Neonatal Vitamin D and Associations with Longitudinal Changes of Eczema up to 25 Years of Age.

BACKGROUND: Early-life vitamin D is a potentially modifiable risk factor for the development of eczema, but there is a lack of data on longitudinal associations. METHOD: We measured 25(OH)D3 levels from neonatal dried blood spots in 223 high-allergy-risk children. Latent class analysis was used to define longitudinal eczema phenotype up to 25 years (4 subclasses). Skin prick tests (SPTs) to 6 allergens and eczema outcomes at 6 time points were used to define eczema/sensitization phenotypes. Associations between 25(OH)D3 and prevalent eczema and eczema phenotypes were assessed using logistic regression models. RESULTS: Median 25(OH)D3 level was 32.5 nmol/L (P25-P75 = 23.1 nmol/L). Each 10 nmol/L increase in neonatal 25(OH)D3 was associated with a 26% reduced odds of early-onset persistent eczema (adjusted multinomial odds ratio (aMOR) = 0.74, 95% CI = 0.56-0.98) and 30% increased odds of early-onset-resolving eczema (aMOR = 1.30, 95% CI = 1.05-1.62) when compared to minimal/no eczema up to 12 years. Similar associations were seen for eczema phenotype up to 25 years. We did not see any strong evidence for the association between neonatal 25(OH)D3 and prevalent eczema or eczema/sensitization phenotype. CONCLUSIONS: Higher neonatal 25(OH)D3 levels, a reflection of maternal vitamin D levels in pregnancy, may reduce the risk of early-onset persistent eczema.

Prenatal vitamin D supplementation mitigates inflammation-related alveolar remodeling in neonatal mice.

The development of chronic lung disease in the neonate, also known as bronchopulmonary dysplasia (BPD), is the most common long-term complication in prematurely born infants. In BPD, the disease-characteristic inflammatory response culminates in nonreversible remodeling of the developing gas exchange area, provoked by the impact of postnatal treatments such as mechanical ventilation (MV) and oxygen treatment. To evaluate the potential of prenatal treatment regimens to modulate this inflammatory response and thereby impact the vulnerability of the lung toward postnatal injury, we designed a multilayered preclinical mouse model. After administration of either prenatal vitamin D-enriched (VitD+; 1,500 IU/g food) or -deprived (VitD-; <10 IU/kg) food during gestation in C57B6 mice (the onset of mating until birth), neonatal mice were exposed to hyperoxia (FiO2 = 0.4) with or without MV for 8 h at days 5-7 of life, whereas controls spontaneously breathed room air. Prenatal vitamin D supplementation resulted in a decreased number of monocytes/macrophages in the neonatal lung undergoing postnatal injury together with reduced TGF-ß pathway activation. In consequence, neonatal mice that received a VitD+ diet during gestation demonstrated less extracellular matrix (ECM) remodeling upon lung injury, reflected by the reduction of pulmonary α-smooth muscle actin-positive fibroblasts, decreased collagen and elastin deposition, and lower amounts of interstitial tissue in the lung periphery. In conclusion, our findings support strategies that attempt to prevent vitamin D insufficiency during pregnancy as they could impact lung health in the offspring by mitigating inflammatory changes in neonatal lung injury and ameliorating subsequent remodeling of the developing gas exchange area.NEW & NOTEWORTHY Vitamin D-enriched diet during gestation resulted in reduced lung inflammation and matrix remodeling in neonatal mice exposed to clinically relevant, postnatal injury. The results underscore the need to monitor the subclinical effects of vitamin D insufficiency that impact health in the offspring when other risk factors come into play.

High variability of COVID-19 case fatality rate in Germany.

