bluuebunny/crossref_metadata_2025 huggingface dataset:
Exercise as treatment for alcohol use disorders: systematic review and meta-analysis
Authors: Hallgren Mats , Vancampfort Davy , Giesen Esther S , Lundin Andreas , Stubbs Brendon
Published: January 2017

Objectives

To conduct a systematic review and meta-analysis investigating effects of exercise for people with alcohol use disorders (AUDs) across multiple health outcomes. We also investigated the prevalence and predictors of dropout from exercise studies in AUDs.

Design

Systematic review and random effects meta-analysis with meta-regression analyses.

Data sources

3 major electronic databases were searched from inception until April 2016 for exercise intervention studies in adults with AUDs.

Eligibility criteria

Studies of acute exercise in people with AUDs; and randomised and non-randomised trials examining effects of long-term (≥2 weeks) exercise.

Results

21 studies and 1204 unique persons with AUDs (mean age 37.8 years, mean illness duration 4.4 years) were included. Exercise did not reduce daily alcohol consumption (standardised mean difference (SMD) =−0.886, p=0.24), or the Alcohol Use Disorders Identification Test (AUDIT) total scores (SMD=−0.378, p=0.18). For weekly consumption (n=3 studies), a statistically significant difference was observed favouring exercise (SMD=−0.656, p=0.04), but not after adjustment for publication bias (SMD=−0.16, 95% CI −0.88 to 0.55). Exercise significantly reduced depressive symptoms versus control (randomised controlled trials (RCTs) =4; SMD=−0.867, p=0.006, I2=63%) and improved physical fitness (VO2) (RCTs=3; SMD=0.564, p=0.01, I2=46%). The pooled dropout rate was 40.3% (95% CI 23.3% to 60.1%) which was no different to control conditions (OR=0.73, p=0.52). Dropouts were higher among men (β=0.0622, p<0.0001, R2=0.82).

Limitations

It was not possible to investigate moderating effects of smoking.

Conclusions

Available evidence indicates exercise appears not to reduce alcohol consumption, but has significant improvements in other health outcomes, including depression and physical fitness. Additional long-term controlled studies of exercise for AUDs are required.
Children's experiences of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME): a systematic review and meta-ethnography of qualitative studies
Authors: Parslow Roxanne M , Harris Sarah , Broughton Jessica , Alattas Adla , Crawley Esther , Haywood Kirstie , Shaw Alison
Published: January 2017

Objective

To synthesis the qualitative studies of children's experiences of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME).

Design

Systematic review and meta-ethnography.

Background

CFS/ME is an important disabling illness, with uncertain cause and prognosis. As a result, children with CFS/ME can find themselves living with greater uncertainty and stigma, exacerbating the impact of the condition. There is a growing body of qualitative research in CFS/ME, yet there has been no attempt to systematically synthesis the studies involving children.

Methods

Studies exploring the experiences of children diagnosed with CFS/ME, published or unpublished, using qualitative methods were eligible. MEDLINE, EMBASE, PsycINFO and CINAHL databases were searched as well as grey literature, reference lists and contacting authors. Quality assessment was done independently using the Critical Appraisal Skills Programme (CASP) checklist. Studies were synthesised using techniques of meta-ethnography.

Results

Ten studies involving 82 children with CFS/ME aged 8–18 were included. Our synthesis describes four third-order constructs within children's experiences: (1) disruption and loss: physical, social and the self; (2) barriers to coping: suspension in uncertainty, problems with diagnosis and disbelief; (3) facilitators to coping: reducing uncertainty, credible illness narratives, diagnosis and supportive relationships and (4) hope, personal growth and recovery. CFS/ME introduces profound biographical disruption through its effects on children's ability to socialise, perform school and therefore how they see their future. Unfamiliarity of the condition, problems with diagnosis and felt stigma prevent children from forming a new illness identity. Children adopt coping strategies such as building credible explanations for their illness.

Conclusions

Physical, social, emotional and self-dimensions of life should be included when treating and measuring outcomes from healthcare in paediatric CFS/ME. There is a need for greater recognition and diagnosis of childhood CFS/ME, specialist advice on activity management and improved communication between health and education providers to help children cope with their condition.
Risk of pneumonia in patients with isolated minor rib fractures: a nationwide cohort study
Authors: Ho Sai-Wai , Teng Ying-Hock , Yang Shun-Fa , Yeh Han-Wei , Wang Yu-Hsun , Chou Ming-Chih , Yeh Chao-Bin
Published: January 2017

Objectives

Isolated minor rib fractures (IMRFs) after blunt chest traumas are commonly observed in emergency departments. However, the relationship between IMRFs and subsequent pneumonia remains controversial. This nationwide cohort study investigated the association between IMRFs and the risk of pneumonia in patients with blunt chest traumas.

Design

Nationwide population-based cohort study.

Setting

Patients with IMRFs were identified between 2010 and 2011 from the Taiwan National Health Insurance Research Database.

Participants

Non-traumatic patients were matched through 1:8 propensity-score matching according to age, sex, and comorbidities (namely diabetes, hypertension, cardiovascular disease, asthma and chronic obstructive pulmonary disease (COPD)) with the comparison cohort. We estimated the adjusted HRs (aHRs) by using the Cox proportional hazard model. A total of 709 patients with IMRFs and 5672 non-traumatic patients were included.

Main outcome measure

The primary end point was the occurrence of pneumonia within 30 days.

