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Abstract Background High-level evidence regarding the technique of abdominal wall closure for patients undergoing emergency midline laparotomy is sparse. Therefore, we conducted a randomized controlled trial (RCT) to evaluate the efficacy and safety of two commonly applied abdominal wall closure strategies after primary emergency midline laparotomy. Methods/design CONTINT was a multi-center pragmatic open-label exploratory randomized controlled parallel trial. Two different abdominal wall closure strategies in patients undergoing primary midline laparotomy for an emergency surgical intervention with a suspected septic focus in the abdominal cavity were compared: the continuous, all-layer suture and the interrupted suture technique. The primary composite endpoint was burst abdomen within 30 days after surgery or incisional hernia within 12 months. As reliable data on this composite primary endpoint were not available for patients undergoing emergency surgery, it was planned to initially recruit 80 patients and conduct an interim analysis after these had completed the 12 months follow-up. Results From August 31, 2009, to June 28, 2012, 124 patients were randomized of whom 119 underwent surgery and were analyzed according to the intention-to-treat (ITT) principal. The primary composite endpoint did not differ between the continuous suture (C: 27.1%) and the interrupted suture group (I: 30.0%). None of the individual components of the primary endpoint (reoperation due to burst abdomen after 30 days (C: 13.5%, I: 15.1%) and reoperation due to incisional hernia (C: 3.0%, I:11.1%)) differed between groups. Time needed for fascial closure was longer in the interrupted suture group (C: 12.8 ± 4.5 min, I: 17.4 ± 6.1 min). BMI was associated with burst abdomen during the first 30 days with an OR of 1.17 (95% CI 1.04–1.32). Conclusion This RCT showed no difference between continuous suture with slowly absorbable suture versus interrupted rapidly absorbable sutures after primary emergency midline laparotomy in rates of postoperative burst abdomen and incisional hernia after one year. However, the trial was stopped after the interim analysis due to futility as there was no chance to show superiority of one suture technique.

Abstract Introduction Conventional polyethylene (PE) wear has been reported to be associated with femoral offset reconstruction and cup orientation after THA. Thus, the present study aimed (1) to determine the polyethylene wear rate of 32 mm ceramic heads with highly cross-linked polyethylene (HXLPE) inlays up to 10 years postoperatively and (2) to identify patient and surgery-related factors affecting the wear rate. Methods A prospective cohort study was performed, investigating 101 patients with 101 cementless THAs and ceramic (32 mm) on HXLPE bearings after 6–24 months, 2–5 years and 5–10 years postoperatively. The linear wear rate was determined using a validated software (PolyWare®, Rev 8, Draftware Inc, North Webster, IN, USA) by two reviewers, blinded to each other. A linear regression model was used to identify patient and surgery-related factors on HXLPE -wear. Results After an initial bedding-in phase of 1 year after surgery, the mean linear wear rate was 0.059 ± 0.031 mm/y at ten years (mean 7.7 years; SD 0.6 years, range 6–10), being below the osteolysis relevant threshold of 0.1 mm/year. The regression analysis demonstrated that age at surgery, BMI, cup inclination or anteversion and the UCLA score were not associated with the linear HXLPE-wear rate. Only increased femoral offset showed a significant correlation with an increased HXLPE-wear rate (correlation coefficient of 0.303; p = 0.003) with a moderate clinical effect size (Cohen’s f²=0.11). Conclusion In contrast to conventional PE inlays, hip arthroplasty surgeons may be less concerned about osteolysis-related wear of the HXLPE if the femoral offset is slightly increased. This allows focusing on joint anatomy reconstruction, hip stability and leg length.

Purpose: The Histolog® Scanner (SamanTree Medical SA, Lausanne, Switzerland) is a large field-of-view confocal laser scanning microscope designed to allow intraoperative margin assessment by the production of histological images ready for assessment in the operating room. We evaluated the feasibility and the performance of the Histolog® Scanner (HS) to correctly identify infiltrated margins in clinical practice of lumpectomy specimens. It was extrapolated if the utilization of the HS has the potential to reduce infiltrated margins and therefore reduce re-operation rates in patients undergoing breast conserving surgery (BCS) due to a primarily diagnosed breast cancer including ductal carcinoma in situ. Methods: This is a single-center, prospective, non-interventional, diagnostic pilot study including 50 consecutive patients receiving BCS. The complete surface of the specimen was scanned using the HS intraoperatively. The surgery and the intraoperative margin assessment of the specimen was performed according to the clinical routine consisting of conventional specimen radiography as well as the clinical impression of the surgeon. Three surgeons and an experienced pathologist assessed the scans produced by the HS for cancer cells on the surface. The potential of the HS to correctly identify involved margins was compared to the results of the conventional specimen radiography alone as well as the clinical routine. The histopathological report served as the gold standard. Results: 50 specimens corresponding to 300 surfaces were scanned by the HS. The mean sensitivity of the surgeons to identify involved margins with the HS was 37.5% ± 5.6%, the specificity was 75.2% ± 13.0%. The assessment of resection margins by the pathologist resulted in a sensitivity of 37.5% and a specificity of 81.0%, while the local clinical routine resulted in a sensitivity of 37.5% and a specificity of 78.2%. Conclusion: Acquisition of high-resolution histological images using the HS was feasible in clinical practice. Sensitivity and specificity were comparable to clinical routine. With more specific training and experience on image interpretation and acquisition, the HS may have the potential to enable more accuracy in the margin assessment of BCS specimens.

Policy assessment is often limited to the evaluation of the physical effectiveness or economic efficiency. To analyse how policies intervene in the complex reality, qualitative and quantitative complex system modelling approaches from the field of Systems Thinking (STM), System Dynamics (SDM) or Agent-based modelling (ABM) can provide valuable insights. This article aims to illuminate the opportunities and limitations of these three exploratory modelling approaches for policy assessment. It addresses stakeholders in policy advices and decision makers designing policies and gives an overview of modelling approaches to evaluate the complex and social impact of policies including side-effects and non-linear system behaviour. After a short review of policy modelling in general, we compare STM, SDM and ABM regarding their methodology, modelling process and applicability in practical policy advice. We suggest that STM as a qualitative modelling approach is applicable to foster short-term policy design processes. In contrast, SDM and ABM as a time-resolved quantitative technique enable deeper system insights but requires more effort regarding model quantification. They are ideal to analyse how policies affect long-term societal problems like sustainability transformations. Finally, we propose first measures to establish such complex system modelling approaches, which today represent only a niche in policy evaluation.

In recent decades, infusion solutions such as NaCl 0.9% and lactate Ringer’s solution have been replaced in clinical practice. Since 2017, the national guidelines for perioperative infusion therapy in children recommend balanced isotonic solutions to maintain fluid balance. The composition of balanced infusion solutions varies with respect to their electrolyte content. Hyperchloremia may be mistaken for hypovolemia and may interfere with volume therapy in pediatric patients. Sterofundin ISO® balanced solution contains 127 mmol/L chloride and may cause hyperchloremic acidosis if administered in large volumes. Objectives: The purpose of this study was to compare the effects of Sterofundin ISO® (SF) therapy with the balanced isochloremic solution Deltajonin® (DJ) (106 mmol/L chloride) on the acid–base status in infants undergoing craniofacial surgery. Methods: This retrospective, non-blinded study included 100 infants undergoing craniectomy due to isolated nonsyndromic sagittal craniosynostosis. The first 50 infants received Sterofundin ISO®. Due to changes in national guidelines, the infusion was changed to the isoionic Deltajonin® in an additional 50 infants in 2017. Pre- and postoperative values of chloride, pH, base excess, bicarbonate, and albumin and phosphate were determined, and the strong-ion difference, strong-ion gap, anion gap, and weak acids were calculated. Results: Both groups were comparable in terms of their age, sex, underlying disease, preoperative electrolytes (except K at 3.9 ± 0.3 mmol/L (SF) vs. 4.1 ± 0.3 mmol/L (DJ) and lactate 8.7 ± 2.1 (SF) vs. 9.6 ± 2.6 mmol/L (DJ)). In the Sterofundin ISO® group, hyperchloremic metabolic acidosis was observed in 19 patients, whereas only 2 infants in the Deltajonin® group had hyperchloremic metabolic acidosis. The postoperative chloride level was 111 ± 2.7 mmol/L (SF) vs. 108 ± 2.4 mmol/L (DJ). The difference in anion gap was 12.5 ± 3.0 mmol/L (SF) vs. 14.6 ± 2.8 mmol/L (DJ), and the difference in SIDa (apparent strong-ion difference) was 30.9 mmol/L (SF) vs. 33.8 mmol/L (DJ). Conclusions: Hyperchloremic acidosis can be induced by the volume replacement with high-chloride-concentration crystalloids such as Sterofundin ISO®. This can be detected using the Stewart model.

