Despite numerous available treatment strategies, the management of complex proximal humeral fractures remains demanding. Impaired bone quality and considerable comorbidities pose special challenges ...in the growing aging population. Complications after operative treatment are frequent, in particular loss of reduction with varus malalignment and subsequent screw cutout. Locking plate fixation has become a standard in stabilizing these fractures, but surgical revision rates of up to 25% stagnate at high levels. Therefore, it seems of utmost importance to select the right treatment for the right patient. This article provides an overview of available classification systems, indications for operative treatment, important pathoanatomic principles, and latest surgical strategies in locking plate fixation. The importance of correct reduction of the medial cortices, the use of calcar screws, augmentation with bone cement, double-plate fixation, and auxiliary intramedullary bone graft stabilization are discussed in detail.
Aggregation of misfolded proteins and the associated loss of neurons are considered a hallmark of numerous neurodegenerative diseases. Optineurin is present in protein inclusions observed in various ...neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), Huntington's disease, Alzheimer's disease, Parkinson's disease, Creutzfeld-Jacob disease and Pick's disease. Optineurin deletion mutations have also been described in ALS patients. However, the role of optineurin in mechanisms of protein aggregation remains unclear. In this report, we demonstrate that optineurin recognizes various protein aggregates via its C-terminal coiled-coil domain in a ubiquitin-independent manner. We also show that optineurin depletion significantly increases protein aggregation in HeLa cells and that morpholino-silencing of the optineurin ortholog in zebrafish causes the motor axonopathy phenotype similar to a zebrafish model of ALS. A more severe phenotype is observed when optineurin is depleted in zebrafish carrying ALS mutations. Furthermore, TANK1 binding kinase 1 (TBK1) is colocalized with optineurin on protein aggregates and is important in clearance of protein aggregates through the autophagy-lysosome pathway. TBK1 phosphorylates optineurin at serine 177 and regulates its ability to interact with autophagy modifiers. This study provides evidence for a ubiquitin-independent function of optineurin in autophagic clearance of protein aggregates as well as additional relevance for TBK1 as an upstream regulator of the autophagic pathway.
Post-translational modifications (PTMs) regulate various aspects of protein function, including degradation. Mass spectrometric methods relying on pulsed metabolic labeling are popular to quantify ...turnover rates on a proteome-wide scale. Such data have traditionally been interpreted in the context of protein proteolytic stability. Here, we combine theoretical kinetic modeling with experimental pulsed stable isotope labeling of amino acids in cell culture (pSILAC) for the study of protein phosphorylation. We demonstrate that metabolic labeling combined with PTM-specific enrichment does not measure effects of PTMs on protein stability. Rather, it reveals the relative order of PTM addition and removal along a protein's lifetime-a fundamentally different metric. This is due to interconversion of the measured proteoform species. Using this framework, we identify temporal phosphorylation sites on cell cycle-specific factors and protein complex assembly intermediates. Our results thus allow tying PTMs to the age of the modified proteins.
Besides climate change impacts on water availability and hydrological risks, the consequences on water quality is just beginning to be studied. This review aims at proposing a synthesis of the most ...recent existing interdisciplinary literature on the topic. After a short presentation about the role of the main factors (warming and consequences of extreme events) explaining climate change effects on water quality, the focus will be on two main points. First, the impacts on water quality of resources (rivers and lakes) modifying parameters values (physico-chemical parameters, micropollutants and biological parameters) are considered. Then, the expected impacts on drinking water production and quality of supplied water are discussed. The main conclusion which can be drawn is that a degradation trend of drinking water quality in the context of climate change leads to an increase of at risk situations related to potential health impact.
•Social-value information is mostly absent from ecosystem services assessments.•SolVES calculates a quantitative, spatially explicit social-value indicator.•The indicator compares favorably with ...results from more common analysis methods.•SolVES links the social-value indicator to underlying environmental data.•Complex relationships among values, attitudes, and preferences can be assessed.
