bluuebunny/crossref_metadata_2025_split huggingface dataset:
ROAD TO BUILDING AND SUSTAINING NOVEL CLINICAL RESEARCH CAPACITY IN RESOURCE-LIMITED SETTINGS: LESSONS LEARNT SO FAR FROM RWANDA
Authors: Musanabaganwa Clarisse , Musabyimana Jean Pierre , Karita Etienne , Diop Blondin , Nambajimana Abidan , Dushimiyimana Valentine , Karame Prosper , Russell Jim , Ndoli Jules , Bahati Prince , Hategekimana Theobald , Sendegeya Augustin , Condo Jeannine , Binagwaho Agnes 
Published: February 2017

BackgroundHarnessing research for enhancing capacity for evidence-informed policies is key for sustainability in countries that are still facing poverty-related diseases. During current customised medicine and drug-resistance era, priority has shifted to clinical research making clinical trials a powerful tool in availing tailored and affordable drugs and medical interventions. There is need to address disparities in clinical research capabilities worldwide, particularly sub-Saharan Africa, where disease burden is rampant. We share our achievements and lessons learnt so far from establishing three new clinical research sites among the eleven targeted for in Rwanda.MethodsReferral, provincial and specialty hospitals have been selected by the Ministry of Health as potential clinical research sites. Based on the International Conference on Harmonization in Good Clinical Practice (ICH-GCP), a baseline assessment was conducted. Three best-scoring hospitals were developed to become clinical research sites by: alignment with the national priorities; acceleration of current laboratory accreditation processes, improvement of data management, clinical infrastructure, financial management systems; careful recruitment, continuous training and a retention plan of critical research staff; collaborations with private clinical research organisations; marketing of research sites to funders; strengthening institutional review boards; creation of local ownership; and diversification of the research portfolio.ResultsClinical research sites established are Centre Hospitalier Universitaire de Kigali (CHUK) in Kigali city, Centre Hospitalier Universitaire de Butare (CHUB) in Southern province, and Butaro Hospital in Northern province with 26, 26 and 11 dedicated staff, respectively. Sites have minimally a clinical research laboratory under accreditation process, 5 private medical/examination room, a counselling rooms, a data management unit, a waiting area, a pharmacy with restriction-area, administrative area, tele-conference/training room.ConclusionsDevelopment of novel clinical research capacity in resource-limited settings is feasible, with considerable time and resources. Political initiative is a key element for sustainability. Staff retention is the main challenge. For minimising the risk, partnerships between experienced clinical organisations and sponsors are vital for financial stability and knowledge transfer.
IDENTIFICATION OF NOVEL PLASMA AND SALIVARY BIOSIGNATURES FOR THE DIAGNOSIS OF TB DISEASE AND MONITORING OF TREATMENT RESPONSE
Authors: Jacobs Ruschca , Chegou Novel , Walzl Gerhard 
Published: February 2017

BackgroundNew tools are urgently needed for the rapid diagnosis of TB disease, especially in resource-constrained settings. We investigated the usefulness of host markers detected in plasma and saliva as biomarkers for the diagnosis of TB disease and monitoring of treatment response.MethodsWe prospectively collected plasma and saliva samples from 55 individuals that presented with signs and symptoms suggestive of TB disease at a health centre in Cape Town, South Africa, prior to the establishment of a clinical diagnosis. Patients were later classified as having TB disease (n=22) or other respiratory diseases (ORD) (n=33), using a combination of clinical, radiological and laboratory findings. The concentrations of 74 host markers were evaluated in plasma and saliva samples from all study participants using a multiplex cytokine platform.ResultsOut of the 74 host markers evaluated, 18 markers detected in plasma, and two detected in saliva, showed potential as TB diagnostic candidates, with area under the ROC curve ≥0.70. A six-marker plasma biosignature comprising of NCAM, SAP, IL-1ρ, sCD40L, IL-13 and Apo A-1 diagnosed TB disease with a sensitivity of 100% (95% CI: 86.3−100%) and specificity of 89.3%(95% CI, 67.6–97.3%), whereas a five-marker salivary biosignature comprising of IL-1ρ, IL-23, ECM-1, HCC1 and fibrinogen diagnosed TB disease with a sensitivity of 88.9% (95% CI: 76.7−99.9%) and specificity of 89.7% (95% CI: 60.4−96.6%), both regardless of HIV status. The plasma concentrations of 11 of the host markers and 8 of the markers detected in saliva changed during treatment, indicating that they may be useful in monitoring of TB treatment response.ConclusionsWe have identified novel plasma and salivary biosignatures which may be useful in the diagnosis of TB disease and monitoring of the response to TB treatment. Our findings have potential to be translated into point-of-care screening tests after further validation.
Individual patient data meta-analysis of combined treatments versus psychotherapy (with or without pill placebo), pharmacotherapy or pill placebo for adult depression: a protocol
Authors: Weitz Erica , Kleiboer Annet , van Straten Annemieke , Hollon Steven D , Cuijpers Pim 
Published: February 2017

