frame deletions in the DNA-binding domain (DBD), and 32 individuals with other types of variants including whole-gene deletions, nonsense and frameshift variants, and point mutations outside the DBD. We corroborate previously described clinical characteristics including developmental delay, intellectual disability, autism spectrum disorder diagnoses/features thereof, cognitive/behavioral anomalies, hypotonia, feeding difficulties, abnormal brain MRI findings, and seizures. We also confirm a vision phenotype that includes optic nerve hypoplasia, optic atrophy, and cortical visual impairment. Additionally, we expand the vision phenotype to include alacrima and manifest latent nystagmus (fusional maldevelopment), and we broaden the behavioral phenotypic spectrum to include a love of music, an unusually good long-term memory, sleep difficulties, a high pain tolerance, and touch sensitivity. Furthermore, we provide additional evidence for genotype-phenotype correlations, specifically supporting a more severe phenotype associated with DBD variants.

Armillaria limonea is a white rot wood decay fungus and root disease pathogen that has confirmed presence in New Zealand only, where it is presumed to be indigenous. It is closely related to A. luteobubalina in Australia and South America, and to South American A. montagnei. A. limonea occurs naturally on woody debris and as a cause of butt rot in living trees in podocarp-hardwood and southern beech (Nothofagus) forests where it contributes beneficially to carbon and nutrient recycling. It fruits prolifically in native forests, forming large clusters of "toadstool" fruitbodies during winter. Like many other Armillaria species it is recognized by characteristic white mycelial fans or ribbons produced beneath host bark, and by its bootlace-like rhizomorphs by which it spreads vegetatively from colonized buried woody material or stump root systems to infect living host plants.

The “quantum threat” to our current, convenient cryptographic algorithms is getting closer, with demonstrable progress by commercial quantum computing efforts. It is now more important than ever that we combine all of our tools into a new quantum-safe toolbox to develop the next generation of quantum-safe networking solutions. Here we combine an integrated quantum entropy source with quantum-resistant algorithms in the GnuGPG open-source software; leading to a fully quantum-safe version of GnuGPG. The quantum entropy source itself is capable of a raw rate of randomness in excess of 10 Gbps. After post-processing, quantum random numbers are used by the quantum-resistant algorithms to allow GnuGPG to perform its usual public-key cryptographic tasks, such as digitally signing documents, but now in a secure quantum-safe way.

Contains fulltext : 245031.pdf (Publisher’s version ) (Closed access) PURPOSE: Postsynaptic density protein-95 (PSD-95), encoded by DLG4, regulates excitatory synaptic function in the brain. Here we present the clinical and genetic features of 53 patients (42 previously unpublished) with DLG4 variants. METHODS: The clinical and genetic information were collected through GeneMatcher collaboration. All the individuals were investigated by local clinicians and the gene variants were identified by clinical exome/genome sequencing. RESULTS: The clinical picture was predominated by early onset global developmental delay, intellectual disability, autism spectrum disorder, and attention deficit-hyperactivity disorder, all of which point to a brain disorder. Marfanoid habitus, which was previously suggested to be a characteristic feature of DLG4-related phenotypes, was found in only nine individuals and despite some overlapping features, a distinct facial dysmorphism could not be established. Of the 45 different DLG4 variants, 39 were predicted to lead to loss of protein function and the majority occurred de novo (four with unknown origin). The six missense variants identified were suggested to lead to structural or functional changes by protein modeling studies. CONCLUSION: The present study shows that clinical manifestations associated with DLG4 overlap with those found in other neurodevelopmental disorders of synaptic dysfunction; thus, we designate this group of disorders as DLG4-related synaptopathy.

Introduction Studies support the use of the low FODMAP diet (LFD) in irritable bowel syndrome (IBS). Whether an optimal threshold of restriction exists is yet to be determined, but Methods A systematic review was performed of publications reporting total FODMAP and fructan intakes pre and post dietary intervention. LFD dietary trials (n=15) were identified on PubMed using MESH terms ‘low FODMAP’, ‘irritable bowel syndrome’ and ‘fructans’. From the articles identified, studies having no data on total FODMAP intake or fructan intake were excluded (n=6). Percentage change in total FODMAP intake pre- and post dietary intervention were assessed in eligible articles (n=9). All eligible articles (n=9) had data on total FODMAPs (n=7 after restriction stage and n=2 in long term) and 7 articles had data on fructan intakes (n=5 after the restriction stage and n=2 at long term). Studies assessing fructan intake in healthy participants were included for comparison (n=2). Results Total FODMAPs at baseline or in the control group was 13.0–29.6 g/d (n=7 studies) and following the LFD restriction phase 3.1–22.0 g/d (n= 7 studies), with a 24.1–85.8% reduction across studies (see graph 1). Of the 7 studies, 6 achieved the suggested threshold Conclusions The total FODMAP threshold of Reference Tuck CJ, Reed DE, Muir JG, Vanner SJ. Implementation of the low FODMAP diet in functional gastrointestinal symptoms: A real—World experience. Neurogastroenterol. Motil. 2019, 1–13

