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Objectives Resting heart rate (HR) taken in the office has been shown to be associated with cardiovascular outcomes in the general population, hypertension and heart failure. It is unknown whether 24-h oscillographic pulse rate measurement as an approximation of HR derived from ambulatory blood pressure monitoring (ABPM) associates with cardiovascular outcomes in hypertensive patients. Methods We evaluated ABPM recordings from 56 901 patients with complete 3373 421 HR measures entering the final analysis from the Spanish Blood Pressure Monitoring Registry for a median follow-up time of 5.1 years. We explored the association of office HR, mean 24-h HR, mean day HR, mean night HR as well as day-night HR differences, morning mean HR, morning HR surge and night peak HR to all-cause death, cardiovascular death and noncardiovascular death. Data were analyzed by Cox regression analysis, analysis of variance and chi-square test. Results The Spanish ABPM Registry recorded data in 223 primary care centers in Spain from 2004 until 31 December 2014 at the end of recruitment. Office HR was 3.5 bpm higher than mean 24-h HR, office mean HR versus mean night was 10.4 bpm higher and mean day versus mean night HR 9.3 bpm higher, while there were no relevant difference between office and mean day HR. Office mean, 24-h day and night HR more than 90 bpm were associated with an increased risk for all-cause and noncardiovascular death, whereas for cardiovascular death only mean night HR was predictive. The strongest association to all-cause death was observed with mean night HR [hazard ratio 3.80 (2.87-5.03)], mean 24-h HR [2.85 (2.30-3.54)] and mean day HR [2.22 (1.83-2.70)]. Day-night dipping of more than 8 bpm was associated with a 20% lesser risk on all-cause, cardiovascular and noncardiovascular death. Results were robust after adjusting for relevant risk indicators. Conclusion HR parameters derived from ABPM provide important information, in particular association with death by mean night HR, mean 24-h HR and reduced day-night HR dipping less than 8 bpm superior to office HR.

To evaluate the role of cerebral ultrasonography studies (CUSS) in detecting intracerebral and cranial pathologies (hemorrhages, ischemia, skull fractures) in near-term and term neonates following assisted vaginal delivery. Prospective single-center study (11/2017-11/2018) at the University Children's Hospital of Saarland, Homburg, Germany including newborns with a gestational age ≥ 36 weeks born by assisted vaginal delivery. In all newborns, a standardized CUSS was performed within the first three days of life prior to discharge. 200 neonates (43.0 % female, 57.0 % male; gestational age 39.6 ± 1.3 weeks) were included in this study (birth weight 3345.6 ± 450.6 g, body length 51.7 ± 2.5 cm, head circumference 35.0 ± 1.5 cm). 67 (33.5 %) neonates had minor external injuries of the scalp. 5 children showed clinical neurologic abnormalities: 4 (2.0 %) seizures and 1 facial palsy (0.5 %). In 34 (17.0 %) patients, minor incidental intracranial abnormalities unrelated to mode of delivery were detected on CUSS. No intracerebral, cranial pathologies or skull fractures were seen on routine CUSS. Routine CUSS in newborns after assisted vaginal delivery did not yield clinically relevant results in our cohort. Clinical observation and selective CUSS in symptomatic newborns might be more efficient than routine CUSS.ZIEL: Bewertung der Rolle von zerebralen Ultraschalluntersuchungen (cUS) bei der Erkennung von intrazerebralen und kranialen Pathologien (Blutungen, Ischämie, Schädelfrakturen) bei Neugeborenen nach vaginal-operativer Entbindung kurz vor oder am Termin. Prospektive Studie an einem einzigen Zentrum (11/2017–11/2018) am Universitätskinderklinikum, Homburg, Deutschland, die Neugeborene mit einem Gestationsalter von ≥ 36 Wochen nach vaginal-operativer Entbindung einschließt. Bei allen Neugeborenen wurde innerhalb der ersten drei Lebenstage vor Entlassung ein standardisierter cUS durchgeführt. 200 Neugeborene (43,0 % weiblich, 57,0 % männlich; Gestationsalter 39,6 ± 1,3 Wochen) wurden in diese Studie eingeschlossen (Geburtsgewicht 3345,6 ± 450,6 g, Körperlänge 51,7 ± 2,5 cm, Kopfumfang 35,0 ± 1,5 cm). 67 Neugeborene (33,5 %) hatten leichte, äußere Verletzungen der Kopfhaut. 5 Kinder wiesen klinische neurologische Anomalien auf: 4 Krampfanfälle (2,0 %) und 1 Faszialisparese (0,5 %). Bei 34 Patienten (17,0 %) wurden im cUS geringfügige zufällige intrakraniale Anomalien festgestellt, die nicht mit dem Entbindungsmodus zusammenhingen. Beim Routine-cUS wurden keine intrazerebralen oder kranialen Pathologien oder Schädelfrakturen festgestellt. Routine-cUS bei Neugeborenen nach vaginal-operativer Entbindung erbrachte in unserer Kohorte keine klinisch relevanten Ergebnisse. Klinische Beobachtung und selektiver cUS sind bei symptomatischen Neugeborenen möglicherweise effizienter als routinemäßiger cUS.

Radical nephroureterectomy is the gold standard of treatment for high-risk non-metastatic urothelial carcinoma of the upper urinary tract. However, the optimal surgical approach remains a controversial debate. This study compared the perioperative and oncological outcomes of open and robot-assisted radical nephroureterectomies.131 consecutive radical nephroureterectomies (66 robot-assisted nephroureterectomies vs. 65 open nephroureterectomies) for urothelial carcinoma of the upper urinary tract at a single tertiary referral center were included from 2009 to 2019. The perioperative and oncological outcomes were compared between both surgical approaches, including logistic regression analysis, propensity score matching, Kaplan Meier analyses, and Cox regression models.Overall, robot-assisted surgery had less blood loss (150 ml vs. 250, p = 0.004) and less positive surgical margins (1.5% vs. 15.4%, p = 0.004) at a comparable operating time (robotic 188min vs. 178). Any grade complications were more frequent after open surgery (40.9% vs. 63.1%, p = 0.011), and the length of stay was shorter after robotic nephroureterectomy (9 days vs. 12, p 0.001). These differences remained significant in the propensity score matched analysis, except for the complication rates, which were still lower for the robotic approach, but no longer significant. At a median follow-up of 30.9 months (range 1.4-129.5), neither the progression-free survival (PFS, 2-year: robotic 66.7% vs. open 55.3%), nor the overall survival differed significantly (OS, 2-year: robotic 76.2% vs. open 68.4%). In the Cox regression, the surgical approach did not impact the PFS or OS. Lymph node metastases (HR 3.32, p = 0.008) had the strongest impact on the PFS besides patient age (HR 1.51 per 10 years, p = 0.025) and prior cystectomy (HR 2.42, p = 0.026) in the multivariate analysis.Robot-assisted radical nephroureterectomy had significant perioperative advantages at comparable oncological outcomes compared to open surgery for the treatment of urothelial carcinoma of the upper urinary tract at a high volume center, experienced in robotic surgery.

The pathogenesis of autoimmune complications triggered by SARS‐CoV2 has not been completely elucidated. Here, we performed an analysis of the cellular immune status, cell ratios, and monocyte populations of patients with COVID‐19 treated in the intensive care unit (ICU) (cohort 1, N = 23) and normal care unit (NCU) (cohort 2, n = 10) compared with control groups: patients treated in ICU for noninfectious reasons (cohort 3, n = 30) and patients treated in NCU for infections other than COVID‐19 (cohort 4, n = 21). Patients in cohort 1 presented significant differences in comparison with the other cohorts, including reduced frequencies of lymphocytes, reduced CD8+T‐cell count, reduced percentage of activated and intermediate monocytes and an increased B/T8 cell ratio. Over time, patients in cohort 1 who died presented with lower counts of B, T, CD4+T, CD8+T‐lymphocytes, NK cells, and activated monocytes. The B/T8 ratio was significantly lower in the group of survivors. In cohort 1, significantly higher levels of IgG1 and IgG3 were found, whereas cohort 3 presented higher levels of IgG3 compared to controls. Among many immune changes, an elevated B/T8‐cell ratio and a reduced rate of activated monocytes were mainly observed in patients with severe COVID‐19. Both parameters were associated with death in cohort 1., Patients with severe COVID‐19 present a particular set of immune changes in comparison to patients with mild disease and controls. These include consumption of certain monocyte and lymphocyte populations and an elevated B/T8 Ratio. COVID‐19 patients in general share a proinflammatory immunoglobulin profile with elevated proportions of IgG1 and/or IgG3.