Abstract Clinical photon-counting CT (PCCT) offers a spatial resolution of about 200 µm and might allow for acquisitions close to conventional dental CBCTs. In this study, the capabilities of this new system in comparison to dental CBCTs shall be evaluated. All 8 apical osteolysis identified in CBCT were identified by both readers in all three PCCT scan protocols. Mean visibility scores showed statistical significant differences for root canals(p = 0.0001), periodontal space(p = 0.0090), cortical(p = 0.0003) and spongious bone(p = 0.0293) in favor of high and medium dose PCCT acquisitions. Overall, both devices showed excellent image quality of all structures assessed. Interrater-agreement showed high values for all protocols in all structures. Bland–Altman plots revealed a high concordance of both modalities with the reference measurements. In vitro, ultra-high resolution PCCT can reliably identify different diagnostic entities and structures relevant for dental diagnostics similar to conventional dental CBCT with similar radiation dose. Acquisitions of five cadaveric heads were performed in an experimental CT-system containing an ultra-high resolution PC detector (0.25 mm pixel size in isocenter) as well as in a dental CBCT scanner. Acquisitions were performed using dose levels of 8.5 mGy, 38.0 mGy and 66.5 mGy (CTDI16cm) in case of PCCT and of 8.94 mGy (CTDI16cm) in case of CBCT. The quality of delineation of hard tissues, root-canals, periodontal-space as well as apical osteolysis was assessed by two readers. Mean visibility scores and interrater-agreement (overall agreement (%)) were calculated. Vertical bone loss (bl) and thickness (bt) of the buccal bone lamina of 15 lower incisors were measured and compared to reference measurements by ore microscopy and clinical probing.

Abstract Different cone beam computed tomography (CBCT) protocols have shown promising results for imaging furcation defects. This study evaluates the suitability of low-dose (LD)-CBCT for this purpose. Fifty-nine furcation defects of nine upper and 16 lower molars in six human cadavers were measured by a high-dose (HD)-CBCT protocol, a LD-CBCT protocol, and a surgical protocol. HD-CBCT and LD-CBCT measurements were made twice by two investigators and were compared with the intrasurgical measurements, which served as the reference. Furcation defect volumes generated from HD-CBCT and LD-CBCT imaging were segmented by one rater. Cohen’s kappa and intraclass correlation coefficient (ICC) values were calculated to determine intra- and interrater reliability. The level of significance was set at α = 0.05. In total, 59 furcation defects of nine upper and 16 lower human molars were assessed. Comparing CBCT furcation defect measurements with surgical measurements revealed a Cohen’s kappa of 0.5975 (HD-and LD-CBCT), indicating moderate agreement. All furcation defects identified by HD-CBCT were also detected by LD-CBCT by both raters, resulting in a Cohen’s kappa of 1. For interrater agreement, linear furcation defect measurements showed an ICC of 0.992 for HD-CBCT and 0.987 for LD-CBCT. The intrarater agreement was 0.994(r1)/0.992(r2) for HD-CBCT and 0.987(r1)/0.991(r2) for LD-CBCT. The intermodality agreement was 0.988(r1)/0.991(r2). Paired t-test showed no significant differences between HD-CBCT and LD-CBCT measurements. LD-CBCT is a precise and reliable method for detecting and measuring furcation defects in mandibular and maxillary molars in this experimental setting. It has the potential to improve treatment planning and treatment monitoring with a far lower radiation dose than conventional HD-CBCT.

Abstract 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

Knee range of motion and patient-reported outcome measures (PROMs) are often used as screening tools to assess the severity of knee osteoarthritis and guide the decision to refer patients to an arthroplasty clinic. However, there is little understanding regarding the correlation between these factors. Thus, the purpose of this study was to determine the correlation between patient-reported clinical function measured with the Oxford Knee Score (OKS), pain assessed using the visual analog scale (VAS), knee range of motion (ROM), and characteristic radiographic features in patients with advanced osteoarthritis of the knee. A prospective analysis of a consecutive series of 138 patients with advanced unilateral osteoarthritis (OA) of the knee was performed. The severity of radiographic OA was classified according to the most commonly used Kellgren and Lawrence classification (K&L). Spearman’s rank correlation analysis and multiple linear regression analysis were performed. The OKS was used as a dependent variable and was adjusted for pain, ROM, and nine standardized radiographic parameters on multiple views of the tibiofemoral and patellofemoral joint. OKS and pain correlated weakly with the K&L grade (r = −0.289; p = 0.001; r = 0.258; p = 0.002). K&L grade and the degree of patellofemoral joint space narrowing were identified as independent factors being associated with a poorer OKS (coefficient −4.528, p = 0.021; coefficient −2.211, p = 0.038). Slightly worse results were identified for OKS and pain in patients with K&L grade 4 osteoarthritis compared to patients with K&L grade 3 osteoarthritis (∆OKS 5.5 points, p < 0.001; ∆VAS 1.7 points, p = 0.003). There was no significant difference for passive range of motion between patients with K&L grade 3 or 4. When counseling patients with advanced knee osteoarthritis who may be eligible for knee arthroplasty, it is essential to give primary consideration to pain levels and self-reported limitations experienced during daily activities. Relying solely on knee ROM and PROMs is not an effective screening method for guiding the decision to refer patients to an arthroplasty clinic.

Abstract 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.gov NCT04571801 . Registered October 1, 2020

Abstract Background Partial pancreatoduodenectomy (PD) is the indicated surgical procedure for a wide range of benign and malignant diseases of the pancreatic head and distal bile duct and offers the only potential cure for pancreatic head cancer. The current gold standard, open PD (OPD) performed via laparotomy, is associated with morbidity in around 40% of cases, even at specialised centres. Robotic PD (RPD) might offer a viable alternative to OPD and has been shown to be feasible. Encouraging perioperative results have been reported for RPD in a number of small, non-randomised studies. However, since those studies showed a considerable risk of bias, a thorough comparison of RPD with OPD is warranted. Methods The EUROPA (EvalUation of RObotic partial PAncreatoduodenectomy) trial is designed as a randomised controlled unblinded exploratory surgical trial with two parallel study groups. A total of 80 patients scheduled for elective PD will be randomised after giving written informed consent. Patients with borderline or non-resectable carcinoma of the pancreatic head as defined by the National Comprehensive Cancer Network guidelines, distant metastases or an American Society of Anaesthesiologists (ASA) score > III will be excluded. The experimental intervention, RPD, will be compared with the control intervention, OPD. An intraoperative dropout of approximately eight patients per group is expected because they may receive another type of surgical procedure than planned. Overall, 64 patients need to be analysed. The primary endpoint of the trial is overall postoperative morbidity within 90 days after index operation, measured using the Comprehensive Complication Index (CCI). The secondary endpoints include the feasibility of recruitment and assessment of clinical, oncological and safety parameters and quality of life and cost-effectiveness. Discussion The EUROPA trial is the first randomised controlled trial comparing RPD with OPD. Differences in postoperative morbidity will be evaluated to design a future multicentre confirmatory efficacy trial. Trial registration German Clinical Trial Register DRKS00020407 . Registered on 9 March 2020