IntroductionThere are many proven treatments (psychotherapy, pharmacotherapy or their combination) for the treatment of depression. Although there is growing evidence for the effectiveness of combination treatment (psychotherapy + pharmacotherapy) over pharmacotherapy alone, psychotherapy alone or psychotherapy plus pill placebo, for depression, little is known about which specific groups of patients may respond best to combined treatment versus monotherapy. Conventional meta-analyses techniques have limitations when tasked with examining whether specific individual characteristics moderate the effect of treatment on depression. Therefore, this protocol outlines an individual patient data (IPD) meta-analysis to explore which patients, with which clinical characteristics, have better outcomes in combined treatment compared with psychotherapy (alone or with pill placebo), pharmacotherapy and pill placebo.Methods and AnalysisStudy searches are completed using an established database of randomised controlled trials (RCTs) on the psychological treatment of adult depression that has previously been reported. Searches were conducted in PubMed, PsycInfo, Embase and the Cochrane Central Register of Controlled Trials. RCTs comparing combination treatment (psychotherapy + pharmacotherapy) with psychotherapy (with or without pill placebo), pharmacotherapy or pill placebo for the treatment of adult depression will be included. Study authors of eligible trials will be contacted and asked to contribute IPD. Conventional meta-analysis techniques will be used to examine differences between studies that have contributed data and those that did not. Then, IPD will be harmonised and analysis using multilevel regression will be conducted to examine effect moderators of treatment outcomes.DisseminationStudy results outlined above will be published in peer-reviewed journals. Study results will contribute to better understanding whether certain patients respond best to combined treatment or other depression treatments and provide new information on moderators of treatment outcome that can be used by patients, clinicians and researchers.Trial registration numberCRD42016039028.
Autologous Heat Shock Protein Peptide Vaccination for Newly Diagnosed Glioblastoma: Impact of Peripheral PD-L1 Expression on Response to Therapy
Authors: Bloch Orin , Lim Michael , Sughrue Michael E. , Komotar Ricardo J. , Abrahams John M. , O'Rourke Donald M. , D'Ambrosio Anthony , Bruce Jeffrey N. , Parsa Andrew T. 
Published: February 2017

AbstractPurpose: Standard therapy for newly diagnosed glioblastoma (GBM) is surgical resection, followed by concurrent radiotherapy and temozolomide chemotherapy. In this phase II clinical trial, the addition of an autologous heat-shock protein vaccine to standard therapy was evaluated. Tumor-induced immunosuppression, mediated by expression of PD-L1 on tumor and circulating immune cells, may impact the efficacy of vaccination. Expression of PD-L1 on peripheral myeloid cells was evaluated for the first time as a predictor of survival.Experimental Design: In this single arm, phase II study, adult patients with GBM underwent surgical resection followed by standard radiation and chemotherapy. Autologous vaccine (Prophage) was generated from resected tumors and delivered in weekly vaccinations after completion of radiotherapy. The primary endpoint was overall survival.Results: Forty-six patients received the vaccine with a median overall survival of 23.8 months [95% confidence interval (CI), 19.8–30.2]. Median overall survival for patients with high PD-L1 expression on myeloid cells was 18.0 months (95% CI, 10.0–23.3) as compared with 44.7 months (95% CI, incalculable) for patients with low PD-L1 expression (hazard ratio 3.3; 95% CI, 1.4–8.6; P = 0.007). A multivariate proportional hazards model revealed MGMT methylation, Karnofsky performance status, and PD-L1 expression as the primary independent predictors of survival.Conclusions: Vaccination with autologous tumor-derived heat shock proteins may improve survival for GBM patients when combined with standard therapy and warrants further study. Systemic immunosuppression mediated by peripheral myeloid expression of PD-L1 is a recently identified factor that may significantly impact vaccine efficacy. Clin Cancer Res; 23(14); 3575–84. ©2017 AACR.
Deep Sequencing of Urinary RNAs for Bladder Cancer Molecular Diagnostics
Authors: Sin Mandy L.Y. , Mach Kathleen E. , Sinha Rahul , Wu Fan , Trivedi Dharati R. , Altobelli Emanuela , Jensen Kristin C. , Sahoo Debashis , Lu Ying , Liao Joseph C. 
Published: February 2017