Background Alpha-1-antitrypsin deficiency (AATD) is a rare genetic disorder that is associated with low levels of circulating alpha-1-antitrypsin in serum. In comparison to the genotype PiZZ, PiSZ usually leads to lower risk of emphysema, better lung function and better survival. The aim of this study was to analyze the relationship between cigarette smoking (packyears) and the AATD genotypes (PiZZ and PiSZ) concerning quality of life (SGRQ), transfer factor of the lung for carbon monoxide (TLCO), forced expiratory volume in one second (FEV 1 ) and exacerbation rate. Methods We compared PiZZ and PiSZ individuals from the German registry for individuals with AATD (AATDR) in univariate analysis and multivariate linear regression models. All subjects were stratified into three groups according to their cumulative nicotine consumption (0 py; 0 Results 868 PiZZ individuals (mean age 52.6 ± 12.8 years (43.5% female)) and 114 PiSZ individuals (mean age 50.3 ± 17.4 years (46.5% female)) were compared. In contrast to never- and intensive (ex-) smokers, moderate (ex-) smoking PiSZ individuals had a significantly better SGRQ total score (B = −8.148; p = 0.020) and less exacerbations (B = −0.354; p = 0.037) than individuals with PiZZ in multivariate analysis. Conclusions The differences in quality of life and exacerbation frequency between PiZZ and PiSZ individuals diminish by intensive (ex-) smoking.

Background and aims Data of experimental rodent models suggest that hypoxia with subsequent increase in erythropoietin stimulates the expression of the phosphaturic hormone fibroblast growth factor 23 (FGF23). Methods and results To translate the findings of animal studies into human physiology, herein we exposed eight healthy volunteers to high altitude (2656 m above sea level) for four days. The volunteers were randomized on a low-phosphorous diet (n = 4) or a normal phosphorus diet (n = 4). Although high-altitude exposure caused a significant increase in plasma erythropoietin (EPO) (before high-altitude exposure: low phosphorus: median EPO 6.6 mIU/ml [interquartile range (IQR) 6.0; 8.2], normal phosphorus: median EPO 9.0 mIU/ml [IQR 7.9; 11.5]; at day 2: low phosphorus: median EPO 21.3 mIU/ml [IQR 19.5; 23.8], normal phosphorus: median EPO 19.4 mIU/ml [IQR 18.0; 20.8]), there was no consistent increase in plasma c-terminal FGF23 or plasma intact FGF23. We observed only a single, intermittent peak in c-terminal FGF23 levels after 5 h of maximal aerobic exercise. Conclusion These data do not support a substantial effect of moderate hypoxia alone on the expression of FGF23, but they suggest that combined exercise and high-altitude exposure may temporarily induce FGF23 expression.

Epidemiological and clinical studies have shown a relevant association between heart rate and cardiovascular mortality. Experimental studies identified vascular effects of heart rate reduction with the If channel inhibitor ivabradine. Therefore, the effects of heart rate reduction on endothelial function and indices of arterial stiffness were examined in patients with stable coronary artery disease in a prospective, placebo-controlled clinical crossover study.Twenty-three patients (18 men and 5 women) with a resting heart rate (HR) of at least 70 beats per minute (bpm) and stable coronary artery disease were enrolled in this study. In a cross-over design, all patients were treated with ivabradine (Iva, 7.5 mg b.i.d.) and placebo for 6 months each. Iva reduced heart rate by 11.4 bpm (Iva 58.8 ± 8.2 bpm vs. placebo 70.2 ± 8.3 bpm, P 0.0001). Augmentation index (AIx75), carotid-femoral pulse wave velocity (cfPWV) and central aortic blood pressure were measured using applanation tonometry (SphygmoCor). HRR by Iva increased AIx75 by 12.4% (Iva 24.3 ± 10.5% vs. placebo 21.3 ± 10.1%, P 0.05) and reduced cfPWV by 14.1% (Iva 6.3 ± 1.7 m/s vs. placebo 7.3 ± 1.4 m/s, P 0.01). Iva increased mean central blood pressure by 7.8% (Iva 107.5 ± 15.4 mmHg vs. placebo 99.1 ± 12.2 mmHg, P 0.001). Endothelial function was determined measuring the flow-mediated vasodilation (FMD) of the brachial artery. HRR by Iva increased FMD by 18.5% (Iva 7.3 ± 2.2% vs. placebo 6.0 ± 2.0%, P 0.001). Aortic distensibility was characterized by MRI. HRR by Iva increased aortic distensibility by 33.3% (Iva 0.003 ± 0.001/mmHg vs. placebo 0.002 ± 0.010/mmHg, P 0.01) and circumferential cyclic strain by 37.1% (Iva 0.062 ± 0.027 vs. placebo 0.039 ± 0.018, P 0.0001).Heart rate reduction with Iva increased endothelium-dependent vasodilation and reduced arterial stiffness in patients with stable CAD. These findings corroborate and expand the results collected in experimental studies and indicate the importance of heart rate as a determinant of vascular function.

The aim of this study was to develop clinical preoperative, intraoperative, and postoperative scores for early identification of patients who are at risk of nonocclusive mesenteric ischemia (NOMI).A retrospective analysis.Single center.From January 2008 to December 2014, all patients from the Department of Thoracic and Cardiovascular Surgery were included on the basis of the hospital database.All mesenteric angiographically identified NOMI patients were compared with non-NOMI patients.The study population of 8,748 patients was randomized into a cohort for developing the scores (non-NOMI 4,214 and NOMI 235) and a cohort for control (non-NOMI 4,082 and NOMI 217). Risk factors were identified using forward and backward Wald test and were included in the predictive scores for the occurrence of NOMI. C statistic showed that the scores had a high discrimination for the prediction of NOMI preoperatively (C statistic 0.79; p0.001), intraoperatively (C statistic 0.68; p0.001), and postoperatively (C statistic 0.85; p0.001). A combination of the preoperative, intraoperative, and postoperative risk scores demonstrated the highest discrimination (C statistic 0.87; p0.001). The combined score included the following risk factors: renal insufficiency (preoperative); use of cardiopulmonary bypass and intra-aortic balloon pump support (intraoperative); and reexploration for bleeding, renal replacement therapy, and packed red blood cells ≥ 4 units (postoperative). The results were similar in the control group.These scores could be useful to identify patients at risk for NOMI and promote a rapid diagnosis and therapy.

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.

Background Effective antimicrobial treatment is key to reduce mortality associated with bacterial sepsis in patients on intensive care units (ICUs). Dose adjustments are often necessary to account for pathophysiological changes or renal replacement therapy. Extracorporeal membrane oxygenation (ECMO) is increasingly being used for the treatment of respiratory and/or cardiac failure. However, it remains unclear whether dose adjustments are necessary to avoid subtherapeutic drug levels in septic patients on ECMO support. Here, we aimed to evaluate and comparatively assess serum concentrations of continuously applied antibiotics in intensive care patients being treated with and without ECMO. Methods Between October 2018 and December 2019, we prospectively enrolled patients on a pneumological ICU in southwest Germany who received antibiotic treatment with piperacillin/tazobactam, ceftazidime, meropenem, or linezolid. All antibiotics were applied using continuous infusion, and therapeutic drug monitoring of serum concentrations (expressed as mg/L) was carried out using high-performance liquid chromatography. Target concentrations were defined as fourfold above the minimal inhibitory concentration (MIC) of susceptible bacterial isolates, according to EUCAST breakpoints. Results The final cohort comprised 105 ICU patients, of whom 30 were treated with ECMO. ECMO patients were significantly younger (mean age: 47.7 vs. 61.2 years; p Conclusions ECMO treatment was associated with significantly reduced serum concentrations of specific antibiotics. Future studies are needed to assess the pharmacokinetic characteristics of antibiotics in ICU patients on ECMO support.

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.

Purpose Vaginal cuff dehiscence (VCD) is one of the major surgical complications following hysterectomy with data on incidence rates varying largely and studies assessing risk factors being sparse with contradictive results. The aim of this study was to assess the incidence rate of and risk factors for VCD in a homogenous cohort of women treated for benign uterine pathologies via total laparoscopic hysterectomy (TLH) with standardized follow-up. Methods All patients undergoing TLH at the Department of Gynecology and Obstetrics, Saarland University Hospital between November 2010 and February 2019 were retrospectively identified from a prospectively maintained service database. Results VCD occurred in 18 (2.9%) of 617 patients included. In univariate and multivariate analyses, a lower level of surgeon laparoscopic expertise (odds ratio 3.19, 95% confidence interval (CI) 1.0–9.38; p = 0.03) and lower weight of removed uterus (odds ratio 0.99, 95% CI 0.98–0.99; p = 0.02) were associated positively with the risk of VCD. Conclusion In this homogenous cohort undergoing TLH, laparoscopic expertise and uterine weight influenced the risk of postoperative VCD. These findings might help to further reduce the rate of this complication.

