bluuebunny/crossref_metadata_2025_split huggingface dataset:
Imaging-detected acute muscle injuries in athletes participating in the Rio de Janeiro 2016 Summer Olympic Games
Authors: Crema Michel D , Jarraya Mohamed , Engebretsen Lars , Roemer Frank W , Hayashi Daichi , Domingues Romulo , Skaf Abdalla Y , Guermazi Ali 
Published: December 2017

BackgroundAcute muscle injuries in elite athletes are responsible for a large portion of time loss injuries.AimTo describe the frequency, the anatomic distribution, and severity of imaging-detected acute muscle injuries among athletes who competed in the Rio de Janeiro 2016 Summer Olympics.MethodsWe recorded all sports injuries reported by the National Olympic Committee medical teams and the Organising Committee medical staff during the 2016 Summer Olympics. Imaging of acute muscle injuries was performed at the IOC’s polyclinic within the Olympic Village using ultrasound and 3.0 T and 1.5 T MRI scanners. The assessment of images was performed centrally by three musculoskeletal radiologists. The distribution of injuries by anatomic location and sports discipline and the severity of injuries were recorded.ResultsIn total, 11 274 athletes from 207 teams were included. A total of 1101 injuries were reported. Central review of radiological images revealed 81 acute muscle injuries in 77 athletes (66% male, mean age: 25.4 years, range 18–38 years). Athletics (track and field) athletes were the most commonly affected (n=39, 48%), followed by football players (n=9, 11%). The majority of injuries affected muscles from lower limbs (n=68, 84%), with the hamstring being the most commonly involved. Most injuries were grade 2 injuries according to the Peetrons classification (n=44, 54%), and we found 18 injuries exhibiting intramuscular tendon involvement on MRI.ConclusionImaging-detected acute muscle injuries during the 2016 Summer Olympics affected mainly thigh muscles in athletics disciplines.
Trials of transvaginal mesh devices for pelvic organ prolapse: a systematic database review of the US FDA approval process
Authors: Heneghan Carl J , Goldacre Ben , Onakpoya Igho , Aronson Jeffrey K , Jefferson Tom , Pluddemann Annette , Mahtani Kamal R 
Published: December 2017

IntroductionTransvaginal mesh devices are approved in the USA by the Food and Drug Administration (FDA), through the 510(k) system. However, there is uncertainty about the benefit to harm balance of mesh approved for pelvic organ prolapse. We, therefore, assessed the evidence at the time of approval for transvaginal mesh products and the impact of safety studies the FDA mandated in 2012 because of emerging harms.MethodsWe used FDA databases to determine the evidence for approval of transvaginal mesh. To create a ‘family tree’ of device equivalence, we used the 510(k) regulatory approval of the 1985 Mersilene Mesh (Ethicon) and the 1996 ProteGen Sling (Boston Scientific), searched for all subsequently related device approvals, and for the first published randomised trial evidence. We assessed compliance with all FDA 522 orders issued in 2012 requiring postmarketing surveillance studies.ResultsWe found 61 devices whose approval ultimately relied on claimed equivalence to the Mersilene Mesh and the ProteGen Sling. We found no clinical trials evidence for these 61 devices at the time of approval. Publication of randomised clinical trials occurred at a median of 5 years after device approval (range 1–14 years). Analysis of 119 FDA 522 orders revealed that in 79 (66%) the manufacturer ceased market distribution of the device, and in 26 (22%) the manufacturer had changed the indication. Only seven studies (six cohorts and new randomised controlled trial) covering 11 orders were recruiting participants (none had reported outcomes).ConclusionsTransvaginal mesh products for pelvic organ prolapse have been approved on the basis of weak evidence over the last 20 years. Devices have inherited approval status from a few products. A publicly accessible registry of licensed invasive devices, with details of marketing status and linked evidence, should be created and maintained at the time of approval.
Novel United Kingdom prognostic model for 30-day mortality following transcatheter aortic valve implantation
Authors: Martin Glen P , Sperrin Matthew , Ludman Peter F , de Belder Mark A , Redwood Simon R , Townend Jonathan N , Gunning Mark , Moat Neil E , Banning Adrian P , Buchan Iain , Mamas Mamas A 
Published: December 2017