Summary Histone deacetylases play crucial roles in the regulation of chromatin structure and gene expression in the eukaryotic cell, and disruption of their activity causes a wide range of developmental disorders in humans. Loss-of-function alleles of HDAC4, a founding member of the class IIa deacetylases, have been reported in brachydactyly-mental retardation syndrome (BDMR). However, while disruption of HDAC4 activity and deregulation of its downstream targets may contribute to the BDMR phenotype, loss of HDAC4 function usually occurs as part of larger deletions of chromosome 2q37; BDMR is also known as chromosome 2q37 deletion syndrome, and the precise role of HDAC4 within the phenotype remains uncertain. Thus, identification of missense variants should shed new light on the role of HDAC4 in normal development. Here, we report seven unrelated individuals with a phenotype distinct from that of BDMR, all of whom have heterozygous de novo missense variants that affect a major regulatory site of HDAC4, required for signal-dependent 14-3-3 binding and nucleocytoplasmic shuttling. Two individuals possess variants altering Thr244 or Glu247, whereas the remaining five all carry variants altering Pro248, a key residue for 14-3-3 binding. We propose that the variants in all seven individuals impair 14-3-3 binding (as confirmed for the first two variants by immunoprecipitation assays), thereby identifying deregulation of HDAC4 as a pathological mechanism in a previously uncharacterized developmental disorder., Loss-of-function variants in histone deacetylase 4 (HDAC4) have been reported to cause brachydactyly-mental retardation (BDMR) syndrome through haploinsufficiency. This report describes 7 individuals with a phenotype distinct from BDMR, all with missense variants in a conserved 14-3-3 site, which are hypothesized to result in a novel gain-of-function effect in HDAC4.

AimsThe aim of the study was to assess the provision of dietetic services for coeliac disease (CD), irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD).MethodsHospitals within all National Health Service trusts in England were approached (n=209). A custom-designed web-based questionnaire was circulated via contact methods of email, post or telephone. Individuals/teams with knowledge of gastrointestinal (GI) dietetic services within their trust were invited to complete.Results76% of trusts (n=158) provided GI dietetic services, with responses received from 78% of these trusts (n=123). The median number of dietitians per 100 000 population was 3.64 (range 0.15–16.60), which differed significantly between regions (p=0.03). The most common individual consultation time for patients with CD, IBS and IBD was 15–30 min (43%, 44% and 54%, respectively). GI dietetic services were delivered both via individual and group counselling, with individual counselling being the more frequent delivery method available (93% individual vs 34% group). A significant proportion of trusts did not deliver any specialist dietetic clinics for CD, IBS and IBD (49% (n=60), 50% (n=61) and 72% (n=88), respectively).ConclusionThere is an inequity of GI dietetic services across England, with regional differences in the level of provision and extent of specialist care. Allocated time for clinics appears to be insufficient compared with time advocated in the literature. Group clinics are becoming a more common method of dietetic service delivery for CD and IBS. National guidance on GI dietetic service delivery is required to ensure equity of dietetic services across England.

There have been few clinical or scientific reports of autosomal dominant tubulointerstitial kidney disease due to REN mutations (ADTKD-REN), limiting characterization. To further study this, we formed an international cohort characterizing 111 individuals from 30 families with both clinical and laboratory findings. Sixty-nine individuals had a REN mutation in the signal peptide region (signal group), 27 in the prosegment (prosegment group), and 15 in the mature renin peptide (mature group). Signal group patients were most severely affected, presenting at a mean age of 19.7 years, with the prosegment group presenting at 22.4 years, and the mature group at 37 years. Anemia was present in childhood in 91% in the signal group, 69% prosegment, and none of the mature group. REN signal peptide mutations reduced hydrophobicity of the signal peptide, which is necessary for recognition and translocation across the endoplasmic reticulum, leading to aberrant delivery of preprorenin into the cytoplasm. REN mutations in the prosegment led to deposition of prorenin and renin in the endoplasmic reticulum-Golgi intermediate compartment and decreased prorenin secretion. Mutations in mature renin led to deposition of the mutant prorenin in the endoplasmic reticulum, similar to patients with ADTKD-UMOD, with a rate of progression to end stage kidney disease (63.6 years) that was significantly slower vs. the signal (53.1 years) and prosegment groups (50.8 years) (significant hazard ratio 0.367). Thus, clinical and laboratory studies revealed subtypes of ADTKD-REN that are pathophysiologically, diagnostically, and clinically distinct.

