Genome-wide Association Study of Long COVID

SummaryInfections can lead to persistent or long-term symptoms and diseases such as shingles after varicella zoster, cancers after human papillomavirus, or rheumatic fever after streptococcal infections1, 2. Similarly, infection by SARS-CoV-2 can result in Long COVID, a condition characterized by symptoms of fatigue and pulmonary and cognitive dysfunction3–5. The biological mechanisms that contribute to the development of Long COVID remain to be clarified. We leveraged the COVID-19 Host Genetics Initiative6, 7to perform a genome-wide association study for Long COVID including up to 6,450 Long COVID cases and 1,093,995 population controls from 24 studies across 16 countries. We identified the first genome-wide significant association for Long COVID at theFOXP4locus.FOXP4has been previously associated with COVID-19 severity6, lung function8, and cancers9, suggesting a broader role for lung function in the pathophysiology of Long COVID. While we identify COVID-19 severity as a causal risk factor for Long COVID, the impact of the genetic risk factor located in theFOXP4locus could not be solely explained by its association to severe COVID-19. Our findings further support the role of pulmonary dysfunction and COVID-19 severity in the development of Long COVID.</jats:p

Polymicrobal Pneumonia in a Corticosteroid-Treated Patient with Chronic Obstructive Lung Disease

The immunosuppressive properties of corticosteroids are well established and cause a depression of pulmonary defense mechanisms. We report the case of a patient treated with short-term corticosteroids for an exacerbation of chronic obstructive lung disease who developed a multiple organism pneumonia

The latest time to make confession of faith and the relationship between faith and deeds in the treatise of galanbawî about the verse 158 of surat al-an’am

Osmanlı âlimlerinden İsmâîl el-Gelenbevî, En’âm Sûresi 6/158. ayetle ilgili bir risâle yazmıştır ve bu risâlesinde, ilgili ayetten hareketle imanın son kabul zamanı ve iman-amel ilişkisi hakkında birtakım yorumlarda bulunmaktadır. Ona göre bu ayetten hareketle imanın son kabul zamanı, kıyamet alâmetlerinin ortaya çıkmaya başladığı zamandır. Müellife göre iman-amel ilişkisiyle ilgili Mu’tezilî müfessir Zemahşerî’nin yaptığı iman-amel bütünlüğü yönündeki yorum da yanlıştır. Doğru olan, iman ve amelin iki ayrı unsur olduğu ve kalbinde zerre kadar iman bulunan kişinin, Cehennem’de ebediyyen kalmayacağıdır.An Ottoman scholar Ismail al-Galanbawee has written a treatise about the verse 158 of Sûrat al-An‘âm. In this work, he makessome comments about the latest time to make confession of faith, and the relationship between faith and deed. According to him, from this verse, the latest time to make confession of faith is when signs of doom occur. According to the author, the comment about the unity of deeds and faith made by a Mu’tazilite interpreter of the Qur’ân, Zamakhsharî is wrong. What’s right is that faith and deeds are two separate elements, and that who has even an iota of faith in his heart, there will not be in Hell forever

Source, timing, frequency and flux of ice-rafted detritus to the Northeast Atlantic margin, 30-12 ka: testing the Heinrich precursor hypothesis

Increased fluxes of ice-rafted detritus (IRD) from European ice sheets have been documented some 1000–1500 years before the arrival of Laurentide Ice Sheet (LIS)-sourced IRD during Heinrich (H) events. These early fluxes have become known as ‘precursor events’, and it has been suggested that they have mechanistic significance in the propagation of H events. Here we present a re-analysis of one of the main cores used to generate the precursor concept, OMEX-2K from the Goban Spur covering the last 30 ka, in order to identify whether the British–Irish Ice Sheet (BIIS) IRD fluxes occur only as precursors before H layers. IRD characterization and planktonic foraminiferal δ18O measurements constrained by a new age model have enabled the generation of a continuous record of IRD sources, timing, frequency and flux, and of local contemporary hydrographic conditions. The evidence indicates that BIIS IRD precursors are not uniquely, or mechanistically, linked to H events, but are part of the pervasive millennial-scale cyclicity. Our results support an LIS source for the IRD comprising H layers, but the ambient glacial sections are dominated by assemblages typical of the Irish Sea Ice Stream. Light isotope excursions associated with H events are interpreted as resulting from the melting of the BIIS, with ice-sheet destabilization attributed to eustatic jumps generated by LIS discharge during H events. This positive-feedback mechanism probably caused similar responses in all circum-Atlantic ice-sheet margins, and the resulting gross freshwater flux contributed to the perturbation of the Atlantic Meridional Overturning Circulation during H events

Psychometric and factor analytic evaluation of the 15D health-related quality of life instrument: the case of Greece

