Preterm birth and small for gestational age in relation to alcohol consumption during pregnancy: stronger associations among vulnerable women? Results from two large Western-European studies

Pfinder M, Kunst AE, Feldmann R, van Eijsden M, Vrijkotte TGM. Preterm birth and small for gestational age in relation to alcohol consumption during pregnancy: stronger associations among vulnerable women? Results from two large Western-European studies. BMC Pregnancy and Childbirth. 2013;13(1): 49.BACKGROUND: Inconsistent data on the association between prenatal alcohol exposure and a range of pregnancy outcomes, such as preterm birth (PTB) and small for gestational age (SGA) raise new questions. This study aimed to assess whether the association between low-moderate prenatal alcohol exposure and PTB and SGA differs according to maternal education, maternal mental distress or maternal smoking. METHODS: The Amsterdam Born Children and their Development (ABCD) Study (N=5,238) and the German Health Interview and Examination Survey for Children and Adolescents (KiGGS) (N=16,301) are both large studies. Women provide information on alcohol intake in early pregnancy, 3 months postpartum and up to 17 years retrospectively. Multivariate logistic regression analyses and stratified regression analyses were performed to examine the association between prenatal alcohol exposure and PTB and SGA, respectively. RESULTS: No association was found between any level of prenatal alcohol exposure (non-daily, daily, non-abstaining) and SGA. The offspring of daily drinkers and non-abstainers had a lower risk of PTB [ABCD: odds ratio (OR) 0.31, 95% confidence interval (CI) 0.13, 0.77; KiGGS: OR 0.75, 95% CI 0.57, 0.99]. Interactions with maternal education, maternal distress or maternal smoking were not significant. CONCLUSIONS: Although these results should be interpreted with caution, both studies showed no adverse effects of low-moderate prenatal alcohol exposure on PTB and SGA, not even in the offspring of women who were disadvantaged in terms of low education, high levels of distress, or smoking during pregnancy

Investigation of hospital discharge cases and SARS-CoV-2 introduction into Lothian care homes

Background The first epidemic wave of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in Scotland resulted in high case numbers and mortality in care homes. In Lothian, over one-third of care homes reported an outbreak, while there was limited testing of hospital patients discharged to care homes. Aim To investigate patients discharged from hospitals as a source of SARS-CoV-2 introduction into care homes during the first epidemic wave. Methods A clinical review was performed for all patients discharges from hospitals to care homes from 1st March 2020 to 31st May 2020. Episodes were ruled out based on coronavirus disease 2019 (COVID-19) test history, clinical assessment at discharge, whole-genome sequencing (WGS) data and an infectious period of 14 days. Clinical samples were processed for WGS, and consensus genomes generated were used for analysis using Cluster Investigation and Virus Epidemiological Tool software. Patient timelines were obtained using electronic hospital records. Findings In total, 787 patients discharged from hospitals to care homes were identified. Of these, 776 (99%) were ruled out for subsequent introduction of SARS-CoV-2 into care homes. However, for 10 episodes, the results were inconclusive as there was low genomic diversity in consensus genomes or no sequencing data were available. Only one discharge episode had a genomic, time and location link to positive cases during hospital admission, leading to 10 positive cases in their care home. Conclusion The majority of patients discharged from hospitals were ruled out for introduction of SARS-CoV-2 into care homes, highlighting the importance of screening all new admissions when faced with a novel emerging virus and no available vaccine

SARS-CoV-2 Omicron is an immune escape variant with an altered cell entry pathway

Vaccines based on the spike protein of SARS-CoV-2 are a cornerstone of the public health response to COVID-19. The emergence of hypermutated, increasingly transmissible variants of concern (VOCs) threaten this strategy. Omicron (B.1.1.529), the fifth VOC to be described, harbours multiple amino acid mutations in spike, half of which lie within the receptor-binding domain. Here we demonstrate substantial evasion of neutralization by Omicron BA.1 and BA.2 variants in vitro using sera from individuals vaccinated with ChAdOx1, BNT162b2 and mRNA-1273. These data were mirrored by a substantial reduction in real-world vaccine effectiveness that was partially restored by booster vaccination. The Omicron variants BA.1 and BA.2 did not induce cell syncytia in vitro and favoured a TMPRSS2-independent endosomal entry pathway, these phenotypes mapping to distinct regions of the spike protein. Impaired cell fusion was determined by the receptor-binding domain, while endosomal entry mapped to the S2 domain. Such marked changes in antigenicity and replicative biology may underlie the rapid global spread and altered pathogenicity of the Omicron variant

