bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exosome-Based Detection of EGFR T790M in Plasma from Non–Small Cell Lung Cancer Patients
Authors: Castellanos-Rizaldos Elena , Grimm Dominik G. , Tadigotla Vasisht , Hurley James , Healy John , Neal Patricia L. , Sher Mia , Venkatesan Raajdeep , Karlovich Chris , Raponi Mitch , Krug Anne , Noerholm Mikkel , Tannous Jihane , Tannous Bakhos A. , Raez Luis E. , Skog Johan K. 
Published: March 2018

Abstract
Purpose: About 60% of non–small cell lung cancer (NSCLC) patients develop resistance to targeted epidermal growth factor receptor (EGFR) inhibitor therapy through the EGFR T790M mutation. Patients with this mutation respond well to third-generation tyrosine kinase inhibitors, but obtaining a tissue biopsy to confirm the mutation poses risks and is often not feasible. Liquid biopsies using circulating free tumor DNA (cfDNA) have emerged as a noninvasive option to detect the mutation; however, sensitivity is low as many patients have too few detectable copies in circulation. Here, we have developed and validated a novel test that overcomes the limited abundance of the mutation by simultaneously capturing and interrogating exosomal RNA/DNA and cfDNA (exoNA) in a single step followed by a sensitive allele-specific qPCR.
Experimental Design: ExoNA was extracted from the plasma of NSCLC patients with biopsy-confirmed T790M-positive (N = 102) and T790M-negative (N = 108) samples. The T790M mutation status was determined using an analytically validated allele-specific qPCR assay in a Clinical Laboratory Improvement Amendment laboratory.
Results: Detection of the T790M mutation on exoNA achieved 92% sensitivity and 89% specificity using tumor biopsy results as gold standard. We also obtained high sensitivity (88%) in patients with intrathoracic disease (M0/M1a), for whom detection by liquid biopsy has been particularly challenging.
Conclusions: The combination of exoRNA/DNA and cfDNA for T790M detection has higher sensitivity and specificity compared with historical cohorts using cfDNA alone. This could further help avoid unnecessary tumor biopsies for T790M mutation testing. Clin Cancer Res; 24(12); 2944–50. ©2018 AACR.
A Phase I Clinical Trial of AZD1775 in Combination with Neoadjuvant Weekly Docetaxel and Cisplatin before Definitive Therapy in Head and Neck Squamous Cell Carcinoma
Authors: Méndez Eduardo , Rodriguez Cristina P. , Kao Michael C. , Raju Sharat , Diab Ahmed , Harbison R. Alex , Konnick Eric Q. , Mugundu Ganesh M. , Santana-Davila Rafael , Martins Renato , Futran Neal D. , Chow Laura Q.M. 
Published: March 2018

Abstract
Purpose: The WEE1 tyrosine kinase regulates G2–M transition and maintains genomic stability, particularly in p53-deficient tumors which require DNA repair after genotoxic therapy. Thus, a need arises to exploit the role of WEE1 inhibition in head and neck squamous cell carcinoma (HNSCC) mostly driven by tumor-suppressor loss. This completed phase I clinical trial represents the first published clinical experience using the WEE1 inhibitor, AZD1775, with cisplatin and docetaxel.
Patients and Methods: We implemented an open-label phase I clinical trial using a 3+3 dose-escalation design for patients with stage III/IVB HNSCC with borderline-resectable or -unresectable disease, but who were candidates for definitive chemoradiation. Escalating AZD1775 was administered orally twice a day over 2.5 days on the first week, then in combination with fixed cisplatin (25 mg/m2) and docetaxel (35 mg/m2) for 3 additional weeks. The primary outcome measure was adverse events to establish MTD. Secondary measures included response rates, pharmacokinetics (PK), pharmacodynamics, and genomic data.
Results: The MTD for AZD1775 was established at 150 mg orally twice per day for 2.5 days. RECISTv1.1 responses were seen in 5 of 10 patients; histologic adjustment revealed three additional responders. The only drug-limiting toxicity was grade 3 diarrhea. The PK C8hr target of 240 nmol/L was achieved on day 4 at all three doses tested. Pharmacodynamic analysis revealed a reduction in pY15-Cdk, and increases in γH2AX, CC3, and RPA32/RPA2 were noted in responders versus nonresponders.
Conclusions: The triplet combination of AZD1775, cisplatin, and docetaxel is safe and tolerable. Preliminary results show promising antitumor efficacy in advanced HNSCC, meriting further investigation at the recommended phase II dose. Clin Cancer Res; 24(12); 2740–8. ©2018 AACR.
Association of Human Immunodeficiency Virus Infection and Risk of Peripheral Artery Disease
Authors: Beckman Joshua A. , Duncan Meredith S. , Alcorn Charles W. , So-Armah Kaku , Butt Adeel A. , Goetz Matthew Bidwell , Tindle Hilary A. , Sico Jason J. , Tracy Russel P. , Justice Amy C. , Freiberg Matthew S. 
Published: March 2018

