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Introduction: Posttraumatic MRI of ACL tears show a high prevalence of bone bruise (BB) without macroscopic proof of chondral damage. Controversial results are described concerning the association between BB and outcome after ACL tear. Aim of this study is to evaluate the influence of distribution, severity and volume of BB in isolated ACL injuries on function, quality of life and muscle strength following ACL reconstruction (ACLR)., Materials and Methods: MRI of n = 122 patients treated by ACLR without concomitant pathologies were evaluated. BB was differentiated by four localizations: medial/lateral femoral condyle (MFC/LFC) and medial/lateral tibial plateau (MTP/LTP). Severity was graded according to Costa-Paz. BB volumes of n = 46 patients were quantified (software-assisted volumetry). Outcome was measured by Lysholm Score (LS), Tegner Activity Scale (TAS), IKDC, isokinetics and SF-36. Measurements were conducted preoperatively (t0), 6 weeks (t1), 26 weeks (t2) and 52 weeks (t3) after ACLR., Results: The prevalence of BB was 91.8%. LTP was present in 91.8%, LFC 64.8%, MTP 49.2% and MFC 28.7%. 18.9% were classified Costa-Paz I, 58.2% II and 14.8% III. Total BB volume was 21.84 ± 15.27 cm 3 , the highest value for LTP (14.31 ± 9.93 cm 3 ). LS/TAS/IKDC/SF-36/isokinetics improved significantly between t0-t3 (p < 0.001). Distribution, severity and volume had no influence on LS/TAS/IKDC/SF-36/isokinetics (n.s.)., Conclusions: No impact of BB after ACLR on function, quality of life and objective muscle strength was shown, unaffected by concomitant pathologies. Previous data regarding prevalence and distribution is confirmed. These results help surgeons counselling patients regarding the interpretation of extensive BB findings. Long-time follow-up studies are mandatory to evaluate an impact of BB on knee function due to secondary arthritis., (© 2023. The Author(s).)

As survival rates associated with the multimodal treatment of malignant bone cancer (osteosarcoma and Ewing's sarcoma) are satisfactory, health-related quality of life and the return to activity and sports by the affected patients have attracted increasing attention in recent years. Nowadays, limbs can be salvaged for most patients using modular endoprostheses. Such patients are typically adolescents and young adults who have high activity levels and thereby high demands for multimodal cancer treatment. This study aimed to evaluate the activity levels and sporting proficiencies that can be attained after modular endoprosthetic treatment of bone sarcomas as well as the extent to which physiotherapeutic and sports interventions influence functional outcome and activity levels.This non-systematic review of the literature focused on the return to activity and sports after modular endoprosthetic treatment of lower extremities bone sarcomas in adolescents and young adults. The electronic database PubMed was screened for relevant publications on this issue. A treatment algorithm for return to activity and sports in tumor orthopaedics is proposed.The objective activity level (gait cycles per day and gait intensities) in patients treated for bone sarcomas is reduced in short- and long-term follow-ups compared with healthy controls and patients with other cancers (leukaemia). Although a negative impact is observed in terms of motor performance, it shows improvement over time. Functional assessment at 12 postoperative months is sensible as neoadjuvant chemotherapy is completed by then. In long-term follow-up, patients with bone sarcomas can achieve high sports activity levels, i.e., type of sport, frequency/week and UCLA score, after modular endoprosthetic reconstruction. The maximum level is attained at 5 years postoperatively. Nevertheless, there is a shift from high- and intermediate- to low-impact sports. Only 20% of the patients participate in school sports regularly without limitations. The localisation of bone sarcoma, but not the rate of postoperative complications, influences the postoperative activity level. Individualised sports-related interventions during and after multimodal treatment can improve the short-term activity levels; moreover, "serious games" can improve motor performance and postural control. There is no evidence that intense activity levels leads to early loosening of the endoprosthesis. There is insufficient valid data on activity and sports after modular endoprosthetic treatment of bone sarcomas of the upper extremities.High preoperative activity levels of young patients with bone sarcomas must be considered in tumour orthopaedics. Limitations on sports activities have a significant negative impact on the quality of life and mental health of such patients. Therefore, tumour orthopaedic treatment has to focus on preserving an improvement in these factors. The overall existing evidence concerning this issue is weak. Additional studies to evaluate the ability to return to specific sports activities are desirable, as well as prospective interventional studies., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

We present a new open source dataset FLODIS that links estimates of flood-induced human displacements, fatalities, and economic damages to flooded areas observed through remote sensing. The dataset connects displacement data from the Internal Displacement Monitoring Centre (IDMC), as well as data on fatalities and damages from the Emergency Events Database (EM-DAT), with the Global Flood Database (GFD), a satellite-based inventory of historic flood footprints. It thereby provides a spatially explicit estimate of the flood hazard underlying each individual disaster event. FLODIS contains two datasets with event-specific information for 335 human displacement events and 695 mortality/damage events that occurred around the world between 2000 and 2018. Additionally, we provide estimates of affected population, GDP, and critical infrastructure, as well as socio-economic indicators; and we provide geocoding for displacement events ascribed to other types of disasters, such as tropical cyclones, so that they may be linked to corresponding hazard estimates in future work. FLODIS facilitates integrated flood risk analysis, allowing, for example, for detailed assessments of local flood-damage and displacement vulnerability., (© 2023. The Author(s).)

Aim: We have previously reported that polyfunctional T cell responses can be induced to the cancer testis antigen NY-ESO-1 in melanoma patients injected with mature autologous monocyte-derived dendritic cells (DCs) loaded with long NY-ESO-1-derived peptides together with α-galactosylceramide (α-GalCer), an agonist for type 1 Natural Killer T (NKT) cells., Objective: To assess whether inclusion of α-GalCer in autologous NY-ESO-1 long peptide-pulsed DC vaccines (DCV + α-GalCer) improves T cell responses when compared to peptide-pulsed DC vaccines without α-GalCer (DCV)., Design, Setting and Participants: Single-centre blinded randomised controlled trial in patients ≥ 18 years old with histologically confirmed, fully resected stage II-IV malignant cutaneous melanoma, conducted between July 2015 and June 2018 at the Wellington Blood and Cancer Centre of the Capital and Coast District Health Board., Interventions: Stage I. Patients were randomised to two cycles of DCV or DCV + α-GalCer (intravenous dose of 10 × 10 6 cells, interval of 28 days). Stage II. Patients assigned to DCV + α-GalCer were randomised to two further cycles of DCV + α-GalCer or observation, while patients initially assigned to DCV crossed over to two cycles of DCV + α-GalCer., Outcome Measures: Primary: Area under the curve (AUC) of mean NY-ESO-1-specific T cell count detected by ex vivo IFN-γ ELISpot in pre- and post-treatment blood samples, compared between treatment arms at Stage I. Secondary: Proportion of responders in each arm at Stage I; NKT cell count in each arm at Stage I; serum cytokine levels at Stage I; adverse events Stage I; T cell count for DCV + α-GalCer versus observation at Stage II, T cell count before versus after cross-over., Results: Thirty-eight patients gave written informed consent; 5 were excluded before randomisation due to progressive disease or incomplete leukapheresis, 17 were assigned to DCV, and 16 to DCV + α-GalCer. The vaccines were well tolerated and associated with increases in mean total T cell count, predominantly CD4 + T cells, but the difference between the treatment arms was not statistically significant (difference - 6.85, 95% confidence interval, - 21.65 to 7.92; P = 0.36). No significant improvements in T cell response were associated with DCV + α-GalCer with increased dosing, or in the cross-over. However, the NKT cell response to α-GalCer-loaded vaccines was limited compared to previous studies, with mean circulating NKT cell levels not significantly increased in the DCV + α-GalCer arm and no significant differences in cytokine response between the treatment arms., Conclusions: A high population coverage of NY-ESO-1-specific T cell responses was achieved with a good safety profile, but we failed to demonstrate that loading with α-GalCer provided an additional advantage to the T cell response with this cellular vaccine design., Clinical Trial Registration: ACTRN12612001101875. Funded by the Health Research Council of New Zealand., (© 2023. The Author(s).)

