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Aims Atrial fibrillation (AF) after heart transplantation (HTX) is associated with worse clinical outcomes. The current study aimed to analyse the association between AF before HTX and AF within 30 days after HTX. Methods and results This study included 639 adults who received HTX at Heidelberg Heart Center. Patients were subdivided into four groups depending on the status of AF before and after HTX. Analyses comprised recipient and donor data, medication, echocardiographic features, permanent pacemaker implantation, stroke, and mortality after HTX. Three hundred thirty‐two patients (52.0%) had neither AF before nor after HTX, 15 patients (2.3%) had no AF before HTX but showed AF after HTX, 219 patients (34.3%) showed AF before HTX but had no AF after HTX, and 73 patients (11.4%) had AF before and after HTX. Patients with AF before and after HTX had a higher 1 year post‐transplant mortality (39.7%) than patients without AF before or after HTX (18.1%, P

Goal of this study was the assessment of long-term outcome of arthroscopically assisted repair of Palmer 1B/Atzei 1 triangular fibrocartilage complex tears and the comparison with short- and mid-term results. The study included nineteen patients (mean 49.2 years of age) with a mean follow-up time of 13.6 years (13.1–14.3 years). Examination parameters included disabilities of arm, shoulder, and hand (DASH) questionnaire, modified Mayo Wrist Score (MMWS), Krimmer Score, determination of range of motion in comparison to the contralateral extremity. Grip and pinch grip strength measurement and pain level assessment was performed, as well. The mean MMWS after at least 13.1 years was 95.8 (85–100, SD 5.6). Mean DASH Score was 10.2 (0–55.8, SD 13.6). Mean Krimmer Score was 97.2 (85–100, SD 4.8). Grip strength reached 101% of the contralateral unaffected hand. Range of motion did not differ significantly in comparison to the healthy contralateral extremity. None of the patients suffered from major complications. Fourteen of nineteen patients regarded pain level reduction as excellent. Five patients reported a relevant pain level reduction. Sixteen of nineteen patients regarded functional outcome as excellent, the other three patients reported on a pleasing improvement of the functional outcome. Arthroscopically assisted repair of Palmer 1B/Atzei 1 triangular fibrocartilage complex tears may be an efficacious and safe surgical technique for ulnar-sided TFCC tears in the long term.

Aims Right bundle branch block (RBBB) after heart transplantation (HTX) is a common finding, but its impact on post‐transplant survival remains uncertain. This study investigated the post‐transplant outcomes of patients with complete RBBB (cRBBB) ≤ 30 days after HTX. Methods This registry study analysed 639 patients receiving HTX at Heidelberg Heart Center between 1989 and 2019. Patients were stratified by diagnosis of cRBBB ≤ 30 days after HTX. Analysis included recipient and donor data, medication, echocardiographic features, graft rejections, atrial fibrillation, heart rates, permanent pacemaker implantation and mortality after HTX including causes of death. Results One hundred thirty‐nine patients showed cRBBB ≤ 30 days after HTX (21.8%), 20 patients with pre‐existing cRBBB in the donor heart (3.2%) and 119 patients with newly acquired cRBBB (18.6%). Patients with newly acquired cRBBB had a worse 1‐year post‐transplant survival (36.1%, P

Context Long-term data are scarce on large cohorts with sporadic (sMTC) and hereditary medullary thyroid carcinoma (hMTC). Objectives To compare long-term disease-specific survival (DSS) and outcomes between sMTC and hMTC groups. Design Retrospective analysis. Setting German tertiary referral center. Patients A total of 673 patients with MTC that underwent surgery from January 1974 to July 2019. Intervention None (observational study). Main Outcome Measure Differences between sMTC and hMTC in long-term, stage-dependent survival and outcomes. Results Surgery was performed at median ages of 49 years for sMTC (n = 477, 44% male) and 29 years for hMTC (n = 196, 43% male; P < 0.0001). The mean follow-up times were 9.2 ± 8.0 (sMTC) and 14.6 ± 10.3 years (hMTC). Age and tumor stage at diagnosis were significantly different between the 2 groups (P < 0.0001). The sMTC and hMTC groups had different overall DSS (log rank, P = 0.0183), but similar stage-dependent DSS (log rank, P = 0.1242-0.8981). In a multivariate analysis, sMTC and hMTC did not differ in DSS (hazard ratio [HR] = 1.56; 95% CI, 0.94-2.57), but in both groups, a worse DSS was significantly associated with age at diagnosis (HR = 1.04; 95% CI, 1.02-1.05), male sex (HR = 0.49; 95% CI, 0.32–0.76), and stages III and IV at diagnosis (HR = 20.00; 95% CI, 2.74-145.91 and HR = 97.47; 95% CI, 13.07-726.67, respectively). The groups had significantly different (P < 0.0001) outcomes (i.e., cured, minimal residual disease, structural detectable disease, and death), but similar stage-dependent outcomes (P = 0.9449-0.0511), except for stage III (P = 0.0489). Conclusion Patients with sMTC and hMTC had different ages of onset, but similar stage-dependent DSS and outcomes after the MTC diagnosis. This finding suggested that tumor behavior was similar in sMTC and hMTC.

The purpose of this study was to report long-term objective and patient-reported outcome after arthroscopic debridement of central degenerative triangular fibrocartilage complex (TFCC) lesions. A total of 17 patients with central degenerative TFCC (Palmer type 2C) lesions and ulnar positive variance who were treated by arthroscopic debridement were retrospectively reviewed. Mean follow-up was 8.8 years. Assessment facilitating the Modified Mayo Wrist score (MMWS), the Disabilities of the Arm, Shoulder, and Hand questionnaire (DASH score), recording of pain level and of patient satisfaction, and radiological examination were done. Patients reached a pain level of 1.7 VAS, MMW score of 92, and DASH score of 22. No significant differences could be detected between the operated and the contralateral extremity regarding range of motion and grip strength for all patients. No perioperative complications occurred. Arthroscopic debridement of central degenerative TFCC lesions is safe, reliable, and efficacious even for ulnar positive variance. Therapeutic IV.

Leaking pancreatic fluid can contribute to postoperative pancreatic fistula (POPF), which can complicate pancreatic surgery. Surgeons lack reliable tools to identify pancreatic leaks, so a novel hydrogel indicator called SmartPAN was developed for intraoperative application. In this preclinical efficacy assessment study, SmartPAN was capable of detecting sites associated with biochemical leak and POPF-related symptoms, thereby guiding effective closure. Thus, SmartPAN may help to reduce POPF development in upcoming clinical trials.

Distributed load-management is seen as a means to enhance the integration of fluctuating renewable energy sources into the energy system and address the increasing strain on the German electricity grid. However, the advantages and disadvantages of different service provision approaches for this application, in particular blockchain-based solutions in contrast to aggregators, have not yet been investigated, a research avenue important to inform policymakers in the early stages of market and technology development. The sustainability and feasibility of three approaches, public blockchain, consortium blockchain and an aggregator using a relational database, were evaluated for their suitability to provide grid redispatch services through prosumer engagement, according to seven criteria by applying a multi-criteria analysis (MCA). The three feasibility criteria considered were scalability, regulatory acceptance and implementation network capacity, while the four sustainability criteria considered were privacy, security, costs and energy consumption. The analysis showed that public blockchain is least suitable for this application, whilst consortium blockchain and an aggregator using a relational database perform similarly on sustainability criteria, with the consortium blockchain performing better on security and the aggregator model on energy consumption. From a feasibility perspective, an aggregator using a relational database clearly outperformed blockchain solutions, suggesting better suitability at this point in time, with a need for regulatory innovation to allow for the future adoption of blockchain models.

Background Spinal cord stimulation (SCS) is an effective method to treat neuropathic pain; however, it is challenging to compare different stimulation modalities in an individual patient, and thus, it is largely unknown which of the many available SCS modalities is most effective. Specifically, electrodes leading out through the skin would have to be consecutively connected to different, incompatible SCS devices and be tested over a time period of several weeks or even months. The risk of wound infections for such a study would be unacceptably high and blinding of the trial difficult. The PARS-trial seizes the capacity of a new type of wireless SCS device, which enables a blinded and systematic intra-patient comparison of different SCS modalities over extended time periods and without increasing wound infection rates. Methods The PARS-trial is designed as a double-blinded, randomized, and placebo-controlled multi-center crossover study. It will compare the clinical effectiveness of the three most relevant SCS paradigms in individual patients. The trial will recruit 60 patients suffering from intractable neuropathic pain of the lower extremities, who have been considered for SCS therapy and were already implanted with a wireless SCS device prior to study participation. Over a time period of 35 days, patients will be treated consecutively with three different SCS paradigms (“burst,” “1 kHz,” and “1.499 kHz”) and placebo stimulation. Each SCS paradigm will be applied for 5 days with a washout period of 70 h between stimulation cycles. The primary endpoint of the study is the level of pain self-assessment on the visual analogue scale after 5 days of SCS. Secondary, exploratory endpoints include self-assessment of pain quality (as determined by painDETECT questionnaire), quality of life (as determined by Quality of Life EQ-5D-5L questionnaire), anxiety perception (as determined by the Hospital Anxiety and Depression Scale), and physical restriction (as determined by the Oswestry Disability Index). Discussion Combining paresthesia-free SCS modalities with wireless SCS offers a unique opportunity for a blinded and systematic comparison of different SCS modalities in individual patients. This trial will advance our understanding of the clinical effectiveness of the most relevant SCS paradigms. Trial registration German Clinical Trials Register, DRKS00018929. Registered on 14 January 2020.

