Nucleated red blood cells and serum lactate values on days 2 and 5 are associated with mortality and morbidity in VLBW infants.

AIM: To correlate nucleated red blood cell counts and serum lactate concentrations on day 2 and 5 of life with morbidity and mortality in very low birth weight infants and to determine corresponding cutoff values. METHODS: Retrospective analysis in a cohort of very low birth weight infants. RESULTS: 250 very low birth weight infants were included in this study. Gestational age ranged from 23 to 35 weeks (mean 29.04) and birth weight was 320-1500 g (mean 1047.9). 55 (22%) patients developed intraventricular hemorrhage, 55 (22%) bronchopulmonary dysplasia, 12 (4.8%) periventricular leukomalacia, 93 (37.2%) retinopathy of prematurity, and 1 (0.4%) necrotizing enterocolitis. Mortality rate was 25/250 (10%). Nucleated red blood cells and serum lactate on day 2 of life were associated with mortality (p < 0.001). Serum lactate on day 5 of life demonstrated an association with retinopathy of prematurity (p = 0.017), bronchopulmonary dysplasia (p = 0.044), and intraventricular hemorrhage (p < 0.001). Cutoff values predicting mortality were >89.5 nucleated red blood cells/100 leucocytes (sensitivity 68.2%, specificity 89.0%) and serum lactate concentrations >8.5 mmol/l (sensitivity 69.6%, specificity 93.5%) on day 2 of life. CONCLUSION: We conclude that both nucleated red blood cell count and serum lactate concentration are valuable biomarkers in predicting important outcome parameters in very low birth weight infants.

Risks and Benefits of Ultrasound, Nerve Stimulation, and Their Combination for Guiding Peripheral Nerve Blocks: A Retrospective Registry Analysis.

BACKGROUND: Ultrasound, nerve stimulation, and their combination are all considered acceptable ways to guide peripheral nerve blocks. Which approach is most effective and associated with the fewest complications is unknown. We therefore used a large registry to analyze whether there are differences in vascular punctures, multiple skin punctures, and unintended paresthesia. METHODS: Twenty-six thousand seven hundred and thirty-three cases were extracted from the 25-center German Network for Regional Anesthesia registry between 2007 and 2016 and grouped into ultrasound-guided puncture (n = 10,380), ultrasound combined with nerve stimulation (n=8173), and nerve stimulation alone (n = 8180). The primary outcomes of vascular puncture, multiple skin punctures, and unintended paresthesia during insertion were compared with conditional logistic regression after 1:1:1 propensity score matching. Results are presented as odds ratios and 95% CIs. RESULTS: Propensity matching successfully paired 2508 patients with ultrasound alone (24% of 10,380 patients), 2508 patients with a combination of ultrasound/nerve stimulation (31% of 8173 patients), and 2508 patients with nerve stimulation alone (31% of 8180 patients). After matching, no variable was imbalanced (standardized differences <0.1). Compared with ultrasound guidance alone, the odds of multiple skin punctures (2.2 [1.7-2.8]; P < .001) and vascular puncture (2.7 [1.6-4.5]; P < .001) were higher with nerve stimulation alone, and the odds for unintended paresthesia were lower with nerve stimulation alone (0.3 [0.1-0.7]; P = .03). The combined use of ultrasound/nerve stimulation showed higher odds of multiple skin punctures (1.5 [1.2-1.9]; P = .001) and lower odds of unintended paresthesia (0.4 [0.2-0.8]; P = .007) compared with ultrasound alone. Comparing the combined use of ultrasound/nerve stimulation with ultrasound alone, the odds for vascular puncture (1.3 [0.7-2.2]; P = .4) did not differ significantly. Systemic toxicity of local anesthetics was not observed in any patient with ultrasound guidance alone, in 1 patient with the combined use of ultrasound and nerve stimulation, and in 1 patient with nerve stimulation alone. CONCLUSIONS: Use of ultrasound alone reduced the odds of vascular and multiple skin punctures. However, the sole use of ultrasound increases the odds of paresthesia.

Longitudinal magnetic resonance imaging in progressive supranuclear palsy: A new combined score for clinical trials.