Background:
The effect of human immunodeficiency virus (HIV) on the development of peripheral artery disease (PAD) remains unclear. We investigated whether HIV infection is associated with an increased risk of PAD after adjustment for traditional atherosclerotic risk factors in a large cohort of HIV-infected (HIV+) and demographically similar HIV-uninfected veterans.

Methods:
We studied participants in the Veterans Aging Cohort Study from April 1, 2003 through December 31, 2014. We excluded participants with known prior PAD or prevalent cardiovascular disease (myocardial infarction, stroke, coronary heart disease, and congestive heart failure) and analyzed the effect of HIV status on the risk of incident PAD events after adjusting for demographics, PAD risk factors, substance use, CD4 cell count, HIV-1 ribonucleic acid, and antiretroviral therapy. The primary outcome is incident peripheral artery disease events. Secondary outcomes include mortality and amputation in subjects with incident PAD events by HIV infection status, viral load, and CD4 count.

Results:

Among 91 953 participants, over a median follow up of 9.0 years, there were 7708 incident PAD events. Rates of incident PAD events per 1000 person-years were higher among HIV+ (11.9; 95% confidence interval [CI], 11.5–12.4) than uninfected veterans (9.9; 95% CI, 9.6–10.1). After adjustment for demographics, PAD risk factors, and other covariates, HIV+ veterans had an increased risk of incident PAD events compared with uninfected veterans (hazard ratio [HR], 1.19; 95% CI, 1.13–1.25). This risk was highest among those with time-updated HIV viral load >500 copies/mL (HR, 1.51; 95% CI, 1.38–1.65) and CD4 cell counts <200 cells/mm
3
(HR, 1.91; 95% CI, 1.71–2.13). In contrast, HIV+ veterans with time updated CD4 cell count ≥500 cells/mm
3
had no increased risk of PAD (HR, 1.03; 95% CI, 0.96–1.11). Mortality rates after incident PAD events are high regardless of HIV status. HIV infection did not affect rates of amputation after incident PAD events.

Conclusions:

Infection with HIV is associated with a 19% increased risk of PAD beyond that explained by traditional atherosclerotic risk factors. However, for those with sustained CD4 cell counts <200 cells/mm
3
, the risk of incident PAD events is nearly 2-fold higher whereas for those with sustained CD4 cell counts ≥500 cells/mm
3
there is no excess risk of incident PAD events compared with uninfected people.
Shared and Distinct Rupture Discriminants of Small and Large Intracranial Aneurysms
Authors: Varble Nicole , Tutino Vincent M. , Yu Jihnhee , Sonig Ashish , Siddiqui Adnan H. , Davies Jason M. , Meng Hui 
Published: March 2018

Background and Purpose—
Many ruptured intracranial aneurysms (IAs) are small. Clinical presentations suggest that small and large IAs could have different phenotypes. It is unknown if small and large IAs have different characteristics that discriminate rupture.

Methods—
We analyzed morphological, hemodynamic, and clinical parameters of 413 retrospectively collected IAs (training cohort; 102 ruptured IAs). Hierarchal cluster analysis was performed to determine a size cutoff to dichotomize the IA population into small and large IAs. We applied multivariate logistic regression to build rupture discrimination models for small IAs, large IAs, and an aggregation of all IAs. We validated the ability of these 3 models to predict rupture status in a second, independently collected cohort of 129 IAs (testing cohort; 14 ruptured IAs).

Results—
Hierarchal cluster analysis in the training cohort confirmed that small and large IAs are best separated at 5 mm based on morphological and hemodynamic features (area under the curve=0.81). For small IAs (<5 mm), the resulting rupture discrimination model included undulation index, oscillatory shear index, previous subarachnoid hemorrhage, and absence of multiple IAs (area under the curve=0.84; 95% confidence interval, 0.78–0.88), whereas for large IAs (≥5 mm), the model included undulation index, low wall shear stress, previous subarachnoid hemorrhage, and IA location (area under the curve=0.87; 95% confidence interval, 0.82–0.93). The model for the aggregated training cohort retained all the parameters in the size-dichotomized models. Results in the testing cohort showed that the size-dichotomized rupture discrimination model had higher sensitivity (64% versus 29%) and accuracy (77% versus 74%), marginally higher area under the curve (0.75; 95% confidence interval, 0.61–0.88 versus 0.67; 95% confidence interval, 0.52–0.82), and similar specificity (78% versus 80%) compared with the aggregate-based model.