BACKGROUND IVM was implemented in medically assisted reproduction 25 years ago. IVM does not involve controlled ovarian stimulation (COS) and is mainly indicated in patients with a high risk of ovarian hyperstimulation syndrome, in particular in patients with polycystic ovary syndrome (PCOS); it is also an acknowledged option in fertility protection. However, the in-vitro culture of immature oocytes raises concerns over their developmental potential and the putative impact on children’s health. Although an increasing number of studies on obstetric and neonatal outcomes of IVM children and their development have been published in recent years, study designs are difficult to compare, since IVM is used in women with various indications and IVM protocols do not follow the same standards. OBJECTIVE AND RATIONALE The aim of this systematic review was to evaluate the current evidence from IVM children of an impact of in-vitro culture of immature oocytes. Primary outcome parameters were birthweight and children’s development up to the age of 2 years. We also compared pregnancy pathologies and the outcome of IVM children and COS children in relation to maternal indications, in particular PCOS, and to the type of IVM protocols with or without ovulation trigger as the secondary outcome parameters. IVM is an accepted clinical option for many centres; however, a comprehensive analysis of the available data is needed to establish whether the use of human oocytes that are fully matured in vitro is safe for both children and their mothers. SEARCH METHODS Google Scholar and PubMed were used for identifying peer-reviewed original articles and reviews through January 2020. A total of 191 studies were screened and 16 studies were included in the qualitative synthesis. Studies were stratified according to indications, the use of an ovulation trigger and multiplicity. OUTCOMES Birthweights of IVM singletons and multiples were comparable to their respective COS controls: birthweights were also similar if the analysis was restricted to mothers with PCOS. IVM children had a comparable birthweight to COS children, irrespective of whether an ovulation trigger was used in IVM cycles or not. The frequency of gestational diabetes (GD) in singleton pregnancies was comparable between IVM and COS, regardless of infertility background. There was also no difference in GD frequency between IVM and COS, if an hCG ovulation trigger in IVM cycles was used or not. Hypertensive disorders in singleton pregnancies of women with PCOS were significantly more frequent after IVM compared to COS, in particular if IVM cycles were performed only with in-vitro matured oocytes. There was no difference in the preterm birth rate of singleton pregnancies between IVM and COS. Preterm birth rates were still similar if only women diagnosed with PCOS were compared and whether an ovulation trigger in IVM was used or not. The malformation rate in IVM children did not differ in COS children versus children after natural conception. At the age of 2 years, IVM singletons showed similar anthropometric and mental development compared to COS children or children from natural conception. WIDER IMPLICATIONS The higher incidence of hypertensive disorders in IVM pregnancies needs monitoring during pregnancy. Current data on the development of IVM children are encouraging, although the quality of many studies is limited and long-term data beyond 2 years are scarce. Further studies should be based on generally accepted IVM protocols. Studies on long-term outcomes beyond 2 years are needed to search for potential long-time sequelae of IVM.

Einleitung Etwa 1% aller Männer sind von Azoospermie betroffen; davon suchen bis zu 15% Rat bezüglich einer Infertilitätsbehandlung. Informationen über prädiktive Faktoren für betroffene Paare sind hierbei sehr begrenzt. Patienten, Materialien und Methoden Wir führten eine retrospektive Analyse medizinischer Aufzeichnungen von 118 Zyklen intrazytoplasmatischer Spermieninjektionen nach vorheriger testikulärer Spermienextraktion wegen Azoospermie durch. Die Behandlungen wurden zwischen Januar 2008 und Oktober 2015 vorgenommen. Von 188 Zyklen waren 66 erste Behandlungszyklen; 35 waren zweite Behandlungszyklen, und 17 waren dritte Behandlungszyklen. Eine statistische Signifikanz wurde bei p < 0,05 angenommen. Es wurden prädiktive Faktoren für eine erfolgreiche Schwangerschaft ausgewertet; dazu gehörten männliches/weibliches Alter, männlicher/weiblicher Body-Mass-Index, männlicher/weiblicher Tabakkonsum und histologische Ergebnisse von testikulären Biopsien. Ergebnisse Die Embryonenqualität und die Anzahl der transferrierten Embryonen waren positiv mit einer erfolgreichen Schwangerschaft assoziiert (p = 0,003). Männer, deren Partnerinnen schwanger wurden, hatten einen signifikant niedrigeren Body-Mass-Index verglichen mit Männern, deren Partnerinnen nicht schwanger wurden (p = 0,023). Weder weibliches Gewicht noch Alter noch Tabakkonsum beim Mann oder bei der Frau waren signifikante Faktoren. Bei Männern mit einer tubulären Atrophie ≥ SIGG Grad 4 war die Wahrscheinlichkeit einer Schwangerschaft gering, ungeachtet dem Vorfinden reifer Spermien und der Anzahl durchgeführter Zyklen. Schlussfolgerung Übergewichtigen Patienten sollte zu einer Gewichtsreduktion vor Beginn der Behandlung geraten werden, und die Beratung samt Erfolgsraten sollte Informationen über histologische und positive Biopsieergebnisse enthalten. Introduction Azoospermia affects about 1% of men, of whom up to 15% inquire about infertility treatment. Information about predictive factors for these couples is very limited. Patients, Materials and Methods We performed a retrospective analysis of the clinical records of 118 cycles of intracytoplasmic sperm injection treatment after testicular sperm extraction for male azoospermia carried out between January 2008 and October 2015. Of those, 66 were first, 35 second, and 17 third cycles. Statistical significance was set at p < 0.05. Predictive factors for successful pregnancy were evaluated and included male/female age, male/female body mass index, male/female nicotine use, and histological results of testes biopsies. Results Embryo quality and the number of embryos transferred were positively associated with pregnancy success (p = 0.003). Males whose partners conceived had a significantly lower body mass index than those whose partners did not conceive (p = 0.023). Neither female weight nor age nor smoking status of the male or female were significant factors. In cases with tubular atrophy ≥ SIGG grade 4 the chance of pregnancy was poor, irrespective of the existence of mature sperm and the number of cycles performed. Conclusion Overweight male patients should be advised about weight reduction prior to treatment, and counseling about success rates should include histological and spermpositive biopsy results.

Aims Amiodarone and digitalis are frequently used drugs in patients with heart failure. Both have separately been linked to reduced post‐transplant survival, but their combined impact on mortality after HTX remains uncertain. This study investigated the effects of combined amiodarone and digitalis use before HTX on post‐transplant outcomes. Methods and results This registry study analysed 600 patients receiving HTX at Heidelberg Heart Center between 1989 and 2016. Patients were stratified by amiodarone and digitalis use before HTX. Analysis included patient characteristics, medication, echocardiographic features, heart rates, permanent pacemaker implantation, atrial fibrillation, and post‐transplant survival including causes of death. One hundred eighteen patients received amiodarone before HTX (19.7%), hereof 67 patients with digitalis (56.8%) and 51 patients without digitalis before HTX (43.2%). Patients with and without amiodarone before HTX showed a similar 1 year post‐transplant survival (72.0% vs. 78.4%, P = 0.11), but patients with combined amiodarone and digitalis before HTX had a worse 1 year post‐transplant survival (64.2%, P = 0.01), along with a higher percentage of death due to transplant failure (P = 0.03). Echocardiographic analysis of these patients showed a higher percentage of an enlarged right ventricle (P = 0.02), left atrium (P = 0.02), left ventricle (P = 0.03), and a higher rate of reduced left ventricular ejection fraction (P = 0.03). Multivariate analysis indicated combined amiodarone and digitalis use before HTX as a significant risk factor for 1 year mortality after HTX (hazard ratio: 1.69; 95% confidence interval: 1.02–2.77; P = 0.04). Conclusions Combined pre‐transplant amiodarone and digitalis therapy is associated with increased post‐transplant mortality.