Background: The quantitative differences of left and right ventricular (LV, RV) parameters of using different cardiac MRI (CMR) post-processing techniques and their clinical impact are less studied. We aimed to assess the differences and their clinical impact between the conventional contouring (CC) and the threshold-based (TB) methods using 70% and 50% thresholds in different hypertrabeculated conditions., Methods: This retrospective study included 30 dilated cardiomyopathy, 30 left ventricular non-compaction (LVNC), 30 arrhythmogenic cardiomyopathy patients, 30 healthy athletes and 30 healthy volunteers. All participants underwent CMR imaging on 1.5 T. Cine sequences were used to derive measures of the cardiac volumes, function, total muscle mass (TMi) and trabeculae and papillary muscle mass (TPMi) using CC and TB segmentation methods., Results: Comparing the CC and the 70% and 50% threshold TB methods, the LV and RV volumes were significantly lower, the ejection fraction (EF) and the TMi were significantly higher with the TB methods. Between the two threshold setups, only TPMi was significantly higher with the 70% threshold. Regarding the clinical benefits, the LVNC was the only group in whom all the diagnostic and therapeutic decisions and risk stratification were influenced using the TB method. Diagnostic changes occurred in three-quarters of the population, and all the cardiomyopathy groups were affected regarding the decision-making about pharmaco- and device therapy., Conclusions: Using the TB method, only TPMi was significantly higher with the 70% threshold than the 50% setup, and both of them differed significantly from the CC technique, with relevant clinical impacts in all patient groups., Competing Interests: Declaration of Competing Interest The authors have no conflict of interests., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The cortical desmoid (DFCI) of the posteromedial femoral condyle is considered an asymptomatic incidental finding in adolescents without clinical relevance. The aim of this study was to evaluate the clinical relevance of DFCI from both a tumor orthopedic and sports medicine point of view., Methods: n = 23 patients (13.74 ± 2.74 years; nineteen female, four male) with DFCI of the posteromedial femoral condyle were included. A localized posteromedial knee pain on exertion was differentiated from non-specific knee pain. Symptom duration, additional pathologies, number of MRIs, sports activity and training intensity, downtime, therapeutic modalities, and relief/remission of symptoms were documented. The Tegner activity scale (TAS) and Lysholm score (LS) were collected. The influence of specific posteromedial pain, MRI presence of paratendinous cysts, sports level as well as physiotherapy on downtime and LS/TAS was statistically analyzed., Results: 100% reported knee symptoms at initial presentation. A localized posteromedial pain was documented in 52%. In 16/23 (70%) additional functional pathologies were diagnosed. Patients were physically highly active with high training intensities (6.52 ± 5.87 h/week) and performance level (65% competitive vs. 35% recreational). Patients underwent 1.91 ± 0.97 MRIs (max four). Symptom duration was 10.48 ± 11.02 weeks. A follow-up examination was performed after 12.62 ± 10.41 months ( n = two lost to follow-up). 17/21 had physiotherapy, on average 17.06 ± 13.33 units. Overall downtime was 13.39 ± 12.50 weeks, the return-to-sports (RTS) rate 81%. 100%/38% reported a relief/remission of complaints. LS was 93.29 ± 7.95, median TAS before onset of knee complaints/at follow-up 7 (6-7)/7 (5-7). Specific posteromedial pain, presence of paratendinous cysts, sports level and physiotherapy had no significant influence on downtime and outcome parameters (n.s.)., Conclusions: DFCI as a pathognomonic finding is recurrently encountered in the MRIs of children and adolescents. This knowledge is essential to spare patients from overtreatment. Contrary to the literature, the present results implicate a clinical relevance of DFCI particularly in those who are physically highly active with localized pain on exertion. Structured physiotherapy as basic treatment is recommended.

Background: The actual number of accidents in e‑scooter drivers in Germany seems to be significantly higher than the current figures from the Statistisches Bundesamt suggest. This epidemiological study examines e‑scooter injuries and compares them with e‑bike and bicycle injuries., Objective: In order to create a comparable database on the dangers of e‑scooters, e‑bikes and bicycles, the typical injury patterns were analyzed and prevention options derived from them., Material and Methods: All accidents involving e‑scooters, e‑bikes and bicycles that were presented via the university emergency room of a level 1 trauma center between 15 June 2019 and 31 October 2020 were prospectively investigated., Results: In our study, 68 accidents in e‑scooter drivers were included, of which only 11.8% (n = 8) were recorded by the police. Significantly more of them were male than female (p = 0.032) with a mean age of 31.1 (±13) years. At the same time, we registered 34 accidents in e‑bike riders and 356 in cyclists. In all three groups, most injuries occurred to the head, followed by injuries to the upper extremities. Significantly more e‑scooter drivers had an ISS ≥ 16 than in the group of injured cyclists (p = 0.016). E‑scooter riders who had an accident had a significantly longer length of stay in hospital, than e‑bike riders (p = 0.003) and cyclists (p = 0.001), 52.9% (n = 18) of e‑bike riders and 53.3% (n = 113) cyclists wore a helmet, compared to only 1.5% (n = 1) of e‑scooter riders. The most common cause of accidents among e‑bike riders (17.7%; n = 6) and cyclists (10.4%; n = 37) was slipping away on tram rails, while for e‑scooter riders it was colliding with a curb (7.4%; n = 5)., Conclusion: The three patient collectives examined showed different causes and profiles of injuries. The reasons for an increased proportion of seriously injured people compared to cyclists are electromobility, driving under the influence of alcohol and inadequate wearing of a helmet on e‑scooters when head injuries dominate. 73.5% (n = 50) of the e‑scooter accidents recorded by us were not registered by the police and therefore do not appear in the current statistics of the statistisches Bundesamt. As a result, a much higher number of e‑scooter accidents can be assumed. Preventive measures could include the introduction of compulsory helmets, a higher number of traffic controls and the expansion of bike tracks., (© 2022. The Author(s).)

Background: Due to an increasing competence orientation of medical studies, surgical curricula are being adapted in many places. In addition to surgical knowledge and practical skills, these should also teach competencies in differential diagnostics and treatment. The teaching of surgical knowledge through lectures and seminars and the demonstration of practical skills, e.g., through the use of logbooks in the Bock Practical Surgery (BP), only allows limited active engagement with surgical competencies on differential diagnostics and treatment. A reflection-based portfolio allows, through the independent written elaboration of surgical topics, an active engagement with the competencies and promises a higher learning effect. In the context of the implementation of such a portfolio as part of the proof of activity in BP, the effects on the acquisition of competencies and on the way of learning were investigated., Material and Methods: Using a mixed methods approach, we compared competence acquisition using a reflection-based portfolio with learning using a logbook. Students conducted a self-assessment of competencies using questionnaire surveys before and after the BP. Through focus group interviews with discussions among students using a guideline, we explored the different ways of acquiring competencies. In addition, the examination and evaluation results of both cohorts were compared., Results and Discussion: Students' self-assessed competency acquisition and examination and evaluation results showed no differences when comparing the two cohorts. During the focus group interviews, we were able to show that in the perception of the students, surgical competencies can be made more visible and thus more explicit with the help of a reflection-based portfolio. In addition, self-regulated learning was promoted without neglecting practical skills. Students demanded greater supervision and guidance by mentors in both groups., (© 2022. The Author(s).)

(1) Background: The treatment of proximal humeral fractures (PHFs) is debated controversially. Current clinical knowledge is mainly based on small single-center cohorts. The goal of this study was to evaluate the predictability of risk factors for complications after the treatment of a PHF in a large clinical cohort in a multicentric setting. (2) Methods: Clinical data of 4019 patients with PHFs were retrospectively collected from 9 participating hospitals. Risk factors for local complications of the affected shoulder were assessed using bi- and multivariate analyses. (3) Results: Fracture complexity with n = 3 or more fragments, cigarette smoking, age over 65 years, and female sex were identified as predictable individual risk factors for local complications after surgical therapy as well as the combination of female sex and smoking and the combination of age 65 years or older and ASA class 2 or higher. (4) Conclusion: Humeral head preserving reconstructive surgical therapy should critically be evaluated for patients with the risk factors abovementioned.

Background: Organization of mass sport events in the COVID-19 era is utterly complicated. Containments measures, required to avoid a virus outbreak, force athletes to compete under circumstances they never experienced before, most likely having a deleterious effect on their performance., Purpose: We aimed to design a so-called athlete-friendly bubble system for the International Swimming League 2020 event, which is strict enough to avoid a COVID-19 outbreak, but still provides a supportive environment for the athletes., Methods: To avoid the feeling of imprisonment, athletes were permitted to spend a certain amount of time in the parks surrounding the hotels. Such alleviations were possible to apply with strict adherence to the hygienic and social distancing protocols and regular COVID-19 testing. Evaluation of every COVID-19 positive case was key, and if prolonged PCR positivity or false positive PCR result was identified, the unnecessary quarantine was planned to be lifted. Return to play protocol (RTP) was planned, in case of a COVID-19 infection of an athlete inside the bubble. To test, if the athlete-friendly system provided a supportive environment, we evaluated athlete performance., Results: 11,480 PCR tests were performed for 1,421 individuals. 63 COVID-19 positive cases were detected, of which 5 turned out to be clinically insignificant, either because of prolonged PCR positivity or because of a false positive result. 93.1% of the positive cases were detected in the local crew, while no athlete got infected inside the bubble, as the two infected athletes were tested positive upon arrival. RTP was provided for two athletes. 85% of the athletes showed improvement during the bubble and 8 world records were broken., Conclusion: The applied protocol proved to be effective, as no athlete got infected inside the bubble, moreover, the athlete-friendly system supported the athletes to improve their performance.

