Background. In May and June 2011 the largest known outbreak of hemolytic uremic syndrome (HUS) occurred in northern Germany. Because, quite unusually, a large number of adults was affected and the ...causative Escherichia coli strain, serotype O104:H4, showed an atypical virulence factor pattern, it was speculated that this outbreak was associated with an aggressive course and an unfavorable prognosis also in children. Methods. Retrospective analysis of medical records of 90 children and comparison to previous outbreak and sporadic case series. Results. Median age was unusually high (11.5 years) compared with that in historical series. Only 1 patient (1.1%) died in the acute phase. Most patients (67/90 74%) received supportive care only. Renal replacement therapy was required in 64 of 90 (71%) of the children. Neurological complications, mainly seizures and altered mental stage, were present in 23 of 90 (26%) patients. Ten patients received plasmapheresis, 6 eculizumab, and 7 a combination of both. After a median follow-up of 4 months, renal function normalized in 85 of 90 (94%) patients, whereas 3 patients had chronic kidney disease stage 3 or 4, and 1 patient (1.1%) still requires dialysis. Complete neurological recovery occurred in 18 of 23 patients. Mild to moderate and major residual neurological changes were present in 3 patients and 1 patient, respectively, although all patients were still improving. Conclusions. E. coli O104:H4 caused the largest HUS outbreak in children reported in detail to date and most patients received supportive treatment only. Initial morbidity, as well as short-term outcome, due to this pathogen, is comparable to previous pediatric series of Shiga toxin—producing E. coli HUS.
Xist is indispensable for X chromosome inactivation. However, how Xist RNA directs chromosome-wide silencing and why some regions are more efficiently silenced than others remains unknown. Here, we ...explore the function of Xist by inducing ectopic Xist expression from multiple different X-linked and autosomal loci in mouse aneuploid and female diploid embryonic stem cells in which Xist-mediated silencing does not lead to lethal functional monosomy. We show that ectopic Xist expression faithfully recapitulates endogenous X chromosome inactivation from any location on the X chromosome, whereas long-range silencing of autosomal genes is less efficient. Long interspersed elements facilitate inactivation of genes located far away from the Xist transcription locus, and genes escaping X chromosome inactivation show enrichment of CTCF on X chromosomal but not autosomal loci. Our findings highlight important genomic and epigenetic features acquired during sex chromosome evolution to facilitate an efficient X chromosome inactivation process.Xist RNA is required for X chromosome inactivation but it is not well understood how Xist silences some regions more efficiently than others. Here, the authors induce ectopic Xist expression from multiple different X-linked and autosomal loci in cells to explore Xist function.
Immunogenicity of the Ad26.COV2.S Vaccine for COVID-19 Stephenson, Kathryn E; Le Gars, Mathieu; Sadoff, Jerald ...
JAMA : the journal of the American Medical Association,
04/2021, Letnik:
325, Številka:
15
Journal Article
Recenzirano
Odprti dostop
IMPORTANCE: Control of the global COVID-19 pandemic will require the development and deployment of safe and effective vaccines. OBJECTIVE: To evaluate the immunogenicity of the Ad26.COV2.S vaccine ...(Janssen/Johnson & Johnson) in humans, including the kinetics, magnitude, and phenotype of SARS-CoV-2 spike-specific humoral and cellular immune responses. DESIGN, SETTING, AND PARTICIPANTS: Twenty-five participants were enrolled from July 29, 2020, to August 7, 2020, and the follow-up for this day 71 interim analysis was completed on October 3, 2020; follow-up to assess durability will continue for 2 years. This study was conducted at a single clinical site in Boston, Massachusetts, as part of a randomized, double-blind, placebo-controlled phase 1 clinical trial of Ad26.COV2.S. INTERVENTIONS: Participants were randomized to receive 1 or 2 intramuscular injections with 5 × 1010 viral particles or 1 × 1011 viral particles of Ad26.COV2.S vaccine or placebo administered on day 1 and day 57 (5 participants in each group). MAIN OUTCOMES AND MEASURES: Humoral immune responses included binding and neutralizing antibody responses at multiple time points following immunization. Cellular immune responses included immunospot-based and intracellular cytokine staining assays to measure T-cell responses. RESULTS: Twenty-five participants were randomized (median age, 42; age range, 22-52; 52% women, 44% male, 4% undifferentiated), and all completed the trial through the day 71 interim end point. Binding and neutralizing antibodies emerged rapidly by day 8 after initial immunization in 90% and 25% of vaccine recipients, respectively. By day 57, binding and neutralizing antibodies were detected in 100% of vaccine recipients after a single immunization. On day 71, the geometric mean titers of spike-specific binding antibodies were 2432 to 5729 and the geometric mean titers of neutralizing antibodies were 242 to 449 in the vaccinated groups. A variety of antibody subclasses, Fc receptor binding properties, and antiviral functions were induced. CD4+ and CD8+ T-cell responses were induced. CONCLUSION AND RELEVANCE: In this phase 1 study, a single immunization with Ad26.COV2.S induced rapid binding and neutralization antibody responses as well as cellular immune responses. Two phase 3 clinical trials are currently underway to determine the efficacy of the Ad26.COV2.S vaccine. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04436276