Results

The incidence of pneumonia following IMRFs was 1.6% (11/709). The aHR for the risk of pneumonia after IMRFs was 8.94 (95% CI=3.79 to 21.09, p<0.001). Furthermore, old age (≥65 years; aHR=5.60, 95% CI 1.97 to 15.89, p<0.001) and COPD (aHR=5.41, 95% CI 1.02 to 3.59, p<0.001) were risk factors for pneumonia following IMRFs. In the IMRF group, presence of single or two isolated rib fractures was associated with an increased risk of pneumonia with aHRs of 3.97 (95% CI 1.09 to 14.44, p<0.001) and 17.13 (95% CI 6.66 to 44.04, p<0.001), respectively.

Conclusions

Although the incidence of pneumonia following IMRFs is low, patients with two isolated rib fractures were particularly susceptible to pneumonia. Physicians should focus on this complication, particularly in elderly patients and those with COPD.
Trends and changes in paediatric tonsil surgery in Sweden 1987–2013: a population-based cohort study
Authors: Borgström Anna , Nerfeldt Pia , Friberg Danielle , Sunnergren Ola , Stalfors Joacim
Published: January 2017

Objectives

The objective of this study was to longitudinally describe the history of tonsil surgery in Swedish children and adolescents regarding incidence, indications for surgery, surgical methods and the age and gender distributions.

Setting

A retrospective longitudinal population-based cohort study based on register data from the Swedish National Patient Register (NPR) and population data from Statistics Sweden.

Participants

All Swedish children 1–<18 years registered in the NPR with a tonsil surgery procedure 1987–2013.

Results

167 894 tonsil surgeries were registered in the NPR 1987–2013. An increase in the total incidence rate was observed, from 22/10 000 person years in 1987 to 47/10 000 in 2013. The most marked increase was noted in children 1–3 years of age, increasing from 17 to 73/10 000 person years over the period. The proportion children with obstructive/sleep disordered breathing (SDB) indications increased from 42.4% in 1987 to 73.6% in 2013. Partial tonsillectomy, tonsillotomy (TT), increased since 1996 and in 2013 55.1% of all tonsil procedures were TTs.

Conclusions

There have been considerable changes in clinical practice for tonsil surgery in Swedish children over the past few decades. Overall, a doubling in the total incidence rate was observed. This increase consisted mainly of an increase in surgical procedures due to obstructive/SDB indications, particularly among the youngest age group (1–3 years old). TT has gradually replaced tonsillectomy as the predominant method for tonsil surgery.
Prevalence of obesity and overweight in African learners: a protocol for systematic review and meta-analysis
Authors: Adom Theodosia , Puoane Thandi , De Villiers Anniza , Kengne André Pascal
Published: January 2017

Introduction

Obesity and overweight are an emerging problem in Africa. Obese children are at increased risk of developing hypertension, high cholesterol, orthopaedic problems and type 2 diabetes as well as increased risk of adult obesity. Prevention of childhood overweight and obesity therefore needs high priority. The review approach is particularly useful in establishing whether research findings are consistent and can be generalised across populations and settings. This systematic review aims to assess the magnitude and distribution of overweight and obesity among primary school learners within populations in Africa.

Methods and analysis

A comprehensive search of key bibliographic databases including MEDLINE (PubMed), MEDLINE (EbscoHost), CINAHL (EbscoHost), Academic Search Complete (EbscoHost) and ISI Web of Science (Science Citation Index) will be conducted for published literature. Grey literature will be also be obtained. Full-text articles of eligible studies will be obtained and screened following predefined inclusion criteria. The quality of reporting as well as risk of bias of included studies will be assessed, data extracted and synthesised. The results will be summarised and presented by country and major regional groupings. Meta-analysis will be conducted for identical variables across studies. This review will be reported following the MOOSE Guidelines for Meta-Analysis and Systematic Reviews of Observational Studies.

Ethics and dissemination

Ethics is not a requirement since no primary data will be collected. All data that will be presented in this review are based on published articles. The findings of this systematic review will be submitted for publication in peer-reviewed journals and disseminated in national and international conferences and also in policy documents to appropriate bodies for decision-making, where needed. It is expected that the findings will identify some research gaps for further studies.
How prepared are UK medical graduates for practice? A rapid review of the literature 2009–2014
Authors: Monrouxe Lynn V , Grundy Lisa , Mann Mala , John Zoe , Panagoulas Eleni , Bullock Alison , Mattick Karen
Published: January 2017

Objective

To understand how prepared UK medical graduates are for practice and the effectiveness of workplace transition interventions.

Design

A rapid review of the literature (registration #CRD42013005305).

Data sources

Nine major databases (and key websites) were searched in two timeframes (July–September 2013; updated May–June 2014): CINAHL, Embase, Educational Resources Information Centre, Health Management Information Consortium, MEDLINE, MEDLINE in Process, PsycINFO, Scopus and Web of Knowledge.

Eligibility criteria for selecting studies

Primary research or studies reporting UK medical graduates' preparedness between 2009 and 2014: manuscripts in English; all study types; participants who are final-year medical students, medical graduates, clinical educators, patients or NHS employers and all outcome measures.

Data extraction

At time 1, three researchers screened manuscripts (for duplicates, exclusion/inclusion criteria and quality). Remaining 81 manuscripts were coded. At time 2, one researcher repeated the process for 2013–2014 (adding six manuscripts). Data were analysed using a narrative synthesis and mapped against Tomorrow's Doctors (2009) graduate outcomes.

Results

Most studies comprised junior doctors' self-reports (65/87, 75%), few definedpreparednessand a programmatic approach was lacking. Six themes were highlighted: individual skills/knowledge, interactional competence, systemic/technological competence, personal preparedness, demographic factors and transitional interventions. Graduates appear prepared for history taking, physical examinations and some clinical skills, but unprepared for other aspects, including prescribing, clinical reasoning/diagnoses, emergency management, multidisciplinary team-working, handover, error/safety incidents, understanding ethical/legal issues and ward environment familiarity. Shadowing and induction smooth transition into practice, but there is a paucity of evidence around assistantship efficacy.

