bluuebunny/crossref_metadata_2025 huggingface dataset:
A High‐yield Fall Risk and Adverse Events Screening Questions From the Stopping Elderly Accidents, Death, and Injuries (STEADI) Guideline for Older Emergency Department Fall Patients
Authors: Sri‐on Jiraporn , Tirrell Gregory Philip , Kamsom Anucha , Marill Keith A. , Shankar Kalpana Narayan , Liu Shan W.
Published: March 2018

Objectives

The objectives were to examine whether responses to the Stopping Elderly Accidents, Death, and Injuries (STEADI) questions responses predicted adverse events after an older adult emergency department (ED) fall visits and to identify factors associated with such recurrent fall.

Methods

We conducted a prospective study at two urban, teaching hospitals. We included patients aged ≥ 65 years who presented to the ED for an accidental fall. Data were gathered for fall‐relevant comorbidities, high‐risk medications for falls, and the responses to 12 questions from the STEADI guideline recommendation. Our outcomes were the number of 6‐month adverse events that were defined as mortality, ED revisit, subsequent hospitalization, recurrent falls, and a composite outcome.

Results

There were 548 (86.3%) patients who completed follow‐up and 243 (44.3%) patients experienced an adverse event after a fall within 6 months. In multivariate analysis, seven questions from the STEADI guideline predicted various outcomes. The question “Had previous fall” predicted recurrent falls (odds ratio [OR] = 2.45, 95% confidence interval [CI] = 1.52 to 3.97), the question “Feels unsteady when walking sometimes” (OR = 2.34, 95% CI = 1.44 to 3.81), and “Lost some feeling in their feet” predicted recurrent falls. In addition to recurrent falls risk, the supplemental questions “Use or have been advised to use a cane or walker,” “Take medication that sometimes makes them feel light‐headed or more tired than usual,” “Take medication to help sleep or improve mood,” and “Have to rush to a toilet” predicted other outcomes.

Conclusion

A STEADI score of ≥4 did not predict adverse outcomes although seven individual questions from the STEADI guidelines were associated with increased adverse outcomes within 6 months. These may be organized into three categories (previous falls, physical activity, and high‐risk medications) and may assist emergency physicians to evaluate and refer high‐risk fall patients for a comprehensive falls evaluation.
Outcomes of Patients With Syncope and Suspected Dementia
Authors: Holden Timothy R. , Shah Manish N. , Gibson Tommy A. , Weiss Robert E. , Yagapen Annick N. , Malveau Susan E. , Adler David H. , Bastani Aveh , Baugh Christopher W. , Caterino Jeffrey M. , Clark Carol L. , Diercks Deborah B. , Hollander Judd E. , Nicks Bret A. , Nishijima Daniel K. , Stiffler Kirk A. , Storrow Alan B. , Wilber Scott T. , Sun Benjamin C.
Published: March 2018

Objectives

Syncope and near‐syncope are common in patients with dementia and a leading cause of emergency department (ED) evaluation and subsequent hospitalization. The objective of this study was to describe the clinical trajectory and short‐term outcomes of patients who presented to the ED with syncope or near‐syncope and were assessed by their ED provider to have dementia.

Methods

This multisite prospective cohort study included patients 60 years of age or older who presented to the ED with syncope or near‐syncope between 2013 and 2016. We analyzed a subcohort of 279 patients who were identified by the treating ED provider to have baseline dementia. We collected comprehensive patient‐level, utilization, and outcomes data through interviews, provider surveys, and chart abstraction. Outcome measures included serious conditions related to syncope and death.

Results

Overall, 221 patients (79%) were hospitalized with a median length of stay of 2.1 days. A total of 46 patients (16%) were diagnosed with a serious condition in the ED. Of the 179 hospitalized patients who did not have a serious condition identified in the ED, 14 (7.8%) were subsequently diagnosed with a serious condition during the hospitalization, and an additional 12 patients (6.7%) were diagnosed postdischarge within 30 days of the index ED visit. There were seven deaths (2.5%) overall, none of which were cardiac‐related. No patients who were discharged from the ED died or had a serious condition in the subsequent 30 days.

Conclusions

Patients with perceived dementia who presented to the ED with syncope or near‐syncope were frequently hospitalized. The diagnosis of a serious condition was uncommon if not identified during the initial ED assessment. Given the known iatrogenic risks of hospitalization for patients with dementia, future investigation of the impact of goals of care discussions on reducing potentially preventable, futile, or unwanted hospitalizations while improving goal‐concordant care is warranted.
Drink Less Enjoy More: effects of a multi‐component intervention on improving adherence to, and knowledge of, alcohol legislation in a UK nightlife setting
Authors: Quigg Zara , Hughes Karen , Butler Nadia , Ford Kat , Canning Ian , Bellis Mark A.
Published: March 2018

Aims

To estimate the association between implementation of a community‐based multi‐component intervention (Drink Less Enjoy More) and sales of alcohol to pseudo‐intoxicated patrons and nightlife patron awareness of associated legislation.

Design

Cross‐sectional pre‐intervention and follow‐up measurements, including alcohol test purchases (using pseudo‐intoxicated patrons) in licensed premises (stratified random sample; 2013, 2015) and a survey with nightlife patrons (convenience sample; 2014, 2015).

Setting

One UK municipality with a large night‐time economy.

Participants

Licensed premises (pre = 73; follow‐up = 100); nightlife patrons (pre = 214; follow‐up = 202).

Intervention

The Drink Less Enjoy More intervention included three interacting components: community mobilization and awareness‐raising; responsible bar server training; and active law enforcement of existing legislation prohibiting sales of alcohol to, and purchasing of alcohol for, a person who appears to be alcohol intoxicated: ‘intoxicated’, herein for economy.