ObjectiveExisting clinical prediction models (CPM) for short-term mortality after transcatheter aortic valve implantation (TAVI) have limited applicability in the UK due to moderate predictive performance and inconsistent recording practices across registries. The aim of this study was to derive a UK-TAVI CPM to predict 30-day mortality risk for benchmarking purposes.MethodsA two-step modelling strategy was undertaken: first, data from the UK-TAVI Registry between 2009 and 2014 were used to develop a multivariable logistic regression CPM using backwards stepwise regression. Second, model-updating techniques were applied using the 2013–2014 data, thereby leveraging new approaches to include frailty and to ensure the model was reflective of contemporary practice. Internal validation was performed by bootstrapping to estimate in-sample optimism-corrected performance.ResultsBetween 2009 and 2014, up to 6339 patients were included across 34 centres in the UK-TAVI Registry (mean age, 81.3; 2927 female (46.2%)). The observed 30-day mortality rate was 5.14%. The final UK-TAVI CPM included 15 risk factors, which included two variables associated with frailty. After correction for in-sample optimism, the model was well calibrated, with a calibration intercept of 0.02 (95% CI −0.17 to 0.20) and calibration slope of 0.79 (95% CI 0.55 to 1.03). The area under the receiver operating characteristic curve, after adjustment for in-sample optimism, was 0.66.ConclusionThe UK-TAVI CPM demonstrated strong calibration and moderate discrimination in UK-TAVI patients. This model shows potential for benchmarking, but even the inclusion of frailty did not overcome the need for more wide-ranging data and other outcomes might usefully be explored.
Ataxia with oculomotor apraxia type 2: an evolving axonal neuropathy
Authors: Choudry Tahira N , Hilton-Jones David , Lennox Graham , Houlden Henry 
Published: December 2017

A 23-year-old woman had presented initially to a podiatrist complaining of poorly fitting shoes during her adolescence. After extensive neurological review, she was diagnosed with ataxia with oculomotor apraxia type 2. This is a progressive autosomal recessive ataxia associated with cerebellar atrophy, peripheral neuropathy and an elevated serum α-fetoprotein. Within Europe, it is the most frequent autosomal recessive ataxia after Friedreich’s ataxia and is due to mutations in the senataxin (SETX) gene. The age of onset is approximately 15 years.The diagnosis of oculomotor apraxia type 2 is often challenging. We provide a framework for assessing a young ataxic patient with or without oculomotor apraxia and review clues that will aid diagnosis. The prognosis, level of disability, cancer and immunosuppression risk all markedly differ between the conditions. Patients and their families need the correct diagnosis for genetic counselling, management and long-term surveillance with appropriate subspecialty services.
Experiences in calibrating and evaluating lumped karst hydrological models
Authors: Hartmann Andreas 
Published: December 2017

Abstract
Karst systems play an important part in providing clean drinking water for many countries worldwide. Their sustainable management often requires the application of karst hydrological models to quantify the water volumes available and to assess their sensitivity to changes in climate or land use. The available literature provides a broad overview of different modelling approaches to simulate karst hydrology, but guidance for the application of these approaches is scarce. This paper provides personal insights into the application, calibration and evaluation of lumped karst hydrological models. An introduction to model calibration and sensitivity analysis is given, with links to further reading and ready-to-use toolboxes. It is followed by three case studies of karst model applications at three different scales (the plot scale, aquifer scale and continental scale), which apply model calibration and sensitivity analysis to obtain realistic simulations. These three case studies elaborate how the necessary trade-off between the available data and process representation in the model structures was achieved. General recommendations and a workflow for future karst model applications are given.
SIRT6 Is a Target of Regulation by UBE3A That Contributes to Liver Tumorigenesis in an ANXA2-Dependent Manner
Authors: Kohli Saishruti , Bhardwaj Abhishek , Kumari Richa , Das Sanjeev 
Published: December 2017

Abstract
UBE3A is an E3 ubiquitin ligase well known for its role in the proteasomal degradation of p53 in human papillomavirus (HPV)-associated cancers. Here we report that UBE3A ubiquitylates and triggers degradation of the tumor-suppressive sirtuin SIRT6 in hepatocellular carcinoma. UBE3A ubiquitylated the highly conserved Lys160 residue on SIRT6. FOXO1-mediated transcriptional repression of UBE3A was sufficient to stabilize SIRT6 and to epigenetically repress ANXA2, a key mediator of UBE3A oncogenic function. Thus, UBE3A-mediated SIRT6 degradation promoted the proliferative capacity, migration potential, and invasiveness of cells. In mouse models of hepatocellular carcinoma, SIRT6 downregulation and consequent induction of ANXA2 were critical for UBE3A-mediated tumorigenesis. Furthermore, in clinical specimens, increased UBE3A levels correlated with reduced SIRT6 levels and elevated ANXA2 levels in increasing tumor grades. Overall, our findings show how the tumor suppressor SIRT6 is regulated in hepatocellular carcinoma and establish the mechanism underlying UBE3A-mediated tumorigenesis in this disease.
Significance: These findings provide mechanistic insights into regulation of the tumor suppressive sirtuin SIRT6 and its implications for the development of hepatocellular carcinoma. Cancer Res; 78(3); 645–58. ©2017 AACR.
Tumor-Associated Fatigue in Cancer Patients Develops Independently of IL1 Signaling
Authors: Grossberg Aaron J. , Vichaya Elisabeth G. , Christian Diana L. , Molkentine Jessica M. , Vermeer Daniel W. , Gross Phillip S. , Vermeer Paola D. , Lee John H. , Dantzer Robert 
Published: December 2017