Psychosocial and biological factors influence the perception of physical changes during pregnancy. Some pregnant women present to the obstetric emergency department (ED) with diverse symptoms not requiring urgent medical action. These visits result in over-consultation, tying up resources and inflating health care expenses. This study outlines factors associated with multiple ED visits during pregnancy, measures the prevalence of anxiety and depression, and explores the choice of maternity clinic for delivery aiming to elucidate options for care strategies. This prospective, cross-sectional, questionnaire-based bicentric study was performed in the obstetric outpatient departments of two university hospitals in Germany and recruited pregnant women between 12/2016 and 11/2017. The questionnaire included socio-demographics, obstetric history, anxiety (GAD-7), depression (PHQ-9), and health status (WHO-5, SF-12). This analysis included 496 women and showed that women with numerous ED visits were significantly younger (p

Background Based on two benchmark studies perioperative chemotherapy (CTx) has become standard treatment for locally advanced esophagogastric adenocarcinoma (EGA) in Europe. However, only half of the patients in both studies actually received postoperative CTx (aCTx). Thus, we evaluated the prognostic impact of preoperative CTx (nCTx) and aCTx combined versus nCTx alone. Furthermore, we aimed to identify subgroups potentially beneficial of aCTx and factors associated with its non-administration. Methods We retrospectively analyzed 299 consecutive patients with EGA, who underwent complete resection (all M0, R0) after nCTx in our institution and were eligible for aCTx. Patients with and without aCTx were compared regarding clinicopathological data, treatment, morbidity, and long-term prognosis. Results 129 patients (43.1%) did not receive aCTx. Administration of aCTx did not significantly improve overall (OS) and recurrence free survival (RFS) (median OS: 78.2 months vs. not reached, p = 0.331; RFS: 43.3 vs. 41.1 months, p = 0.118), but was an independent positive predictor of RFS (HR 1.6 95%CI 1.1–2.5, p = 0.024). aCTx improved RFS in non-intestinal tumors (p = 0.023) and patients receiving FLOT regimen (p = 0.038). By logistic regression analysis factors predictive of non-administration of aCTx were older age (>65 years: OR 3.2, p = 0.028), longer hospital stay (15–28 days: OR 2.6, p = 0.001; >28 days: OR 5.2, p Conclusion Advanced age, histopathologic non-response, and prolonged convalescence due to postoperative morbidity lead to omission of aCTx. However, this study could not provide evidence to support the beneficial role of aCTx in perioperative chemotherapy regimens for a selected patient collective with EGA and excellent prognosis.

BACKGROUND/OBJECTIVES: Retinopathy of prematurity (ROP) is a severe neonatal complication potentially leading to visual impairment and blindness. Known risk factors include preterm birth, low birth weight and respiratory support. Limited and contradictory data exist on the risk of maternal smoking during pregnancy on the development of ROP. This study aims to investigate smoking as an independent risk factor for the development of severe ROP (≥stage 3). SUBJECTS/METHODS: This is a single centre retrospective case-control study of prospectively collected clinical data of infants born before 32 weeks of gestation between 2001 and 2012 at a tertiary care university hospital. The association between maternal smoking during pregnancy and the development of severe ROP was analyzed by multivariate logistic regression. RESULTS: In total, n = 751 infants born

Background: Small bowel adenocarcinoma (SBA) is a dreadful disease. Patient prognosis is limited due to late presentation and ineffective chemotherapy. PD-1/PD-L1 checkpoint immunotherapy is regarded as a promising approach in several cancer entities. The association of PD-1/PD-L1 expression and its impact on patient prognosis with SBA is unclear. Material and methods: Seventy-five consecutive patients who underwent surgery for SBA were retrospectively analyzed and stained for PD-L1 expression in the tumour or the stroma. Analysis of mismatch repair genes was performed to determine microsatellite status. Kaplan–Meier estimate was used to analyze patient survival. Univariate and multivariable Cox regression-analyses were used to assess the impact of PD-L1 expression and microsatellite status on patient survival. Results: PD-L1 was weakly upregulated within the tumour or the stroma and associated with prolonged survival (p = .0071 and p = .0472, respectively). Fifty-one tumours (68%) revealed microsatellite stability (MSS) and 24 tumours (32%) were microsatellite instable (MSI) without correlating with patient survival (p = .611). Neither PD-L1 expression in the tumour nor in the stroma was identified as an independent risk factor influencing survival (p = .572 and p = .3055). Conclusion: Although PD-L1 expression is associated with prolonged survival, it was not identified as an independent prognostic marker. Microsatellite status did not influence long-term survival.

Despite safety concerns, β2-sympathomimetics are still widely used as tocolytic agents. β-Blockers in turn are used to treat vasculo-proliferative diseases of the newborn such as retinopathy of prematurity (ROP), which may lead to visual impairment and blindness. The scope of this study was to investigate whether antenatal exposure to the β2-sympathomimetic fenoterol contributes to the development of ROP. For this single-center retrospective case–control study of prospectively collected clinical data, all infants born before 32 weeks of gestation between 2001 and 2012 were included. The association of prenatal exposure to fenoterol and the development of ROP were analyzed by multivariate logistic regression. n = 1134 infants

Aims Severely elevated pre‐transplant pulmonary vascular resistance (PVR) has been linked to adverse effects after heart transplantation (HTX). The impact of a moderately increased PVR before HTX on post‐transplant outcomes remains uncertain. The aim of this study was to investigate the effects of an elevated pre‐transplant PVR ≥ 300 dyn·s·cm−5 (≥3.75 Wood units) on outcomes after HTX. Methods and results This observational retrospective single‐centre study included 561 patients receiving HTX at Heidelberg Heart Center between 1989 and 2015. Patients were stratified by degree of pre‐transplant PVR. Analyses covered demographics, post‐transplant medication, mortality and causes of death after HTX, early post‐transplant atrial fibrillation (AF), and length of the initial hospital stay after HTX. Ninety‐four patients (16.8%) had a PVR ≥ 300 dyn·s·cm−5 (≥3.75 Wood units). These patients had a higher rate of early post‐transplant AF [20.2 vs. 10.7%, difference: 9.5%, 95% confidence interval (CI): 0.9–18.1%, P = 0.01] and an increased 30 day post‐transplant mortality (25.5 vs. 6.4%, hazard ratio: 4.4, 95% CI: 2.6–7.6, P < 0.01), along with a higher percentage of death due to transplant failure (21.2 vs. 4.1%, difference: 17.1%, 95% CI: 8.7–25.5%, P < 0.01). Multivariate analysis revealed a PVR ≥ 300 dyn·s·cm−5 (≥3.75 Wood units) as a significant risk factor for increased 30 day mortality after HTX (hazard ratio: 4.4, 95% CI: 2.5–7.6, P < 0.01). Kaplan–Meier estimator showed a lower 2 year survival after HTX (P < 0.01) in patients with a PVR ≥ 300 dyn·s·cm−5 (≥3.75 Wood units). Conclusions Elevated pre‐transplant PVR ≥ 300 dyn·s·cm−5 (≥3.75 Wood units) is associated with early post‐transplant AF and increased mortality after HTX.

Highlights • Assessment of flow rates of the hepatic artery during pancreatoduodenectomy. • Identification of pre- and intraoperative factors influencing liver blood flow. • Relevance of a celiac axis stenosis by pancreatoduodenectomy., Introduction Pancreatoduodenectomy is the treatment of choice for a range of benign and malignant diseases. The pancreatic head must be separated from its supplying vessels, especially the gastroduodenal artery, during this operation. However, dissection of the gastroduodenal artery can disturb blood supply to the liver and result in liver ischemia. There is currently no well-established algorithm to evaluate and ensure sufficient blood flow in patients with altered hepatic artery blood flow. To address this important issue, this study aims to establish a basis for assessing liver blood supply during pancreatoduodenectomy. Furthermore, factors influencing arterial blood flow and related postoperative complications will be evaluated. Methods and analysis The HEPARFLOW study is a single institutional single-arm prospective exploratory observational clinical trial. All consecutive patients undergoing elective partial or total pancreatoduodenectomy will be screened for inclusion until 100 patients are enrolled. Blood flow in the proper hepatic artery, gastroduodenal artery, portal vein, and additional vessels supplying the liver will be measured during pancreatoduodenectomy using Doppler flowmetry. All patients will be followed up for 90 days after surgery. At each visit, standard clinical data, postoperative complications and mortality will be recorded. Discussion This will be the first study to prospectively assess intraoperative flow rates of the hepatic artery and portal vein to evaluate liver blood supply during pancreatoduodenectomy. The preoperative and intraoperative factors influencing blood flow in the hepatic arteries will be identified. This study may also reveal the hemodynamic and clinical relevance of a compression of the celiac axis during pancreatoduodenectomy. Ethics and dissemination This study was approved by the Ethics Committee of the University of Heidelberg (S-073/2018). The results will be published in a peer-reviewed journal and will be presented at medical meetings.