Measurements

The primary outcomes were alcohol service refusal to pseudo‐intoxicated patrons and nightlife patron knowledge of alcohol legislation (illegal to sell alcohol to, and purchase alcohol for, intoxicated people), adjusted for potential confounders including characteristics of the area, venue, test purchase and nightlife patron.

Findings

Pre‐intervention, 16.4% of alcohol sales were refused, compared with 74.0% at follow‐up (P < 0.001). In adjusted analyses, the odds of service refusal were higher at follow‐up [adjusted odds ratio (aOR) = 14.63, P < 0.001]. Service refusal was also associated with server gender and patron drunkenness within the venue. Among drinkers, accurate awareness of alcohol legislation was higher at follow‐up (sales: pre = 44.5%; follow‐up = 66.0%; P < 0.001/purchase: pre = 32.5%; follow‐up = 56.0%; P < 0.001). In adjusted analyses, knowledge of legislation was higher at follow‐up (sales: aOR = 2.73, P < 0.001; purchasing: aOR = 2.73, P < 0.001). Knowledge of legislation was also associated with participant age (purchasing) and expectations of intoxication (sales).

Conclusion

A community‐based multi‐component intervention concerning alcohol sales legislation in the United Kingdom (UK) was associated with a reduction in sales of alcohol to pseudo‐intoxicated patrons in on‐licensed premises in a UK nightlife setting and an improvement in nightlife patron awareness of associated legislation.
Issue Voting as a Constrained Choice Problem
Authors: Moral Mert , Zhirnov Andrei
Published: March 2018

Prevalent models of issue voting view vote choice as a choice among party policies. Choice sets are implicitly assumed to be the same for all voters, and their composition is left to researchers' discretion. This article aims to relax such assumptions by presenting a model with a varying probability of inclusion in the choice set. We apply the “constrained choice conditional logistic regression” to survey data from the 1989 parliamentary election in Norway to examine the effects of party identification of voters and electoral viability and policy extremity of parties on individual voters' choice set compositions. Further, we look into the effect of parties' policy positions on their electoral fates under alternative assumptions about the composition of voters' choice sets. We find that voters' choice set composition conditions both the effects of their policy considerations on vote choice and those of parties' policy offerings on their electoral fates.
Partisan Elites as Culprits? How Party Cues Shape Partisan Perceptual Gaps
Authors: Bisgaard Martin , Slothuus Rune
Published: March 2018

Partisanship often colors how citizens perceive real‐world conditions. For example, an oft‐documented finding is that citizens tend to view the state of the national economy more positively if their party holds office. These partisan perceptual gaps are usually taken as a result of citizens' own motivated reasoning to defend their party identity. However, little is known about the extent to which perceptual gaps are shaped by one of the most important forces in politics: partisan elites. With two studies focusing on perceptions of the economy—a quasi‐experimental panel study and a randomized experiment—we show how partisan perceptual differences are substantially affected by messages coming from party elites. These findings imply that partisan elites are more influential on, and more responsible for, partisan perceptual differences than previous studies have revealed.
Multiple drug intolerance syndrome and multiple drug allergy syndrome: Epidemiology and associations with anxiety and depression
Authors: Blumenthal K. G. , Li Y. , Acker W. W. , Chang Y. , Banerji A. , Ghaznavi S. , Camargo C. A. , Zhou L.
Published: March 2018

Background

The epidemiology of multiple drug intolerance syndrome (MDIS) and multiple drug allergy syndrome (MDAS) is poorly characterized. We used electronic health record (EHR) data to describe prevalences of MDIS and MDAS and to examine associations with anxiety and depression.

Methods

Patients with ≥3 outpatient encounters at Partners HealthCare System from 2008 to 2015 were included. Patients with MDIS had intolerances to ≥3 drug classes, and patients with MDAS had hypersensitivities to ≥2 drug classes. Psychiatric conditions and comorbidities were defined from the EHR and used in multivariable logistic regression models to assess the relation between anxiety/depression and MDIS/MDAS.

Results

Of 746 888 patients, 47 634 (6.4%) had MDIS and 8615 (1.2%) had MDAS; 3171 (0.4%) had both. Anxiety (adjusted odds ratio [aOR] 1.72 [1.65, 1.80]), depression (aOR 1.46 [1.41, 1.52]), and both anxiety and depression (aOR 1.97 [1.86, 2.08]) were associated with increased odds of MDIS. Depression was associated with increased odds of MDAS (aOR 1.41 [1.28, 1.56]), but there were no clear associations with anxiety (aOR 1.13 [0.99, 1.30]) nor both depression and anxiety (aOR 1.13 [0.92, 1.38]).

Conclusion

While 6% of patients had MDIS, only 1% had MDAS. MDIS was associated with both anxiety and depression; patients with both anxiety and depression had an almost twofold increased odds of MDIS. MDAS was associated with a 40% increased odds of depression, but there was no significant association with anxiety. Psychological assessments may be useful in the evaluation and treatment of patients with MDIS and MDAS; physiologic causes for MDAS warrant further investigation.
Advancing the Science of Self‐Management in Adults With Long‐Term Left Ventricular Assist Devices
Authors: Casida Jesus , Aikens James , Pagani Francis , Ewald Gregory , Craddock Heidi , Pavol Marykay , Schroeder Sarah , Yang James
Published: March 2018

