Associations between multiple sclerosis and incidence of heart diseases : Systematic review and meta-analysis of observational studies

Background: Observational studies have described associations between multiple sclerosis (MS) and heart diseases, but the results were mixed. Methods: Medline, Embase, and Cochrane CENTRAL were searched up to 5 October 2020 according to a protocol (PROSPERO registration number CRD42020184493). We included longitudinal non-randomized studies of exposure comparing the incidence of acquired heart diseases between people with multiple sclerosis (pwMS) and people without multiple sclerosis. We used ROBINS-E and the GRADE approach to assess risk of bias and the certainty of evidence, respectively. Data were pooled using random-effect models. Results: Of 5,159 studies, nine studies met the inclusion criteria. MS was associated with an increased risk for myocardial infarction (HR 1.6, 95% CI 1.2 to 2.0, I2 86%, n = 1,209,079) and heart failure (HR 1.7, 95% CI 1.3 to 2.2, I2 49%, n = 489,814). The associations were more pronounced among women and younger people in subgroup analyses. We found no difference for ischemic heart disease (HR 1.0, 95% CI 0.8 to 1.4, I2 86%, n = 679,378) and bradycardia (HR 1.5, 95% CI 0.4 to 5.0, I2 50%, n = 187,810). The risk of atrial fibrillation was lower in pwMS (HR 0.7, 95% CI 0.6 to 0.8, I2 0%, n = 354,070), but the risk of bias was high, and the certainty of evidence was rated as very low. One study found more cases of infectious endocarditis among pwMS (HR 1.2, 95% CI 1.0 to 1.4, n = 83,712). Conclusions: Myocardial infarction and heart failure should be considered in people with multiple sclerosis during follow-up examinations

Serum cytokines MCP-1 and GCS-F as potential biomarkers in pediatric inflammatory bowel disease

Background Inflammatory bowel diseases (IBDs) with the subtypes ulcerative colitis (UC) and Crohn disease (CD), are chronic autoimmune inflammatory disorders of the gastrointestinal tract. Cytokines are associated with the development and progression in pediatric IBD. We measured cytokine levels in pediatric IBD patients to assess their potential function as biomarkers in disease assessment. Method In this prospective cohort study, we enrolled 33 children with IBD. All patients were in stable remission for 3 months on enrollment. Patients who developed a relapse within six months after enrollment were classified as relapsers. Blood sampling was performed at enrolment and for relapsers in relapse and post-relapse. Serum concentrations of 14 cytokines, chemokines and growth factors (IL-1α, IL-1β, IL-6, IL-12p40, IP-10, TNF-α, IFN-γ, IL-10, IL-8, MIP-1α, MCP-1, MCP-3, G-CSF, GM-CSF) were measured simultaneously using multiplex bead-based sandwich immunoassay on Luminex 100 system. Results MCP-1 was significantly higher in CD patients compared to UC patients at each disease stage: stable remission (P<0.048), unstable remission (P<0.013), relapse (P<0.026) and post-relapse (P<0.024). G-CSF was significantly increased in UC patients developing a relapse and in post-relapse stage compared to UC patients in remission (P<0.02 and p<0.03, respectively). Conclusion MCP-1 showed potential as a diagnostic biomarker in CD patients independent of disease activity as it was able to discriminate between subtypes of pediatric IBD. In UC patients, G-CSF was significantly elevated in relapsers indicating its use and role as a potential prognostic biomarker

Low Vitamin D Status Predicts Poor Clinical Outcome in Advanced Melanoma Treated With Immune Checkpoint or BRAF/MEK Inhibitors: A Prospective Non-Interventional Side-by-Side Analysis

In melanoma and other malignancies, low vitamin D status is associated with increased risk and poor prognosis. However, there are limited data of the impact of 25(OH)D serum concentration (s.c.) on clinical outcome in advanced melanoma. We tested the hypothesis that vitamin D status is predictive of efficacy and safety in patients treated for metastasized melanoma with B-rapidly accelerated fibrosarcoma (BRAF), mitogen-activated protein kinase kinase (MEK), cytotoxic T lymphocyte-associated protein-4 (CTLA-4), and/or programmed cell death protein-1 (PD-1) inhibitors. Severe vitamin D deficiency [defined as 25(OH)D s.c. <10 ng/ml] was associated with markedly reduced overall (OS) and progress-free (PFS) survival, with increased tumor load [TL; measured as s.c. of S100 protein or lactate dehydrogenase (LDH)], and with a trend for higher frequency of adverse events (AEs). An increase in average 25(OH)D s.c. of 1 ng/ml was associated with a 3.9% reduced risk for progressive disease [hazard ratio (HR) = 0.961, p = 0.044], with a reduction of LDH s.c. of 3.86 U/l (p = 0.034, indicating a reduction of TL), and with a trend for reduced frequency of AEs (AE ratio -0.005; p = 0.295). Patients with average 25(OH)D s.c. ≥10 ng/ml and BRAF-mutant melanoma showed a trend for a higher frequency of AEs as compared to individuals with BRAF wild-type melanomas. Our data indicate that vitamin D deficiency is associated with poor clinical outcome in patients treated for metastasized melanoma with BRAF/MEK inhibitors or immunotherapy. Although it needs to be proven in future interventional trials whether optimizing serum 25(OH)D improves clinical outcome in these patients, we recommend that 25(OH)D s.c. should be analyzed and vitamin D deficiency treated in all patients with advanced melanoma

