bluuebunny/crossref_metadata_2025 huggingface dataset:
Directional Penalties for Optimal Matching in Observational Studies
Authors: Yu Ruoqi , Rosenbaum Paul R.
Published: May 2019

Multivariate 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

Objective

To 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 Methods

Within 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.

Results

Of 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.>

Conclusions

Brachytherapy 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 Purpose

Impaired 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 Approach

Gene 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 Results

The 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 Implications

PPARδ 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

Sommaire

Au 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

Although 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

Introduction and Aims

We 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 Methods

A 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.

Results

The 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 Conclusions

We 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

Aim

To 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 methods

DELIVER 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.

Results

In 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.

Conclusions

Among 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

Aims

Enteropeptidase 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 methods

In 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.

Results

A 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.

Conclusions

SCO‐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.
To replicate, or not to replicate – that should not be a question
Authors: Chalcraft David R.
Published: May 2019

Recent simulations suggest that ecologists can enhance the predictive ability of models by designing experiments that maximise the number of levels of an experimental factor by sacrificing replication. Here, I describe how these simulations were based on a faulty metric of prediction success and reinforce the importance of replication.
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

Objectives

Neuroinflammation, 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.

Methods

We 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.

Results

Nine 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.

Significance

Our 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.
Inhibition of Pseudomonas aeruginosa biofilm formation and expression of virulence genes by selective epimerization in the peptide Esculentin‐1a(1‐21)NH2
Authors: Casciaro Bruno , Lin Qiao , Afonin Sergii , Loffredo Maria Rosa , de Turris Valeria , Middel Volker , Ulrich Anne S. , Di YuanPu Peter , Mangoni Maria Luisa
Published: May 2019

Pseudomonas aeruginosa is a pathogenic bacterium known to cause serious human infections, especially in immune‐compromised patients. This is due to its unique ability to transform from a drug‐tolerant planktonic to a more dangerous and treatment‐resistant sessile life form, called biofilm. Recently, two derivatives of the frog skin antimicrobial peptide esculentin‐1a, i.e. Esc(1‐21) and its D‐amino acids containing diastereomer Esc(1‐21)‐1c, were characterized for their powerful anti‐Pseudomonal activity against both forms. Prevention of biofilm formation already in its early stages could be even more advantageous for counteracting infections induced by this bacterium. In this work, we studied how the diastereomer Esc(1‐21)‐1c can inhibit Pseudomonas biofilm formation in comparison to the parent peptide and two clinically‐used conventional antibiotics, i.e. colistin and aztreonam, when applied at dosages below the minimal growth inhibitory concentration. Biofilm prevention was correlated to the peptides’ ability to inhibit Pseudomonas motility and to reduce the production of virulent metabolites, for example, pyoverdine and rhamnolipids. Furthermore, the molecular mechanism underlying these activities was evaluated by studying the peptides’ effect on the expression of key genes involved in the virulence and motility of bacteria, as well as by monitoring the peptides’ binding to the bacterial signaling nucleotide ppGpp. Our results demonstrate that the presence of only two D‐amino acids in Esc(1‐21)‐1c is sufficient to downregulate ppGpp‐mediated expression of biofilm‐associated genes, presumably as a result of higher peptide stability and therefore prolonged interaction with the nucleotide. Overall, these studies should assist efficient design and optimization of new anti‐infective agents with multiple pharmacologically beneficial properties.
Drivers of spatial change in urban housing submarkets
Authors: Costello Greg , Leishman Chris , Rowley Steven , Watkins Craig
Published: May 2019

Spatial urban housing submarkets are now widely used constructs. Recent housing market modelling strategies have emphasised the need for flexibility in modelling approaches in order to best accommodate submarkets which account for spatial variations in hedonic prices. But this raises important unanswered questions concerning the stability of submarket structures over time, and the role of housing market dynamics in breaking down or shifting submarket boundaries. The influence of new supply, in particular, may have a stabilising or destabilising effect on differences in hedonic prices, depending on the wider housing market context. In this paper we examine the temporal influence of new supply, intra‐urban migration and socio‐economic change as a means of understanding the impact of key drivers of submarket boundary change. Using the Greater Perth region of Western Australia as a case study, we estimate income elasticities of demand for housing services that vary spatially within the urban area. We find evidence that higher income elasticities, new development, socio‐economic change and intra‐urban migration are associated with changes in the spatial structure of housing prices within the metropolitan housing market.
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

Background

Haemophilia 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.

