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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.

Chronic kidney disease (CKD) represents a global public health problem with high disease related morbidity and mortality. Since CKD etiology is heterogeneous, early recognition of patients at risk for progressive kidney injury is important. Here, we evaluated the tubular epithelial derived glycoprotein dickkopf-3 (DKK3) as a urinary marker for the identification of progressive kidney injury in a non-CKD cohort of patients with chronic obstructive pulmonary disease (COPD) and in an experimental model. In COSYCONET, a prospective multicenter trial comprising 2,314 patients with stable COPD (follow-up 37.1 months), baseline urinary DKK3, proteinuria and estimated glomerular filtration rate (eGFR) were tested for their association with the risk of declining eGFR and the COPD marker, forced expiratory volume in one second. Baseline urinary DKK3 but not proteinuria or eGFR identified patients with a significantly higher risk for over a 10% (odds ratio: 1.54, 95% confidence interval: 1.13-2.08) and over a 20% (2.59: 1.28-5.25) decline of eGFR during follow-up. In particular, DKK3 was associated with a significantly higher risk for declining eGFR in patients with eGFR over 90 ml/min/1.73m2 and proteinuria under 30 mg/g. DKK3 was also associated with declining COPD marker (2.90: 1.70-4.68). The impact of DKK3 was further explored in wild-type and Dkk3-/- mice subjected to cigarette smoke-induced lung injury combined with a CKD model. In this model, genetic abrogation of DKK3 resulted in reduced pulmonary inflammation and preserved kidney function. Thus, our data highlight urinary DKK3 as a possible marker for early identification of patients with silent progressive CKD and for adverse outcomes in patients with COPD.

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.

Purpose The aim of this study was to evaluate the efficacy, safety and predictability of transepithelial photorefractive keratectomy (TransPRK) for correcting myopia, astigmatism and hyperopia. Setting Department of Ophthalmology, Saarland University Medical Center, Homburg/Saar, Germany DESIGN:: Meta-analysis of retrospective or prospective studies METHODS:: Relevant studies were collected from Medline and included when meeting the following predefined criteria: randomized controlled trials, at least one of main outcome measures efficacy, safety or predictability and one common TRPK laser ("Schwind Amaris"). The parameters estimates and 95% confidence intervals (CI) were derived from random-effects meta-analysis to account for possible heterogeneity. Results Since hyperopia studies did not meet the inclusion criteria, the results are centered around myopia and astigmatism. Sixteen studies with a total of 1,924 treated eyes were included in the meta-analysis. The mean efficacy, safety and predictability had a probability of 94% CI=0.86-0.97, 0% CI= 0.00-0.03 and 89% CI=0.82-0.93, respectively. The mean correction index, difference vector and index of success had a value of 1.01 CI=1.01-1.02, 0.2 CI=0.06-0.34 and 0.12 CI=0.07-0.18, respectively. Conclusion This summary estimate shows that the TransPRK is highly effective, safe and predictable in correcting myopia and/or astigmatism.

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.

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.

Background The prehospital identification of stroke patients with large-vessel occlusion (LVO), that should be immediately transported to a thrombectomy capable centre is an unsolved problem. Our aim was to determine whether implementation of a state-wide standard operating procedure (SOP) using the Los Angeles Motor Scale (LAMS) is feasible and enables correct triage of stroke patients to hospitals offering (comprehensive stroke centres, CSCs) or not offering (primary stroke centres, PSCs) thrombectomy. Methods Prospective study involving all patients with suspected acute stroke treated in a 4-month period in a state-wide network of all stroke-treating hospitals (eight PSCs and two CSCs). Primary endpoint was accuracy of the triage SOP in correctly transferring patients to CSCs or PSCs. Additional endpoints included the number of secondary transfers, the accuracy of the LAMS for detection of LVO, apart from stroke management metrics. Results In 1123 patients, use of a triage SOP based on the LAMS allowed triage decisions according to LVO status with a sensitivity of 69.2% (95% confidence interval (95%-CI): 59.0–79.5%) and a specificity of 84.9% (95%-CI: 82.6–87.3%). This was more favourable than the conventional approach of transferring every patient to the nearest stroke-treating hospital, as determined by geocoding for each patient (sensitivity, 17.9% (95%-CI: 9.4–26.5%); specificity, 100% (95%-CI: 100–100%)). Secondary transfers were required for 14 of the 78 (17.9%) LVO patients. Regarding the score itself, LAMS detected LVO with a sensitivity of 67.5% (95%-CI: 57.1–78.0%) and a specificity of 83.5% (95%-CI: 81.0–86.0%). Conclusions State-wide implementation of a triage SOP requesting use of the LAMS tool is feasible and improves triage decision-making in acute stroke regarding the most appropriate target hospital.