Abstract
Purpose: The majority of bladder cancer patients present with localized disease and are managed by transurethral resection. However, the high rate of recurrence necessitates lifetime cystoscopic surveillance. Developing a sensitive and specific urine-based test would significantly improve bladder cancer screening, detection, and surveillance.
Experimental Design: RNA-seq was used for biomarker discovery to directly assess the gene expression profile of exfoliated urothelial cells in urine derived from bladder cancer patients (n = 13) and controls (n = 10). Eight bladder cancer specific and 3 reference genes identified by RNA-seq were quantitated by qPCR in a training cohort of 102 urine samples. A diagnostic model based on the training cohort was constructed using multiple logistic regression. The model was further validated in an independent cohort of 101 urines.
Results: A total of 418 genes were found to be differentially expressed between bladder cancer and controls. Validation of a subset of these genes was used to construct an equation for computing a probability of bladder cancer score (PBC) based on expression of three markers (ROBO1, WNT5A, and CDC42BPB). Setting PBC = 0.45 as the cutoff for a positive test, urine testing using the three-marker panel had overall 88% sensitivity and 92% specificity in the training cohort. The accuracy of the three-marker panel in the independent validation cohort yielded an AUC of 0.87 and overall 83% sensitivity and 89% specificity.
Conclusions: Urine-based molecular diagnostics using this three-marker signature could provide a valuable adjunct to cystoscopy and may lead to a reduction of unnecessary procedures for bladder cancer diagnosis. Clin Cancer Res; 23(14); 3700–10. ©2017 AACR.
Transcriptional Mechanisms of Resistance to Anti–PD-1 Therapy
Authors: Ascierto Maria L. , Makohon-Moore Alvin , Lipson Evan J. , Taube Janis M. , McMiller Tracee L. , Berger Alan E. , Fan Jinshui , Kaunitz Genevieve J. , Cottrell Tricia R. , Kohutek Zachary A. , Favorov Alexander , Makarov Vladimir , Riaz Nadeem , Chan Timothy A. , Cope Leslie , Hruban Ralph H. , Pardoll Drew M. , Taylor Barry S. , Solit David B. , Iacobuzio-Donahue Christine A. , Topalian Suzanne L. 
Published: February 2017

AbstractPurpose: To explore factors associated with response and resistance to anti–PD-1 therapy, we analyzed multiple disease sites at autopsy in a patient with widely metastatic melanoma who had a heterogeneous response.Materials and Methods: Twenty-six melanoma specimens (four premortem, 22 postmortem) were subjected to whole exome sequencing. Candidate immunologic markers and gene expression were assessed in 10 cutaneous metastases showing response or progression during therapy.Results: The melanoma was driven by biallelic inactivation of NF1. All lesions had highly concordant mutational profiles and copy number alterations, indicating linear clonal evolution. Expression of candidate immunologic markers was similar in responding and progressing lesions. However, progressing cutaneous metastases were associated with overexpression of genes associated with extracellular matrix and neutrophil function.Conclusions: Although mutational and immunologic differences have been proposed as the primary determinants of heterogeneous response/resistance to targeted therapies and immunotherapies, respectively, differential lesional gene expression profiles may also dictate anti–PD-1 outcomes. Clin Cancer Res; 23(12); 3168–80. ©2017 AACR.See related commentary by Wilmott et al., p. 2921
Potential Deaths Averted and Serious Adverse Events Incurred From Adoption of the SPRINT (Systolic Blood Pressure Intervention Trial) Intensive Blood Pressure Regimen in the United States
Authors: Bress Adam P. , Kramer Holly , Khatib Rasha , Beddhu Srinivasan , Cheung Alfred K. , Hess Rachel , Bansal Vinod K. , Cao Guichan , Yee Jerry , Moran Andrew E. , Durazo-Arvizu Ramon , Muntner Paul , Cooper Richard S. 
Published: February 2017

