bluuebunny/crossref_metadata_2025_split huggingface dataset:
Directional Penalties for Optimal Matching in Observational Studies
Authors: Yu Ruoqi , Rosenbaum Paul R. 
Published: May 2019

AbstractMultivariate matching in observational studies tends to view covariate differences symmetrically: a difference in age of 10 years is thought equally problematic whether the treated subject is older or younger than the matched control. If matching is correcting an imbalance in age, such that treated subjects are typically older than controls, then the situation in need of correction is asymmetric: a matched pair with a difference in age of 10 years is much more likely to have an older treated subject and a younger control than the opposite. Correcting the bias may be easier if matching tries to avoid the typical case that creates the bias. We describe several easily used, asymmetric, directional penalties and illustrate how they can improve covariate balance in a matched sample. The investigator starts with a matched sample built in a conventional way, then diagnoses residual covariate imbalances in need of reduction, and achieves the needed reduction by slightly altering the distance matrix with directional penalties, creating a new matched sample. Unlike penalties commonly used in matching, a directional penalty can go too far, reversing the direction of the bias rather than reducing the bias, so the magnitude of the directional penalty matters and may need adjustment. Our experience is that two or three adjustments, guided by balance diagnostics, can substantially improve covariate balance, perhaps requiring fifteen minutes effort sitting at the computer. We also explore the connection between directional penalties and a widely used technique in integer programming, namely Lagrangian relaxation of problematic linear side constraints in a minimum cost flow problem. In effect, many directional penalties are Lagrange multipliers, pushing a matched sample in the direction of satisfying a linear constraint that would not be satisfied without penalization. The method and example are in an R package DiPs at CRAN.
Long‐term incidence of secondary bladder and rectal cancer in patients treated with brachytherapy for localized prostate cancer: a large‐scale population‐based analysis
Authors: Mazzone Elio , Mistretta Francesco A. , Knipper Sophie , Palumbo Carlotta , Tian Zhe , Pecoraro Angela , Preisser Felix , Gallina Andrea , Shariat Shahrokh F. , Saad Fred , Graefen Markus , Montorsi Francesco , Briganti Alberto , Karakiewicz Pierre I. 
Published: May 2019

ObjectiveTo examine the incidence and time trends of secondary bladder cancer (BCa) and rectal cancer (RCa) after brachytherapy (BT) relative to radical prostatectomy (RP).Materials and MethodsWithin the Surveillance, Epidemiology and End Results (SEER) database (1988–2015), we identified patients with localized PCa as an only or first primary cancer, who underwent BT or RP. Cumulative incidence plots and multivariable competing‐risks regression (CRR) models were used. Sensitivity analyses focused on patients’ age and year of diagnosis intervals and tested the effect of an unmeasured confounder.ResultsOf 318 058 patients with localized prostate cancer (PCa), 55 566 (18.4%) underwent BT. After propensity score‐matching, 20‐year secondary BCa incidence was 6.0% in patients who had undergone BT vs 2.4% in those who had undergone RP (P < 0.001) and the respective 20‐year secondary RCa incidence was 1.1% vs 0.5% (P < 0.001). In multivariable CRR models, BT predicted higher secondary BCa (hazard ratio [HR] 1.58; P < 0.001) and RCa rates (HR 1.59; P < 0.001) vs RP. Sensitivity analyses replicated the same results after stratification according to age and showed HRs of decreasing magnitude for historical, intermediate and contemporary years of diagnosis. An unmeasured confounder with an HR of 2 would render the effect of BT statistically insignificant if it affected patients in the RP group with a ratio of 2 relative to those in the BT group. Finally, temporal trends showed a decrease of secondary 5‐year BCa and RCa rates.>ConclusionsBrachytherapy predominantly increases the risk of secondary BCa and, to a lesser extent, that of RCa. Follow‐up of such patients is therefore required. It is encouraging that both secondary BCa, and RCa rates, in particular, have recently decreased, RCa.
PPARδ agonist prevents endothelial dysfunction via induction of dihydrofolate reductase gene and activation of tetrahydrobiopterin salvage pathway
Authors: Zhang Zihui , Xie Xinya , Yao Qinyu , Liu Jia , Tian Ying , Yang Chunmiao , Xiao Lei , Wang Nanping 
Published: May 2019