Conclusions

Educational interventions are needed to address areas of unpreparedness (eg, multidisciplinary team-working, prescribing and clinical reasoning). Future research in areas we are unsure about should adopt a programmatic and rigorous approach, with clear definitions of preparedness, multiple stakeholder perspectives along with multisite and longitudinal research designs to achieve a joined-up, systematic, approach to understanding future educational requirements for junior doctors.
Associations of reallocating sitting time into standing or stepping with glucose, insulin and insulin sensitivity: a cross-sectional analysis of adults at risk of type 2 diabetes
Authors: Edwardson Charlotte L , Henson Joe , Bodicoat Danielle H , Bakrania Kishan , Khunti Kamlesh , Davies Melanie J , Yates Thomas
Published: January 2017

Objective

To quantify associations between sitting time and glucose, insulin and insulin sensitivity by considering reallocation of time into standing or stepping.

Design

Cross-sectional.

Setting

Leicestershire, UK, 2013.

Participants

Adults aged 30–75 years at high risk of impaired glucose regulation (IGR) or type 2 diabetes. 435 adults (age 66.8±7.4 years; 61.7% male; 89.2% white European) were included.

Methods

Participants wore an activPAL3 monitor 24 hours/day for 7 days to capture time spent sitting, standing and stepping. Fasting and 2-hour postchallenge glucose and insulin were assessed; insulin sensitivity was calculated by Homeostasis Model Assessment of Insulin Secretion (HOMA-IS) and Matsuda-Insulin Sensitivity Index (Matsuda-ISI). Isotemporal substitution regression modelling was used to quantify associations of substituting 30 min of waking sitting time (accumulated in prolonged (≥30 min) or short (<30 min) bouts) for standing or stepping on glucose regulation and insulin sensitivity. Interaction terms were fitted to assess whether the associations with measures of glucose regulation and insulin sensitivity was modified by sex or IGR status.

Results

After adjustment for confounders, including waist circumference, reallocation of prolonged sitting to short sitting time and to standing was associated with 4% lower fasting insulin and 4% higher HOMA-IS; reallocation of prolonged sitting to standing was also associated with a 5% higher Matsuda-ISI. Reallocation to stepping was associated with 5% lower 2-hour glucose, 7% lower fasting insulin, 13% lower 2-hour insulin and a 9% and 16% higher HOMA-IS and Matsuda-ISI, respectively. Reallocation of short sitting time to stepping was associated with 5% and 10% lower 2-hour glucose and 2-hour insulin and 12% higher Matsuda-ISI. Results were not modified by IGR status or sex.

Conclusions

Reallocating a small amount of short or prolonged sitting time with standing or stepping may improve 2-hour glucose, fasting and 2-hour insulin and insulin sensitivity. Findings should be confirmed through prospective and intervention research.

Trial registration number

ISRCTN31392913, Post-results.
AHEAD Study: an observational study of the management of anticoagulated patients who suffer head injury
Authors: Mason Suzanne , Kuczawski Maxine , Teare M Dawn , Stevenson Matt , Goodacre Steve , Ramlakhan Shammi , Morris Francis , Rothwell Joanne
Published: January 2017

Objectives

Management of anticoagulated patients after head injury is unclear due to lack of robust evidence. This study aimed to determine the adverse outcome rate in these patients and identify risk factors associated with poor outcome.

Design

Multicentre, observational study using routine patient records.

Setting

33 emergency departments in England and Scotland.

Participants

3566 adults (aged ≥16 years) who had suffered blunt head injury and were currently taking warfarin.

Main outcome measures

Primary outcome measure was rate of adverse outcome defined as death or neurosurgery following initial injury, clinically significant CT scan finding or reattendance with related complication within 10 weeks of initial hospital attendance. Secondary objectives included identifying risk factors for adverse outcome using univariable and multivariable analyses.

Results

Clinical data available for 3534/3566 patients (99.1%), median age 79 years; mean initial international normalised ratio (INR) 2.67 (SD 1.34); 81.2% Glasgow Coma Scale (GCS) 15: 59.8% received a CT scan with significant head injury-related finding in 5.4% (n=208); 0.5% underwent neurosurgery; 1.2% patients suffered a head injury-related death. Overall adverse outcome rate was 5.9% (95% CI 5.2% to 6.7%). Patients with GCS=15 and no associated symptoms had lowest risk of adverse outcome (risk 2.7%; 95% CI 2.1 to 3.6). Patients with GCS=15 multivariable analysis (using imputation) found risk of adverse outcome to increase when reporting at least one associated symptom: vomiting (relative risk (RR) 1.8; 95% CI 1.0 to 3.4), amnesia (RR 3.5; 95% CI 2.1 to 5.7), headache (RR 1.3; 95% CI 0.8 to 2.2), loss of consciousness (RR 1.75; 95% CI 1.0 to 3.0). INR measurement did not predict adverse outcome in patients with GCS=15 (RR 1.1; 95% CI 1.0 to 1.2).

Conclusions

In alert warfarinised patients following head injury, the presence of symptoms is associated with greater risk of adverse outcome. Those with GCS=15 and no symptoms are a substantial group and have a low risk of adverse outcome.

