Structured immune work-up in healthy children with a first episode of severe bacterial infection: a 7-year single-center study

Background: Severe bacterial infections (SBI) in otherwise healthy children are rare and may represent an underlying impairment of the immune system including primary immunodeficiency (PID). However, it is unclear if and how children should be assessed. Methods: We retrospectively analyzed data from hospital records of previously healthy children aged 3 days to 18 years with SBI including pleuropneumonia, meningitis, and/or sepsis. Patients were diagnosed or immunologically followed-up between 2013/01/01 and 2020/03/31. Results: Out of 432 children with SBI, 360 children could be analyzed. Follow-up data were available for 265 (74%) children, of whom 244 children (92%) had immunological testing. Laboratory abnormalities were found in 51 of 244 patients (21%), with 3 deaths (1%). There were 14 (6%) children with immunodeficiency considered clinically relevant (3 complement deficiencies, 1 autoimmune neutropenia, 10 humoral immunodeficiencies) and 27 (11%) with milder humoral abnormalities or findings suggestive of delayed adaptive immune maturation. Conclusions: A substantial proportion of children with SBI may benefit from routine immunological testing, revealing (potentially) clinically relevant impaired immune function in 6-17% of children. The identification of immune abnormalities allows for specific counselling of families and optimization of preventive measures such as booster vaccinations to avoid future SBI episodes

Gender differences in the association between grip strength and mortality in older adults: results from the KORA-age study

Published version. Source at http://doi.org/10.1186/s12877-016-0381-4. License CC BY 4.0.Background: Reduced muscular strength in the old age is strongly related to activity impairment and mortality. However, studies evaluating the gender-specific association between muscularity and mortality among older adults are lacking. Thus, the objective of the present study was to examine gender differences in the association between muscular strength and mortality in a prospective population-based cohort study. Methods: Data used in this study derived from the Cooperative Health Research in the Region of Augsburg (KORA)-Age Study. The present analysis includes 1,066 individuals (mean age 76 ± 11 SD years) followed up over 3 years. Handgrip strength was measured using the Jamar Dynamometer. A Cox proportional hazard model was used to determine adjusted hazard ratios of mortality with 95% confidence intervals (95% CI) for handgrip strength. Potential confounders (i.e. age, nutritional status, number of prescribed drugs, diseases and level of physical activity) were pre-selected according to evidence-based information. Results: During the follow-up period, 56 men (11%) and 39 women (7%) died. Age-adjusted mortality rates per 1,000 person years (95% CI) were 77 (59–106), 24 (13–41) and 14 (7–30) for men and 57 (39–81), 14 (7–27) and 1 (0–19) for women for the first, second and third sex-specific tertile of muscular strength, respectively. Low handgrip strength was significantly associated with all-cause mortality among older men and women from the general population after controlling for significant confounders. Hazard ratios (95% CI) comparing the first and second tertile to the third tertle were 3.33 (1.53–7.22) and 1.42 (0.61-3.28), respectively. Respective hazard ratios (95% CI) for mortality were higher in women than in men ((5.23 (0.67–40.91) and 2.17 (0.27–17.68) versus 2.36 (0.97–5.75) and 0. 97 (0.36–2.57)). Conclusions: Grip strength is inversely associated with mortality risk in older adults, and this association is independent of age, nutritional status, number of prescribed drugs, number of chronic diseases and level of physical activity. The association between muscular strength and all-cause mortality tended to be stronger in women. It seems to be particularly important for the weakest to enhance their levels of muscular strength in order to reduce the risk of dying early

A −436C>A Polymorphism in the Human FAS Gene Promoter Associated with Severe Childhood Malaria

Human genetics and immune responses are considered to critically influence the outcome of malaria infections including life-threatening syndromes caused by Plasmodium falciparum. An important role in immune regulation is assigned to the apoptosis-signaling cell surface receptor CD95 (Fas, APO-1), encoded by the gene FAS. Here, a candidate-gene association study including variant discovery at the FAS gene locus was carried out in a case-control group comprising 1,195 pediatric cases of severe falciparum malaria and 769 unaffected controls from a region highly endemic for malaria in Ghana, West Africa. We found the A allele of c.−436C>A (rs9658676) located in the promoter region of FAS to be significantly associated with protection from severe childhood malaria (odds ratio 0.71, 95% confidence interval 0.58–0.88, pempirical = 0.02) and confirmed this finding in a replication group of 1,412 additional severe malaria cases and 2,659 community controls from the same geographic area. The combined analysis resulted in an odds ratio of 0.71 (95% confidence interval 0.62–0.80, p = 1.8×10−7, n = 6035). The association applied to c.−436AA homozygotes (odds ratio 0.47, 95% confidence interval 0.36–0.60) and to a lesser extent to c.−436AC heterozygotes (odds ratio 0.73, 95% confidence interval 0.63–0.84), and also to all phenotypic subgroups studied, including severe malaria anemia, cerebral malaria, and other malaria complications. Quantitative FACS analyses assessing CD95 surface expression of peripheral blood mononuclear cells of naïve donors showed a significantly higher proportion of CD69+CD95+ cells among persons homozygous for the protective A allele compared to AC heterozygotes and CC homozygotes, indicating a functional role of the associated CD95 variant, possibly in supporting lymphocyte apoptosis