Concentrations of Soluble Angiotensin Converting Enzyme 2 (sACE2) in Children and Adults with and without COVID-19

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing the coronavirus disease 2019 (COVID-19) pandemic, leads to illness and death. Various risk factors for a severe course, such as higher age, male gender and pre-existing illnesses are known. However, pathophysiological risk factors are largely unclear. Notably, the mild course of disease in children is conspicuous. Angiotensin converting enzyme 2 (ACE2) serves as a receptor for SARS-CoV-2 and is a key enzyme in infection. Differences in the distribution of ACE2 can provide insights into different courses of COVID19. Our aim was to elucidate the role of ACE2 as a pathophysiological risk factor by measuring soluble ACE2 (sACE2) via ELISA in blood samples (lithium-heparin-plasma or serum) of 367 individuals including children and adults with and without COVID-19. sACE2-levels were compared between the groups according to age and sex. In adults and children with COVID-19, sACE2-concentrations are significantly higher compared to healthy individuals. sACE2-levels increase with age and are lower in children compared to adults with COVID-19. Sex doesn’t significantly influence sACE2- concentration. It remains unclear whether sACE2 concentrations increase because of the infection and what factors could influence this response. In conclusion, the increase of sACE2-concentration with age could indicate that ACE2 concentrations mirror increased COVID-19 severity

Patient factors associated with titration of medical therapy in patients with heart failure with reduced ejection fraction: data from the QUALIFY international registry

Aims: Failure to prescribe key medicines at evidence-based doses is associated with increased mortality and hospitalization forpatients with Heart Failure with reduced Ejection Fraction (HFrEF). We assessed titration patterns of guideline-recommendedHFrEF medicines internationally and explored associations with patient characteristics in the global, prospective, observational,longitudinal registry. Methods and results: Data were collected from September 2013 through December 2014, with 7095 patients from 36 coun-tries [>18 years, previous HF hospitalization within 1–15 months, left ventricular ejection fraction (LVEF)≤40%] enrolled, withdosage data at baseline and up to 18 months from 4368 patients. In 4368 patients (mean age 63 ± 17 years, 75% male)≥100%target doses at baseline: 30.6% (ACEIs), 2.9% (ARBs), 13.9% (BBs), 53.8% (MRAs), 26.2% (ivabradine). Atfinal follow-up,≥100%target doses achieved in more patients for ACEI (34.8%), BB (18.0%), and ivabradine (30.5%) but unchanged for ARBs (3.2%)and MRAs (53.7%). Adjusting for baseline dosage, uptitration during follow-up was more likely with younger age, highersystolic blood pressure, and in absence of chronic kidney disease or diabetes for ACEIs/ARBs; younger age, higher body massindex, higher heart rate, lower LVEF, and absence of coronary artery disease for BBs. For ivabradine, uptitration was morelikely with higher resting heart rate. Conclusions: The international QUALIFY Registry suggests that few patients with HFrEF achieve target doses ofdisease-modifying medication, especially older patients and those with co-morbidity. Quality improvement initiatives are ur-gently required

Human papillomavirus vaccination of girls in the German model region Saarland: Insurance data-based analysis and identification of starting points for improving vaccination rates

In Germany, the incidence of cervical cancer, a disease caused by human papillomaviruses (HPV), is higher than in neighboring European countries. HPV vaccination has been recommended for girls since 2007. However, it continues to be significantly less well received than other childhood vaccines, so its potential for cancer prevention is not fully realized. To find new starting points for improving vaccination rates, we analyzed pseudonymized routine billing data from statutory health insurers in the PRÄZIS study (prevention of cervical carcinoma and its precursors in women in Saarland) in the federal state Saarland serving as a model region. We show that lowering the HPV vaccination age to 9 years led to more completed HPV vaccinations already in 2015. Since then, HPV vaccination rates and the proportion of 9- to 11-year-old girls among HPV-vaccinated females have steadily increased. However, HPV vaccination rates among 15-year-old girls in Saarland remained well below 50% in 2019. Pediatricians vaccinated the most girls overall, with a particularly high proportion at the recommended vaccination age of 9–14 years, while gynecologists provided more HPV catch-up vaccinations among 15-17-year-old girls, and general practitioners compensated for HPV vaccination in Saarland communities with fewer pediatricians or gynecologists. We also provide evidence for a significant association between attendance at the children´s medical check-ups “U11” or “J1” and HPV vaccination. In particular, participation in HPV vaccination is high on the day of U11. However, obstacles are that U11 is currently not financed by all statutory health insurers and there is a lack of invitation procedures for both U11 and J1, resulting in significantly lower participation rates than for the earlier U8 or U9 screenings, which are conducted exclusively with invitations and reminders. Based on our data, we propose to restructure U11 and J1 screening in Germany, with mandatory funding for U11 and organized invitations for HPV vaccination at U11 or J1 for both boys and girls

