bluuebunny/crossref_metadata_2025_split huggingface dataset:
Estimating treatment effects in randomised controlled trials with non-compliance: a simulation study
Authors: Ye Chenglin , Beyene Joseph , Browne Gina , Thabane Lehana 
Published: June 2014

ObjectiveRandomised controlled trials (RCTs) are often considered as the gold standard for assessing new health interventions. Patients are randomly assigned to receive an intervention or control. The effect of the intervention can be estimated by comparing outcomes between groups, whose prognostic factors are expected to balance by randomisation. However, patients’ non-compliance with their assigned treatment will undermine randomisation and potentially bias the estimate of treatment effect. Through simulation, we aim to compare common approaches in analysing non-compliant data under different non-compliant scenarios.SettingsBased on a real study, we simulated hypothetical trials by varying three non-compliant factors: the type, randomness and degree of non-compliance. We compared the intention-to-treat (ITT), as-treated (AT), per-protocol (PP), instrumental variable (IV) and complier average casual effect (CACE) analyses to estimate large (50% improvement over the control), moderate (25% improvement) and null (same as the control) treatment effects. Different approaches were compared by the bias of estimate, mean square error (MSE) and 95% coverage of the true value.ResultsFor a large or moderate treatment effect, the ITT estimate was considerably biased in all scenarios. The AT, PP, IV and CACE estimates were unbiased when non-compliant behaviours were random. The IV estimate was unbiased when non-compliant behaviours were symmetrically dependent on patients’ conditions. The PP estimate was mostly unbiased when patients in the control group did not have access to the intervention. When the intervention was not different from the control, the ITT was less biased than the other approaches. Similar results were found when comparing the MSE and 95% coverage.ConclusionsThe standard ITT analysis under non-compliance is biased when the intervention has a moderate or large effect. Alternative analyses can provide unbiased or less biased estimates. Based on the results, we make some suggestions on choosing optimal approaches for analysing specific non-compliant scenarios.
A protocol for an exploratory phase I mixed-methods study of enhanced integrated care for care home residents with advanced dementia: the Compassion Intervention
Authors: Elliott Margaret , Harrington Jane , Moore Kirsten , Davis Sarah , Kupeli Nuriye , Vickerstaff Victoria , Gola Anna , Candy Bridget , Sampson Elizabeth L , Jones Louise 
Published: June 2014

IntroductionIn the UK approximately 700 000 people are living with, and a third of people aged over 65 will die with, dementia. People with dementia may receive poor quality care towards the end of life. We applied a realist approach and used mixed methods to develop a complex intervention to improve care for people with advanced dementia and their family carers. Consensus on intervention content was achieved using the RAND UCLA appropriateness method and mapped to sociological theories of process and impact. Core components are: (1) facilitation of integrated care, (2) education, training and support, (3) investment from commissioners and care providers. We present the protocol for an exploratory phase I study to implement components 1 and 2 in order to understand how the intervention operates in practice and to assess feasibility and acceptability.Methods and analysisAn ‘Interdisciplinary Care Leader (ICL)’ will work within two care homes, alongside staff and associated professionals to facilitate service integration, encourage structured needs assessment, develop the use of personal and advance care plans and support staff training. We will use qualitative and quantitative methods to collect data for a range of outcome and process measures to detect effects on individual residents, family carers, care home staff, the intervention team, the interdisciplinary team and wider systems. Analysis will include descriptive statistics summarising process and care home level data, individual demographic and clinical characteristics and data on symptom burden, clinical events and quality of care. Qualitative data will be explored using thematic analysis. Findings will inform a future phase II trial.Ethics and disseminationEthical approval was granted (REC reference 14/LO/0370). We shall publish findings at conferences, in peer-reviewed journals, on the Marie Curie Cancer Care website and prepare reports for dissemination by organisations involved with end-of-life care and dementia.
Guidance: The practical management of the gastrointestinal symptoms of pelvic radiation disease
Authors: Andreyev H Jervoise N , Muls Ann C , Norton Christine , Ralph Charlotte , Watson Lorraine , Shaw Clare , Lindsay James O 
Published: June 2014