Supplemental Digital Content is available in the text., Objectives: Sepsis-induced acute kidney injury is the dominant acute kidney injury etiology in critically ill patients and is often associated with a need for renal replacement therapy. The indication and timing of renal replacement therapy are controversially discussed. We hypothesized that the product of the G1-cell cycle arrest biomarkers tissue inhibitor of metalloproteinase-2 and insulin-like growth factor-binding protein 7 ([TIMP-2] × [IGFBP7]), and the soluble urokinase-type plasminogen activator receptor are of diagnostic value for the prediction of septic acute kidney injury courses requiring renal replacement therapy. Design: In this prospective study, critically ill patients were enrolled immediately after the fulfillment of Sepsis-3 criteria. Urinary [TIMP-2] × [IGFBP7] levels over time and serum soluble urokinase-type plasminogen activator receptor levels once at inclusion were measured. The primary endpoint was the development of septic acute kidney injury with the need for renal replacement therapy. Area under the receiver operating characteristic curves, de Long’s tests, and logistic regression models were calculated. Setting: Two ICUs at Heidelberg University Hospital between May 2017 and July 2018. Patients: One-hundred critically ill patients with positive Sepsis-3 criteria. Interventions: None. Measurement and Main Results: Nineteen patients required renal replacement therapy. Diagnostic performance of urinary [TIMP-2] × [IGFBP7] improved over time with the highest area under the receiver operating characteristic curve of 0.89 (95% CI, 0.80–0.98) 24 hours after study inclusion. Soluble urokinase-type plasminogen activator receptor levels at inclusion showed an area under the receiver operating characteristic curve of 0.83 (0.75–0.92). The best discrimination ability for the primary outcome measure was achieved for [TIMP-2] × [IGFBP7] at 24 hours after inclusion by applying a cutoff value of greater than or equal to 0.6 (ng/mL)2/1,000 (sensitivity 90.9, specificity 67.1). Soluble urokinase-type plasminogen activator receptor performed best by using a cutoff value of greater than or equal to 8.53 ng/mL (sensitivity 84.2, specificity 82.7). A combination of newly tested biomarkers with cystatin C resulted in a significantly improved diagnostic accuracy. Cystatin C in combination with [TIMP-2] × [IGFBP7] 24 hours outperformed all standard renal parameters (area under the receiver operating characteristic curve 0.93 [0.86–1.00]). Conclusions: [TIMP-2] × [IGFBP7] and soluble urokinase-type plasminogen activator receptor are promising biomarker candidates for the risk stratification of septic acute kidney injury patients with the need for renal replacement therapy.

Objectives PORTAS-3 was designed to compare the frequency of pneumothorax or haemothorax in a primary open versus closed strategy for port implantation. Background data The implantation strategy for totally implantable venous access ports with the optimal benefit/risk ratio remains unclear. Methods PORTAS-3 was a multicentre, randomized, controlled, parallel-group superiority trial. Adult patients with oncological disease scheduled for elective port implantation were randomized to a primary open or closed strategy. Primary endpoint was the rate of pneumothorax or haemothorax. Assuming a difference of 2.5% between the 2 groups, a sample size of 1154 patients was needed to prove superiority of the open group. A logistic regression model after the intention-to-treat principle was applied for analysis of the primary endpoint. Results Between November 9, 2014 and September 5, 2016, 1205 patients were randomized. Of these, 1159 (open n = 583; closed n = 576) were finally analyzed. The rate of pneumothorax or haemothorax was significantly reduced with the open strategy [odds ratio 0.27, 95% confidence interval (CI) 0.09-0.88; P = 0.029]. Operation time was shorter for the closed strategy. Primary success rates, tolerability, morbidity, dose rate of radiation, and 30-day mortality did not differ significantly between the groups. Conclusion A primary open strategy by cut-down of the cephalic vein, if necessary enhanced by a modified Seldinger technique, reduces the frequency of pneumothorax or haemothorax after central venous port implantation significantly compared with a closed strategy by primary puncture of the subclavian vein without routine sonographic guidance. Therefore, open surgical cut-down should be the reference standard for port implantation in comparable cohorts. Trial registration German Clinical Trials Register DRKS 00004900.

Background Hyperspectral imaging (HSI) could provide extended haemodynamic monitoring of perioperative tissue oxygenation and tissue water content to visualize effects of haemodynamic therapy and surgical trauma. The objective of this study was to assess the capacity of HSI to monitor skin microcirculation and possible relations to perioperative organ dysfunction in patients undergoing pancreatic surgery. Methods The hyperspectral imaging TIVITA® Tissue System was used to evaluate superficial tissue oxygenation (StO2), deeper layer tissue oxygenation (near-infrared perfusion index (NPI)), haemoglobin distribution (tissue haemoglobin index (THI)) and tissue water content (tissue water index (TWI)) in 25 patients undergoing pancreatic surgery. HSI parameters were measured before induction of anaesthesia (t1), after induction of anaesthesia (t2), postoperatively before anaesthesia emergence (t3), 6 h after emergence of anaesthesia (t4) and three times daily (08:00, 14:00, 20:00 ± 1 h) at the palm and the fingertips until the second postoperative day (t5–t10). Primary outcome was the correlation of HSI with perioperative organ dysfunction assessed with the perioperative change of SOFA score. Results Two hundred and fifty HSI measurements were performed in 25 patients. Anaesthetic induction led to a significant increase of tissue oxygenation parameters StO2 and NPI (t1–t2). StO2 and NPI decreased significantly from t2 until the end of surgery (t3). THI of the palm showed a strong correlation with haemoglobin levels preoperatively (t2:r = 0.83, p < 0.001) and 6 h postoperatively (t4: r = 0.71, p = 0.001) but not before anaesthesia emergence (t3: r = 0.35, p = 0.10). TWI of the palm and the fingertip rose significantly between pre- and postoperative measurements (t2–t3). Higher blood loss, syndecan level and duration of surgery were associated with a higher increase of TWI. The perioperative change of HSI parameters (∆t1–t3) did not correlate with the perioperative change of the SOFA score. Conclusion This is the first study using HSI skin measurements to visualize tissue oxygenation and tissue water content in patients undergoing pancreatic surgery. HSI was able to measure short-term changes of tissue oxygenation during anaesthetic induction and pre- to postoperatively. TWI indicated a perioperative increase of tissue water content. Perioperative use of HSI could be a useful extension of haemodynamic monitoring to assess the microcirculatory response during haemodynamic therapy and major surgery. Trial registration German Clinical Trial Register, DRKS00017313 on 5 June 2019

Background: Oxygen therapy is often used in emergency departments and intensive care units. The prevention of hypoxia with associated complications remains the main target, but a high-concentrated usual oxygen therapy seems not to be the best strategy. We hypothesize that physiological pressure of arterial oxygen (paO2) reduces mortality, onset of new infections and organ dysfunctions in critically ill patients compared with supraphysiological paO2.Methods: In this retrospective exploratory cohort study we included 112 critically ill adult patients treated in a surgical critical care unit. All patients were assigned to two groups defined a priori based on paO2 mean values measured in the first 24 hours of mechanical ventilation: first group paO2 75-100 mmHg (n=43), second group patients with paO2 > 100mmHg (n=69). Primary outcome was the cumulative survival, defined from the day of admission in the intensive care unit (ICU) until death or end of the hospital stay. Secondary outcome was the incidence of infections and new organ dysfunctions in both groups. Results: The baseline characteristics like age, body mass index (BMI), lactate and severity of disease scores were similar in both groups. A total of 27 of 69 patients (39,1%) in the group paO2 > 100mmHg and 12 of 43 patients (27,9%) in the group paO2 75-100mmHg died during their ICU stay or further hospital stay (p=0.54). There were no statistically significant differences in the incidence of new infections and new organ dysfunctions between the two groups. Positive end expiratory pressure (PEEP) and fraction of inspired oxygen (FiO2) were in the group of patients with paO2 > 100mmHg significantly lower 8,4 mbar vs. 9,5 mbar (p=0.03).Conclusions: There was no significant increase in overall mortality or new onset of infections and organ dysfunctions in critically ill adult ICU patients requiring oxygen therapy with supraphysiological paO2 (> 100 mmHg) compared to patients with physiological paO2 (75-100 mmHg). Further studies are needed to define the optimal paO2 parameter.

Purpose This is the first study to systematically evaluate the diagnostic accuracy of intraoperative specimen radiography on margin level and its potential to reduce second surgeries in patients treated with neoadjuvant chemotherapy. Methods This retrospective study included 174 cases receiving breast conserving surgery (BCS) after neoadjuvant chemotherapy (NACT) of primary breast cancer. Conventional specimen radiography (CSR) was performed to assess potential margin infiltration and recommend an intraoperative re-excision of any radiologically positive margin. The histological workup of the specimen served as gold standard for the evaluation of the accuracy of CSR and the potential reduction of second surgeries by CSR-guided re-excisions. Results 1044 margins were assessed. Of 47 (4.5%) histopathological positive margins, CSR identified 9 correctly (true positive). 38 infiltrated margins were missed (false negative). This resulted in a sensitivity of 19.2%, a specificity of 89.2%, a positive predictive value (PPV) of 7.7%, and a negative predictive value (NPV) of 95.9%. The rate of secondary procedures was reduced from 23 to 16 with a number needed to treat (NNT) of CSR-guided intraoperative re-excisions of 25. In the subgroup of patients with cCR, the prevalence of positive margins was 10/510 (2.0%), PPV was 1.9%, and the NNT was 85. Conclusion Positive margins after NACT are rare and CSR has only a low sensitivity to detect them. Thus, the rate of secondary surgeries cannot be significantly reduced by recommending targeted re-excisions, especially in cases with cCR. In summary, CSR after NACT is inadequate for intraoperative margin assessment but remains useful to document removal of the biopsy site clip.