AbstractFatigue is the most common symptom of cancer at diagnosis, yet causes and effective treatments remain elusive. As tumors can be highly inflammatory, it is generally accepted that inflammation mediates cancer-related fatigue. However, evidence to support this assertion is mostly correlational. In this study, we directly tested the hypothesis that fatigue results from propagation of tumor-induced inflammation to the brain and activation of the central proinflammatory cytokine, IL1. The heterotopic syngeneic murine head and neck cancer model (mEER) caused systemic inflammation and increased expression of Il1b in the brain while inducing fatigue-like behaviors characterized by decreased voluntary wheel running and exploratory activity. Expression of Il1b in the brain was not associated with any alterations in motivation, measured by responding in a progressive ratio schedule of food reinforcement, depression-like behaviors, or energy balance. Decreased wheel running occurred prior to Il1b detection in the brain, when systemic inflammation was minimal. Furthermore, mice null for two components of IL1β signaling, the type 1 IL1 receptor or the receptor adapter protein MyD88, were not protected from tumor-induced decreases in wheel running, despite attenuated cytokine action and expression. Behavioral and inflammatory analysis of four additional syngeneic tumor models revealed that tumors can induce fatigue regardless of their systemic or central nervous system inflammatory potential. Together, our results show that brain IL1 signaling is not necessary for tumor-related fatigue, dissociating this type of cancer sequela from systemic cytokine expression.Significance: These findings challenge the current understanding of fatigue in cancer patients, the most common and debilitating sequela associated with malignancy. Cancer Res; 78(3); 695–705. ©2017 AACR.
Merkel Cell Carcinoma in the Age of Immunotherapy: Facts and Hopes
Authors: Colunga Aric , Pulliam Thomas , Nghiem Paul 
Published: December 2017

Abstract
Merkel cell carcinoma (MCC) is a rare (∼2,000 U.S. cases/year) but aggressive neuroendocrine tumor of the skin. For advanced MCC, cytotoxic chemotherapy only infrequently (&lt;10% of cases) offers durable clinical responses (&gt;1 year), suggesting a great need for improved therapeutic options. In 2008, the Merkel cell polyomavirus (MCPyV) was discovered and is clonally integrated in approximately 80% of MCC tumors. The remaining 20% of MCC tumors have large numbers of UV-associated mutations. Importantly, both the UV-induced neoantigens in virus-negative tumors and the MCPyV T antigen oncogenes that are required for virus-positive tumor growth are immunogenic. Indeed, antigen-specific T cells detected in patients are frequently dysfunctional/“exhausted,” and the inhibitory ligand, PD-L1, is often present in MCC tumors. These findings led to recent clinical trials involving PD-1 pathway blockade in advanced MCC. The combined data from these trials involving three PD-1 pathway blocking agents—avelumab, pembrolizumab, and nivolumab—indicated a high frequency of durable responses in treated patients. Of note, prior treatment with chemotherapy was associated with decreased response rates to PD-1 checkpoint blockade. Over the past year, these striking data led to major changes in advanced MCC therapy, including the first-ever FDA drug approval for this disease. Despite these successes, approximately 50% of patients with MCC do not persistently benefit from PD-1 pathway blockade, underscoring the need for novel strategies to broaden antitumor immune responses in these patients. Here, we highlight recent progress in MCC including the underlying mechanisms of immune evasion and emerging approaches to augment the efficacy of PD-1 pathway blockade. Clin Cancer Res; 24(9); 2035–43. ©2017 AACR.
FAM198B Is Associated with Prolonged Survival and Inhibits Metastasis in Lung Adenocarcinoma via Blockage of ERK-Mediated MMP-1 Expression
Authors: Hsu Chia-Ying , Chang Gee-Chen , Chen Yi-Ju , Hsu Yi-Chiung , Hsiao Yi-Jing , Su Kang-Yi , Chen Hsuan-Yu , Lin Chien-Yu , Chen Jin-Shing , Chen Yu-Ju , Hong Qi-Sheng , Ku Wen-Hui , Wu Chih-Ying , Ho Bing-Ching , Chiang Ching-Cheng , Yang Pan-Chyr , Yu Sung-Liang 
Published: December 2017