Methods

From 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.

Results

Ten 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).

Conclusion

Liver 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 carcinoma

Aims

The 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 results

Representative 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).

Conclusion

We 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.
Production and characterisation of duck albumen hydrolysate using enzymatic process
Authors: Quan Tran Hong , Benjakul Soottawat
Published: May 2019

Influences of different ultrasound treatments combined with heat pretreatment on enzymatic hydrolysis, emulsifying properties and antioxidant activities of hydrolysates from duck egg albumen were studied. Heat pretreatment at 95 °C for 30 min inhibited both serine and cysteine protease inhibitors effectively. Ultrasonication of heated duck albumen at 60% amplitude for 10 min yielded the highest surface hydrophobicity. Coincidentally, aforementioned pretreatment rendered the hydrolysate with highest degree of hydrolysis (DH) than other pretreatments when Alcalase was used. The resulting hydrolysate showed the highest antioxidant activities including DPPH radical and ABTS radical cation scavenging activities and ferric reducing antioxidant power as well as emulsifying properties when hydrolysis time of 90 min was used. The hydrolysate possessed the peptides with molecular weight of 219–255 Da with the highest ABTS radical scavenging activity. Thus, heat pretreatment, followed by ultrasonication of duck albumen under appropriate condition could increase DH, antioxidant activities and emulsifying properties of duck albumen hydrolysate.
Phenotyping of interstitial cystitis/bladder pain syndrome
Authors: Akiyama Yoshiyuki , Hanno Philip
Published: May 2019

Interstitial cystitis/bladder pain syndrome is a chronic, potentially debilitating condition characterized by pain perceived to be related to the bladder in conjunction with lower urinary tract symptoms, and includes a wide variety of clinical phenotypes with diverse etiologies. Currently the only clinically relevant proven phenotype of interstitial cystitis/bladder pain syndrome is the Hunner lesion. Whether the presence of Hunner lesions is a hallmark of a distinct disease cohort or a potentially transient feature of non‐Hunner lesion phenotype has been debated but remains controversial. There are few documented examples of a patient converting between the two forms. Growing clinical and basic evidence supports eliminating the Hunner lesion phenotype from the bladder pain syndrome umbrella and considering it a distinct disease. The Hunner lesion phenotype is characterized by distinct bladder histology, including subepithelial chronic inflammatory changes and epithelial denudation, and specific clinical characteristics (older onset age, severe bladder‐centric symptoms, reduced bladder capacity, and favorable response to the lesion‐targeted therapies). To define the Hunner lesion phenotype, it is necessary to develop an atlas of standardized images of cystoscopic (and, if possible, pathological) appearances of Hunner lesions. A true potential and clinically relevant phenotype of interstitial cystitis/bladder pain syndrome may be patients with non‐bladder‐centric symptoms, characterized by the affect dysregulation and somatic symptoms, and a greater bladder capacity in absence of Hunner lesions. In the present workshop, we concluded that the Hunner lesion is a valid phenotype and can reasonably be considered a disease in its own right. Assessment of bladder capacity and the extent of symptoms (bladder beyond or bladder centric) may help phenotyping of interstitial cystitis/bladder pain syndrome. Proper phenotyping is essential for the diagnosis and treatment of interstitial cystitis/bladder pain syndrome, and for facilitating research.
Validity of the Brazilian version of the Dental Subscale of Children's Fear Survey Schedule
Authors: Cademartori Mariana Gonzalez , Cara Gleidi , Pinto Gabriela dos Santos , da Costa Vanessa Polina Pereira
Published: May 2019

Background

Dental Subscale of Children's Fear Survey Schedule (CFSS‐DS) is a tool widely used to assess dental fear in children.