This study tested the applicability of the individual and family self‐management theory (IFSMT) to self‐management (SM) in patients with left ventricular assist devices (LVADs). From an existing data set, we extracted the following variables that correspond to IFSMT's conceptual dimensions: anxiety, depression, and cognition (context dimension); self‐efficacy (SM process dimension); adherence and quality of life (QOL; outcome dimensions). Descriptive statistics and partial least squares path modeling procedures were used for data analyses. A total of 100 patients (mean age 52 ± 13.4 years) with continuous flow LVAD designs comprised the present study. Most patients were White (78%), married (69%), college‐educated (72%), and on disability (53%). Their mean anxiety and depression scores were slightly above normal, while their cognitive function scores were slightly lower than normal. LVAD care self‐efficacy, adherence, and QOL were within normal ranges. Factor loadings ranged from 0.50 to 1.0, and there were significant forward path relationships among the context, process, and outcome dimensions (β ranges from 0.02 to 0.60, all P values < 0.05). In conclusion, the IFSMT provides a good fit for SM in LVAD. Further research is needed to clarify how best to improve LVAD SM practice and treatment outcomes.
Ocular microcirculation measurement with laser speckle flowgraphy and optical coherence tomography angiography in glaucoma
Authors: Kiyota Naoki , Kunikata Hiroshi , Shiga Yukihiro , Omodaka Kazuko , Nakazawa Toru
Published: March 2018

Purpose

To compare glaucoma severity with ocular microcirculation, measured with either laser speckle flowgraphy (LSFG) or optical coherence tomography angiography (OCTA).

Methods

We retrospectively studied 82 eyes of 82 open‐angle glaucoma (OAG) patients who underwent same‐day LSFG and OCTA examinations, with 20 eyes of 20 healthy subjects as controls. In OCTA images, vessel density (VD) (%) was calculated in concentric regions (regions 1, 2 and 3: R1, R2 and R3, respectively) defined by 1.6‐, 3.2‐ and 3.6‐mm‐diameter circles around the optic nerve head (ONH). In R3, the large vessels were automatically masked to calculate pure capillary density (auto R3 VD). LSFG‐measured mean blur rate (MBR) was examined in the overall ONH (MA), vessel‐area ONH (MV) and tissue‐area ONH (MT).

Results

Auto R3 VD had high reproducibility (coefficient of variation: 1.65–3.88%) and accurately reflected manual R3 VD [mean bias: −0.0087% (auto R3 VD – manual R3 VD)]. MA and MT decreased significantly with OAG severity, especially in the early OAG stages (control vs. mild: p = 0.003 and p < 0.001, respectively). R1 VD did not change with severity. R2 and auto R3 VD decreased significantly with OAG severity, especially in the severe stages (R2, mild vs. severe: p = 0.008; auto R3 VD, mild vs. severe: p < 0.001, moderate vs. severe: p = 0.028).

Conclusion

Optical coherence tomography angiography‐derived auto R3 VD is novel, reproducible and accurately reflects manual measurements. It is useful for differentiating moderate and advanced glaucoma, while LSFG‐derived MT is useful for identifying early glaucoma.
Comparability of subjective and objective measurements of nuclear density in cataract patients
Authors: Makhotkina Natalia Y. , Berendschot Tos T. J. M. , van den Biggelaar Frank J. H. M. , Weik Alexander R. H. , Nuijts Rudy M. M. A.
Published: March 2018

Purpose

To evaluate the relationship between subjective and objective measurements of lens density and the energy of phacoemulsification.

Setting

University Eye Clinic, Maastricht University Medical Centre, Maastricht, the Netherlands.

Design

Cross‐sectional study.

Methods

The study population included 69 patients. Nuclear opalescence (NO) was graded with the Lens Opacities Classification System III (LOCS III). Thereafter, lens density was measured objectively with Scheimpflug imaging, anterior segment optical coherent tomography and spectral fundus reflectometry (SFR). Cumulative dissipative energy (CDE) and total ultrasound time (US t.t.) of the phacoemulsification were noted. The relationship between the different measurement techniques and energy of phacoemulsification was assessed using Spearman's correlation coefficients.

Results

We found moderate to strong correlations between LOCS III and objective measurements of the lens density (rho's from 0.53 to 0.78, p < 0.05) and a moderate correlation between three objective measurement techniques (rho's between 0.29 and 0.57, p < 0.05). There was a moderate correlation between CDE, US t.t. and lens density measurements (rho's from 0.29 to 0.55, p < 0.05), and the highest correlation was found between CDE and NO scores. Exclusion of patients with advanced cortical and posterior subcapsular opacities improved the correlation between SFR and lens density measurements but not the correlation with the energy of phacoemulsification.

Conclusion

Lens Opacities Classification System III has shown the highest correlation with phacoemulsification energy and may be a preferred technique for prediction of use of phacoemulsification energy. Advanced cortical and posterior opacities may interfere with the quality of objective measurements but do not affect the correlation between lens density measurements and phacoemulsification energy.
Optic disc–fovea distance and myopia progression in school children: the Beijing Children Eye Study
Authors: Guo Yin , Liu Li Juan , Tang Ping , Feng Yi , Wu Min , Lv Yan Yun , Xu Liang , Jonas Jost B.
Published: March 2018

Purpose

To assess changes in the optic disc–fovea distance (DFD) with progressing myopia in school children.

Methods

The school‐based, prospective, longitudinal study included grade‐1 children in 2011 who were yearly re‐examined until 2016. We measured DFD, optic disc diameters and width of parapapillary gamma zone (parapapillary region without Bruch's membrane (BM)) on fundus photographs.