We construct a representative index of largest Indian energy companies listed on the National Stock Exchange (NIFTY 50). We test for presence of regimes, non-linearities, and jumps in the price signal. We benchmark performance against alternative models, including single-regime models and models with no jumps. We then benchmark the quality of regime identification against other indices examined in the literature, such as Nikkei 225 and FTSE 100. Overall, find that our regime-switching model performs well in identifying the regimes in this comparative setting. Based on our model selection criteria, we prefer a regime-augmented model to a model that allows no regime identification. But overall, we prefer a model with jumps and regimes over those that do not allow for jump-diffusion and Markov regime-switching.

This study uses single-equation dynamic models to estimate petrol demand in India. Estimated long-run elasticities are higher than their short-run counterparts, which is in line with expectations based on the existing literature. We find price elasticities of -0.418 (long-run) and -0.189 (short run), which indicates that when price increases by 10%, demand tends to reduce by approximately 4% as consumers adjust their consumption behaviour. Prices appear to be more elastic in India rather than USA where studies estimate petrol elasticities to be in the range of -0.02 to -0.04 in the short term. We further find evidence that long-run elasticities are not as high as estimated elsewhere. We address issues around modelling of habit formation, habit persistence, and unobserved heterogeneity. Results are essential for transportation policymaking, especially in the context of taxation, understanding price stability, estimating the effects of duty increases on demand, and the potential implications for carbon taxes. The results are also important for wider policy considerations such as climate protections goals, reducing local emissions, dependency on fossil fuels, and strategic energy security.

This article examines the dynamics of pandemic-induced uncertainty on credit growth, stock prices, economic activity, bond yields, and prices (assets and goods) in a panel dataset, recently assembled using IMF archives, of advanced and emerging economies. for this purpose, we implement a Symbolic Transfer Entropy approach proposed by Camacho et al. (2021), which represents an improved specification for detecting Granger-type causality in panel datasets. Specifically, this procedure yields a more robust specification when linearity assumptions break down, when in the presence of structural breaks, or when the data generating process is heterogeneous across the cross-section units. Aggregate economic variables are compared against the world pandemic uncertainty index (WPUI), which is based on the work of Ahir, Bloom, and Furceri (2020) and measures economic uncertainty related to pandemics and other disease outbreaks across the world. Amidst concerns that past economic shocks have left permanent scars on long-term growth, known as hysteresis, we find no robust evidence of a long-run causal effect between pandemic-induced uncertainty and most of key aggregate economic variables. On the other hand, the results indicate that pandemic jump tail risk is priced within equities.

Functional bowel disorders (FBDs) affect around 20% of the population worldwide and are associated with reduced quality of life and high healthcare costs. Dietary therapies are frequently implemented to assist with symptom relief in these individuals, however, there are concerns regarding their complexity, restrictiveness, nutritional adequacy, and effectiveness. Thus, to overcome these limitations, a novel approach, the 5Ad Dietary Protocol, was designed and tested for its efficacy in reducing the severity of a range of gastrointestinal symptoms in 22 subjects with FBDs. The protocol was evaluated in a repeated measures MANOVA design (baseline week and intervention week). Measures of stool consistency and frequency were subtyped based on the subject baseline status. Significant improvements were seen in all abdominal symptom measures (

Malan syndrome is an overgrowth disorder described in a limited number of individuals. We aim to delineate the entity by studying a large group of affected individuals. We gathered data on 45 affected individuals with a molecularly confirmed diagnosis through an international collaboration and compared data to the 35 previously reported individuals. Results indicate that height is > 2 SDS in infancy and childhood but in only half of affected adults. Cardinal facial characteristics include long, triangular face, macrocephaly, prominent forehead, everted lower lip and prominent chin. Intellectual disability is universally present, behaviorally anxiety is characteristic. Malan syndrome is caused by deletions or point mutations of NFIX clustered mostly in exon 2. There is no genotype-phenotype correlation except for an increased risk for epilepsy with 19p13.2 microdeletions. Variants arose de novo, except in one family in which mother was mosaic. Variants causing Malan and Marshall-Smith syndrome can be discerned by differences in the site of stop codon formation. We conclude that Malan syndrome has a well recognizable phenotype that usually can be discerned easily from Marshall-Smith syndrome but rarely there is some overlap. Differentiation from Sotos and Weaver syndrome can be made by clinical evaluation only. This article is protected by copyright.