Background:
SPRINT (Systolic Blood Pressure Intervention Trial) demonstrated a 27% reduction in all-cause mortality with a systolic blood pressure (SBP) goal of <120 versus <140 mm Hg among US adults at high cardiovascular disease risk but without diabetes mellitus, stroke, or heart failure. To quantify the potential benefits and risks of SPRINT intensive goal implementation, we estimated the deaths prevented and excess serious adverse events incurred if the SPRINT intensive SBP treatment goal were implemented in all eligible US adults.

Methods:

SPRINT eligibility criteria were applied to the 1999 to 2006 National Health and Nutrition Examination Survey and linked with the National Death Index through December 2011. SPRINT eligibility included age ≥50 years, SBP of 130 to 180 mm Hg (depending on the number of antihypertensive medications being taken), and high cardiovascular disease risk. Exclusion criteria were diabetes mellitus, history of stroke, >1 g proteinuria, heart failure, estimated glomerular filtration rate <20 mL·min
−1
·1.73 m
−2
, or dialysis. Annual mortality rates were calculated by dividing the Kaplan-Meier 5-year mortality by 5. Hazard ratios for all-cause mortality and heart failure and absolute risks for serious adverse events in SPRINT were used to estimate the number of potential deaths and heart failure cases prevented and serious adverse events incurred with intensive SBP treatment.

Results:
The mean age was 68.6 years, and 83.2% and 7.4% were non-Hispanic white and non-Hispanic black, respectively. The annual mortality rate was 2.20% (95% confidence interval [CI], 1.91–2.48), and intensive SBP treatment was projected to prevent ≈107 500 deaths per year (95% CI, 93 300–121 200) and give rise to 56 100 (95% CI, 50 800–61 400) episodes of hypotension, 34 400 (95% CI, 31 200–37 600) episodes of syncope, 43 400 (95% CI, 39 400–47 500) serious electrolyte disorders, and 88 700 (95% CI, 80 400–97 000) cases of acute kidney injury per year. The analysis-of-extremes approach indicated that the range of estimated lower- and upper-bound number of deaths prevented per year with intensive SBP control was 34 600 to 179 600. Intensive SBP control was projected to prevent 46 100 (95% CI, 41 800–50 400) cases of heart failure annually.

Conclusions:
If fully implemented in eligible US adults, intensive SBP treatment could prevent ≈107 500 deaths per year. A consequence of this treatment strategy, however, could be an increase in serious adverse events.
基諾語擦音的來源
Authors: Hayashi Norihiko 
Published: February 2017

提要
基諾語是在中國雲南省西雙版納傣族自治州景洪市居住的基諾族的語言，屬於漢藏語系藏緬語族彝緬語群。基諾語有兩大方言，即悠樂話與補遠話。本文分析了基諾語悠樂話和補遠話的擦音的來源，得出了以下結論：
一、由共時層面來說，悠樂話有十個擦音，即/f, v, s, z, ʃ, r, ç, j, x, ɣ/，而補遠話只有四個擦音，即/f, s, ɕ, x/。本文同時還討論了補遠話/w, j/與悠樂話擦音的對應關係，儘管它們或可當作半元音。
二、悠樂話保留著原始基諾語的擦音體系，而補遠話的擦音已在一定條件下合併了。並且，補遠話/f, ɕ, x/中的一部分實際上源自原始基諾語的/*l̥/。
三、西雙版納地區有很多語言，其中傣仂語(侗傣語族)與漢語景洪方言是主要語言。基諾語悠樂話與補遠話從中吸收了很多帶擦音的外來詞。這些外來擦音大部份與傣仂語或漢語方言的擦音相同，但是 ɕ-與 ʂ-卻是合併為一個擦音後才進入基諾語悠樂話與補遠話的。
海南島的哥隆話
Authors: Chin Andy C. 
Published: February 2017

