Stable-Isotopic Composition of Precipitation Over the Northern Slope of the Central Himalaya

Stable-water-isotope data (deltaD and delta(18)O) from three groups of samples (fresh-snow and snow-pit samples collected on Qomolangma (Mount Everest) and Xixabangma during field seasons 1997,1998 and 2001, and precipitation samples collected at Tingri station during summer 2000) are presented and used to survey the isotopic composition of precipitation over the northern slope of the central Himalaya. Multi-year snow-pit samples on Qomolangma have a local meteoric water-line (slope = 8) close to the global value. Deuterium excess (d = deltaD - 8delta(18)O) values at Tingri are much lower than those in fresh snow from Qomolangma, probably due to differences in moisture source and air-mass trajectories as well as local weather conditions. There is no obvious seasonal trend for d values in the Qomolangma region. A negative relationship exists between delta(18)O and d values in both fresh snow on Qomolangma and precipitation at Tingri. Fresh-snow samples collected from different altitudes on Xixabangma allow us to investigate the altitude effect on delta(18)O values in snow. Of four storm events, only one has an obvious altitude effect on delta(18)O variation and a very low gradient of -0.1% per 100 in elevation.

The influence of sampling design on tree-ring-based quantification of forest growth

Tree-rings offer one of the few possibilities to empirically quantify and reconstruct forest growth dynamics over years to millennia. Contemporaneously with the growing scientific community employing tree-ring parameters, recent research has suggested that commonly applied sampling designs (i.e. how and which trees are selected for dendrochronological sampling) may introduce considerable biases in quantifications of forest responses to environmental change. To date, a systematic assessment of the consequences of sampling design on dendroecological and-climatological conclusions has not yet been performed. Here, we investigate potential biases by sampling a large population of trees and replicating diverse sampling designs. This is achieved by retroactively subsetting the population and specifically testing for biases emerging for climate reconstruction, growth response to climate variability, long-term growth trends, and quantification of forest productivity. We find that commonly applied sampling designs can impart systematic biases of varying magnitude to any type of tree-ring-based investigations, independent of the total number of samples considered. Quantifications of forest growth and productivity are particularly susceptible to biases, whereas growth responses to short-term climate variability are less affected by the choice of sampling design. The world's most frequently applied sampling design, focusing on dominant trees only, can bias absolute growth rates by up to 459% and trends in excess of 200%. Our findings challenge paradigms, where a subset of samples is typically considered to be representative for the entire population. The only two sampling strategies meeting the requirements for all types of investigations are the (i) sampling of all individuals within a fixed area; and (ii) fully randomized selection of trees. This result advertises the consistent implementation of a widely applicable sampling design to simultaneously reduce uncertainties in tree-ring-based quantifications of forest growth and increase the comparability of datasets beyond individual studies, investigators, laboratories, and geographical boundaries.

Biological, diagnostic and therapeutic relevance of the MET receptor signaling in head and neck cancer.

Head and neck cancer constitutes the 6th most common malignancy worldwide and affects the crucial anatomical structures and physiological functions of the upper aerodigestive tract. Classical therapeutic strategies such as surgery and radiotherapy carry substantial toxicity and functional impairment. Moreover, the loco-regional control rates as well as overall survival still need to be improved in subgroups of patients. The scatter-factor/hepatocyte growth factor receptor tyrosine kinase MET is an established effector in the promotion, maintenance and progression of malignant transformation in a wide range of human malignancies, and has been gaining considerable interest in head and neck cancer over the last 15 years. Aberrant MET activation due to overexpression, mutations, tumor-stroma paracrine loops, and cooperative/redundant signaling has been shown to play prominent roles in epithelial-to-mesenchymal transition, angiogenesis, and responses to anti-cancer therapeutic modalities. Accumulating preclinical and translational evidence highly supports the increasing interest of MET as a biomarker for lymph node and distant metastases, as well as a potential marker of stratification for responses to ionizing radiation. The relevance of MET as a therapeutic molecular target in head and neck cancer described in preclinical studies remains largely under-evaluated in clinical trials, and therefore inconclusive. Also in the context of anti-cancer targeted therapy, a large body of preclinical data suggests a central role for MET in treatment resistance towards multiple therapeutic modalities in malignancies of the head and neck region. These findings, as well as the potential use of combination therapies including MET inhibitors in these tumors, need to be further explored.

The influence of tibial morphology on the design of an anatomical tibial baseplate for TKA.