The objective of this study was to describe the clinical characteristics of syndromic neonatal diabetes in a family with a GATA6 mutation. A girl, currently aged 12 years 3 months, was born with intrauterine growth retardation: weight 1600 g (–4.3 SDS) at term. After birth, foramen ovale and patent ductus arteriosus (PDA) were diagnosed by echocardiography. Diabetes was diagnosed on the 9th day after birth. Exocrine pancreatic insufficiency was clinically diagnosed at about 2 years of age and pancreatic agenesis was revealed later by magnetic resonance imaging. Her father had undergone surgery during infancy for PDA and had developed insulin dependent diabetes at 12 years of age. Ultrasound revealed a thin pancreas with normal length and anatomical structure. He has subclinical exocrine pancreatic insufficiency, low insulin needs and no late complications of diabetes up to the age of 40 years. Sequencing of GATA6 identified a heterozygous splicing mutation, 1136-2A>G, in the girl and her father. Testing of the paternal grandparents showed that the mutation was likely to have arisen de novo in the father. Identification of a GATA6 mutation explains the cardiac anomalies and diabetes in this family. This case highlights the marked intra-familial variability of both exocrine and endocrine pancreatic phenotypes in patients with GATA6 mutations.

Whole-exome and targeted sequencing of 13 individuals from 10 unrelated families with overlapping clinical manifestations identified loss-of-function and missense variants in KIAA1109 allowing delineation of an autosomal-recessive multi-system syndrome, which we suggest to name Alkuraya-Kučinskas syndrome (MIM 617822). Shared phenotypic features representing the cardinal characteristics of this syndrome combine brain atrophy with clubfoot and arthrogryposis. Affected individuals present with cerebral parenchymal underdevelopment, ranging from major cerebral parenchymal thinning with lissencephalic aspect to moderate parenchymal rarefaction, severe to mild ventriculomegaly, cerebellar hypoplasia with brainstem dysgenesis, and cardiac and ophthalmologic anomalies, such as microphthalmia and cataract. Severe loss-of-function cases were incompatible with life, whereas those individuals with milder missense variants presented with severe global developmental delay, syndactyly of 2 nd and 3 rd toes, and severe muscle hypotonia resulting in incapacity to stand without support. Consistent with a causative role for KIAA1109 loss-of-function/hypomorphic variants in this syndrome, knockdowns of the zebrafish orthologous gene resulted in embryos with hydrocephaly and abnormally curved notochords and overall body shape, whereas published knockouts of the fruit fly and mouse orthologous genes resulted in lethality or severe neurological defects reminiscent of the probands' features.

Tissue engineering using three-dimensional porous scaffolds has shown promise for the restoration of normal function in injured and diseased tissues and organs. Rigorous control over scaffold architecture in melt extrusion additive manufacturing is highly restricted mainly due to pronounced variations in the deposited strand diameter upon any variations in process conditions and polymer viscoelasticity. We have designed an I-optimal, split-plot experiment to study the extrudate swell in melt extrusion additive manufacturing and to control the scaffold architecture. The designed experiment was used to generate data to relate three responses (swell, density, and modulus) to a set of controllable factors (plotting needle diameter, temperature, pressure, and the dispensing speed). The fitted regression relationships were used to optimize the three responses simultaneously. The swell response was constrained to be close to 1 while maximizing the modulus and minimizing the density. Constraining the extrudate swell to 1 generates design-driven scaffolds, with strand diameters equal to the plotting needle diameter, and allows a greater control over scaffold pore size. Hence, the modulus of the scaffolds can be fully controlled by adjusting the in-plane distance between the deposited strands. To the extent of the model's validity, we can eliminate the effect of extrudate swell in designing these scaffolds, while targeting a range of porosity and modulus appropriate for bone tissue engineering. The result of this optimization was a predicted modulus of 14 MPa and a predicted density of 0.29 g/cm

BACKGROUND: Ultrarare Marshall-Smith and Malan syndromes, caused by changes of the gene nuclear factor I X (NFIX), are characterised by intellectual disability (ID) and behavioural problems, although questions remain. Here, development and behaviour are studied and compared in a cross-sectional study, and results are presented with genetic findings. METHODS: Behavioural phenotypes are compared of eight individuals with Marshall-Smith syndrome (three male individuals) and seven with Malan syndrome (four male individuals). Long-term follow-up assessment of cognition and adaptive behaviour was possible in three individuals with Marshall-Smith syndrome. RESULTS: Marshall-Smith syndrome individuals have more severe ID, less adaptive behaviour, more impaired speech and less reciprocal interaction compared with individuals with Malan syndrome. Sensory processing difficulties occur in both syndromes. Follow-up measurement of cognition and adaptive behaviour in Marshall-Smith syndrome shows different individual learning curves over time. CONCLUSIONS: Results show significant between and within syndrome variability. Different NFIX variants underlie distinct clinical phenotypes leading to separate entities. Cognitive, adaptive and sensory impairments are common in both syndromes and increase the risk of challenging behaviour. This study highlights the value of considering behaviour within developmental and environmental context. To improve quality of life, adaptations to environment and treatment are suggested to create a better person-environment fit.