Preterm birth serves as one of the leading causes of neonatal mortality worldwide. The underlying mechanisms that contribute to preterm birth are not yet fully understood. However, an association between periodontitis and preterm birth has been proposed. The periodontal status and presence of periodontal pathogens in women with different birth outcomes have been previously examined. However, varying definitions of periodontitis and different microbiological methods make their interpretation challenging. The aim of this case-control study on women with and without preterm birth was to investigate their periodontal status using the current classification system for periodontal diseases. Moreover, differences in the periodontal microbiome of the study participants were investigated. Therefore, we collected data on oral and periodontal parameters in 77 puerperal women divided into two groups based on gestational age at delivery: 33 patients with preterm birth (PTB, 37 weeks). These data included pocket probing depth (PPD), clinical attachment loss (CAL), bleeding on probing (BOP), gingival-bleeding index, DMFT index, and gynecologic and dental history. In addition, their oral microbiome was explored. Median CAL and percentage PPD ≥ 4 mm were significantly higher in the PTB group than in the TB group (p = 0.0128 and p = 0.047, respectively). Birth weight was significantly higher in periodontally healthy women than in those with gingivitis (p = 0.0078) or periodontitis (p = 0.0127). The periodontal microbiome differed significantly between groups. Our results are underlining the possible association between periodontitis and preterm delivery. Women with periodontitis had babies with significantly lower birth weights. The microbiome varied between the groups.

Abstract Background Ankle sprains and fractures are most common injuries in orthopedic and trauma surgery. The concurrent occurrence of syndesmosis ruptures in these injuries represents a more complex problem, as they often remain undetected. A proper and accurate treatment of injuries of the syndesmosis, both isolated and combined with fractures, is necessary to avoid long-term consequences (chronic instability, cartilage damage, and post-traumatic osteoarthritis). The most popular treatment option is a static screw fixation and the newly developed dynamic TightRope® (Arthrex, Naples, FL, USA). The aim of this pilot study is to compare monitor ankle range of motion and maximum ankle power in gait as functional outcome parameters of instrumented gait analysis, as well as clinical and radiographic outcome for assessing the stabilization of acute syndesmosis rupture with either a static implant (a 3.5 mm metallic screw) or a dynamic device (TightRope®). Methods This prospective, randomized, controlled, clinical trial will be carried out at the Center for Orthopedics, Trauma Surgery and Spinal Cord Injury of the University Hospital Heidelberg. Adult patients, who suffer from an acute syndesmosis rupture, both isolated and in combination with fractures of the lateral malleolus (Weber C and Maisonneuve fractures) and who are undergoing surgery at our trauma center will be included in our study. The patients will be randomized to the different treatment options (screw fixation or “TightRope®”). Subsequent to the surgical treatment, all patients will receive the same standardized follow-up procedures including a gait analysis and MRI of the ankle at 6 months follow-up. The primary endpoint of the study is the successful healing of the syndesmosis and biomechanical investigation with gait analysis. Discussion The results of the gait analysis from the current study will help to impartially and reliably evaluate the clinical and biomechanical outcome of both treatment options of acute syndesmosis ruptures. We hypothesize that the dynamic fixation provides an equivalent or better biomechanical, clinical, and radiographic outcome in comparison to the screw fixation. Trial registration German Clinical Trials Register (DRKS) DRKS00013562 . Registered on July, 12, 2017.

Abstract Background High-dose (HD) chemotherapy followed by autologous blood stem-cell transplantation (ASCT) is the standard treatment for multiple myeloma (MM) patients. However, the collection of sufficient peripheral blood stem cell (PBSC) grafts can be challenging, and the question arises whether reinfusion of low-dose grafts will lead to a hematopoietic recovery. Methods The hematopoietic recovery of 148 MM patients who underwent HD melphalan chemotherapy and received PBSC transplants with varying CD34+ cells doses (3–4 × 106 [n = 86], 2–2.5 × 106 [n = 53],

Abstract Background The arthroscopic method offers a less invasive technique of Bankart repair for traumatic anterior shoulder instability. The aim of the study is to determine the mid−/long-term functional outcome, failure rates and predictors of failure after primary arthroscopic Bankart repair for traumatic anterior shoulder instability. Methods A total of 100 patients were primarily operated using arthroscopic Bankart repair after traumatic anterior shoulder instability. Medical records were retrospectively reviewed, and patients were assessed using postal questionnaire after a mean follow-up of 8.3 years [3–14]. Clinical assessment was performed using Constant score, Rowe score, and American Shoulder and Elbow Surgeons score. Results The overall recurrence rate was 22%. The Kaplan-Meier failure-free survival estimates. were 80% at 5 years and 70% at 10 years. Nearly half (54.5%) of recurrences occurred at 2 years postoperative. Compared with normal shoulder, there were statistical differences in all 3 scores. Failure rate was significantly affected by age at the time of surgery with 86% of recurrence cases observed in patients aged 30 years or younger. Nevertheless, Younger age at the time of surgery (P = 0.007) as well age at the time of initial instability (P = 0.03) was found to correlate negatively with early recurrence within 2 years of surgery. Among those with recurrent instability, recurrence rate was found to be higher if there had been more than 5 instability episodes preoperatively (P = 0.01). Return to the preinjury sport and occupational level was possible in 41 and 78%, respectively. Conclusion Failure-free survival rates dropped dramatically over time. Alternative reconstruction techniques should be considered in those aged ≤30 years due to the high recurrence rate.

Background: After liver transplantation (LTX), patients are susceptible to opportunistic infections resulting in reduced outcomes within the early post-transplantation period. The postoperative monitoring of LTX patients has gained much importance in recent years. However, reliable plasmatic markers predicting 90-day outcomes are still lacking. Methods: In the post hoc analysis of a prospective, observational study, butyrylcholinesterase (BChE), mid-regional proadrenomedullin (MR-proADM), as well as conventional inflammatory markers (procalcitonin, C-reactive protein) were evaluated in 93 patients at seven consecutive timepoints within the first 28 days following LTX. Results: Persistently reduced activity of BChE and elevated MR-proADM levels indicated reduced 90-day survival following LTX. Furthermore, reduced BChE and increased MR-proADM activity could indicate early post-transplantation bacterial infections, whereas conventional inflammatory biomarkers showed no diagnostic efficacy within the observation period. Conclusion: Concurrent assessment of BChE and MR-proADM activity might serve as a bedside diagnostic tool for early bacterial infections following liver transplantation. Thus, a combined utilization of the two biomarkers may be a useful tool in the risk evaluation of patients following liver transplantation.