Trial registration number

NCT02461498.
Ethnic differences in anthropometric measures and abdominal fat distribution: a cross-sectional pooled study in Inuit, Africans and Europeans
Authors: Rønn Pernille F , Andersen Gregers S , Lauritzen Torsten , Christensen Dirk L , Aadahl Mette , Carstensen Bendix , Jørgensen Marit E
Published: January 2017

Background

Ethnic variation in abdominal fat distribution may explain differences in cardiometabolic risk between populations. However, the ability of anthropometric measures to quantify abdominal fat is not clearly understood across ethnic groups. The aim of this study was to investigate the associations between anthropometric measures and visceral (VAT) and subcutaneous abdominal adipose tissue (SAT) in Inuit, Africans and Europeans.

Methods

We combined cross-sectional data from 3 studies conducted in Greenland, Kenya and Denmark using similar methodology. A total of 5275 individuals (3083 Inuit, 1397 Africans and 795 Europeans) aged 17–95 years with measures of anthropometry and ultrasonography of abdominal fat were included in the study. Multiple regression models with fractional polynomials were used to analyse VAT and SAT as functions of body mass index (BMI), waist circumference, waist-to-hip ratio, waist-to-height ratio and body fat percentage.

Results

The associations between conventional anthropometric measures and abdominal fat distribution varied by ethnicity in almost all models. Europeans had the highest levels of VAT in adjusted analyses and Africans the lowest with ethnic differences most apparent at higher levels of the anthropometric measures. Similar ethnic differences were seen in the associations with SAT for a given anthropometric measure.

Conclusions

Conventional anthropometric measures like BMI and waist circumference do not reflect the same amount of VAT and SAT across ethnic groups. Thus, the obesity level at which Inuit and Africans are at increased cardiometabolic risk is likely to differ from that of Europeans.
Long-term effects of youth unemployment on mental health: does an economic crisis make a difference?
Authors: Thern Emelie , de Munter Jeroen , Hemmingsson Tomas , Rasmussen Finn
Published: January 2017

Background

Ill health is a risk factor and a consequence of unemployment, which might vary depending on the national rate of unemployment. We investigated the long-term effect of youth unemployment on mental health and explored the possible interaction during periods of high (economic crisis) and low (non-crisis) unemployment rates.

Methods

A register-linked population-based cohort study was conducted including individuals aged 17–24 years. The crisis cohort (n=6410) took part in the Labour Force Survey during the economic crisis (1991–1994) in Sweden and the non-crisis cohort (n=8162) took part in the same survey before the crisis (1983–1986). Follow-up was 19 years. Adjusted HRs and 95% CIs for an inpatient care discharge mental diagnosis with employed people as the reference group were calculated by Cox regressions models.

Results

In fully adjusted models, <3 months (HR: 1.69; 95% CI 1.14 to 2.49), 3–6 months (2.19; 1.43 to 3.37) and >6 months (2.70; 1.71 to 4.28) of unemployment were associated with increased risks of getting a mental diagnosis in the crisis cohort. In the non-crisis cohort the risks were: 1.92; 1.40 to 2.63, 2.60; 1.72 to 3.94 and 3.33; 2.00 to 5.57, respectively. No interactions between labour force status and level of unemployment were found.

Conclusions

Youth unemployment is related to mental health problems, independent of the overall national rate of unemployment, which is important as the youth unemployment rates are currently at stable high level.
Twenty years of social capital and health research: a glossary
Authors: Moore S , Kawachi I
Published: January 2017

Research on social capital in public health is approaching its 20th anniversary. Over this period, there have been rich and productive debates on the definition, measurement and importance of social capital for public health research and practice. As a result, the concepts and measures characterising social capital and health research have also evolved, often drawing from research in the social, political and behavioural sciences. The multidisciplinary adaptation of social capital-related concepts to study health has made it challenging for researchers to reach consensus on a common theoretical approach. This glossary thus aims to provide a general overview without recommending any particular approach. Based on our knowledge and research on social capital and health, we have selected key concepts and terms that have gained prominence over the last decade and complement an earlier glossary on social capital and health.
Fine-mapping of genes determining extrafusal fiber properties in murine soleus muscle
Authors: Carroll A. M. , Cheng R. , Collie-Duguid E. S. R. , Meharg C. , Scholz M. E. , Fiering S. , Fields J. L. , Palmer A. A. , Lionikas A.
Published: January 2017

Muscle fiber cross-sectional area (CSA) and proportion of different fiber types are important determinants of muscle function and overall metabolism. Genetic variation plays a substantial role in phenotypic variation of these traits; however, the underlying genes remain poorly understood. This study aimed to map quantitative trait loci (QTL) affecting differences in soleus muscle fiber traits between the LG/J and SM/J mouse strains. Fiber number, CSA, and proportion of oxidative type I fibers were assessed in the soleus of 334 genotyped female and male mice of the F34generation of advanced intercross lines (AIL) derived from the LG/J and SM/J strains. To increase the QTL detection power, these data were combined with 94 soleus samples from the F2intercross of the same strains. Transcriptome of the soleus muscle of LG/J and SM/J females was analyzed by microarray. Genome-wide association analysis mapped four QTL (genome-wide P < 0.05) affecting the properties of muscle fibers to chromosome 2, 3, 4, and 11. A 1.5-LOD QTL support interval ranged between 2.36 and 4.67 Mb. On the basis of the genomic sequence information and functional and transcriptome data, we identified candidate genes for each of these QTL. The combination of analyses in F2and F34AIL populations with transcriptome and genomic sequence data in the parental strains is an effective strategy for refining QTL and nomination of the candidate genes.
Long Noncoding RNA LINC00092 Acts in Cancer-Associated Fibroblasts to Drive Glycolysis and Progression of Ovarian Cancer
Authors: Zhao Linjie , Ji Gaili , Le Xiaobing , Wang Chenlu , Xu Lian , Feng Min , Zhang Yaguang , Yang Huiliang , Xuan Yu , Yang Yanfei , Lei Lingzi , Yang Qilian , Lau Wayne Bond , Lau Bonnie , Chen Yi , Deng Xiangbing , Yao Shaohua , Yi Tao , Zhao Xia , Wei Yuquan , Zhou Shengtao
Published: January 2017

