bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluating duration of response to treatment in systemic lupus erythematosus clinical trials
Authors: Kim Mimi , Merrill Joan T , Kalunian Kenneth , Hanrahan Leslie , Izmirly Peter 
Published: August 2018

ObjectiveTo evaluate response duration and identify predictors of transitioning into and out of the response state in patients with SLE receiving standard of care (SoC) in 52-week clinical trials.MethodsA multistate model (MSM) allowing for bidirectional transitions between response and non-response states was fit to data on 759 patients with SLE with active disease randomised to SoC. The probability of being in response at 52 weeks, average duration of response (sojourn time) and mean total time in response for SLE Responder Index (SRI-4, SRI-5, SRI-6) and BILAG-based Composite Lupus Assessment (BICLA) were estimated. Predictors of attainment and loss of SRI-5 response were also assessed.ResultsThe MSM estimated probability of being in response at 52 weeks ranged from 42% (SRI-6) to 61% (SRI-4). Mean duration of response ranged from 20.4 weeks (BICLA) to 31.5 weeks (SRI-4). Mean total time in response was 16.4–24.8 weeks. Baseline characteristics predictive of shorter SRI-5 response duration were African descent (p=0.005), longer history of disease (p=0.03), higher anti-dsDNA antibody titres (p=0.039), lower lymphocyte count (p=0.008) and lower haemoglobin (p=0.006). Younger age (p<0.001) and higher protein/creatinine ratio (p<0.001) were associated with higher likelihood of achieving SRI-5 but also shorter response duration.ConclusionFactors associated with disease severity were more predictive of shorter response duration than of 52-week response status. Analysing landmark response rates and response duration using MSM may be a more powerful way to distinguish effective investigational treatments from background SoC, although this remains to be evaluated in future trials.
Oral Alpha, Beta, and Gamma HPV Types and Risk of Incident Esophageal Cancer
Authors: Agalliu Ilir , Chen Zigui , Wang Tao , Hayes Richard B. , Freedman Neal D. , Gapstur Susan M. , Burk Robert D. 
Published: August 2018

Abstract
Background: Several studies have examined association between human papillomaviruses (HPV) and esophageal cancer, but results have been inconsistent. This is the first prospective study to investigate associations between α, β and γ HPV detection in the oral cavity and risk of esophageal cancer.
Methods: We conducted a nested case–control study among 96,650 cancer-free participants in the American Cancer Society Cancer Prevention Cohort and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Incident esophageal cancer cases (n = 125) were identified during an average 3.9 years of follow-up. Three controls per case (n = 372) were selected and matched on age, sex, race/ethnicity, and time since mouthwash collection. α, β, and γ HPV DNA in oral samples were detected using a next-generation sequencing assay. Conditional logistic regression models were used to estimate OR and 95% confidence intervals (CIs), adjusting for smoking and alcohol consumption. Statistical significance was evaluated using permutation test.
Results: Prevalence of oral α, β, and γ HPV was 18.4%, 64.8%, and 42.4% in cases and 14.3%, 55.1%, and 33.6% in controls, respectively. Oral HPV16 detection was not associated with esophageal cancer (OR = 0.54, 95% CI, 0.1–4.84) and none of the esophageal squamous cell carcinoma cases (n = 28) were HPV16 positive. Some oral HPV types were more common in cases than controls; however, none of the associations were statistically significant.
Conclusions: Although HPVs in the oral cavity are very common, this study showed no evidence of association between oral HPVs and esophageal cancer.
Impact: Oral HPVs may not contribute to risk of esophageal cancer. Cancer Epidemiol Biomarkers Prev; 27(10); 1168–75. ©2018 AACR.
Loss of Function of Canonical Notch Signaling Drives Head and Neck Carcinogenesis
Authors: Nyman Patrick E. , Buehler Darya , Lambert Paul F. 
Published: August 2018

Abstract

Purpose:
Head and neck squamous cell carcinoma (HNSCC), a common cancer worldwide, is etiologically associated with tobacco use, high alcohol consumption, and high-risk human papillomaviruses (HPV). The Notch signaling pathway, which is involved in cell differentiation decisions with differential downstream targets and effects depending on tissue type and developmental stage, has been implicated in human HNSCC. NOTCH1 is among the most frequently mutated genes in both HPV-positive and HPV-negative HNSCC. These mutations are predicted to inactivate the function of Notch. Other studies have argued the opposite—Notch signaling is increased in HNSCC.