Abstract Background The placement of prophylactic intra-abdominal drains has been common practice in abdominal operations including pancreatic surgery. The PANDRA trial showed that the omission of drains following pancreatic head resection was non-inferior to intra-abdominal drainage in terms of postoperative reinterventions and superior in terms of clinically relevant pancreatic fistula rate and fistula-associated complications. The aim of the present PANDRA II trial is to evaluate the clinical outcome with versus without prophylactic drain placement after distal pancreatectomy. Methods The PANDRA II trial is a mono-center, randomized controlled, non-inferiority trial with two parallel study groups. In the control group at least one passive intra-abdominal drain is placed at the pancreatic resection margin. In the experimental group no drains are placed. The primary endpoint of this trial will be the Comprehensive Complication Index (CCI) measuring all postoperative complications within 90 days. Secondary endpoints are in-hospital mortality and morbidity, including the rates of postoperative pancreatic fistula, chyle leak, postpancreatectomy hemorrhage, delayed gastric emptying, reinterventions and reoperations, surgical site infection, and abdominal fascia dehiscence. Moreover, length of hospital stay, duration of intensive care unit stay, and the rate of readmission after discharge from hospital (up to day 90 after surgery) are assessed. We will need to analyze 252 patients to test the hypothesis that no drainage is non-inferior to drain placement in terms of the CCI (δ 7.5 points) in a one-sided t test with a one-sided level of significance of 2.5% and a power of 80%. Discussion The results of the PANDRA II trial will help to evaluate the effect of an omission of prophylactic intraperitoneal drainage on the rate of complications after open or minimally invasive distal pancreatectomy. Trial registration German Clinical Trials Register (DRKS), DRKS00013763. Registered on 6 March 2018.

Abstract Background Thigh pain and cortical hypertrophies (CH) have been reported in the short term for specific short hip stem designs. The purpose of the study was to investigate 1) the differences in clinical outcome, thigh pain and stem survival for patients with and without CHs and 2) to identify patient and surgery-related factors being associated with the development of CHs. Methods A consecutive series of 233 patients with 246 hips was included in the present retrospective diagnostic cohort study, who had received a total hip arthroplasty (THA) between December 2007 and 2009 with a cementless, curved, short hip stem (Fitmore, Zimmer, Warsaw, IN, USA). Clinical and radiographic follow-up, including the radiographic parameters for hip geometry reconstruction, were prospectively assessed 1, 3, and 6 to 10 years after surgery. Results Cortical hypertrophies were observed in 56% of the hips after a mean of 7.7 years, compared to 53% after 3.3 years being mostly located in Gruen zone 3 and 5. There was no significant difference for the Harris Hip Score and UCLA score for patients with and without CHs. Only one patient with a mild CH in Gruen zone 5 and extensive heterotopic ossifications around the neck of the stem reported thigh pain. The Kaplan Meier survival rate after 8.6 years was 99.6% (95%-CI; 97.1–99.9%) for stem revision due to aseptic loosening and no association with CHs could be detected. Postoperative increase in hip offset was the only risk factor being associated with the development of CHs in the regression model (ΔHO; OR 1.1 (1.0–1.2); p = 0.001). Conclusions The percentage of cortical hypertrophies remained almost constant in the mid-term compared to the short-term with the present cementless short hip stem design. The high percentage of cortical hypertrophies seems not be a cause for concern with this specific implant in the mid-term. Level of evidence Diagnostic Level IV

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

Abstract Background Septic coagulopathy represents a very dynamic disease entity, tilting from initial hypercoagulability towards a subsequent hypocoagulable disease state, entitled overt disseminated intravascular coagulation. Acute fibrinolysis shutdown has recently been described to be a crucial component of initial hypercoagulability in critically ill patients, although the underlying pathomechanisms, the specific temporal kinetics and its outcome relevance in patients with sepsis remain to be determined. Methods In total, 90 patients (30 with septic shock, 30 surgical controls and 30 healthy volunteers) were enrolled. Blood samples were collected at sepsis onset or prior and immediately after the surgical procedure as well as 3 h, 6 h, 12 h, 24 h, 48 h and 7 d later, whereas blood samples from healthy volunteers were collected once. Besides viscoelastic and aggregometric point-of-care testing (POCT), enzyme-linked immunosorbent and thrombin generation assays and liquid chromatography–mass spectrometry-based measurements were performed. Results As assessed by viscoelastic POCT, fibrinolysis shutdown occurred early in sepsis. Significant increases in tissue plasminogen activator had no effect on thromboelastometrical lysis indices (LIs). Contrariwise, plasminogen activator inhibitor-1 was already significantly increased at sepsis onset, which was paralleled by significantly increased LIs in patients suffering from septic shock in comparison with both control groups. This effect persisted throughout the 7-day observation period and was most pronounced in severely ill as well as non-surviving septic patients. Thromboelastometrical LI, therefore, proved to be suitable for early diagnosis [e.g. LI 45 min: area under the curve (AUC) up to 0.933] as well as prognosis (e.g. LI 60 min: AUC up to 1.000) of septic shock. Conclusions Early inhibition of plasminogen activation leads to acute fibrinolysis shutdown with improved clot stability and is associated with increased morbidity and mortality in septic patients. Trial registration This study was approved by the local ethics committee (Ethics Committee of the Medical Faculty of Heidelberg; Trial-Code No. S247-2014/German Clinical Trials Register (DRKS)-ID: DRKS00008090; retrospectively registered: 07.05.2015). All study patients or their legal representatives signed written informed consent.

In this observational prospective multicenter study conducted between October 2016 and October 2018, we tested the hypothesis that the use of prehospital non-invasive ventilation (phNIV) to treat patients with acute respiratory insufficiency (ARI) caused by severe acute exacerbations of chronic obstructive pulmonary disease (AECOPD) and acute cardiopulmonary oedema (ACPE) is effective, time-efficient and safe. The data were collected at four different physician response units and three admitting hospitals in a German EMS system. Patients with respiratory failure due to acute exacerbation of chronic obstructive pulmonary disease and acute cardiopulmonary oedema were enrolled. A total of 545 patients were eligible for the final analysis. Patients were treated with oxygen supplementation, non-invasive ventilation or invasive mechanical ventilation. The primary outcomes were defined as changes in the clinical parameters and the in-hospital course. The secondary outcomes included time efficiency, peri-interventional complications, treatment failure rate, and side-effects. Oxygenation under phNIV improved equally to endotracheal intubation (ETI), and more effectively in comparison to standard oxygen therapy (SOT) (paO2 SOT vs. non-invasive ventilation (NIV) vs. ETI: 82 mmHg vs. 125 mmHg vs. 135 mmHg, p-value SOT vs. NIV < 0.0001). In a matched subgroup analysis phNIV was accompanied by a reduced time of mechanical ventilation (phNIV: 1.8 d vs. ETI: 4.2 d) and a shortened length of stay at the intensive care unit (3.4 d vs. 5.8 d). The data support the hypothesis that the treatment of severe AECOPD/ACPE-induced ARI using prehospital NIV is effective, time efficient and safe. Compared to ETI, a matched comparison supports the hypothesis that prehospital implementation of NIV may provide benefits for an in-hospital course.

The authors would like to make a correction in a recently published paper [...]

This study aimed to evaluate the Mediterranean Diet Adherence Screener (MEDAS) in a study investigating the anti-inflammatory effect of a 6-week Mediterranean diet intervention on periodontal parameters. Data from a randomized clinical trial were analyzed for correlations between the MEDAS score and oral inflammatory parameters (bleeding on probing (BOP), gingival index (GI), and periodontal inflamed surface area (PISA)) and select nutrient intakes estimated by a food frequency questionnaire (FFQ) and a 24-h dietary recall (24dr). A mixed model, calculations of Spearman ρ, Lin’s Concordance Coefficient (CC), and Mann–Whitney U test were used for the statistical analyses. The MEDAS score was significantly negatively correlated with periodontal inflammation (BOP: CoE −0.391, p < 0.001; GI −0.407, p < 0.001; PISA −0.348, p = 0.001) and positively correlated with poly unsaturated fatty acids/total fat, vitamin C, and fiber intake estimates obtained from the FFQ and 24dr (ρ 0.38–0.77). The FFQ and 24dr produced heterogeneously comparable intake results for most nutrients (CC 0–0.79, Spearman ρ 0.16–0.65). Within the limitations of this study, the MEDAS was able to indicate nutritional habits associated with different levels of periodontal inflammation. Accordingly, the MEDAS can be a sufficient and useful diet screener in dental studies. Due to its correlation with oral inflammatory parameters, the MEDAS might also be useful in dental practice.