BACKGROUND Finding the right balance between tibial coverage and minimal implant overhang is an important factor in TKA. Another significant cause of failure is component malrotation. METHODS An average master shape of the proximal tibia at TKA resection level was calculated using fine slice computed tomographies of 117 cadaveric knees. To find out whether alternate implant contours would be necessary depending on the patient's body size, we established five subgroups to compare. CAD-Analysis was performed to simulate the overhang produced after ±4°/±7°/±10° rotation. RESULTS A master shape for the tibial resection cut (with a 5° posterior slope, 7 mm under lateral joint line) could be determined. Neither left vs. right knee joint, nor male vs. female nor the size subdivision appears to alter the calculated master shape significantly. The optimized shape allowing for ±4° of rotational freedom was found to be the best variant. CONCLUSIONS Valid methods have been obtained to design a two-dimensional average shape of the tibial plateau. The modifications described in this study might come in useful, when designing future implant designs. CLINICAL RELEVANCE An optimized fit at the tibial plateau and lower rates of component malrotation may result in better outcomes after TKA.

Association between Head Injury and Helmet Use in Alpine Skiers: Cohort Study from a Swiss Level I Trauma Center.

The association between helmet use during alpine skiing and incidence and severity of head injuries was analyzed. All patients admitted to a level 1 trauma center for traumatic brain injuries (TBIs) sustained from skiing accidents during the seasons 2000-2001 and 2010-2011 were eligible. Primary outcome was the association between helmet use and severity of TBI measured by Glasgow Coma Scale (GCS), computed tomography (CT) results, and necessity of neurosurgical intervention. Of 1362 patients injured during alpine skiing, 245 (18%) sustained TBI and were included. TBI was fatal in 3%. Head injury was in 76% minor (Glasgow Coma Scale, 13-15), 6% moderate, and 14% severe. Number and percentage of TBI patients showed no significant trend over the investigated seasons. Forty-five percent of the 245 patients had pathological CT findings and 26% of these required neurosurgical intervention. Helmet use increased from 0% in 2000-2001 to 71% in 2010-2011 (p<0.001). The main analysis, comparing TBI in patients with or without a helmet, showed an adjusted odds ratio (OR) of 1.44 (p=0.430) for suffering moderate-to-severe head injury in helmet users. Analyses comparing off-piste to on-slope skiers revealed a significantly increased OR among off-piste skiers of 7.62 (p=0.004) for sustaining a TBI requiring surgical intervention. Despite increases in helmet use, we found no decrease in severe TBI among alpine skiers. Logistic regression analysis showed no significant difference in TBI with regard to helmet use, but increased risk for off-piste skiers. The limited protection of helmets and dangers of skiing off-piste should be targeted by prevention programs.

Evaluating an e-mental health program (“deprexis”) as adjunctive treatment tool in psychotherapy for depression: design of a pragmatic randomized controlled trial

Background Major depressive disorder (MDD) places a significant disease burden on individuals as well as on societies. Several web-based interventions for MDD have shown to be effective in reducing depressive symptoms. However, it is not known whether web-based interventions, when used as adjunctive treatment tools to regular psychotherapy, have an additional effect compared to regular psychotherapy for depression. Methods/design This study is a currently recruiting pragmatic randomized controlled trial (RCT) that compares regular psychotherapy plus a web-based depression program (¿deprexis¿) with a control condition exclusively receiving regular psychotherapy. Adults with a depressive disorder (N?=?800) will be recruited in routine secondary care from therapists over the course of their initial sessions and will then be randomized within therapists to one of the two conditions. The primary outcome is depressive symptoms measured with the Beck Depression Inventory (BDI-II) at three months post randomization. Secondary outcomes include changes on various indicators such as anxiety, somatic symptoms and quality of life. All outcomes are again assessed at the secondary endpoint six months post randomization. In addition, the working alliance and feasibility/acceptability of the treatment condition will be explored. Discussion This is the first randomized controlled trial to examine the feasibility/acceptability and the effectiveness of a combination of traditional face-to-face psychotherapy and web-based depression program compared to regular psychotherapeutic treatment in depressed outpatients in routine care.

Viral load versus CD4⁺ monitoring and 5-year outcomes of antiretroviral therapy in HIV-positive children in Southern Africa: a cohort-based modelling study.