Despite widespread recognition that social-value information is needed to inform stakeholders and decision makers regarding trade-offs in environmental management, it too often remains absent from ecosystem service assessments. Although quantitative indicators of social values need to be explicitly accounted for in the decision-making process, they need not be monetary. Ongoing efforts to map such values demonstrate how they can also be made spatially explicit and relatable to underlying ecological information. We originally developed Social Values for Ecosystem Services (SolVES) as a tool to assess, map, and quantify nonmarket values perceived by various groups of ecosystem stakeholders. With SolVES 2.0 we have extended the functionality by integrating SolVES with Maxent maximum entropy modeling software to generate more complete social-value maps from available value and preference survey data and to produce more robust models describing the relationship between social values and ecosystems. The current study has two objectives: (1) evaluate how effectively the value index, a quantitative, nonmonetary social-value indicator calculated by SolVES, reproduces results from more common statistical methods of social-survey data analysis and (2) examine how the spatial results produced by SolVES provide additional information that could be used by managers and stakeholders to better understand more complex relationships among stakeholder values, attitudes, and preferences. To achieve these objectives, we applied SolVES to value and preference survey data collected for three national forests, the Pike and San Isabel in Colorado and the Bridger–Teton and the Shoshone in Wyoming. Value index results were generally consistent with results found through more common statistical analyses of the survey data such as frequency, discriminant function, and correlation analyses. In addition, spatial analysis of the social-value maps produced by SolVES provided information that was useful for explaining relationships between stakeholder values and forest uses. Our results suggest that SolVES can effectively reproduce information derived from traditional statistical analyses while adding spatially explicit, social-value information that can contribute to integrated resource assessment, planning, and management of forests and other ecosystems.
As human pressures on ecosystems continue to increase, research involving the effective incorporation of social values information into the context of comprehensive ecosystem services assessments is ...becoming more important. Including quantified, spatially explicit social value metrics in such assessments will improve the analysis of relative tradeoffs among ecosystem services. This paper describes a GIS application, Social Values for Ecosystem Services (SolVES), developed to assess, map, and quantify the perceived social values of ecosystem services by deriving a non-monetary Value Index from responses to a public attitude and preference survey. SolVES calculates and maps the Value Index for social values held by various survey subgroups, as distinguished by their attitudes regarding ecosystem use. Index values can be compared within and among survey subgroups to explore the effect of social contexts on the valuation of ecosystem services. Index values can also be correlated and regressed against landscape metrics SolVES calculates from various environmental data layers. Coefficients derived through these analyses were applied to their corresponding data layers to generate a predicted social value map. This map compared favorably with other SolVES output and led to the addition of a predictive mapping function to SolVES for value transfer to areas where survey data are unavailable. A more robust application is being developed as a public domain tool for decision makers and researchers to map social values of ecosystem services and to facilitate discussions among diverse stakeholders involving relative tradeoffs among different ecosystem services in a variety of physical and social contexts.
► Social Values for Ecosystem Services (SolVES) is a value mapping application. ► A Value Index provides a quantitative, non-monetary metric of social values. ► Landscape metrics can be correlated and regressed against the Value Index. ► SolVES can assist with integrating social values into natural resource decisions. ► SolVES demonstrates potential as a value transfer tool.
Afatinib is an oral, irreversible ErbB family blocker that has shown activity in epidermal growth factor receptor (EGFR)-mutated lung cancer. We hypothesized that the agent would have greater ...antitumor activity compared with cetuximab in recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) patients, whose disease has progressed after platinum-containing therapy.
An open-label, randomized, phase II trial was conducted in 43 centers; 124 patients were randomized (1 : 1) to either afatinib (50mg/day) or cetuximab (250mg/m2/week) until disease progression or intolerable adverse events (AEs) (stage I), with optional crossover (stage II). The primary end point was tumor shrinkage before crossover assessed by investigator (IR) and independent central review (ICR).
A total of 121 patients were treated (61 afatinib, 60 cetuximab) and 68 crossed over to stage II (32 and 36 respectively). In stage I, mean tumor shrinkage by IR/ICR was 10.4%/16.6% with afatinib and 5.4%/10.1% with cetuximab (P = 0.46/0.30). Objective response rate was 16.1%/8.1% with afatinib and 6.5%/9.7% with cetuximab (IR/ICR). Comparable disease control rates were observed with afatinib (50%) and cetuximab (56.5%) by IR; similar results were seen by ICR. Most common grade ≥3 drug-related AEs (DRAEs) were rash/acne (18% versus 8.3%), diarrhea (14.8% versus 0%), and stomatitis/mucositis (11.5% versus 0%) with afatinib and cetuximab, respectively. Patients with DRAEs leading to treatment discontinuation were 23% with afatinib and 5% with cetuximab. In stage II, disease control rate (IR/ICR) was 38.9%/33.3% with afatinib and 18.8%/18.8% with cetuximab.
Afatinib showed antitumor activity comparable to cetuximab in R/M HNSCC in this exploratory phase II trial, although more patients on afatinib discontinued treatment due to AEs. Sequential EGFR/ErbB treatment with afatinib and cetuximab provided sustained clinical benefit in patients after crossover, suggesting a lack of cross-resistance.