Objective: Obesity surgery provides sustainable weight loss, improvement of comorbidities, and improved quality of life (QOL). There is few evidence on the patient perspective and goals. This study compared expected and achieved weight loss, body shape, and QOL. Methods: Patients completed the Moorehead-Ardelt QOL questionnaire (MAQOL) and questionnaires on actual and expected weight loss and body shape, comorbidities, and goals of obesity surgery preoperatively and within 24 months postoperatively. Results: 44 patients completed questionnaires pre- and postoperatively. BMI, MAQOL and comorbidities significantly improved postoperatively. Patients’ expected weight loss goal corresponded to a postoperative BMI of 32.6 ± 5.6 kg/m2 and was not different from their achieved BMI within 24 months after surgery (33.9 ± 6.3 kg/m2, p = 0.276). Self-reported body shape improved but did not reach preoperatively expected goals. During the weight loss period, patients adapted their weight loss and body shape goals to higher levels. Patients attributed a higher part of their success in weight loss to surgery postoperatively (79.5 ± 22.0 vs. 89.1 ± 18.4%, p = 0.028). Conclusion: Patients lost as much weight as they had expected and later modified the goals to even greater weight loss. Body shape improved but did not reach expected levels. QOL improved independently from weight loss and body shape. Patients attributed successful weight loss predominantly to surgery.

Abstract Background This was a prespecified secondary analysis of a randomized trial that analyzed bone density and pain response following fractionated intensity-modulated radiotherapy (IMRT) versus three-dimensional conformal radiotherapy (3DCRT) for palliative management of spinal metastases. Methods/materials Sixty patients were enrolled in the single-institutional randomized exploratory trial, randomly assigned to receive IMRT or 3DCRT (30 Gy in 10 fractions). Along with pain response (measured by the Visual Analog Scale (VAS) and Chow criteria), quantitative bone density was evaluated at baseline, 3, and 6 months in both irradiated and unirradiated spinal bodies, along with rates of pathologic fractures and vertebral compression fractures. Results Relative to baseline, bone density increased at 3 and 6 months following IMRT by a median of 24.8% and 33.8%, respectively (p

Abstract Background One of the most important aspects of designing a clinical trial is selecting appropriate outcomes. Patient-reported outcomes (PROs) can provide a personal assessment of the burden and impact of a malignant disease and its treatment. PROs comprise a wide range of outcomes including basic clinical symptom scores and complex metrics such as health-related quality of life (HRQoL). There is limited data on how postoperative complications following cancer surgery affect symptoms and HRQoL. For this reason the primary aim of the PATRONUS study is to investigate how perioperative complications affect cancer-related symptoms and HRQoL in patients undergoing abdominal cancer surgery. The PATRONUS study is designed and will be initiated and conducted by medical students under the direct supervision of clinician scientists based on the concept of inquiry-based learning. Methods PATRONUS is a non-interventional prospective multicentre cohort study. Patients undergoing elective oncological abdominal surgery will be recruited at regional centres of the clinical network of the German Surgical Society (CHIR-Net) and associated hospitals. A core set of 12 cancer associated symptoms will be assessed via the PRO version of the Common Terminology Criteria for Adverse Events. The cancer-specific HRQoL will be measured via the computerised adaptive testing version of the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30. PROs will be measured eight times over a period of six months. The short-term clinical outcome measure is the rate of postoperative complications (grade II to V) within 30 days according to the Clavien-Dindo classification. The long-term clinical outcome is overall survival within six months postoperative. Discussion PATRONUS will provide essential insights into the patients’ assessment of their well-being and quality of life in direct relation to clinical outcome parameters following abdominal cancer surgery. Furthermore, PATRONUS will investigate the feasibility of multicentre student-led clinical research. Trial registration German Clinical Trials Register: DRKS00013035 (registered on October 26, 2017). Universal Trial Number (UTN): U1111–1202-8863.

Despite widespread drug exposure, for example during gestation or in prematurely born children, organ-specific developmental toxicity of most drugs is poorly understood. Developmental and functional abnormalities are a major cause of kidney diseases during childhood; however, the potential causal relationship to exposure with nephrotoxic drugs during nephrogenesis is widely unknown. To identify developmental nephrotoxic drugs in a large scale, we established and performed an automated high-content screen to score for phenotypic renal alterations in the Tg(wt1b:EGFP) zebrafish line. During early nephrogenesis, embryos were exposed to a compound library of approved drugs. After treatment, embryos were aligned within microtiter plates using 3D-printed orientation tools enabling the robust acquisition of consistent dorsal views of pronephric kidneys by automated microscopy. To qualitatively and quantitatively score and visualize phenotypes, we developed software tools for the semi-automated analysis, processing and visualization of this large image-based dataset. Using this scoring scheme, we were able to categorize compounds based on their potential developmental nephrotoxic effects. About 10% of tested drugs induced pronephric phenotypes including glomerular and tubular malformations, or overall changes in kidney morphology. Major chemical compound groups identified to cause glomerular and tubular alterations included dihydropyridine derivatives, HMG CoA reductase inhibitors, fibrates, imidazole, benzimidazole and triazole derivatives, corticosteroids, glucocorticoids, acetic acid derivatives and propionic acid derivatives. In conclusion, the presented study demonstrates the large-scale screening of kidney-specific toxicity of approved drugs in a live vertebrate embryo. The associated technology and tool-sets can be easily adapted for other organ systems providing a unique platform for in vivo large-scale assessment of organ-specific developmental toxicity or other biomedical applications. Ultimately, the presented data and associated visualization and browsing tools provide a resource for potentially nephrotoxic drugs and for further investigations.

OBJECTIVES:To test the feasibility of a randomized controlled study design comparing epidural analgesia (EDA) with continuous wound infiltration (CWI) in respect to postoperative complications and mobility to design a future multicentre randomized controlled trial. DESIGN, SETTING, PARTICIPANTS:CWI has been developed to address drawbacks of EDA. Previous studies have established the equivalent analgesic potential of CWI compared to EDA. This is a single centre, non-blinded pilot randomized controlled trial at a tertiary surgical centre. Patients undergoing elective non-colorectal surgery via a midline laparotomy were randomized to EDA or CWI. Endpoints included recruitment, feasibility of assessing postoperative mobility with a pedometer and morbidity. No primary endpoint was defined and all analyses were explorative. INTERVENTIONS:CWI with local anaesthetics (experimental group) vs. thoracic EDA (control). RESULTS:Of 846 patients screened within 14 months, 71 were randomized and 62 (31 per group) included in the intention-to-treat analysis. Mobility was assessed in 44 of 62 patients and revealed no differences within the first 3 postoperative days. Overall morbidity did not differ between the two groups (measured via the comprehensive complication index). Median pain scores at rest were comparable between the two groups, while EDA was superior in pain treatment during movement on the first, but not on the second and third postoperative day. Duration of preoperative induction of anaesthesia was shorter with CWI than with EDA. Of 17 serious adverse events, 3 were potentially related to EDA, while none was related to CWI. CONCLUSION:This trial confirmed the feasibility of a randomized trial design to compare CWI and EDA regarding morbidity. Improvements in the education and training of team members are necessary to improve recruitment. TRIAL REGISTRATION:DRKS00008023.