Aim

To translate and to verify the psychometric properties, including factor analyses of the Brazilian version of the CFSS‐DS (B‐CFSS‐DS) in two settings.

Design

The CFFS‐DS was translated into the Portuguese language. In the first cross‐sectional study (dental setting), 128 children (age: 4‐12 years) participated. Mothers were interviewed; children's dental fear was assessed through the CFSS‐DS and the Venham picture test; and child behaviour was assessed using the Frankl Scale. The second was a longitudinal study, with 103 schoolchildren (age: 4‐12 years). Two receiver operating characteristic curves were drawn to establish the cut‐off points.

Results

The B‐CFSS‐DS version showed good internal consistency in dental and school settings (Cronbach's α = 0.88 and 0.77 respectively) and a good test‐retest reliability (Weighted Kappa = 0.767), as well as good criterion and discriminant validities. Factor analyses showed four factors.

Conclusion

The Brazilian version of the CFSS‐DS is a valid tool for dental fear assessment in children aged 4‐12 years. Further studies with representative samples should be performed to strengthen the findings of this study, especially in the school setting.
Dopamine receptor D2 and ankyrin repeat domain containing one in temporomandibular disorder of adolescents
Authors: Franco Gizele Batista , Faturri Aluhe Lopes , Meger Michelle Nascimento , de Paiva Bertoli Fernanda Mara , Wambier Letícia Maira , Scariot Rafaela , de Souza Juliana Feltrin , Küchler Erika Calvano , Brancher João Armando
Published: May 2019

Background

Temporomandibular disorder (TMD) is a multifactorial condition that combines environmental and genetic factors and its prevalence increases during adolescence.

Aim

To investigate the association between TMD and genetic polymorphisms in the DRD2 and ANKK1 in a population of Brazilian adolescents.

Design

The TMD group included adolescents diagnosed with any of the following TMD subgroups according to the RDC/TMD criteria: myofascial pain, arthralgia and disc displacement and painful TMD. Genomic DNA for molecular analysis was extracted from buccal cells, and genetic polymorphism rs6275 in DRD2 and rs1800497 in ANKK1 were genotyped by real‐time polymerase chain reactions using the TaqMan assay. Data were analysed using the Epi Info 3.5.7 and Stata software, with significance level of 0.05.

Results

Two hundred fifty‐one individuals were included in this study, 148 subjects presented TMD. For disc displacement, the genetic polymorphisms rs6275 was associated in a recessive model (P = 0.04), whereas the rs6276 and rs1800497 presented only a borderline association in a recessive and dominant models, respectively (P = 0.07 and P = 0.06).

Conclusion

The genetic polymorphism rs6275 in DRD2 was associated with disc displacement in Brazilian adolescents.
Large neighborhood search for the bike request scheduling problem
Authors: Vergeylen Nicholas , Sörensen Kenneth , Vansteenwegen Pieter
Published: May 2019