Conclusions—
Small (<5 mm) and large (≥5 mm) IAs have different hemodynamic and clinical, but not morphological, rupture discriminants. Size-dichotomized rupture discrimination models performed better than the aggregate model.
Distribution and Temporal Trends From 1993 to 2015 of Ischemic Stroke Subtypes
Authors: Ornello Raffaele , Degan Diana , Tiseo Cindy , Di Carmine Caterina , Perciballi Laura , Pistoia Francesca , Carolei Antonio , Sacco Simona 
Published: March 2018

Background and Purpose—
Preventive strategies, together with demographic and socioeconomic changes, might have modified the worldwide distribution of ischemic stroke (IS) subtypes. We investigated those changes by means of a systematic review and meta-analysis.

Methods—
We evaluated all population- and hospital-based studies reporting the distribution of IS etiologic subtypes according to the TOAST criteria (Trial of ORG 10172 in Acute Stroke Treatment). Studies were identified by searching articles indexed on PubMed and Scopus from January 1, 1993, to June 30, 2017. Two independent investigators extracted data and checked them for accuracy. Proportions of each etiologic subtype were pooled according to a random effect meta-analytic model weighted by study size; temporal trends were assessed using a mixed-effect meta-regression model.

Results—

Sixty-five studies including patients from 1993 to 2015 were finally included. Overall, ISs were attributed to cardioembolism (22%; 95% confidence interval [CI], 20–23); large artery atherosclerosis (23%; 95% CI, 21–25); small artery occlusion (22%; 95% CI, 21–24); other determined cause (3%; 95% CI, 3–3); and undetermined cause (26%; 95% CI, 24–28). Cardioembolism was the leading IS etiologic subtype in whites (28%; 95% CI, 26–29) and large artery atherosclerosis in Asians (33%; 95% CI, 31–36). Meta-regression showed an increasing temporal trend for cardioembolism in whites (2.4% annually,
P
=0.008) and large artery atherosclerosis in Asians (5.7% annually,
P
<0.001), and a decrease for small artery occlusion in whites (−4.7% annually,
P
=0.001); there was considerable heterogeneity across all the analyses.

Conclusions—
According to our systematic review and meta-analysis, cardioembolism in whites and large artery atherosclerosis in Asians are the leading causes of IS. The heterogeneous distribution of etiologic subtypes of IS may depend on the demographic and socioeconomic characteristics of the different populations. More extensive protocols should be adopted to reduce the persistently relevant proportion of undetermined cause IS.
The Cultural Impact of Islamic Mass Immigration on the Italian Legal System
Authors: Falletti E. 
Published: March 2018

Although Italy is a country with a strong tradition of emigration, only in the last twenty- five years have Italians had to face new and pressing social, juridical and cultural problems related to a surge in immigration. The majority of immigrants during this period have been from areas steeped in with a Muslim majority such as Northern and Central Africa and the Middle East. The cultural encounter between the Italian Catholic tradition and the newcomers’ faith and customs has been very pronounced, and often problematic.
The aim of this paper is to investigate the most relevant issues that arise from the interface between the cultural and legal aspects of Islamic culture pertaining to immigrants living in Italy with the Italian legal system. The areas considered are related to self-determination, personal integrity and family law, and were selected for their relevance to analyzing the impact of cultural differences on public policies and social behavior. The methodology used draws from both a comparative and a multidisciplinary approach.
‘That is how the real mad people behave’: Beliefs about and treatment of mental disorders by traditional medicine-men in Accra, Ghana
Authors: Kpobi Lily , Swartz Leslie 
Published: March 2018