BACKGROUND: Two recent, randomized, placebo-controlled phase II/III trials (clinicaltrials.gov: NCT01110720, NCT01049399) of davunetide and tideglusib in progressive supranuclear palsy (PSP) generated prospective, 1-year longitudinal datasets of high-resolution T1-weighted three-dimensional MRI. OBJECTIVE: The objective of this study was to develop a quantitative MRI disease progression measurement for clinical trials. METHODS: The authors performed a fully automated quantitative MRI analysis employing atlas-based volumetry and provide sample size calculations based on data collected in 99 PSP patients assigned to placebo in these trials. Based on individual volumes of 44 brain compartments and structures at baseline and 52 weeks of follow-up, means and standard deviations of annualized percentage volume changes were used to estimate standardized effect sizes and the required sample sizes per group for future 2-armed, placebo-controlled therapeutic trials. RESULTS: The highest standardized effect sizes were found for midbrain, frontal lobes, and the third ventricle. Using the annualized percentage volume change of these structures to detect a 50% change in the 1-year progression (80% power, significance level 5%) required lower numbers of patients per group (third ventricle, n = 32; midbrain, n = 37; frontal lobe, n = 43) than the best clinical scale (PSP rating scale total score, n = 58). A combination of volume changes in these 3 structures reduced the number of required patients to only 20 and correlated best with the progression in the clinical scales. CONCLUSIONS: We propose the 1-year change in the volumes of third ventricle, midbrain, and frontal lobe as combined imaging read-out for clinical trials in PSP that require the least number of patients for detecting efficacy to reduce brain atrophy. © 2017 International Parkinson and Movement Disorder Society.

Less pain after transvaginal cholecystectomy: single-center pooled analysis.

BACKGROUND: We previously reported outcome after transvaginal cholecystectomy (TVC) from two cohort studies and a randomized controlled trial. We now present a pooled analysis of postoperative pain scores. DESIGN: Single-center data of postoperative pain after TVC from a level II hospital between October 2007 and June 2012. METHODS: Female patients, above 18 years with symptomatic cholecystolithiasis, received either TVC or conventional laparoscopic cholecystectomy (CLC). Follow up 4 days. The primary outcome of the study was pain after surgery. Pain was measured via a visual rating scale. Descriptive statistics include age, body mass index (BMI), ASA grade, surgical times, number of trocars, complications and hospital stay as well as pain medication. Pain data were assessed against histologic findings. RESULTS: The combined register included 316 patients. Of these, 7 patients were excluded from analysis due to conversion to open surgery, complications and denial of follow-up. There were 141 patients in the TVC and 168 in the CLC group. There was no difference in age, ASA grade, surgical times, complications or hospital stay. BMI was significantly different with an average BMI of 27.1 in the TVC and 28.7 in the CLC group (p = 0.027). The numbers of trocars were significantly different as expected. There was no difference in postoperative pain medication. Pain scores were significantly different on day two to four. Multivariate testing revealed no dependence between postoperative pain and histologic findings. CONCLUSION: On smaller patient numbers, we were previously unable to demonstrate a consistently, significant difference for postoperative pain in our cohort and randomized studies. The pooled analysis suggests that there is an advantage with less postoperative pain after transvaginal compared to standard laparoscopic cholecystectomy.

Photobiomodulation therapy in breast cancer-related lymphedema: a randomized placebo-controlled trial.

BACKGROUND: The aim of our study was to examine the effects of photobiomodulation therapy (PBMT) in the treatment of breast cancer-related lymphedema using a compactly designed treatment regime consisting of eight therapy sessions in combination with a cluster laser device covering a total area size of 78.54 cm² over the axillary. METHODS: Forty patients with unilateral lymphedema were enrolled in this double-blind, placebo-controlled trial in order to evaluate effects of PBMT on lymphedema-related pain, quality of life, grip strength and limb volume difference. Subjects received irradiation for ten minutes per session using a cluster laser covering a beam area of 78.54 cm². The applied energy was 384 Joules resulting in an energy density of 4.89 J/cm². RESULTS: Post-treatment, a 50% reduction in median pain scores and an increase in mean quality of life were observed. Mean grip strength was persistently higher after eight sessions of PBMT compared with pretreatment; however, no statistically significant intergroup differences (P > 0.05) were found over the time course. CONCLUSION: PBMT using a compactly designed treatment regime in combination with a cluster laser device did not significantly improve quality of life, pain scores, grip strength and limb volume over the time course.

Clinical practice audit concerning antimicrobial prophylaxis in paediatric neurosurgery: results from a German paediatric oncology unit.