This paper introduces an efficient algorithm for the bike request scheduling problem (BRSP). The BRSP is built around the concept of request, defined as the pickup or dropoff of a number of identical items (bikes) at a specific station, within a certain time window, and with a certain priority. The aim of the BRSP is to sequence requests on (and hence determine the routes of) a set of vehicles, in such a way that the sum of the priorities of the executed requests is maximized, all time windows are respected, and the capacity of the vehicles is not exceeded. The generation of the set of requests is explicitly not a part of the problem definition of the BRSP. The primary application of the BRSP, from which it derives its name, is to determine the routes of a set of repositioning vehicles in a bike sharing system, although other applications exist. The algorithm introduced in this paper is based on a set of related greedy randomized adaptive search procedure followed by variable neighborhood descent (GRASP + VND) operators embedded in a large neighborhood search (LNS) framework. Since this paper presents the first heuristic for the BRSP, a computational comparison to existing approaches is not possible. We therefore compare the solutions found by our LNS heuristic to those found by an exact solver (Gurobi). These experiments confirm that the proposed algorithm scales to realistic dimensions and is able to find near‐optimal solutions in seconds.
Helping hospitalized smokers in Hong Kong quit smoking by understanding their risk perception, behaviour, and attitudes related to smoking
Authors: Li William Ho Cheung , Ho K. Y. , Xia Viveka W. , Wang M. P. , Lam Katherine K. W. , Chan Sophia S. C. , Lam T. H.
Published: May 2019

Aim

To understand the risk perceptions, behaviour, attitudes, and experiences related to smoking among hospitalized Chinese smokers.

Background

Understanding hospitalized smokers’ perceptions of risks associated with smoking, along with their behaviour, attitudes, and smoking‐related experiences, is essential prerequisite to design effective interventions to help them quit smoking.

Design

A phenomenological research design was adopted.

Methods

A purposive sampling approach was used. Between May 2016‐January 2017, 30 hospitalized smokers were invited for an interview.

Results

Four themes were generated: (a) associations between perception of illness and smoking; (b) perceived support from healthcare professionals to quit smoking; (c) impact of hospitalization on behaviour, attitudes, and experiences; and (d) perceived barriers to quitting smoking.

Conclusion

Development of an innovative intervention that helps to demystify misconceptions about smoking through brief interventions and active referrals is recommended to enhance the effectiveness of healthcare professionals promoting smoking cessation for hospitalized smokers.

Impact

To date, no study examining smoking behaviour among hospitalized patients in Hong Kong has been conducted. Misconceptions about smoking and health, barriers to quitting that outweighed perceived benefits, lack of support from healthcare professionals, and difficulty overcoming withdrawal symptoms or cigarette cravings precluded hospitalized smokers sustaining smoking abstinence after discharge. Smoking is detrimental to physical health. Smoking cessation has beneficial effects on treatment efficacy and prognosis and helps to reduce the economic burden on society from smoking‐attributable diseases.
Loss of retinal ganglion cells in a new genetic mouse model for primary open‐angle glaucoma
Authors: Reinehr Sabrina , Koch Dennis , Weiss Maximilian , Froemel Franziska , Voss Christina , Dick H. Burkhard , Fuchshofer Rudolf , Joachim Stephanie C.
Published: May 2019

Primary open‐angle glaucoma (POAG) is one of the most common causes for blindness worldwide. Although an elevated intraocular pressure (IOP) is the main risk factor, the exact pathology remained indistinguishable. Therefore, it is necessary to have appropriate models to investigate these mechanisms. Here, we analysed a transgenic glaucoma mouse model (βB1‐CTGF) to elucidate new possible mechanisms of the disease. Therefore, IOP was measured in βB1‐CTGF and wildtype mice at 5, 10 and 15 weeks of age. At 5 and 10 weeks, the IOP in both groups were comparable (P > 0.05). After 15 weeks, a significant elevated IOP was measured in βB1‐CTGF mice (P < 0.001). At 15 weeks, electroretinogram measurements were performed and both the a‐ and b‐wave amplitudes were significantly decreased in βB1‐CTGF retinae (both P < 0.01). Significantly fewer Brn‐3a+ retinal ganglion cells (RGCs) were observed in the βB1‐CTGF group on flatmounts (P = 0.02), cross‐sections (P < 0.001) and also via quantitative real‐time PCR (P = 0.02). Additionally, significantly more cleaved caspase 3+ RGCs were seen in the βB1‐CTGF group (P = 0.002). Furthermore, a decrease in recoverin+ cells was observable in the βB1‐CTGF animals (P = 0.004). Accordingly, a significant down‐regulation of Recoverin mRNA levels were noted (P < 0.001). Gfap expression, on the other hand, was higher in βB1‐CTGF retinae (P = 0.023). Additionally, more glutamine synthetase signal was noted (P = 0.04). Although no alterations were observed regarding photoreceptors via immunohistology, a significant decrease of Rhodopsin (P = 0.003) and Opsin mRNA (P = 0.03) was noted. We therefore assume that the βB1‐CTGF mouse could serve as an excellent model for better understanding the pathomechanisms in POAG.
Oral iron‐based interventions for prevention of critical outcomes in pregnancy and postnatal care: An overview and update of systematic reviews
Authors: Abraha Iosief , Bonacini Maria Isabella , Montedori Alessandro , Di Renzo Gian Carlo , Angelozzi Patrizio , Micheli Marta , Germani Antonella , Carloni Danilo , Scaccetti Augusto , Palmieri Gianluca , Casali Marta , Nenz Chiara Maria Grazia , Gargano Elisabetta , Pazzaglia Michela , Agea Elisabetta , Berchicci Laura , Tesoro Simonetta , Albi Nicola , Minelli Olivia , Pasqua Barbara Luciani , Onorato Marina , Epicoco Giorgio , Marchesi Mauro
Published: May 2019