BackgroundA recent randomised trial suggested that an algorithmic approach to investigating and managing gastrointestinal symptoms of pelvic radiation disease (PRD) is beneficial and that specially trained nurses can manage patients as effectively as a gastroenterologist.AimsThe aim of the development and peer review of the guide was to make the algorithm used in the trial accessible to all levels of clinician.MethodsExperts who manage patients with PRD were asked to review the guide, rating each section for agreement with the recommended measures and suggesting amendments if necessary. Specific comments were discussed and incorporated as appropriate, and this process was repeated for a second round of review.Results34 gastroenterologists, 10 nurses, 9 dietitians, 7 surgeons and 5 clinical oncologists participated in round one. Consensus (defined prospectively as 60% or more panellists selecting ‘strongly agree’ or ‘agree’) was reached for 27 of the original 28 sections in the guide, with a median of 75% of panellists agreeing with each section. 86% of panellists agreed that the guide was acceptable for publication or acceptable with minor revisions. 55 of the original 65 panellists participated in round two. 89% agreed it was acceptable for publication after the first revision. Further minor amendments were made in response to round two.ConclusionsDevelopment of the guide in response to feedback included▸ improvement of occasional algorithmic steps▸ a more user-friendly layout▸ clearer timeframes for referral to other teams▸ expansion of reference list▸ addition of procedures to the appendix.
Republished: Drug-induced gastrointestinal disorders
Authors: Philpott H L , Nandurkar S , Lubel J , Gibson P R 
Published: June 2014

Abstract
Drug-induced gastrointestinal disorders can mimic conditions, such as inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) and, hence, recognition can prevent unnecessary investigations and treatment. While the knowledge and awareness relating to the adverse gastrointestinal effects of some medications, such as non-steroidal anti-inflammatory drugs are well established, other commonly prescribed drugs, such as antipsychotics, antidepressants and metformin are less well understood and warrant further study. This review attempts to integrate recent information regarding adverse drug reactions and place this in a useful clinical context.
Republished: Is hypertension associated with job strain? A meta-analysis of observational studies
Authors: Babu Giridhara R , Jotheeswaran A T , Mahapatra Tanmay , Mahapatra Sanchita , Kumar Ananth , Detels Roger , Pearce Neil 
Published: June 2014

Abstract
Job strain results from a combination of high workload and few decision-making opportunities in the workplace. There is inconsistent evidence regarding the association between job strain and hypertension, and methodological shortcomings preclude firm conclusions. Thus, a meta-analysis of observational studies on hypertension among occupational groups was conducted to determine whether job strain was associated with hypertension. In January 2012, we carried out a comprehensive, topic-specific electronic literature search of the Ovid MEDLINE, EMBASE and PsychoINFO databases complemented by individual help from non-communicable disease experts. Experimental/interventional studies and studies on personality disorders were excluded. Nine of 894 identified studies met the eligibility criteria and were included in the meta-analysis. The pooled OR of the nine studies was 1.3 (95% CI 1.14 to 1.48; p&lt;0.001), of case–control studies 3.17 (95% CI 1.79 to 5.60; p&lt;0.001) and of cohort studies 1.24 (95% CI 1.09 to 1.41; p&lt;0.001), all of which indicated statistically significant positive associations between job strain and hypertension. In a subgroup analysis, cohort studies of good methodological quality showed significant associations between job strain and hypertension, while those of poor methodological quality showed no association or subgroup differences. We conclude that despite methodological differences, case–control and cohort studies of good methodological quality showed positive associations between hypertension and job strain.
Targeting 4-1BB Costimulation to the Tumor Stroma with Bispecific Aptamer Conjugates Enhances the Therapeutic Index of Tumor Immunotherapy
Authors: Schrand Brett , Berezhnoy Alexey , Brenneman Randall , Williams Anthony , Levay Agata , Kong Ling-Yuan , Rao Ganesh , Zhou Shouhao , Heimberger Amy B. , Gilboa Eli 
Published: June 2014

AbstractDespite the recent successes of using immune modulatory Abs in patients with cancer, autoimmune pathologies resulting from the activation of self-reactive T cells preclude the dose escalations necessary to fully exploit their therapeutic potential. To reduce the observed and expected toxicities associated with immune modulation, here we describe a clinically feasible and broadly applicable approach to limit immune costimulation to the disseminated tumor lesions of the patient, whereby an agonistic 4-1BB oligonucleotide aptamer is targeted to the tumor stroma by conjugation to an aptamer that binds to a broadly expressed stromal product, VEGF. This approach was predicated on the premise that by targeting the costimulatory ligands to products secreted into the tumor stroma, the T cells will be costimulated before their engagement of the MHC–peptide complex on the tumor cell, thereby obviating the need to target the costimulatory ligands to noninternalizing cell surface products expressed on the tumor cells. Underscoring the potency of stroma-targeted costimulation and the broad spectrum of tumors secreting VEGF, in preclinical murine tumor models, systemic administration of the VEGF-targeted 4-1BB aptamer conjugates engendered potent antitumor immunity against multiple unrelated tumors in subcutaneous, postsurgical lung metastasis, methylcholantrene-induced fibrosarcoma, and oncogene-induced autochthonous glioma models, and exhibited a superior therapeutic index compared with nontargeted administration of an agonistic 4-1BB Ab or 4-1BB aptamer. Cancer Immunol Res; 2(9); 867–77. ©2014 AACR.
Vanguarda conservadora
Authors: Schechner Richard 
Published: June 2014