Introduction: A rupture of the pectoralis major muscle is a rare injury pattern overall, but it is frequently described in athletes, particularly in weightlifting. The risk of sustaining this type of injury is present especially during the eccentric phase of muscle loading. An association between such injuries and the abuse of anabolic steroids is described in the literature, but there is no coherent evidence to support this. We report the case of a young patient with a normal habitus who suffered a humeral rupture of the pectoralis major muscle during recreational sports. There was no history of excessive weight training or use of anabolic steroids., Case History: This 33-year-old patient reported a sudden onset of left pectoral pain during training on the chest fly machine as well as a whip-like popping sound, followed by an immediate painful restriction of movement in the left arm. A clinical examination revealed a mild haematoma located on the left medial upper arm with localised tenderness and a discrete asymmetry of the contour of the pectoral muscles. Due to the typical medical history, we established the indication for surgical exploration although the clinical picture was rather discrete and only an incomplete rupture was seen in an MRI scan. Intraoperatively, we detected a complete rupture of the sternocostal part of the pectoralis major muscle with marked retraction and haematoma. Reinforcement and reinsertion were performed at the "footprint" using titanium anchors (2 x 5.5mm Corkscrew FT, Arthrex, Florida). The patient was able to resume his sports activities at the pre-traumatic level four months after surgery., Conclusion: A rupture of the insertion of the pectoralis major muscle must also be considered in amateur athletes with a typical history. The characteristic clinical symptoms described in the literature mostly refer to competitive athletes and bodybuilders, but these injuries can also be diagnosed in amateur athletes with lower muscle mass by subtle clinical examination. Nevertheless, there is a considerable risk of underestimating the extent of the injury. In case of doubt, surgical exploration should be performed promptly in amateur athletes. Surgical refixation of the humeral rupture of the pectoralis major muscle is the gold standard and should not be reserved to high-performance athletes., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

This retrospective cross-sectional epidemiological study deals with sport-specific injury patterns in show jumping. A total of 363 show jumpers of all levels (S) answered a retrospective questionnaire about injuries and overuse damages which occurred in the course of their careers. Demographic data and information on injuries in various body regions were collected. In addition to descriptive analysis, significance tests were performed. For better statistical comparability with other sports, exposure time was extrapolated with total career duration and weekly training hours, and injuries per 1000 jumping hours were calculated. The study included 251 (69%) women and 112 (31%) men, who were on average 26.9 ± 10.9 years old. The injury rate for the entire collective was 3.7 per 1000 h of exposure. The most frequently affected body region was the head (31%). Overuse complaints play a subordinate role and mainly affect the upper extremities (65%). The riders of the professional lower performance levels are less likely to injure themselves per 1000 h than riders of the higher performance levels. Riders who often or always wore a helmet suffered significantly fewer head injuries ( p = 0.008) and had a significantly lower total injury duration than riders who did not wear a helmet ( p = 0.006). Similarly, the study showed that riders who often or always wore a safety vest suffered significantly fewer spinal injuries ( p = 0.017) and had significantly fewer injuries per 1000 riding hours ( p = 0.031) than riders who did not wear a safety vest. Based on the present results, there should be an extension of the general helmet requirement and a requirement to wear safety vests in show jumping in general.

Competing Interests: Martin Glombitza declares that he signed a consultant contract with BonAlive in May 2017.

Background: Locking plate osteosynthesis via an L-shaped lateral approach is the gold standard in treating displaced intra-articular calcaneal fractures. High complication rates are known for this approach. The most frequent complications are wound edge necrosis and superficial wound infections. To reduce complication rates, a locking intramedullary nail (C-Nail) was developed that can be implanted minimally invasively via a sinus tarsi approach. We compared the postoperative complication rate and the outcome of plate osteosynthesis versus C-Nail in displaced intra-articular calcaneal fractures., Methods: All patients with calcaneal fractures who received osteosynthesis with either plate or C-Nail between January 2016 and October 2019 in our institution were retrospectively analyzed. A subgroup analysis was performed with matched pairs (matching Sanders type, age, Böhler's angle postoperative in normal range, 33 pairs). Endpoints were postoperative complication rate, bone healing, full weight-bearing and functional outcome. Treatment groups were compared using Fisher's exact test for binary data, and Mann-Whitney U-test for continuous data. A p-value < 0.05 was considered statistically significant., Results: One hundred and one calcaneal fractures were included (C-Nail n = 52, plate n = 49). Patients with C-Nail developed significantly less postoperative complications (p = 0.008), especially wound edge necrosis (p < 0.001). Screw malposition was found more often in the C-Nail group. The rates of achieving full weight-bearing as well as bone healing were comparable in both groups, but in each case significant faster in the C-nail subgroup. The results of the matched-pairs analysis were comparable., Conclusions: The postoperative complication rate was significantly lower in the C-Nail group. The C-Nail appears to be a successful alternative in the treatment of calcaneal fractures, even in Sanders IV fractures because of the minimal-invasive implantation as well as the high primary stability. Long-term analysis of this new implant including elaboration on functional outcome is planned., Trial Registration: Deutsches Register Klinischer Studien (DRKS) DRKS00020395 . Date of registration 3 January 2020.

Introduction : The goals of osteomyelitis therapy are successful control of infection and reconstruction of the bone. The gold standard for filling defects is the autologous bone graft. Bioactive glass S53P4 is an inorganic bone substitute. We compared the outcome of using bioactive glass (BAG) versus autologous bone graft (AB) in patients with infected non-union. Methods : Patients with chronic osteomyelitis and infected non-union who received either bioactive glass or autologous bone grafts between 2013 and 2017 were analyzed retrospectively. The primary endpoint was successful control of infection during follow-up. Secondary endpoints were bone healing, functional outcome, and occurrence of complications. Results : Eighty-three patients were analyzed (BAG n = 51 , AB n = 32 ). Twenty-one patients experienced reinfection (BAG n = 15 , 29 %; AB n = 6 , 19 %). Seventy-eight patients achieved full weight bearing (BAG n = 47 , 92 %; AB n = 31 , 97 %). Sixty-four patients had complete bone healing at the end of the follow-up period (BAG n = 39 , 77 %; AB n = 25 , 78 %). There were no significant differences between the groups with respect to the primary or secondary endpoints. Patients with multidrug-resistant pathogens had a significantly higher rate of incomplete bone healing ( p = 0 .033) and a 3-fold higher risk of complications in both groups. Conclusions : Bioactive glass appears to be a suitable bone substitute not only for successful control of infection and defect filling but also for bone healing in cases of infected non-union. In our study, bioactive glass was neither superior nor inferior to autologous bone graft with regard to the primary and secondary endpoints. Further studies with larger numbers of patients are required., Competing Interests: The authors declare that they have no conflict of interest., (Copyright: © 2021 Eva Steinhausen et al.)

In Germany, Inline Skater Hockey (ISH) is played by about 7500 active players on inline skates with equipment comparable to ice hockey using a hard-plastic ball. The aim of this retrospective epidemiological cross-sectional study is to record the frequency and types of injuries in this sport, for which there is a lack of medically adequate studies in the literature. A questionnaire comprising 112 items was used to collect demographic data, injuries in eight body regions and defined overuse injuries. 274 ISH players with an average age of 24.5 ± 6.2 years and an exposure time of 2787 ± 2063 hours were examined. 5701 injuries were recorded, 60.5 % of which were minor bruises, abrasions and wounds. The total injury rate per 1000 hours was 9.6 ± 17.7, with an injury-related break of 12.8 ± 21.8 weeks per player. Field players with visors had highly significantly fewer head injuries (2.8 ± 6.1 vs. 8.9 ± 13.1; p < 0.001) with highly significantly (p < 0.001) fewer lacerations, nasal bone fractures, eye injuries and dental injuries. There was a weak negative correlation between facial protection and number of head injuries (r = -0.386, p < 0.001). In conclusion, frequency and types of injuries in ISH are comparable to ice hockey during training. In accordance with ice hockey, protective equipment in ISH can significantly reduce the occurrence of head injuries. Preventive attention should be paid to the wearing of a full visor and to education about the occurrence of concussions despite the use of a protective helmet., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

Background: Coagulopathy following severe trauma contributes significantly to mortality. Impaired clotting factors have been observed in adult trauma patients, but in pediatric trauma victims their activity has not yet been investigated., Methods: Sixteen pediatric trauma patients were evaluated according to the ISS and assigned to two cohorts. An additional control group (CO; n = 10) was formed. Routine coagulation parameters and the soluble clotting factors (F) were tested. Nonparametric data was analyzed using the Mann-Whitney U test. Results are reported as median and interquartile range., Results: The ISS of severely (SI, n = 8) and mildly (MI, n = 8) injured children differed significantly (25 [19-28] vs. 5 [4-6]; p < 0.001). INR was elevated in the SI cohort only when compared to the CO (1.21 [1.04-1.58] vs. 0.96 [0.93-1.00]; p = 0.001). Differences between SI and MI were found for FII (67 [53-90] vs. 82 [76-114] %; p = 0.028), FV (76 [47-88] vs. 92 [82-99] %; p = 0.028), and FXIII (67 [62-87] vs. 90 [77-102] %; p = 0.021). Comparison of the SI with the CO (FII 122 [112-144] %; p < 0.001; FV 123 [100-142] %; p = 0.002; and FXIII 102 [79-115] %; p = 0.006) also revealed a reduction in the activity of these factors. Furthermore, fibrinogen (198 [80-242] vs. 296 [204-324] mg/dl; p = 0.034), FVII (71 [63-97] vs. 114 [100-152] %; p = 0.009), FIX (84 [67-103] vs. 110 [90-114] %; p = 0.043), and FX (70 [61-85] vs. 122 [96-140] %; p = 0.001) were reduced in the SI in comparison with the CO. Finally, FVIII was considerably, yet not significantly, increased in both patient cohorts (235 [91-320] % and 197 [164-238] %, respectively)., Conclusions: This study proves that children suffer a depletion of clotting factors following severe injury which basically reflects the findings for adult trauma patients. Attempts to correct the impaired clotting factor activity could be based on a specific hemostatic therapy involving administration of coagulation factors. Nevertheless, therapeutic implications need to be investigated in future studies.