The majority of patients with epithelial ovarian cancer are diagnosed at a late stage when the peritoneal metastases exist; however, there is little knowledge of the metastatic process in this disease setting. In this study, we report the identification of the long noncoding RNA LINC00092 as a nodal driver of metastatic progression mediated by cancer-associated fibroblasts (CAF). Prometastatic properties of CAFs in vitro and in vivo were found to associate with elevated expression of the chemokine CXCL14. In clinical specimens, elevated levels of CXCL14 in CAFs also correlated with poor prognosis. Notably, CXCL14-high CAFs mediated upregulation of LINC00092 in ovarian cancer cells, the levels of which also correlated with poor prognosis in patients. Mechanistic studies showed that LINC00092 bound a glycolytic enzyme, the fructose-2,6-biphosphatase PFKFB2, thereby promoting metastasis by altering glycolysis and sustaining the local supportive function of CAFs. Overall, our study uncovered a positive feedback loop in the metabolism of CXCL14-positive CAFs and ovarian cancer cells that is critical for metastatic progression. Cancer Res; 77(6); 1369–82. ©2017 AACR.
U.S. FDA Approval Summary: Nivolumab for Treatment of Unresectable or Metastatic Melanoma Following Progression on Ipilimumab
Authors: Hazarika Maitreyee , Chuk Meredith K. , Theoret Marc R. , Mushti Sirisha , He Kun , Weis Shawna L. , Putman Alexander H. , Helms Whitney S. , Cao Xianhua , Li Hongshan , Zhao Hong , Zhao Liang , Welch Joel , Graham Laurie , Libeg Meredith , Sridhara Rajeshwari , Keegan Patricia , Pazdur Richard
Published: January 2017

On December 22, 2014, the FDA granted accelerated approval to nivolumab (OPDIVO; Bristol-Myers Squibb) for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. Approval was based on a clinically meaningful, durable objective response rate (ORR) in a non-comparative analysis of 120 patients who received 3 mg/kg of nivolumab intravenously every 2 weeks with at least 6-month follow-up in an ongoing, randomized, open-label, active-controlled clinical trial. The ORR as assessed by a blinded independent review committee per RECIST v1.1 was 31.7% (95% confidence interval, 23.5–40.8). Ongoing responses were observed in 87% of responding patients, ranging from 2.6+ to 10+ months. In 13 patients, the response duration was 6 months or longer. The risks of nivolumab, including clinically significant immune-mediated adverse reactions (imARs), were assessed in 268 patients who received at least one dose of nivolumab. The FDA review considered whether the ORR and durations of responses were reasonably likely to predict clinical benefit, the adequacy of the safety database, and systematic approaches to the identification, description, and patient management for imARs in product labeling. Clin Cancer Res; 23(14); 3484–8. ©2017 AACR.
Molecular Pathways: Targeting Protein Tyrosine Phosphatases in Cancer
Authors: Bollu Lakshmi Reddy , Mazumdar Abhijit , Savage Michelle I. , Brown Powel H.
Published: January 2017

The aberrant activation of oncogenic signaling pathways is a universal phenomenon in cancer and drives tumorigenesis and malignant transformation. This abnormal activation of signaling pathways in cancer is due to the altered expression of protein kinases and phosphatases. In response to extracellular signals, protein kinases activate downstream signaling pathways through a series of protein phosphorylation events, ultimately producing a signal response. Protein tyrosine phosphatases (PTP) are a family of enzymes that hydrolytically remove phosphate groups from proteins. Initially, PTPs were shown to act as tumor suppressor genes by terminating signal responses through the dephosphorylation of oncogenic kinases. More recently, it has become clear that several PTPs overexpressed in human cancers do not suppress tumor growth; instead, they positively regulate signaling pathways and promote tumor development and progression. In this review, we discuss both types of PTPs: those that have tumor suppressor activities as well as those that act as oncogenes. We also discuss the potential of PTP inhibitors for cancer therapy. Clin Cancer Res; 23(9); 2136–42. ©2017 AACR.
STXBP4 Drives Tumor Growth and Is Associated with Poor Prognosis through PDGF Receptor Signaling in Lung Squamous Cell Carcinoma
Authors: Otaka Yukihiro , Rokudai Susumu , Kaira Kyoichi , Fujieda Michiru , Horikoshi Ikuko , Iwakawa-Kawabata Reika , Yoshiyama Shinji , Yokobori Takehiko , Ohtaki Yoichi , Shimizu Kimihiro , Oyama Tetsunari , Tamura Jun'ichi , Prives Carol , Nishiyama Masahiko
Published: January 2017

Purpose: Expression of the ΔN isoform of p63 (ΔNp63) is a diagnostic marker highly specific for lung squamous cell carcinoma (SCC). We previously found that Syntaxin Binding Protein 4 (STXBP4) regulates ΔNp63 ubiquitination, suggesting that STXBP4 may also be an SCC biomarker. To address this issue, we investigated the role of STXBP4 expression in SCC biology and the impact of STXBP4 expression on SCC prognosis.