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.

Background Most comparisons between robot-assisted (RAPN) and open partial nephrectomy (OPN) indicate the superiority of RAPN, but the learning curve is often not considered. Methods All consecutive partial nephrectomies from the very first RAPN at a single tertiary referral center (n=818, 500 RAPN vs. 313 OPN) were retrospectively analyzed. Complications, success rates, and surgical outcomes were compared. Inequalities between cohorts and the inherent learning curve were controlled by subgroup comparisons, regression analyses, and propensity score matching. Results Overall, RAPN had fewer complications, less blood loss, and shorter length of stay. However, an inherent learning curve caused higher complications for the first 4 years. Thereafter, perioperative outcomes clearly favored RAPN, even for more complex tumors. Conclusions In one of the largest monocentric cohorts over more than 10 years, RAPN was found to be superior to OPN. However, not all advantages of RAPN are immediate because a learning curve must be passed. This article is protected by copyright. All rights reserved.

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.

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)

Use of protective angiotensin-converting enzyme inhibitors (ACE-I) in patients with cardiovascular disease (CVD) is sometimes limited by incident coughing. In clinical trials, cough occurred also on placebo. We performed a meta-analysis including randomized, placebo-controlled trials reporting cough on ACE-I in patients with CVD. We evaluated the attributable fraction of cough on ACE-I accounting rate on placebo: placebo-adjusted ACE-I (%) = (ACE-I (%) - Placebo (%)) / ACE-I (%). In total, 65,054 patients from 22 included studies were analyzed. Placebo-adjusted ACE-I cough was 37% of 13.5% reported cases on ACE-I, while 8.5% reported cases on placebo were equivalent to 63% of cases on ACE-I, indicating potential other factors for cough than ACE-I in a substantial number of cough cases on ACE-I. Placebo-adjusted ACE-I cough had the highest rates of arterial hypertension (85%) and the lowest of heart failure (29%). Therefore, other causes of cough, particularly in heart failure, should be excluded before ACE-I withdrawal.

Background Alpha-1-antitrypsin deficiency (AATD) is a genetic disorder that is associated with a higher risk of chronic obstructive pulmonary disease (COPD) and emphysema. The annual declines in lung function (FEV1) and transfer factor of the lung for carbon monoxide (TLCO) predict all-cause mortality. Material and methods We investigated the longitudinal follow-up data over 11 years (mean follow-up period of 4.89 years) from the German AATD registry and analyzed the relationship between annual loss of FEV1 and TLCO and sex, age, body mass index (BMI), nicotine consumption, occupational dust exposure, St. George's Respiratory Questionnaire (SGRQ) score, baseline FEV1 or TLCO, alpha-1-antitrypsin (AAT) serum level, exacerbation frequency and the duration of smoking abstinence by multiple linear generalized estimating equations models (GEE-models). Results We evaluated the data of 100 individuals with post-bronchodilator FEV1 measurements and from 116 individuals with TLCO measurements. The mean overall decline was −54.06 ± 164.62 ml/year in FEV1 and -0.17 ± 0.70 mmol/min/kPa/year in TLCO. Accelerated deterioration of FEV1 was associated with occupational dust exposure (p = 0.026), shorter duration of smoking abstinence (p = 0.008), higher baseline FEV1 (p = 0.003), higher annual exacerbation frequency (p = 0.003) and higher frequency of glucocorticoids intake (p = 0.004). Furthermore, patients with an elevated decline in TLCO showed significant impaired health-related quality of life at baseline (p = 0.039) and lower AAT serum levels (p Conclusions Annual decline in FEV1 is related to the exacerbation rate, occupational dust exposure and the duration of smoking abstinence.