Results

Of 382 grade‐1 children examined in 2011, 294 (77.0%) children (mean age in 2011: 6.4 ± 0.5 years) returned to be examined in 2016. In relative terms, the increase in DFD (1.15 ± 0.33 mm) was more due to an increase in gamma zone width (+300% or 0.29 ± 0.30 mm) than an increase in macular BM length (+18% or 0.74 ± 0.21 mm). In multivariate regression analysis, longer increase in DFD was correlated (regression coefficient r2 = 0.79) with longer axial elongation during the study period (p < 0.001; standardized regression coefficient β: 0.61; non‐standardized regression coefficient B: 0.30; 95% confidence interval (CI): 0.26, 0.33), larger increase in gamma zone width (p < 0.001; β: 0.35; B: 0.40; 95%CI: 0.32, 0.48) and longer axial length in 2011 (p = 0.01; β:0.07; B:0.03; 95%CI:0.01, 0.06). Larger increase in gamma zone width was associated (r2 = 0.73) with larger increase in DFD (p < 0.001; β: 0.51; B: 0.46; 95%CI: 0.39, 0.53), larger increase in the vertical‐to‐horizontal disc diameter ratio (p < 0.001; β: 0.43; B:1.21; 95%CI: 1.00, 1.42) and longer vertical disc diameter (p < 0.001; β: 0.15; B:0.24; 95%CI: 0.14, 0.34).

Conclusion

In adolescent school children, axial elongation‐associated increase in DFD was mainly due to an enlargement (+300%) of parapapillary gamma zone, while macular BM length increased to minor degree (+18%). Gamma zone enlargement was correlated with axial elongation‐associated vertical optic disc rotation, potentially due to an increased backward pull of the optic nerve on the temporal optic disc border.
Underlying maternal and pregnancy‐related conditions account for a substantial proportion of neonatal morbidity in late preterm infants
Authors: Bonnevier Anna , Brodszki Jana , Björklund Lars J. , Källén Karin
Published: March 2018

Aim

We studied the impact of maternal and pregnancy‐related conditions and the effect of gestational age itself, on the health of infants born late preterm.

Methods

Singletons born in gestational weeks 34 + 0 to 41 + 6 in 1995–2013 in the southern region of Sweden were identified from a perinatal register. We found 14 030 infants born late preterm and 294 814 born at term. A hierarchical system was developed to examine the impact of pregnancy complications. The outcomes studied were as follows: neonatal death, central nervous system (CNS) or respiratory disease, infection, neonatal admission and respiratory support. Odds ratios (OR) and 95% confidence intervals (95% CI) were obtained using logistic regression analyses.

Results

Late preterm infants were at increased risk for all outcomes compared to term infants, with adjusted ORs from 13.1 (95% CI: 12.7–13.6) for neonatal admission to 2.3 (95% CI: 1.8–2.9) for infections. Late preterm birth after preterm prelabour rupture of membranes was associated with an overall lower risk compared to late preterm births due to other causes. Exposure to antepartum haemorrhage or maternal diabetes increased the risk for CNS and respiratory morbidity.

Conclusion

Morbidity decreased in late preterm infants with increasing gestational age. Underlying conditions accounted for a substantial part of the morbidity.
The contributions of welfare typologies to international social work practices
Authors: Yu Sam Wai Kam
Published: March 2018

This paper is concerned with the link between studies of welfare typologies and studies of international social work. Its objective is to show how welfare typologies could be used to strengthen the role of international social work practices to support international exchange of ideas on welfare issues. To meet this objective, three analytical tasks are implemented. The first task is to show that professional imperialism could weaken the potential of international social work practices to promote international exchange of ideas on welfare issues. The second task is to discuss the importance of welfare typologies in supporting the development of international social work by challenging professional imperialism. The third task is to discuss a research project on a defamilization typology. This project provides empirical evidence of the contributions made by welfare typologies to international social work practices.
A pharmacological rationale for improved everolimus dosing in oncology and transplant patients
Authors: ter Heine R. , van Erp N. P. , Guchelaar H. J. , de Fijter J. W. , Reinders M. E. J. , van Herpen C. M. , Burger D. M. , Moes D. J. A. R.
Published: March 2018

Aims

Everolimus is a drug from the class of mammalian target of rapamycin inhibitors used for both immunosuppressant and oncological indications. We postulate that there is room for improvement of dosing, as the optimal immunosuppressive dose in calcineurin‐free regimens is unknown and since the once daily dosing regimen for oncological indications is often associated with treatment‐limiting toxicity.

Methods

We developed a mechanistic population pharmacokinetic model for everolimus in cancer and transplant patients and explored alternative dosing regimens.

Results

We found that formulation did not influence bioavailability and that use of >20 mg prednisolone daily increased everolimus clearance. In transplant patients, the approved dose of 0.75–1 mg twice daily (BID) results in subtherapeutic trough levels (<6 μg l–1) and that a higher starting dose of 2.25–3 mg BID is required.

Conclusion

For oncological indications, our results encourage the investigation of dosing everolimus 3.75 mg BID in terms of superiority in safety and noninferiority in efficacy.
Vitamin D Analogues Tacalcitol and Calcipotriol Inhibit Proliferation and Migration of T98G Human Glioblastoma Cells
Authors: Emanuelsson Ida , Wikvall Kjell , Friman Tomas , Norlin Maria
Published: March 2018