ObjectivesLoss of body weight is often seen in pancreatic cancer and also predicts poor prognosis. Thus, maintaining muscle mass is an essential treatment goal. The primary aim was to investigate whether progressive resistance training impacts muscle and adipose tissue compartments. Furthermore, the effect of body composition on overall survival (OS) was investigated.MethodsIn the randomized SUPPORT-study, 65 patients were assigned to 6-month resistance training (2x/week) or a usual care control group. As secondary endpoint, muscle strength of the upper and lower extremities was assessed before and after the intervention period. Routine CT scans were assessed on lumbar L3/4 level for quantification of total-fat-area, visceral-fat-area, subcutaneous-fat-area, intramuscular-fat-area, visceral-to-subcutaneous fat ratio (VFR), muscle-area (MA), muscle-density and skeletal-muscle-index (SMI). OS data were retrieved.ResultsOf 65 patients, 53 had suitable CT scans at baseline and 28 completed the intervention period with suitable CT scans. There were no significant effects observed of resistance training on body composition (p>0.05; effect sizes ω2p ConclusionThere is anabolic potential in patients with resectable pancreatic cancer. A progressive resistance training may help patients to maintain their muscle mass and avoid muscle depletion. CT-quantified muscle mass at the level of L3/4 showed a good correlation to muscle strength. Therefore, maintaining muscle mass and muscle strength through structured resistance training could help patients to maintain their physical functioning. A high VFR at baseline and a high loss of muscle mass are predictors of poor OS. Registered on ClinicalTrials.gov (NCT01977066).

Background. Nowadays, invasive fungal infections (IFI) are of increasing importance and associated with an increased mortality. However, reliable diagnostic tools for the identification of patients suffering from an IFI are rare and associated with relevant weaknesses. Methods. Within this secondary analysis of an observational clinical study, an innovative biomarker panel (consisting of 62 biomarkers in total) was screened for the identification of septic shock patients suffering from an IFI. Fungal growth in blood cultures, intraoperative swabs, and Aspergillus spp. in deep respiratory tract specimens with accompanying pulmonary infiltrates were classified as infection, whereas Candida spp. in the respiratory tract or in fluids from drainages were classified as colonization. Plasma samples of 50 septic shock patients at six predefined timepoints within a period of 28 days following the onset of septic shock were available. Results. In total, 11 out of the 50 patients (22%) were shown to suffer from an IFI, whereas 22 patients (44%) presented with a fungal colonization. Within the presented biomarker panel, plasma levels of soluble intercellular adhesion molecule- (sICAM-) 1, thrombospondin-1, and vinculin were shown to be the most promising. sICAM-1 was shown to be increased in patients with an IFI, whereas thrombospondin-1 and vinculin revealed decreased plasma levels as compared to colonized patients as well as patients without any fungal findings at any time. Conclusion. Plasmatic measurements of sICAM-1, thrombospondin-1, and vinculin may help to facilitate the diagnosis of an IFI in human septic shock and to identify patients with an increased risk for an IFI. This trial is registered with DRKS00005463.

Abstract Background This study aimed to analyse the frequency and clinical relevance of sacral insufficiency fractures (SIFs) after high-dose carbon-ion based irradiation of sacral chordomas. Methods A total of 56 patients were included in this retrospective study. Twenty one patients (37%) were treated with definitive radiotherapy (RT), and 35 patients (63%) received postoperative RT using carbon ions, either in combination with photons or as single-modality treatment (median radiation dose 66 Gy RBE, range 60–74 Gy). Follow-up examinations including MRI of the pelvis were performed at 3-monthly intervals in the first year and consecutively at 6-monthly intervals. Median follow-up was 35.5 months (range 2–83). Results SIFs were diagnosed in 29 patients (52%) after a median follow-up of 11 months (range 1–62 months). Most sacral fractures (79%) occurred within 2 years after RT. For the overall study population, the fracture-free survival probability amounted to values of 0.68 (95% CI, 0.53–0.79) after 1 year, 0.46 (95% CI, 0.31–0.60) after 2 years, and 0.31 (95% CI, 0.16–0.47) after 5 years. Statistical analysis showed no significant difference regarding the fracture rates between patients who received an operation and postoperative RT and patients treated with definitive RT. About one third of the patients with SIFs (34%; 10 of 29 patients) had associated clinical symptoms, most notably pain. All patients with symptomatic fractures required strong analgesics and often intensive pain management. Conclusions Sacral fractures after high-dose carbon ion-based RT of sacral chordomas were shown to be a considerable radiogenic late effect, affecting about half of the treated patients. However, only one third of these fractures were clinically symptomatic requiring regular medical care and pain therapy. Further hazard factor analysis in the future with larger patient numbers will possibly enable the identification of high-risk patients for developing SIFs with the ultimate goal to prevent symptomatic fractures.

Abstract Background This was a prespecified secondary analysis of a randomized trial, which analyzed bone density following stereotactic body radiotherapy (SBRT) versus conventional three-dimensional conformal radiotherapy (3DCRT) as part of palliative management of painful spinal metastases. Methods Fifty-five patients were enrolled in this single-institutional randomized exploratory trial (NCT02358720). Participants were randomly assigned to receive SBRT (single-fraction 24 Gy) or 3DCRT (30 Gy/10 fractions). Quantitative bone density was evaluated at baseline, 3 and 6 months in both irradiated and unirradiated spinal bodies, along with rates of pathologic fractures and vertebral compression fractures. Results As compared to baseline, bone density became significantly higher at 3 and 6 months following SBRT by a median of 33.8% and 72.1%, respectively (p

Abstract Background The effect of radiotherapy, in particular the application of different multi-fraction schedules in the management of unstable spinal bone metastases (SBM), is incompletely understood. This study aims to compare the radiological response regarding various dose and fractionation schedules of radiotherapy in the palliative treatment of SBM. Methods We retrospectively assessed 1047 patients with osteolytic SBM, treated with palliative radiotherapy at our department between 2000 and 2015. Lung cancer (40.2%), breast (16.7%) and renal cancer (15.2%) were the most common solid tumors in this study. Different common multi-fraction regimen (5x4Gy, 10x3Gy, 14 × 2.5Gy and 20x2Gy) were compared with regard to radiological response and recalcification at 3 and 6 months after radiotherapy. The Taneichi score was used for classification of osteolytic SBM. Results Median follow up was 6.3 months. The median overall survival (OS) in the short-course radiotherapy (SCR) group using less than 10 treatment fractions was 5.5 months vs. 9.5 months in the long-course radiotherapy (LCR) group using in excess of 10 fractions (log rank p

Background: In the context of the cholinergic anti-inflammatory pathway, the clinical trial Anticholium® per Se (EudraCT Number: 2012-001650-26, ClinicalTrials.gov NCT03013322) addressed the possibility of taking adjunctive physostigmine salicylate treatment in septic shock from bench to bedside. Pharmacokinetics (PK) are likely altered in critically ill patients; data on physostigmine PK and target concentrations are sparse, particularly for continuous infusion. Our objective was to build a population PK (popPK) model for physostigmine, and further evaluate pharmacodynamics (PD) and concentration-response relationship in this setting. Methods: In the randomized, double-blind, placebo-controlled trial, 20 patients with perioperative septic shock either received an initial dose of 0.04 mg/kg physostigmine salicylate, followed by continuous infusion of 1 mg/h for up to 120 h, or equivalent volumes of 0.9% sodium chloride (placebo group). Physostigmine plasma concentrations and acetylcholinesterase (AChE) activity were measured; concentration-response associations were evaluated, and popPK and PD modeling was performed with NONMEM. Results: Steady state physostigmine plasma concentrations reached 7.60 ± 2.81 ng/mL (mean ± standard deviation [SD]). PK was best described by a two-compartment model with linear clearance. Significant covariate effects were detected for body weight and age on clearance, as well as a high inter-individual variability of the central volume of distribution. AChE activity was significantly reduced to 30.5%–50.6% of baseline activity during physostigmine salicylate infusion. A sigmoidal direct effect PD model best described enzyme inhibition by physostigmine, with an estimated half maximal effective concentration (EC50) of 5.99 ng/mL. Conclusions: PK of physostigmine in patients with septic shock displayed substantial inter-individual variability with body weight and age influencing the clearance. Physostigmine inhibited AChE activity with a sigmoidal concentration-response effect.