Experimental Design: We carried out a clinicopathologic analysis of STXBP4 expression in 87 lung SCC patients. Whole transcriptome analysis using RNA-seq was performed in STXBP4-positive and STXBP4-negative tumors of lung SCC. Soft-agar assay and xenograft assay were performed using overexpressing or knockdown SCC cells.

Results: Significantly higher levels of STXBP4 expression were correlated with accumulations of ΔNp63 in clinical lung SCC specimens (Spearman rank correlation ρ = 0.219). Notably, STXBP4-positive tumors correlated with three important clinical parameters: T factor (P < 0.001), disease stage (P = 0.030), and pleural involvement (P = 0.028). Whole transcriptome sequencing followed by pathway analysis indicated that STXBP4 is involved in functional gene networks that regulate cell growth, proliferation, cell death, and survival in cancer. Platelet-derived growth factor receptor alpha (PDGFRα) was a key downstream mediator of STXBP4 function. In line with this, shRNA mediated STXBP4 and PDGFRA knockdown suppressed tumor growth in soft-agar and xenograft assays.

Conclusions: STXBP4 plays a crucial role in driving SCC growth and is an independent prognostic factor for predicting worse outcome in lung SCC. These data suggest that STXBP4 is a relevant therapeutic target for patients with lung SCC. Clin Cancer Res; 23(13); 3442–52. ©2017 AACR.
TNF Signaling through RIP1 Kinase Enhances SN38-Induced Death in Colon Adenocarcinoma
Authors: Cabal-Hierro Lucia , O'Dwyer Peter J.
Published: January 2017

Elucidation of TNF-directed mechanisms for cell death induction and maintenance of tumor growth has revealed a role for receptor-interacting protein kinases 1 and 3 (RIPK1/RIP1 and RIPK3/RIP3), components of the necrosome complex, as determinants of cell fate. Here, the participation of TNF signaling was analyzed with regard to the cytotoxic action of different DNA-damaging agents in a panel of colon cancer cells. While most of these cell lines were insensitive to TNF, combination with these drugs increased sensitivity by inducing cell death and DNA damage, especially in the case of the topoisomerase inhibitor SN38. Changes in levels of RIP1 and RIP3 occurred following monotherapy with SN38 or in combination with TNF. Downregulation of RIP1 resulted in increased resistance to SN38, implying a requirement for RIP1 in mediating cytotoxicity through the TNF/TNFR signaling pathway. Downregulation of RIP1 in a xenograft model impaired tumor growth inhibition from SN38 treatment, suggesting the potential of RIP1 to determine the clinical outcome of irinotecan treatment. These results indicate that TNF plays a key role in determining the cytotoxic effectiveness of SN38 in colorectal cancer and suggests a re-evaluation of TNF-based interventions to enhance therapeutic efficacy.

Implications: The capacity of RIP1 to influence drug sensitivity suggests RIP1 may have biomarker potential. Mol Cancer Res; 15(4); 395–404. ©2017 AACR.
International Variation in Outcomes Among People with Cardiovascular Disease or Cardiovascular Risk Factors and Impaired Glucose Tolerance: Insights from the NAVIGATOR Trial
Authors: Harumi Higuchi dos Santos Marilia , Sharma Abhinav , Sun Jie‐Lena , Pieper Karen , McMurray John J.V. , Holman Rury R. , Lopes Renato D.
Published: January 2017

Background

Regional differences in risk of diabetes mellitus and cardiovascular outcomes in people with impaired glucose tolerance are poorly characterized. Our objective was to evaluate regional variation in risk of new‐onset diabetes mellitus, cardiovascular outcomes, and treatment effects in participants from the NAVIGATOR (Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research) trial.

Methods and Results

NAVIGATOR
randomized people with impaired glucose tolerance and cardiovascular risk factors or with established cardiovascular disease to valsartan (or placebo) and to nateglinide (or placebo) with a median 5‐year follow‐up. Data from the 9306 participants were categorized by 5 regions: Asia (n=552); Europe (n=4909); Latin America (n=1406); North America (n=2146); and Australia, New Zealand, and South Africa (n=293). Analyzed outcomes included new‐onset diabetes mellitus; cardiovascular death; a composite cardiovascular outcome of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke; and treatment effects of valsartan and nateglinide. Respective unadjusted 5‐year risks for new‐onset diabetes mellitus, cardiovascular death, and the composite cardiovascular outcome were 33%, 0.4%, and 4% for Asia; 34%, 2%, and 6% for Europe; 37%, 4%, and 8% for Latin America; 38%, 2%, and 6% for North America; and 32%, 4%, and 8% for Australia, New Zealand, and South Africa. After adjustment, compared with North America, European participants had a lower risk of new‐onset diabetes mellitus (hazard ratio 0.86, 95%
CI
0.78–0.94;
P
=0.001), whereas Latin American participants had a higher risk of cardiovascular death (hazard ratio 2.68, 95%
CI
1.82–3.96;
P
<0.0001) and the composite cardiovascular outcome (hazard ratio 1.48, 95%
CI
1.15–1.92;
P
=0.003). No differential interactions between treatment and geographic location were identified.

Conclusions

Major regional differences regarding the risk of new‐onset diabetes mellitus and cardiovascular outcomes in
NAVIGATOR
participants were identified. These differences should be taken into account when planning global trials.