The active form of vitamin D (1α,25‐dihydroxyvitamin D) acts as a steroid hormone and binds to the vitamin D receptor. This receptor is expressed in most cell types including cells in the central nervous system (CNS). Vitamin D has several functions in the body including effects on brain development, neuroprotection and immunological regulation. It has been shown that vitamin D has antiproliferative activities in different cancer cell lines. Tacalcitol and calcipotriol are synthetic analogues of 1α,25‐dihydroxyvitamin D with reduced effect on calcium metabolism. The aim of this study was to analyse the effects of tacalcitol and calcipotriol on cell viability, proliferation and migration in the human glioblastoma cell line T98G. Glioblastoma is the most lethal type of primary tumours in the CNS. Both analogues decreased cell viability and/or growth, dose‐dependently, in concentrations between 1 nM and 10 μM. Manual counting indicated suppressive effects by the vitamin D analogues on proliferation. Treatment with tacalcitol strongly suppressed thymidine incorporation, indicating that the vitamin D analogues mainly inhibit proliferation. Also, effects on cell migration were measured with wound‐healing assay. Both calcipotriol and tacalcitol reduced the migration rate of T98G cells compared to vehicle‐treated cells. However, they had no effect on caspase‐3 and ‐7 activities, suggesting that their mechanism of action does not involve induction of apoptosis. The current results indicate that the vitamin D analogues tacalcitol and calcipotriol strongly reduce proliferation and migration of human glioblastoma T98G cells, suggesting a potential role for this type of compounds in treatment of brain cancer.
A 28‐day Sub‐acute Genotoxic and Behavioural Assessment of Garcinielliptone FC
Authors: Coelho Vanessa R. , Prado Lismare S. , Rossato Raíssa R. , Ferraz Alexandre B. F. , Vieira Caroline G. , de Souza Luana P. , Pfluger Pricila , Regner Gabriela G. , Valle Marina T. C. , Leal Mirna B. , Dallegrave Eliane , Corrêa Dione S. , Picada Jaqueline N. , Pereira Patrícia
Published: March 2018

Garcinielliptone FC (GFC) is a polyisoprenylated benzophenone isolated from Platonia insignis Mart (Clusiaceae) with promising anticonvulsant properties. However, its safe use and other effects on the central nervous system require assessment. This study assessed the toxicological effects of GFC using the comet assay and the micronucleus test in mice treated for 28 days. A behavioural model was employed to detect possible injuries on the central nervous system. Mice treated with GFC (2, 10 and 20 mg/kg; i.p.) daily for 28 days were submitted to rotarod test, open‐field test and tail suspension test (TST). After the behaviour tasks, biological samples were assessed to evaluate genotoxic and mutagenic effects using the comet assay and the micronucleus test. Garcinielliptone FC did not impair the performance of the animals in the rotarod and open‐field tests, with no antidepressant‐like effect in TST. No genotoxic effects in blood and cerebral cortex were observable in the comet assay; however, there was a significant increase in index and frequency of damage in liver after treatment with GFC 20 mg/kg. Garcinielliptone FC did not increase micronucleus frequency in bone marrow. At the tested doses, GFC was not toxic to the CNS and did not induce genotoxic damage to blood or bone narrow cells. DNA damage to liver tissue was caused only by the highest dose, although no mutagenic potential was observed.
HLA‐A*02:07 Allele Associates with Clarithromycin‐Induced Cutaneous Adverse Drug Reactions in Chinese Patients
Authors: Chen Sheng‐An , Zhang Li‐Rong , Yang Fan‐Ping , Yang Lin‐Lin , Yang Ying , Chen Zi‐Hua , Jiang Meng‐Lin , Xiong Hao , Zhu Hui‐Zhong , Qi Zheng , Xing Qing‐He , Luo Xiao‐Qun
Published: March 2018

Genetic risk factors could cause cutaneous adverse drug reactions (cADRs) in patients after treatment with clarithromycin. This study explored the association of HLA class I genes with clarithromycin‐cADRs in Han Chinese patients. A total of 12 clarithromycin‐cADR patients and 34 clarithromycin‐tolerant controls were recruited for the high‐resolution genotyping of HLA class I genes (HLA‐A, HLA‐B and HLA‐C). The population controls consisted of 283 Han Chinese retrieved from the MHC database for validated comparison. A molecular docking analysis of HLA‐A*02:07 protein and clarithromycin was conducted using glide module with Schrödinger Suite. Among all tested HLA alleles, the carrier frequencies of HLA‐A*02:07 (58% versus 5.9%, OR = 22.40, 95% CI = 3.58–139.98, p = 8.20 × 10E‐5, pc = 1.1 × 10E‐3) and HLA‐B*46:01 (50% versus 5.9%, OR = 16.00, 95% CI = 2.59–98.99, p = 0.002, pc = 0.03) were significantly higher in clarithromycin‐cADRs than in clarithromycin‐tolerant controls. However, when compared to population controls, only HLA‐A*02:07, and not HLA‐B*46:01, reached statistical significance (58% versus 15.5%, OR = 7.61, 95% CI = 2.31–25.04, p = 1.2 × 10E‐4, pc = 1.7 × 10E‐3). Furthermore, molecular docking data revealed that clarithromycin could bind to and interact with HLA‐A*02:07 in two possible binding situations. These data suggest that HLA‐A*02:07 might be a genetic risk factor for developing clarithromycin‐cADRs in Han Chinese and serve as a useful biomarker for personalized medicine to prevent clarithromycin‐cADRs.
Preventing family transmission of anxiety: Feasibility RCT of a brief intervention for parents
Authors: Cartwright‐Hatton Sam , Ewing Donna , Dash Suzanne , Hughes Zoe , Thompson Ellen J. , Hazell Cassie M. , Field Andy P. , Startup Helen
Published: March 2018

Objectives

Children of anxious parents are at high risk of anxiety disorders themselves. The evidence suggests that this is due to environmental rather than genetic factors. However, we currently do little to reduce this risk of transmission. There is evidence that supporting parenting in those with mental health difficulties can ameliorate this risk. Therefore, the objective of this study was to test the feasibility of a new one‐session, group‐based, preventive parenting intervention for parents with anxiety disorders.