Purpose: To investigate the dimensionality, construct validity in the form of factorial, convergent, discriminant, and known-groups validity, as well as scale reliability of the fifteen dimensional (15D) instrument. Methods: 15D data were collected from a large Greek general population sample (N = 3,268) which was randomly split into two halves. Data from the first sample were used to examine the distributional properties of the 15 items, as well as the factor structure adopting an exploratory approach. Data from the second sample were used to perform a confirmatory factor analysis of the 15 items, examine the goodness of fit of several measurement models, and evaluate reliability and known-groups validity of the resulting subscales, along with convergent and discriminant validity of the constructs. Results: Exploratory factor analysis, using a distribution-free method, revealed a three-factor solution of the 15D (functional ability, physiological needs satisfaction, emotional well-being). Confirmatory factor analysis provided support for the three-factor solution but suggested that certain modifications should be made to this solution, involving freeing certain elements of the matrix of factor loadings and of the covariance matrix of measurement errors in the observed variables. Evidence of convergent validity was provided for all three factors, but discriminant validity was supported only for the emotional well-being construct. Scale reliability and known-groups validity of the resulting three subscales were satisfactory. Conclusions: Our results confirm the multidimensional structure of the 15D and the existence of three latent factors that cover important aspects of the health-related quality of life domain (physical and emotional functioning). The implications of our results for the validity of the 15D and suggestions for future research are outlined

Monogenic early-onset lymphoproliferation and autoimmunity: Natural history of STAT3 gain-of-function syndrome.

BACKGROUND: In 2014, germline signal transducer and activator of transcription (STAT) 3 gain-of-function (GOF) mutations were first described to cause a novel multisystem disease of early-onset lymphoproliferation and autoimmunity. OBJECTIVE: This pivotal cohort study defines the scope, natural history, treatment, and overall survival of a large global cohort of patients with pathogenic STAT3 GOF variants. METHODS: We identified 191 patients from 33 countries with 72 unique mutations. Inclusion criteria included symptoms of immune dysregulation and a biochemically confirmed germline heterozygous GOF variant in STAT3. RESULTS: Overall survival was 88%, median age at onset of symptoms was 2.3 years, and median age at diagnosis was 12 years. Immune dysregulatory features were present in all patients: lymphoproliferation was the most common manifestation (73%); increased frequencies of double-negative (CD4-CD8-) T cells were found in 83% of patients tested. Autoimmune cytopenias were the second most common clinical manifestation (67%), followed by growth delay, enteropathy, skin disease, pulmonary disease, endocrinopathy, arthritis, autoimmune hepatitis, neurologic disease, vasculopathy, renal disease, and malignancy. Infections were reported in 72% of the cohort. A&nbsp;cellular and humoral immunodeficiency was observed in 37% and 51% of patients, respectively. Clinical symptoms dramatically improved in patients treated with JAK inhibitors, while a variety of other immunomodulatory treatment modalities were less efficacious. Thus far, 23 patients have undergone bone marrow transplantation, with a 62% survival rate. CONCLUSION: STAT3 GOF patients present with a wide array of immune-mediated disease including lymphoproliferation, autoimmune cytopenias, and multisystem autoimmunity. Patient care tends to be siloed, without a clear treatment strategy. Thus, early identification and prompt treatment implementation are lifesaving for STAT3 GOF syndrome

Monogenic Early-Onset Lymphoproliferation and Autoimmunity: The Natural History of STAT3 GOF Syndrome.

Background In 2014, germline signal transducer and activator of transcription (STAT) 3 gain-of-function (GOF) mutations were first described to cause a novel multisystem disease of early-onset lymphoproliferation and autoimmunity. Objective This pivotal cohort study defines the scope, natural history, treatment, and overall survival of a large global cohort of patients with pathogenic STAT3 GOF variants. Methods We identified 191 patients from 33 countries with 72 unique mutations. Inclusion criteria included symptoms of immune dysregulation and a biochemically confirmed germline heterozygous GOF variant in STAT3. Results Overall survival was 88%, median age at onset of symptoms was 2.3 years, and median age at diagnosis was 12 years. Immune dysregulatory features were present in all patients: lymphoproliferation was the most common manifestation (73%); increased frequencies of double-negative (CD4−CD8−) T cells were found in 83% of patients tested. Autoimmune cytopenias were the second most common clinical manifestation (67%), followed by growth delay, enteropathy, skin disease, pulmonary disease, endocrinopathy, arthritis, autoimmune hepatitis, neurologic disease, vasculopathy, renal disease, and malignancy. Infections were reported in 72% of the cohort. A cellular and humoral immunodeficiency was observed in 37% and 51% of patients, respectively. Clinical symptoms dramatically improved in patients treated with JAK inhibitors, while a variety of other immunomodulatory treatment modalities were less efficacious. Thus far, 23 patients have undergone bone marrow transplantation, with a 62% survival rate. Conclusion : STAT3 GOF patients present with a wide array of immune-mediated disease including lymphoproliferation, autoimmune cytopenias, and multisystem autoimmunity. Patient care tends to be siloed, without a clear treatment strategy. Thus, early identification and prompt treatment implementation are lifesaving for STAT3 GOF syndrome. Key word

Therapeutic strategies targeting connexins

The connexin family of channel-forming proteins is present in every tissue type in the human anatomy. Connexins are best known for forming clustered intercellular channels, structurally known as gap junctions, where they serve to exchange members of the metabolome between adjacent cells. In their single-membrane hemichannel form, connexins can act as conduits for the passage of small molecules in autocrine and paracrine signalling. Here, we review the roles of connexins in health and disease, focusing on the potential of connexins as therapeutic targets in acquired and inherited diseases as well as wound repair, while highlighting the associated clinical challenges