Abstract
Purpose: The comprehensive understanding of mechanisms involved in the tumor metastasis is urgently needed for discovering novel metastasis-related genes for developing effective diagnoses and treatments for lung cancer.
Experimental Design: FAM198B was identified from an isogenic lung cancer metastasis cell model by microarray analysis. To investigate the clinical relevance of FAM198B, the FAM198B expression of 95 Taiwan lung adenocarcinoma patients was analyzed by quantitative real-time PCR and correlated to patients' survivals. The impact of FAM198B on cell invasion, metastasis, and tumor growth was examined by in vitro cellular assays and in vivo mouse models. In addition, the N-glycosylation–defective FAM198B mutants generated by site-directed mutagenesis were used to study protein stability and subcellular localization of FAM198B. Finally, the microarray and pathway analyses were used to elucidate the underlying mechanisms of FAM198B-mediated tumor suppression.
Results: We found that the high expression of FAM198B was associated with favorable survival in Taiwan lung adenocarcinoma patients and in a lung cancer public database. Enforced expression of FAM198B inhibited cell invasion, migration, mobility, proliferation, and anchorage-independent growth, and FAM198B silencing exhibited opposite activities in vitro. FAM198B also attenuated tumor growth and metastasis in vivo. We further identified MMP-1 as a critical downstream target of FAM198B. The FAM198B-mediated MMP-1 downregulation was via inhibition of the phosphorylation of ERK. Interestingly deglycosylation nearly eliminated the metastasis suppression activity of FAM198B due to a decrease of protein stability.
Conclusions: Our results implicate FAM198B as a potential tumor suppressor and to be a prognostic marker in lung adenocarcinoma. Clin Cancer Res; 24(4); 916–26. ©2017 AACR.
The Impact of Smoking and TP53 Mutations in Lung Adenocarcinoma Patients with Targetable Mutations—The Lung Cancer Mutation Consortium (LCMC2)
Authors: Aisner Dara L. , Sholl Lynette M. , Berry Lynne D. , Rossi Michael R. , Chen Heidi , Fujimoto Junya , Moreira Andre L. , Ramalingam Suresh S. , Villaruz Liza C. , Otterson Gregory A. , Haura Eric , Politi Katerina , Glisson Bonnie , Cetnar Jeremy , Garon Edward B. , Schiller Joan , Waqar Saiama N. , Sequist Lecia V. , Brahmer Julie , Shyr Yu , Kugler Kelly , Wistuba Ignacio I. , Johnson Bruce E. , Minna John D. , Kris Mark G. , Bunn Paul A. , Kwiatkowski David J. 
Published: December 2017

Abstract
Purpose: Multiplex genomic profiling is standard of care for patients with advanced lung adenocarcinomas. The Lung Cancer Mutation Consortium (LCMC) is a multi-institutional effort to identify and treat oncogenic driver events in patients with lung adenocarcinomas.
Experimental Design: Sixteen U.S. institutions enrolled 1,367 patients with lung cancer in LCMC2; 904 were deemed eligible and had at least one of 14 cancer-related genes profiled using validated methods including genotyping, massively parallel sequencing, and IHC.
Results: The use of targeted therapies in patients with EGFR, ERBB2, or BRAF p.V600E mutations, ALK, ROS1, or RET rearrangements, or MET amplification was associated with a survival increment of 1.5 years compared with those with such mutations not receiving targeted therapy, and 1.0 year compared with those lacking a targetable driver. Importantly, 60 patients with a history of smoking derived similar survival benefit from targeted therapy for alterations in EGFR/ALK/ROS1, when compared with 75 never smokers with the same alterations. In addition, coexisting TP53 mutations were associated with shorter survival among patients with EGFR, ALK, or ROS1 alterations.
Conclusion: Patients with adenocarcinoma of the lung and an oncogenic driver mutation treated with effective targeted therapy have a longer survival, regardless of prior smoking history. Molecular testing should be performed on all individuals with lung adenocarcinomas irrespective of clinical characteristics. Routine use of massively parallel sequencing enables detection of both targetable driver alterations and tumor suppressor gene and other alterations that have potential significance for therapy selection and as predictive markers for the efficacy of treatment. Clin Cancer Res; 24(5); 1038–47. ©2017 AACR.
Effect of Cinacalcet Combined with Calcitriol on the Clinical Outcome and Bone Metabolism in Patients on Hemodialysis with Severe Secondary Hyperparathyroidism
Authors: Yuan Fang , Chen Xing , Wang Chang , Li Zheng , Liu Hong 
Published: December 2017