Background and PurposeImpaired endothelium‐dependent relaxation (EDR) is a hallmark of endothelial dysfunction. A deficiency of tetrahydrobiopterin (BH4) causes endothelial NOS to produce ROS rather than NO. PPARδ is an emerging target for pharmacological intervention of endothelial dysfunction. Thus, the present study examined the role of PPARδ in the regulation of dihydrofolate reductase (DHFR), a key enzyme in the BH4 salvage pathway.Experimental ApproachGene expression was measured by using qRT‐PCR and western blotting. Biopterins and ROS were determined by using HPLC. NO was measured with fluorescent dye and electron paramagnetic resonance spectroscopy. Vasorelaxation was measured by Multi Myograph System.Key ResultsThe PPARδ agonist GW501516 increased DHFR and BH4 levels in endothelial cells (ECs). The effect was blocked by PPARδ antagonist GSK0660. Chromatin immunoprecipitation identified PPAR‐responsive elements within the 5′‐flanking region of the human DHFR gene. The promoter activity was examined with luciferase assays using deletion reporters. Importantly, DHFR expression was suppressed by palmitic acid (PA, a saturated fatty acid) but increased by docosahexaenoic acid (DHA, a polyunsaturated fatty acid). GSK0660 prevented DHA‐induced increased DHFR expression. Conversely, the suppressive effect of PA was mitigated by GW501516. In mouse aortae, GW501516 ameliorated the PA‐impaired EDR. However, this vasoprotective effect was attenuated by DHFR siRNA or methotrexate. In EC‐specific Ppard knockout mice, GW501516 failed to improve vasorelaxation.Conclusion and ImplicationsPPARδ prevented endothelial dysfunction by increasing DHFR and activating the BH4 salvage pathway. These results provide a novel mechanism for the protective roles of PPARδ against vascular diseases.
L'élaboration et la mise en œuvre des recommandations issues d'évaluations de programmes au gouvernement du Canada
Authors: Bourgeois Isabelle , Leblanc Léandre 
Published: May 2019

SommaireAu gouvernement du Canada, les rapports d'évaluation de programmes contiennent des recommandations qui visent l'amélioration de leurs modalités et de leur mise en œuvre. L'élaboration de recommandations peut constituer une étape laborieuse de la démarche évaluative et mobiliser plusieurs parties prenantes. Cependant, peu d'études ont été réalisées afin de déterminer comment ces recommandations sont élaborées et si elles sont ensuite mises en œuvre par les responsables des programmes. Cet article présente les résultats d'un sondage mené auprès des directions d'évaluations fédérales afin de mieux cerner les enjeux relatifs à l'élaboration et à la mise en œuvre des recommendations. Les résultats témoignent d'un niveau élevé d'implication des parties prenantes à la démarche évaluative et à l'élaboration des recommandations, ce qui soutient une utilisation accrue des évaluations. Les résultats de l'étude confirment ceux d'études antérieures et démontrent que les recommandations sont principalement axées sur l'amélioration de l'efficacité et de l'efficience des programmes plutôt que sur la prise de décision plus stratégique.
Cysteine‐rich protein 61 regulates the chemosensitivity of chronic myeloid leukemia to imatinib mesylate through the nuclear factor kappa B/Bcl‐2 pathway
Authors: Song Yanfang , Lin Qing , Cai Zhaolian , Hao Taisen , Zhang Yaohan , Zhu Xianjin 
Published: May 2019