OBJECTIVES: The objective of the study is to determine the impact of changing reference standards (RS), namely spirometry vs. whole-body plethysmography (WBP), on estimation of the diagnostic accuracy of fractional exhaled nitric oxide (FeNO) and clinical signs and symptoms (CSS) as index tests regarding asthma diagnosis. STUDY DESIGN AND SETTING: This was a diagnostic study conducted in 393 patients attending a private practice of pneumologists with complaints suspicious of asthma. First, the index tests were compared with the diagnostic results of spirometry in terms of forced expiratory volume in the first second (FEV1) responsiveness. Second, the index tests were compared with the results of WBP in terms of specific airway resistance and FEV1 responsiveness. Areas under the curve (AUC) were compared with a generalized estimating equation approach based on binary logistic regression. RESULTS: FeNO values and CSS 'wheezing' and 'allergic rhinitis' showed higher specificities (P

Background and Purpose: This randomized study aimed to evaluate whether the use of a stroke clock demanding active feedback from the stroke physician accelerates acute stroke management. Methods: For this randomized controlled study, a large-display alarm clock was installed in the computed tomography room, where admission, diagnostic work-up, and intravenous thrombolysis occurred. Alarms were set at the following target times after admission: (1) 15 minutes (neurological examination completed); (2) 25 minutes (computed tomography scanning and international normalized ratio determination by point-of-care laboratory completed); and (3) 30 minutes (intravenous thrombolysis started). The responsible stroke physician had to actively provide feedback by pressing a buzzer button. The alarm could be avoided by pressing the button before time out. Times to therapy decision (primary end point, defined as the end of all diagnostic work-up required for decision for or against recanalizing treatment), neurological examination, imaging, point-of-care laboratory, needle, and groin puncture were assessed by a neutral observer. Functional outcome (modified Rankin Scale) was assessed at day 90. Results: Of 107 participants, 51 stroke clock patients exhibited better stroke-management metrics than 56 control patients. Times from door to (1) end of all indicated diagnostic work-up (treatment decision time; 16.73 versus 26.00 minutes, P P P =0.002), (4) end of computed tomography angiography (14.00 versus 17.17 minutes, P =0.001), (5) end of point-of-care laboratory testing (12.14 versus 20.00 minutes, P P =0.016) were improved. In contrast, door-to-groin puncture times and functional outcomes at day 90 were not significantly different. Conclusions: This study showed that the use of a stroke clock demanding active feedback significantly improves acute stroke-management metrics and, thus, represents a potential low-cost strategy for streamlining time-sensitive stroke treatment.

Background Angiotensin-converting enzyme (ACE) 2 is known to be a functional receptor for SARS-CoV-2 in the current pandemic. Soluble ACE2 (sACE2) concentrations are elevated in patients with various cardiovascular disorders including heart failure. Methods In a total of 182 consecutive adult patients with complex congenital heart disease (CHD) and 63 healthy controls, sACE2 concentrations were measured in serum using the Human ACE2® assay by Cloud-Clone Corporation and associated with clinical, laboratory and echocardiographic parameters. Results Median sACE2 levels were increased in patients with complex CHD as compared to healthy controls (761.9 pg/ml vs 365.2 pg/ml, p p p = 0.002) and lower sACE2 levels with the use of ACE inhibitors or ARB (p = 0.001). Conclusion Soluble ACE2 concentrations were significantly increased in all types of complex CHD with highest levels found in patients with NYHA class ≥ III. Moreover, a higher NYHA class ≥ III was the most significant determinant that was independently associated with elevated sACE2 concentrations. Graphic abstract

Background In patients with iron deficiency anemia, ferric carboxymaltose (FCM) and ferric derisomaltose (FDI) allow high-dose iron repletion. While FCM is reported to induce hypophosphatemia, the frequency of hypophosphatemia after an equivalent dosage of FDI had not been assessed prospectively. Methods In the prospective, single-center, double-blind HOMe aFers study, 26 women with iron deficiency anemia (hemoglobin Results Hypophosphatemia occurred more frequently in women treated with FCM (9 out of 12 [75%]) than in those treated with FDI (1 out of 13 [8%]; p = 0.001). Within 24 h after iron supplementation, women in the FCM group had significant higher plasma intact FGF23 (p p p = 0.021 at day 7 ± 2 after iron supplementation). We did not observe differences in skeletal and cardiovascular markers, potentially because of the limited number of participants. Conclusions While both FCM and FDI provide efficient iron repletion in participants with iron deficiency anemia, FCM induced hypophosphatemia more often than FDI. Trial registration Clinical Trials.gov NCT02905539. Registered on 8 September 2016. 2015-004808-36 (EudraCT Number) U1111-1176-4563 (WHO Universal Trial Number) DRKS00010766 (Deutsches Register Klinischer Studien)

After national recommendations, palivizumab is administered in Germany to high-risk infants to prevent hospitalizations related to respiratory syncytial virus (RSV) infection. Limited data are available to characterize those children who receive palivizumab in 2 consecutive RSV seasons.This was a comparative analysis of data from a postmarketing observational study (German SYNAGIS Registry, AbbVie Germany GmbHCo.KG, Wiesbaden) detailing RSV-related risk factors and main indications for palivizumab in 920 children who received at ≥1 palivizumab injection in a second season between 2010 and 2016 [second season population (SSP)].Median birth weight and gestational age at birth as well as the proportion of children with hemodynamically significant congenital heart disease, with any form of chronic lung disease of prematurity or with any form of neuromuscular impairment, were significantly higher in the SSP. Accordingly, hemodynamically significant congenital heart disease, chronic lung disease and other reasons (including neuromuscular impairment) and not prematurity were the main indications for palivizumab in the SSP. The RSV-related hospitalization rate confirmed by viral testing in the SSP (receiving palivizumab prophylaxis) was 0.9%. No deaths due to RSV were reported.Second season recipients of palivizumab differ from one season recipients of palivizumab in terms of risk factors and main indications for prophylaxis. Keeping in mind the limitations of an uncontrolled prospective observational study, these results support the effectiveness of palivizumab (concerning the RSV rehospitalization rate) and do not reveal new safety alerts in a large SSP.

To prospectively evaluate the relationship of established inflammatory markers and presepsin on nonocclusive mesenteric ischemia and to correlate presepsin levels to the occurrence and severity of nonocclusive mesenteric ischemia.Patients were prospectively enrolled and blood samples taken, followed by a retrospective evaluation of laboratory values and angiographic findings. The study was ethics committee approved.Patients with clinical suspicion of nonocclusive mesenteric ischemia underwent catheter angiography of the superior mesenteric artery. Images were assessed by two experienced radiologists on consensus basis using a previously published standardized reporting system (Homburg-Nonocclusive Mesenteric Ischemia-Score). Two groups were formed according to the severity of nonocclusive mesenteric ischemia, mild and severe, patients without clinical signs of nonocclusive mesenteric ischemia formed the reference group. These data were correlated to inflammatory blood markers assessed pre- and postoperatively: C-reactive protein, leucocytes, procalcitonin, and presepsin as well as outcome data.Between January 2010 and March 2011, a total of 839 patients undergoing cardiovascular surgery participated in this study.Mild nonocclusive mesenteric ischemia was diagnosed in 4.5%, and severe nonocclusive mesenteric ischemia in 3.2%. Median postoperative presepsin concentrations were significantly greater in mild and severe nonocclusive mesenteric ischemia than in non-nonocclusive mesenteric ischemia. Statistics showed that postoperative presepsin better discriminated mild and severe nonocclusive mesenteric ischemia than any other tested biomarker.Elevated postoperative plasma presepsin concentrations are an independent predictor of mild and severe nonocclusive mesenteric ischemia. The established inflammatory blood markers significantly correlate with the development and severity of nonocclusive mesenteric ischemia.

Background Knowledge of the anatomical dimensions of distinct areas of the vertebral bodies and vertebral arches of the subaxial cervical spine are indispensable in the planning of osteosynthesis. The minute dimensions and complex anatomical orientation of the posterior vertebral arch structures in the subaxial spine render the insertion of screws - where needed - a challenging procedure. The pedicle option carries the risk of serious complications while the alternative of lateral mass only permits the insertion of short screws. Objective The transverse process of the subaxial vertebrae offers unique possibilities on all counts and seems quite comparable in its dimensions with the pedicle. To our knowledge it has not been used previously for the insertion of screws in the subaxial spine. Methods Therefore, the scans of 66 cervical spines were analysed for distinct lines of both structures. Results The widths and lengths of the dorsal part of the transverse processes and of the pedicles are similar between both sides. Clear differences between females and males could be observed. The widths of both structures were closer to each other in C3 than in C4 to C7, while the lengths derived the most in C7. Conclusion The dorsal part of the transverse process might be suitable for the insertion of screws to stabilize the vertebral arch of the subaxial cervical spine. Gender adaptation might be required.