Objective

The aim of this work was to summarize and update the evidence concerning oral iron‐based interventions compared to placebo or no iron‐based interventions to prevent critical outcomes in pregnancy or treat critical outcomes in the postpartum phase.

Method

Published systematic reviews (Feb 2018) and primary studies (from 2015 to March 2018) retrieved from MEDLINE, EMBASE, and the Cochrane Library were examined. The AMSTAR (Assessing the Methodological Quality of Systematic Reviews) tool was used to assess the quality of reviews. GRADE was used to rate the quality of the evidence for critical outcomes.

Results

Antenatal care: Compared to placebo/no treatment, iron‐based therapies reduced maternal anemia at term by 59% (seven trials at low risk of bias, RR 0.41, 95% CI 0.23‐0.73; I2 = 86%; moderate‐quality evidence) and maternal iron deficiency anemia by 67% (RR 0.33, 95% CI 0.16‐0.69; I2 = 49%). There was no evidence of difference between iron‐based therapies vs control in terms of side effects (RR 1.42, 95% CI 0.91‐2.21), preterm delivery (13 studies: RR 0.93, 95% CI 0.84‐1.03; low‐quality evidence), low birthweight (RR 0.94, 95% CI 0.79‐1.13; low‐quality evidence) and infant mortality (RR 0.93, 0.72‐1.20; low‐quality evidence).

Postnatal care

There was insufficient evidence to determine whether iron‐based therapies can reduce postpartum anemia.

Conclusion

Iron supplementation is effective in preventing maternal anemia at term but not low birthweight, preterm delivery or infant mortality.
A Chinese practice guideline of the assisted reproductive technology strategies for women with advanced age
Authors: Jiang Li , Chen Yaolong , Wang Qi , Wang Xiaoqin , Luo Xufei , Chen Junqiao , Han Hongjing , Sun Yingpu , Shen Huan ,   Chinese Society of Reproductive Medicine (CSRM)
Published: May 2019