Design

Feasibility Randomized Controlled Trial.

Methods

A total of 100 parents with anxiety disorders, recruited from adult mental health services in England (and child aged 3–9 years), were randomized to receive the new intervention (a 1‐day, group workshop), or to treatment as usual. Children's anxiety disorder and anxiety symptoms were assessed to 12 months by outcome assessors who were blind to group allocation. Exploratory analyses were conducted on an intention to treat basis, as far as possible.

Results

A total of 51 participants were randomized to the intervention condition and 49 to the control condition (82% and 80% followed to 12 months, respectively). The attendance rate was 59%, and the intervention was highly acceptable to parents who received it. The RCT was feasible, and 12‐month follow‐up attrition rates were low. Children whose parents were in the control condition were 16.5% more likely to have an anxiety disorder at follow‐up than those in the intervention group. No adverse events were reported.

Conclusions

An inexpensive, light‐touch, psycho‐educational intervention may be useful in breaking the intergenerational cycle of transmission of anxiety disorders. A substantive trial is warranted.

Practitioner points

Anxiety disorders run in families, but we currently do little to help anxious parents to raise confident children. A brief group workshop was highly acceptable to such parents and was very inexpensive to run.

Children of parents who took part in the brief intervention were 16.5% less likely to have an anxiety disorder, 1 year later, than children whose parents were in the control group.

This was a feasibility study, and while it showed that both the intervention and the research were feasible, the study needs replicating with a much larger sample.

Many parents faced barriers to attending the workshop, and future efforts should focus on widening accessibility.

We were unable to obtain sufficient self‐report data from children, so the outcomes are based on parent report only.
Human hepatocytes and cytochrome P450‐selective inhibitors predict variability in human drug exposure more accurately than human recombinant P450s
Authors: Lindmark Bo , Lundahl Anna , Kanebratt Kajsa P , Andersson Tommy B , Isin Emre M
Published: March 2018

Background and Purpose

Drugs metabolically eliminated by several enzymes are less vulnerable to variable compound exposure in patients due to drug–drug interactions (DDI) or if a polymorphic enzyme is involved in their elimination. Therefore, it is vital in drug discovery to accurately and efficiently estimate and optimize the metabolic elimination profile.

Experimental Approach

CYP3A and/or CYP2D6 substrates with well described variability in vivo in humans due to CYP3A DDI and CYP2D6 polymorphism were selected for assessment of fraction metabolized by each enzyme (fmCYP) in two in vitro systems: (i) human recombinant P450s (hrP450s) and (ii) human hepatocytes combined with selective P450 inhibitors. Increases in compound exposure in poor versus extensive CYP2D6 metabolizers and by the strong CYP3A inhibitor ketoconazole were mathematically modelled and predicted changes in exposure were compared with in vivo data.

Key Results

Predicted changes in exposure were within twofold of reported in vivo values using fmCYP estimated in human hepatocytes and there was a strong linear correlation between predicted and observed changes in exposure (r2 = 0.83 for CYP3A, r2 = 0.82 for CYP2D6). Predictions using fmCYP in hrP450s were not as accurate (r2 = 0.55 for CYP3A, r2 = 0.20 for CYP2D6).

Conclusions and Implications

The results suggest that variability in human drug exposure due to DDI and enzyme polymorphism can be accurately predicted using fmCYP from human hepatocytes and CYP‐selective inhibitors. This approach can be efficiently applied in drug discovery to aid optimization of candidate drugs with a favourable metabolic elimination profile and limited variability in patients.
Oxycodone‐induced tolerance to respiratory depression: reversal by ethanol, pregabalin and protein kinase C inhibition
Authors: Hill Rob , Dewey William L , Kelly Eamonn , Henderson Graeme
Published: March 2018

Background and Purpose

Oxycodone, a prescription opioid, is a major drug of abuse, especially in the USA, and contributes significantly to opioid overdose deaths each year. Overdose deaths result primarily from respiratory depression. We have studied respiratory depression by oxycodone and have characterized how tolerance develops on prolonged exposure to the drug. We have investigated the role of PKC in maintaining tolerance and have examined whether ethanol or pregabalin reverses oxycodone‐induced tolerance.

Experimental Approach

Respiration was measured in male CD‐1 mice by whole‐body plethysmography. Mice were preinjected with oxycodone then implanted with mini‐pumps (s.c.) delivering 20, 45 or 120 mg·kg−1·day−1 oxycodone for 6 days and subsequently challenged with oxycodone (3 mg·kg−1, i.p.) or morphine (10 mg·kg−1, i.p.) to assess the level of tolerance.

Key Results

Oxycodone‐treated mice developed tolerance to oxycodone and cross tolerance to morphine‐induced respiratory depression. Tolerance was less with 20 mg·kg−1·day−1 than with 45 or 120 mg·kg−1·day−1 oxycodone treatment. At doses that do not depress respiration, ethanol (0.3 g·kg−1), pregabalin (20 mg·kg−1) and calphostin C (45 μg·kg−1) all reversed oxycodone‐induced tolerance resulting in significant respiratory depression. Reversal of tolerance was less in mice treated with oxycodone (120 mg·kg−1·day−1). In mice receiving ethanol and calphostin C or ethanol and pregabalin, there was no greater reversal of tolerance than seen with either drug alone.