AbstractAlthough the targeted tyrosine kinase inhibitor imatinib mesylate (IM) has achieved significant responses against CML in the clinical setting, a small proportion of patients fail to respond to IM treatment and their disease continues to progress, indicating resistance to IM therapy. As a secreted extracellular matrix protein, cysteine‐rich protein 61 (Cyr61) plays an important role in the resistance of solid tumors to chemotherapy, but its role in CML is unclear. In the present study, we observed that Cyr61 levels were upregulated in the plasma and bone marrow (BM) of patients with CML as well as in K562 cells. This upregulation of Cyr61 significantly decreased IM‐induced cellular apoptosis of K562 cells through nuclear factor kappa B/B‐cell lymphoma 2 pathways. Inhibition of Cyr61 restored the chemosensitivity of K562 cells to IM both in vitro and in vivo. Thus, our results showed for the first time that Cyr61 plays an important role in regulating the chemosensitivity of CML cells to IM, suggesting that selectively targeting Cyr61 directly or its relevant effector pathways may provide potential value in improving the clinical response of patients with CML to IM treatment.
Health‐related quality of life among people who use methamphetamine
Authors: McKetin Rebecca , Voce Alexandra , Burns Richard , Shanahan Marian 
Published: May 2019

AbstractIntroduction and AimsWe assessed health‐related quality of life amongst people who use methamphetamine, examined how this related to different patterns of methamphetamine use and what other factors were associated with decrements in quality of life in this sample.Design and MethodsA cross‐sectional survey of 169 at least monthly methamphetamine users. Health utility scores were derived using the Assessment of Quality of Life – 4D for the past month (0 reflects death and 1 represents full health; the population mean Assessment of Quality of Life score in Australia is 0.81). Dependence on methamphetamine was a score of 4+ on the Severity of Dependence Scale. Other measures included days of methamphetamine use and other substance use in the past month, injecting methamphetamine, demographics, psychiatric symptoms (score of 4+ on the Brief Psychiatric Rating Scale items) and a lifetime DSM‐IV diagnosis of schizophrenia.ResultsThe mean utility score was 0.52 (95% confidence interval 0.48–0.56). Methamphetamine dependence was associated with lower utility (−0.10, P = 0.003) after adjustment for other univariate correlates of utility. Other factors independently associated with lower utility were being a woman (−0.14, P < 0.001), depression (−0.10, P = 0.008), self‐neglect (−0.08, P = 0.035), schizophrenia (−0.17, P = 0.003) and fewer years of schooling (0.02 per year, P = 0.037).Discussion and ConclusionsWe found poor quality of life in this sample of methamphetamine users relative to the general population, this being associated with both dependence on methamphetamine and other factors, particularly poor mental health. We also found poorer health amongst women.
Comparable glycaemic control and hypoglycaemia in adults with type 2 diabetes after initiating insulin glargine 300 units/mL or insulin degludec: The DELIVER Naïve D real‐world study
Authors: Sullivan Sean D. , Nicholls Charlie J. , Gupta Rishab A. , Menon Arjun A. , Wu Jasmanda , Westerbacka Jukka , Bosnyak Zsolt , Frias Juan P. , Bailey Timothy S. 
Published: May 2019