Contains fulltext : 206572.pdf (Publisher’s version ) (Open Access) We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities.

This thesis is submitted in three chapters. Chapter 1 considers a regime-switching Levy framework, where all parameter values depend on the value of a continuous time Markov chain as per Chevallier and Goutte (2017), is employed to study US Corporate Option-Adjusted Spreads (OASs). For modelling purposes we assume a Normal Inverse Gaussian distribution, allowing heavier tails and skewness. After the Expectation - Maximization algorithm is applied to this general class of regime switching models, we compare the obtained results with time series models without jumps, including one with regime switching and one without. We find that a regime-switching Levy model clearly defines two regimes for A-, AA-, and AAA-rated OASs. We find further evidence of regime-switching effects, with data showing relatively pronounced jump intensity around the time of major crisis periods, thereby confirming the presence and importance of volatility regimes. Results indicate that ignoring the complex and dynamic dependence structure in favour of certain model assumptions may lead to a significant underestimation of risk. To the best of our knowledge, this study is the first time that Markov-switching Levy models have been employed to analyze the structure of option-adjusted spreads. Chapter 2 considers a little-used dataset to study the Japan's Real Estate Investment Trusts (REITs) market. We make use of copula theory and test for dependence between equity and REIT returns using several popular copula families. The copula families in our specification were: Gaussian, Student-$t$, Clayton, Frank, and Gumbel. The p-values were computed using parametric bootstrap replications. We motivate the argument presented, and provide the goodness-of-fit test results based on the Rosenblatt transform. We find that the dependence between the innovations of JREIT Composite and JREIT Office returns can be modelled by a Student-$t$ copula with 2.7 degrees of freedom and correlation parameter $\hat{\nu}$ = 0.93. All other models are rejected. To the best of our knowledge, this study represents the first time that copula theory has been applied to study REITs in Japan. Chapter 3 critiques a recent contribution to the financial econometrics literature, namely Chu et al. (2017), which provides the first examination of the time-series price behaviour of the most popular cryptocurrencies. We argue that insufficient attention was paid to correctly diagnosing the distribution of GARCH innovations. When these data issues are controlled for, their results lack robustness and may lead to either underestimation or overestimation of future risks. The main aim of this paper therefore is to provide an improved econometric specification. Particular attention is paid to correctly diagnosing the distribution of GARCH innovations by means of Kolmogorov type non-parametric tests and Khmaladze's martingale transformation. Numerical computation is carried out by implementing a Gauss-Kronrod quadrature. Parameters of GARCH models are estimated using maximum likelihood. For calculating p-values, the parametric bootstrap method is used. Further reference is made to the merits and demerits of statistical techniques presented in the related and recently published literature.

Glypicans are a family of cell-surface heparan sulfate proteoglycans that regulate growth-factor signaling during development and are thought to play a role in the regulation of morphogenesis. Whole-exome sequencing of the Australian family that defined Keipert syndrome (nasodigitoacoustic syndrome) identified a hemizygous truncating variant in the gene encoding glypican 4 (GPC4). This variant, located in the final exon of GPC4, results in premature termination of the protein 51 amino acid residues prior to the stop codon, and in concomitant loss of functionally important N-linked glycosylation (Asn514) and glycosylphosphatidylinositol (GPI) anchor (Ser529) sites. We subsequently identified seven affected males from five additional kindreds with novel and predicted pathogenic variants in GPC4. Segregation analysis and X-inactivation studies in carrier females provided supportive evidence that the GPC4 variants caused the condition. Furthermore, functional studies of recombinant protein suggested that the truncated proteins p.Gln506* and p.Glu496* were less stable than the wild type. Clinical features of Keipert syndrome included a prominent forehead, a flat midface, hypertelorism, a broad nose, downturned corners of mouth, and digital abnormalities, whereas cognitive impairment and deafness were variable features. Studies of Gpc4 knockout mice showed evidence of the two primary features of Keipert syndrome: craniofacial abnormalities and digital abnormalities. Phylogenetic analysis demonstrated that GPC4 is most closely related to GPC6, which is associated with a bone dysplasia that has a phenotypic overlap with Keipert syndrome. Overall, we have shown that pathogenic variants in GPC4 cause a loss of function that results in Keipert syndrome, making GPC4 the third human glypican to be linked to a genetic syndrome.