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

Humane rekombinante Antikörper gegen Mycobacterium tuberculosis Antigene

Tuberculosis (TB) remains a threat to public health. Diagnostic of TB is often expensive or time-consuming. The use of recombinant antibodies for direct detection of M. tuberculosis (Mtb) antigens in human specimens could facilitate a simple point of care TB test. A diverse series of antigens was evaluated for this task, including 16 kDa, ESAT-6, CFP-10, LAM, AlaDH, 85 A, 85 B and 85 D. Twenty-two recombinant antibodies against 16 kDa, CFP-10, 85 A, 85 B and 85 D were generated by panning of human naïve phage display libraries. A recombinant a-LAM antibody was generated by isolation of the variable gene segments of the IgM encoding sequences from a hybridoma clone. These antibodies were purified as scFv from E. coli or scFv-Fc (scFab-Fc) from HEK293-6E cells, and characterized in detail. It was found, that the a-LAM antibody was only producible in a multivalent scFab-Fc format. Seven antibodies showed a supposed preferential germline gene combination against the 16 kDa antigen. Sandwich detection of 16 kDa and CFP-10 was not possible. Specific antibodies against 85 A, 85 B and 85 D were isolated, allowing for the first time discrimination of individual components of the 85 complex. Furthermore, sandwich detection of recombinant antigen 85 A or 85 B was possible. However multimeric conformation of the antigen was enhancing the recognition. Lack of multimers reduced binding to a minimum. Although no sandwich detection of Mtb samples was possible, a functional a-85 B immuno blot assay was developed. In summary, a variety of antibodies was generated with potential for further development of a TB diagnostic assay or for use in infection research, drug development or passive immunization.Tuberkulose (TB) ist immer noch eine Bedrohung für die öffentliche Gesundheit. Die Diagnose von TB ist häufig teuer oder zeitaufwendig. Der Gebrauch von rekombinanten Antikörpern (AK) zur direkten Detektion von M. tuberculosis (Mtb) Antigenen in humanen Proben könnte einen simplen TB Schnelltest ermöglichen. Eine mannigfaltige Serie von Antigenen wurde für diesen Zweck untersucht, einschließlich 16 kDa, ESAT-6, CFP-10, LAM, AlaDH, 85 A, 85 B und 85 D. Zweiundzwanzig rekombinante AK gegen 16 kDa, CFP-10, 85 A, 85 B und 85 D wurden mittels Panning von humanen naïven Phagendisplaybibliotheken generiert. Ein rekombinanter a-LAM AK wurde generiert durch Isolierung der variablen Gensegmente der IgM kodierenden Sequenzen eines Hybridoms. Diese AK wurden als scFv aus E. coli oder als scFv-Fc (scFab-Fc) aus HEK293-6E Zellen aufgereinigt und detailliert charakterisiert. Der a-LAM AK war nur als multivalenter scFab-Fc produzierbar. Sieben AK zeigten eine bevorzugte Genkombination gegen das 16 kDa Antigen. Ein Sandwichnachweis von 16 kDa und CFP-10 war nicht möglich. Spezifische AK gegen 85 A, 85 B und 85 D konnten isoliert werden, die erstmals eine Unterscheidung individueller Komponenten des 85 Komplexes ermöglichen. Weiterhin war der Sandwichnachweis von rekombinantem 85 A oder 85 B möglich, wobei eine multimere Antigenkonformation die Erkennung verbesserte. Das Fehlen von Multimeren reduzierte die Bindung auf ein Minimum. Ein Sandwichnachweis von Mtb Proben war nicht möglich, jedoch konnte ein funktionaler a-85 B Immunoblottest entwickelt werden. Insgesamt wurden eine Vielzahl von AK generiert mit Potential für die weitere Entwicklung eines TB Schnelltests, für die Verwendung in der Infektionsforschung, für die Medikamentenentwicklung oder zur passiven Immunisierung

Novel human recombinant antibodies against Mycobacterium tuberculosis antigen 85B