BACKGROUND: During the first wave of the COVID-19 pandemic a high case fatality rate (CFR) was noticed worldwide including also Germany where the first European cases have been observed. The WHO recommended immediate intubation for patients with dyspnoea which has since been revised after reviewing the initial clinical outcome. The objective of this study is to analyze CFR and assess if there is an advantage of a more conservative management of COVID-19 induced hypoxemia. METHODS: PCR confirmed COVID-19 infections and death counts were obtained for all German districts from 27 Jan 2020 until 15 Feb 2021 using official reports of Robert Koch Institute Berlin, Germany. A moving average CFRt was constructed by dividing disease related deaths two weeks after a given index day by the number of infections two weeks prior to that date. In addition to a local comparison also mortality outcomes in other German speaking countries were compared. RESULTS: The mean CFR is estimated to be 2.92% based on 71.965 fatalities and 2.465.407 cases. There was a large regional scattering of CFRs across the German districts. Differences of the mortality pattern were observed also at state level and preserved across different sex and age groups while being largely independent of case numbers. Although Munich city had higher infection rates, more patients died during the first wave in Hamburg (OR 1.6, 95% CI 1.3-1.9) which was mirrored also by higher death risk at Hamburg intensive care units (OR 2.0, 95% CI 1.3-3.1). While the majority of Munich hospitals favoured a conservative management of hypoxemia including high flow nasal cannula (HFNC), Hamburg hospitals followed a more aggressive scheme of early mechanical ventilation (MV). Austria and Switzerland experienced higher CFRs than Germany during the first wave but after changing their treatment guidelines, both countries experienced lower CFRs during the second wave. CONCLUSION: Using retrospective public health data, different case fatality rates have been observed across Germany. A more conservative management of COVID-19 induced Adult Respiratory Distress Syndrome (ARDS) is justified also by epidemiological data.

Exome variants associated with asthma and allergy.

The mutational spectrum of asthma and allergy associated genes is not known although recent biobank based exome sequencing studies included these traits. We therefore conducted a secondary analysis of exome data from 281,104 UK Biobank samples for association of mostly rare variants with asthma, allergic rhinitis and atopic dermatitis. Variants of interest (VOI) were tabulated, shared genes annotated and compared to earlier genome-wide SNP association studies (GWAS), whole genome sequencing, exome and bisulfit sequencing studies. 354 VOI were significantly associated with asthma, allergic rhinitis and atopic dermatitis. They cluster mainly in two large regions on chromosome 6 and 17. After exclusion of the variants associated with atopic dermatitis and redundant variants, 321 unique VOI remain in 122 unique genes. 30 genes are shared among the 87 genes with increased and the 65 genes with decreased risk for allergic disease. 85% of genes identified earlier by common GWAS SNPs are not replicated here. Most identified genes are located in interferon É£ and IL33 signaling pathway. These genes include already known but also new pharmacological targets, including the IL33 receptor ST2/IL1RL1, as well as TLR1, ALOX15, GSDMA, BTNL2, IL13 and IKZF3. Future pharmacological studies will need to included these VOI for stratification of the study population paving the way to individualized treatment.

[The early phase of the COVID-19 pandemic in Bavaria, Germany]. / Die frühe Phase der COVID-19-Pandemie in Bayern.

INTRODUCTION: The effect of non pharmacological interventions (NPIs) during an epidemic disease outbreak is well accepted dating back to historical events. NPIs involve numerous measurements like hygiene rules or contact restriction that are applied during given situations, while so far only limited quantitative data exist to rate the overall effectiveness. METHODS: Using the official counts of Robert Koch Institute in Berlin/Germany, press reports and Twitter messages, the early phase of the current COVID-19/Sars-CoV2 in Bavaria is being reconstructed. RESULTS: The first cases have been observed in Munich by the end of January 2020. While the initial outbreak could be sufficiently covered using isolation and quarantine measurements, the consecutive early spreading falls into three phases, starting with winter school holidays at the end of February, a number of beer festivals in the following week, and general elections on March, 15. The disaster plan on March, 16 indicates the end of the early phase. Using the official case counts, a rather coherent picture evolves although representative epidemiological studies are still missing. The epidemic started with a few cases during the winter holidays, increased exponentially afterwards including significant more cases by beer festivals and another significant excess of cases following the election that occurred in Bavaria only. Compared to other German countries, Bavaria reached the highest prevalence which could not be reversed by even the most restrictive containment measurements. CONCLUSION: To be effective, NPIs need to applied early, if possible even before the beginning of the exponential phase.

Human milk oligosaccharide profiles and allergic disease up to 18 years.