More women postpone childbearing nowadays while female fertility begins to decline with advancing age. Furthermore, with the rolling out of the two‐child policy, there is a huge demand for a second child for Chinese aged women. There are various assisted reproductive technology (ART) strategies applied for age‐related infertility without solid evidence. On behalf of the Society of Reproductive Medicine, Chinese Medical Association, we would like to develop a Chinese guideline of ART strategies for age‐related infertility. This guideline was produced following the recommendations for standard guidelines described in the 2012 WHO Handbook for guideline development. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework was also followed. A protocol was formulated and a Guideline Development Group was formed with specialists of reproductive medicine, methodologists from Chinese GRADE working group, and patient representative. Questions regarding the ART strategies for aged infertility were formulated and 8 most important ones were chosen to be structured in PICO format (Population, Intervention, Comparison, Outcomes). Comprehensive search and review of the literature were performed and the quality of the evidence was assessed and rated based on certain criteria and be categorized as high, moderate, low, or very low. Twenty‐five recommendations were formulated among members of the Guidelines Development Group (Delphi method) basing on the overall quality of the evidence, in addition to the balance between benefits and harms, values and preferences, and resource implications. The final recommendations were agreed on by consensus during face‐to‐face meetings. This is the first Chinese practice guideline in reproductive medicine developed following the standard and scientific method.
Beyond uncertainty: Negative findings for the association between the use of proton pump inhibitors and risk of dementia
Authors: Park Sun‐Kyeong , Nam Jin Hyun , Lee Hyesung , Chung Hyunsoo , Lee Eui‐Kyung , Shin Ju‐Young
Published: May 2019

Objectives

We investigated the risk of dementia associated with the use of proton pump inhibitors (PPIs) as compared with the use of histamine‐2 receptor antagonist (H2RA).

Methods

We conducted retrospective propensity score‐matched cohort study using the National Health Insurance Service‐National Sample Cohort. Subjects were defined as the patients newly prescribed with PPI or H2RA between 2003 and 2013 without prior prescriptions of PPI/H2RA or diagnosis of dementia from their history within the past 1 year. We followed up participants until dementia occurrence, death, or the end of the study, whichever occurred first, with an intention‐to‐treat approach. A 1‐year lag time between exposure and outcome measure was used to reduce protopathic bias. The incidence rate per 1000 person‐years was estimated. The incidence rate of PPI was compared with that of H2RA, defined as incidence rate ratio (IRR), calculated with a 95% confidence interval. To control for potential confounds, propensity score matching at a 1:1 ratio was conducted, and the crude IRR was adjusted by risk factors.

Results

Our propensity score‐matched cohort included 87 562 patients on PPIs and 87 562 patients on H2RAs. The IRR was 1.01 (95% confidence interval 0.96–1.06) with 1‐year lag time. IRR showed the decreased trend as the longer lag time. Also, no treatment duration or dose–response relationship was observed.

Conclusions

Our finding demonstrated that PPIs did not associate with dementia more strongly than did H2RA. On this basis, we suggest that the previously reported risk for dementia associated with PPI may have been overestimated.
Effects of aromatherapy massage on pain, functional state, and quality of life in an elderly individual with knee osteoarthritis
Authors: Pehlivan Seda , Karadakovan Ayfer
Published: May 2019

Aim

To investigate the effects of aromatherapy massage on pain, functional state and life quality of elderly individuals with knee osteoarthritis.

Methods

This controlled and experimental study was conducted in two nursing homes. In this study, 90 elderly individuals with knee osteoarthritis were randomized as aromatherapy, massage and control groups. Data were collected in weeks 0, 4, and 8 using Patient Information Form, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Knee Osteoarthritis Evaluation Scale, OsteoArthritis Knee and Hip Quality of Life Scale (OAKHQoL). Aromatherapy and massage groups received a total of 15–20 min total classic leg massage twice weekly for 3 weeks. In the aromatherapy group, two essential oils (ginger and rosemary) were added to the black seed oil.

Results

In the aromatherapy group, WOMAC (pain and functional state) scores were lower and quality of life scores were higher than the massage and control groups in week 4, and these differences were statistically significant (p < .001). These significant differences were present in the massage group when compared with the control (p < .001). These significant differences in the aromatherapy group were also sustained decreasingly in week 8 (p < .001), while the means were not different from baseline in the massage group (p > .05).

Conclusions

Aromatherapy massage performed in elderly patients with knee osteoarthritis reduced pain and improved functional status and quality of life. The week 8 findings showed that aromatherapy has more favorable and longer sustained effects than the massage.