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

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

BACKGROUND The net benefit from local ablative therapy for pulmonary oligometastases remains unknown. The outcomes of stereotactic ablative radiotherapy (SABR) for metastatic lung lesions (MLLs) were analyzed retrospectively and compared with those of SABR for primary lung lesions (PLLs). METHODS Medical records of patients treated with lung SABR between 2011 and 2014 were retrospectively reviewed. Basic patient, lesion and treatment characteristics were compared using the Pearson chi-square test for categorical and Mann-Whitney U test for continuous variables. To estimate the rates of local control (LC), progression-free survival (PFS), survival after the first progression post-SABR (SAPF) and overall survival (OS), the Kaplan-Meier method was used, and the differences between groups were assessed by means of the log rank test. The uni- and multivariate Cox proportional hazards regression model was used to identify predictive factors for these endpoints. RESULTS Twenty-nine MLLs in 18 consecutive patients and 51 PLLs in 42 patients were treated stereotactically and included in the study. Median follow-up was 14 months (range, 4-40 months). Although patients with MLLs had a significantly better cardiopulmonary function (P=0.0001), more conservative dose-fractionation schedules were prescribed (P=0.0001), but this did not result in a significant difference in LC (P=0.98), PFS (P=0.06) and OS (P=0.14). Multivariate analysis revealed that the dose per fraction (≥ or

ZusammenfassungGegenstand und Ziel: Die Hüftgelenkskapsel unterliegt bei der Hüftgelenksdysplasie (HD) erhöhten Zugkräften, die zu einer Entzündung des Kapselgewebes führen. Eine entzündungsassoziierte Zunahme der Nervenverteilungsdichte wurde in verschiedenen Organen nachgewiesen und könnte auch im Rahmen einer HD Ursache für Hüftgelenksschmerz und Koxarthrose sein. Ziel dieser Studie war, bei Hunden mit normo- bzw. dysplastischen Hüftgelenken Unterschiede in der Nervenverteilungsdichte innerhalb der Hüftgelenkskapsel aufzuzeigen. Material und Methoden: Bei 16 aus anderen Gründen euthanasierten Labrador Retrievern erfolgte anhand des radiologischen Befunds eine Kate gorisierung der Hüftgelenke als normoplastisch (Gruppe 1, n = 18) oder dysplastisch (Gruppe 2, n = 14). Die histologischen Präparate der Hüftgelenkskapseln wurden nach Färbung der Nerven fasern mit der Sihler-Färbemethode eingescannt und mittels einer Matrix in 10 gleich große Quadranten, nummeriert von dorsomedial (Q01) nach kraniodorsolateral (Q10), unterteilt. Durch Berechnung des prozentualen Anteils schwarzer Pixel mittels halbautomatischer Bildanalyse wurde die Nervenverteilungsdichte für jeweils das gesamte Präparat und die einzelnen Quadranten analysiert. Der statistische Vergleich erfolgte mittels t-Test für unabhängige Stichproben. Ergebnisse: Bei Hunden mit HD zeigte sich im kraniodorsolateralen Anteil der Hüftgelenkskapsel eine signifikant höhere Nervenverteilungsdichte (p = 0,03). Die mittlere Nervenverteilungsdichte für die gesamte Hüftgelenkskapsel differierte zwischen den beiden Gruppen nicht signifikant. Schlussfolgerung: Eine erhöhte Nervenverteilungsdichte im kraniodorsalen Anteil der Hüftgelenkskapsel bei Hunden mit HD könnte Folge der großen Zugkräfte in diesem Bereich und eine Ursache für die mit der HD einhergehende Schmerzhaftigkeit und Koxarthrose sein. Klinische Relevanz: Die Ergebnisse liefern die pathophysiologische Grundlage für den Erfolg der Deperiostierung des kranialen Azetabulumrandes im Rahmen einer Hüftgelenksdenervation zur Erzielung einer suffizienten Schmerzlinderung und Entzündungsreduktion bei Hunden mit HD.

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 evidence concerning prognostic parameters for clinical decision-making in penile cancer is either weak or missing. We therefore analysed the prognostic value of the revised TNM and WHO classification systems on relapse and survival with special emphasis on HPV status. We collected clinical data and tissue samples of 121 patients from centres in Germany and Russia. HPV genotyping and p16INK4a immunostaining were performed. The histological subtype and TNM were reclassified by two experienced uropathologists. Survival analyses were performed by Kaplan-Meier estimator and log-rank test. Uni- and multivariable analyses were performed by Cox proportional hazard model and Fisher’s exact test for contingency analysis. HPV status was not found to be an independent prognostic factor. Histological subtypes differ in prognosis with the best outcome found in warty and the worst in basaloid carcinomas. Patients with pT1b defined by poor differentiation or lymphovascular invasion (LVI) had the shortest metastasis-free survival compared with pT1a (log-rank, p = 0.02). Lymph node metastasis and LVI were significantly associated with poor metastasis-free, cancer-specific and overall survival and could be identified as the only independent prognostic parameters. Prognostic value of TNM could not be improved using the 8th versus the 7th edition. In contrast to HPV status, histological subtypes are of prognostic value and should be an essential part of pathologic reports. The impact of the HPV status needs to be analysed in a subtype-specific manner. Parameters describing lymphatic dissemination have the highest impact on prognosis. Inclusion of tumour grade and LVI into a single T-category (pT1b) seems questionable.

