Identification, stabilization, and prompt referral of children with signs of severe febrile disease (danger signs) in rural communities are crucial for preventing complications and death from severe ...malaria, pneumonia, and diarrhea. We set out to determine the treatment-seeking practices and treatment patterns for children < 5 years of age with an acute febrile illness, with or without danger signs of severe disease, in a highly malaria-endemic area of northern Uganda. Three household surveys were conducted from November through December each year in 2018, 2019, and 2020. Overall, 30% of the children in the study were reported to have had a WHO-classified danger sign including convulsions, unconsciousness/unusually sleepy, inability to feed or drink, and vomiting everything. Only half of the children in this study sought care from a health provider. However, significantly more children with danger signs of severe disease sought and received treatment and diagnostics from a health provider, compared with those without danger signs (adjusted odds ratio: 1.6, 95% confidence interval: 1.2–2.0;
P
< 0.01). In the total population studied, care seeking in the public sector was 26% and similar to care seeking in the private sector (24%). Community health workers were used as the first source of care by 12% of the children. Approximately 38% of the children who were reported to have danger signs of severe disease requiring prompt referral and treatment did not seek care from a health provider. Understanding and addressing barriers to accessing healthcare could contribute to better treatment seeking practices.
Craniofrontonasal syndrome (CFNS), an X-linked disorder caused by loss-of-function mutations of EFNB1, exhibits a paradoxical sex reversal in phenotypic severity: females characteristically have ...frontonasal dysplasia, craniosynostosis and additional minor malformations, but males are usually more mildly affected with hypertelorism as the only feature. X-inactivation is proposed to explain the more severe outcome in heterozygous females, as this leads to functional mosaicism for cells with differing expression of EPHRIN-B1, generating abnormal tissue boundaries-a process that cannot occur in hemizygous males. Apparently challenging this model, males occasionally present with a more severe female-like CFNS phenotype. We hypothesized that such individuals might be mosaic for EFNB1 mutations and investigated this possibility in multiple tissue samples from six sporadically presenting males. Using denaturing high performance liquid chromatography, massively parallel sequencing and multiplex-ligation-dependent probe amplification (MLPA) to increase sensitivity above standard dideoxy sequencing, we identified mosaic mutations of EFNB1 in all cases, comprising three missense changes, two gene deletions and a novel point mutation within the 5' untranslated region (UTR). Quantification by Pyrosequencing and MLPA demonstrated levels of mutant cells between 15 and 69%. The 5' UTR variant mutates the stop codon of a small upstream open reading frame that, using a dual-luciferase reporter construct, was demonstrated to exacerbate interference with translation of the wild-type protein. These results demonstrate a more severe outcome in mosaic than in constitutionally deficient males in an X-linked dominant disorder and provide further support for the cellular interference mechanism, normally related to X-inactivation in females.
The biological activity of the glycoprotein hormone erythropoietin (EPO) is dependent mainly on the structure of its N‐linked glycans. We aimed to readily attach defined N‐glycans to EPO through ...copper‐catalyzed azide alkyne cycloaddition. EPO variants with an alkyne‐bearing non‐natural amino acid (Plk) at the N‐glycosylation sites 24, 38, and 83 were obtained by amber suppression followed by protein purification and refolding. Click conjugation of the alkynyl EPOs with biantennary N‐glycan azides provided biologically active site‐specifically modified EPO glycoconjugates.
Suppress, fold and click: The biological activity of erythropoietin (EPO) is dependent mainly on the structure of its N‐linked glycans. We used a semisynthetic approach (amber suppression followed by refolding and click conjugation) to generate biologically active erythropoietin variants site‐specifically conjugated with defined complex‐type N‐glycans through copper‐catalyzed azide–alkyne cycloaddition.
Bohring-Opitz syndrome is characterized by severe intellectual disability, distinctive facial features and multiple congenital malformations. We sequenced the exomes of three individuals with ...Bohring-Opitz syndrome and in each identified heterozygous de novo nonsense mutations in ASXL1, which is required for maintenance of both activation and silencing of Hox genes. In total, 7 out of 13 subjects with a Bohring-Opitz phenotype had de novo ASXL1 mutations, suggesting that the syndrome is genetically heterogeneous.
Multiple pterygium syndromes (MPSs) comprise a group of multiple-congenital-anomaly disorders characterized by webbing (pterygia) of the neck, elbows, and/or knees and joint contractures ...(arthrogryposis). In addition, a variety of developmental defects (e.g., vertebral anomalies) may occur. MPSs are phenotypically and genetically heterogeneous but are traditionally divided into prenatally lethal and nonlethal (Escobar) types. To elucidate the pathogenesis of MPS, we undertook a genomewide linkage scan of a large consanguineous family and mapped a locus to 2q36-37. We then identified germline-inactivating mutations in the embryonal acetylcholine receptor γ subunit (
CHRNG) in families with both lethal and nonlethal MPSs. These findings extend the role of acetylcholine receptor dysfunction in human disease and provide new insights into the pathogenesis and management of fetal akinesia syndromes.
Intellectual disability (ID) is a common neurodevelopmental disorder affecting 1-3% of the general population. Mutations in more than 10% of all human genes are considered to be involved in this ...disorder, although the majority of these genes are still unknown.
We investigated 19 small non-consanguineous families with two to five affected siblings in order to identify pathogenic gene variants in known, novel and potential ID candidate genes. Non-consanguineous families have been largely ignored in gene identification studies as small family size precludes prior mapping of the genetic defect.