Experimental Design:
To assess the role of Notch signaling in HPV-positive and HPV-negative HNSCC, we utilized genetically engineered mouse (GEM) models for conventional keratinizing HNSCC, in which either HPV16 E6 and E7 oncoproteins or a gain-of-function mutant p53 are expressed, and in which we inactivated canonical Notch signaling via expression of a dominant negative form of MAML1 (DNMAML1), a required transcriptional coactivator of Notch signaling.

Results:
Loss of canonical Notch signaling increased tumorigenesis in both contexts and also caused an increase in nuclear β-catenin, a marker for increased tumorigenic potential. When combined with loss of canonical Notch signaling, HPV oncogenes led to the highest frequency of cancers overall and the largest number of poorly differentiated (high-grade) cancers.

Conclusions:
These findings inform on the contribution of loss of canonical Notch signaling in head and neck carcinogenesis.
Increased Synthesis of MCL-1 Protein Underlies Initial Survival of EGFR-Mutant Lung Cancer to EGFR Inhibitors and Provides a Novel Drug Target
Authors: Song Kyung-A , Hosono Yasuyuki , Turner Crystal , Jacob Sheeba , Lochmann Timothy L. , Murakami Yoshiko , Patel Neha U. , Ham Jungoh , Hu Bin , Powell Krista M. , Coon Colin M. , Windle Brad E. , Oya Yuko , Koblinski Jennifer E. , Harada Hisashi , Leverson Joel D. , Souers Andrew J. , Hata Aaron N. , Boikos Sosipatros , Yatabe Yasushi , Ebi Hiromichi , Faber Anthony C. 
Published: August 2018

Abstract
Purpose: EGFR inhibitors (EGFRi) are effective against EGFR-mutant lung cancers. The efficacy of these drugs, however, is mitigated by the outgrowth of resistant cells, most often driven by a secondary acquired mutation in EGFR, T790M. We recently demonstrated that T790M can arise de novo during treatment; it follows that one potential therapeutic strategy to thwart resistance would be identifying and eliminating these cells [referred to as drug-tolerant cells (DTC)] prior to acquiring secondary mutations like T790M.
Experimental Design: We have developed DTCs to EGFRi in EGFR-mutant lung cancer cell lines. Subsequent analyses of DTCs included RNA-seq, high-content microscopy, and protein translational assays. Based on these results, we tested the ability of MCL-1 BH3 mimetics to combine with EGFR inhibitors to eliminate DTCs and shrink EGFR-mutant lung cancer tumors in vivo.
Results: We demonstrate surviving EGFR-mutant lung cancer cells upregulate the antiapoptotic protein MCL-1 in response to short-term EGFRi treatment. Mechanistically, DTCs undergo a protein biosynthesis enrichment resulting in increased mTORC1-mediated mRNA translation of MCL-1, revealing a novel mechanism in which lung cancer cells adapt to short-term pressures of apoptosis-inducing kinase inhibitors. Moreover, MCL-1 is a key molecule governing the emergence of early EGFR-mutant DTCs to EGFRi, and we demonstrate it can be effectively cotargeted with clinically emerging MCL-1 inhibitors both in vitro and in vivo.
Conclusions: Altogether, these data reveal that this novel therapeutic combination may delay the acquisition of secondary mutations, therefore prolonging therapy efficacy. Clin Cancer Res; 24(22); 5658–72. ©2018 AACR.
The Eurasian Economic Union: Problems and Prospects
Authors: Verdiyeva Seljan 
Published: August 2018

Abstract
On 29 May 2014, during the meeting of Supreme Eurasian Economic Council, the Presidents of Russia, Belarus and Kazakhstan signed the Treaty on the Eurasian Economic Union (EAEU). Presently, the EAEU consists of the Russian Federation, Belarus, Kazakhstan, Armenia and the Kyrgyz Republic. Nonetheless, the EAEU is lobbying for an ambitious plan of enlargement and is aiming to expand across the entire Eurasian region. The EAEU claims to be the second union after the European Union with the deepest integration aspirations, containing similar institutions and decision-making approaches. This article argues that there are a number of challenges for the effective functioning of EAEU and that its Member States are not yet fully committed to liberalization in practice, contrary to the aspirations they are advocating.
Comparison of Patient‐ and Parent‐Reported Quality of Life for Patients Treated for Persistent Obstructive Sleep Apnea
Authors: Bergeron Mathieu , Duggins Angela L. , Cohen Aliza P. , Ishman Stacey L. 
Published: August 2018