Background: Traditional healing methods are considered central to mental health care in low-income countries such as Ghana, because they are perceived to be more easily accessible, more affordable and generally ascribe similar causal beliefs to those of the patients. However, not much is known about the work of traditional healers largely because their methods are shrouded in mysticism and secrecy. There is a need to understand the ideology and beliefs of traditional healers surrounding mental disorders, including knowledge about their practices in mental health care. Aims: In this article, we discuss the causal beliefs and treatment methods of traditional medicine-men from Accra, Ghana. We also describe their diagnostic and treatment methods for mental disorders. Methods: Eight medicine-men, indigenous to the Greater Accra Region, were interviewed through individual semi-structured interviews. The data were analysed through thematic analysis. Results: The medicine-men’s beliefs about mental illness were dominated by supernatural ideas. Mental illness was also seen as a form of punishment or resulting from envy, and there was a strong reliance on spiritual direction from the gods for diagnosis and treatment. Conclusion: These themes are discussed with emphasis on their potential implications for patients, as well as for collaborative efforts.
In Vitro Susceptibility of Ciprofloxacin‐Resistant Methicillin‐Resistant Staphylococcus aureus to Ototopical Therapy
Authors: Walker David D. , David Michael Z. , Catalano Dominic , Daum Robert , Gluth Michael B. 
Published: March 2018

ObjectiveDespite the rising incidence of methicillin‐resistant Staphylococcus aureus (MRSA) otologic infections, choice of treatment remains controversial. Only fluoroquinolone‐containing ototopical preparations are approved by the US Food and Drug Administration for middle ear application. Furthermore, American Academy of Otolaryngology–Head and Neck Surgery Foundation guidelines advocate ototopical monotherapy for both tympanostomy tube otorrhea and acute otitis externa. Unfortunately, MRSA may be ciprofloxacin resistant. This causes confusion regarding antibiotic selection, because susceptibility profiles reflect a minimum inhibitory concentration (MIC), referenced against systemic, not ototopical, drug delivery dosing. The goal of this study is to determine the ciprofloxacin MIC for ciprofloxacin‐resistant MRSA isolates from otologic infections and compare that value to the expected drug concentration achieved by fluoroquinolone ear drops and determine MRSA genotype for each isolate.Study DesignIn vitro assay with retrospective medical record review.SettingTertiary care university hospital.Subjects and MethodsThirty otologically sourced ciprofloxacin‐resistant MRSA isolates collected from adult and pediatric patients. MICs were calculated by broth dilution method. Isolates underwent multilocus sequence typing and polymerase chain reaction for arcA and Panton‐Valentine leukocidin to establish the genotype.ResultsMICs ranged from 16 to 1025 µg/mL. There was a relationship between MIC and genotype; of the 7 isolates with an MIC value greater than 512 µg/mL, 6 were sequence type (ST)8.ConclusionThese findings support the practice of ototopical monotherapy for patients with uncomplicated ciprofloxacin‐resistant MRSA otitis externa. However, they raise concern that ototopical therapy may not be adequate to treat highly resistant strains of MRSA infecting the middle ear space.
Routine CT scanning of patients retrieved to a tertiary centre on veno-venous extracorporeal membrane oxygenation: a retrospective risk benefit analysis
Authors: Richmond Kate M. , Warburton Katharine G. , Finney Simon J. , Shah Sachin , Reddi Benjamin A.J. 
Published: March 2018

Introduction: Comprehensive clinical examination can be compromised in patients on veno-venous extracorporeal membrane oxygenation (VV-ECMO). Adjunctive diagnostic imaging strategies range from bedside imaging only to routine computed tomography (CT). The risk-benefit of either approach remains to be evaluated. Patients retrieved to the Royal Brompton Hospital (RBH) on VV-ECMO routinely undergo admission CT imaging of head, chest, abdomen and pelvis. This study aimed to identify how frequently changes in therapy or adverse events could be attributed to routine CT scanning. Methods: Demographic and clinical data were gathered retrospectively from patients retrieved to RBH on VV-ECMO (January 2014-2016). Scans were categorized as ‘routine’ or requested to clarify a specific clinical uncertainty. Clinical records were reviewed to identify attributable management changes and CT- related adverse events. Seventy-two patients were retrieved on VV-ECMO (median age 44 years) and 65 scanned on admission (mean radiation dose 2344mGy-cm). Routine head CT head yielded novel clinical information in 11 patients, 10 of whom had unexpected intracranial haemorrhage and, subsequently, had their anticoagulation withheld. Routine thoracic CT identified unexpected positive findings in three patients (early fibrosis, pulmonary vasculitis, pneumomediastinum), eliciting management variation in one (steroid administration). Routine abdomen/pelvis CT identified new information in three patients (adrenal haemorrhage, hepatosteatosis, splenic infarction), changing the management in one (withholding anticoagulation). Results: CT scanning was not associated with consequential adverse events (e.g. accidental decannulation, gas entrainment into the circuit, hypoxia, hypotension). Median transfer/scan time was 78 minutes, requiring five ITU staff-members. In our cohort, a policy of routine head CT changed the management in 17% of patients; the yield from routine chest, abdomen and pelvis CT was modest. CT transfer was safe, but resource intensive. Conclusion: Prospective studies should evaluate whether routine CT impacts outcome.
Assessment of the content reporting for therapeutic exercise interventions among existing randomized controlled trials on knee osteoarthritis
Authors: O’Neil Jennifer , McEwen Daniel , Del Bel Michael J , Jo Donguk , Thevenot Odette , MacKiddie Olivia S , Brosseau Lucie 
Published: March 2018