BACKGROUND: Perioperative antimicrobial prophylaxis (PAP) has been identified as an important target for internal audits, concerning the judicious use of antibiotics. Paediatric oncology patients with brain tumours face an increased risk of surgical site infection (SSI) after neurosurgery and receive routine PAP in this setting. PATIENTS AND METHODS: All patients younger than 18 years admitted to the paediatric oncology centre (POC) with a neurosurgical intervention. Systematic audit of routine clinical data is divided in two groups: retrospective (Jan 01, 2012-March 31, 2014) and prospective (April 01, 2014-March 31, 2015) referring to an internal PAP guideline, invented in Jan. 2014). Surveillance of SSI up to 30 days after the operation with standard criteria (Centres for Disease Control and Prevention, USA). RESULTS: In total, 53 neurosurgical operations were analysed in 33 paediatric oncology patients. Twelve patients received more than one operation. The detailed analysis of PAP revealed prophylactic cefuroxim doses about 30 mg/kg instead of 50 mg/kg and no repeated dosing in operations lasting longer than 4 h. In addition, Cefotaxim, which is not indicated as PAP in neurosurgery, was used instead of Cefuroxim (or Ampicillin-Sulbactam) in 23 % of all cases in the retrospective and 18 % of all cases in the prospective audit. PAP for more than 3 doses (>24 h) was administered in 66 % in the retrospective group and in 60 % in the prospective group (p = n.s.). In both groups, no SSI was detected. DISCUSSION: This first comprehensive audit of PAP in paediatric oncology patients undergoing neurosurgery outlines significant opportunities to improve clinical practice in terms of correct dosing, the correct choice of the antibiotic, a correct timing schedule and a shorter duration of PAP. In addition, our results illustrate in detail the challenges in clinical practice when an evidence-based approach to improve a standard workflow has to be implemented.

Long-term outcomes in radically treated synchronous vs. metachronous oligometastatic non-small-cell lung cancer.

BACKGROUND: Radical treatment for oligometastatic non-small-cell lung cancer (NSCLC) has a curative potential for selected patients. The present retrospective study was designed to examine the relevance of synchronous vs. metachronous manifestations as a potential prognostic factor when ablative treatments are performed in oligometastatic disease. METHODS: Seventy-five patients with radically treated oligometastatic NSCLC were identified, of whom 39 presented with synchronous and 36 with metachronous metastatic manifestations. For patients with synchronous metastases, an additional therapy of the thoracic locoregional disease with a curative intent (either surgery or radiochemotherapy) was required. All patients with metachronous metastases had a documented remission of the primary tumor. Ablative treatment of the complete extent of oligometastatic disease consisted (as a minimum requirement) of either complete surgical resection or definitive ablative stereotactic radiotherapy. A comparative survival analysis of two groups of patients with oligometastatic NSCLC (synchronous vs. metachronous) and a complementary analysis of prognostic factors for the whole group of patients (by means of Cox regression analysis) was performed. Endpoints were median overall and progression-free survival (OS, PFS, respectively). RESULTS: Of the 75 patients, 57 presented with a solitary metastasis, in only 7 patients metastastatic lesions were present in ≥2 organs and 66 patients had a Karnofsky performance score (KPS) of 80 % or 90 %. The median follow-up was 54.0 months (95 % CI 28-81), the median OS 21.8 months (16.1-27.6) and the median PFS 13.7 months (9.7-17.6). In univariable Cox regression analysis, no single clinical factor was significantly associated with OS. For PFS both 'metastatic involvement of ≥2 organs vs. 1 organ' (hazard ratio (HR) 0.43, 0.23-0.83, p = 0.012) and a 'KPS of 90 % vs. 70-80 %' (HR 4.32, 1.73-10.89, p = 0.02) were significant prognostic factors as calculated by multivariable analysis. Comparing the cohorts with synchronous (n = 39) vs. metachronous oligometastases (n = 36), no differences in median OS and PFS were found. Both cohorts were well-balanced except for the KPS, which was significantly superior in patients with synchronous oligometastases. CONCLUSIONS: Radical treatment of oligometastatic NSCLC was associated with acceptable long-term survival rates in patients with good KPS and it was equally effective for synchronous and metachronous manifestations.

Power calculations and placebo effect for future clinical trials in progressive supranuclear palsy.

BACKGROUND: Two recent randomized, placebo-controlled trials of putative disease-modifying agents (davunetide, tideglusib) in progressive supranuclear palsy (PSP) failed to show efficacy, but generated data relevant for future trials. METHODS: We provide sample size calculations based on data collected in 187 PSP patients assigned to placebo in these trials. A placebo effect was calculated. RESULTS: The total PSP-Rating Scale required the least number of patients per group (N = 51) to detect a 50% change in the 1-year progression and 39 when including patients with ≤ 5 years disease duration. The Schwab and England Activities of Daily Living required 70 patients per group and was highly correlated with the PSP-Rating Scale. A placebo effect was not detected in these scales. CONCLUSIONS: We propose the 1-year PSP-Rating Scale score change as the single primary readout in clinical neuroprotective or disease-modifying trials. The Schwab and England Activities of Daily Living could be used as a secondary outcome. © 2016 International Parkinson and Movement Disorder Society.