To our knowledge, there is no German study, which has examined the relationship between a postponement of surgery (from emergency service to standard working time) and the corresponding risk of postoperative complications in children and adolescents with acute appendicitis. The aim of this study is to examine if surgery of acute appendicitis in childhood can be postponed from night shift to the next working day without negative effects for the patient. In a retrospective analysis (September 2001 to June 2007), the files of 225 paediatric surgical patients with acute appendicitis have been analysed concerning history, histology, course of treatment and development of complications. The cohort was divided into groups by their histology (common, “A”, complicated appendicitis, “B”) and by the median time (10 h) from admission to surgery (immediate, “C”, delayed surgery, “D”). These groups have been analysed and compared. Groups A and B did not differ concerning time to admittance (p = 0.922). Seven patients developed complications (n = 7/225, 3.1%). Six complications were seen in group C (n = 6/113, 5.3%) compared to 1 in group D (n = 1/112, 0.9%), the difference was not significant (p = 0.119). None of the patients of group B developed complications after delayed surgery. Median follow-up was 10 days (IQR 7–15). In view of the development of complications, there was no evidence that the time between inpatient admission and surgery had any impact on the postoperative result. Thus, there is usually no need to perform surgery in common appendicitis during night shift.

Nikolas Bernhard,1 Philipp M Lepper,1 Claus Vogelmeier,2 Martina Seibert,1 Stefan Wagenpfeil,3 Robert Bals,1 Sebastian Fähndrich1 1Department of Internal Medicine V – Pulmonology, Allergology, Intensive Care Medicine, Saarland University Hospital, Homburg, 2Department of Medicine, Pulmonary and Critical Care Medicine, University Medical Center Giessen and Marburg, Philipps-University Marburg, Member of the German Center for Lung Research (DZL), 3Faculty of Medicine, Institute of Medical Biometry, Epidemiology and Medical Informatics, Saarland University, Campus Homburg, Germany Background: Alpha-1-antitrypsin deficiency (AATD) is a rare hereditary disease that is associated with a higher risk to develop chronic obstructive pulmonary disease and liver cirrhosis. Previous cross-sectional studies on AATD individuals have shown a relationship between worse St George’s Respiratory Questionnaire (SGRQ) scores and elevated exacerbation rate or high cigarette consumption. There is a lack of longitudinal data on the relationship between the exacerbation rate and worsening of SGRQ during disease. The aim of this study was to provide not only cross-sectional data but also information about the deterioration in quality of life over a follow-up period up to 7 years (median follow-up period of 3.33 years).Methods: We investigated questionnaire-based data of the German AATD registry concerning the relationship between SGRQ and exacerbation frequency, smoking history, forced expiratory volume in 1 second (FEV1) and carbon monoxide diffusion capacity (DLCO) first in cross-sectional analysis and later in longitudinal analysis.Results: Eight hundred sixty-eight individuals with protease inhibitor ZZ (PiZZ) genotype with an average age of 52.6±12.8 years had an SGRQ score of 45.7±20.6. SGRQ significantly correlated with the exacerbation frequency within the last 2 years (r=0.464; P

Only limited data are available on the extent of the vasa vasorum of the human thoracic aorta, although this could be important with regard to certain pathophysiological states, i.e. aortic aneurysm or atherosclerosis. A preliminary investigation shows that the vascularization of the human thoracic aorta reaches deeper layers than generally believed.

Background One of the known weaknesses of spirometry is its dependence on patients’ cooperation, which can only partially be alleviated by educational efforts. Therefore, procedures less dependent on cooperation might be of value in clinical practice. We investigated the diagnostic accuracy of ultrasound-based capnovolumetry for the identification of airway obstruction. Methods Consecutive patients from a pulmonary outpatient clinic were included in the diagnostic study. As reference standard, the presence of airway obstruction was evaluated via spirometry and bodyplethysmography. Capnovolumetry was performed as index test with an ultrasound spirometer providing a surrogate measure of exhaled carbon dioxide. Receiver operating characteristic (ROC) analysis was performed using the ratio of slopes of expiratory phases 3 and 2 (s3/s2) ≥ 0.10 as primary capnovolumetric parameter for the recognition of airway obstruction. Logistic regression was performed as secondary analysis to identify further useful capnovolumetric parameters. The diagnostic potential of capnovolumetry to identify more severe degrees of airway obstruction was evaluated additionally. Results Of 1400 patients recruited, 1287 patients were included into the analysis. Airway obstruction was present in 29% of patients. The area under the ROC-curve (AUC) of s3/s2 was 0.678 (95% CI 0.645, 0.710); sensitivity of s3/s2 ≥ 0.10 was 47.7 (95% CI 42.7, 52.8)%, specificity 79.0 (95% CI 76.3, 81.6)%. When combining this parameter with three other parameters derived from regression analysis (ratio area/volume phase 3, slope phase 3, volume phase 2), an AUC of 0.772 (95% CI 0.743, 0.801) was obtained. For severe airway obstruction (FEV1 ≤ 50% predicted) sensitivity of s3/s2 ≥ 0.10 was 75.9 (95% CI 67.1, 83.0)%, specificity 75.8 (95% CI 73.3, 78.1)%; for very severe airway obstruction (FEV1 ≤ 30% predicted) sensitivity was 86.7 (95% CI 70.3, 94.7)%, specificity 72.8 (95% CI 70.3, 75.2)%. Sensitivities increased and specificities decreased considerably when the combined capnovolumetric score was used as index test. Conclusions Capnovolumetry by way of an ultrasound spirometer had a statistically significant albeit moderate potential for the recognition of airway obstruction in a heterogeneous population of patients typically found in clinical practice. Diagnostic accuracy of the capnovolumetric device increased with the severity of airway obstruction. Trial registration The study is registered under DRKS00013935 at German Clinical Trials Register (DRKS).

The aim of this retrospective single-center study was to examine ultrasound-detected complications after diagnostic parenchymal renal biopsies. After 471 ultrasound-guided kidney biopsies (225 native kidneys and 246 renal allografts), ultrasound revealed hematomas (21.9%), arterio-venous fistulas (8.9%), active bleeding (1.1%) and hematuria (0.4%). Only 0.8% of all patients required invasive intervention such as coiling (n = 3) and surgical procedures (n = 1). Three episodes of bleeding (0.6%) were solved with manual compression. One patient (0.2%) needed an irrigation catheter because of hematuria. Furthermore, six patients (1.3%) received blood transfusion. Ultrasound-guided biopsies are safe. With modern ultrasound machines using multi-frequency transducers with high resolution and harmonic imaging, even marginal bleeding after renal biopsy is detected.

Recent findings strongly support a role for small regulatory RNAs in the regulation of human lifespan yet little information exists about the precise underlying mechanisms. Although extensive studies on model organisms have indicated that reduced activity of the nutrient response pathway, for example as a result of dietary restriction, can extend lifespan through the suppression of the protein kinase mechanistic target of rapamycin (mTOR), it still is subject of debate whether this mechanism is operative in humans as well. Here, we present findings indicating that human microRNA (miR)-496 targets 2 sites within the human mTOR 3'UTR. Coexpression of miR-496 with different fusion transcripts, consisting of the luciferase transcript and either wild-type mTOR 3'UTR or mTOR 3'UTR transcript with the miR-496 binding sites singly or combined mutated, confirmed this prediction and revealed cooperativity between the 2 binding sites. miR-496 reduced the mTOR protein level in HeLa-K cells, and the levels of miR-496 and mTOR protein were inversely correlated in Peripheral Blood Mononuclear Cells (PBMC), with old individuals (n = 40) harbouring high levels of miR-496 relative to young individuals (n = 40). Together, these findings point to the possibility that miR-496 is involved in the regulation of human aging through the control of mTOR.

Catheter-related infections are a serious complication of continuous thoracic epidural analgesia. Tunnelling catheters subcutaneously may reduce infection risk. We thus tested the hypothesis that tunnelling of thoracic epidural catheters is associated with a lower risk of catheter-related infections.Twenty-two thousand, four hundred and eleven surgical patients with continuous thoracic epidural analgesia included in the German Network for Regional Anaesthesia registry between 2007 and 2014 were grouped by whether their catheters were tunnelled (n=12 870) or not (n=9541). Catheter-related infections in each group were compared with Student's unpaired t and χ(2) tests. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated with logistic regression, adjusting for potential confounding factors, including age, ASA physical status score, use of catheter for ≥4 days, multiple skin puncture, hospital, and surgical department.There were fewer catheter-related infections in patients with tunnelled catheters (4.5 vs 5.5%, P0.001). Mild infections were also less common (4.0 vs 4.6%, P=0.009), as were moderate infections (0.4 vs 0.8%, P0.001). After adjustment for potential confounding factors, tunnelling remained an independent prevention for any grade of infection (adjusted OR 0.51, 95% CI 0.42-0.61, P0.001) and for mild infections (adjusted OR 0.54, 95% CI 0.43-0.66, P0.001) and moderate and severe infections (adjusted OR 0.44, 95% CI 0.28-0.70, P=0.001).Tunnelling was associated with a lower risk of thoracic epidural catheter-related infections.