AbstractAimTo compare glycaemic control, hypoglycaemia and treatment discontinuation of insulin glargine 300 units/mL (Gla‐300) and insulin degludec (IDeg) in a real‐world study of insulin‐naïve adults with type 2 diabetes (T2D).Materials and methodsDELIVER Naive D was a retrospective observational study that used electronic medical record data from the IBM Watson Health Explorys database. Insulin‐naïve adults with T2D who started Gla‐300 or IDeg between March 2015 and September 2017 were identified. Patients were active in the system for ≥12 months before and ≥6 months after starting Gla‐300 or IDeg and had HbA1c measurements during 6‐month baseline and 3‐ to 6‐month follow‐up. Outcomes were compared among 1:1 propensity score‐matched cohorts.ResultsIn the matched cohorts (n = 638 each), the mean age was 59 years, approximately 53% were male, and mean HbA1c was 9.67% (82 mmol/mol). Mean (SD) HbA1c decreases were comparable in the Gla‐300 and IDeg cohorts (−1.67% [2.22] and −1.58% [2.20]; P = 0.51), as were HbA1c target attainment [<7% (53 mmol/mol): 23.8% and 27.4%; P = 0.20; <8% (64 mmol/mol): 55.0% and 57.1%; P = 0.63] and treatment discontinuation (29.2% and 32.6%; P = 0.14). Overall and inpatient/emergency department‐associated hypoglycaemia incidences and event rates were similar in both cohorts using fixed 6‐month or variable on‐treatment follow‐up.ConclusionsAmong real‐world insulin‐naïve adults with T2D, initiation of Gla‐300 or IDeg resulted in comparable improvements in glycaemic control and similar rates of hypoglycaemia. These real‐world data complement and confirm a randomized trial and other real‐world studies.
SCO‐792, an enteropeptidase inhibitor, improves disease status of diabetes and obesity in mice
Authors: Yashiro Hiroaki , Hamagami Kenichi , Hiyoshi Hideyuki , Sugama Jun , Tsuchimori Kazue , Yamaguchi Fuminari , Moritoh Yusuke , Sasaki Minoru , Maekawa Tsuyoshi , Yamada Yukio , Watanabe Masanori 
Published: May 2019

AbstractAimsEnteropeptidase is a serine protease localized on the duodenal brush border that catalyzes the conversion of inactive trypsinogen into active trypsin, thereby regulating protein breakdown in the gut. We evaluated the effects of SCO‐792, a novel enteropeptidase inhibitor, in mice.Materials and methodsIn vivo inhibition of enteropeptidase was evaluated via an oral protein challenge. Pharmacological effects were evaluated in normal mice, in diet‐induced obese (DIO) mice and in obese and diabetic ob/ob mice.ResultsA single oral administration of SCO‐792 inhibited plasma branched‐chain amino acids (BCAAs) in an oral protein challenge test in mice, indicating in vivo inhibition of enteropeptidase. Repeated treatment with SCO‐792 induced reduction in food intake and decrease in body weight in DIO and ob/ob mice. Plasma FGF21 levels were increased in SCO‐792‐treated DIO mice, an observation that was probably independent of reduction in food intake. Hyperglycaemia was markedly improved in SCO‐792‐treated ob/ob mice. A hyperinsulinaemic‐euglycaemic clamp study revealed improved muscle insulin sensitivity in SCO‐792‐treated ob/ob mice. SCO‐792 also improved plasma and liver lipid profiles and decreased plasma alanine transaminase, suggesting a potential treatment for liver diseases. Dietary supplementation with essential amino acids attenuated the effect of SCO‐792 on reduction in food intake and decrease in body weight in normal mice, suggesting a pivotal role for enteropeptidase in these biological phenomena.ConclusionsSCO‐792 inhibited enteropeptidase in vivo, reduced food intake, decreased body weight, increased insulin sensitivity, improved glucose and lipid control, and ameliorated liver parameters in mouse models with obesity and/or diabetes. SCO‐792 may exhibit similar effects in patients.
Effect of timing and exposure of sunflower pollen on a common gut pathogen of bumble bees
Authors: LoCascio George M. , Pasquale River , Amponsah Eugene , Irwin Rebecca E. , Adler Lynn S. 
Published: May 2019