traduzido deSCHECHNER, Richard. The Conservative Avantgarde. Este paper foi apresentado no Departamento de Antropologia da USP, em São Paulo, em junho de 2012.tradução: Diana Paola Gómez MateusUniversidade de São Paulo, São Paulo, São Paulo, Brasilrevisão técnica: John C. DawseyUniversidade de São Paulo, São Paulo, São Paulo, Brasil
Smooth Muscle Specific Rac1 Deficiency Induces Hypertension by Preventing p116
RIP
3
‐Dependent RhoA Inhibition
Authors: André Gwennan , Sandoval Juan E. , Retailleau Kevin , Loufrani Laurent , Toumaniantz Gilles , Offermanns Stefan , Rolli‐Derkinderen Malvyne , Loirand Gervaise , Sauzeau Vincent 
Published: June 2014

Background
Increasing evidence implicates overactivation of RhoA as a critical component of the pathogenesis of hypertension. Although a substantial body of work has established that Rac1 functions antagonize RhoA in a broad range of physiological processes, the role of Rac1 in the regulation of vascular tone and blood pressure is not fully elucidated.

Methods and Results

To define the role of Rac1 in vivo in vascular smooth muscle cells (
vSMC
), we generated smooth muscle (SM)‐specific Rac1 knockout mice (SM‐Rac1‐KO) and performed radiotelemetric blood pressure recordings, contraction measurements in arterial rings,
vSMC
cultures and biochemical analyses. SM‐Rac1‐KO mice develop high systolic blood pressure sensitive to Rho kinase inhibition by fasudil. Arteries from SM‐Rac1‐KO mice are characterized by a defective NO‐dependent vasodilation and an overactivation of RhoA/Rho kinase signaling. We provide evidence that Rac1 deletion‐induced hypertension is due to an alteration of
cGMP
signaling resulting from the loss of Rac1‐mediated control of type 5 PDE activity. Consequently,
cGMP
‐dependent phosphorylation and binding of RhoA with its inhibitory partner, the phosphatase‐RhoA interacting protein (p116
RIP3
), are decreased.

Conclusions

Our data reveal that the depletion of Rac1 in SMC decreases
cGMP
‐dependent p116
RIP3
/RhoA interaction and the subsequent inhibition of RhoA signaling. Thus, we unveil an in vivo role of Rac1 in arterial blood pressure regulation and a new pathway involving p116
RIP3
that contributes to the antagonistic relationship between Rac1 and RhoA in vascular smooth muscle cells and their opposite roles in arterial tone and blood pressure.
Modulation of Mitochondrial Function and Autophagy Mediates Carnosine Neuroprotection Against Ischemic Brain Damage
Authors: Baek Seung-Hoon , Noh Ah Reum , Kim Kyeong-A. , Akram Muhammad , Shin Young-Jun , Kim Eun-Sun , Yu Seong Woon , Majid Arshad , Bae Ok-Nam 
Published: June 2014

Background and Purpose—
Despite the rapidly increasing global burden of ischemic stroke, no therapeutic options for neuroprotection against stroke currently exist. Recent studies have shown that autophagy plays a key role in ischemic neuronal death, and treatments that target autophagy may represent a novel strategy in neuroprotection. We investigated whether autophagy is regulated by carnosine, an endogenous pleiotropic dipeptide that has robust neuroprotective activity against ischemic brain damage.

Methods—
We examined the effect of carnosine on mitochondrial dysfunction and autophagic processes in rat focal ischemia and in neuronal cultures.

Results—
Autophagic pathways such as reduction of phosphorylated mammalian target of rapamycin (mTOR)/p70S6K and the conversion of microtubule-associated protein 1 light chain 3 (LC3)-I to LC3-II were enhanced in the ischemic brain. However, treatment with carnosine significantly attenuated autophagic signaling in the ischemic brain, with improvement of brain mitochondrial function and mitophagy signaling. The protective effect of carnosine against autophagy was also confirmed in primary cortical neurons.