IntroductionEpidural analgesia is currently considered the gold standard in postoperative pain management for the minimally invasive Nuss procedure for pectus excavatum. Alternative analgesic ...strategies (eg, patient-controlled analgesia and paravertebral nerve block) fail in accomplishing adequate prolonged pain management. Furthermore, the continuous use of opioids, often prescribed in addition to all pain management strategies, comes with side effects. Intercostal nerve cryoablation seems a promising novel technique. Hence, the primary objective of this study is to determine the impact of intercostal nerve cryoablation on postoperative length of hospital stay compared with standard pain management of young pectus excavatum patients treated with the minimally invasive Nuss procedure.Methods and analysisThis study protocol is designed for a single centre, prospective, unblinded, randomised clinical trial. Intercostal nerve cryoablation will be compared with thoracic epidural analgesia in 50 young pectus excavatum patients (ie, 12–24 years of age) treated with the minimally invasive Nuss procedure. Block randomisation, including stratification based on age (12–16 years and 17–24 years) and sex, with an allocation ratio of 1:1 will be performed.Postoperative length of hospital stay will be recorded as the primary outcome. Secondary outcomes include (1) pain intensity, (2) operative time, (3) opioid usage, (4) complications, including neuropathic pain, (5) creatine kinase activity, (6) intensive care unit admissions, (7) readmissions, (8) postoperative mobility, (9) health-related quality of life, (10) days to return to work/school, (11) number of postoperative outpatient visits and (12) hospital costs.Ethics and disseminationThis protocol has been approved by the local Medical Ethics Review Committee, METC Zuyderland and Zuyd University of Applied Sciences. Participation in this study will be voluntary and informed consent will be obtained. Regardless of the outcome, the results will be disseminated through a peer-reviewed international medical journal.Trial registration numberNCT05731973.
Meta-analyses of association results for blood pressure using exome-centric single-variant and gene-based tests identified 31 new loci in a discovery stage among 146,562 individuals, with follow-up ...and meta-analysis in 180,726 additional individuals (total n = 327,288). These blood pressure-associated loci are enriched for known variants for cardiometabolic traits. Associations were also observed for the aggregation of rare and low-frequency missense variants in three genes, NPR1, DBH, and PTPMT1. In addition, blood pressure associations at 39 previously reported loci were confirmed. The identified variants implicate biological pathways related to cardiometabolic traits, vascular function, and development. Several new variants are inferred to have roles in transcription or as hubs in protein-protein interaction networks. Genetic risk scores constructed from the identified variants were strongly associated with coronary disease and myocardial infarction. This large collection of blood pressure-associated loci suggests new therapeutic strategies for hypertension, emphasizing a link with cardiometabolic risk.
Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association study (GWAS) analysis of common SNPs. Leveraging phased haplotypes ...from the 1000 Genomes Project, we report a GWAS meta-analysis of ~185,000 CAD cases and controls, interrogating 6.7 million common (minor allele frequency (MAF) > 0.05) and 2.7 million low-frequency (0.005 < MAF < 0.05) variants. In addition to confirming most known CAD-associated loci, we identified ten new loci (eight additive and two recessive) that contain candidate causal genes newly implicating biological processes in vessel walls. We observed intralocus allelic heterogeneity but little evidence of low-frequency variants with larger effects and no evidence of synthetic association. Our analysis provides a comprehensive survey of the fine genetic architecture of CAD, showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect size.
Aims/hypothesis
Obesity is a major risk factor for type 2 diabetes, but little is known about the contribution of BMI-associated loci to type 2 diabetes risk in East Asian populations.
Methods
In ...this study, 30 known BMI-associated variants and a genetic risk score (GRS) calculated by summing the BMI-increasing alleles of these variants were tested for associations with type 2 diabetes and related glycaemic traits in 1,873 cases of type 2 diabetes and 1,839 controls in Han Chinese individuals. Logistic and linear regression analyses were performed to determine the association with type 2 diabetes risk or related glycaemic traits, respectively, under an additive model with or without adjustment for BMI.