Purpose/Rationale: Physical exercise interventions for the management of knee osteoarthritis are well known to be effective and accessible forms of rehabilitation and symptom management. However, without adequate reporting of these interventions, accurate replication and clinical use is negatively impacted. Objectives: The main objective of this article was to assess content reporting using The Consensus on Exercise Reporting Template list and 2016 American College of Sports Medicine guidelines among moderate- to high-quality exercise interventions randomized controlled trials (total score of ≥6/10 on the PEDro scale) involving individuals with knee osteoarthritis. Results: The Consensus on Exercise Reporting Template mean total score for all 47 included randomized controlled trials was 4.42 out of 19, demonstrating generally low quality of reporting. The Consensus on Exercise Reporting Template list and the 2016 American College of Sports Medicine guidelines scores were moderately correlated (based on 95% confidence interval, intraclass correlation coefficient = 0.508) for aerobic interventions only. Conclusion: The content analysis of exercise interventions in knee osteoarthritis demonstrated low scores for moderate- to high-quality trials. Improved standardized reporting is recommended to ensure knowledge transfer and replication of effective exercise programs for individuals with knee osteoarthritis.
Evaluation of risk factors for false-negative results with an antigen-specific peripheral blood-based quantitative T cell assay (T-SPOT®.TB) in the diagnosis of active tuberculosis: A large-scale retrospective study in China
Authors: Yang Chi , Zhang Shaojun , Yao Lan , Fan Lin 
Published: March 2018

Objective To investigate the diagnostic efficacy of an interferon-γ release assay, T-SPOT®. TB, for diagnosing active tuberculosis (TB) and to identify risk factors for false-negative results. Methods This retrospective study enrolled consecutive patients with active TB and with non-TB respiratory diseases to evaluate the risk factors for false-negative results when using the T-SPOT®. TB assay for the diagnosis of active TB. Patients with active TB were categorized as having confirmed pulmonary TB, clinically diagnosed pulmonary TB or extrapulmonary TB (EPTB). Results This study analysed 4964 consecutive patients; 2425 with active TB and 2539 with non-TB respiratory diseases. Multivariate logistic regression analyses identified the following five factors that were all associated with an increased false-negative rate with the T-SPOT®. TB assay: increased age (odds ratio [OR] 1.018; 95% confidence interval [CI] 1.013, 1.024); decreased CD8+ count (OR 0.307; 95% CI 0.117, 0.803); negative sputum acid-fast bacilli (AFB) smear staining (OR 1.821; 95% CI 1.338, 2.477); negative mycobacterial cultures (OR 1.379; 95% CI 1.043, 1.824); and absence of EPTB (OR 1.291; 95% CI 1.026, 1.623). Conclusions Increased age, decreased CD8+ count, negative sputum AFB smear results, negative sputum mycobacterial cultures and absence of EPTB might lead to an increased false-negative rate when using the T-SPOT®. TB assay.
Emotional working memory in patients with major depressive disorder
Authors: Li Mi , Feng Lei , Liu Xingwang , Zhang Ming , Fu Bingbing , Wang Gang , Lu Shengfu , Zhong Ning , Hu Bin 
Published: March 2018

Objective This study was performed to examine the working memory (WM) encoding and retrieval abilities in patients with major depressive disorder (MDD) and determine whether a mood-congruent memory effect is present. Methods The modified Sternberg WM paradigm with positive, negative, and neutral emotional pictures was used to investigate the WM abilities of 26 patients with MDD and 26 healthy controls (HCs). Results No significant difference in picture WM was found between the MDD and HC groups; however, the accuracy of picture position WM was significantly lower and the response time was significantly longer in the MDD than HC group, regardless of the picture or position WM. Additionally, in the MDD group, the accuracy of negative picture/position WM was significantly higher than that of positive picture/position WM. Conclusions These results suggest that in patients with MDD, spatial WM impairment was more severe than object WM. In addition, these patients’ WM retrieval was impaired, resulting in a decrease in WM retrieval ability, which may be an important cause of the slow thought in patients with MDD. Moreover, patients with depression have a mood-congruent memory effect, which may be an important factor in the occurrence and maintenance of depression.