<b><i>Objective:</i></b> To observe the clinical outcome and the effect of bone metabolism of cinacalcet combined with calcitriol in maintenance hemodialysis (MHD) patients with severe secondary hyperparathyroidism (SHPT). <b><i>Methods:</i></b> Thirty MHD patients with SHPT were enrolled into the study. All patients were given cinacalcet 25–75 mg and 0.5 μg calcitriol daily. Serum Ca, P, intact parathyroid hormone (iPTH), and bone metabolic markers were measured. The clinical symptoms and their changes were investigated. <b><i>Results:</i></b> The baseline levels of iPTH, Ca, and P were 1,787.3 ± 1,321 pg/mL, 2.54 ± 0.19 mmol/L, and 2.06 ± 0.15 mmol/L respectively. After 3 months treatment, iPTH decreased by 70%. Serum Ca and P fell to 2.39 ± 0.17 and 1.56 ± 0.50 mmol/L (<i>p</i> &#x3c; 0.05), respectively. After 6 months, the bone-specific alkaline phosphatase, osteocalcin, and β-cross levels were decreased by 50, 37, and 49% respectively compared with corresponding values before treatment. A decline in the bone density patients was inhibited. <b><i>Conclusion:</i></b> Cinacalcet combined with low dose calcitriol can improve high calcium, high phosphorus, and high iPTH in MHD patients with severe SHPT and also improve bone metabolism. It can be used as a favorable choice for SHPT treatment.
Pharmacologic Prevention of Incident Atrial Fibrillation
Authors: Dewland Thomas A. , Soliman Elsayed Z. , Yamal Jose-Miguel , Davis Barry R. , Alonso Alvaro , Albert Christine M. , Simpson Lara M. , Haywood L. Julian , Marcus Gregory M. ,   for the ALLHAT Collaborative Research Group*
Published: December 2017

Background
Although atrial fibrillation (AF) guidelines indicate that pharmacological blockade of the renin–angiotensin system may be considered for primary AF prevention in hypertensive patients, previous studies have yielded conflicting results. We sought to determine whether randomization to lisinopril reduces incident AF or atrial flutter (AFL) compared with chlorthalidone in a large clinical trial cohort with extended post-trial surveillance.

Methods and Results

We performed a secondary analysis of the ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial), a randomized, double-blind, active-controlled clinical trial that enrolled hypertensive individuals ≥55 years of age with at least one other cardiovascular risk factor. Participants were randomly assigned to receive amlodipine, lisinopril, or chlorthalidone. Individuals with elevated fasting low-density lipoprotein cholesterol levels were also randomized to pravastatin versus usual care. The primary outcome was the development of either AF or AFL as diagnosed by serial study ECGs or by Medicare claims data. Among 14 837 participants without prevalent AF or AFL, 2514 developed AF/AFL during a mean 7.5±3.2 years of follow-up. Compared with chlorthalidone, randomization to either lisinopril (hazard ratio, 1.04; 95% confidence interval, 0.94–1.15;
P
=0.46) or amlodipine (hazard ratio, 0.93; 95% confidence interval, 0.84–1.03;
P
=0.16) was not associated with a significant reduction in incident AF/AFL.

Conclusions
Compared with chlorthalidone, treatment with lisinopril is not associated with a meaningful reduction in incident AF or AFL among older adults with a history of hypertension.

Clinical Trial Registration

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00000542.
Beyond Compliance: Law-Making through Latin American Cases before the World Court
Authors: Almeida Paula Wojcikiewicz 
Published: December 2017

Abstract
Departing from a contemporary approach to international adjudication, this article aims to evaluate, firstly, the limits of compliance and its residual character when assessing the effectiveness of the International Court of Justice with regards to Latin American states. Secondly, it deals with the importance of going beyond the traditional function of inter-state dispute settlement to assess the contribution of Latin American states to international law through cases submitted to the Court, independently from case-specific compliance. This is because a judgment that has not been complied with may substantially contribute to international law and produce important impacts on domestic authorities. Latin American cases constitute an example of this phenomenon.