Results
The GRS was significantly associated with increased BMI (β SE 0.070 0.016;
p
= 1.33 × 10
−5
) in the overall population. Each additional BMI-increasing allele in the GRS increased type 2 diabetes risk by 1.029-fold (95% CI 1.008, 1.050;
p
= 0.0056) without adjustment for BMI, and the association was slightly attenuated after adjustment for BMI (OR 1.022; 95% CI 1.002, 1.043;
p
= 0.035). In non-diabetic controls, the GRS was also associated with HOMA of beta cell function (HOMA-B) with adjustment for BMI (β SE −0.876 0.345;
p
= 0.011). Notably, the association of GRS with type 2 diabetes was abolished after adjusting for HOMA-B (OR 1.012; 95% CI 0.986, 1.039;
p
= 0.380).
Conclusions/interpretation
Our results suggested that genetic predisposition to obesity leads to increased risk of type 2 diabetes, independent of BMI and partly through impaired beta cell function.
ABCC2 (MRP2, cMOAT) expression has been implicated in cisplatin resistance in vitro. In mice, cisplatin disposition and toxicity were unaffected by Abcc2 knockout (Abcc2−/−). Moreover, in cancer ...patients (n = 237), cisplatin pharmacokinetics (P > 0.12) and efficacy (P > 0.41) were not associated with seven of the single‐nucleotide polymorphisms (SNPs) in ABCC2. These SNPs were also not correlated with ABCC2 expression in the NCI60 panel (P > 0.26) or with cisplatin‐induced cytotoxicity (P = 0.21). These findings highlight the importance of verifying drug–transporter interactions with in vitro tests in humans.
Clinical Pharmacology & Therapeutics (2012); 91 6, 1022–1026. doi:10.1038/clpt.2011.330
Periodontitis is a chronic multifactorial inflammatory disease of the supportive tissues of the teeth. Pathophysiological evidence suggests a possible common inflammatory background between ...periodontitis and cardiovascular diseases (CVD). Pathological and epidemiological associations between these two diseases have been presented, but are still debated. This study aimed to investigate the association between the inflammatory burden of periodontitis and the presence and extent of coronary calcification. Secondary aims were to study other cardiovascular parameters and cardiovascular risk predictors in relation to periodontitis and dental health.
Healthy periodontitis or non-periodontitis patients 45–70 years of age were included in a prospective cross-sectional study. Full-mouth examinations were performed by a periodontist to determine their Periodontal Inflamed Surface Area (PISA) score and other dental parameters. To assess the cardiovascular conditions, Coronary Artery Calcium (CAC) scores, endothelial function assessments by the EndoPAT ™, and several physical and biochemical examinations were performed.
Seventy-one patients were included. Elevated CAC scores and endothelial dysfunction were not significantly related to PISA or dental health. PISA was significantly related to the Framingham and Reynolds CVD risk predictors, but were no longer significant after correction for confounders. The same applied to the significant relations between tooth loss, dental plaque and bleeding scores and the CVD risk predictors.
Periodontitis is associated with increased CVD risk, but is not an independent risk factor. This link is still important to make to bridge the gap between dentistry and general medicine and to identify patients at risk for CVD in an earlier stage.
To define the learning process of minimally invasive repair of pectus excavatum by the Nuss procedure through assessment of consecutive procedural metrics.
A single-center retrospective observational ...cohort study was conducted of all consecutive Nuss procedures performed by individual surgeons without previous experience between June 2006 and December 2018. Surgeons were proctored during their initial 10 procedures. The learning process after the proctoring period was evaluated using nonrisk-adjusted cumulative sum (ie, observed minus expected) failure charts of complications. An acceptable and unacceptable complication rate of 10% and 20% were used. Logarithmic trend lines were used to assess over-time performance regarding operation time.
Two-hundred twenty-two consecutive Nuss procedures by 3 general thoracic surgeons were evaluated. Cumulative sum charts showed an average performance from the first procedure after being proctored onward for all surgeons, whereas surgeon B demonstrated a statistically significant complication rate equal to or less than 10% after 59 cases. Post-hoc sensitivity analyses using a stricter acceptable and unacceptable complication rate of 6% and 12% also showed an average performance for all surgeons. Although, the median time between consecutive procedures ranged from 7 to 35 days, no frequency–outcome relationship was observed. In addition, surgeons required the same average operation time throughout their entire experience.
After a 10-procedure proctoring period, repair of pectus excavatum by the Nuss procedure is a safe procedure to adopt and perform without a typical (complication based) learning curve while performing at least 1 procedure per 35 days.
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