Homozygous truncating mutations in the helix-loop-helix transcription factor PTF1A are a rare cause of pancreatic and cerebellar agenesis. The correlation of Ptf1a dosage with pancreatic phenotype in a mouse model suggested the possibility of finding hypomorphic PTF1A mutations in patients with pancreatic agenesis or neonatal diabetes but no cerebellar phenotype. Genome-wide single nucleotide polymorphism typing in two siblings with neonatal diabetes from a consanguineous pedigree revealed a large shared homozygous region (31 Mb) spanning PTF1A. Sanger sequencing of PTF1A identified a novel missense mutation, p.P191T. Testing of 259 additional patients using a targeted next-generation sequencing assay for 23 neonatal diabetes genes detected one additional proband and an affected sibling with the same homozygous mutation. All four patients were diagnosed with diabetes at birth and were treated with insulin. Two of the four patients had exocrine pancreatic insufficiency requiring replacement therapy but none of the affected individuals had neurodevelopmental delay. Transient transfection assays of the mutant protein demonstrated a 75% reduction in transactivation activity. This study shows that the functional severity of a homozygous mutation impacts the severity of clinical features found in patients.

From the autumn of 1944 to the spring of 1945 thousands of the Red Army's characteristic triangle envelopes arrived in kolkhozes in Uzbekistan's Andijan oblast addressed to two young women, Inobatxon Xoldarova and O'g'ulxon Qurbonova, whose portraits and labor accomplishments had appeared in Russian--and Uzbek-language army newspapers. The authors were Red Army soldiers of various nationalities, stationed across the Soviet Union and the newly liberated cities of Eastern and Central Europe, who wrote congratulations and thanks, requesting photos and letters in reply and sometimes proposing further friendship, acquaintance, and marriage. Just after the German capitulation in May 1945 a soldier in west-central Ukraine penned a lilting note of introduction to O'g'ulxon. Apart from its first line, the letter was written in Russian: Fiery, hot hello [Uzbek: Alangali issik solom] Hello from Novograd-Volynskii. This day or evening I inform you with this letter, when you receive it I don't know, maybe at night or during the day, the exact time won't interest you. [...] Best wishes in your life, hot, fiery hello. Hello, unknown Ogulkhan. With greetings to you from Mukhamed Ergashov. First, I decided to write this letter to show my great thanks. If you don't like this letter, you can throw it underfoot! My only desire is to meet you. If you have a friend [znakomyi], tell me. I suspected you as my countrywoman [.zemliachka] in the newspaper Leninskoe znamia and decided to write these words. I'll tell a bit about myself. I am also from Andizhan, from khodzhabad [sic] district serve in the ranks of the red army.... The other day I saw the end of the war. Maybe you and I will see one another. Ogulkhan, if I receive a response from you, then I will write with more detail about myself or more precisely. If you can read Russian, then I will write in Russian, or if you can't I can write in our language [esli mozhete chitat' po ruskii to budu pisat' po ruski, Libo nimozhete mogu napisat' po svoemu (sic)]. So long I am finished writing so long with regards unknown, Mukhamed or Misha. Write a response to this address.... Mikhail Ergashov I await your reply. (1) The little we know of Ergashov is based on his neatly written note. Based on his mastery of the Cyrillic alphabet (introduced to Uzbekistan in 1939), he was probably a young and recent Uzbek call-up. Though full of spelling and punctuation errors, his Russian was idiomatic and free, indicating that he had augmented the Russian learned at school in the Russian-language service environment. His query about O'g'ulxon's marital status implied he was a bachelor; he was also a common soldier, because he added no service details about rank or medals. Instead, his language served as his primary accomplishment, signaling to O'g'ulxon that he was, like her, a progressive and successful contributor to the Soviet war effort and therefore a fitting match. Ergashov's self-presentation offered a dilemma for O'g'ulxon that gets to the heart of Uzbek participation in the Soviet war effort: had she been able or willing to reply, to whom should she have addressed the letter? Was he Misha or Mukhamed Ergashov? Russian or Uzbek or perhaps both? Ergashov's indecision was not a personal shortcoming but a reflection of a seismic transition in Eurasian history, triggered by the Bolshevik revolution and accelerated by the war effort. Uzbek men at war became Soviet in new ways: changing Islamic ritual practice, drinking alcohol, gaining military skills, interacting with men of multiple nationalities, leaving their home regions, learning Russian, embracing Russian nicknames, and even taking Slavic wives. (2) Interethnic tensions and disastrous combat performances in the war's first years had led the Red Army to ensure that Uzbek and other Central Asian soldiers were supported by propaganda materials rooted in their national languages and cultural traditions, according to the dictates of the Soviet friendship of peoples. …