1. Several bee species are declining due to multiple factors, including pathogens. Ingestion of sunflower (Helianthus annuus) pollen can dramatically reduce the bumble bee gut pathogen Crithidia bombi, but little is known about how timing and exposure to sunflower pollen consumption affects pathogen load.2. Two experiments were carried out to investigate how exposure to sunflower pollen relative to pathogen exposure affects Crithidia bombi in Bombus impatiens. Foraging trials with pollen‐producing and male‐sterile (pollen absent) sunflower lines were performed to investigate whether sunflower pollen affected pathogen transmission in a single foraging bout, and 7‐day laboratory trials were done to investigate whether timing and duration of exposure to sunflower pollen after infection affected C. bombi.3. In foraging trials, pollen presence on inflorescences inoculated with C. bombi did not affect transmission (pathogen cell counts of foraging workers) 1 week later, suggesting that a brief experience with sunflower pollen concurrent with pathogen exposure is insufficient to reduce infection. In laboratory trials, consuming sunflower pollen for the first 3.5 days or all 7 days after infection reduced cell counts compared with a negative control pollen, but consuming sunflower pollen starting 3.5 days after infection did not. Consuming sunflower pollen for 7 days was significantly and substantially more effective than any other treatment. Thus, both duration and timing of exposure to sunflower pollen may affect pathogen load.4. These results are important for understanding ecological disease dynamics in natural settings with free‐flying bumble bees, and may inform decisions about using medicinal diets to manage bumble bee health commercially.
Neuroinflammation in neocortical epilepsy measured by PET imaging of translocator protein
Authors: Dickstein Leah P. , Liow Jeih‐San , Austermuehle Alison , Zoghbi Sami , Inati Sara K. , Zaghloul Kareem , Zanotti‐Fregonara Paolo , Theodore William H. 
Published: May 2019

AbstractObjectivesNeuroinflammation, implicated in epilepsy, can be imaged in humans with positron emission tomography (PET) ligands for translocator protein 18 kDa (TSPO). Previous studies in patients with temporal lobe epilepsy and mesial temporal sclerosis found increased [11C]PBR28 uptake ipsilateral to seizure foci. Neocortical foci present more difficult localization problems and more variable underlying pathology.MethodsWe studied 11 patients with neocortical seizure foci using [11C]PBR28 or [11C] N,N‐diethyl‐2‐(4‐methoxyphenyl)‐5,7‐dimethylpyrazolo[1,5‐a]pyrimidine‐3‐acetamide (DPA) 713, and 31 healthy volunteers. Seizure foci were identified with structural magnetic resonance imaging (MRI) and ictal video–electroencephalography (EEG) monitoring. Six patients had surgical resections; five had focal cortical dysplasia type 2A or B and one microdysgenesis. Brain regions were delineated using FreeSurfer and T1‐weighted MRI. We measured brain radioligand uptake (standardized uptake values [SUVs]) in ipsilateral and contralateral regions, to compare calculated asymmetry indices [AIs; 200% *(ipsilateral − contralateral)/(ipsilateral + contralateral)] between epilepsy patients and controls, as well as absolute [11C]PBR28 binding as the ratio of distribution volume to free fraction (VT/fP) in 9 patients (5 high affinity and 4 medium affinity binders) and 11 age‐matched volunteers (5 high‐affinity and 6 medium affinity) who had metabolite‐corrected arterial input functions measured.ResultsNine of 11 patients had AIs exceeding control mean 95% confidence intervals in at least one region consistent with the seizure focus. Three of the nine had normal MRI. There was a nonsignificant trend for patients to have higher binding than volunteers both ipsilateral and contralateral to the focus in the group that had absolute binding measured.SignificanceOur study demonstrates the presence of focal and distributed inflammation in neocortical epilepsy. There may be a role for TSPO PET for evaluation of patients with suspected neocortical seizure foci, particularly when other imaging modalities are unrevealing. However, a complex method, inherent variability, and increased binding in regions outside seizure foci will limit applicability.
Hepatectomy in patients with inherited blood coagulation disorders can be safely performed with adequate coagulation factor replacement
Authors: Kobayashi Kosuke , Kokudo Takashi , Yamaguchi Takamune , Shirata Chikara , Uldry Emilie , Akamatsu Nobuhisa , Arita Junichi , Kaneko Junichi , Yasumoto Atsushi , Demartines Nicolas , Hasegawa Kiyoshi , Halkic Nermin 
Published: May 2019