Septic shock substantially alters the pharmacokinetic properties of β-lactams with a subsequently high risk of insufficiently low serum concentrations and treatment failure. Considering their pharmacokinetic (PK)/pharmacodynamic (PD) index, prolonged infusions (PI) of β-lactams extend the time that the unbound fraction of the drug remains above the minimal inhibitory concentration MIC (ft &gt, MIC) and may improve patient survival. The present study is a monocentric, retrospective before-and-after analysis of septic shock patients treated with β-lactams. Patients of the years 2015-2017 received intermittent bolus application whereas patients of 2017–2020 received PI of β-lactams. The primary outcome was mortality at day 30 and 90 after diagnosis of septic shock. Mortality rates in the PI group were significantly lower on day 30 (PI: 41%, n = 119/290 vs. IB: 54.8%, n = 68/114, p = 0.0097) and day 90 (PI: 47.9%, n = 139/290 vs. IB: 62.9%, n = 78/124, p = 0.005). After propensity-score matching, 30- and 90-day mortality remained lower for the PI group (−10%, p = 0.14). PI was further associated with a reduction in the duration of invasive ventilation and a stronger decrease in SOFA scores within a 14d-observation period. PI of β-lactams was associated with a significant reduction of mortality in patients with septic shock and may have beneficial effects on invasive ventilation and recovery from sepsis-related organ failure.

Chêneau-brace is an effective therapy tool for treatment in adolescent idiopathic scoliosis (AIS). Data on potential interdependent changes of the sagittal profile including the cervical spine are still sparse. The purpose of this study was to evaluate in-brace changes of the thoracic and lumbar spine and their influence on the pelvis and the cervical spine and apical vertebral rotation was reported. Ninety-three patients with AIS undergoing Chêneau-bracing were included. Patients were stratified by lumbar, thoracic and global spine alignment into normolordotic vs. hyperlordotic or normokyphotic vs. hypokyphotic or anteriorly aligned vs. posteriorly aligned groups. The coronal Cobb angle was significantly decreased in all groups indicating good correction while in-brace therapy. Sagittally, in-brace treatment led to significant flattening of lumbar lordosis (LL) in all stratified groups. Thoracic kyphosis (TK) was significantly flattened in the normokyphotic group, but no TK changes were noticed in the hypokyphotic group. Pelvic tilt (PT) stayed unchanged during the in-brace therapy. Chêneau-brace showed marginal changes in the lower cervical spine but had no influence on the upper cervical spine. The apical vertebral axis in primary and secondary curves was unchanged during the first radiological follow-up. Results from this study contribute to better understanding of initial spine behavior in sagittal and axial plane in the context of bracing.

Several risk factors leading to loosening of the glenoid have been described; however, there is no detailed information available on the exact numbers or percentages for each patient-related risk factor, implant-related risk factor, or risk factors related to surgical technique. Therefore, the aim of this multicenter study was to analyze these risk factors in a large cohort of patients treated with a 3rd-generation cemented total shoulder arthroplasty. Four-hundred seventy-one shoulder arthroplasties with a mean follow-up of 8.1 years were included. There were 318 women and 153 men. The mean age at the time of arthroplasty was 68 (range 35–90) years. The dominant shoulder was treated in 294 cases and the nondominant in 177. The following risk factors for loosening of the cemented keeled glenoid component were examined: gender, age, hand dominance, glenoid morphology, reaming on the glenoid side (reaming down the complete subchondral bone layer), glenohumeral mismatch, glenoid component design, and fatty degeneration of the rotator cuff. No influence on radiographic glenoid loosening was found for patient age at surgery, gender, hand dominance, preparation technique on the glenoid side, or fatty degeneration of the rotator cuff (p > 0.067). Excessive reaming on the native glenoid led to a 3.7-fold higher risk for glenoid component loosening (p

Postoperative Komplikationen in der Wirbelsaulenchirurgie sind haufig. Uber die Zeitpunkte des jeweiligen Komplikationseintritts im postoperativen Verlauf wurde bisher nur sparlich berichtet. Die Erfassung der Haufigkeitsgipfel postoperativer Komplikationen hat jedoch wesentlichen Einfluss auf die Aufklarung der Patienten sowie die postoperativen Verlaufskontrollen. In dieser monozentrischen retrospektiven Studie wurden die postoperativen Komplikationen von 1179 Patienten, die zwischen 2010 und 2015 mittels Spondylodese operativ versorgt worden waren, erfasst. Die Patienten wurden 3, 6, 12, 24 und 36 Monate postoperativ nachuntersucht. Gemas der bestehenden Lokalisation und Pathologieart wurden die Patienten in Gruppen eingeteilt und die erfassten Komplikationen statistisch analysiert. Aufgrund einer Komplikation wurde bei 16,9 % der 1179 Patienten eine Revision vorgenommen. Die meisten Komplikationen traten binnen der ersten 3 Monate auf (72,9 %). Der haufigste Grund fur diese Revision war eine tiefe Wundinfektion (42,7 %). Die meisten Infektionen entwickelten die Patienten innerhalb der ersten 3 Monate nach der Operation (91,8 % aller Infektionen), sodass diese als Fruhinfektionen definiert werden konnen. Der Haufigkeitsgipfel des Materialversagens zeigte sich im 2. postoperativen Jahr mit 46 % aller erfasster Materialversagen (2,5 % der Gesamtkomplikationen). Der Haufigkeitsgipfel postoperativer Komplikationen nach Spondylodese tritt bereits innerhalb der ersten 3 postoperativen Monate ein. Die Wundinfektion stellt die haufigste Komplikation dar. Dennoch ist eine regelmasige und langfristige postoperative klinisch-radiologische Verlaufskontrolle notwendig, da v. a. das Materialversagen erst innerhalb des 2. postoperativen Jahres einen Haufigkeitsgipfel aufweist.

Objective: The introduction of a stemless prosthesis in shoulder arthroplasty represents a novel design whereby the proximal humerus is restored anatomically, while leaving the diaphysis of the humerus untouched. The aim of this study was to present the mid-term results of total evolutive shoulder system (TESS; Biomet®), a stemless shoulder prosthesis. Methods: The study included 38 consecutive patients (18 men and 20 women; mean age: 66 years; range: 55-81 years) treated with shoulder arthroplasty between 2009 and 2011 with TESS for primary glenohumeral arthritis. Total shoulder arthroplasty (TSA) was performed in 28 cases (74%), hemi-shoulder arthroplasty (HSA) in 10 (26%). Constant score, active range of motion, patient satisfaction rate, and radiological assessment were analyzed. Mean time of follow-up was 37 months. Results: Constant score improved from 21.8 points (28.6 adjusted for age) preoperatively to 74.1 points (86.6 adjusted for age) postoperatively. Active range of motion increased significantly from the pre- to postoperative status. Eighty-nine percent were very satisfied or satisfied with shoulder replacement surgery. One cemented glenoid was revised due to aseptic loosening. None of the components were found to be loose at the final follow-up. No signs of stress shielding were seen. Conclusions: This study shows promising results of this implant concept in the short- to mid-term. These results are comparable with the results achieved with long-established arthroplasty designs. Level of Evidence: Level IV, Therapeutic Study. Keywords: Stemless shoulder arthroplasty, Glenohumeral osteoarthritis, T.E.S.S., Primary shoulder osteoarthritis, Total shoulder arthroplasty

ObjectiveScheduled endoscopic dilatation of dominant strictures (DS) in primary sclerosing cholangitis (PSC) might improve outcome relative to endoscopic treatment on demand, but evidence is limited. Since randomisation is difficult in clinical practice, we present a large retrospective study comparing scheduled versus on-demand endoscopic retrograde cholangiopancreatography (ERCP) based on patient preferences.DesignBetween 1987 and 2017, all new patients with PSC had been offered scheduled ERCP with dilatation of a DS if diagnosed; the latter was repeated at defined intervals until morphological resolution, independent of clinical symptoms (treatment group). Patients who refused participation were clinically evaluated annually and received endoscopic treatment only on demand (control group). The primary clinical endpoint was transplantation-free survival. Secondary outcomes were overall survival, bacterial cholangitis episodes, hepatic decompensation of liver cirrhosis and endoscopy-related adverse events.ResultsThe final study included 286 patients, 133 (46.5%) receiving scheduled ERCP and 153 (53.5%) receiving on-demand ERCP. After a mean follow-up of 9.9 years, the rate of transplantation-free survival was higher in patients receiving scheduled ERCP (51% vs 29.3%; pConclusionIn our large retrospective study, regular ERCP with endoscopic balloon dilatation significantly benefits patients with PSC with DS, diagnosed both at initial presentation and during surveillance, even if asymptomatic. Further studies have to find out how to best identify stricture patients non-invasively.