Predictors of Societal Costs in Dementia Patients and Their Informal Caregivers: A Two-Year Prospective Cohort Study.

OBJECTIVES: Dementia poses a substantial economic burden on society. Knowing which factors predict high costs in dementia may help to better target interventions and optimize resource allocation. This study aimed to identify predictors of the total societal costs in dementia patients and their informal caregivers. DESIGN: Prospective cohort study with 2-year follow up. SETTING AND PARTICIPANTS: 192 community-dwelling patients with dementia and their primary informal caregivers in the Netherlands. MEASUREMENTS: Data on health care resource utilization, informal carer time and caregivers' work absenteeism were collected by cost diaries and interviews. Predictors of total costs were identified for patient-caregiver dyads, and for patients and informal caregivers separately by performing univariate and multivariate generalized linear models. RESULTS: Societal costs of patient-caregiver dyads averaged €75,084 (SEM: €4,263) in the first year and €99,369 (SEM: €6,441) in the second year. Sixty percent was attributed to costs of informal care. Patient impairments in activities of daily living (ADLs) and instrumental activities of daily living (IADLs), disruptions during daily activities of the caregiver, and receiving case management were significantly associated with higher costs in dyads. The same predictors remained significant for patients' costs separately, and for informal caregivers, a poorer caregiver's quality of life and having more chronic diseases determined higher costs. CONCLUSIONS: The societal costs of dementia are substantial and mainly due to high costs of informal care. The burden for caregivers caused by a disrupted schedule and patients' ADL and IADL dependencies contributed most to the total costs. Interventions targeting these factors effectively might result in relevant economic benefits for society.

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.

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-1ß, 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.

Associations between baseline heart rate and blood pressure and time to events in heart failure with reduced ejection fraction patients: Data from the QUALIFY international registry.

AIMS: A high resting heart rate (RHR) and low systolic blood pressure (SBP) are a risk factor and a risk indicator, respectively, for poor heart failure (HF) outcomes. This analysis evaluated the associations between baseline RHR and SBP with outcomes and treatment patterns in patients with HF and reduced ejection fraction (HFrEF) in the QUALIFY (QUality of Adherence to guideline recommendations for LIFe-saving treatment in heart failure surveY) international registry. METHODS AND RESULTS: Between September 2013 and December 2014, 7317 HFrEF patients with a previous HF hospitalization within 1-15 months were enrolled in the QUALIFY registry. Complete follow-up data were available for 5138 patients. The relationships between RHR and SBP and outcomes were assessed using a Cox proportional hazards model and were analysed according to baseline values as high RHR (H-RHR) ≥75 bpm versus low RHR (L-RHR) <75 bpm and high SBP (H-SBP) ≥110 mmHg versus low SBP (L-SBP) <110 mmHg and analysed according to each of the following four phenotypes: H-RHR/L-SBP, L-RHR/L-SBP, H-RHR/H-SBP and L-RHR/H-SBP (reference group). Compared to the reference group, H-RHR/L-SBP was associated with the worst outcomes for the combined primary endpoint of cardiovascular death and HF hospitalization (hazard ratio [HR] 1.83, 95% confidence interval [CI] 1.51-2.21, p < 0.001), cardiovascular death (HR 2.70, 95% CI 1.69-4.33, p < 0.001), and HF hospitalization (HR 1.62, 95% CI 1.30-2.01, p < 0.001). Low-risk patients with L-RHR/H-SBP achieved more frequently ≥50% of target doses of angiotensin-converting enzyme inhibitors (ACEIs) and beta-blockers (BBs) than the other groups. However, 48% and 46% of low-risk patients were not well treated with ACEIs and BBs, respectively (≤50% of target dose or no treatment). CONCLUSION: In patients with HFrEF and recent hospitalization, elevated RHR and lower SBP identify patients at increased risk for cardiovascular endpoints. While SBP and RHR are often recognized as barriers that deter physicians from treating with high doses of recommended drugs, they are not the only reason leaving many patients suboptimally treated.

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 COVID-19. 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.

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.

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.