Cardiac surgery is associated with a high risk of postoperative acute kidney injury (AKI) and subsequent loss of kidney function. We explored the clinical utility of urinary dickkopf-3 (DKK3), a renal tubular stress marker, for preoperative identification of patients at risk for AKI and subsequent kidney function loss.This observational cohort study included patients who had cardiac surgery in a derivation cohort and those who had cardiac surgery in a validation cohort (RenalRIP trial). The study comprised consecutive patients who had elective cardiac surgery at the Saarland University Medical Centre (Homburg, Germany; derivation cohort) and those undergoing elective cardiac surgery (selected on the basis of a Cleveland Clinical Foundation score of 6 or higher) who were enrolled in the prospective RenalRIP multicentre trial (validation cohort) and who were randomly assigned to remote ischaemic preconditioning or a sham procedure. The association between the ratio of preoperative urinary concentrations of DKK3 to creatinine (DKK3:creatinine) and postoperative AKI, defined according to the Kidney Disease Improving Global Outcomes criteria, and subsequent kidney function loss, as determined by estimated glomerular filtration rate, was assessed.In the 733 patient in the derivation cohort, urinary concentrations of DKK3 to creatinine that were higher than 471 pg/mg were associated with significantly increased risk for AKI (odds ratio [OR] 1·65, 95% CI 1·10-2·47, p=0·015), independent of baseline kidney function. Compared with clinical and other laboratory measurements, urinary concentrations of DKK3:creatinine significantly improved AKI prediction (net reclassification improvement 0·32, 95% CI 0·23-0·42, p0·0001). High urinary DKK3:creatinine concentrations were independently associated with significantly lower kidney function at hospital discharge and after a median follow-up of 820 days (IQR 733-910). In the RenalRIP trial, preoperative urinary DKK3:creatinine concentrations higher than 471 pg/mg were associated with a significantly higher risk for AKI (OR 1·94, 95% CI 1·08-3·47, p=0·026), persistent renal dysfunction (OR 6·67, 1·67-26·61, p=0·0072), and dialysis dependency (OR 13·57, 1·50-122·77, p=0·020) after 90 days compared with DKK3:creatinine concentrations of 471 pg/mg or less. Urinary DKK3:creatinine concentrations higher than 471 pg/mg were associated with significantly higher risk for AKI (OR 2·79, 95% CI 1·45-5·37) and persistent renal dysfunction (OR 3·82, 1·32-11·05) only in patients having a sham procedure, but not remote ischaemic preconditioning (AKI OR 1·35, 0·76-2·39 and persistent renal dysfunction OR 1·05, 0·12-9·45).Preoperative urinary DKK3 is an independent predictor for postoperative AKI and for subsequent loss of kidney function. Urinary DKK3 might aid in the identification of patients in whom preventive treatment strategies are effective.No study funding.

Prognostic markers for the definition of the individual metastatic risk in renal cell carcinoma are still missing. The aim of our study was to establish a total number of specific aberrations (TNSA) genetic score as a new prognostic test for metastatic risk evaluation. Fluorescence in situ hybridization (FISH) was performed on isolated cell nuclei of 100 ccRCCs (50 M1/50 M0) and 100 FFPE sections (second cohort, 32 M1/68 M0). For each chromosomal region (1q21.3, 7q36.3, 9p21.3p24.1, 20q11.21q13.32) cut-off values were determined by receiver-operator curve (ROC)-curve analysis. TNSA was calculated based on the dichotomized specific CNVs. The prognostic significance of CNVs was proven by Cox and logistic regression. TNSA was the best predictor of metastasis and recurrence free survival in both cohorts. We derived an algorithm for risk stratification by combining TNSA and T-category, which increased the prognostic accuracy to 87% (specificity = 86%, sensitivity = 88%). This model divides patients into two risk groups with significantly different RFS, CSS, and OS (P = 3.8×10-5 , P = 5×10-6 and P = 3.57×10-8 respectively). The genetic risk model was superior to Leibovich score and was able to identify patients with metachronous metastatic spread which were incorrectly classified as "low" or "intermediate risk." We present a new tool for individual risk stratification by combining genetic alterations with clinico-pathologic parameters. Interphase FISH proves to be a dependable method for prognostic evaluation in primary tumor tissue on isolated cell nuclei as well as on FFPE sections. Especially in organ-confined tumors the genetic score seems to be an important tool to identify patients at high risk for metastatic disease.

INTRODUCTION Allograft rejection (AR), chronic allograft injury (CAI) and acute tubular necrosis (ATN) can lead to renal allograft dysfunction after kidney transplantation. Interstitial fibrosis/tubular atrophy (Banff classification 2005) describes chronic allograft injury with no specific etiology, thus explaining the common final endpoint of various (immunologic and non immunologic) etiologies. The aim of this study was to evaluate correlations between the Doppler sonographic RI-values and histopathological changes of renal allografts biopsies during rejection, acute tubular necrosis and chronic allograft injury as well as the influence of donor and recipient features on the intrarenal RI-values. METHODS 102 allograft biopsies and ultrasound reports of 69 patients with kidney transplantation performed at the hospital Klinikum rechts der Isar (Technische Universitat Munchen, Germany) between 2009 and 2013 were analyzed retrospectively (41 biopsies of living donors, 61 biopsies of deceased donors). Chronic allograft injury was described using the IFTA (interstitial fibrosis and tubular atrophy) or the ECAI score (extended chronic allograft injury score). The ECAI score was built out of the chronic histological lesions glomerulopathy, interstitial fibrosis, tubular atrophy and fibrous intimal thickening (cg + ci + ct + cv) of the BANFF scoring. RESULTS Intrarenal RI-values were significantly higher in patients with allograft rejection than without rejection (median 0,79 vs. 0,73; inter quartile range: 0,20 vs. 0,13; p = 0,018). The same was found for T-and non-T cell mediated rejection (median 0,78 vs. 0,73; inter quartile range 0,20 vs. 0,13; p = 0,039). There were no significant differences in the RI-values between the subtypes of T-cell mediated rejection (type IA-IIB). Furthermore, there were no significant differences of RI-values regarding antibody-mediated rejection (present vs. not present) or type of rejection (T-cell- vs. antibody mediated rejection). Patients with rejection and simultaneously chronic allograft injury showed significantly higher RI-values than patients with only chronic allograft injury. Analyses using the IFTA or the ECAI score showed comparable results (IFTA p = 0,043; Score p = 0,021). The intrarenal RI-value was neither able to detect chronic allograft injury nor to distinguish between acute tubular necrosis and rejection. The intrarenal RI-value showed a significant correlation with recipient age (p

Background The individual course of CKD may vary, and improved methods for identifying which patients will experience short-term eGFR loss are needed. Assessing urinary Dickkopf-3 (DKK3), a stress-induced tubular epithelia–derived profibrotic glycoprotein, may provide information about ongoing tubulointerstitial fibrosis and short-term eGFR loss. Methods To investigate urinary DKK3’s potential as a biomarker of short-term eGFR loss (over 12 months), we prospectively assessed eGFR and urinary DKK3 levels in patients with CKD of various etiologies at baseline and annual follow-ups. We also measured urinary DKK3 in a general population sample and patients with diagnostic kidney biopsies or IgA nephropathy under treatment. Results Median urinary DKK3-to-creatinine concentration at baseline was significantly higher in patients with CKD than the general population sample (431 versus 33 pg/mg). In the CKD cohort, having a urinary DKK3-to-creatinine level >4000 pg/mg was independently and significantly associated after multiple adjustments with mean annual decline in eGFR of 7.6% over 12 months. Urinary DKK3 significantly improved prediction of kidney function decline compared with eGFR or albuminuria alone. Urinary DKK3-to-creatinine levels were related to the extent of tubulointerstitial fibrosis in kidney biopsies. In patients with IgA nephropathy, a rise in urinary DKK3 was associated with significant eGFR decline within 6 months, whereas stable or decreasing urinary DKK3 indicated a more favorable course. Conclusions Urinary DKK3 levels identify patients at high risk for eGFR decline over the next 12 months regardless of the cause of kidney injury and beyond established biomarkers, potentially providing a tool to monitor CKD progression and assess effects of interventions.