Bracing constitutes the mainstay treatment for mild scoliosis. The 3D reconstruction of the spine using low-dose stereoradiographic imaging (LSI) is increasingly being used to determine the true shape of the deformity and to assess the success of bracing. The aim of the study was to validate the measurement of 3D spinopelvic parameters and vertebral rotation in the setting of bracing treatment via a reliability study conducted in adherence to the guidelines for reporting reliability and agreement studies (GRRAS). Full spine stereoradiographs of patients with adolescent idiopathic scoliosis (AIS) who underwent Cheneau bracing were retrospectively analyzed. The 3D reconstruction was performed by two experienced operators in a blinded manner and randomized order. Rotation of every vertebra was computed in the coronal, sagittal and axial planes. Sagittal spinopelvic parameters were evaluated. All measurements were statistically compared to determine agreement of the measurement of brace correction using the intraclass correlation coefficient (ICC). In this study, 45 patients (81% females) aged 12.5 ± 2 years were included. The mean absolute difference was less than 3.5° for all measured angles, less than 4 mm for sagittal vertical axis (SVA) and less than 1.5 mm for lateral pelvic shift. The ICC was high for all parameters (ICC >0.81). Despite the overall high reliability, the reliability of axial rotation was lower in the upper and middle thoracic spine and the lower lumbar spine. Brace wearing during full spine LSI acquisition does not affect spinal measurements. The LSI under bracing treatment produces reliable measurements of spinopelvic parameters as well as vertebral rotation. These reproducible 3D data enable spine surgeons to assess the true shape of the deformity, to quantify rotation of each vertebra and enhance the understanding of the efficacy of bracing treatment.

Despite antifungal prophylaxis following liver transplantation (LTX), patients are at risk for the development of subsequent opportunistic infections, such as an invasive fungal disease (IFD). However, culture-based diagnostic procedures are associated with relevant weaknesses. Culture and next-generation sequencing (NGS)-based fungal findings as well as corresponding plasma levels of s-D-glucan (BDG), galactomannan (GM), interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), interleukin (IL)-2, -4, -6, -10, -17A and mid-regional proadrenomedullin (MR-proADM) were evaluated in 93 patients at 6 consecutive time points within 28 days following LTX. A NGS-based diagnostic approach was shown to be suitable for the early identification of fungal pathogens in patients following LTX. Moreover, MR-proADM and IL-17A in plasma proved suitable for the identification of patients with an IFD. Plasma measurements of MR-proADM and IL-17A as well as a NGS-based diagnostic approach were shown to be attractive methodologies to attenuate the weaknesses of routinely used culture-based diagnostic procedures for the determination of an IFD in patients following LTX. However, an additional confirmation within a larger multicenter trial needs to be recommended. German Clinical Trials Register: DRKS00005480 .

Serum creatinine (SCr)- or urine output-based definitions of acute kidney injury (AKI) have important limitations in neonates. This study evaluates the diagnostic value of urinary biomarkers in very low-birth-weight (VLBW) infants receiving indomethacin for closure of a patent ductus arteriosus (PDA). Prospective cohort study in 14 indomethacin-treated VLBW infants and 18 VLBW infants without indomethacin as controls. Urinary biomarkers were measured before, during, and after indomethacin administration. Indomethacin therapy was associated with significantly higher SCr concentrations at 36, 84, and 120 h compared to controls. At 36 h, three indomethacin-treated patients met the criteria for neonatal modified Kidney Disease: Improving Global Outcomes (KDIGO) AKI. The product of urinary tissue inhibitor of metalloproteinase-2 and insulin-like growth factor-binding protein 7 ([TIMP-2]•[IGFBP7]) was significantly elevated in the AKI subgroup at 12 h (P

Background Fumaric acid esters (FAEs) are used to treat psoriasis and are known to cause lymphopenia in roughly 60% of the patients. Much remains to be elucidated about the biological effects of FAEs on lymphocytes. Objective To evaluate the influence of long-term FAE (Fumaderm® ) treatment on peripheral blood CD4+ and CD8+ T cells, CD19+ B cells and CD56+ natural killer (NK) cells in psoriasis. Methods In this single-centre retrospective observational subcohort study, we obtained leucocyte and lymphocyte subset counts before initiating FAE therapy in 371 psoriasis patients (mean age, 47.8 years; 63.3% males) and monitored them during treatment (mean treatment duration, 2.9 years). Multiparametric flow cytometry was used for immunophenotyping. Results FAEs significantly reduced the numbers of CD4+ T, CD8+ T, CD19+ B and CD56+ NK cells. Among lymphocyte subsets, the mean percentage reduction from baseline was always highest for CD8+ T cells, with a peak of 55.7% after 2 years of therapy. The risk of T-cell lymphopenia increased significantly with the age of the psoriasis patients at the time that FAE therapy was initiated. It was significantly decreased for the combination therapy with methotrexate and folic acid (vitamin B9) supplementation. Supporting evidence was found suggesting that T-cell lymphopenia enhances the effectiveness of FAE therapy. Conclusions Monitoring distinct T-cell subsets rather than just absolute lymphocyte counts may provide more meaningful insights into both the FAE treatment safety and efficacy. We therefore suggest optimizing pharmacovigilance by additionally monitoring CD4+ and CD8+ T-cell counts at regular intervals, especially in patients of middle to older age. Thus, further prospective studies are needed to establish evidence-based recommendations to guide dermatologists in the management of psoriasis patients who are taking FAEs and who develop low absolute T-cell counts.

Recently, a tumor-autonomous cytochrome P450 (CYP)-3A5-mediated resistance to cancer therapy has been demonstrated in pancreatic ductal adenocarcinoma. Expression of CYP3A5, which is involved in the degradation of irinotecan, has also been reported in colorectal cancer (CRC). The aim of the present study was to analyze CYP3A5 expression in the normal colon, colon adenoma, CRC and normal tissues, as well as to examine whether CYP3A5 expression in CRC has an impact on tumor response to irinotecan treatment. Immunohistochemistry was used to assess 85 tissue samples from 65 patients with CRC, along with 15 samples of normal colon and 45 samples of colon adenoma (including tubular, tubulovillous, and sessile serrated adenomas), and a tissue microarray (TMA) comprised of 26 different normal tissue types. Expression of CYP3A5 was evaluated with a semi-quantitative score. Tumor response to irinotecan therapy was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 guidelines. In normal tissues, CYP3A5 was expressed in epithelial cells of the colon, gallbladder, kidney, liver, small intestine, stomach, thyroid gland and tonsil, as well as in nerves. Expression in colon mucosa was heterogeneous, with only weak staining in the minority of specimens. CYP3A5 exhibited markedly higher expression in adenomas compared with normal colon tissues. A statistically significant inverse correlation was identified between CYP3A5 expression in CRC tissues and tumor response to irinotecan therapy. Irinotecan treatment itself did not alter CYP3A5 expression in CRC tissues. As CYP3A5 is involved in the degradation of irinotecan, the significantly higher intratumoral expression of CYP3A5 in patients with CRC who do not respond to irinotecan-based chemotherapy may indicate a causal role of CYP3A5 in tumor resistance.

The randomized controlled PROPP trial (DKRS00004191) showed that pylorus-resecting pancreatoduodenectomy (PR) is not superior to the pylorus-preserving procedure (PP) in terms of perioperative outcome, specifically in reduction of delayed gastric emptying. Non-superiority of PR was also confirmed in a recent meta-analysis of randomized controlled trials. However, long-term data on morbidity and quality of life after PP compared to PR are sparse. The aim of this study was to investigate long-term outcomes of patients included in the PROPP trial. Between February 2013 and June 2016, a total of 188 patients underwent PD and were intraoperatively randomized to either preservation or resection of the pylorus (95 vs. 93 patients). For long-term follow-up, morbidity and quality of life (EORTC QLQ-C30/PAN26) were monitored until January 1, 2018. Statistical analysis was performed on an intention-to-treat basis. The mean duration of follow-up was 34.3 (± 11.3) months. Sixty-three of the 188 patients had died (PP n = 33, PR n = 30), 29 patients were lost to follow-up (PP n = 17, PR n = 12), and the remaining 96 patients were included in long-term follow-up (PP n = 45, PR n = 51). There was no difference between PP and PR patients regarding endocrine and exocrine pancreatic function, receipt of adjuvant/palliative chemotherapy, cancer recurrence, and other relevant characteristics. Late cholangitis occurred significantly more often in patients following pylorus resection (P = 0.042). Reoperations, readmissions to hospital, and quality of life scores except pain were comparable between the two study groups. Similar to short-term results, long-term follow-up showed no significant differences between pylorus resection compared to pylorus preservation.