Introduction: Autologous T-cells transduced to express a chimeric antigen receptor (CAR) directed against CD19 elicit high response rates in relapsed or refractory (r/r) B-cell non-Hodgkin lymphoma (B-NHL). However, r/r B-NHL remissions are durable in fewer than half of recipients of second-generation CAR T-cells. Third-generation (3G) CARs employ two costimulatory domains, resulting in improved CAR T-cell efficacy in vitro and in animal models in vivo. This investigator-initiated, phase I dose escalation trial, termed ENABLE, will investigate the safety and preliminary efficacy of WZTL-002, comprising autologous T-cells expressing a 3G anti-CD19 CAR incorporating the intracellular signalling domains of CD28 and Toll-like receptor 2 (TLR2) for the treatment of r/r B-NHL., Methods and Analysis: Eligible participants will be adults with r/r B-NHL including diffuse large B-cell lymphoma and its variants, follicular lymphoma, transformed follicular lymphoma and mantle cell lymphoma. Participants must have satisfactory organ function, and lack other curative options. Autologous T-cells will be obtained by leukapheresis. Following WZTL-002 manufacture and product release, participants will receive lymphodepleting chemotherapy comprising intravenous fludarabine and cyclophosphamide. A single dose of WZTL-002 will be administered intravenously 2 days later. Targeted assessments for cytokine release syndrome and immune cell effector-associated neurotoxicity syndrome, graded by the American Society Transplantation and Cellular Therapy criteria, will be made. A modified 3+3 dose escalation scheme is planned starting at 5×10 4  CAR T-cells/kg with a maximum dose of 1×10 6  CAR T-cells/kg. The primary outcome of this trial is safety of WZTL-002. Secondary outcomes include feasibility of WZTL-002 manufacture and preliminary measures of efficacy., Ethics and Dissemination: Ethical approval for the study was granted by the New Zealand Health and Disability Ethics Committee (reference 19/STH/69) on 23 June 2019 for Protocol V.1.2. Trial results will be reported in a peer-reviewed journal, and results presented at scientific conferences or meetings., Trial Registration Number: NCT04049513., Competing Interests: Competing interests: Trial principal investigator, RW, and co-investigator, PG, are employees of the Malaghan Institute of Medical Research, a charitable research institute and study sponsor. The other co-investigators have no competing interests to declare. PL has proprietary interest in the intellectual property of the 1928T2z construct. CB is co-Founder and Scientific Advisory Board Member of Mana Therapeutics is on the Advisory Board of Cellectis, has Stock ownership in Torque Therapeutics and Neximmune and is a Board Member of Caballeta Bio., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Infections affect about 30-50% of intensive care unit patients resulting in substantial morbidity and mortality. Multimodal interventions proved to be successful in the prevention of healthcare-associated infections. Appropriate hand hygiene including correct disinfection technique and timing is essential. Aim: The aim of our study was to investigate the hand hygiene practice among the intensive care unit healthcare workers by immediate feedback system implementation and compliance study. Method: A 3-week-long observational study was conducted at the Department of Anaesthesiology and Intensive Therapy, Semmelweis University, during November and December, 2018. Data regarding hand hygiene technique were collected by using the Semmelweis Scanner technology, while compliance data were recorded by direct observations. Statistical analysis was performed by Kruskal-Wallis test, Fisher's exact test and χ 2 -test. Results: 604 measurements were recorded by the electronic system. Hand disinfection was appropriate in 86.5% of cases. The median value of coverage was 99.87%. The trend of these indices showed persistently high values. A lower error rate was observed in the physiotherapy group compared to others (doctors: p<0.01, nurses: p = 0.03, assistant nurses: p = 0.03). 162 opportunities were recorded during direct observations. The mean compliance rate was 60.49%, with the lowest among doctors (53.97%). The difference was non-significant compared to nurses (62.92%, p = 0.26). Conclusions: Hand hygiene technique during the study period was found to be highly and permanently appropriate, while compliance was lower than expected. The immediate feedback system may be useful in achieving appropriate hand disinfection technique, although further interventions are needed for higher compliance rates. Orv Hetil. 2019; 160(49): 1957-1962.

In Germany, a regional social health insurance fund provides an integrated care program for patients with schizophrenia (IVS). Based on routine data of the social health insurance, this evaluation examined the effectiveness and cost-effectiveness of the IVS compared to the standard care (control group, CG). The primary outcome was the reduction of psychiatric inpatient treatment (days in hospital), and secondary outcomes were schizophrenia-related inpatient treatment, readmission rates, and costs. To reduce selection bias, a propensity score matching was performed. The matched sample included 752 patients. Mean number of psychiatric and schizophrenia-related hospital days of patients receiving IVS (2.3 ± 6.5, 1.7 ± 5.0) per quarter was reduced, but did not differ statistically significantly from CG (2.7 ± 7.6, 1.9 ± 6.2; p = 0.772, p = 0.352). Statistically significant between-group differences were found in costs per quarter per person caused by outpatient treatment by office-based psychiatrists (IVS: €74.18 ± 42.30, CG: €53.20 ± 47.96; p < 0.001), by psychiatric institutional outpatient departments (IVS: €4.83 ± 29.57, CG: €27.35 ± 76.48; p < 0.001), by medication (IVS: €471.75 ± 493.09, CG: €429.45 ± 532.73; p = 0.015), and by psychiatric outpatient nursing (IVS: €3.52 ± 23.83, CG: €12.67 ± 57.86, p = 0.045). Mean total psychiatric costs per quarter per person in IVS (€1117.49 ± 1662.73) were not significantly lower than in CG (€1180.09 ± 1948.24; p = 0.150). No statistically significant differences in total schizophrenia-related costs per quarter per person were detected between IVS (€979.46 ± 1358.79) and CG (€989.45 ± 1611.47; p = 0.084). The cost-effectiveness analysis showed cost savings of €148.59 per reduced psychiatric and €305.40 per reduced schizophrenia-related hospital day. However, limitations, especially non-inclusion of costs related to management of the IVS and additional home treatment within the IVS, restrict the interpretation of the results. Therefore, the long-term impact of this IVS deserves further evaluation.

Vaccines that elicit targeted tumor antigen-specific T-cell responses have the potential to be used as adjuvant therapy in patients with high risk of relapse. However, the responses induced by vaccines in cancer patients have generally been disappointing. To improve vaccine function, we investigated the possibility of exploiting the immunostimulatory capacity of type 1 Natural killer T (NKT) cells, a cell type enriched in lymphoid tissues that can trigger improved antigen-presenting function in dendritic cells (DCs). In this phase I dose escalation study, we treated eight patients with high-risk surgically resected stage II-IV melanoma with intravenous autologous monocyte-derived DCs loaded with the NKT cell agonist α-GalCer and peptides derived from the cancer testis antigen NY-ESO-1. Two synthetic long peptides spanning defined immunogenic regions of the NY-ESO-1 sequence were used. This therapy proved to be safe and immunologically effective, inducing increases in circulating NY-ESO-1-specific T cells that could be detected directly ex vivo in seven out of eight patients. These responses were achieved using as few as 5 × 10 5 peptide-loaded cells per dose. Analysis after in vitro restimulation showed increases in polyfunctional CD4 + and CD8 + T cells that were capable of manufacturing two or more cytokines simultaneously. Evidence of NKT cell proliferation and/or NKT cell-associated cytokine secretion was seen in most patients. In light of these strong responses, the concept of including NKT cell agonists in vaccine design requires further investigation.

We present the case of an adolescent male developing an ankylosis of the knee after septic arthritis following anterior cruciate ligament reconstruction (ACLR). The patient was shifted to our institution with postoperative septic arthritis associated with a systemic septic condition. Before, repeated arthroscopic surgery had been conducted without any improvement. MRI showed a concomitant osteomyelitis. The infection (Gächter IV, Staphylococcus aureus) was controlled by an open surgical approach and graft removal. An increasing joint stiffness was documented. X-rays showed an ankylosis at 30° of flexion and early closure of growth plates. Functional knee scores showed significantly worse results. Early diagnosis and a stage-adapted treatment in septic arthritis following ACLR are mandatory. In advanced stages or concomitant osteomyelitis an open approach and graft removal may be appropriate. The antibiotic treatment should be adapted consistently., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Ex vivo generated monocyte-derived dendritic cell (moDC)-vaccines have long been touted as promising immunotherapeutic agents for cancer treatment, although the response rate generally remains low. The reasons for this are still unclear and confounded by the diversity in manufacturing protocols that may affect moDC function. Preclinical studies have shown that the stimulatory function of dendritic cells can be improved by engaging invariant NKT cells in vivo through the presentation of the glycolipid alpha-galactosylceramide via CD1d. However, expression of CD1d on moDC has been shown to be negatively correlated with expression of CD1a, which in turn has been suggested to be a surrogate marker for IL-12 secreting type-1 polarized moDC, the preferred functional characteristics for cancer vaccines. Here we challenge this notion by showing that plasma-derived lipids drive functional levels of CD1d expression, while CD1a expression can vary considerably in these cells without being correlated with a loss of polarization or immunogenicity.