ObjectivesTo evaluate the impact of the treatment of persistent pediatric obstructive sleep apnea (OSA) on quality of life (QOL) with patient‐reported outcomes tools and to compare parent‐ and self‐reported Pediatric Quality of Life Inventory (PedsQL) scores.Study DesignProspective case series.SettingMultidisciplinary upper airway center at a tertiary pediatric institution.Subjects and MethodsChildren with persistent OSA referred to our multidisciplinary upper airway center from 2014 to 2016. Patients and their families completed validated questionnaires for QOL, including the Family Impact Questionnaire, the Obstructive Sleep Apnea–18, the PedsQL, and the Epworth Sleepiness Scale for Children and Adolescents. They completed the same surveys after treatment.ResultsTwenty‐three children (7 females) and their families were included in the study. Patients had a mean age of 12.7 years. Pretreatment, the mean obstructive apnea‐hypopnea index was 15.0 events/hour (95% CI, 8.7‐21.3); after treatment, the mean was 3.9 events/hour (P =. 003). The mean PedsQL score for children improved from 60.5 to 74.2 (P =. 04). The PedsQL score for parents did not significantly improve (61.6 to 63.8, P =. 39). There was a significant though weak association between OSA severity (R2 = 0.25, P =. 03) and PedsQL scores. The Family Impact Questionnaire negative subscore and Epworth Sleepiness Scale for Children and Adolescents scores did not change with treatment.ConclusionsFor children treated for persistent OSA, we found that self‐reported QOL significantly improved after treatment; however, parent‐reported QOL did not significantly change. It is unclear if parents underestimate or patients overestimate QOL after treatment. We suggest that patient‐reported outcomes be obtained when feasible.
Validity and reproducibility of the Functional Gait Assessment in persons after stroke
Authors: Van Bloemendaal Maijke , Bout Walter , Bus Sicco A , Nollet Frans , Geurts Alexander CH , Beelen Anita 
Published: August 2018

Objective: To evaluate construct validity and reproducibility of the Functional Gait Assessment (FGA) for measuring walking balance capacity in persons after stroke. Design: Cross-sectional study. Setting: Inpatient and outpatient rehabilitation center. Subjects: Fifty-two persons post-stroke (median (25% and 75% percentiles)) time post-stroke 6 (5–10) weeks) with independent walking ability (mean gait speed 1.1 ± .4 m/s). Methods: Subjects completed a standardized FGA twice within one to eight days by the same investigator. Validity was evaluated by testing hypotheses on the association with two timed walking tests, Berg Balance Scale, and the mobility domain of the Stroke Impact Scale using correlation coefficients ( r), and with Functional Ambulation Categories using the Kruskal–Wallis test. Reproducibility of FGA scores was assessed with intraclass correlation coefficient and standard error of measurement. Results: Subjects scored a median of 22 out of 30 points at the first FGA. Moderate to high significant correlations ( r .61–.83) and significant differences in FGA median scores between the Functional Ambulation Categories were found. Eight hypotheses (80%) could be confirmed. Inter-rater, intra-rater, and test–retest reliability of the total scores were excellent. The standard error of measurement and minimal detectable change were 2 and 6 points, respectively. No relevant ceiling effect was observed. Conclusion: The FGA demonstrated good measurement properties in persons after stroke and yielded no ceiling effect in contrast to other capacity measures. In clinical practice, a measurement error of 6 points should be taken into account in interpreting changes in walking balance.
Active screening of gastrointestinal helminth infection in migrant workers in Thailand
Authors: Kaewpitoon Soraya J , Sangwalee Wararat , Kujapun Jirawoot , Norkaew Jun , Chuatanam Jirayut , Ponphimai Sukanya , Chavengkun Wasugree , Padchasuwan Natnapa , Meererksom Thirayu , Tongtawee Taweesak , Matrakool Likit , Panpimanmas Sukij , Wakkhuwatapong Parichart , Kaewpitoon Natthawut 
Published: August 2018