Conclusion and Implications

These data suggest that oxycodone‐induced tolerance is mediated by PKC and that reversal of tolerance by ethanol or pregabalin may be a contributory factor in oxycodone overdose deaths.
Separating the wheat from the chaff: A disaggregate analysis of the effects of public spending in the US
Authors: Bouakez Hafedh , Larocque Denis , Normandin Michel
Published: March 2018

In this paper, we undertake a systematic disaggregate analysis of the effects of government spending on economic activity in the US. The level of disaggregation we consider is the highest available and is unprecedented in the empirical literature. More specifically, public consumption and public investment are decomposed into various subcategories, which are measured at the levels of the federal (defence and non‐defence), and state and local governments. For each subcategory, we estimate a structural vector autoregression that identifies public spending shocks through the conditional heteroskedasticity of the structural disturbances, thus relaxing the identifying restrictions commonly used in the literature. Our analysis reveals significant heterogeneity in the effects of public spending shocks on output both across subcategories and government levels. Shocks to spending on durables and structures are found to have the largest and most persistent effect on aggregate output, with a peak multiplier that exceeds 1. Our results also suggest that there is little association between the size of a given category of public expenditures and the magnitude of its effect on output.

Séparer le bon grain de l’ivraie : une analyse désagrégée des effets des dépenses publiques aux États‐Unis. Dans ce texte, on entreprend une analyse désagrégée des effets des dépenses gouvernementales sur l’activité économique aux États‐Unis. Le niveau de désagrégation considéré est le plus grand possible et est sans précédent dans la littérature empirique. Plus spécifiquement, la consommation et l’investissement publics sont décomposés en diverses sous‐catégories qui sont mesurées pour le gouvernement fédéral (défense et non‐défense), ainsi que pour les gouvernements des états et locaux. Pour chaque sous‐catégorie, on estime un vecteur autorégressif structurel qui identifie les chocs de dépenses publiques à travers l’hétéroscédastictité conditionnelle des perturbations structurelles, pour ainsi relâcher les restrictions d’identification communément utilisées dans la littérature. L’analyse révèle une hétérogénéité significative dans les effets des chocs de dépenses publiques sur la production agrégée selon les sous‐catégories et les niveaux de gouvernement. Les chocs dans les dépenses sur les biens durables et les structures tendent à avoir les effets les plus grands et les plus persistants sur la production agrégée avec un effet multiplicateur qui excède 1. Les résultats suggèrent qu’il y a peu de rapport entre la taille d’une catégorie donnée dans les dépenses publiques et l’ampleur de l’effet sur la production agrégée.
c‐Src inhibitor selectively inhibits triple‐negative breast cancer overexpressed Vimentin in vitro and in vivo
Authors: Lou Longquan , Yu Ziyi , Wang Yue , Wang Shui , Zhao Yi
Published: March 2018

Oncogene c‐Src has been found to be a potential target for the treatment of triple‐negative breast cancer (TNBC). However, the therapeutic effects of the c‐Src inhibitor on TNBC patients are controversial compared to those on cell lines. The molecular mechanisms of the inhibitory effects of the c‐Src inhibitor on TNBC remain unclear. Herein, we showed that a specific c‐Src inhibitor, PP2, was effective in inhibiting phosphorylation of c‐Src in 4 cell lines: T‐47D, SK‐BR‐3, SUM1315MO2, and MDA‐MB‐231, regardless of hormone receptors and human epidermal growth factor receptor 2 (HER2) expression levels. Giving PP2 preferentially reduced the S phase of cell cycles and inhibited colony formation in SUM1315MO2 and MDA‐MB‐231, but not in SK‐BR‐3 and T‐47D cells. Furthermore, PP2 effectively blocked cell migration/invasion and epithelial‐mesenchymal transition (EMT) in TNBC cell lines, SUM1315MO2 and MDA‐MB‐231. An EMT biomarker, vimentin, was highly expressed in 2 TNBC cell lines when they were compared with SK‐BR‐3 and T‐47D cells. Further depletion of vimentin by shRNA remarkably attenuated the inhibitory effects of the c‐Src inhibitor on TNBC cells in vitro and in vivo, indicating a crucial action of vimentin to affect the function of c‐Src in TNBC. This study provides an important rationale for the clinic to precisely select TNBC patients who would benefit from c‐Src inhibitor treatment. This finding suggests that traditional markers for TNBC are not sufficient to precisely define this aggressive type of cancer. Vimentin is identified as an important biomarker to enable categorization of TNBC.
Sonodynamic therapy‐assisted immunotherapy: A novel modality for cancer treatment
Authors: Zhang Qianyu , Bao Cuixia , Cai Xiaojun , Jin Longwei , Sun Lingling , Lang Yuehong , Li Libo
Published: March 2018

Sonodynamic therapy (SDT), which is based on photodynamic therapy (PDT), is a new cancer treatment modality. Unlike PDT, which has poor tissue penetration, ultrasound can penetrate deeply into tissues and largely target tumor tissue to mediate the cytotoxicity of sonosensitizers. We hypothesize that, similar to PDT, SDT may perform effectively as a cancer vaccine. Thus, we developed a therapeutic strategy to explore whether SDT can eliminate primary tumors, inhibit metastases, and prevent tumor relapse. In the present study, we found that HiPorfin (HPD)‐induced SDT killed tumor cells, promoted calreticulin expression on the cell surface and elicited immune responses. Meanwhile, we observed that SDT induced functional antitumor vaccination and abscopal effects in H22 tumor‐bearing mice. Furthermore, this strategy conferred an immunological memory, which could protect against tumor recurrence after the elimination of the initial tumor. These results showed important effects of SDT on immune responses.
The PLGF/c‐MYC/miR‐19a axis promotes metastasis and stemness in gallbladder cancer
Authors: Li Huaifeng , Jin Yunpeng , Hu Yunping , Jiang Lin , Liu Fatao , Zhang Yijian , Hao Yajuan , Chen Shili , Wu Xiangsong , Liu Yingbin
Published: March 2018