Dural puncture, paraesthesia and vascular puncture are the most common complications of epidural catheter insertion. Their association with variation in midline needle insertion depth is unknown. This study evaluated the risk of dural and vascular punctures and the unwanted events paraesthesia and multiple skin punctures related to midline needle insertion depth. A total of 14,503 epidural catheter insertions including lumbar (L1–L5; n = 5367), low thoracic (T7–T12, n = 8234) and upper thoracic (T1–T6, n = 902) insertions, were extracted from the German Network for Regional Anaesthesia registry between 2007 and 2015. The primary outcomes were compared with logistic regression and adjusted (adj) for confounders to determine the risk of complications/events. Results are presented as odds ratios (OR, [95% confidence interval]). Midline insertion depth depended on body mass index, sex, and spinal level. After adjusting for confounders increased puncture depth (cm) remained an independent risk factor for vascular puncture (adjOR 1.27 [1.09–1.47], p = 0.002) and multiple skin punctures (adjOR 1.25 [1.21–1.29], p

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

Background: Mechanistic target of rapamycin (mTOR) regulates lipid and glucose metabolism thus playing a key role in metabolic diseases like type 2 diabetes mellitus (T2DM). Recently, we demonstrated a functional interaction of microRNA-496 (miR-496) with mTOR and its impact on the regulation of human ageing. Objectives: As T2DM is most prevalent in older adults, we hypothesized that miR-496 may also have an impact on mTOR regulation in T2DM. Methods: Based on real-time PCR and enzyme-linked immunosorbent assay, mTOR gene and protein expression as well as miR-496 expression were monitored in peripheral blood mononuclear cells (PBMC) from T2DM patients (median age: 71) and healthy age- and BMI matched controls (median age: 69). ­Results: We demonstrated significant upregulation of phospho-mTOR and P70S6 Kinase (P70S6K) levels and significant downregulation of miR-496 in PBMC from elderly T2DM patients in comparison to a BMI and age-matched control cohort. Moreover, significant upregulation of phospho-mTOR protein and significant downregulation of miR-496 were observed in advanced stages of obesity. Conclusions: BMI-dependent upregulation of mTOR and the inverse expression profile of miR-496 observed in elderly T2DM patients suggest a correlation with T2DM. Hence, our results indicate a potential association of miR-496 with mTOR expression in elderly T2DM patients and obesity. Since phosphorylation of P70S6K was also elevated in T2DM patients, we conclude that mTOR signaling through TORC1 may be affected in the regulation of T2DM.

Following national recommendations, palivizumab is administered in Germany to high-risk infants to prevent hospitalizations related to Respiratory Syncytial Virus infection.In this post marketing observational study (German SYNAGIS™ Registry) data on risk factors and the clinical course of children, who received at least one palivizumab injection between 2009-2016 (01 September to June 30) were entered into an internet-based data entry system by the attending physicians after informed consent.63 572 immunizations were documented for 12 729 evaluable patients (EVP) from 2009 to 2016, with an average of 5.0 immunizations per patient per season. 45% of infants received more than 5 injections. The predominant primary reason for immunization was premature birth (74%). In the EVP the rate of hospitalizations with causal relationship to RSV was 0.7% (=92/12 729) or 1.2% in a worst case scenario including patients with missing RSV test. In patients with hemodynamically significant congenital heart disease as main indication, RSV-related hospitalization rate was 0.8%. Intensive care was necessary in 16.9% (median duration 3 days), mechanical ventilation in 8.0%. No death related to RSV infection was reported.Keeping in mind the limitations of an uncontrolled prospective observational study, our results confirm the effectiveness and safety of palivizumab prophylaxis. The total number of patients with hsCHD is lower than expected. A better adjustment to the regional epidemiology would probably reduce the need for more than 5 injections.Palivizumab wird in Deutschland Hochrisikokindern nach den Empfehlungen der Fachgesellschaften verabreicht um Hospitalisierungen zu verhindern, die durch eine RSV Infektion bedingt sind.In einer prospektiven Post-Marketing Surveillance Studie (Deutsches SYNAGIS™ Register) wurden Daten zu Risikofaktoren und zum Verlauf von Kindern erhoben, die zwischen 2009 und 2016 (1. Sept. – 30. Juni) mindestens eine Gabe Palivizumab erhalten haben. Nach Zustimmung der Sorgeberechtigten wurden die Daten von den behandelnden Ärzten in ein internetbasiertes Register eingegeben.Insgesamt erhielten zwischen 2009 und 2016 12 729 auswertbare Patienten (EVP) 63 572 Palivizumab Injektionen (im Mittel 5.0/Patient und Saison); 45% erhielten mehr als 5 Gaben. Frühgeburtlichkeit war die Hauptindikation (74%). Die Rate der RSV-bedingten Hospitalisierungen in der EVP betrug 0,7% (=92/12 729) bzw.1,2% in einem Worst-Case Szenario unter Einschluss der Patienten ohne RSV Test. Bei Patienten mit hämodynamisch signifikanter angeborener Herzerkrankung (hsCHD) betrug die RSV-bedingte Rehospitalisierungsrate 0,8%. Eine Intensivtherapie war in 16,9% erforderlich (mediane Dauer 3 Tage), invasive Beatmung in 8%. Es wurden keine RSV-bedingten Todesfälle berichtet.Vorbehaltlich der Limitationen eines nicht kontrollierten prospektiven Registers bestätigen die aktuellen Daten des Deutschen Synagis™ die Effektivität der Palivizumab Prophylaxe. Die absolute Anzahl der Kinder mit Hauptindikation hsCHD ist kleiner, als erwartet. Eine bessere Anpassung an die lokale Epidemiologie würde wahrscheinlich die Notwendigkeit von mehr als 5 Gaben pro Saison reduzieren.

Intensive chemotherapy, with or without following autologous or allogeneic stem cell transplantation (HSCT), is often the only curative treatment option for patients with hematological malignancies and leave many survivors physically and psychologically impaired. Electrical muscle stimulation (EMS) is a proven tool to improve physical performance in seniors and patients with chronic diseases. We therefore investigated the safety and feasibility of EMS in 45 patients undergoing autologous HSCT (n = 13), allogeneic HSCT (n = 11) and intensive chemotherapy (n = 21). Furthermore, physical (assessed by 6-min walking distance (6MWD) and short physical performance battery (SPPB)) and psychological performance (assessed by multidimensional fatigue inventory (MFI) and the EORTC QOL-C30 questionnaire) were measured before chemotherapy (T1) and at discharge from hospital (T2). Four patients died due to septic shock, two withdrew consent before the start of EMS training and five stopped EMS training during the study because of chemotherapy-related complications, loss of motivation or loss of ability to use EMS autonomously. Thirty-four out of 45 (76%) patients used EMS throughout the study period and participated in physical and psychological tests at time points 1 and 2. EMS-related adverse events were hematoma (n = 1) and muscle pain (n = 2). No bleeding events > 1 according to the WHO bleeding scale occurred. Decline in 6MWD from T1 to T2 was 24 m. The SPPB score stayed the same with 11 points at T1 and T2. Most MFI subscales showed stable fatigue levels and quality of life (QoL) did not decrease significantly throughout therapy. EMS is feasible and safe in patients undergoing intensive chemotherapy. Trial registration: NCT03467087

Intraventricular hemorrhage (IVH) is a major complication in preterm neonates with significant long-term morbidity and an increased mortality rate. The role of the immature coagulation system in the pathogenesis of IVH in these infants is still under debate. The aim of this study was to provide reference values for coagulation studies within the first 24h of life, and to relate these findings to the incidence of IVH.In this retrospective study, a total of 250 (male: 123/female: 127; VLBW: 150 and ELBW: 100) infants were included over a 4-year-period. Coagulation studies were performed within the first 24h of life in all infants. Multiple regression analysis was employed to demonstrate a potential association between IVH and a number of known risk and protective factors for IVH (antenatal steroids, birth weight, gender, IUGR, APGAR score at 10minutes, platelet count, INR, PTT, fibrinogen).Mean birth weight was 1047.9±305.6 (range: 320-1490g). Both cellular (platelets, nucleated red blood cells) and plasmatic coagulation parameters (INR, fibrinogen and antithrombin III) were dependent on birth weight. Moreover, INR levels (p0.05) were significantly increased in neonates with IVH of any grade. Also, INR was positively correlated with the severity of IVH (Spearman's correlation coefficient: 0.193; p=0.003). While overall fibrinogen levels were not associated with IVH, a fibrinogen level100mg/dL significantly increased the risk for IVH (p0.01).Our data provide a robust set of reference values for both cellular and humoral coagulation studies in VLBW and ELBW infants for the first 24h of life. The results of our study indicate that abnormal INR levels and fibrinogen levels100mg/dL are significantly associated with the occurrence of IVH in this susceptible cohort.