Annual cervical cancer screening is recommended in Germany as a part of the statutory preventive care. Abnormal results can provoke psychological distress and anxiety, compromising women’s adherence. Little is known about how a cervical dysplasia impacts adherence follow-up visits and prevention habits over time. To optimize care strategies, this study aims to identify women at risk for nonadherence to follow-up visits after a screening event. Between November 2015 and May 2017, participants with an abnormal Pap smear at the Heidelberg and Leipzig University Hospitals received a four-part questionnaire (sociodemographic data, PHQ-D, self-designed fear and prevention habit questions) at the first consultation (T1) and subsequently after 3 (T2) and 6 (T3) months; healthy controls completed the questionnaire at T1. 132 women with an abnormal Pap smear [with conization: S1 (n = 68, 51.5%), without intervention: S2 (n = 64, 48.5%)] and healthy controls (K, n = 101) generally adhered to gynecological checkups, except S1 6 months after the first diagnosis (S1/T3 − 0.47, signed rank p

In this paper we investigate the impact of different electric vehicle charging strategies on spot market power prices for the case of Germany. We also provide a detailed analysis of uncertainties resulting from vehicle-to-grid (V2G), the most flexible charging option. Since the integration of renewable energy sources requires flexibility, we compare V2G with two competing systemic flexibility options provided by highly flexible power plants and resulting from EU high voltage grid expansion, respectively. In all cases we find that V2G has by far the most significant impact on prices, mainly smoothing them, while reducing, for example, the surplus electricity from renewable energy sources. V2G also has the strongest influence on prices compared to the systemic flexibility options of more flexible power plants or network expansion. In addition, we show that it is important to take the structural difference between working days and weekends into account. Especially on weekend days, which are usually characterized by low power demand, V2G raises power prices the most. Finally, the price effects are accompanied by a saturation effect, which is already noticeable in the German case at two million vehicles.

AIM To study liver stiffness (LS) during pregnancy and its association with complications during pregnancy. METHODS In this observational, diagnostic study, 537 pregnant women were prospectively enrolled at the Department of Obstetrics and Gynecology, University hospital Heidelberg and Salem Medical Center. LS was measured using the Fibroscan device (Echosens, Paris) in all women and in 41 cases 24 h after delivery. Clinical and morphological data were recorded and abdominal ultrasound and standard laboratory tests were performed. No complications were observed in 475 women (controls) while preeclampsia and intrahepatic cholestasis of pregnancy (ICP) developed in 22 and 40 women, respectively. RESULTS In controls, LS increased significantly from initially 4.5 ± 1.2 kPa in the second trimester to 6.0 ± 2.3 kPa (P < 0.001) in the third trimester. In the third trimester, 41% of women had a LS higher than 6 kPa. Elevated LS in controls was significantly correlated with alkaline phosphatase, leukocytes, gestational age and an increase in body weight and body mass index (BMI). In women with pregnancy complications, LS was significantly higher as compared to controls (P < 0.0001). Moreover, in multivariate analysis, LS was an independent predictor for preeclampsia with an odds ratio of 2.05 (1.27-3.31) and a cut-off value of 7.6 kPa. In contrast, ICP could not be predicted by LS. Finally, LS rapidly decreased in all women within 24 h after delivery from 7.2 ± 3.3 kPa down to 4.9 ± 2.2 kPa (P < 0.001). CONCLUSION During pregnancy, LS significantly and reversibly increases in the final trimester of pregnant women without complications. In women with preeclampsia, LS is significantly elevated and an independent non-invasive predictor.

OBJECTIVES The BI-RADS© classification provides a standardized way to describe ultrasound findings in breast cancer diagnostics. However, there is little information regarding which BI-RADS© descriptors are most strongly associated with malignancy, to better distinguish BI-RADS© 3 (follow-up imaging) and 4 (diagnostic biopsy) breast masses. METHODS Patients were recruited as part of an international, multicenter trial (NCT02638935). The trial enrolled 1294 women (6 excluded) categorized as BI-RADS© 3 or 4 upon routine B-mode ultrasound examination. Ultrasound images were evaluated by three expert physicians according to BI-RADS©. All patients underwent histopathological confirmation (reference standard). We performed univariate and multivariate analyses (chi-square test, logistic regression, and Krippendorff's alpha). RESULTS Histopathologic evaluation showed malignancy in 368 of 1288 masses (28.6%). Upon performing multivariate analysis, the following descriptors were significantly associated with malignancy (P

In their article on recent advances in alcoholic liver disease (ALD), Avila and coworkers1 also mention the little-studied approach of inhibiting overexpressed cytochrome P450 2E1 (CYP2E1), which is induced by chronic ethanol consumption,2 causes generation of reactive oxidative species (ROS) and oxidative stress and stimulates hepatic steatosis and fibrosis.3 4 ROS also results in lipid peroxidation products such as 4-hydroxynonenal, which binds to DNA and generates highly carcinogenic etheno DNA adducts.4 In rodents, ALD can be partly prevented by CYP2E1 knock out5 or by administration of the strong noncompetitive CYP2E1 inhibitor clomethiazole.6 Conversely, ALD is enhanced in mice overexpressing CYP2E1,7 underlying the potential role of CYP2E1 activity in ALD. To study whether CYP2E1 inhibition also improves ALD in humans, we performed an open, randomised controlled clinical trial (EudraCT-Number 2012-005730-11, online supplemental materials 1–3), as approved by the responsible Ethics Committee of the Medical Faculty of Heidelberg University (AFmo-586/2014) (online supplemental material 4) and the German authorities (BfArM) in alcohol-dependent patients who were admitted to the hospital for alcohol detoxification therapy (ADT). After giving written informed consent (online supplemental material 5), ADT was performed either with clomethiazole …

Without decarbonizing cities energy and climate objectives cannot be achieved as cities account for approximately two thirds of energy consumption and emissions. This goal of decarbonizing cities has to be facilitated by promoting net-zero/positive energy buildings and districts and replicating them, driving cities towards sustainability goals. Many projects in smart cities demonstrate novel and groundbreaking low-carbon solutions in demonstration and lighthouse projects. However, as the historical, geographic, political, social and economic context of urban areas vary greatly, it is not always easy to repeat the solution in another city or even district. It is therefore important to look for the opportunities to scale up or repeat successful pilots. The purpose of this paper is to explore common trends in technologies and replication strategies for positive energy buildings or districts in smart city projects, based on the practical experience from a case study in Leipzig—one of the lighthouse cities in the project SPARCS. One of the key findings the paper has proven is the necessity of a profound replication modelling to deepen the understanding of upscaling processes. Three models analyzed in this article are able to provide a multidimensional representation of the solution to be replicated.

We aimed to evaluate the medium-term efficacy of sleeve gastrectomy (SG)We identified severely obese patients [body mass index (BMI)35 kg/mNinety-six patients were investigated; 44 (45.8%) were women. The mean pre-operative BMI was 45.2 kg/mBariatric surgery with SG may be preferable to RYGB for obese patients with NAFLD and T2DM based on the rates of remission of markers of these co-morbidities. However, our results need to be confirmed in prospective trials. Understanding the metabolic effects of specific bariatric surgical procedures may facilitate the development of a personalised approach to weight-loss surgery.

IntroductionIn recent years, minimally invasive distal pancreatectomy (MIDP) has been used with increasing frequency to accelerate patient recovery. Distal pancreatectomy has an overall morbidity rate of 30%–40%. The known advantages of minimally invasive techniques must be rigorously compared with those of open surgery before they can be completely implemented into clinical practice.Methods and analysisDISPACT-2 is a multicentre randomised controlled trial comparing minimally invasive (conventional laparoscopic or robotic assisted) with open distal pancreatic resection in patients undergoing elective surgery for benign as well as malign diseases of the pancreatic body and tail. After screening for eligibility and obtaining informed consent, a total of 294 adult patients will be preoperatively randomised in a 1:1 ratio. The primary hypothesis is that MIDP is non-inferior to open distal pancreatectomy in terms of postoperative mortality and morbidity expressed as the Comprehensive Complication Index (CCI) within 3 months after index operation, with a non-inferiority margin of 7.5 CCI points. Secondary endpoints include pancreas-specific complications, oncological safety and patient reported outcomes. Follow-up for each individual patient will be 2 years.Ethics and disseminationThe DISPACT-2 trial has been approved by the Ethics Committee of the medical faculty of Heidelberg University (S-693/2017). Results of the primary endpoint will be available in 2024 and will be published at national and international meetings. Full results will be made available in an open access, peer-reviewed journal. The website www.dispact.de contains up-to-date information regarding the trial.Trial registration numberDRKS00014011

Although there is a clear indication that stages of residential decision making are characterized by their own stakeholders, activities, and outcomes, many studies on residential low-carbon technology adoption only implicitly address stage-specific dynamics. This paper explores stakeholder influences on residential photovoltaic adoption from a procedural perspective, so-called stakeholder dynamics. The major objective is the understanding of underlying mechanisms to better exploit the potential for residential photovoltaic uptake. Four focus groups have been conducted in close collaboration with the independent institute for social science research SINUS Markt- und Sozialforschung in East Germany. By applying a qualitative content analysis, major influence dynamics within three decision stages are synthesized with the help of egocentric network maps from the perspective of residential decision-makers. Results indicate that actors closest in terms of emotional and spatial proximity such as members of the social network represent the major influence on residential PV decision-making throughout the stages. Furthermore, decision-makers with a higher level of knowledge are more likely to move on to the subsequent stage. A shift from passive exposure to proactive search takes place through the process, but this shift is less pronounced among risk-averse decision-makers who continuously request proactive influences. The discussions revealed largely unexploited potential regarding the stakeholders local utilities and local governments who are perceived as independent, trustworthy and credible stakeholders. Public stakeholders must fulfill their responsibility in achieving climate goals by advising, assisting, and financing services for low-carbon technology adoption at the local level. Supporting community initiatives through political frameworks appears to be another promising step.