Bone morphogenetic protein 15 (BMP15) is a key intraovarian growth factor regulating mammalian fertility, yet expression and localisation of different BMP15 protein forms within ovarian follicles around the time of the preovulatory LH surge remains unclear. Using immunoblotting and immunocytochemistry, the present study identified that post-translationally processed BMP15 proregion and mature proteins are increasingly expressed and localised with cumulus and granulosa cells from mice treated with pregnant mare's serum gonadotropin (PMSG) + human chorionic gonadotrophin (hCG). However, this increased expression was absent in cumulus-oocyte complexes matured in vitro. Pull-down assays further revealed that the recombinant BMP15 proregion is capable of specific interaction with isolated granulosa cells. To verify an oocyte, and not somatic cell, origin of Bmp15 mRNA and coregulated growth differentiation factor 9 (Gdf9), in situ hybridisation and quantitative polymerase chain reaction results confirmed the exclusive oocyte localisation of Bmp15 and Gdf9, regardless of treatment or assay method. Relative oocyte expression levels of Bmp15 and Gdf9 decreased significantly after PMSG + hCG treatment; nevertheless, throughout all treatments, the Bmp15:Gdf9 mRNA expression ratio remained unchanged. Together, these data provide evidence that the preovulatory LH surge leads to upregulation of several forms of BMP15 protein secreted by the oocyte for putative sequestration and/or interaction with ovarian follicular somatic cells.

Concept and design of an independent scientific evaluation of different pathways of care for schizophrenia patients in Germany with respect to effectiveness and efficiency are presented. In this prospective, observational study, schizophrenia patients receiving an integrated care treatment, the intervention group (IG), are compared with patients under routine care conditions treated by the same physician (first control group, CG 1). A second control group (CG 2) of patients treated by office-based psychiatrists not participating in the integrated care program will be recruited and their data compared with the two other groups. The total amount of psychiatric hospital days after 12 months is defined as primary outcome parameter. Secondary outcome parameters comprise the frequency of psychiatric inpatient readmissions, severity of schizophrenia symptoms, remission rates and quality of life. Patients undergo assessments at baseline, month 6 and 12 using standardized and experimental questionnaires. Routine data of a regional German social health insurance fund complement information on included patients. Additionally, a cost-effectiveness and cost-utility analysis will be performed. Until now, 137 psychiatrists included 980 patients in the integrated care project in Lower Saxony, Germany, and 47 psychiatrists (IG and both CGs) are willing to participate in the independent evaluation. For the first time, a prospective observational controlled evaluation study of a countrywide integrated care project planning to recruit 500 schizophrenia patients has started using comprehensive assessments as well as routine data of a social health insurance fund.

There is no standard treatment for recurrent glioblastoma multiforme (GBM). Retreatment with temozolomide (TMZ) is one treatment option. We reasoned this could be more effective if combined with a vaccine that preferentially targeted TMZ-resistant cells. To test the feasibility and safety of such an approach, a phase 1 trial was conducted in which patients with GBM tumors relapsing after standard chemoradiotherapy were retreated with TMZ in combination with a vaccine consisting of monocyte-derived dendritic cells (DC) pulsed with autologous tumor cells that had previously been exposed to TMZ in vivo in the course of primary treatment. Of 14 participants, nine patients completed the initial phase of priming vaccinations and two cycles of TMZ, one proved to have radionecrosis, one rapidly progressed, and in three the yield of DC vaccine was insufficient to proceed with treatment. Other than expected toxicities related to TMZ, there were no adverse events attributable to the combined treatment. Two patients had objective radiological responses. Six month progression-free survival was 22 %, similar to retreatment with TMZ alone. Anti-tumor immune responses were assessed in peripheral blood mononuclear cells using interferon-γ ELISpot, with two patients meeting criteria for a vaccine-induced immune response, one of whom remained disease-free for nearly three years. Another patient with an anti-tumor immune response at baseline that was sustained post-vaccination experienced a 12-month period of progression-free survival. In summary, the combined treatment was safe and well-tolerated but feasibility in the recurrent setting was marginal. Evidence of immune responses in a few patients broadly correlated with better clinical outcome.

Objectives: An immense body of knowledge has been created by establishing various job-exposure matrices (JEMs) to assess occupational exposures in community- and industry-based cohort studies. These JEMs could be made available to occupational epidemiologists using knowledge-sharing technologies, thereby saving considerable amounts of time and money for researchers investigating occupation-related research questions. In this paper, the authors give an example of how a detailed JEM can be easily transformed into a job-specific module (JSM) for use in community-based studies., Methods: OccIDEAS is operationalised as a web-based software, combining the use of JSMs with an individual expert exposure assessment to assess occupational exposures in various industries according to a set of predefined rules. The authors used a JEM focusing on endocrine-disrupting chemicals from a German study on testicular cancer in the automobile industry to create a JSM in OccIDEAS., Results: The JEM was easily translated into OccIDEAS requiring about 50 h of work by an epidemiologist familiar with the German JEM to learn about the OccIDEAS structure, establish the required set of exposure rules and to translate the JEM into OccIDEAS. Language did not represent an obstacle for translation either. To make the data available in an international context, an interpreter had to translate the German tasks and exposures after they were coded into OccIDEAS., Conclusions: JEMs which are constructed based on identifying tasks that determine exposure can be easily transformed into a JSM. Occupational epidemiologists are invited to contribute to the international scope of OccIDEAS by providing their previously established JEMs to make existing data on occupational exposures widely available to the epidemiological community.

Introduction: In a previous analysis of a case-control study of testicular cancer nested in a cohort of automobile workers, we observed an increased risk for testicular cancer among workers who had ever been involved in occupational metal-cutting tasks. We investigated whether this risk increase was due to exposure to metal-working fluids (MWF)., Methods: Occupational exposure to MWF was assessed in detail using a job-specific questionnaire for metal-cutting work. We calculated ORs and associated 95% CIs individually matched for age (±2 years) and adjusted for a history of cryptorchidism by conditional logistic regression., Results: The prevalence of exposure to MWF was 39.8% among cases and 40.1% among controls. For total germ cell tumours and seminomas we did not observe risk increases for metal-cutting tasks or occupational exposure to MWF (OR 0.95; 95% CI 0.69 to 1.32 and OR 0.88; 95% CI 0.58 to 1.35, respectively). However, dermal exposure to oil-based MWF was associated with an increased risk for non-seminomatous testicular cancer. Dermal exposure to oil-based MWF for more than 5000 h showed particularly high risk estimates (OR 4.72; 95% CI 1.48 to 15.09)., Discussion: Long-term dermal exposure to oil-based MWF was a risk factor for the development of non-seminomatous testicular germ cell cancer. Possible measures to reduce exposure include the introduction of engineering control measures such as venting or enclosing of machines, and enforcing the use of personal protective equipment during metal cutting.

Objectives: A system for retrospective occupational exposure assessment combining the efficiency of a job exposure matrix (JEM) and the precision of a subsequent individual expert exposure assessment (IEEA) was developed. All steps of the exposure assessment were performed by an interdisciplinary expert panel in the context of a case-control study on male germ cell cancer nested in the car manufacturing industries., Methods: An industry-specific JEM was developed and automatic exposure estimation was performed based on this JEM. A subsample of exposure ratings was done by IEEA to identify determinants of disagreement between the JEM and the individual review. Possible determinants were analyzed by calculating odds ratios (ORs) of disagreement between ratings with regard to different dimensions (e.g. high versus low intensity of exposure). Disagreement in ≥20% of the sampled exposure ratings with a statistically significant OR was chosen as a threshold for inclusion of the exposure ratings into a final IEEA., Results: The most important determinants of disagreement between JEM and individual review were working outside of the production line (disagreement 80%), low probability of exposure (disagreement 25%), and exposure depending on specific activities like usage of specific lacquers (disagreement 32%) for jobs within the production line. These determinants were the selection criteria of exposure ratings for the subsequent final IEEA., Conclusions: Combining a JEM and a subsequent final IEEA for a selected subset of exposure ratings is a feasible and labor-saving approach for exposure assessment in large occupational epidemiological studies.