Abstract Background The prevention of postoperative complications is of prime importance after complex elective abdominal operations. Preoperative patient education may prevent postoperative complications and improve patients’ wellbeing, but evidence for its efficacy is poor. The aims of the PEDUCAT trial were (a) to assess the impact of preoperative patient education on postoperative complications and patient-reported outcomes in patients scheduled for elective complex visceral surgery and (b) to evaluate the feasibility of cluster randomization in this setting. Methods Adult patients (age ≥ 18 years) scheduled for elective major visceral surgery were randomly assigned in clusters to attend a preoperative education seminar or to the control group receiving the department’s standard care. Outcome measures were the postoperative complications pneumonia, deep vein thrombosis (DVT), pulmonary embolism, burst abdomen, and in-hospital fall, together with patient-reported outcomes (postoperative pain, anxiety and depression, patient satisfaction, quality of life), length of hospital stay (LOS), and postoperative mortality within 30 days after the index operation. Statistical analysis was primarily by intention to treat. Results In total 244 patients (60 clusters) were finally included (intervention group 138 patients; control group 106 patients). Allocation of hospital wards instead of individual patients facilitated study conduct and reduced confusion about group assignment. In the intervention and control groups respectively, pneumonia occurred in 7.4% versus 8.3% (p = 0.807), pulmonary embolism in 1.6% versus 1.0% (p = 0.707), burst abdomen in 4.2% versus 1.0% (p = 0.165), and in-hospital falls in 0.0% versus 4.2% of patients (p = 0.024). DVT did not occur in any of the patients. Mortality rates (1.4% versus 1.9%, p = 0.790) and LOS (14.2 (+/− 12.0) days versus 16.1 (+/− 15.0) days, p = 0.285) were also similar in the intervention and control groups. Conclusions Cluster randomization was feasible in the setting of preoperative patient education and reduced the risk of contamination effects. The results of this trial indicate good postoperative outcomes in patients undergoing major visceral surgery without superiority of preoperative patient education compared to standard patient care at a high-volume center. However, preoperative patient education is a helpful instrument not only for teaching patients but also for training the nursing staff. Trial registration German Clinical Trials Registry, DRKS00004226. Registered on 23 October 2012. Registered 8 days after the first enrollment.

Abstract Background Stereotactic body radiation therapy (SBRT) using intensity-modulated radiotherapy (IMRT) with dose escalation by simultaneous integrated boost (SIB) can be a safe modality for treating spinal bone metastases with enhanced targeting accuracy and improve local tumor control. Methods/Design This is a single-center, prospective, randomized, controlled trial. One hundred and twenty patients with spinal bone metastases will receive palliative radiation therapy at the Heidelberg University Hospital. SBRT will be given in five or ten fractions with or without SIB. Four treatment arms are planned: IMRT with 30 Gy in ten fractions, IMRT with 30 Gy in ten fractions and SIB to 40 Gy, IMRT with 20 Gy in five fractions, and IMRT with 20 Gy in five fractions and SIB to 30Gy in five fractions will be compared. The target parameters will be measured at baseline level and at three and six months after radiation. Discussion The primary endpoint of this study was to assess and compare the local tumor control (by means of different fractionation schedules and biological doses to the tumor area). Secondary endpoints are acute and chronic adverse events, pain relief, quality of life, and fatigue. Trial registration ClinicalTrials.gov, NCT02832765 . Registered on 27 July 2016.

Abstract Background Insertion of a Totally Implantable Access Port (TIAP) can be performed either via Central Vein Puncture (CVP) or Brachiocephalic Vein Cut-down (venous section-VS). The primary success rate of TIAP implantation using VS rarely ever achieves 100%. The objective of this study was to describe a modified VS approach using a hydrophilic coated wire (TVS). Methods From 01.01.2015 to 31.12.2015, all patients receiving TIAP implantations were screened. During this time, all patients in whom the primary VS procedure was found to be unsuccessful were analysed. Results In 2015, 1152 patients had TIAP implantations performed by 24 different surgeons. Of these, 277 patients needed a second line rescue strategy either by CVP (n = 69) or TVS (n = 208). There were no statistically significant differences regarding demographics or indication for TIAP implantation between CVP and TVS. The operation time and the qualification of the operating surgeon between CVP and TVS did not differ significantly. After the introduction of the guidewire with a hydrophilic coated wire, the need for CVP decreased significantly from 12.7% to 8.8% (p

Abstract Background Severe sepsis and septic shock remain a major challenge, even in modern intensive care. In Germany, about 68,000 patients die annually because of septic diseases, characterized by a complex systemic inflammatory response. Causal treatment of the underlying infection is essential for successful management of sepsis, but the course can be positively influenced by supportive and adjuvant measures. The cholinergic anti-inflammatory pathway (CAP) represents a new approach to adjunctive therapy of septic diseases and can be pharmacologically activated by the acetylcholinesterase inhibitor physostigmine (Anticholium®). Promising effects can be found in several in vitro and in vivo models of sepsis, such as a reduction in pro-inflammatory cytokines and improved survival. Methods Anticholium® per Se is a randomized, double-blind, placebo-controlled, monocentric trial to assess whether the CAP can be transferred from bench to bedside. In this pilot study, 20 patients with perioperative sepsis and septic shock as a result of intra-abdominal infection are enrolled. According to randomization, participants are treated with physostigmine salicylate (verum group) or 0.9% sodium chloride (placebo group) for up to 5 days. The mean Sequential Organ Failure Assessment (SOFA) score during treatment and subsequent intensive care of up to 14 days is used as surrogate outcome (primary endpoint). Secondary outcome measures include 30- and 90-day mortality. An embedded pharmacokinetics and pharmacodynamics study investigates plasma concentrations of physostigmine and its metabolite eseroline. Further analyses will contribute to our understanding of the role of various cytokines in the pathophysiology of human sepsis. A computer-generated list is used for block randomization. Discussion This randomized, controlled, monocentric trial investigates for the first time the adjunctive use of physostigmine (Anticholium®) in patients with perioperative sepsis and septic shock and may be a pivotal step toward the clinical use in this indication. Trial registration EudraCT Number: 2012-001650-26 (entered 14 August 2012), ClinicalTrials.gov identifier: NCT03013322 (registered on 1 Jan 2017).

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 >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 14 day-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.

Abstract Background This retrospective analysis aimed to analyse the stability of spinal bone metastases in colorectal cancer (CRC) patients following radiotherapy (RT) by use of a validated score and to assess prognostic factors for stability and survival. Methods Ninety-four patients with osteolytic spinal bone metastases from CRC were treated at the Department of Radiation Oncology at the University Hospital Heidelberg between 2000 and 2014. The stability of each affected vertebral body was assessed according to the validated Taneichi bone stability score on the basis of the treatment planning CT scan prior to RT and also based on the follow-up CT examinations at 3 and 6 months after RT. Additionally, bone survival rates (time between first day of RT and death from any cause) as well as prognostic factors for bone survival were evaluated for all study patients. Results Before RT, 59 patients (63%) were rated unstable according to the Taneichi score. Pathological fractures within the irradiated region were diagnosed in 43 patients (46%) prior to RT. New fractures or progression of previously collapsed vertebrae were diagnosed in 4 patients (4%) after irradiation. Significant re-calcification and stabilization of former unstable bone metastases was only observed in 3/59 patients (3%) and 5/59 patients (9%). The median bone survival was 4.2 months (range 0.5–67.3 months) and 6 months after RT 61% of the patients were dead. Karnofsky performance score (KPS) (< 70% vs. ≥ 70%), chemotherapy and bisphosphonate therapy were predictive prognostic factors for bone survival. Conclusions Our study population is characterized by poor bone survival and low re-calcification rates of unstable spinal bone lesions 3 and 6 months after RT. To avoid unnecessary hospitalisation and improve remaining QoL, short fractionated treatment schedules of RT may be prefered in this highly palliative situation, particularly for patients with a KPS