Clinical Trial Registration

URL:
http://www.ClinicalTrials.gov
. Unique identifier:
NCT
00097786.
Clinical Selection Strategies to Identify Ischemic Stroke Patients With Large Anterior Vessel Occlusion
Authors: Scheitz Jan F. , Abdul-Rahim Azmil H. , MacIsaac Rachael L. , Cooray Charith , Sucharew Heidi , Kleindorfer Dawn , Khatri Pooja , Broderick Joseph P. , Audebert Heinrich J. , Ahmed Niaz , Wahlgren Nils , Endres Matthias , Nolte Christian H. , Lees Kennedy R.
Published: January 2017

Background and Purpose—

The National Institutes of Health Stroke Scale (NIHSS) correlates with presence of large anterior vessel occlusion (LAVO). However, the application of the full NIHSS in the prehospital setting to select patients eligible for treatment with thrombectomy is limited. Therefore, we aimed to evaluate the prognostic value of simple clinical selection strategies.

Methods—

Data from the Safe Implementation of Thrombolysis in Stroke International Stroke Thrombolysis Registry (January 2012–May 2014) were analyzed retrospectively. Patients with complete breakdown of NIHSS scores and documented vessel status were included. We assessed the association of prehospital stroke scales and NIHSS symptom profiles with LAVO (internal carotid artery, carotid-terminus or M1-segment of the middle cerebral artery).

Results—

Among 3505 patients, 23.6% (n=827) had LAVO. Pathological finding on the NIHSS item best gaze was strongly associated with LAVO (adjusted odds ratio 4.5, 95% confidence interval 3.8–5.3). All 3 face–arm–speech–time test (FAST) items identified LAVO with high sensitivity. Addition of the item best gaze to the original FAST score (G-FAST) or high scores on other simplified stroke scales increased specificity. The NIHSS symptom profiles representing total anterior syndromes showed a 10-fold increased likelihood for LAVO compared with a nonspecific clinical profile. If compared with an NIHSS threshold of ≥6, the prehospital stroke scales performed similarly or even better without losing sensitivity.

Conclusions—

Simple modification of the face–arm–speech–time score or evaluating the NIHSS symptom profile may help to stratify patients’ risk of LAVO and to identify individuals who deserve rapid transfer to comprehensive stroke centers. Prospective validation in the prehospital setting is required.
Splenectomy Does Not Improve Long-Term Outcome After Stroke
Authors: Zierath Dannielle , Shen Angela , Stults Astiana , Olmstead Theresa , Becker Kyra J.
Published: January 2017

Background and Purpose—

Immune responses to brain antigens after stroke contribute to poor outcome. We hypothesized that splenectomy would lessen the development of such responses and improve outcome.

Methods—

Male Lewis rats (275–350 g) underwent 2-hour middle cerebral artery occlusion immediately after splenectomy or sham splenectomy. Animals were survived to 4 weeks (672 hrs), and immune responses to myelin basic protein determined at euthanasia. Infarct volume was determined in a subset of animals euthanized at 72 hours. Behavioral outcomes were assessed to 672 hours.

Results—

Splenectomy was associated with worse neurological scores early after stroke, but infarct size at 72 hours was similar in both groups. Behavioral outcomes and immune responses to myelin basic protein were also similar among splenectomized and sham-operated animals 672 hours after middle cerebral artery occlusion.

Conclusions—

Splenectomy did not alter the immune responses to brain antigens or improve outcome after stroke. Differences between this study and other studies of splenectomy and stroke are examined.
The European Union and Image Resilience during Times of Crisis: The Role of Public Diplomacy
Authors: Cross Mai’a K. Davis , La Porte Teresa
Published: January 2017

A resilient actor is one with the capacity to recover from setbacks and obstacles, whether stemming from endogenous or exogenous factors. Beyond actual recovery, this article argues that there is also an important perceptional dimension. Image resilience is the capacity on the part of actors to overcome and deal with the widespread negative perceptions that often follow on the heels of these setbacks. The article argues that the ability to cultivate image resilience rests significantly on the power of public diplomacy. Through establishing a strong image for an actor over the longer term, public diplomacy enables that actor to be more resilient during times of crisis. The European Union is a particularly good case study to shed light on this. Using original interview evidence, this article examines a specific example of how the European Union was ultimately able to strengthen its image resilience in the United States through public diplomacy.
Interpretive Fallibility and the Psychoanalytic Dialogue
Authors: Cooper Steven H.
Published: January 2017

The concept of the analyst's interpretive fallibility is utilized to understand and organize the ways in which contemporary psychoanalytic theory has expanded on Freud's notions regarding the hypothetical nature of interpretation. This expansion involves a particular axis regarding the analyst's stance, an axis that cuts across theoretical scaffolding to include the analyst's view of symmetry and asymmetry in the analytic setting and the epistemological positions and preferences accorded to analyst and analysand. The ways in which the analyst constructs and imposes meaning are examined more specifically in the theories of Roy Schafer and Ernest S. Wolf The benefits and problems of constructivism in analytic stance are evaluated and illustrated through a case example. Finally, the notion of psychoanalytic neurality is reconsidered with regard to a series of tensions between the construction and foreclosure of meaning in the analytic situation.
When Being in the Minority Pays Off
Authors: Ody-Brasier Amandine , Fernandez-Mateo Isabel
Published: January 2017

Economic sociologists have studied how social relationships shape market prices by focusing mostly on vertical interactions between buyers and sellers. In this article, we examine instead the price consequences of horizontal relationships that arise from intergroup processes among sellers. Our setting is the market for Champagne grapes. Using proprietary transaction-level data, we find that female grape growers—a minority in the growers’ community—charge systematically higher prices than do male grape growers. We argue that the underlying mechanism for this unexpected pattern of results involves the relationships developed and maintained by minority members. Specifically, in-depth fieldwork reveals that female growers get together to compensate for their isolation from the majority. This behavior enables them to overcome local constraints on the availability of price-relevant information, constraints that stem from prevailing norms of market behavior: individualism and secrecy. We discuss the implications of these findings for the study of how relationships shape price-setting processes, for the sociological literature on intergroup relations, and for our understanding of inequality in markets.
In Vivo Estimates of the Position of Advanced Bionics Electrode Arrays in the Human Cochlea
Authors: Skinner Margaret W. , Holden Timothy A. , Whiting Bruce R. , Voie Arne H. , Brunsden Barry , Neely J. Gail , Saxon Eugene A. , Hullar Timothy E. , Finley Charles C.
Published: January 2017

Objectives:

A new technique for determining the position of each electrode in the cochlea is described and applied to spiral computed tomography data from 15 patients implanted with Advanced Bionics HiFocus I, Ij, or Helix arrays.