Contains fulltext : 168023.pdf (Publisher’s version ) (Closed access) Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a lethal lung developmental disorder caused by heterozygous point mutations or genomic deletion copy-number variants (CNVs) of FOXF1 or its upstream enhancer involving fetal lung-expressed long noncoding RNA genes LINC01081 and LINC01082. Using custom-designed array comparative genomic hybridization, Sanger sequencing, whole exome sequencing (WES), and bioinformatic analyses, we studied 22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. We describe novel deletion CNVs at the FOXF1 locus in 13 unrelated ACDMPV patients. Together with the previously reported cases, all 31 genomic deletions in 16q24.1, pathogenic for ACDMPV, for which parental origin was determined, arose de novo with 30 of them occurring on the maternally inherited chromosome 16, strongly implicating genomic imprinting of the FOXF1 locus in human lungs. Surprisingly, we have also identified four ACDMPV families with the pathogenic variants in the FOXF1 locus that arose on paternal chromosome 16. Interestingly, a combination of the severe cardiac defects, including hypoplastic left heart, and single umbilical artery were observed only in children with deletion CNVs involving FOXF1 and its upstream enhancer. Our data demonstrate that genomic imprinting at 16q24.1 plays an important role in variable ACDMPV manifestation likely through long-range regulation of FOXF1 expression, and may be also responsible for key phenotypic features of maternal uniparental disomy 16. Moreover, in one family, WES revealed a de novo missense variant in ESRP1, potentially implicating FGF signaling in the etiology of ACDMPV.

© 2019 American Society of Human Genetics The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.

This paper examines the time series properties of cryptocurrency assets, such as Bitcoin, using established econometric inference techniques, namely models of the GARCH family. The contribution of this study is twofold. I explore the time series properties of cryptocurrencies, a new type of financial asset on which there appears to be little or no literature. I suggest an improved econometric specification to that which has been recently proposed in Chu et al (2017), the first econometric study to examine the price dynamics of the most popular cryptocurrencies. Questions regarding the reliability of their study stem from the authors mis-diagnosing the distribution of GARCH innovations. Checks are performed on whether innovations are Gaussian or GED by using Kolmogorov type non-parametric tests and Khmaladze's martingale transformation. Null of gaussianity is strongly rejected for all GARCH(p,q) models, with $p,q \in \{1,\ldots,5 \}$, for all cryptocurrencies in sample. For tests of normality, I make use of the Gauss-Kronrod quadrature. Parameters of GARCH models are estimated with generalized error distribution innovations using maximum likelihood. For calculating P-values, the parametric bootstrap method is used. Arguing against Chu et al (2017), I show that there is a strong empirical argument against modelling innovations under some common assumptions., 28 pages, 27 figures

A regime-switching Levy framework, where all parameter values depend on the value of a continuous time Markov chain as per Chevallier and Goutte (2017), is employed to study US Corporate Option-Adjusted Spreads (OASs). For modelling purposes we assume a Normal Inverse Gaussian distribution, allowing heavier tails and skewness. After the Expectation-Maximization algorithm is applied to this general class of regime switching models, we compare the obtained results with time series models without jumps, including one with regime switching and one without. We find that a regime-switching Levy model clearly defines two regimes for A-, AA-, and AAA-rated OASs. We find further evidence of regime-switching effects, with data showing relatively pronounced jump intensity around the time of major crisis periods, thereby confirming the presence and importance of volatility regimes. Results indicate that ignoring the complex and dynamic dependence structure in favour of certain model assumptions may lead to a significant underestimation of risk.

This paper considers the role of private debt in determining the impact of a financial crisis. By examining both theoretical and empirical aspects of this topic, I address the following key questions. What are the risks to the broader economy associated with high private and household debt? What are the mechanisms by which private debt and deleveraging may restrain economic activity? Using evidence from a panel dataset of OECD countries over the period 1981-2016, I argue that high household debt levels aggravate crises in the following ways: recessions are deeper, and recoveries are weaker, when they are preceeded by larger surges in household debt. Analogous observations are made for booms and busts in the housing market.

We employ a little-used dataset to study the Japan's Real Estate Investment Trusts (REITs) market. We make use of copula theory and test for dependence between equity and REIT returns using several popular copula families. The copula families in our specification were: Gaussian, Student-t, Clayton, Frank, and Gumbel. The p-values were computed using parametric bootstrap replications. We motivate the argument presented, and provide the goodness-of-fit test results based on the Rosenblatt transform. We find that the dependence between the innovations of JREIT Composite and JREIT Office returns can be modelled by a Student-t copula with 2.7 degrees of freedom and correlation parameter v = 0.93. All other models are rejected. To the best of our knowledge, this study represents the first time that copula theory has been applied to study REITs in Japan.