Background Sepsis is triggered by an infection and represents one of the greatest challenges of modern intensive care medicine. With regard to a targeted antimicrobial treatment strategy, the earliest possible pathogen detection is of crucial importance. Until now, culture-based detection methods represent the diagnostic gold standard, although they are characterized by numerous limitations. Culture-independent molecular diagnostic procedures represent a promising alternative. In particular, the plasmatic detection of circulating, cell-free DNA by next-generation sequencing (NGS) has shown to be suitable for identifying disease-causing pathogens in patients with bloodstream infections. Methods The DigiSep-Trial is a randomized, controlled, interventional, open-label, multicenter trial characterizing the effect of the combination of NGS-based digital precision diagnostics with standard-of-care microbiological analyses compared to solely standard-of-care microbiological analyses in the clinical picture of sepsis/septic shock. Additional anti-infective expert consultations are provided for both study groups. In 410 patients (n = 205 per arm) with sepsis/septic shock, the study examines whether the so-called DOOR-RADAR (Desirability of Outcome Ranking/Response Adjusted for Duration of Antibiotic Risk) score (representing a combined endpoint including the criteria (1) intensive/intermediate care unit length of stay, (2) consumption of antibiotics, (3) mortality, and (4) acute kidney injury (AKI)) can be improved by an additional NGS-based diagnostic concept. We also aim to investigate the cost-effectiveness of this new diagnostic procedure. It is postulated that intensive/intermediate care unit length of stay, mortality rate, incidence of AKI, the duration of antimicrobial therapy as well as the costs caused by complications and outpatient aftercare can be reduced. Moreover, a significant improvement in patient’s quality of life is expected. Discussion The authors´ previous work suggests that NGS-based diagnostics have a higher specificity and sensitivity compared to standard-of-care microbiological analyses for detecting bloodstream infections. In combination with the here presented DigiSep-Trial, this work provides the optimal basis to establish a new NGS-driven concept as part of the national standard based on the best possible evidence. Trial registrations DRKS-ID DRKS00022782. Registered on August 25, 2020 ClinicalTrials.govNCT04571801. Registered October 1, 2020

INTRODUCTION: Sepsis and septic shock are the most severe forms of infection affecting predominantly elderly people, preterm and term neonates, and young infants. Even in high-income countries sepsis causes about 8% of admissions to pediatric intensive care units (PICUs). Early diagnosis, rapid anti-infective treatment, and prompt hemodynamic stabilization are crucial for patient survival. In this context, it is essential to identify the causative pathogen as soon as possible to optimize antimicrobial treatment. To date, culture-based diagnostic procedures (e.g., blood cultures) represent the standard of care. However, they have 2 major problems: on the one hand, in the case of very small sample volumes (and thus usually in children), they are not sufficiently sensitive. On the other hand, with a time-to-result of 2 to 5 days, blood cultures need a relatively long time for the anti-infective therapy to be calculated. To overcome these problems, culture-independent molecular diagnostic procedures such as unbiased sequence analysis of circulating cell-free DNA (cfDNA) from plasma samples of septic patients by next-generation sequencing (NGS) have been tested successfully in adult septic patients. However, these results still need to be transferred to the pediatric setting. METHODS: The Next GeneSiPS-Trial is a prospective, observational, non-interventional, multicenter study used to assess the diagnostic performance of an NGS-based approach for the identification of causative pathogens in (preterm and term) neonates (d1-d28, n = 50), infants (d29 to

Recent data suggest that the type of anesthesia used during the resection of solid tumors impacts the long-term survival of patients favoring total-intravenous-anesthesia (TIVA) over inhalative-anesthesia (INHA). Here we sought to query this impact on survival in patients undergoing resection of glioblastoma (GBM). All patients receiving elective resection of a newly diagnosed, isocitrate-dehydrogenase-1-(IDH1)-wildtype GBM under general anesthesia between January 2010 and June 2017 in the Department of Neurosurgery, Heidelberg University Hospital, were included. Patients were grouped according to the applied anesthetic technique. To adjust for potential prognostic confounders, patients were matched in a 1:2 ratio (TIVA vs. INHA), taking into account the known prognostic factors: age, extent of resection, O-6-methylguanine-DNA-methyltransferase-(MGMT)-promoter-methylation-status, pre-operative Karnofsky-performance-index and adjuvant radio- and chemotherapy. The primary endpoint was progression-free-survival (PFS) and the secondary endpoint was overall-survival (OS). In the study period, 576 patients underwent resection of a newly diagnosed, IDH-wildtype GBM. Patients with incomplete follow-up-data, on palliative treatment, having emergency or awake surgery; 54 patients remained in the TIVA-group and 417 in the INHA-group. After matching, 52 patients remained in the TIVA-group and 92 in the INHA-group. Median PFS was 6 months in both groups. The median OS was 13.5 months in the TIVA-group and 13.0 months in the INHA-group. No significant survival differences associated with the type of anesthesia were found either before or after adjustment for known prognostic factors. This retrospective study supports the notion that the current anesthetic approaches employed during the resection of IDH-wildtype GBM do not impact patient survival. Supplementary Information The online version contains supplementary material available at 10.1007/s10143-020-01452-7.

Introduction Microcirculatory alterations are key mechanisms in sepsis pathophysiology leading to tissue hypoxia, edema formation, and organ dysfunction. Hyperspectral imaging (HSI) is an emerging imaging technology that uses tissue-light interactions to evaluate biochemical tissue characteristics including tissue oxygenation, hemoglobin content and water content. Currently, clinical data for HSI technologies in critical ill patients are still limited. Methods and analysis TIVITA® Tissue System was used to measure Tissue oxygenation (StO2), Tissue Hemoglobin Index (THI), Near Infrared Perfusion Index (NPI) and Tissue Water Index (TWI) in 25 healthy volunteers and 25 septic patients. HSI measurement sites were the palm, the fingertip, and a suprapatellar knee area. Septic patients were evaluated on admission to the ICU (E), 6 h afterwards (E+6) and three times a day (t3-t9) within a total observation period of 72 h. Primary outcome was the correlation of HSI results with daily SOFA-scores. Results Serial HSI at the three measurement sites in healthy volunteers showed a low mean variance expressing high retest reliability. HSI at E demonstrated significantly lower StO2 and NPI as well as higher TWI at the palm and fingertip in septic patients compared to healthy volunteers. StO2 and TWI showed corresponding results at the suprapatellar knee area. In septic patients, palm and fingertip THI identified survivors (E-t4) and revealed predictivity for 28-day mortality (E). Fingertip StO2 and THI correlated to SOFA-score on day 2. TWI was consistently increased in relation to the TWI range of healthy controls during the observation time. Palm TWI correlated positively with SOFA scores on day 3. Discussion HSI results in septic patients point to a distinctive microcirculatory pattern indicative of reduced skin oxygenation and perfusion quality combined with increased blood pooling and tissue water content. THI might possess risk-stratification properties and TWI could allow tissue edema evaluation in critically ill patients. Conclusion HSI technologies could open new perspectives in microcirculatory monitoring by visualizing oxygenation and perfusion quality combined with tissue water content in critically ill patients – a prerequisite for future tissue perfusion guided therapy concepts in intensive care medicine.

Despite the intensive research on residential photovoltaic adoption, there is a lack of understanding regarding the social dynamics that drive adoption decisions. Innovation diffusion is a social process, whereby communication structures and the relations between sender and receiver influence what information is perceived and how it is interpreted. This paper addresses this research gap by investigating stakeholder influences in household decision-making from a procedural perspective, so-called stakeholder dynamics. A literature review derives major influence dynamics which are then synthesized based on egocentric network maps for distinct process stages. The findings show a multitude of stakeholders that can be relevant in influencing photovoltaic adoption decisions of owner-occupied households. Household decision-makers are mainly influenced by stakeholders of their social network like family, neighbors, and friends as well as PV-related services like providers and civil society groups. The perceived closeness and likeability of a stakeholder indicate a higher level of influence because of greater trust involved. Furthermore, the findings indicate that social influence shifts gradually from many different stakeholders to a few core stakeholders later on in the decision-making process. These insights suggest that photovoltaic (PV) adoption may be more reliably predicted if a process perspective is taken into account that not only distinguishes between different stakeholders but considers their dynamic importance along the process stages. In addition, especially time- and location-bound factors affect the influence strength. This clearly shows the importance of local and targeted interventions to accelerate the uptake.