OBJECTIVES Many paediatric antiretroviral therapy (ART) programmes in Southern Africa rely on CD4⁺ to monitor ART. We assessed the benefit of replacing CD4⁺ by viral load monitoring. DESIGN A mathematical modelling study. METHODS A simulation model of HIV progression over 5 years in children on ART, parameterized by data from seven South African cohorts. We simulated treatment programmes with 6-monthly CD4⁺ or 6- or 12-monthly viral load monitoring. We compared mortality, second-line ART use, immunological failure and time spent on failing ART. In further analyses, we varied the rate of virological failure, and assumed that the rate is higher with CD4⁺ than with viral load monitoring. RESULTS About 7% of children were predicted to die within 5 years, independent of the monitoring strategy. Compared with CD4⁺ monitoring, 12-monthly viral load monitoring reduced the 5-year risk of immunological failure from 1.6 to 1.0% and the mean time spent on failing ART from 6.6 to 3.6 months; 1% of children with CD4⁺ compared with 12% with viral load monitoring switched to second-line ART. Differences became larger when assuming higher rates of virological failure. When assuming higher virological failure rates with CD4⁺ than with viral load monitoring, up to 4.2% of children with CD4⁺ compared with 1.5% with viral load monitoring experienced immunological failure; the mean time spent on failing ART was 27.3 months with CD4⁺ monitoring and 6.0 months with viral load monitoring. Conclusion: Viral load monitoring did not affect 5-year mortality, but reduced time on failing ART, improved immunological response and increased switching to second-line ART.

German Total Ankle Replacement Register of the German Foot and Ankle Society (D. A. F.) - presentation of design and reliability of the data as well as first results

INTRODUCTION Even though arthroplasty of the ankle joint is considered to be an established procedure, only about 1,300 endoprostheses are implanted in Germany annually. Arthrodeses of the ankle joint are performed almost three times more often. This may be due to the availability of the procedure - more than twice as many providers perform arthrodesis - as well as the postulated high frequency of revision procedures of arthroplasties in the literature. In those publications, however, there is often no clear differentiation between revision surgery with exchange of components, subsequent interventions due to complications and subsequent surgery not associated with complications. The German Orthopaedic Foot and Ankle Association's (D. A. F.) registry for total ankle replacement collects data pertaining to perioperative complications as well as cause, nature and extent of the subsequent interventions, and postoperative patient satisfaction. MATERIAL AND METHODS The D. A. F.'s total ankle replacement register is a nation-wide, voluntary registry. After giving written informed consent, the patients can be added to the database by participating providers. Data are collected during hospital stay for surgical treatment, during routine follow-up inspections and in the context of revision surgery. The information can be submitted in paper-based or online formats. The survey instruments are available as minimum data sets or scientific questionnaires which include patient-reported outcome measures (PROMs). The pseudonymous clinical data are collected and evaluated at the Institute for Evaluative Research in Medicine, University of Bern/Switzerland (IEFM). The patient-related data remain on the register's module server in North Rhine-Westphalia, Germany. The registry's methodology as well as the results of the revisions and patient satisfaction for 115 patients with a two year follow-up period are presented. Statistical analyses are performed with SAS™ (Version 9.4, SAS Institute, Inc., Cary, NC, USA). RESULTS About 2½ years after the register was launched there are 621 datasets on primary implantations, 1,427 on follow-ups and 121 records on re-operation available. 49 % of the patients received their implants due to post-traumatic osteoarthritis, 27 % because of a primary osteoarthritis and 15 % of patients suffered from a rheumatic disease. More than 90 % of the primary interventions proceeded without complications. Subsequent interventions were recorded for 84 patients, which corresponds to a rate of 13.5 % with respect to the primary implantations. It should be noted that these secondary procedures also include two-stage procedures not due to a complication. "True revisions" are interventions with exchange of components due to mechanical complications and/or infection and were present in 7.6 % of patients. 415 of the patients commented on their satisfaction with the operative result during the last follow-up: 89.9 % of patients evaluate their outcome as excellent or good, 9.4 % as moderate and only 0.7 % (3 patients) as poor. In these three cases a component loosening or symptomatic USG osteoarthritis was present. Two-year follow-up data using the American Orthopedic Foot and Ankle Society Ankle and Hindfoot Scale (AOFAS-AHS) are already available for 115 patients. The median AOFAS-AHS score increased from 33 points preoperatively to more than 80 points three to six months postoperatively. This increase remained nearly constant over the entire two-year follow-up period. CONCLUSION Covering less than 10 % of the approximately 240 providers in Germany and approximately 12 % of the annually implanted total ankle-replacements, the D. A. F.-register is still far from being seen as a national registry. Nevertheless, geographical coverage and inclusion of "high-" (more than 100 total ankle replacements a year) and "low-volume surgeons" (less than 5 total ankle replacements a year) make the register representative for Germany. The registry data show that the number of subsequent interventions and in particular the "true revision" procedures are markedly lower than the 20 % often postulated in the literature. In addition, a high level of patient satisfaction over the short and medium term is recorded. From the perspective of the authors, these results indicate that total ankle arthroplasty - given a correct indication and appropriate selection of patients - is not inferior to an ankle arthrodesis concerning patients' satisfaction and function. First valid survival rates can be expected about 10 years after the register's start.