Renal denervation can reduce blood pressure in patients with uncontrolled hypertension. The adherence to prescribed antihypertensive medication following renal denervation is unknown. This study investigated adherence to prescribed antihypertensive treatment by liquid chromatography-high resolution tandem mass spectrometry in plasma and urine at baseline and 6 months after renal denervation in 100 patients with resistant hypertension, defined as baseline office systolic blood pressure ≥140 mmHg despite treatment with ≥3 antihypertensive agents. At baseline, complete adherence to all prescribed antihypertensive agents was observed in 52 patients, 46 patients were partially adherent, and two patients were completely non-adherent. Baseline office blood pressure was 167/88 ± 19/16 mmHg with a corresponding 24-h blood pressure of 154/86 ± 15/13 mmHg. Renal denervation significantly reduced office and ambulatory blood pressure at 6-month follow-up by 15/5 mmHg (p 0.001/p 0.001) and 8/4 mmHg (p 0.001/p = 0.001), respectively. Mean adherence to prescribed treatment was significantly reduced from 85.0 % at baseline to 80.7 %, 6 months after renal denervation (p = 0.005). The blood pressure decrease was not explained by improvements in adherence following the procedure. Patients not responding to treatment significantly reduced their drug intake following the procedure. Adherence was highest for angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and beta blockers (90 %) and lowest for vasodilators (21 %). In conclusion, renal denervation can reduce office and ambulatory blood pressure in patients with resistant hypertension despite a significant reduction in adherence to antihypertensive treatment after 6 months.

Deficiencies of folate, vitamins B12 and D are common age-related conditions. Vitamin B12 and folate are necessary for DNA methylation. Telomeres appear to be regulated by DNA methylation. Here, we study the effect of B vitamins supplementation on telomere length and global DNA methylation in a prospective study. In total, 60 elderly subjects were supplemented for 1 year with either vitamin B12, B6, folate, vitamin D and calcium (group A n = 31) or only vitamin D and calcium (group B n = 29). LINE-1 methylation, relative telomere length (T/S), vitamin B12, folate, homocysteine (tHcy) , 5-methyltetrahydrofolate (5-methylTHF), S-adenosylhomocysteine (SAH), S-adenosylmethionine (SAM), cystathionine and vitamin D were quantified before and after supplementation. At baseline, tHcy was high, vitamin D was low, and T/S did not differ between groups A and B. Vitamin supplementation increased LINE-1 methylation in group A at site 317 but reduced LINE-1 methylation in group B at site 327. There was no correlation between T/S and LINE-1 methylation at baseline. Multiple backward regression analysis revealed baseline tHcy and 5-methylTHF are significant predictors of T/S. After supplementation in group B but not in group A, LINE-1 methylation correlated inversely with T/S, and LINE-1 methylation variation was an independent predictor of T/S variation. B vitamins decreased tHcy significantly in group A. Multiple backward regression analysis showed 5-methylTHF in group A and tHcy in group B were significant predictors for LINE-1 methylation. At baseline, the lower LINE-1 methylation observed in subjects with 5-methylTHF >10 nmol/l was in agreement with a reduced methyl group transfer due to a lower SAM formation. In group B, an increase in telomere length was correlated with lower LINE-1 methylation. Subjects with hyperhomocysteinemia >12 µmol/L had compared to those with normal tHcy a reduced LINE-1 methylation accompanied by a higher SAM and SAH (that inhibits demethylation of SAM) as well as lower 5-methylTHF. Additionally, subjects with tHcy > 12 µmol/L had longer telomeres when compared with subjects having tHcy

To evaluate the effect of keratocyte supernatant (harvesting time, riboflavin concentration and UV-A-light illumination) on migration and proliferation of human corneal epithelial cells (HCECs) by CXL, in vitro.Primary human keratocytes isolated from 8 normal and 6 keratoconus corneas were cultured. Thereafter, keratocytes in 0%, 0.05% or 1% riboflavin solution were split into samples without and with 370 nm UVA-light-illumination. After removal of the riboflavin solution, keratocytes were incubated in the mentioned keratocyte culture medium at 37 °C and keratocyte supernatant was harvested after 5 and 24 hours. Keratocyte supernatant without riboflavin and UVA treatment, was used as control. HCECs were cultured until reaching confluence, the HCEC culture medium was replaced by the keratocyte supernatant and HCEC migration was analyzed using the wound-healing assay. HCEC proliferation was determined by the cell proliferation ELISA BrdU (colorimetric) kit. Statistical analysis was performed using a linear mixed model in the framework of a Generalized Estimating Equations (GEE) approach to analyze the effect of harvesting time, riboflavin concentration and UV-A-light illumination using IBM-SPSS version 22.Riboflavin concentration, UVA-light illumination and harvesting time of normal or keratoconus keratocyte supernatant had no significant impact on HCEC proliferation (p 0.10). Riboflavin concentration did not show significant impact on HCEC migration using normal or keratoconus keratocyte supernatant (p 0.10), however, longer harvesting time of normal or keratoconus keratocyte supernatant significantly increased (p = 0.01 for both) and UVA-light illumination of keratoconus keratocyte supernatant (p 0.001) significantly decreased HCEC migration.Harvesting time, riboflavin concentration and UV-A-light illumination of normal and keratoconus keratocyte cultures has no impact on proliferation of HCECs, in the short term. However, 24 hours harvesting time (both for normal and keratoconus keratocytes) increases and UVA-light-illumination of keratoconus keratocyte cultures decreases HCEC migration.

Accumulation and aggregation of amyloid-β (Aβ) are considered etiologic processes in Alzheimer's disease (AD). However, the roles of other AβPP cleavage products in disease pathology remain elusive. Here, we measured levels of the major secreted AβPP processing products sAβPPα, sAβPPβ, and Aβ species in postmortem collected ventricular CSF of 196 AD patients and 74 controls. In AD we identified Aβ₄₂ to decrease continuously with progressing Braak stages, whereas Aβ₄₀ was upregulated in early stages of the disease (Braak stage 4) and down-regulated with progressing pathology. Interestingly, both sAβPPα and sAβPPβ were upregulated in AD as compared to controls (sAβPPα, p = 0.02; sAβPPβ, p = 0.01). Moreover, we observed a strong positive correlation of both alternative AβPP processing products, sAβPPα and sAβPPβ (r²= 0.781; p < 0.0001). Together, our results argue for generally enhanced AβPP processing in AD patients and emphasize the necessity of analyzing the roles of all AβPP processing products in AD pathology.

The use of methamphetamine (MA), a highly addictive stimulant, is rapidly increasing, with MA being widely abused as the scene drug “Crystal Meth” (CM). CM has been associated with severe oral health effects, resulting in so-called “Meth mouth”. This term appeared for the first time in 2005 in the literature and describes the final complex of symptoms including rampant caries, periodontal diseases and excessive tooth wear. The aim of this study was to investigate the effects of chronic CM abuse on teeth and intraoral tissue with respect to potential symptoms of Meth mouth. In cooperation with two centres for addiction medicine, we performed clinical intraoral investigations in 100 chronic CM users and 100 matched-pair controls. We undertook a caries and periodontal examination by using the clinical parameters DMF-T/DMF-S, bleeding on probing index (BOP) and periodontal screening index (PSI) and tested individual oral hygiene by using approximal space plaque index (API). All clinical data were analysed by the t test for independent samples. We found significantly larger numbers of caries (p

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.Retrospective analysis in a cohort of very low birth weight infants.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 were89.5 nucleated red blood cells/100 leucocytes (sensitivity 68.2%, specificity 89.0%) and serum lactate concentrations8.5 mmol/l (sensitivity 69.6%, specificity 93.5%) on day 2 of life.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.

Prolonged catheter use is controversial because of the risk of catheter-related infection, but the extent to which the risk increases over time remains unknown. We thus assessed the time-dependence of catheter-related infection risk up to 15 days.Our analysis was based on the German Network for Regional Anesthesia, which includes 25 centers. We considered 44,555 patients who had surgery between 2007 and 2014 and had continuous regional anesthesia as well as complete covariable details. Cox regression analysis was performed and adjusted for confounding covariables to examine the relationship between catheter duration and probability of infection-free catheter use.After adjustment for confounding factors, the probability of infection-free catheter use decreases with each day of peripheral and epidural catheter use. In peripheral catheters, it was 99% at day 4 of catheter duration, 96% at day 7, and 73% at day 15. In epidural catheters, it was 99% at day 4 of catheter duration, 95% at day 7, and 73% at day 15. Only 31 patients (0.07%) had severe infections that prompted surgical intervention. Among these were five catheters that initially had only mild or moderate signs of infection and were left in situ; all progressed to severe infections.Infection risk in catheter use increases over time, especially after four days. Infected catheters should be removed as soon as practical.An online visual overview is available for this article at http://links.lww.com/ALN/B683.