Brushtail possums exhibit a distinct preovulatory pattern of prolactin (Prl) secretion suggesting that Prl is involved in normal reproductive function. In some mammals, Prl is essential for corpus luteum (CL) function and/or modulation of steroidal effects on hypothalamic-pituitary activity. The aim of this study was to test the effects of biologically active recombinant possum Prl (recPosPrl) on both pituitary gland and CL function in possums. To confirm biological activity, administration of recPosPrl-N2C1 (10 μg) resulted in an 18-fold stimulation (P<0.05) of progesterone (P(4)) production by possum granulosa cells in vitro. Based on these findings, minipumps containing either recPosPrl-N2C1 (n=10) or saline (n=8) were inserted into lactating female possums. The expression levels of pituitary-derived PRL, LHB, FSHB and GNRHR and CL-derived LHR mRNA were quantified. Following a resumption of reproductive activity, no differences in ovulation incidence or plasma Prl concentrations were observed. Plasma Prl levels were less variable (P<0.001) in Prl-treated possums, confirming a self-regulatory role for Prl in this species. There was a marked down-regulation (P<0.001) of FSHB mRNA at the mid-luteal stage in Prl-treated possums, whereas mean PRL, LHB, GNRHR and LHR mRNA expression levels were not different between experimental groups. Plasma P(4) concentrations were not different (P=0.05) in Prl-treated possums, although tended to be higher in the peri-ovulatory and early-luteal phase. We conclude in the brushtail possum that Prl is self-regulated via a short-feedback loop common to all mammals studied and is able to modulate FSHB expression probably at the level of the hypothalamus and/or pituitary gland., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objective: To examine whether exposures or activities in farming, forestry and related occupations explain the excess incidence of germ cell cancer (GCC) observed among male employees in one of the six car-manufacturing plants that is located in a geographic area where farming is frequent., Methods: A cohort based case-control study was conducted among workers in six car-manufacturing plants located in areas with different industrial structure. The study involved 188 cases of germ cell cancer identified through active retrieval in 38 hospitals and 1000 controls, drawn from administrative accounting files, individually matched by year of birth (± 2 years). Information regarding tasks and exposures and potential confounding variables were obtained by face-to-face or telephone interviews. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using a conditional logistic regression model adjusted for cryptorchidism and other potential confounders., Results: In this case-control study 5.3% of cases and 6.3% of controls ever worked in agriculture or livestock farming. No increased risks were observed for working in agriculture (OR=0.8 95% CI: 0.4-1.6), livestock farming (OR=0.8 95% CI: 0.4-1.6) or for exposure to pesticides (OR=0.7 95% CI: 0.3-1.7), for exposure to fertilizers (OR=0.8 95% CI: 0.4-1.8) and disinfectants (OR=1.0 95% CI: 0.3-2.8). There were no statistically significant increases in risk associated with ever exposure to salt based wood protection agents (OR=2.3 95% CI: 0.6-9.1), working with plywood (OR=1.4 95% CI: 0.6-3.2), coated wood (OR=1.4 95% CI: 0.5-3.9) or working in forestry (OR=1.7 95% CI: 0.5-6.4). Lagging of exposures did not alter the results., Conclusions: The observed excess incidence in the cohort of automotive workers can be hardly explained by previous or concurrent work in farming or forestry. Because of the small numbers of subjects ever employed in farming the statistical power in assessing associations between agricultural work and agricultural exposures was limited and does not allow final conclusions about the association of farming related exposures and GCC risk., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Testicular cancer is one of the commonest cancers in men of working age, and is increasing in incidence in Europe and North America. One suggested mechanism of causation is that there is impaired differentiation of germ cells in the pre- or perinatal period, followed by malignant transformation in later life, possibly by a hormonal mechanism. Endocrine disrupting chemicals (EDCs) have been a major focus of interest for etiological research into testicular cancer because they interact with various hormonal pathways. Several EDCs including bisphenol A, phthalates, metals, polychlorinated biphenyls, and organochlorines have been investigated, but there are few studies and those that exist have not been able to assess exposure well. In addition, several studies, particularly those with better exposure assessment, have suggested that workers in electrical occupations have increased risks of testicular cancer. Electromagnetic radiation may have subthermal effects or may disrupt hormone release. Chronodisruption such as due to shift-work could potentially increase the risk of testicular cancer via disruption of hormonal cycles, but only one study has so far investigated this possibility. Lastly, solvent exposure, particularly to dimethylformamide, has been suggested to be associated with testicular cancer, but almost all these studies are based on job title only, with no specific assessment of solvent exposure. In conclusion, there is little evidence available on which to base definitive statements about occupational causes of testicular cancer. Future studies need to improve exposure assessment and develop ways to adjust for possible prenatal factors.

Background: To examine whether the previously observed excess risk of male germ cell cancer in a cohort of car-manufacturing workers can be attributed to occupational activities inside and/or outside the car industry., Methods: A nested case-control study among workers in six plants included 205 cases of germ cell cancer and 1,105 controls, individually matched by year of birth (±2 years). Job periods of the individual occupational histories were coded based on the International Standard Classification of Occupations (ISCO) and the industrial classification of economic activities (NACE). Odds ratios (ORs) and corresponding 95%-confidence intervals (CI) for ever-never and cumulative employment were calculated by conditional multivariate logistic regression adjusted for cryptorchidism., Results: Significantly increased risks were observed for machinery fitters and assemblers (A) (OR = 1.8, 95% CI 1.25-2.53) and "workers not elsewhere classified" (OR = 2.10, 95% CI 1.27-3.54), but no trend was observed for employment duration in either occupational group. Stratification of job group A by metal-cutting and non-cutting jobs yielded ORs of 1.87 (95% CI 1.31-2.67) and of 1.24 (95% CI 0.68-2.28), respectively. Among "plumbers, welders, sheet & structural metal workers" (adjusted OR 1.4, 95% CI 0.99-1.95) only "structural metal preparers and erectors" showed a substantially increased risk (OR = 2.30; 95% CI 1.27-4.27)., Conclusions: Our results do not fully explain the increased incidence of germ cell cancer in the cohort, but support previous findings showing increased risks among metal workers. These risks were most strongly pronounced in metal-cutting activities., (© 2010 Wiley-Liss, Inc.)

During anterior scoliosis instrumentation with a dual-rod system, the vertebrae are dissected anterolaterally. After surgery, some patients report a change in temperature perception and perspiration in the lower extremities. Sympathetic lesions might be an explanation for this. The aim of this clinical study was to investigate sympathetic function after anterior scoliosis instrumentation. A total of 24 female patients with idiopathic scoliosis (mean age at follow-up, 23.8 years) who had undergone anterior instrumentation on average 6.6 years earlier were included. Due to the suspected relevance of the sympathetic L2 ganglion, two groups were created: a T12 group, in which instrumentation down to T12 was carried out (n = 12), and an L3 group, in which instrumentation down to L3 was done (n = 12). Sympathetic function was assessed by measuring skin temperature at the back of the foot, a plantar ninhydrin sweat test and sympathetic skin responses (SSRs) following electrical stimulation. The side on which the surgical approach was carried out was compared with the contralateral, control side. Health-related quality of life was investigated using the Scoliosis Research Society SRS-22 patient questionnaire. In the T12 group, mean temperatures of 29.6 degrees C on the side of the approach versus 29.5 degrees C on the control side were measured (P > 0.05); in the L3 group, the mean temperatures were 33.2 degrees C on the approach side versus 30.5 degrees C on the control side (P = 0.001). A significant difference between the T12 group and the L3 group (P < 0.001) was observed on the approach side, but not on the control side (P = 0.15). The ninhydrin sweat test showed reduced perspiration in 11 of 12 patients in the L3 group on the approach side in comparison with the control side (P = 0.002). In the T12 group, no significant differences were noted between the left and right feet. SSRs differed significantly between the two groups (P = 0.005). They were detected in all nine analyzable patients in the T12 group on both sides. In the L3 group, they were found on the approach side only in 4 of 11 analyzable patients versus 11 patients on the control side. The results of the SRS-22 questionnaire did not show any significant differences between the two groups. In conclusion, anterior scoliosis instrumentation with a dual-rod system including vertebrae down to L3 regularly leads to lesions in the sympathetic trunk. These are detectable with an increase in temperature, reduced perspiration and reduced SSRs. The caudal level of instrumentation (T12 vs. L3) has an impact on the extent of impairment, supporting the suspected importance of the L2 ganglion. The clinical outcome does not seem to be significantly limited by sympathetic trunk lesions.

IGFs are known to be key regulators of ovarian follicular growth in eutherian mammals, but little is known regarding their role in marsupials. To better understand the potential role of IGFs in the regulation of follicular growth in marsupials, expression of mRNAs encoding IGF1, IGF2, IGF1R, IGF-binding protein 2 (IGFBP2), IGFBP4 and IGFBP5 was localized by in situ hybridization in developing ovarian follicles of the brushtail possum. In addition, the effects of IGF1 and IGF2 on granulosa cell function were tested in vitro. Both granulosa and theca cells synthesize IGF mRNAs, with the theca expressing IGF1 mRNA and granulosa cell expressing IGF2 mRNA. Oocytes and granulosa cells express IGF1R. Granulosa and theca cells expressed IGFBP mRNAs, although the pattern of expression differed between the BPs. IGFBP5 mRNA was differentially expressed as the follicles developed with granulosa cells of antral follicles no longer expressing IGFBP5 mRNA, suggesting an increased IGF bioavailability in the antral follicle. The IGFBP protease, PAPPA mRNA, was also expressed in granulosa cells of growing follicles. Both IGF1 and IGF2 stimulated thymidine incorporation but had no effect on progesterone production. Thus, IGF may be an important regulator of ovarian follicular development in marsupials as has been shown in eutherian mammals.