Summary Background Patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (HNSCC) progressing after first-line platinum regimens have a poor prognosis and few treatment ...options. Afatinib, an irreversible ERBB family blocker, has shown efficacy in a phase 2 study in this setting. We aimed to assess the efficacy and safety of afatinib compared with methotrexate as second-line treatment in patients with recurrent or metastatic HNSCC progressing on or after platinum-based therapy. Methods In this open-label, phase 3, randomised controlled trial conducted in 101 centres in 19 countries, we enrolled patients aged 18 years or older with histologically or cytologically confirmed HNSCC that was recurrent, metastatic, or both who had progressed on or after first-line platinum-based therapy, were not amenable for salvage surgery or radiotherapy, and who had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Previous treatment with more than one systemic regimen in this setting was not allowed; previous treatment with EGFR-targeted antibody therapy (but not EGFR-targeted tyrosine-kinase inhibitors) was allowed. We randomly assigned eligible patients in a 2:1 ratio to receive oral afatinib (40 mg/day) or intravenous methotrexate (40 mg/m2 per week), stratified by ECOG performance status and previous EGFR-targeted antibody therapy for recurrent or metastatic disease. Randomisation was done centrally with an interactive voice or web-based response system. Clinicians and patients were not masked to treatment allocation; independent review of tumour response was done in a blinded manner. The primary endpoint was progression-free survival as assessed by an independent, central imaging review committee. Efficacy analyses were done in the intention-to-treat population and safety analyses were done in patients who received at least one dose of study drug. This ongoing study is registered with ClinicalTrials.gov , number NCT01345682. Findings Between Jan 10, 2012, and Dec 12, 2013, we enrolled 483 patients and randomly assigned 322 to afatinib and 161 to methotrexate. After a median follow-up of 6·7 months (IQR 3·1–9·0), progression-free survival was longer in the afatinib group than in the methotrexate group (median 2·6 months 95% CI 2·0–2·7 for the afatinib group vs 1·7 months 1·5–2·4 for the methotrexate group; hazard ratio HR 0·80 95% CI 0·65–0·98, p=0·030). The most frequent grade 3 or 4 drug-related adverse events were rash or acne (31 10% of 320 patients in the afatinib group vs none of 160 patients in the methotrexate group), diarrhoea (30 9% vs three 2%), stomatitis (20 6% vs 13 8%), fatigue (18 6% vs five 3%), and neutropenia (1 <1% vs 11 7%); serious adverse events occurred in 44 (14%) of afatinib-treated patients and 18 (11%) of methotrexate-treated patients. Interpretation Afatinib was associated with significant improvements in progression-free survival and had a manageable safety profile. These findings provide important new insights into the treatment of this patient population and support further investigations with irreversible ERBB family blockers in HNSCC. Funding Boehringer Ingelheim.
Application of knowledge translation (KT) theories, models, and frameworks (TMFs) is one method for successfully incorporating evidence into clinical care. However, there are multiple KT TMFs and ...little guidance on which to select. This study sought to identify and describe available full-spectrum KT TMFs to subsequently guide users.
A scoping review was completed. Articles were identified through searches within electronic databases, previous reviews, grey literature, and consultation with KT experts. Search terms included combinations of KT terms and theory-related terms. Included citations had to describe full-spectrum KT TMFs that had been applied or tested. Titles/abstracts and full-text articles were screened independently by two investigators. Each KT TMF was described by its characteristics including name, context, key components, how it was used, primary target audience, levels of use, and study outcomes. Each KT TMF was also categorized into theoretical approaches as process models, determinant frameworks, classic theories, implementation theories, and evaluation frameworks. Within each category, KT TMFs were compared and contrasted to identify similarities and unique characteristics.
Electronic searches yielded 7160 citations. Additional citations were identified from previous reviews (n = 41) and bibliographies of included full-text articles (n = 6). Thirty-six citations describing 36 full-spectrum were identified. In 24 KT TMFs, the primary target audience was multi-level including patients/public, professionals, organizational, and financial/regulatory. The majority of the KT TMFs were used within public health, followed by research (organizational, translation, health), or in multiple contexts. Twenty-six could be used at the individual, organization, or policy levels, five at the individual/organization levels, three at the individual level only, and two at the organizational/policy level. Categorization of the KT TMFs resulted in 18 process models, eight classic theories, three determinant frameworks, three evaluation frameworks, and four that fit more than one category. There were no KT TMFs that fit the implementation theory category. Within each category, similarities and unique characteristics emerged through comparison.
A systematic compilation of existing full-spectrum KT TMFs, categorization into different approaches, and comparison has been provided in a user-friendly way. This list provides options for users to select from when designing KT projects and interventions.
A protocol outlining the methodology of this scoping review was developed and registered with PROSPERO (CRD42018088564).
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