German federal-state-wide seroprevalence study of 1st SARS-CoV-2 pandemic wave shows importance of long-term antibody test performance

Background Reliable data on the adult SARS-CoV-2 infection fatality rate in Germany are still scarce. We performed a federal state-wide cross-sectional seroprevalence study named SaarCoPS, that is representative for the adult population including elderly individuals and nursing home residents in the Saarland. Methods Serum was collected from 2940 adults via stationary or mobile teams during the 1st pandemic wave steady state period. We selected an antibody test system with maximal specificity, also excluding seroreversion effects due to a high longitudinal test performance. For the calculations of infection and fatality rates, we accounted for the delays of seroconversion and death after infection. Results Using a highly specific total antibody test detecting anti-SARS-CoV-2 responses over more than 180 days, we estimate an adult infection rate of 1.02% (95% CI: [0.64; 1.44]), an underreporting rate of 2.68-fold (95% CI: [1.68; 3.79]) and infection fatality rates of 2.09% (95% CI: (1.48; 3.32]) or 0.36% (95% CI: [0.25; 0.59]) in all adults including elderly individuals, or adults younger than 70 years, respectively. Conclusion The study highlights the importance of study design and test performance for seroprevalence studies, particularly when seroprevalences are low. Our results provide a valuable baseline for evaluation of future pandemic dynamics and impact of public health measures on virus spread and human health in comparison to neighbouring countries such as Luxembourg or France

Meta-Analysis of European Clinical Trials Characterizing the Healthy-Adult Serum 25-hydroxyvitamin D Response to Vitamin D Supplementation

To obtain reliable data that allow health authorities to re-evaluate recommendations for oral vitamin D uptake, we conducted a meta-analysis to investigate the impact of supplementation on serum 25-hydroxyvitamin D (25(OH)D) levels in healthy adults in Europe. Of the publications identified (n = 4005) in our literature search (PUBMED, through 2 January 2022), 49 primary studies (7320 subjects, 73 study arms) were eligible for inclusion in our meta-analysis. The risk of bias was assessed using the Cochrane RoB tool based on seven categories, according to which each study is rated using three grades, and overall was rated as rather low. The median duration of intervention was 136.78 days (range, 1088 days); the mean weighted baseline 25(OH)D concentration and mean age were 33.01 vs. 33.84 nmol/L and 46.8 vs. 44.8 years in the vitamin D and placebo groups, respectively. Using random-effects models, 25(OH)D levels were increased by 36.28 nmol/L (95% CI 31.97–40.59) in the vitamin D group compared to the placebo, with a relative serum increment of 1.77 nmol/L per 2.5 μg of vitamin D daily. Notably, the relative serum 25(OH)D increment was affected by various factors, including the dosage and baseline serum 25(OH)D concentration, decreasing with increasing vitamin D doses and with increasing baseline serum levels. We estimate that supplementation in all healthy adults in Europe with appr. 25 μg of vitamin D (1000 IU) daily would raise serum 25(OH)D levels in 95% of the population to ≥50 nmol/L. Our work provides health authorities with reliable data that can help to re-evaluate recommendations for oral vitamin D supplementation

Meta-Analysis of European Clinical Trials Characterizing the Healthy-Adult Serum 25-hydroxyvitamin D Response to Vitamin D Supplementation

To obtain reliable data that allow health authorities to re-evaluate recommendations for oral vitamin D uptake, we conducted a meta-analysis to investigate the impact of supplementation on serum 25-hydroxyvitamin D (25(OH)D) levels in healthy adults in Europe. Of the publications identified (n = 4005) in our literature search (PUBMED, through 2 January 2022), 49 primary studies (7320 subjects, 73 study arms) were eligible for inclusion in our meta-analysis. The risk of bias was assessed using the Cochrane RoB tool based on seven categories, according to which each study is rated using three grades, and overall was rated as rather low. The median duration of intervention was 136.78 days (range, 1088 days); the mean weighted baseline 25(OH)D concentration and mean age were 33.01 vs. 33.84 nmol/L and 46.8 vs. 44.8 years in the vitamin D and placebo groups, respectively. Using random-effects models, 25(OH)D levels were increased by 36.28 nmol/L (95% CI 31.97–40.59) in the vitamin D group compared to the placebo, with a relative serum increment of 1.77 nmol/L per 2.5 µg of vitamin D daily. Notably, the relative serum 25(OH)D increment was affected by various factors, including the dosage and baseline serum 25(OH)D concentration, decreasing with increasing vitamin D doses and with increasing baseline serum levels. We estimate that supplementation in all healthy adults in Europe with appr. 25 µg of vitamin D (1000 IU) daily would raise serum 25(OH)D levels in 95% of the population to ≥50 nmol/L. Our work provides health authorities with reliable data that can help to re-evaluate recommendations for oral vitamin D supplementation