Ego depletion and persistent performance in a cycling task

We tested the assumption that persistent performance in an exhausting indoor cycling task would depend on momentarily available self-control strength (N = 20 active participants). In a within-subjects design (two points of measurement, exactly seven days apart), participants’ self-control strength was experimentally manipulated (depletion: yes vs. no; order counterbalanced) via the Stroop test before the participants performed a cycling task. In line with our hypothesis, hierarchical linear modelling (HLM) revealed that participants consistently performed worse over a period of 18 minutes when they were ego depleted. In addition, HLM analysis revealed that depleted participants invested less effort in the cycling task, as indicated by their lower heart rate. This effect escalated over time, as indicated by a time × condition interaction. These results indicate that self-control strength is necessary to obtain an optimal level of performance in endurance tasks requiring high levels of persistence. Practical implications are discussed.

The ring vaccination trial: a novel cluster randomised controlled trial design to evaluate vaccine efficacy and effectiveness during outbreaks, with special reference to Ebola

A World Health Organization expert meeting on Ebola vaccines proposed urgent safety and efficacy studies in response to the outbreak in West Africa. One approach to communicable disease control is ring vaccination of individuals at high risk of infection due to their social or geographical connection to a known case. This paper describes the protocol for a novel cluster randomised controlled trial design which uses ring vaccination.In the Ebola ça suffit ring vaccination trial, rings are randomised 1:1 to (a) immediate vaccination of eligible adults with single dose vaccination or (b) vaccination delayed by 21 days. Vaccine efficacy against disease is assessed in participants over equivalent periods from the day of randomisation. Secondary objectives include vaccine effectiveness at the level of the ring, and incidence of serious adverse events.Ring vaccination trials are adaptive, can be run until disease elimination, allow interim analysis, and can go dormant during inter-epidemic periods.

Virtopsy--fatal motor vehicle accident with head injury.

A man wearing no protective helmet was struck by a motor vehicle while riding a bicycle. He was loaded on his left side, and the impact point of his head was his occiput on the car roof girder. He was immediately transported to the general hospital, where he passed away. Postmortem examination using multi-slice computed tomography (MSCT) revealed an extensively comminuted fracture of the posterior part and the base of the skull. Observed were deep direct and contrecoup brain bruises, with the independent fractures of the roof of the both orbits. Massive subdural and subarachnoidal hemorrhage with cerebral edema and shifting of the mid-line towards left side were also detected. MSCT and autopsy results were compared and the body injuries were correlated to vehicle damages. In conclusion, postmortem imaging is a good forensic visualization tool with great potential for documentation and examination of body injuries and pathology.

Evaluation of leaders – does gender still matter?

Purpose: Leadership positions are still stereotyped as male, especially in male-dominated fields such as STEM. Therefore, women in such positions run the risk of being evaluated less favorably than men. Our study investigates how female and male leaders in existing teams (engineering project) are evaluated, and how these evaluations change over time. Design/Methodology: Participants worked in 45 teams to develop specific engineering projects. Evaluations of 45 leaders (33% women) by 258 team members (39% women) were analyzed, that is, leaders’ self-evaluation and their evaluation by team members. Results: Although female and male leaders did not differ in their self-evaluations at the beginning of the project, female leaders evaluated themselves better within time. However, team members evaluated female leaders better than male leaders at the beginning of the project. These gender differences disappeared over the time. Limitations: It should be replicated in a non-student sample. Implications: The results show that female leaders entering a male-dominated field (engineering) are evaluated better by team members than male leaders at the beginning of the team work, in line with the ‘shifting standard model’ (Biernat & Fuegen, 2001). While the initial impression formation of female and male leaders is influenced by category membership, its impact decreases over time as a consequence of individualization (Fiske & Neuberg, 1990); this results in similar evaluations over time. Originality: To our knowledge this is the first study to systematically test perceptions of change in the evaluation over time of female and male leaders in natural setting.