Objective This study aimed to detect gastrointestinal helminth infection in migrant workers in Thailand. Methods A cross-sectional survey study was conducted in 403 migrant workers in the factories of Nakhon Ratchasima Province, northeastern Thailand during October 2016 to June 2017. Gastrointestinal helminth infections were detected by the formalin ether acetate concentration technique and microscopy. The data were analyzed using the χ2-test and logistic regression. Results The rate of gastrointestinal helminth infection was 24.07%. The most common species involved in infection was O pisthorchis viverrini (11.91%), followed by hookworm (5.46%), Trichuris trichiura (5.21%), Strongyloides stercoralis (0.5%), Ascaris lumbricoides (0.5%), and Taenia spp. (0.5%). The majority of infections were found in men aged ≥40 years, married participants, uneducated participants, laborers, those who worked for 1 year, and those who had an income of 9000 to 12,000 THB. Conclusions Gastrointestinal helminth infection is still found in migrant workers. Therefore, active surveillance is required in this large group for investigating and eradicating this type of infection.
Antibiotic stewardship: ripartiamo dalla pratica clinica
Authors: Tascini Carlo 
Published: August 2018

Antibiotic stewardship: a milestone in everyday clinical practice Infectious diseases caused by multi-resistant pathogens are increasing worldwide and are challenging for clinicians, also in urological setting. The alarming situation is worsened by the limited perspective of new antibiotic developments. Several authors demonstrated that in Italy we have alarming data about resistance rates: in Campania about 58% of Escherichia coli are resistant to fluroquinolones, as 46% to sulfamethoxazole-trimethoprim. On the other hand, the resistance rate against fosfomycin is still low less than 5%. More alarming data are reported about Klebsiella pneumoniae: resistance rate to flurquinolones 65% and 58% to sulfamethoxazole-trimethoprim. A continuing uncritical, non-guideline-conform and overuse of antibiotics leads to selection of multidrug-resistant pathogens, which can colonize patients and make the treatment a real challenge. A revision of our approach to urinary tract infections at the light of antibiotic stewardiship principles are urgently required, in particular starting from the everyday clinical practice.
CSF β-amyloid predicts prognosis in patients with multiple sclerosis
Authors: Pietroboni Anna M , Caprioli Michela , Carandini Tiziana , Scarioni Marta , Ghezzi Laura , Arighi Andrea , Cioffi Sara , Cinnante Claudia , Fenoglio Chiara , Oldoni Emanuela , De Riz Milena A , Basilico Paola , Fumagalli Giorgio G , Colombi Annalisa , Giulietti Giovanni , Serra Laura , Triulzi Fabio , Bozzali Marco , Scarpini Elio , Galimberti Daniela 
Published: August 2018

Background: The importance of predicting disease progression in multiple sclerosis (MS) has increasingly been recognized, and hence reliable biomarkers are needed. Objectives: To investigate the prognostic role of cerebrospinal fluid (CSF) amyloid beta1–42 (Aβ) levels by the determination of a cut-off value to classify patients in slow and fast progressors. To evaluate possible association with white matter (WM) and grey matter (GM) damage at early disease stages. Methods: Sixty patients were recruited and followed up for 3–5 years. Patients underwent clinical assessment, brain magnetic resonance imaging (MRI; at baseline and after 1 year), and CSF analysis to determine Aβ levels. T1-weighted volumes were calculated. T2-weighted scans were used to quantify WM lesion loads. Results: Lower CSF Aβ levels were observed in patients with a worse follow-up Expanded Disability Status Scale (EDSS; r = −0.65, p < 0.001). The multiple regression analysis confirmed CSF Aβ concentration as a predictor of patients’ EDSS increase ( r = −0.59, p < 0.0001). Generating a receiver operating characteristic curve, a cut-off value of 813 pg/mL was determined as the threshold able to identify patients with worse prognosis (95% confidence interval (CI): 0.690–0.933, p = 0.0001). No differences in CSF tau and neurofilament light chain (NfL) levels were observed ( p > 0.05). Conclusion: Low CSF Aβ levels may represent a predictive biomarker of disease progression in MS.
Late-Onset Systemic Lupus Erythematosus With Lupus Nephritis in a 74-Year-Old Male: A Brief Case and Review
Authors: Kutky Meherzad , Aloudat Sarah 
Published: August 2018