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.

Purpose. To analyze the association between hypothyroidism and keratoconus, we examined blood thyroid hormone levels and corneal tomographic parameters in healthy subjects and patients with keratoconus.Methods. We included 626 subjects (304 left eyes, 49%; 431 males, 69%; age 38.4 ± 14.3 y). Patients with keratoconus were from our Homburg Keratoconus Center (HKC) (n = 463); patients with hypothyroidism were from the Department of Internal Medicine of Saarland Medical University, Homburg/Saar, Germany (n = 75); and healthy subjects were from the Department of Ophthalmology of Saarland University Medical Center (n = 88). We included only one randomly selected eye of each subject and the first examination data.Exclusion criteria.Previous thyroid medication, previous ocular surgery, and patients with suspected keratoconus (topographic keratoconus classification, [TKC]: 0 Results. The significance levels for a constant parameter, sex, thyroid condition, and age werep<0.0001,p<0.0001,p<0.0001, andp=0.003, respectively. The odds ratios for age, sex, and hypothyroidism were 0.98, 3.05, and 3.34, respectively. Male sex and a euthyroid condition had significantly positive, clinically relevant effects, and age had a significantly negative, but clinically irrelevant effect on the estimated TKC index.Conclusions. Keratoconus appeared to occur more often in patients classified as euthyroid than in patients with hypothyroidism. Thus, hypothyroidism alone could not support the development of keratoconus. Based on these results, it should not be mandatory to screen patients with hypothyroidism for keratoconus or patients with keratoconus for hypothyroidism.

Background Axillary staging is an integral part of the preoperative work-up in patients with breast cancer. Given the increasing number of patients treated with neoadjuvant chemotherapy (NC) and current guidelines to perform sentinel-node biopsy after the completion of neoadjuvant chemotherapy, axillary staging has gained more importance. Beside the prediction of nodal involvement, correct prediction of nodal stage is crucial in order to select respective treatment for the patients. Materials and Methods Patients treated for primary breast cancer from 01/2013 to 01/2018 and received preoperative sonografic axillary staging and surgery were identified from the breast databases of two large volume hospitals. In case of sonografic suspicion of nodal involvement an axillary biopsy was performed. Accuracy of axillary staging was examined regarding the concordance between prediction of nodal involvement and nodal (N) stage with final pathology. A multivariate model was used to identify factors associated with a high accuracy of axillary sonografic staging. Results Among 2220 patients, 112 were excluded due to incomplete clinical data or axillary surgery after completion of neoadjuvant chemotherapy leaving 2108 patients for final analysis. 1535 (73 %) showed a N0 stage on final pathology. Accuracy of axillary staging regarding prediction of nodal involvement was 92 % (1929/2108) with a sensitivity of 80 % and a specificity of 96 %, a positive predictive value of 88 % and a negative predictive of 93 %. Prediction of nodal stage was correct in 1894 of 2018 cases (90 %). Concordance between sonografic prediction of N stage and final pathology decreased with higher nodal stages (N0 - 91 %, N1 84 %, N2 81 %, N3 68 %) and was higher in node negative patients (91 %) compared to node positive patients (86 %; p ≤ 0.05). On multivariate analysis the presence of nodal involvement was the only factor associated with concordance of axillary staging and pathologic nodal stage (OR 0.11 (95 %CI 0.08 - 0.16) p ≤ 0.01). Conclusion In this large population of patients with primary breast cancer, we showed a high accuracy of preoperative axillary staging with respect to nodal involvement and prediction of respective N stage. With a negative predictive value of 93 % regarding node negativity, axillary staging showed accurate outcomes but improvements in sensitivity are necessary in oder to compete with sentinel node biopsy. Citation Format: Julia Caroline Radosa, Martin Deeken, Lisa Stotz, Sarah Huwer, Carolin Müller, Rosemarie Weinmann, Christoph G Radosa, Marc P Radosa, Stefan Wagenpfeil, Erich-Franz Solomayer. Can preoperative axillary staging replace sentinel node biopsy? Comparison of preoperative axillary and final histologic nodal findings in 2108 patients with primary breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-02-11.