BackgroundHaemophilia and von Willebrand disease (VWD) are common inherited bleeding disorders. Although patients with haemophilia or VWD have a high risk of hepatitis virus infection and hepatocellular carcinoma (HCC), little is known about the safety of liver resection in these patients.MethodsFrom 2006 to 2016, there were seven hepatectomies with haemophilia A and three hepatectomies with VWD for malignant liver tumours at tertiary care hospitals in Japan and Switzerland. To evaluate the safety of hepatectomy in the blood coagulation disorder group (BD group), short‐term outcomes in these patients were compared with 20 hepatectomies (non‐BD group) for HCC, matched to a 2:1, operative procedure, period and background liver.ResultsTen liver resections were performed in patients with haemophilia or VWD with administration of recombinant FVIII or VWF concentrate. Comparison of the BD vs non‐BD group revealed no significant differences in the operative time (327 vs 407 minutes, P = 0.359), estimated blood loss (730 vs 820 mL, P = 0.748), red blood cell transfusion rate (10.0% vs 5.0%, P = 0.605), major complication rate (Clavien‐Dindo grade III or IV) (10.0% vs 5.0%, P = 0.605) or mortality rate (0% vs 0%, P > 0.999). Additionally, the length of the postoperative hospital stay was similar between the two groups (13 vs 14 days, P = 0.296).ConclusionLiver resection for treatment of HCC in patients with haemophilia or VWD can be safely performed through an appropriate perioperative administration protocol of coagulation factors.
Clinical evaluation of tumour‐infiltrating lymphocytes as a prognostic factor in patients with human papillomavirus‐associated oropharyngeal squamous cell carcinoma
Authors: Ruangritchankul Komkrit , Sandison Ann , Warburton Fiona , Guerrero‐Urbano Teresa , Reis Ferreira Miguel , Lei Mary , Thavaraj Selvam 
Published: May 2019

Clinical evaluation of tumour‐infiltrating lymphocytes as a prognostic factor in patients with human papillomavirus‐associated oropharyngeal squamous cell carcinomaAimsThe majority of patients with human papillomavirus (HPV)‐associated oropharyngeal squamous cell carcinoma (OpSCC) have favourable survival outcomes, but a significant minority of individuals will die of their disease. There are currently no definitive criteria with which to identify HPV‐associated OpSCC patients with poor outcomes. Recent reports suggest that quantitative evaluation of T‐cell subpopulations in OpSCC may be of prognostic value, but the methods used have limited utility in a clinical diagnostic setting. We therefore sought to determine the clinical prognostic utility of tumour‐infiltrating lymphocyte (TIL) evaluation in patients with HPV‐associated OpSCC within the context of a diagnostic histopathology setting.Methods and resultsRepresentative diagnostic haematoxylin and eosin (H&E)‐stained slides from 232 consecutive HPV‐associated OpSCC patients were classified as containing a high (TILHi; diffuse, lymphocytes in >80% of tumour and stroma), moderate (TILMod; patchy, present in 20–80% of tumour and stroma) or low (TILLo; sparse or absent, present in <20% of tumour and stroma) TILs. Interobserver reliability was assessed, and TIL category was then correlated with overall survival (OS) and disease‐free survival (DFS). Univariate and multivariate analyses showed statistically significant differences in OS and DFS estimates when TILHi and TILMod patients were compared with TILLo patients (P < 0.0001 for TILHi versus TILLo; P < 0.0001 for TILMod versus TILLo). Statistical significance was retained when TILHi and TILMod patients were grouped into a single category (TILHi) and compared with TILLo patients (P < 0.0001).ConclusionWe demonstrate the prognostic utility of TILs in patients with HPV‐associated OpSCC in clinical practice. A binary system classifying HPV‐associated OpSCC into TILHi and TILLo on the basis of routine H&E staining stratifies patients into those with potentially favourable and unfavourable survival outcomes, respectively.