Human germline heterozygous gain-of-function STAT6 variants cause severe allergic disease

STAT6 (signal transducer and activator of transcription 6) is a transcription factor that plays a central role in the pathophysiology of allergic inflammation. We have identified 16 patients from 10 families spanning three continents with a profound phenotype of early-life onset allergic immune dysregulation, widespread treatment-resistant atopic dermatitis, hypereosinophilia with esosinophilic gastrointestinal disease, asthma, elevated serum IgE, IgE-mediated food allergies, and anaphylaxis. The cases were either sporadic (seven kindreds) or followed an autosomal dominant inheritance pattern (three kindreds). All patients carried monoallelic rare variants in STAT6 and functional studies established their gain-of-function (GOF) phenotype with sustained STAT6 phosphorylation, increased STAT6 target gene expression, and TH2 skewing. Precision treatment with the anti-IL-4Rα antibody, dupilumab, was highly effective improving both clinical manifestations and immunological biomarkers. This study identifies heterozygous GOF variants in STAT6 as a novel autosomal dominant allergic disorder. We anticipate that our discovery of multiple kindreds with germline STAT6 GOF variants will facilitate the recognition of more affected individuals and the full definition of this new primary atopic disorder

Ultralight vector dark matter search using data from the KAGRA O3GK run

Among the various candidates for dark matter (DM), ultralight vector DM can be probed by laser interferometric gravitational wave detectors through the measurement of oscillating length changes in the arm cavities. In this context, KAGRA has a unique feature due to differing compositions of its mirrors, enhancing the signal of vector DM in the length change in the auxiliary channels. Here we present the result of a search for U(1)B−L gauge boson DM using the KAGRA data from auxiliary length channels during the first joint observation run together with GEO600. By applying our search pipeline, which takes into account the stochastic nature of ultralight DM, upper bounds on the coupling strength between the U(1)B−L gauge boson and ordinary matter are obtained for a range of DM masses. While our constraints are less stringent than those derived from previous experiments, this study demonstrates the applicability of our method to the lower-mass vector DM search, which is made difficult in this measurement by the short observation time compared to the auto-correlation time scale of DM

A report and review of the recurrent c.811C>T variant and mutation spectrum of Kindler syndrome in East Asians: a diagnostic odyssey of 2 weeks versus 49 years

Kindler Syndrome (KS) is one of the rarest subtypes of epidermolysis bullosa (EB). It is characterised by congenital blistering, skin fragility, photosensitivity, and poikilodermatous skin changes. It is an autosomal recessive condition with an established disease-causing mechanism of having biallelic pathogenic variants in the FERMT1 gene. Multiple variants have been reported worldwide since the discovery in 1954. This case report describes two patients of Chinese descent with molecularly confirmed KS, one diagnosed in infancy while the other in mid-adulthood. It highlights the importance and clinical utility of diagnosing KS in children versus adults. The identification of recurrent c.811C>T variant in both patients also expedited the review of local databases and the existing mutation spectrum KS in East Asians

Decreased Antibiotic Consumption Coincided with Reduction in Bacteremia Caused by Bacterial Species with Respiratory Transmission Potential during the COVID-19 Pandemic

Nonpharmaceutical interventions implemented during the COVID-19 pandemic (2020–2021) have provided a unique opportunity to understand their impact on the wholesale supply of antibiotics and incidences of infections represented by bacteremia due to common bacterial species in Hong Kong. The wholesale antibiotic supply data (surrogate indicator of antibiotic consumption) and notifications of scarlet fever, chickenpox, and tuberculosis collected by the Centre for Health Protection, and the data of blood cultures of patients admitted to public hospitals in Hong Kong collected by the Hospital Authority for the last 10 years, were tabulated and analyzed. A reduction in the wholesale supply of antibiotics was observed. This decrease coincided with a significant reduction in the incidence of community-onset bacteremia due to Streptococcus pyogenes, Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis, which are encapsulated bacteria with respiratory transmission potential. This reduction was sustained during two pandemic years (period 2: 2020–2021), compared with eight pre-pandemic years (period 1: 2012–2019). Although the mean number of patient admissions per year (1,704,079 vs. 1,702,484, p = 0.985) and blood culture requests per 1000 patient admissions (149.0 vs. 158.3, p = 0.132) were not significantly different between periods 1 and 2, a significant reduction in community-onset bacteremia due to encapsulated bacteria was observed in terms of the mean number of episodes per year (257 vs. 58, p p p Staphylococcus aureus or Escherichia coli. Sustained implementation of non-pharmaceutical interventions against respiratory microbes may reduce the overall consumption of antibiotics, which may have a consequential impact on antimicrobial resistance. Rebound of conventional respiratory microbial infections is likely with the relaxation of these interventions

Human germline heterozygous gain-of-function STAT6 variants cause severe allergic disease

STAT6 (signal transducer and activator of transcription 6) is a transcription factor that plays a central role in the pathophysiology of allergic inflammation. We have identified 16 patients from 10 families spanning three continents with a profound phenotype of early-life onset allergic immune dysregulation, widespread treatment-resistant atopic dermatitis, hypereosinophilia with esosinophilic gastrointestinal disease, asthma, elevated serum IgE, IgE-mediated food allergies, and anaphylaxis. The cases were either sporadic (seven kindreds) or followed an autosomal dominant inheritance pattern (three kindreds). All patients carried monoallelic rare variants in STAT6 and functional studies established their gain-of-function (GOF) phenotype with sustained STAT6 phosphorylation, increased STAT6 target gene expression, and TH2 skewing. Precision treatment with the anti-IL-4Rα antibody, dupilumab, was highly effective improving both clinical manifestations and immunological biomarkers. This study identifies heterozygous GOF variants in STAT6 as a novel autosomal dominant allergic disorder. We anticipate that our discovery of multiple kindreds with germline STAT6 GOF variants will facilitate the recognition of more affected individuals and the full definition of this new primary atopic disorder

Global economic burden of unmet surgical need for appendicitis

Background There is a substantial gap in provision of adequate surgical care in many low- and middle-income countries. This study aimed to identify the economic burden of unmet surgical need for the common condition of appendicitis. Methods Data on the incidence of appendicitis from 170 countries and two different approaches were used to estimate numbers of patients who do not receive surgery: as a fixed proportion of the total unmet surgical need per country (approach 1); and based on country income status (approach 2). Indirect costs with current levels of access and local quality, and those if quality were at the standards of high-income countries, were estimated. A human capital approach was applied, focusing on the economic burden resulting from premature death and absenteeism. Results Excess mortality was 4185 per 100 000 cases of appendicitis using approach 1 and 3448 per 100 000 using approach 2. The economic burden of continuing current levels of access and local quality was US $92 492 million using approach 1 and$73 141 million using approach 2. The economic burden of not providing surgical care to the standards of high-income countries was $95 004 million using approach 1 and$75 666 million using approach 2. The largest share of these costs resulted from premature death (97.7 per cent) and lack of access (97.0 per cent) in contrast to lack of quality. Conclusion For a comparatively non-complex emergency condition such as appendicitis, increasing access to care should be prioritized. Although improving quality of care should not be neglected, increasing provision of care at current standards could reduce societal costs substantially