Rationale: Late-onset systemic lupus erythematosus (SLE) represents a specific subgroup of SLE, and although there is no strict age cut-off, 50 years is commonly used as the minimum age for disease onset. In this report, we present a case of a 74-year-old male with late-onset SLE and biopsy-proven lupus nephritis (LN). Presenting concerns of the patient: A 74-year-old male was referred to the nephrology clinic with a rapidly rising creatinine from a baseline of 60 µmol/L to 176 µmol/L. His labs showed pancytopenia, a positive antinuclear antibodies (ANA), and hypocomplementemia. Diagnoses: Renal biopsy showed focal proliferative glomerulonephritis that was immune-mediated and immunofluorescence showed C3, IgM, IgA, IgG, lambda, and C1q diffuse mesangial and glomerular basement membrane staining. Together these findings were in keeping with a diagnosis of stage III LN. Interventions: Treatment included hemodialysis and induction with pulse methylprednisone and cyclophosphamide. He was then placed on the Euro-Lupus Protocol. Outcomes: One year after the diagnosis, he was off dialysis, had no signs of fluid retention or uremia, and his creatinine had stabilized at ~ 330 µmol/L. Lessons learned: To the best of our knowledge, this case represents the oldest known biopsy-confirmed case of late-onset SLE and LN. Late-onset SLE is uncommon and often overlooked as classical symptoms such as malar rash or photosensitivity may not be present. The American College of Rheumatology (ACR) guidelines for treatment of LN can be applied to these patients but physicians should be cognizant of the fact that these patients may not tolerate immunosuppressive therapy as well as younger patients.
Increased Dental Use May Affect Changes in Treated and Untreated Dental Caries in Young Children
Authors: Lin M. , Thornton-Evans G. , Griffin S.O. , Wei L. , Junger M. , Espinoza L. 
Published: August 2018

Introduction: From 1999–2004 to 2011–2014, untreated dental caries prevalence decreased among US children aged 2 to 5 y, regardless of family income. Policies were concurrently initiated for children to increase access to preventive dental services in dental, primary, and community settings and to restorative care in dental settings. Objectives: We aimed to examine 1) whether changes in prevalence and severity of untreated and treated caries between the periods varied by family income and 2) to what degree increased past-year dental visit (PYDV) contributed to the changes. Methods: We used data for 3,822 children in the National Health and Nutrition Examination Survey 1999 to 2004 and 2011 to 2014. Caries prevalence included prevalence of untreated caries with ≥1 decayed teeth (dt) and prevalence of treated caries with ≥1 filled teeth (ft). Caries severity included number of dt and ft among those with ≥1 dt or ft. We estimated changes in caries outcomes among low- and higher-income children with models—one controlling for sociodemographics and another controlling for sociodemographics and PYDV. Significant changes ( P < 0.05) becoming insignificant after controlling for PYDV provide insight on the contribution of PYDV to changes in outcomes. Results: Prevalence of untreated caries decreased for low- and higher-income children, with a slightly larger decrease for low-income children; dt decreased only for low-income children; and estimated decreases did not vary by model. An increase in prevalence of treated caries was observed only among low-income children but became minimized and insignificant after controlling for PYDV. Similarly, after controlling for PYDV, the increase in ft among low-income children lost significance, whereas the increase among higher-income children remained. Conclusion: Untreated caries among children aged 2 to 5 y declined from 1999–2004 to 2011–2014, with larger declines among low-income children. While changes in PYDV contributed to increases in treated caries, particularly for low-income children, additional factors appear to have contributed to decreased untreated caries. Knowledge Transfer Statement: For young children, the degree and direction of changes in caries over the last decade varied by outcome measure (e.g., untreated or treated) and family poverty status. Examining the effect of increased dental utilization on changes in untreated and treated caries outcomes can help identify those policies that contribute to changes in these outcomes and highlight the potential role of the different caries assessment criteria used in dental offices versus those in a population-based survey.