提要
本文是作者於2011和2012年調查海南島西部哥隆話的初步報告。調查目的是比較現代哥隆話跟二十多年前的差別 (如符鎮南(1996)和歐陽覺亞(1998))。此外,我們也比較哥隆話和黎語的一百個基本詞匯,討論哥隆話的系屬。
From the Perspective of the Pervasiveness of Sound Correspondences: 語音對應與苗瑤語比較研究——從普遍對應的角度看
Authors: Wang Feng 
Published: February 2017

提要
普遍對應指對應的表現形式在所有參與比較的語言中都有分佈。放寬這一要求會導致晚期借用混入比較，乃至造成對語源關係的誤判。從這一角度出發，本文考察了原始苗瑤語重構所依賴的語音對應基礎。無論是在普遍對應的嚴格要求下，還是放寬要求，苗瑤語之間的關係語素都是高階比低階多，這可以進一步確認它們之間的親緣關係。應用同樣的比較程式，漢語和原始苗瑤語之間的關係語素也顯示出同樣的分佈，因此，詞階分析支持苗瑤語與漢語之間的親緣關係，而非接觸關係。不可釋原則的應用同樣確認了這一判斷。不可釋原則指無法用施借語言的音韻系統來解釋受借語言中關係語素的表現，就說明二者之間的關係假定為親緣關係比接觸關係更為合理。幾個不可釋的例子可以在漢-苗瑤語關係語素中找到，因此，苗瑤語應該仍然歸屬於漢藏語系。
漢語運動事件指向表達的歷時演變及相關問題
Authors: Shi Wenlei 
Published: February 2017

提要
本文對漢語運動事件指向信息編碼的句法搭配及其與一般路徑、參照背景的排序等的歷時演變做出了綜合描寫和分析。調查發現，漢語指向信息的編碼結構發生了較爲顯著的變化，表現在指向動詞與其他動詞連用的排序、路徑指向與背景的排序、攜帶背景賓語能力等方面。上述歷時演變的動因是漢語句法結構模式的歷時演變，主要表現爲聯合結構逐漸喪失其顯赫地位，進而讓位於動補結構。本文還指出，句法結構演變在概念結構模式上産生了一系列效應。這說明“概念→語義→句法”這樣的投射和决定關係并不總是適用，從歷時的角度來看，語言結構的演變會影響到與之相應的概念結構的演變。
量詞語言中定指不定指的標記方式
Authors: Julie Jiang L. 
Published: February 2017

提要以漢語為代表的語言與日耳曼、羅曼語族的語言相比有許多顯著的不同。例如，漢語類語言的名詞不用帶複數標記，沒有冠詞，但是這類語言有著一系列的量詞。這些量詞在名詞和數詞結合的時候，必須出現。雖然漢語類量詞語言的名詞結構在很大程度上很相似，它們在表達定指與不定指時呈現出相當大的差異。本文研究這些差異，並在Krifka (1995) 和Chierchia (1998)基礎上提出一個對名詞的分析，這個分析能對漢語類語言也能對其他例如必須帶複數標記的語言進行分析。
The Combination of Anatomy and Genioglossus Activity in Predicting the Outcomes of Velopharyngeal Surgery
Authors: Zhao Di , Li YanRu , Xian JunFang , Qu Yue , Cao Xin , Ye JingYing 
Published: February 2017

ObjectiveThis study aims to evaluate the combination of genioglossus (GG) activity and anatomical characteristics in predicting outcomes of velopharyngeal surgery in patients with obstructive sleep apnea (OSA).Study DesignCase series with planned data collection.SettingSleep medical center.Subjects and MethodsForty patients with OSA underwent overnight polysomnography with synchronous genioglossus electromyography (GGEMG) using intraoral electrodes. The upper airway anatomy was evaluated by 3‐dimensional computed tomography in patients with OSA. All patients received the same type of velopharyngeal surgery, consisting of revised uvulopalatopharyngoplasty with uvula preservation and concurrent transpalatal advancement pharyngoplasty. We followed up all patients using polysomnography for at least 3 months postoperatively.ResultsTwenty‐five patients (62.50%) were responders, and 15 patients (37.50%) were nonresponders. The decreased apnea‐hypopnea index was significantly positively correlated to the sleep onset GGEMG (P =. 006) but was negatively correlated to the change in GGEMG (P =. 013) and tonic GGEMG (P =. 018). Multiple regression analysis revealed that the minimal cross‐sectional airway area at the velopharynx (VmCSA) (odds ratio [OR], 1.760; P =. 019) and the sleep onset GGEMG (OR, 0.322; P =. 043) were significant predictors for surgical outcomes. Combined the two predictors, the area under the ROC curve was 0.901 (OR, 0.789; P =. 001) for surgical success, was more valuable than any one predictor. The area under the ROC curve with GGEMG was 0.843, VmCSA was 0.848.ConclusionsThe combination of sleep onset GGEMG and VmCSA can predict the outcome of velopharyngeal surgery in patients with OSA.
Dosimetric Analysis of Neural and Vascular Structures in Skull Base Tumors Treated with Stereotactic Radiosurgery
Authors: Haidar Yarah M. , Bhatt Jay M. , Ghavami Yaser , Moshtaghi Omid , Schwer Amanda , Chenery Stafford , Djalilian Hamid R. 
Published: February 2017