Using exome sequencing, we identified pathogenic mutations in three genes, DDHD2, SLC6A8, and SLC9A6, of which the latter two have previously been implicated in X-linked ID phenotypes. In addition, we identified potentially pathogenic mutations in BCORL1 on the X-chromosome and in MCM3AP, PTPRT, SYNE1, and ZNF528 on autosomes.
We show that potentially pathogenic gene variants can be identified in small, non-consanguineous families with as few as two affected siblings, thus emphasising their value in the identification of syndromic and non-syndromic ID genes.
Zusammenfassung
Hintergrund und Ziele
Mycosis fungoides (MF), das häufigste primär kutane T‐ Zell‐Lymphom, ist durch einen variablen klinischen Verlauf charakterisiert. Dieser ist entweder indolent ...oder infaust bei Progression mit extrakutaner Beteiligung. Das Fehlen von Prognosemodellen bei überwiegend palliativen Therapiemodalitäten erschweren das Patientenmanagement. Ziel dieser Studie war es, Überlebensraten, Treffsicherheit von verfügbaren Prognosemodellen und den Therapieerfolg bei MF‐Patienten zu evaluieren.
Patienten und Methodik
Hundertvierzig MF‐Patienten wurden retrospektiv untersucht. Prognose, Krankheitsprogression beziehungsweise Überlebensraten wurden anhand univariater Cox‐ Regressionsmodellen und Kaplan‐Meier‐ Schätzungen analysiert.
Ergebnisse
Hauttumoren waren im Vergleich zu Erythrodermie mit einem kürzeren progressionsfreien Überleben und Gesamtüberleben sowie einem 3,48‐fach erhöhtem Risiko für Krankheitsprogression verbunden. Der Cutaneous Lymphoma International Prognostic Index identifizierte Risikopatienten lediglich im frühen Krankheitsstadium. Zudem waren die Expression von Ki‐67 > 20%, CD30 > 10%, CD20+ und CD7– unabhängig vom Krankheitsstadium mit einem signifikant schlechteren Outcome verbunden. Eine langfristige Krankheitskontrolle wurde lediglich mit Interferon‐α als Monotherapie oder durch Kombination von Phototherapie mit Interferon‐α oder Retinoiden/Bexaroten erreicht.
Schlussfolgerungen
Unsere Daten unterstützen die Vorhersagekraft von etablierten Prognoseparametern und ‐modellen bei MF. Zusätzlich wurden neue Parameter, die mit einer schlechten Prognose assoziiert sind, identifiziert. Prospektive Studien, die Prognoseindikatoren in Bezug auf Krankheitsstadium und Therapie synergistisch evaluieren sind erforderlich, um die Patientenbetreuung zu verbessern.
Summary Background A high circulating concentration of interleukin 6 is associated with increased risk of coronary heart disease. Blockade of the interleukin-6 receptor (IL6R) with a monoclonal ...antibody (tocilizumab) licensed for treatment of rheumatoid arthritis reduces systemic and articular inflammation. However, whether IL6R blockade also reduces risk of coronary heart disease is unknown. Methods Applying the mendelian randomisation principle, we used single nucleotide polymorphisms (SNPs) in the gene IL6R to evaluate the likely efficacy and safety of IL6R inhibition for primary prevention of coronary heart disease. We compared genetic findings with the effects of tocilizumab reported in randomised trials in patients with rheumatoid arthritis. Findings In 40 studies including up to 133 449 individuals, an IL6R SNP (rs7529229) marking a non-synonymous IL6R variant (rs8192284; p.Asp358Ala) was associated with increased circulating log interleukin-6 concentration (increase per allele 9·45%, 95% CI 8·34–10·57) as well as reduced C-reactive protein (decrease per allele 8·35%, 95% CI 7·31–9·38) and fibrinogen concentrations (decrease per allele 0·85%, 95% CI 0·60–1·10). This pattern of effects was consistent with IL6R blockade from infusions of tocilizumab (4–8 mg/kg every 4 weeks) in patients with rheumatoid arthritis studied in randomised trials. In 25 458 coronary heart disease cases and 100 740 controls, the IL6R rs7529229 SNP was associated with a decreased odds of coronary heart disease events (per allele odds ratio 0·95, 95% CI 0·93–0·97, p=1·53×10−5 ). Interpretation On the basis of genetic evidence in human beings, IL6R signalling seems to have a causal role in development of coronary heart disease. IL6R blockade could provide a novel therapeutic approach to prevention of coronary heart disease that warrants testing in suitably powered randomised trials. Genetic studies in populations could be used more widely to help to validate and prioritise novel drug targets or to repurpose existing agents and targets for new therapeutic uses. Funding UK Medical Research Council; British Heart Foundation; Rosetrees Trust; US National Heart, Lung, and Blood Institute; Du Pont Pharma; Chest, Heart and Stroke Scotland; Wellcome Trust; Coronary Thrombosis Trust; Northwick Park Institute for Medical Research; UCLH/UCL Comprehensive Medical Research Centre; US National Institute on Aging; Academy of Finland; Netherlands Organisation for Health Research and Development; SANCO; Dutch Ministry of Public Health, Welfare and Sports; World Cancer Research Fund; Agentschap NL; European Commission; Swedish Heart-Lung Foundation; Swedish Research Council; Strategic Cardiovascular Programme of the Karolinska Institutet; Stockholm County Council; US National Institute of Neurological Disorders and Stroke; MedStar Health Research Institute; GlaxoSmithKline; Dutch Kidney Foundation; US National Institutes of Health; Netherlands Interuniversity Cardiology Institute of the Netherlands; Diabetes UK; European Union Seventh Framework Programme; National Institute for Healthy Ageing; Cancer Research UK; MacArthur Foundation.
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