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.

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

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.

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.

To assess continence and erectile function (EF) recovery of extended pelvic lymph node dissection (ePLND) versus limited PLND (lPLND) after bilateral nerve-sparing radical prostatectomy (BNSRP).Consecutive prostate cancer (PCa) patients undergoing BNSRP were stratified according to D'Amico into two groups: low-risk-PCa lPLND (obturator) and intermediate-/high-risk-PCa ePLND (obturator, external iliac artery, internal iliac artery, common iliac artery). Continence (no pad/one safety pad) and EF (IIEF-5 ≥ 17) recovery were assessed. Patients with phosphodiesterase type 5 inhibitors, neoadjuvant/adjuvant therapy, positive lymph nodes or positive surgical margins were excluded.From January 2007 to May 2012, a total 966 consecutive patients were included. Four hundred and sixty patients met the inclusion/exclusion criteria: 262 patients had ePLND and 198 patients had lPLND. Mean number of lymph nodes was 20.4 (range 10-65) and 4.7 (range 0-10), respectively (p 0.001). Continence and spontaneous EF recovery after 12 months were 89.7 versus 93.4 % and 40.4 versus 47.5 %, respectively (all p 0.05). Patient age at surgery (p = 0.001), preoperative EF (p 0.001) and pathological tumor stage (p = 0.008), but not ePLND (p = 0.561), were independent predictors of EF recovery. No association was detected for continence recovery. Seven-year BCR-free survival for pT2 PCa was 100 and 94.8 % in lPLND and ePLND, respectively (p = 0.011). For pT3 PCa, this was 94.7 and 81.2 %, respectively (p = 0.287). At 2 years, the trifecta of continence, potency and recurrence freedom was achieved in 47.5 and 44.1 % in lPLND and ePLND, respectively (p = 0.451).ePLND is not associated with increased risk of postoperative incontinence or erectile dysfunction. Only patient age at surgery, preoperative EF and pathological tumor stage represent predictors of EF recovery.

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 study the long-term cardiovascular and non-cardiovascular outcomes among patients admitted with hypertensive crisis. A total of 297 (145 diabetics, 152 nondiabetics) patients with hypertensive crisis were followed up for a median of 30 months. Fatal and nonfatal events were tracked. The traced events defined as hypertensive urgency, acute coronary syndrome, left ventricular failure, atrial fibrillation, cerebrovascular or renal failure were consecutively analyzed during the follow-up.Overall, 140 (47%) patients had nonfatal clinical events (115 diabetics and 25 nondiabetics); 37 (12%) patients had fatal clinical events (26 diabetics and 11 nondiabetics). The rate of fatal and nonfatal events was significantly higher in diabetics. The mean time of survival was 25.7 months, with the shortest periods for stroke and left ventricular failure. For nondiabetic participants, the mean time of survival was 31 months. Cox regression analysis identified diabetes mellitus, acute left ventricular failure, stroke and renal impairment as predictors of mortality. In conclusion, hypertensive crisis is associated with a markedly increased risk for subsequent cardiovascular morbidity and mortality, especially among diabetics who present with heart failure.

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.

While it has been established that Probenecid (PBN) prevents the onset of experimental autoimmune encephalomyelitis (EAE) in mice, it is not clear whether it has any effect on already manifest EAE. The aim of this study was therefore to analyze the therapeutic effect of PBN in pronounced EAE. Mice with manifest clinical symptoms of EAE were either treated with PBN or solvent for 20 days, or they were left untreated. The clinical symptoms were monitored daily. Inflammation, demyelination and oligodendrocyte numbers were determined in the spinal cord. We were able to demonstrate that PBN not only significantly prolonged survival but also prevented the progression of clinical symptoms in the EAE model of multiple sclerosis. In addition, we were able to show that PBN reduced inflammation, T cell infiltration and oligodendrocyte cell loss. PBN was previously shown to inhibit – among other targets – pannexin channels. As pannexin channels provide conduits for ATP, are associated with the inflammasome, and act as “find me-signals” in the process of apoptosis, inhibition of pannexins via PBN might contribute to the PBN-effects observed in this study. The beneficial and therapeutic effects of PBN in the context of EAE demonstrate an intriguing link between PBN and neuroinflammation, which might foster translational interest.