Aims: To analyze the relationship between asbestos exposure and malignant lymphoma in a multicenter case-control study conducted in Germany and Italy according to a common core protocol., Methods: Male and female patients with malignant lymphoma (n = 1,034) between 18 and 80 years of age were prospectively recruited in six study areas in Germany (Ludwigshafen/Upper Palatinate, Heidelberg/Rhine-Neckar-County, Würzburg/Lower Frankonia, Hamburg, Bielefeld/East Westphalia, and Munich) and in two study areas in Sardinia, Italy (Cagliari and Nuoro provinces). A total of 1,173 population control subjects were drawn from population registers. In a structured personal interview, we elicited a complete occupational history, including every occupational period that lasted at least 1 year. On the basis of job task-specific supplementary questionnaires, trained experts assessed the exposure to asbestos. As a measure of cumulative asbestos exposure on a time by intensity scale, fiber-years were calculated. 12 cases (1.2%) and 12 control subjects (1.0%) had a cumulative asbestos exposure of more than 2.6 fiber-years (highest exposure category according to the 90th percentile of exposed control subjects). Odds ratios (OR) and 95% confidence intervals (CI) were calculated using unconditional logistic regression analysis adjusted for age, sex and study region. Patients with specific lymphoma sub-entities were additionally compared with the entire control group., Results: We observed no statistically significant association between cumulative asbestos exposure and the risk of any lymphoma subtype. An elevated risk was found for the association between exposure to more than 2.6 fiber-years and multiple myeloma (OR = 6.0; 95% CI 1.4-25.1); however, numbers were small (n = 3 cases, all of them from Italy; n = 12 control subjects)., Conclusions: Our study does not support an association between asbestos exposure and risk of malignant lymphoma.

The V3 region of the envelope glycoprotein gp120 of the human immunodeficiency virus type 1 (HIV-1) is a potential target for an anti-HIV-1 vaccine. Peptides corresponding to V3 form three variations of a beta-hairpin conformation when bound to anti-V3 HIV-1 neutralizing antibodies. The conformation of a V3(IIIB) peptide bound to the 0.5beta antibody, generated against an X4 gp120, has been postulated to represent the V3 conformation of X4 viruses while the conformations of a V3(MN) and a V3(CONSENSUS) peptide bound to the 447-52D human monoclonal antibody were postulated to represent the R5A and R5B V3 conformations of R5 viruses, respectively. To constrain the conformation of synthetic V3 peptides to these X4, R5A, and R5B conformations, we formed disulfide bonds between Cys residues whose location in a peptide template representing the entire V3(CONSENSUS) epitope recognized by the broadly neutralizing 447-52D antibody was changed systematically. In a previous study [Mor, A., et al. (2009) Biochemistry 48, 3288-3303] we showed that these constrained peptides adopted conformations resembling the three antibody-bound V3 conformations according to the location of the disulfide bonds. Here we show that these constrained peptides, with the exception of peptides in which the disulfide bond flanks the GPGR segment, retain high-affinity binding to the 447-52D antibody. Compared with peptides designed to mimic the X4 conformation, peptides designed to mimic either the R5A or R5B conformation had higher affinity to 447-52D. It is possible that constrained peptides which mimic the R5A and R5B conformations of the V3 and retain high-affinity binding to 447-52D are good candidates for eliciting a broad neutralizing antibody response similar to that of 447-52D.

The third variable region (V3) of the HIV-1 envelope glycoprotein gp120 is a target for virus neutralizing antibodies. The V3 sequence determines whether the virus will manifest R5 or X4 phenotypes and use the CCR5 or CXCR4 chemokine coreceptor, respectively. Previous NMR studies revealed that both R5- and X4-V3 peptides bound to antibodies 0.5beta and 447-52D form beta-hairpin conformations with the GPGR segment at the turn. In contrast, in their free form, linear V3 peptides and a cyclic peptide consisting of the entire 35-residue V3 loop were highly unstructured in aqueous solution. Herein we evaluated a series of synthetic disulfide constrained V3-peptides in which the position of the disulfide bonds, and therefore the ring size, was systematically varied. NMR structures determined for singly and doubly disulfide constrained V3-peptides in aqueous solution were compared with those found for unconstrained V3(JRFL) and V3(IIIB) peptides bound to 447-52D and to 0.5beta, respectively. Our study indicated that cyclic V3 peptides manifested significantly reduced conformational space compared to their linear homologues and that in all cases cyclic peptides exhibited cross-strand interactions suggestive of beta-hairpin-like structures. Nevertheless, the singly constrained V3-peptides retained significant flexibility and did not form an idealized beta-hairpin. Incorporation of a second disulfide bond results in significant overall rigidity, and in one case, a structure close to that of V3(MN) peptide bound to 447-52D Fab was assumed and in another case a structure close to that formed by the linear V3(IIIB) peptide bound to antibody 0.5beta was assumed.

We synthesized two carminic acid (7-alpha-d-glucopyranosyl-9,10-dihydro-3,5,6,8-tetrahydroxy-1-methyl-9,10-dioxo-2-anthracene carboxlic acid, CA)-GnRH conjugates to be used as a model for potential photoactive targeted compounds. CA was conjugated to the epsilon-amino group of [d-Lys(6)]GnRH through its carboxylic moiety or via a beta-alanine spacer (beta-ala). Redox potentials of CA and its conjugates were determined. We used electron spin resonance (ESR) and spin trapping techniques to study the light-stimulated redox properties of CA and its CA-GnRH conjugates. Upon irradiation, the compounds stimulated the formation of reactive oxygen species (ROS), that is, singlet oxygen ((1)O(2)) and oxygen radicals (O(2)(-*) and OH(*)). Both conjugates exhibited higher ROS production than the non-conjugated CA. The bioactivity properties of the CA conjugates and the parent peptide, [d-Lys(6)]GnRH, were tested on primary rat pituitary cells. We found that the conjugates preserved the bioactivity of GnRH as illustrated by their capability to induce ERK phosphorylation and LH release.

The aim of occupational epidemiology is to describe workplace-related diseases and to identify their underlying causes. Its primary goal is to protect workers from hazardous effects of the working process by applying work-related primary and secondary prevention measures. To assess health risks different study designs and a wide array of complex study instruments and methods are frequently employed that cannot be replaced by toxicological investigations. This paper primarily addresses health risks by agent exposures. In this context a central task of occupational epidemiology is careful assessment of exposure. Different data sources, such as work site measurements, register data, archive material, experts' opinion, and the workers' personal estimates of exposure may be used during this process. In addition, biological markers can complement exposure assessment. Since thorough occupational epidemiologic studies allow assessment of disease risks under realistic exposure conditions, their results should be more frequently used to derive workplace-related threshold limit values.

Although some causes for malignant lymphoma are known their etiology is not well understood so far. We analyze the relationship between sun exposure and malignant lymphoma in a multicenter, population-based case-control study. Patients with malignant lymphoma (n = 710, 18-80 years) were prospectively recruited in 6 study regions in Germany. For each case, a gender, region and age-matched control was drawn from population-registers. In personal interviews, lifetime holidays spent in sunny climate, outdoor leisure activities and sunbed or sunlamp use were recorded. On basis of job task-specific supplementary questionnaires, an occupational physician assessed the cumulative working time outside. Odds ratios (OR) and 95%-confidence-intervals (CI) were calculated using conditional logistic regression analysis, adjusted for smoking and alcohol consumption. To increase statistical power, patients with specific lymphoma subentities were additionally compared with the entire control group using unconditional logistic regression. We observed a reduced overall lymphoma risk among subjects having spent vacations at sunny climates or frequently used sunbeds or sunlamps. The analysis of lymphoma subentities revealed similar results with the exception of T-NHL and follicular lymphoma which were positively associated with outdoor leisure activities. While cumulative working time outside appeared unrelated to NHL overall and most subentities, it was negatively associated with follicular lymphoma and weakly positively to HL. This data suggest that exposure to natural and artificial ultraviolet radiation may reduce the OR for lymphoma in this study population.

Aims: To analyze the relationship between exposure to chlorinated and aromatic organic solvents and malignant lymphoma in a multi-centre, population-based case-control study., Methods: Male and female patients with malignant lymphoma (n = 710) between 18 and 80 years of age were prospectively recruited in six study regions in Germany (Ludwigshafen/Upper Palatinate, Heidelberg/Rhine-Neckar-County, Würzburg/Lower Frankonia, Hamburg, Bielefeld/Gütersloh, and Munich). For each newly recruited lymphoma case, a gender, region and age-matched (+/- 1 year of birth) population control was drawn from the population registers. In a structured personal interview, we elicited a complete occupational history, including every occupational period that lasted at least one year. On the basis of job task-specific supplementary questionnaires, a trained occupational physician assessed the exposure to chlorinated hydrocarbons (trichloroethylene, tetrachloroethylene, dichloromethane, carbon tetrachloride) and aromatic hydrocarbons (benzene, toluene, xylene, styrene). Odds ratios (OR) and 95% confidence intervals (CI) were calculated using conditional logistic regression analysis, adjusted for smoking (in pack years) and alcohol consumption. To increase the statistical power, patients with specific lymphoma subentities were additionally compared with the entire control group using unconditional logistic regression analysis., Results: We observed a statistically significant association between high exposure to chlorinated hydrocarbons and malignant lymphoma (Odds ratio = 2.1; 95% confidence interval 1.1-4.3). In the analysis of lymphoma subentities, a pronounced risk elevation was found for follicular lymphoma and marginal zone lymphoma. When specific substances were considered, the association between trichloroethylene and malignant lymphoma was of borderline statistical significance. Aromatic hydrocarbons were not significantly associated with the lymphoma diagnosis., Conclusion: In accordance with the literature, this data point to a potential etiologic role of chlorinated hydrocarbons (particularly trichloroethylene) and malignant lymphoma. Chlorinated hydrocarbons might affect specific lymphoma subentities differentially. Our study does not support a strong association between aromatic hydrocarbons (benzene, toluene, xylene, or styrene) and the diagnosis of a malignant lymphoma.

