New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes

Genomic investigations of unexplained acute hepatitis in children

Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Das kommunikative Zusammenwirken von Sprache und Gestik bei Personen mit Aphasie

de Beer C. Das kommunikative Zusammenwirken von Sprache und Gestik bei Personen mit Aphasie. Berlin: Logos Verlag; 2018

Einflüsse von Symptomatik und kommunikativen Anforderungen auf Sprache und Gestik bei Aphasie – Vier Einzelfälle im Vergleich

de Beer C. Einflüsse von Symptomatik und kommunikativen Anforderungen auf Sprache und Gestik bei Aphasie – Vier Einzelfälle im Vergleich. Sprachtherapie aktuell: Forschung - Wissen -Transfer. 2015;2(2: Schwerpunktthema: Aus der Praxis für die Praxis): e2015-10

A critical evaluation of models of gesture and speech production for understanding gesture in aphasia

de Ruiter J, de Beer C. A critical evaluation of models of gesture and speech production for understanding gesture in aphasia. Aphasiology. 2013;27(9):1015-1030.Background: The background to this study is that aphasiologists have increasingly started to pay attention not only to the speech that people with aphasia produce, but also to their gestures. As there are a number of competing models about the production of gesture and speech in healthy subjects, it is important to evaluate whether, and if so how, these models could be used to guide the research into gesture and speech, and the relationship between these, in speakers with aphasia.Aims: The aims and objectives of this study are to see how existing models of gesture and speech are able to accommodate the findings regarding the gesture and speech behaviour of speakers with aphasia, in the hope that (1) these models could shed light on the use of gesture in aphasic speakers, and potentially suggest new approaches to therapy for people with aphasia and (2) the aphasia gesture data might help fundamental psycholinguistics to evaluate the adequacy of existing gesture and speech models.Methods & Procedures: The methodology here was theoretical. Four models of gesture and speech interaction were critiqued and we reviewed their ability to explain some of the central empirical findings in the area of gesture and speech in aphasia.Outcomes & Results: The outcomes and results of this theoretical analysis were that, with respect to the relationship between gesture and speech in aphasia, (1) the four models under investigation could be reduced to two models, because three of the investigated models were based on the same core assumptions and (2) both of these models adequately explain these findings, but the Growth Point/Sketch/Interface Model is more satisfactory than the Lexical Access Model, because of the better fit with the experimental results on the use of gesture for facilitating word finding, and because it is more compatible with the finding that gestures are also used to enhance communicative efficiency by replacing speech.Conclusions: The two main conclusions from this study were that both the Growth Point/Sketch/Interface Model and the Lexical Access Model are compatible with data on gesture and speech in aphasia, and that the former appears to be preferable on the basis of the evidence available so far

Aktuelle Ansätze zur Diagnostik und Therapie kommunikativer Fähigkeiten bei Personen mit Aphasie

de Beer C, Hogrefe K. Aktuelle Ansätze zur Diagnostik und Therapie kommunikativer Fähigkeiten bei Personen mit Aphasie. Neurologie & Rehabilitation. 2018;24(2: Schwerpunktheft: Neue Entwicklungen in der Diagnostik und Therapie neurogener Kommunikationsstörungen):129–142

Is Oral Care for Dysphagic Patients Wasted Time? A Narrative Review on the Effects of Oral Care on Pneumonia Risk and Guidelines for an Effective and Structured Approach

Mueller N, de Beer C, Frank U. Ist die therapeutische Mundpflege bei Dysphagiepatient*innen verschwendete Zeit? Ein narrativer Review zu Effekten der Mundpflege auf die Pneumoniehäufigkeit und Ableitung einer Handlungsempfehlung. Sprache, Stimme, Gehör . 2022.Aspiration pneumonia is a common cause of death in dysphagia patients. In this review, we investigate whether a structured oral care approach can help to reduce pneumonia risk in dysphagic patients. In addition, guidelines for the implementation of oral care on the basis of the analyzed studies are presented. Oral care has positive effects on the risk of pneumonia in dysphagia patients. Oral care should be based on the principles of simplicity, safety, efficiency and effectiveness, universality and economy and it should include all parts of the oral cavity. Effective oral care takes less than five minutes a day. The tactile stimulation prepares the patient for dysphagia therapy and can be considered wisely-invested time.Aspirationspneumonien sind eine häufige Todesursache bei Dysphagiepatient*innen. In diesem Beitrag wird durch die Evaluation relevanter Studien die Frage untersucht, ob die therapeutische Mundpflege bei Dysphagiepatient*innen zur Verringerung des Pneumonierisikos beitragen kann. Zudem wird auf dieser Grundlage eine Handlungsempfehlung für die Umsetzung der Mundpflege entwickelt. Die ausgewählten Studien zeigen, dass die Mundpflege einen positiven Effekt auf das Pneumonie-Risiko von Dysphagiepatient*innen hat. Sie sollte auf den Grundsätzen Einfachheit, Sicherheit, Arbeitskräfteentlastung, Wirksamkeit, Universalität, Wirtschaftlichkeit und vollständige Mundpflege aller Teile der Mundhöhle beruhen und nimmt weniger als fünf Minuten täglich ein. Sie bereitet durch die taktile Stimulation auf die anschließende Dysphagie-Therapie vor und ist somit sinnvoll investierte Therapiezeit

Features of semantic content expressed via gesture by people with aphasia

de Beer C, Hogrefe K, de Ruiter JP. Features of semantic content expressed via gesture by people with aphasia. Aphasiology. 2018;32(Suppl. 1):18-20