Methods:

ANALYZE imaging software was used to register 3-dimensional image volumes from patients' preoperative and postoperative scans and from a single body donor whose unimplanted ears were scanned clinically, with micro computed tomography and with orthogonal-plane fluorescence optical sectioning (OPFOS) microscopy. By use of this registration, we compared the atlas of OPFOS images of soft tissue within the body donor's cochlea with the bone and fluid/tissue boundary available in patient scan data to choose the midmodiolar axis position and judge the electrode position in the scala tympani or scala vestibuli, including the distance to the medial and lateral scalar walls. The angular rotation 0° start point is a line joining the midmodiolar axis and the middle of the cochlear canal entry from the vestibule.

Results:

The group mean array insertion depth was 477° (range, 286° to 655°). The word scores were negatively correlated (r = −0.59; p = .028) with the number of electrodes in the scala vestibuli.

Conclusions:

Although the individual variability in all measures was large, repeated patterns of suboptimal electrode placement were observed across subjects, underscoring the applicability of this technique.
The effect of nitisinone on homogentisic acid and tyrosine: a two-year survey of patients attending the National Alkaptonuria Centre, Liverpool
Authors: Milan Anna M , Hughes Andrew T , Davison Andrew S , Devine Jean , Usher Jeannette , Curtis Sarah , Khedr Milad , Gallagher James A , Ranganath Lakshminarayan R
Published: January 2017

Background

Alkaptonuria is a rare, debilitating autosomal recessive disorder affecting tyrosine metabolism. Deficiency of homogentisate 1,2-dioxygenase leads to increased homogentisic acid which is deposited as ochronotic pigment. Clinical sequelae include severe early onset osteoarthritis, increased renal and prostate stone formation and cardiac complications. Treatment has been largely based on analgaesia and arthroplasty. The National Alkaptonuria Centre in Liverpool has been using 2 mg nitisinone (NTBC) off-license for all patients in the United Kingdom with alkaptonuria and monitoring the tyrosine metabolite profiles.

Methods

Patients with confirmed alkaptonuria are commenced on 2 mg dose (alternative days) of NTBC for three months with daily dose thereafter. Metabolite measurement by LC-MS/MS is performed at baseline, day 4, three-months, six-months and one-year post-commencing NTBC. Thereafter, monitoring and clinical assessments are performed annually.

Results

Urine homogentisic acid concentration decreased from a mean baseline 20,557 µmol/24 h (95th percentile confidence interval 18,446–22,669 µmol/24 h) by on average 95.4% by six months, 94.8% at one year and 94.1% at two year monitoring. A concurrent reduction in serum homogentisic acid concentration of 83.2% compared to baseline was also measured. Serum tyrosine increased from normal adult reference interval to a mean ± SD of 594 ± 184 µmol /L at year-two monitoring with an increased urinary excretion from 103 ± 81 µmol /24 h at baseline to 1071 ± 726 µmol /24 h two years from therapy.

Conclusions

The data presented represent the first longitudinal survey of NTBC use in an NHS service setting and demonstrate the sustained effect of NTBC on the tyrosine metabolite profile.
Comparison of method-related reference intervals for thyroid hormones: studies from a prospective reference population and a literature review
Authors: Barth Julian H , Luvai Ahai , Jassam Nuthar , Mbagaya Wycliffe , Kilpatrick Eric S , Narayanan Deepa , Spoors Shirley
Published: January 2017

Introduction

Reference intervals are dependent on the reference population, the analytical methods and the way the data are handled statistically. Individual method-related differences have been studied but the comparative differences in reference intervals have not.

Methods

We studied a reference population of healthy adult subjects and measured free thyroxine and thyroid-stimulating hormone by the four most commonly used analytical platforms used in the UK. Subjects were excluded if they were > 65 years or had positive thyroid peroxidase antibodies. We also performed a systematic literature review of thyroid hormone reference interval studies in non-pregnant adults.

Results

In total, 303 subjects were recruited and 42 excluded. The central 95th centile values for thyroid-stimulating hormone (mIU/L) were Abbott Architect (0.51–3.67); Beckman Unicel DxI (0.57–3.60); Roche Cobas (0.60–4.31) and Siemens Advia Centaur XP (0.63–4.29). The 95th centile values for thyroxine (pmol/L) were Abbott Architect (10.6–15.5); Beckman Unicel DxI (7.9–13.0); Roche Cobas (12.5–19.6) and Siemens Advia Centaur XP (11.8–19.0). We identified 55 papers describing thyroid reference intervals in male and non-pregnant female adults. The values for upper and lower reference intervals by manufacturer varied but were not significantly different for thyroid-stimulating hormone but were for thyroxine.

Discussion

Our study demonstrates clearly that there are marked variations in the reference intervals for thyroid hormones between analytical platforms. There is an urgent need for standardization of thyroid hormone assays to permit transferability of results. Until then, guidelines will need to reflect this method-related difference.