In an attempt to develop efficient chemotherapeutic agents targeted at malignant cells that express receptors, we synthesized five new emodin derivatives and their gonadotropin-releasing hormone (GnRH) conjugates to be used as potential photoactive conjugates. Emodin was modified at its hydroxy groups and included different spacers for conjugation of the peptide. We used electron spin resonance (ESR) and spin trapping techniques to study the light-stimulated redox properties of the emodin derivatives and their GnRH conjugates. Upon irradiation, all new emodin derivatives and their conjugates stimulated the formation of singlet oxygen, that is, (1)O(2), and oxygen radicals, that is, O(2)(-)(*) and OH(*). However, substantial differences were found between the tested derivatives as to the efficacy of reactive oxygen species (ROS) production. Because of its superior ROS production properties, [d-Lys(6)(MeoEmo)]GnRH was selected as a leading conjugate. En-route to evaluate its targeting capacity, this potentially cytotoxic conjugate was tested in vitro to determine its hormonal activity and binding affinity to GnRH receptors.

Aims: To identify occupations suspected to be associated with malignant lymphoma and to generate new hypotheses about occupational risks in a multicentre, population based case control study., Methods: Male and female patients with malignant lymphoma (n = 710) aged 18-80 years of age were prospectively recruited in six study regions in Germany. For each newly recruited lymphoma case, a sex, region, and age matched control was drawn from the population registers. Odds ratios and 95% confidence intervals for major occupations and industries were calculated using conditional logistic regression analysis, adjusted for smoking (in pack-years) and alcohol consumption. Patients with specific lymphoma subentities were additionally compared with the entire control group using unconditional logistic regression analysis., Results: The following economic/industrial sectors were positively associated with lymphoma: food products, beverages, tobacco; paper products, publishing and printing; and metals. Chemicals; real estate, renting, and business activities were negatively associated with lymphoma diagnosis. The authors observed an increased overall lymphoma risk among architects; maids; farmers; glass formers; and construction workers. Shoemaking and leather goods making was negatively associated with the lymphoma diagnosis (although based on small numbers). In the occupational group analysis of lymphoma subentities, Hodgkin's lymphoma was significantly associated only with rubber and plastic products making; diffuse large B cell lymphoma risk was considerably increased among metal processors; follicular lymphoma showed highly significant risk increases for several occupational groups (medical, dental, and veterinary workers; sales workers; machinery fitters; and electrical fitters); and multiple myeloma showed a particularly pronounced risk increase for farmers as well as for agriculture and animal husbandry workers., Conclusions: The results partly confirm previously defined occupational risks. Occupational risk factors for follicular lymphomas might differ from the overall risk factors for malignant lymphoma.

Human monoclonal antibody (mAb) 447-52D neutralizes a broad spectrum of HIV-1 isolates, whereas murine mAb 0.5beta, raised against gp120 of the X4 isolate HIV-1(IIIB), neutralizes this strain specifically. Two distinct gp120 V3 peptides, V3(MN) and V3(IIIB), adopt alternative beta-hairpin conformations when bound to 447-52D and 0.5beta, respectively, suggesting that the alternative conformations of this loop play a key role in determining the coreceptor specificity of HIV-1. To test this hypothesis and to better understand the molecular basis underlying an antibody's breadth of neutralization, the solution structure of the V3(IIIB) peptide bound to 447-52D was determined by NMR. V3(IIIB) and V3(MN) peptides bound to 447-52D exhibited the same N-terminal strand conformation, while the V3(IIIB) peptide revealed alternative N-terminal conformations when bound to 447-52D and 0.5beta. Comparison of the three known V3 structures leads to a model in which a 180 degrees change in the orientation of the side chains and the resulting one-residue shift in hydrogen bonding patterns in the N-terminal strand of the beta-hairpins markedly alter the topology of the surface that interacts with antibodies and that can potentially interact with the HIV-1 coreceptors. Predominant interactions of 447-52D with three conserved residues of the N-terminal side of the V3 loop, K312, I314, and I316, can account for its broad cross reactivity, whereas the predominant interactions of 0.5beta with variable residues underlie its strain specificity.

Positively charged cyclic peptides (three to seven amino acids) have been tested for their inhibitory effects on Na+/Ca2+ exchange in the cardiac sarcolemma vesicles. The lead structure of Phe-Arg-Cys-Arg-Cys-Phe-CONH2 (FRCRCFa) has been systematically modified for identification of important pharmacophores. In cyclic peptides (intramolecular S-S bond, the carboxyl terminal is locked with amide (CONH2), and positive charge is retained by one or two arginines, ornithines, or lysines. Thirty-five different cyclic peptides show IC50 values in the range of 2-800 microM, suggesting that some specific structure-activity relationships may determine the inhibitory effects. Shortening of the FRCRCFa length to four amino acids decreases the inhibitory potency by 10-80-fold. The substitution of Arg2 or Arg4 in FRCRCFa with lysine or ornithine decreases the inhibitory potency by 5-12-fold, suggesting that both arginines are beneficial for inhibition. The substitution of Phe1 in FRCRCFa by 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid produces a potent inhibitor (IC50 = 2-4 microM). The N-myristoylated FRCRCFa exhibits an inhibitory potency (IC50 = 8-10 microM) similar to that of the parent FRCRCFa peptide, thereby arousing a new possibility for the development of a cell-permeable blocker of the Na+/Ca2+ exchanger, D-Arg4 or D-Cys5 substitutions in FRCRCFa do not alter the inhibitory effect, whereas the L-to-D substitutions of other amino acids in FRCRCFa reduce the inhibitory potency by 4-5-fold. Thus, the L-to-D substitutions of Arg4 and/or Cys5 have a potential to increase the peptide stability to proteolytic degradation. The insertion of proline outside of the ring of FRCRCFa diminishes the inhibitory potency by 3-6-fold, whereas proline introduction into the ring decreases the inhibitory potency by 16-20-fold. The replacement of Cys3 and Cys5 in FRCRCFa with beta, beta-dimethylcystein has no significant effect on the inhibitory potency, suggesting that the S-S bond is not exposed to the interface of the peptide/receptor interaction. In conclusion, the current data support a proposal that the conformationally constrained Arg-Cys-Arg-Cys structure is obligatory for inhibition of Na+/Ca2+ exchange, whereas hydrophobic additions at the carboxyl and amino ends have limited effects in increasing the inhibitory potency.

Positively charged cyclic hexapeptide Phe-Arg-Cys-Arg-Cys-Phe-CONH2 (FRCRCFa) represents a group of conformationally constrained peptides that block the cardiac sarcolemma Na(+)-Ca2+ exchanger [Khananshvili et al. (1995b) J. Biol. Chem. 270, 16182-16188]. Here, we study the kinetic mechanisms of FRCRCFa-induced inhibition of Na(+)-Ca2+ exchange and its partial reaction, the Ca(2+)-Ca2+ exchange. The Nai-dependent 45Ca uptake and Cai-dependent 45Ca uptake were measured by adding the EGTA quench in the semirapid mixer. The reverse mode of Na(+)-Ca2+ exchange (Nao-dependent Ca efflux) was monitored (t = 10-5000 ms) in the stopped-flow machine by measuring extravesicular free calcium with a fluorescence probe fluo-3. Saturating concentrations of FRCRCFa inhibit completely the forward and reverse modes of exchange, suggesting that the inside-out vesicles contribute to most (if not all) of the exchange activity. A short time exposure (t = 10-20 ms) of FRCRCFa with the vesicles is enough to reach a rapid equilibrium between FRCRCFa and a putative inhibitory site at the extravesicular (cytosolic) side of the membrane. A lower limit for the second-order rate constant of FRCRCFa binding can be estimated as a kon of > 10(6) M-1 s-1. A possible competition between FRCRCFa and either Na+ or Ca2+ has been tested at the extravesicular (cytosolic) side of the membrane. At different extravesicular Cao concentrations of 13-250 microM, FRCRCFa inhibits the Na(+)-Ca2+ and Ca(2+)-Ca2+ exchanges with an IC50 of 11-16 microM, suggesting no competition between FRCRCFa and Ca2+. At different extravesicular Nao concentrations of 40-160 mM, FRCRCFa inhibits Nao-dependent Ca efflux with an IC50 of 12-18 microM, suggesting that FRCRCFa and Na+ do not compete for binding at the extravesicular side. A mild proteolytic treatment of vesicles activates the Nai-dependent 45Ca uptake, but has a little effect on the FRCRCFa-induced inhibition. Thus, the "inhibitory site" is still functional after the proteolytic treatment of the inside-out vesicles. In conclusion, a rapid (< 20 ms) interaction of extravesicular (cytosolic) FRCRCFa with the exchanger prevents the ion translocation through the exchanger, while the inhibitory peptide does not interact with the ion transport sites of the exchanger at the cytosolic side of the membrane.