Histone lysine methyltransferases (KMTs) and demethylases (KDMs) underpin gene regulation. Here we demonstrate that variants causing haploinsufficiency of KMTs and KDMs are frequently encountered in individuals with developmental disorders. Using a combination of human variation databases and existing animal models, we determine 22 KMTs and KDMs as additional candidates for dominantly inherited developmental disorders. We show that KMTs and KDMs that are associated with, or are candidates for, dominant developmental disorders tend to have a higher level of transcription, longer canonical transcripts, more interactors, and a higher number and more types of post-translational modifications than other KMT and KDMs. We provide evidence to firmly associate KMT2C, ASH1L, and KMT5B haploinsufficiency with dominant developmental disorders. Whereas KMT2C or ASH1L haploinsufficiency results in a predominantly neurodevelopmental phenotype with occasional physical anomalies, KMT5B mutations cause an overgrowth syndrome with intellectual disability. We further expand the phenotypic spectrum of KMT2B-related disorders and show that some individuals can have severe developmental delay without dystonia at least until mid-childhood. Additionally, we describe a recessive histone lysine-methylation defect caused by homozygous or compound heterozygous KDM5B variants and resulting in a recognizable syndrome with developmental delay, facial dysmorphism, and camptodactyly. Collectively, these results emphasize the significance of histone lysine methylation in normal human development and the importance of this process in human developmental disorders. Our results demonstrate that systematic clinically oriented pathway-based analysis of genomic data can accelerate the discovery of rare genetic disorders.

Hospital accreditation began almost 100 years ago as an assessment scheme for surgical training in the USA. It developed as a broader, professionally driven institutional assessment and improvement system and is now established in more than 50 countries. Since the turn of the century several international programmes have become available across national borders. Most accreditation programmes assess compliance with published standards across an entire hospital, but some offer certification of specific services. ISO certification commonly uses standard 9004 to assess quality management systems (not specific to healthcare), or 15189 which is specific to medical laboratories. DNV accreditation is based on ISO 9004 adapted to the healthcare setting. Several countries have regulatory systems for compliance with mandatory national standards which are comparable to voluntary accreditation programmes. The value to medical tourism of accreditation and similar external assessment systems lies in reliable independent verification of a hospital’s compliance with validated organisational standards. The criteria, procedures and level of detail in published findings vary between programmes, but are more consistent within programmes which are themselves accredited by the International Society for Quality in Healthcare, ISQua.

Neonatal diabetes is a rare form of diabetes, characterized by onset in the first 6 months of life. A number of cases are due to pancreas agenesis. Recently, PTF1A enhancer mutations have been shown to cause neonatal diabetes associated with pancreatic agenesis. Herein, we report the clinical features of two siblings with PTF1A enhancer mutations, one of whom had neonatal diabetes, whereas the elder sister had a milder form of the disease with onset of diabetes at 9 years of age.

Background Heterozygous mutations in the gene encoding renin (REN) cause autosomal dominant tubulointerstitial kidney disease (ADTKD), early-onset anaemia and hyperuricaemia; only four different mutations have been described in the published literature to date. We report a novel dominant REN mutation discovered in an individual after forty years of renal disease. Case presentation A 57 year old Caucasian woman with chronic kidney disease stage five was reviewed in a regional joint renal genetics clinic. She had initially been diagnosed with chronic pyelonephritis in adolescence, around the same time that she was investigated for anaemia out of keeping with her degree of renal impairment. Hyperuricaemia was identified in her twenties following an episode of gout. A diagnosis of ADTKD was not made until the age of 37 years, when her mother was also found to have kidney disease and commenced haemodialysis. The patient’s renal function continued to slowly deteriorate and, twenty years later, her sister was worked up as a potential donor for kidney transplantation. Revisiting the maternal family history during the transplant work up prompted a referral to clinical genetics and urgent REN genetic testing was requested for the patient, leading to discovery of a heterozygous mutation in the REN gene: c.49 T > C, p.(Trp17Arg). This variant was not identified in her otherwise healthy sister, allowing pre-emptive live renal transplantation to take place shortly afterwards. Conclusions In an era where genetic testing is becoming much more readily available, this case highlights the importance of considering a genetic aetiology in all patients with long-standing renal disease and a relevant family history. Establishing a genetic diagnosis of ADTKD-REN in this individual with chronic anaemia, hyperuricaemia and slowly progressive renal impairment helped to identify a suitable live kidney donor and allowed successful pre-emptive transplantation to take place.