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 for patients with Heart Failure with reduced Ejection Fraction (HFrEF). We assessed titration patterns of guideline-recommended HFrEF 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 countries [>18 years, previous HF hospitalization within 1-15 months, left ventricular ejection fraction (LVEF) ≤ 40%] enrolled, with dosage 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). At final 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, higher systolic blood pressure, and in absence of chronic kidney disease or diabetes for ACEIs/ARBs; younger age, higher body mass index, higher heart rate, lower LVEF, and absence of coronary artery disease for BBs. For ivabradine, uptitration was more likely with higher resting heart rate. CONCLUSIONS: The international QUALIFY Registry suggests that few patients with HFrEF achieve target doses of disease-modifying medication, especially older patients and those with co-morbidity. Quality improvement initiatives are urgently required.

Association of Vitamin D Receptor Gene Polymorphisms With Melanoma Risk: A Meta-analysis and Systematic Review.

BACKGROUND/AIM: Increasing evidence indicates a relevance of the vitamin D endocrine system for pathogenesis of malignant melanoma. We performed a systematic review and meta-analysis to update previous reports that investigated the association between vitamin D receptor (VDR) gene polymorphisms and melanoma risk. MATERIALS AND METHODS: A comprehensive literature search (PubMed, ISI Web of Science) identified a total of 14 studies that were eligible for inclusion in our meta-analysis. In the statistical analysis, the ORs and the 95% CIs were calculated for the dominant and recessive models for seven VDR gene polymorphisms, namely rs2228570 (FokI), rs731236 (TaqI), rs1544410 (BsmI), rs4516035 (A-1012G), rs11568820 (Cdx2), rs7975232 (ApaI) and rs739837 (BglI). Results were illustrated in Forest Plots. Publication bias was tested using Funnel Plots and the Egger's test. RESULTS: Our meta-analysis showed in the dominant model (Bb + BB vs. bb) a significant association of a 15% risk reduction in malignant melanoma incidence for carriers of the rarer allele B of rs1544410 (Bsml). Notably, the dominant model (Ff + ff vs. FF) of rs2228570 (FokI) demonstrates that carriers of the rarer allele f are 22% more likely to develop malignant melanoma. For rs7975232 (ApaI), there is a 20% higher risk of melanoma for carriers of the rarer a allele (Aa + aa vs. AA). The results of the meta-analysis revealed no significant association between melanoma risk and the other investigated VDR polymorphisms. CONCLUSION: The VDR variants FokI, ApaI and BsmI may influence the susceptibility to developing melanoma. These findings support the concept, that the vitamin D endocrine system is of importance for pathogenesis of malignant melanoma.

Long-term Results of Differentiated Anatomic Reconstruction of Bicuspid Aortic Valves.

Importance: Bicuspid aortic valve (BAV) repair has been used in limited cohorts, but its long-term results in a large population are unknown. Objectives: To analyze the long-term stability of BAV repair for survival and the factors associated with repair failure and to evaluate whether a differentiated anatomic repair approach may improve repair stability. Design, Setting, and Participants: In this case series, 1024 patients underwent BAV repair for aortic regurgitation or aneurysm between October 1995 and June 2018, with a mean (SD) follow-up time of 56 (49) months and maximum follow-up of 271 months. Systematic modifications in technique based on anatomic principles were introduced in 2009 and applied for the last 727 patients. Data were acquired prospectively and analyzed retrospectively. Exposures: Repair of BAV with or without concomitant aortic replacement, as well as postoperative clinical and echocardiographic follow-up. Main Outcomes and Measures: Survival and incidence of reoperation or recurrent aortic regurgitation, as well as factors associated with valve repair failure. Results: Among the 1024 patients in the study (920 male [89.8%]; mean [SD] age, 47 [13] years [range, 15-86 years]), the survival rate at 15 years was 82.1%. The cumulative incidence of reoperation was 30.7% (95% CI, 22.7%-38.7%) at 15 years. Cusp calcification (subdistribution hazard ratio, 1.78; 95% CI, 1.14-2.77; P = .01), asymmetric commissural orientation (subdistribution hazard ratio, 1.95; 95% CI, 1.02-3.72; P = .04), and use of a pericardial patch for cusp repair (subdistribution hazard ratio, 5.25; 95% CI, 3.52-7.82; P < .001) were associated with time to reoperation. At 10 years, the incidence of reoperation was significantly reduced among patients who received the anatomic repair concept compared with those who had undergone surgery in the earlier period (8.8% vs 24.6%; P < .001). Conclusions and Relevance: This study suggests that survival after BAV repair is excellent and that a large proportion of BAV repairs will remain stable. Repair stability can be markedly improved by an anatomic repair concept. Cusp calcification and the need for cusp repair using a patch remain the factors most strongly associated with valve failure. In those instances, valve replacement should be preferred.