Background Correction of mitral regurgitation (MR) alters the load on the left ventricle. There are few data on the long-term hemodynamic adaptations of the cardiovascular system after transcatheter mitral valve repair (TMVR). The aim of this study was to determine a comprehensive hemodynamic status using noninvasive pressure-volume analysis. Methods Pressure-volume parameters were calculated from echocardiography with simultaneous arm-cuff blood pressure measurements at baseline before TMVR and 12 months after TMVR. Eighty-eight consecutive patients undergoing edge-to-edge mitral clip implantation because of grade 3+ or 4+, symptomatic (79.5% in New York Heart Association functional class ≥III) MR were prospectively enrolled. The mean left ventricular (LV) ejection fraction was 42 ± 14%. Sixty-seven percent of the patients had secondary MR. Results Twelve months after TMVR, 17.7% of patients had died, and 19.0% were rehospitalized because of decompensated heart failure. MR grade was ≤2+ in 90% of surviving patients, and 77% were in New York Heart Association functional class ≤II. LV end-diastolic volume index decreased from 87 ± 38 to 77 ± 40 mL/m2 (P Conclusions One year after TMVR, patients showed reverse remodeling and improved LV performance that was associated with improved symptom status. This hemodynamic improvement supports TMVR as long-term effective therapy for patients with symptomatic MR.

Objectives Somatic development is impaired in children with congenital heart defects (CHDs), and head circumference seems to be a strong predictor of neurodevelopmental prognosis. The aim of this study was to generate up-to-date reference values for the somatic development (head circumference, body weight, and length/height) of children with CHDs. Study design Our study population consisted of all patients included in the PAN study (Pravalenz angeborener Herzfehler bei Neugeborenen in Deutschland), which was conducted prospectively over a 3-year study period by the Competence Network for Congenital Heart Defects. All children with mild, moderate, and severe CHDs born in 2006-2009 in Germany were enrolled. For computing of z-scores, only children with the following characteristics were included: appropriate for gestational age, nonsyndromic disease, term or post-term delivery, and no cardiac surgery. Results There were 2818 patients included. New z-scores for the described somatic measures of children with mild, moderate, and severe CHDs were computed. Comparisons with the KiGGS study (Gesundheit von Kindern und Jugendlichen in Deutschland) and the Berlin Longitudinal Study revealed significantly lower measurements for all measures—most notably in children with severe CHDs and/or cardiac surgery. In our cohort, no catch-up growth was seen after cardiac surgery. Conclusion Children with severe CHDs demonstrated the most abnormal pattern in growth, including head circumference before and after cardiac surgery, which is indicative of accompanying brain pathology unrelated to operative injury.

Background and Aim Magnetic endoscope imaging (MEI) provides continuous viewing of the position of the endoscope on a monitor without using X-ray and has already been established for colonoscopy. The aim of the present study was to evaluate a new MEI probe for enteroscopy. Methods In this prospective feasibility study, consecutive patients received single-balloon enteroscopy guided by the new MEI probe. Fluoroscopy was also used in all examinations. MEI images were compared to fluoroscopy images with respect to concordance of loop configuration by two independent observers after the examinations. Main outcome measurement was the rate of concordant MEI and fluoroscopy images with respect to loop configuration. Results In all 10 patients, single-balloon enteroscopy with MEI was carried out without any adverse events or technical difficulties. Concordance of MEI and fluoroscopy images was seen in 36/38 images (95%; 95% CI, 82–99%) by both observers. Overall agreement between the two observers was 95% (κ = 0.47, 95% CI, −0.04–1). Conclusion The use of MEI in single-balloon enteroscopy is safe and feasible. Detection and control of loops can be accurately achieved.

Renal denervation can reduce blood pressure in certain patients with resistant hypertension. The effect in patients with isolated systolic hypertension (ISH, ≥140/P P P =0.032/ P P =0.009) and 3/4/2 mm Hg ( P =0.08/ P P =0.130) in diastolic ambulatory blood pressure after 3, 6, and 12 months, respectively. The ambulatory blood pressure reduction was significantly lower after 3 and 12 months in SBP and after 12 months in ambulatory DBP, respectively. In conclusion, renal denervation reduces office and ambulatory blood pressure in patients with ISH. However, this reduction is less pronounced compared with patients with CH.

BACKGROUND Total hip and knee replacements are common surgeries, and an optimal pain treatment is essential for early rehabilitation. Since data from randomized controlled trials on the use of regional anesthesia in joint replacements of the lower extremities are conflicting, we analyzed the international PAIN OUT registry for comparison of regional anesthesia vs. general anesthesia regarding pain and morphine consumption on the first postoperative day. METHODS International Classification of Diseases-9 (ICD-9) codes were used to identify 2,346 cases of knee arthroplasty and 2,315 cases of hip arthroplasty between 2010 and 2016 from the PAIN OUT registry. Those were grouped according to anesthesia provided (general, regional, and a combination of both). On the first day after surgery, pain levels and opioid consumption were compared. Adjusted odds ratios (ORs [and 95% confidence intervals (CIs)]) were calculated with logistic regression, and propensity matching was used as a sensitivity analysis. RESULTS After adjustment for confounders, regional anesthesia was associated with reduced opioid consumption (OR 0.20 [95% CI 0.13 to 0.30], P < 0.001) and less pain (OR 0.53 [95% CI 0.36 to 0.78], P = 0.001) than was general anesthesia in knee surgery. In hip surgery, regional anesthesia was only associated with reduced opioid consumption (OR 0.17 [95% CI 0.11 to 0.26], P < 0.001), whereas pain was comparable (OR 1.23 [95% CI 0.94 to 1.61], P = 0.1). Results from a propensity-matched sensitivity analysis were similar. CONCLUSION In total knee arthroplasty, regional anesthesia was associated with less pain and lower opioid consumption. In total hip arthroplasty, regional anesthesia was associated with lower opioid consumption, but not with reduced pain levels.

Infants with Down syndrome (DS) face an increased risk of respiratory tract infections. Recent studies describe DS as independent risk factor for a complicated clinical course in infants with respiratory syncytial virus (RSV) infection. The prospective observational German Synagis™ Registry comprises data from 249 children below 25 months of age with DS and palivizumab prophylaxis 2009-2016 (1191 administrations; mean 4.8 per patient and season). The median gestational age and the birth weight in patients without and with DS were 31 versus 37 weeks (P 0.001) and 1590 versus 2750 g, respectively (P 0.001). Patients with DS significantly more often had congenital heart disease (CHD), siblings in kindergarten or school, treatment with oxygen at home, immunodeficiency, and neuromuscular impairment. The RSV-related hospitalization rate in patients with DS was 1.20%; the hospitalization rate in patients without DS was 0.71%.Data from 249 children with DS receiving palivizumab prophylaxis in seven consecutive RSV seasons (2009-2016) in Germany reveal important differences between patients with and without DS concerning the main indication for palivizumab use and additional risk factors. Bearing in mind the limitations of an uncontrolled postmarketing observational study, the results confirm the field effectiveness of palivizumab prophylaxis in this special population. What is Known: • Recent studies describe the Down syndrome as independent risk factor for a complicated clinical course in infants with RSV infection. What is New: • Compared with other infants receiving palivizumab prophylaxis, patients with Down syndrome significantly more often had congenital heart disease, siblings in kindergarten or school, treatment with oxygen at home, immunodeficiency, and neuromuscular impairment. • In infants with palivizumab prophylaxis breakthrough, RSV-related hospitalization rates were not significantly higher in those with Down syndrome.

The present study was undertaken to investigate the expression of prostate-specific membrane antigen (PSMA) in normal breast tissues, in cancerous breast tissues and in distant metastases from patients with breast cancer. Immunohistochemical analysis was performed to determine PSMA expression and angiogenic activity using anti-PSMA mAb and anti-CD31 mAb respectively. Immunofluorescence staining was applied to confirm the exact co-localization of PSMA and CD31. We observed different patterns of PSMA expression between normal and cancerous tissues. Normal breast tissues showed PSMA expression only in normal glandular cells. However, primary breast tumors and distant metastases showed PSMA expression in tumor cells and in tumor-associated neovasculature. PSMA score group status in primary breast tumors was significantly associated with histologic type and tumor grade (p = 0.026 and p = 0.004 respectively). Distant metastases showed higher PSMA expression in tumor-associated neovasculature comparing with primary tumors. Moreover, brain tumor-associated neovasculture had significantly higher expression of PSMA comparing with bone tumor-associated neovasculture. The localized binding of PSMA mAb to the neovasculature endothelium was confirmed with the double Immunofluorescence staining. 68Ga-PSAM imaging of a patient with metastatic breast cancer showed strong tracer uptake in all known skeletal metastases. To the best of our knowledge, this study is the second one that has assessed PSMA expression in a large number of breast cancer patients. Our findings showed that PSMA is particularly expressed in tumor-associated neovasculature of breast tumors and its distant metastases, thus enhancing the evidence on the potential usefulness of PSMA as a therapeutic vascular target.