Background and purpose — There is a lack of information on any associations between the functional outcome and age and diagnosis in patients who have undergone shoulder arthroplasty. We therefore evaluated the functional outcome in “young” and “old” patients treated with either hemiarthroplasty (HA) or total shoulder arthroplasty (TSA) with diverse diagnoses. Patients and methods — The functional results of 496 primary shoulder arthroplasties were analyzed using the Constant score (age- and sex-adjusted) and subjective satisfaction. Patients ≤55 years of age at surgery were defined as “young. Diagnoses were primary osteoarthritis (n = 339), posttraumatic osteoarthritis (n = 78), cuff tear arthropathy (n = 36), avascular necrosis (n = 30), and rheumatoid arthritis (n = 13). Mean length of follow-up was 4 (2–14) years. Results — 70% of the TSA patients were very satisfied with the postoperative result, as compared to 39% after HA. The Constant score and patient satisfaction were similar in the “young” and “old” groups. Pain relief was better in the “old” group. The mean improvement in the Constant score after cuff tear arthropathy (22 points) was inferior to that for primary osteoarthritis (36 points), avascular necrosis (34 points), and rheumatoid arthritis (37 points). Inferior mean Constant scores were also seen for posttraumatic osteoarthritis (29 points) compared to primary osteoarthritis (36 points). 63% of patients with primary osteoarthritis were very satisfied, as compared to only 36% of the patients with posttraumatic osteoarthritis. Interpretation — Shoulder arthroplasty is successful in the medium term for different glenohumeral diseases, irrespective of patient age at surgery. However, the appropriate treatment method for cuff tear and posttraumatic conditions of the shoulder remains to be found, particularly in young patients.

Abstract Background Metastatic bone disease is a common and severe complication in patients with advanced cancer. Radiotherapy (RT) has long been established as an effective local treatment for metastatic bone disorder. This study assesses the effects of RT combined with muscle-training exercises in patients with unstable bone metastases of the spinal column from solid tumors. The primary goal of this study is to evaluate the feasibility of muscle-training exercises concomitant to RT. Secondly, quality of life, fatigue, overall and bone survival, and local control will be assessed. Methods/Design This study is a single-center, prospective, randomized, controlled, explorative intervention study with a parallel-group design to determine multidimensional effects of a course of exercises concomitant to RT on patients who have unstable metastases of the vertebral column, first under therapeutic instruction and subsequently performed by the patients themselves independently for strengthening the paravertebral muscles. On the days of radiation treatment the patients will be given four different types of exercises to ensure even isometric muscle training of all the spinal muscles. In the control group progressive muscle relaxation will be carried out parallel to RT. The patients will be randomized into two groups: differentiated muscle training or progressive muscle relaxation with 30 patients in each group. Discussion Despite the clinical experience that RT is an effective treatment for bone metastases, there is insufficient evidence for a positive effect of the combination with muscle-training exercises in patients with unstable bone metastases. Our previous DISPO-1 trial showed that adding muscle-training exercises to RT is feasible, whereas this was not proven in patients with an unstable spinal column. Although associated with several methodological and practical challenges, this randomized controlled trial is needed. Trial registration ClinicalTrials.gov, identifier: NCT02847754 . Registered on 27 July 2016.

BackgroundUse of the arm above shoulder level has been described as a risk factor for developing rotator cuff tears (RCT). There is a lack of information regarding the frequency and distribution of RCT in a population using their arms above shoulder level during daily work. The aim of this study was to analyze clinical and radiographic findings in a population of painters working more than 10 years and to compare the results with a control group (CG).Materials and methods100 individuals working more than 10 years as a painter were compared to 100 matched controls without using their arms above shoulder level. MRI scans were performed in all participants. Clinically, the Constant score, DASH score and range of motion (ROM) of the shoulders were analyzed.ResultsIn the painter group (PG) a tear of the supraspinatus tendon was detected in 45% (10%full-thickness; 35% partial) compared to 8% in the (CG) (3% full-thickness; 5%partial; pConclusionLong-term occupational load on the shoulders in painters seems to be associated with an increased risk for developing RCT. Our findings may provide support for developing preventive strategies for this unique cohort. Level of evidence: III.

BackgroundEye-drop administration errors occur in the majority of patients and increase the risk for treatment failure or systemic adverse events. While lacking knowledge is the principal error cause, most patients overestimate their skills and are unaware of often substantial knowledge gaps. Therefore, the impact of including motivational patient education on long-term eye-drop administration skills of patients was investigated.MethodsThis is a cluster-randomized controlled trial in German community pharmacies. Patient education in both groups comprised observation of the patient during eye-drop administration to identify individual errors, pharmaceutical counseling, and teach-back evaluation of the training. In the intervention group, motivational communication techniques were included to increase error awareness and readiness for patient education. In addition, intervention patients were trained on repeated errors until administration was performed correctly. In contrast, patients in the control group only received feedback on erroneous administration steps without another assessment and reinforced training.ResultsIn total, 152 adult patients were eligible to the study and 91 patients (intervention group N = 46) agreed to participate in a 1-month, 6-month, and 12-month follow-up. Patient education significantly increased the proportion of patients correctly administering eye-drops from 6% (7 out of 56 intervention patients, 1 out of 82 control patients) at baseline to 35% (12 out of 30 intervention patients, 12 out of 39 control patients, p ≤ 0.001) at the 1-month follow-up, and 64% (11 out of 15 intervention patients, 17 out of 29 control patients, p ≤ 0.001) at the 6-month follow-up irrespective of group allocation. In some patients previously resolved errors recurred during follow-up visits. This emphasizes the need for periodical reevaluation of patient administration skills and the provision of prevention strategies besides education.ConclusionPatient education that included demonstration of administration skills and verbal and written counseling on observed errors improved eye-drop administration skills irrespective of the communication technique applied. Whereof, high drop-out rates limited the power to detect a difference between groups. In particular, periodic demonstration of administration skills seemed important for sustainable improvement of administration skills. However, further error prevention strategies such as additional education materials or support by a caregiver may be necessary in some patients.

[This corrects the article DOI: 10.1371/journal.pone.0213824.].

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.

Introduction: Cytomegalovirus (CMV) reactivation occurs in seronegative patients after solid organ transplantation (SOT) particularly from seropositive donors and can be lethal. Generation of CMV-specific T cells helps to prevent CMV reactivation. Therefore, we initiated a clinical phase I CMVpp65 peptide vaccination trial for seronegative end-stage renal disease patients waiting for kidney transplantation. Methods: The highly immunogenic nonamer peptide NLVPMVATV derived from CMV phosphoprotein 65(CMVpp65) in a water-in-oil emulsion (Montanide™) plus imiquimod (Aldara™) as an adjuvant was administered subcutaneously four times biweekly. Clinical course as well as immunological responses were monitored using IFN-γ ELISpot assays and flow cytometry for CMV-specific CD8+ T cells. Results: Peptide vaccination was well tolerated, and no drug-related serious adverse events were detected except for Grade I–II local skin reactions. Five of the 10 patients (50%) mounted any immune response (responders) and 40% of the patients presented CMV-specific CD8+ T cell responses elicited by these prophylactic vaccinations. No responders experienced CMV reactivation in the 18 months post-transplantation, while all non-responders reactivated. Conclusion: CMVpp65 peptide vaccination was safe, well tolerated, and clinically encouraging in seronegative end-stage renal disease patients waiting for kidney transplantation. Further studies with larger patient cohorts are planned.

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.