BACKGROUND: Tuberculosis is the leading cause of death due to bacterial infections worldwide, mainly caused by Mycobacterium tuberculosis. The antigen 85 complex comprises a set of major secreted proteins of M. tuberculosis, which are potential biomarkers for diagnostic. RESULTS: In this work, the first human single chain fragment variable (scFv) antibodies specific for the tuberculosis biomarker 85 B were selected by phage display from naïve antibody gene libraries (HAL7/8). Produced as scFv-Fc in mammalian cells, these antibodies were further characterized and analysed for specificity and applicability in different tuberculosis antigen detection assays. Sandwich detection of recombinant 85 B was successful in enzyme linked immunosorbent assay (ELISA), lateral flow immunoassay and immunoblot. Whereas detection of M. tuberculosis cell extracts and culture filtrates was only possible in direct ELISA and immunoblot assays. It was found that the conformation of 85 B, depending on sample treatment, influenced antigen detection. CONCLUSIONS: Recombinant antibodies, selected by phage display, may be applicable for 85 B detection in various assays. These antibodies are candidates for the development of future point of care tuberculosis diagnostic kits. Using 85 B as a biomarker, the antigen conformation influenced by sample treatment is important

Epitope detection in monocytes (EDIM) for liquid biopsy including identification of GD2 in childhood neuroblastoma-a pilot study

BACKGROUND: Neuroblastoma (NB) is the most common paediatric extracranial solid malignancy. We analysed the role of the epitope detection in monocytes (EDIM) technique for liquid biopsy in NB patients. METHODS: Tumour epitopes transketolase-like 1 (TKTL1), Apo10 (DNaseX) and GD2 were assessed: expression levels in seven NB tumour samples and five NB cell lines were analysed using RT-PCR and flow cytometry. LAN-1 cells were co-cultured with blood and assessed using EDIM. Peripheral blood macrophages of patients with neuroblastoma (n = 38) and healthy individuals (control group, n = 37) were labelled (CD14(+)/CD16(+)) and assessed for TKTL1, Apo10 and GD2 using the EDIM technology. RESULTS: mRNA expression of TKTL1 and DNaseX/Apo10 was elevated in 6/7 NB samples. Spike experiments showed upregulation of TKTL1, Apo10 and GD2 in LAN-1 cells following co-culturing with blood. TKTL1 and Apo10 were present in macrophages of 36/38 patients, and GD2 in 15/19 patients. The 37 control samples were all negative. EDIM expression scores of the three epitopes allowed differentiation between NB patients and healthy individuals. CONCLUSIONS: The EDIM test might serve as a non-invasive tool for liquid biopsy in children suffering from NB. Future studies are necessary for assessing risk stratification, tumour biology, treatment monitoring, and early detection of tumour relapses

SwissPedData: Standardising hospital records for the benefit of paediatric research

Background Improvement of paediatric healthcare is hampered by inefficient processes of generating new evidence. Clinical research often requires extra encounters with patients, is costly, takes place in an artificial situation with a biased selection of patients, and entails long delays until new evidence is implemented into health care. Electronic health records (EHR) contain detailed information on real patients and cover the entirety of patients. However, the use of EHR for research is limited because they are not standardized between hospitals. This leads to disproportionate amounts of work for extracting data of interest and frequently data are incomplete and of poor quality. Aims SwissPedData aims to lay the foundation for a paediatric learning health system in Switzerland by facilitating EHR-based research. In this project, we aimed to assess the way routine clinical data are currently recorded in large paediatric clinics in Switzerland and to develop a national EHR-based common data model (CDM) that covers all processes of routine paediatric care in hospitals. Methods A taskforce of paediatricians from large Swiss children's hospitals reviewed the current status of routine data documentation in paediatric clinical care and the extent of digitalization. We then used a modified Delphi method to reach a broad consensus on a national EHR-based CDM. Results All Swiss children's hospitals use EHR to document some or all aspects of care. 119 paediatricians, representing eight hospitals and all paediatric subspecialties, participated in an extended Delphi process to create SwissPedData. The group agreed on a national CDM that comprises a main module with general paediatric data and sub-modules relevant to paediatric subspecialties. The data dictionary includes 336 common data elements (CDEs): 76 in the main module on general paediatrics and between 11 and 59 CDEs per subspecialty module. Among these, 266 were classified as mandatory, 52 as recommended and 18 as optional. Conclusion SwissPedData is a CDM for information to be collected in EHR of Swiss children's hospitals. It covers all care processes including clinical and paraclinical assessment, diagnosis, treatment, disposition and care site. All participating hospitals agreed to implement SwissPedData in their clinical routine and clinic information systems. This will pave the way for a national paediatric learning health system in Switzerland that enables fast and efficient answers to urgent clinical questions by facilitating high-quality nationwide retrospective and prospective observational studies and recruitment of patients for nested prospective studies and clinical trials