Conclusions—
Taken together, our data suggest that the neuroprotective effect of carnosine is at least partially mediated by mitochondrial protection and attenuation of deleterious autophagic processes. Our findings shed new light on the mechanistic pathways that this exciting neuroprotective agent influences.
Gene Expression Profiling Reveals Distinct Molecular Signatures Associated With the Rupture of Intracranial Aneurysm
Authors: Nakaoka Hirofumi , Tajima Atsushi , Yoneyama Taku , Hosomichi Kazuyoshi , Kasuya Hidetoshi , Mizutani Tohru , Inoue Ituro 
Published: June 2014

Background and Purpose—
The rupture of intracranial aneurysm (IA) causes subarachnoid hemorrhage associated with high morbidity and mortality. We compared gene expression profiles in aneurysmal domes between unruptured IAs and ruptured IAs (RIAs) to elucidate biological mechanisms predisposing to the rupture of IA.

Methods—
We determined gene expression levels of 8 RIAs, 5 unruptured IAs, and 10 superficial temporal arteries with the Agilent microarrays. To explore biological heterogeneity of IAs, we classified the samples into subgroups showing similar gene expression patterns, using clustering methods.

Results—

The clustering analysis identified 4 groups: superficial temporal arteries and unruptured IAs were aggregated into their own clusters, whereas RIAs segregated into 2 distinct subgroups (early and late RIAs). Comparing gene expression levels between early RIAs and unruptured IAs, we identified 430 upregulated and 617 downregulated genes in early RIAs. The upregulated genes were associated with inflammatory and immune responses and phagocytosis including S100/calgranulin genes (
S100A8
,
S100A9
, and
S100A12
). The downregulated genes suggest mechanical weakness of aneurysm walls. The expressions of Krüppel-like family of transcription factors (
KLF2
,
KLF12
, and
KLF15
), which were anti-inflammatory regulators, and
CDKN2A
, which was located on chromosome 9p21 that was the most consistently replicated locus in genome-wide association studies of IA, were also downregulated.

Conclusions—
We demonstrate that gene expression patterns of RIAs were different according to the age of patients. The results suggest that macrophage-mediated inflammation is a key biological pathway for IA rupture. The identified genes can be good candidates for molecular markers of rupture-prone IAs and therapeutic targets.
Solving the puzzle of Parkinson’s disease using induced pluripotent stem cells
Authors: Zhao Ping , Luo Zhiwei , Tian Weihua , Yang Jiayin , Ibáñez David P , Huang Zhijian , Tortorella Micky D , Esteban Miguel A , Fan Wenxia 
Published: June 2014

The prevalence and incidence of Parkinson’s disease (PD) is increasing due to a prolonged life expectancy. This highlights the need for a better mechanistic understanding and new therapeutic approaches. However, traditional in vitro and in vivo experimental models to study PD are suboptimal, thus hampering the progress in the field. The epigenetic reprogramming of somatic cells to induced pluripotent stem cells (iPSCs) offers a unique way to overcome this problem, as these cells share many properties of embryonic stem cells (ESCs) including the potential to be transformed into different lineages. PD modeling with iPSCs is nowadays facilitated by the growing availability of high-efficiency neural-specific differentiation protocols and the possibility to correct or induce mutations as well as creating marker cell lines using designer nucleases. These technologies, together with steady advances in human genetics, will likely introduce profound changes in the way we interpret PD and develop new treatments. Here, we summarize the different PD iPSCs reported so far and discuss the challenges for disease modeling using these cell lines.
Comparison of Danish dichotomous and BI-RADS classifications of mammographic density
Authors: Hodge Rebecca , Hellmann Sophie Sell , Euler-Chelpin My von , Vejborg Ilse , Andersen Zorana Jovanovic 
Published: June 2014