Gallbladder cancer (GBC) is the most common malignant tumor of the biliary tract system. Epithelial–mesenchymal transition (EMT) plays a vital role in the process of tumor metastasis. Mesenchymal‐like cells can serve as a source of cancer stem cells, which can confer the EMT phenotype. Placental growth factor (PLGF) belongs to the vascular endothelial growth factor family and plays a vital role in cancer. However, the underlying molecular mechanisms about the influence of PLGF on EMT in GBC remain unknown. Here we show that PLGF expression levels were higher in GBC tissues than in normal adjacent tissues and were associated with poor prognosis in GBC patients. Exogenous PLGF enhanced the migration, invasion, and tumorsphere formation of GBC cells. Conversely, knockdown of PLGF decreased the aggressive phenotype of GBC cells. Mechanistically, exogenous PLGF upregulated microRNA‐19a (miR‐19a) expression through the activation of c‐MYC. Moreover, Spearman's correlation analysis showed a positive pairwise correlation among PLGF, c‐MYC, and miR‐19a expression in GBC tissues. Taken together, these results suggest that PLGF promotes EMT and tumorsphere formation through inducing miR‐19a expression by upregulating c‐MYC. Thus, PLGF could be a promising molecular therapeutic target for GBC.
3‐Aminomethyl pyridine chalcone derivatives: Design, synthesis, DNA binding and cytotoxic studies
Authors: Durgapal Sunil Dutt , Soni Rina , Umar Shweta , Suresh Balakrishnan , Soman Shubhangi S.
Published: March 2018

Herein we report design, synthesis, and anticancer activity of compounds 6a–h and 11a–j. Compounds 6a–f were designed based on 3‐aminomethyl pyridine attached to different acetamide derivatives and in compounds 6g–h it was attached to coumarin moiety. Coumarin containing compounds 6g–h showed very poor anticancer activity against both A549 (Lungs cancer cell line), and MCF‐7 (Breast cancer cell line) cell lines in MTT assay. Compounds 11a–j were designed as derivatives of 3‐aminomethyl pyridine and 4‐amino chalcones. A series of chalcone derivatives of 3‐aminomethyl pyridine 11a–j have been synthesized and screened for their in vitro anticancer activity and DNA binding affinity. Most of the compounds showed very good antimitotic activity against A549 cell line as compared to fluorouracil. Compounds 11g and 11i were selected for DNA‐binding studies as they showed excellent activity against cancer cell lines in MTT assay. CT‐DNA binding affinity of compounds 11g and 11i have been investigated by UV based DNA titration and fluorescence emission study against DNA‐EtBr complex. Interestingly, compound 11i has displayed excellent antiproliferative activity, with IC50 0.0067 ± 0.0002 μm, against MCF‐7 cell line. Compound 11i has been studied for its cytotoxicity using MTT, LDH, as well as EtBr/AO assay and was found to induce apoptosis in the cancerous cell line.
Our Buddies, Ourselves: The Role of Sexual Homophily in Adolescent Friendship Networks
Authors: Trinh Sarah L. , Lee Jaemin , Halpern Carolyn T. , Moody James
Published: March 2018

The present study tests the assumption that peers wield sufficient influence to induce sexual homophily (i.e., similarities in sexual experiences). Because girls face greater stigma for their sexual experiences than do boys, sexual homophily may be greater in girls' friendship networks than in boys'. Stochastic actor‐based models were used to analyze network data (n = 2,566; ages 14–18) from two high schools in the National Longitudinal Study of Adolescent to Adult Health. Sexual homophily was present in friendship networks. Girls and boys were equally susceptible to their friends' influence, but the former exhibited a stronger preference for befriending same sexual debut status peers than the latter. The findings suggest that adolescents—particularly girls—“curate” their networks to minimize peer ostracism.
Sensitization to minor cat allergen components is associated with type‐2 biomarkers in young asthmatics
Authors: Tsolakis N. , Malinovschi A. , Nordvall L. , Mattsson L. , Lidholm J. , Pedroletti C. , Janson C. , Borres M. P. , Alving K.
Published: March 2018

Background

Cat allergy is a major trigger of asthma world‐wide. Molecular patterns of cat sensitization vary between individuals, but their relationship to inflammation in asthmatics has not been extensively studied.

Objective

To investigate the prevalence and levels of IgE antibodies against different cat allergen components and their relationship to type‐2 inflammation and total IgE among young asthmatic subjects sensitized to furry animals.

Methods

Patients with asthma (age 10‐35 years; n = 266) and IgE sensitization to cat, dog or horse extract (ImmunoCAP), were analysed for IgE to the cat allergen components Fel d 1 (secretoglobin), Fel d 2 (serum albumin), Fel d 4 and Fel d 7 (lipocalins). Independent associations between IgE‐antibody concentrations, and fraction of exhaled nitric oxide (FeNO), blood eosinophil (B‐Eos) count, and total IgE were analysed by multiple linear regression after adjustment for possible confounders.

Results

The level of IgE against Fel d 2 was independently related to FeNO (P = .012) and total IgE (P < .001), and IgE against Fel d 4 associated with Β‐Eos count (P = .009) and total IgE (P < .001). IgE antibodies against Fel d 1 or cat extract did not independently relate to these inflammatory markers (P = .23‐.51).

Conclusions

Levels of IgE to lipocalin (Fel d 4) and serum albumin (Fel d 2), but not to secretoglobin (Fel d 1) or cat extract, were independently associated with type‐2 biomarkers and total IgE in young asthmatics.

Clinical relevance

We suggest that measurement of IgE to minor cat allergen components may be useful when investigating asthma morbidity in cat allergic subjects.