ObjectiveTo examine the relationship between the prescribed target dose and the dose to healthy neurovascular structures in patients with vestibular schwannomas treated with stereotactic radiosurgery (SRS).Study DesignCase series with chart review.SettingSRS center from 2011 to 2013.SubjectsTwenty patients with vestibular schwannomas treated at the center from 2011 to 2013.MethodsTwenty patients with vestibular schwannomas were included. The average radiation dose delivered to healthy neurovascular structures (eg, carotid artery, basilar artery, facial nerve, trigeminal nerve, and cochlea) was analyzed.ResultsTwenty patients with vestibular schwannomas who were treated with fused computed tomography/magnetic resonance imaging–guided SRS were included in the study. The prescribed dose ranged from 10.58 to 17.40 Gy over 1 to 3 hypofractions to cover 95% of the target tumor volume. The mean dose to the carotid artery was 5.66 Gy (95% confidence interval [CI], 4.53‐6.80 Gy), anterior inferior cerebellar artery was 8.70 Gy (95% CI, 4.54‐12.86 Gy), intratemporal facial nerve was 3.76 Gy (95% CI, 3.04‐4.08 Gy), trigeminal nerve was 5.21 Gy (95% CI, 3.31‐7.11 Gy), and the cochlea was 8.70 Gy (95% CI, 7.81‐9.59 Gy).ConclusionsSRS for certain vestibular schwannomas can expose the anterior inferior cerebellar artery (AICA) and carotid artery to radiation doses that can potentially initiate atherosclerotic processes. The higher doses to the AICA and carotid artery correlated with increasing tumor volume. The dose delivered to other structures such as the cochlea and intratemporal facial nerve appears to be lower and much less likely to cause immediate complications when shielded.
Microflora of Retained Intracochlear Electrodes from Infected Cochlear Implants
Authors: Varadarajan Varun V. , Dirain Carolyn O. , Antonelli Patrick J. 
Published: February 2017

ObjectivesCochlear implant infections may be refractory to medical management and require device removal with subsequent reimplantation. During device removal, the intracochlear electrode array is commonly left in place to prevent obliteration of the cochlear lumen. If the electrode is colonized with pathogens, this risks contaminating the replacement implant. In this study, we compare the microorganisms detected on infected cochlear implants against those on the retained electrode using culture and microbial gene‐sequencing techniques.Study DesignProspective single‐cohort study.SettingTertiary medical center.Subjects and MethodsSix patients with refractory cochlear implant infections had the receiver‐stimulator and extracochlear electrode removed to facilitate treatment of the infection. The intracochlear electrode was removed at (delayed) reimplantation. Implant specimens were analyzed by microbial culture and 16S DNA gene sequencing.ResultsStaphylococcus aureus was the organism most commonly identified. None of the 6 patients’ intracochlear electrodes yielded microbes by culture. Two intracochlear electrodes revealed bacterial species, and 1 revealed fungal species by gene sequencing. There was no correlation between the microbes on the infected extracochlear implants and the retained intracochlear electrodes. All subjects underwent reimplantation after resolution of their infections. One of 6 subjects developed a second infection after reimplantation, with S aureus in the primary and secondary infections.ConclusionsThe intracochlear electrodes of infected cochlear implants carry a low microbial burden. Preserving intracochlear electrodes upon removal of infected cochlear implants appears to carry a low risk of contaminating a replacement cochlear implant.