Background In the Copenhagen mammography screening program from 1991 to 2001, mammographic density was classified either as fatty or mixed/dense. This dichotomous mammographic density classification system is unique internationally, and has not been validated before. Purpose To compare the Danish dichotomous mammographic density classification system from 1991 to 2001 with the density BI-RADS classifications, in an attempt to validate the Danish classification system. Material and Methods The study sample consisted of 120 mammograms taken in Copenhagen in 1991–2001, which tested false positive, and which were in 2012 re-assessed and classified according to the BI-RADS classification system. We calculated inter-rater agreement between the Danish dichotomous mammographic classification as fatty or mixed/dense and the four-level BI-RADS classification by the linear weighted Kappa statistic. Results Of the 120 women, 32 (26.7%) were classified as having fatty and 88 (73.3%) as mixed/dense mammographic density, according to Danish dichotomous classification. According to BI-RADS density classification, 12 (10.0%) women were classified as having predominantly fatty (BI-RADS code 1), 46 (38.3%) as having scattered fibroglandular (BI-RADS code 2), 57 (47.5%) as having heterogeneously dense (BI-RADS 3), and five (4.2%) as having extremely dense (BI-RADS code 4) mammographic density. The inter-rater variability assessed by weighted kappa statistic showed a substantial agreement (0.75). Conclusion The dichotomous mammographic density classification system utilized in early years of Copenhagen’s mammographic screening program (1991–2001) agreed well with the BI-RADS density classification system.
The effects of intestinal tract bacterial diversity on mortality following allogeneic hematopoietic stem cell transplantation
Authors: Taur Ying , Jenq Robert R. , Perales Miguel-Angel , Littmann Eric R. , Morjaria Sejal , Ling Lilan , No Daniel , Gobourne Asia , Viale Agnes , Dahi Parastoo B. , Ponce Doris M. , Barker Juliet N. , Giralt Sergio , van den Brink Marcel , Pamer Eric G. 
Published: June 2014

Key Points
Intestinal diversity is predictive of mortality in allo-HSCT.
Outcome prediction in plasmacytoma of bone: a risk model utilizing bone marrow flow cytometry and light-chain analysis
Authors: Hill Quentin A. , Rawstron Andy C. , de Tute Ruth M. , Owen Roger G. 
Published: June 2014

Key Points
Occult marrow disease is demonstrable in 68% of patients with solitary plasmacytoma of bone and is predictive of progression. Trials of adjuvant systemic therapy are warranted in high-risk patients.
Quality of cardiovascular disease care in Ontario’s primary care practices: a cross sectional study examining differences in guideline adherence by patient sex
Authors: Naicker Kiyuri , Liddy Clare , Singh Jatinderpreet , Taljaard Monica , Hogg William 
Published: June 2014

Abstract

Background
Women are disproportionately affected by cardiovascular disease, often experiencing poorer outcomes following a cardiovascular event. Evidence points to inequities in processes of care as a potential contributing factor. This study sought to determine whether any sex differences exist in adherence to process of care guidelines for cardiovascular disease within primary care practices in Ontario, Canada.

Methods
This is a secondary analysis of pooled cross-sectional baseline data collected through a larger quality improvement initiative known as the Improved Delivery of Cardiovascular Care (IDOCC). Chart abstraction was performed for 4,931 patients from 84 primary care practices in Eastern Ontario who had, or were at high risk of, cardiovascular disease. Measures examining adherence to guidelines associated with nine areas of cardiovascular care (coronary artery disease, peripheral vascular disease (PVD), stroke/transient ischemic attack, chronic kidney disease, diabetes, dyslipidemia, hypertension, smoking cessation, and weight management) were collected. Multivariable logistic regression analysis was performed to evaluate sex differences, adjusting for age, physician remuneration, and rurality.

Results
Women were significantly less likely to have their lipid profiles taken (OR = 1.17, 95% CI 1.03-1.33), be prescribed lipid lowering medication for dyslipidemia (OR = 1.54, 95% CI 1.20-1.97), and to be prescribed ASA following stroke (OR = 1.56, 95% CI 1.39-1.75). Women with PVD were significantly less likely to be prescribed ACE inhibitors and/or angiotensin receptor blockers (OR = 1.74, 95% CI 1.25-2.41) and lipid lowering medications (OR = 1.95, 95% CI 1.46-2.62) or ASA (OR = 1.59, 95% CI 1.43-1.78). However, women were more likely to have two blood pressure measurements taken and to be referred to a dietician or weight loss program. Male patients with diabetes were less likely to be prescribed glycemic control medication (OR = 0.84, 95% CI 0.74-0.86).

Conclusions
Sex disparities exist in the quality of cardiovascular care in Canadian primary care practices, which tend to favour men. Women with PVD have a particularly high risk of not receiving appropriate medications. Our findings indicate that improvements in care delivery should be made to address these issues, particularly with regard to the prescribing of recommended medications for women, and preventive measures for men.