Street crossing behavior in younger and older pedestrians: an eye- and head-tracking study

BACKGROUND: Crossing a street can be a very difficult task for older pedestrians. With increased age and potential cognitive decline, older people take the decision to cross a street primarily based on vehicles' distance, and not on their speed. Furthermore, older pedestrians tend to overestimate their own walking speed, and could not adapt it according to the traffic conditions. Pedestrians' behavior is often tested using virtual reality. Virtual reality presents the advantage of being safe, cost-effective, and allows using standardized test conditions. METHODS: This paper describes an observational study with older and younger adults. Street crossing behavior was investigated in 18 healthy, younger and 18 older subjects by using a virtual reality setting. The aim of the study was to measure behavioral data (such as eye and head movements) and to assess how the two age groups differ in terms of number of safe street crossings, virtual crashes, and missed street crossing opportunities. Street crossing behavior, eye and head movements, in older and younger subjects, were compared with non-parametric tests. RESULTS: The results showed that younger pedestrians behaved in a more secure manner while crossing a street, as compared to older people. The eye and head movements analysis revealed that older people looked more at the ground and less at the other side of the street to cross. CONCLUSIONS: The less secure behavior in street crossing found in older pedestrians could be explained by their reduced cognitive and visual abilities, which, in turn, resulted in difficulties in the decision-making process, especially under time pressure. Decisions to cross a street are based on the distance of the oncoming cars, rather than their speed, for both groups. Older pedestrians look more at their feet, probably because of their need of more time to plan precise stepping movement and, in turn, pay less attention to the traffic. This might help to set up guidelines for improving senior pedestrians' safety, in terms of speed limits, road design, and mixed physical-cognitive trainings.

Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial

BACKGROUND Long-term hormone therapy has been the standard of care for advanced prostate cancer since the 1940s. STAMPEDE is a randomised controlled trial using a multiarm, multistage platform design. It recruits men with high-risk, locally advanced, metastatic or recurrent prostate cancer who are starting first-line long-term hormone therapy. We report primary survival results for three research comparisons testing the addition of zoledronic acid, docetaxel, or their combination to standard of care versus standard of care alone. METHODS Standard of care was hormone therapy for at least 2 years; radiotherapy was encouraged for men with N0M0 disease to November, 2011, then mandated; radiotherapy was optional for men with node-positive non-metastatic (N+M0) disease. Stratified randomisation (via minimisation) allocated men 2:1:1:1 to standard of care only (SOC-only; control), standard of care plus zoledronic acid (SOC + ZA), standard of care plus docetaxel (SOC + Doc), or standard of care with both zoledronic acid and docetaxel (SOC + ZA + Doc). Zoledronic acid (4 mg) was given for six 3-weekly cycles, then 4-weekly until 2 years, and docetaxel (75 mg/m(2)) for six 3-weekly cycles with prednisolone 10 mg daily. There was no blinding to treatment allocation. The primary outcome measure was overall survival. Pairwise comparisons of research versus control had 90% power at 2·5% one-sided α for hazard ratio (HR) 0·75, requiring roughly 400 control arm deaths. Statistical analyses were undertaken with standard log-rank-type methods for time-to-event data, with hazard ratios (HRs) and 95% CIs derived from adjusted Cox models. This trial is registered at ClinicalTrials.gov (NCT00268476) and ControlledTrials.com (ISRCTN78818544). FINDINGS 2962 men were randomly assigned to four groups between Oct 5, 2005, and March 31, 2013. Median age was 65 years (IQR 60-71). 1817 (61%) men had M+ disease, 448 (15%) had N+/X M0, and 697 (24%) had N0M0. 165 (6%) men were previously treated with local therapy, and median prostate-specific antigen was 65 ng/mL (IQR 23-184). Median follow-up was 43 months (IQR 30-60). There were 415 deaths in the control group (347 [84%] prostate cancer). Median overall survival was 71 months (IQR 32 to not reached) for SOC-only, not reached (32 to not reached) for SOC + ZA (HR 0·94, 95% CI 0·79-1·11; p=0·450), 81 months (41 to not reached) for SOC + Doc (0·78, 0·66-0·93; p=0·006), and 76 months (39 to not reached) for SOC + ZA + Doc (0·82, 0·69-0·97; p=0·022). There was no evidence of heterogeneity in treatment effect (for any of the treatments) across prespecified subsets. Grade 3-5 adverse events were reported for 399 (32%) patients receiving SOC, 197 (32%) receiving SOC + ZA, 288 (52%) receiving SOC + Doc, and 269 (52%) receiving SOC + ZA + Doc. INTERPRETATION Zoledronic acid showed no evidence of survival improvement and should not be part of standard of care for this population. Docetaxel chemotherapy, given at the time of long-term hormone therapy initiation, showed evidence of improved survival accompanied by an increase in adverse events. Docetaxel treatment should become part of standard of care for adequately fit men commencing long-term hormone therapy. FUNDING Cancer Research UK, Medical Research Council, Novartis, Sanofi-Aventis, Pfizer, Janssen, Astellas, NIHR Clinical Research Network, Swiss Group for Clinical Cancer Research.