BACKGROUND: Human milk oligosaccharides (HMO) are a diverse range of sugars secreted in breast milk that have direct and indirect effects on immunity. The profiles of HMOs produced differ between mothers. OBJECTIVE: We sought to determine the relationship between maternal HMO profiles and offspring allergic diseases up to age 18 years. METHODS: Colostrum and early lactation milk samples were collected from 285 mothers enrolled in a high-allergy-risk birth cohort, the Melbourne Atopy Cohort Study. Nineteen HMOs were measured. Profiles/patterns of maternal HMOs were determined using LCA. Details of allergic disease outcomes including sensitization, wheeze, asthma, and eczema were collected at multiple follow-ups up to age 18 years. Adjusted logistic regression analyses and generalized estimating equations were used to determine the relationship between HMO profiles and allergy. RESULTS: The levels of several HMOs were highly correlated with each other. LCA determined 7 distinct maternal milk profiles with memberships of 10% and 20%. Compared with offspring exposed to the neutral Lewis HMO profile, exposure to acidic Lewis HMOs was associated with a higher risk of allergic disease and asthma over childhood (odds ratio asthma at 18 years, 5.82; 95% CI, 1.59-21.23), whereas exposure to the acidic-predominant profile was associated with a reduced risk of food sensitization (OR at 12 years, 0.08; 95% CI, 0.01-0.67). CONCLUSIONS: In this high-allergy-risk birth cohort, some profiles of HMOs were associated with increased and some with decreased allergic disease risks over childhood. Further studies are needed to confirm these findings and realize the potential for intervention.

High degree of polyclonality hinders somatic mutation calling in lung brush samples of COPD cases and controls.

Chronic obstructive pulmonary disease (COPD) is induced by cigarette smoking and characterized by inflammation of airway tissue. Since smokers with COPD have a higher risk of developing lung cancer than those without, we hypothesized that they carry more mutations in affected tissue. We called somatic mutations in airway brush samples from medium-coverage whole genome sequencing data from healthy never and ex-smokers (n = 8), as well as from ex-smokers with variable degrees of COPD (n = 4). Owing to the limited concordance of resulting calls between the applied tools we built a consensus, a strategy that was validated with high accuracy for cancer data. However, consensus calls showed little promise of representing true positives due to low mappability of corresponding sequence reads and high overlap with positions harbouring known genetic polymorphisms. A targeted re-sequencing approach suggested that only few mutations would survive stringent verification testing and that our data did not allow the inference of any difference in the mutational load of bronchial brush samples between former smoking COPD cases and controls. High polyclonality in airway brush samples renders medium-depth sequencing insufficient to provide the resolution to detect somatic mutations. Deep sequencing data of airway biopsies are needed to tackle the question.

Perceptions of students in health and molecular life sciences regarding pharmacogenomics and personalized medicine.

BACKGROUND: Increasing evidence is demonstrating that a patient's unique genetic profile can be used to detect the disease's onset, prevent its progression, and optimize its treatment. This led to the increased global efforts to implement personalized medicine (PM) and pharmacogenomics (PG) in clinical practice. Here we investigated the perceptions of students from different universities in Bosnia and Herzegovina (BH) towards PG/PM as well as related ethical, legal, and social implications (ELSI). This descriptive, cross-sectional study is based on the survey of 559 students from the Faculties of Medicine, Pharmacy, Health Studies, Genetics, and Bioengineering and other study programs. RESULTS: Our results showed that 50% of students heard about personal genome testing companies and 69% consider having a genetic test done. A majority of students (57%) agreed that PM represents a promising healthcare model, and 40% of students agreed that their study program is well designed for understanding PG/PM. This latter opinion seems to be particularly influenced by the field of study (7.23, CI 1.99-26.2, p = 0.003). Students with this opinion are also more willing to continue their postgraduate education in the PM (OR = 4.68, CI 2.59-8.47, p < 0.001). Furthermore, 45% of students are aware of different ethical aspects of genetic testing, with most of them (46%) being concerned about the patient's privacy. CONCLUSIONS: Our results indicate a positive attitude of biomedical students in Bosnia and Herzegovina towards genetic testing and personalized medicine. Importantly, our results emphasize the key importance of pharmacogenomic education for more efficient translation of precision medicine into clinical practice.