Identification of regulatory variants associated with genetic susceptibility to meningococcal disease.

Non-coding genetic variants play an important role in driving susceptibility to complex diseases but their characterization remains challenging. Here, we employed a novel approach to interrogate the genetic risk of such polymorphisms in a more systematic way by targeting specific regulatory regions relevant for the phenotype studied. We applied this method to meningococcal disease susceptibility, using the DNA binding pattern of RELA - a NF-kB subunit, master regulator of the response to infection - under bacterial stimuli in nasopharyngeal epithelial cells. We designed a custom panel to cover these RELA binding sites and used it for targeted sequencing in cases and controls. Variant calling and association analysis were performed followed by validation of candidate polymorphisms by genotyping in three independent cohorts. We identified two new polymorphisms, rs4823231 and rs11913168, showing signs of association with meningococcal disease susceptibility. In addition, using our genomic data as well as publicly available resources, we found evidences for these SNPs to have potential regulatory effects on ATXN10 and LIF genes respectively. The variants and related candidate genes are relevant for infectious diseases and may have important contribution for meningococcal disease pathology. Finally, we described a novel genetic association approach that could be applied to other phenotypes

The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase 1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age  6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score  652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc = 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N = 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in Asia and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Empirical Analysis of Biomass and Energy Price Volatility

The current debate on biomass price volatility mainly refers to increased market dynamics and integration as well as renewable energy policy intervention. Higher price volatility leads to additional costs that are often shared and transmitted along the supply chain to the final consumers. We empirically analyze whether or not price volatility of woody biomass commodities has increased in recent years. Results indicate that the price volatility of some woody biomass commodities has increased, but it is still lower than of fossil fuels

High-resolution calibration of seismically induced lacustrine deposits with historical earthquake data in the Eastern Alps (Carinthia, Austria)

Lake sediments are increasingly used to reconstruct recurrence intervals of large earthquakes - a prerequisite for the establishment of accurate seismic hazard models - because they can record strong seismic shaking as mass-transport deposits (MTDs), turbidites or sediment deformations and often reach back several thousands of years. To derive quantitative information on paleo-earthquake size, the sedimentary imprints need to be thoroughly calibrated with independent information on seismic shaking strength. A few calibration studies proposed scaling relationships between the shaking strength of historical earthquakes and the type and size of lacustrine sedimentary imprints. Due to incomprehensive lacustrine mapping or an insufficient record of documented earthquakes, however, rigorous testing of these scaling relationships is lacking. Here, we study the sedimentary infill of the past ∼800 years in Wörthersee and Millstättersee, two large lakes in the Eastern Alps (Carinthia, Austria). These lakes have experienced five well-documented historical earthquakes with local seismic intensities ranging from V – IX (EMS-98 scale). We trace the sedimentary signatures (MTDs and turbidites) of these earthquakes based on a vast dataset of multibeam bathymetry, reflection seismic profiles and numerous precisely dated sediment cores. Seismic intensities as low as V½ are recorded as turbidites originating from deltaic slopes, while hemipelagic slopes can fail from intensities of VI onwards. In Wörthersee, earthquake-recording thresholds are highly dependent on the specific core locations due to local variations in slope characteristics (composition, length, and gradient) and transport distance to the core site. This highlights the potential for establishing multi-threshold paleoseismic records based on multiple coring sites in a single basin. In both lakes, exponential size-scaling relationships are inferred between seismic intensity and i) number or volume of mass-transport deposits and ii) the cumulative thickness of turbidites. Moreover, the relative turbidite presence increases linearly with seismic intensity, confirming the results from a previous study in Chilean lakes. Application of the obtained size-scaling relationships on the first major earthquake documented for Austria (1201 CE) suggests a magnitude of ∼6.4 and an epicentre close to Millstätter See. This demonstrates that lake paleoseismology is a powerful tool to obtain quantitative information on the seismic intensity distribution of paleo-earthquakes.ISSN:0277-379