The challenges of the expanded availability of genomic information: an agenda-setting paper.

Rapid advances in microarray and sequencing technologies are making genotyping and genome sequencing more affordable and readily available. There is an expectation that genomic sequencing technologies improve personalized diagnosis and personalized drug therapy. Concurrently, provision of direct-to-consumer genetic testing by commercial providers has enabled individuals' direct access to their genomic data. The expanded availability of genomic data is perceived as influencing the relationship between the various parties involved including healthcare professionals, researchers, patients, individuals, families, industry, and government. This results in a need to revisit their roles and responsibilities. In a 1-day agenda-setting meeting organized by the COST Action IS1303 "Citizen's Health through public-private Initiatives: Public health, Market and Ethical perspectives," participants discussed the main challenges associated with the expanded availability of genomic information, with a specific focus on public-private partnerships, and provided an outline from which to discuss in detail the identified challenges. This paper summarizes the points raised at this meeting in five main parts and highlights the key cross-cutting themes. In light of the increasing availability of genomic information, it is expected that this paper will provide timely direction for future research and policy making in this area.

Do Variants in GSTs Modify the Association between Traffic Air Pollution and Asthma in Adolescence?

Polymorphisms in genes involved in the oxidative stress response may partially explain the documented heterogeneous associations between traffic-related air pollution (TRAP) exposure and asthma and allergies in children. We investigated whether the GSTT1, GSTM1 and GSTP1 gene polymorphisms modified the associations between TRAP exposure during the first year of life and asthma, wheeze and hay fever in adolescence. We used a birth cohort of 620 high risk infants from the Melbourne Atopy Cohort Study. TRAP exposure during the first year of life was defined as the cumulative length of major roads within 150 m of each participant's residence during the first year of life. Wheeze, asthma and hay fever were measured at ages 12 (n = 370) and 18 (n = 434) years. The associations and interactions with glutathione S-transferases (GST s) were investigated using regression models. Overall, there was no relationship between TRAP exposure during the first year of life and current asthma, wheeze and hay fever at ages 12 or 18 years. However, in GSTT1 null carriers, every 100 m increase in cumulative lengths of major road exposure during the first year of life was associated with a 2.31-fold increased risk of wheeze and a 2.15-fold increased risk of asthma at 12 years. TRAP is associated with some respiratory outcomes in carriers of genetic polymorphisms in oxidative stress metabolism genes.

[The last days of Albert Schweitzer]. / Albert Schweitzers letzte Tage.

Schweitzer was one of the leading physicians of the last century. He overcame not only the boundaries of humanities and natural sciences, but also the boundaries of Europe and Africa. He has become a symbol of humanity. But the person of Albert Schweitzer was almost in danger of disappearing behind it. "My hair starts to turn gray. My body begins to feel the exertions I have undertaken, and the burden of the years". This is how the 56-year-old Schweitzer ended his autobiography "Out of my life and thought" in 1931. Even 50 years after Schweitzer's death in 1965, there is still no coherent scientific reappraisal of his work. Part of the posthumous manuscripts was published in recent years in a critical edition, including first biographies that are no longer considered as hagiography, as they would have been in the contemporary literature. The legacy, however, is scattered. Much of the correspondence and the library are located in Schweitzer's former house in Gunsbach in Alsace. The manuscripts are mainly stored in the Central Library Zurich, but also in the Syracuse University New York, while the personal bequest is in the hands of his family or collectors. This presentation is part of a biographical approach and depicts the last weeks in the life of Albert Schweitzer.

Asthma, COPD and overlap syndrome: a longitudinal study in young European adults.

We compared risk factors and clinical characteristics, 9-year lung function change and hospitalisation risk across subjects with the asthma-chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS), asthma or COPD alone, or none of these diseases.Participants in the European Community Respiratory Health Survey in 1991-1993 (aged 20-44 years) and 1999-2001 were included. Chronic airflow obstruction was defined as pre-bronchodilator forced expiratory volume in 1 s (FEV1)/forced vital capacity