bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of clinical parameters on patient‐reported outcome in cataract patients: a multicentre study
Authors: Stolk‐Vos Aline C. , Visser Martijn S. , Klijn Stijn , Timman Reinier , Lansink Peter , Nuijts Rudy , Tjia Khiun , Zijlmans Bart , Kranenburg Leonieke W. , Busschbach Jan V. , Reus Nicolaas J.
Published: March 2018

Purpose

Ophthalmologists tend to evaluate the results of cataract surgery by focusing on the clinical visual and refractive outcomes and the incidence of complications, where patients’ main interest might be their ability to perform daily activities. Therefore, there appears to be a need for optimizing effective communication between patients and ophthalmologist about the outcome of cataract surgery. The aim of this multicentre study was to determine the effects of whether the surgery was performed in one or two eyes, ocular comorbidity and per‐ and postoperative complications on visual function experienced by patients measured with the Catquest‐9SF.

Methods

To measure patient‐reported outcomes, Catquest‐9SF data were collected between 2014 and 2015 in five Dutch hospitals. Data from 870 pairs of questionnaires – completed before and after cataract surgery – were compared with clinical data. Clinical data, retrieved from patients’ medical files, consisted of one or two eye surgery, ocular comorbidity and per‐ and postoperative complications.

Results

Quality of vision improved more in patients who had surgery in both eyes and had fewer postoperative complications (both p < 0.001). We found a nonsignificant trend that quality of vision was worse when ocular comorbidity was present. No significant effect of peroperative complications was observed.

Conclusion

Our results emphasize the added value of the Catquest‐9SF as a tool for visual function experienced by patients; the additional information can complement clinical parameters to improve patient‐centred approaches in clinical practice.
Peripheral retinal changes in highly myopic young Asian eyes
Authors: Chen David Z. , Koh Victor , Tan Marcus , Tan Colin S. , Nah Gerard , Shen Liang , Bhargava Mayuri , Cheng Ching‐Yu , Zhao Paul , Wong Tien Yin , Saw Seang‐Mei
Published: March 2018

Purpose

To determine the type and prevalence of peripheral retinal changes and its relationship with axial length (AL) in a population of young Asian adult males.

Methods

This was a cross‐sectional study of male subjects aged between 19 and 25 years old. High myopes [spherical equivalent refraction, (SER) < −6.00 D] were recruited and underwent further ocular investigations including dilated retinal photography and binocular indirect ophthalmoscopy by two trained ophthalmologists. The frequency of peripheral retinal changes within high myopes was correlated with axial length and also compared with a group of emmetropes (SER between −0.50 D and +1.00 D).

Results

A total of 593 high myopes and 156 emmetropes were recruited. White without pressure (WWOP; n = 458, 46.5%) and lattice degeneration (LD; n = 109, 14.6%) were the commonest findings, and their prevalence was significantly higher among high myopes (LD, 16.9% versus 5.8%; WWOP, 57.2% versus 5.8%; both p < 0.001). Among high myopes, temporal LD was more common (71%) and 35% had more than one area in the same eye. Increasing AL was associated with LD (odds ratio 1.28, p = 0.01) and retinal holes (odd's ratio 1.44, p = 0.02) on multivariate analysis.

Conclusion

White without pressure (WWOP) and LD were the commonest peripheral retinal changes. One‐third of high myopes with LD had more than one area in the same eye. Increasing AL was associated with LD and retinal holes. Studies in older adults should be conducted to develop clinical guidelines for the management of high myopes.
Intraoperative difficulties, complications and self‐assessed visual function in cataract surgery
Authors: Grimfors Magnus , Lundström Mats , Höijer Jonas , Kugelberg Maria
Published: March 2018

Purpose

To study associations between intraoperative difficulties and changes in patient‐perceived and postoperative visual function and visual satisfaction after cataract surgery.

Methods

Swedish multicenter, prospective, cross‐sectional, nonrandomized, National Cataract Register study. A total of 10 979 patients (n = 10 979) who underwent cataract surgery from 2008 to 2011 completed the Catquest‐9SF questionnaire before and 3 months postoperatively. Using Rasch analysis, we converted the nonparametric grading of the answers to parametric data and performed parametric statistical analyses. Multiple regression models were used to examine possible predictors associated with self‐assessed visual function after cataract surgery.

Results

Greater improvement in self‐assessed visual function was seen in patients in whom trypan blue dye was used; those without a posterior capsular tear or an ocular comorbidity; and those who were younger, female and had low preoperative corrected distance visual acuity (CDVA) or high postoperative CDVA compared with their counterparts. Significantly higher self‐assessed postoperative visual function was seen in patients in whom trypan blue dye was used and those with no posterior capsular tear or ocular comorbidity and no use of capsular hooks; and those who were younger and had low preoperative or high postoperative CDVA compared with their counterparts. The risk of general dissatisfaction after cataract surgery was significantly greater in patients with a posterior capsule tear, ocular comorbidity or low postoperative CDVA, and those in whom mechanical pupillary stretching was performed.

Conclusion

Several intraoperative difficulties, posterior capsular tear, ocular comorbidity, age, gender, and preoperative and postoperative CDVAs affect patient improvement and self‐assessed visual function after cataract surgery.
Gender differences in formal credit approaches: rural households in Vietnam
Authors: Tran Thi Kieu Van , Elahi Ehsan , Zhang Liqin , Abid Muhammad , Pham Quang Trung , Tran Thuy Duong
Published: March 2018

In Vietnam, women have poorer access to formal credit than men. This article determines the extent to which borrowing constraints restrict women’s access to formal credit and identifies the socioeconomic characteristics that determine formal credit discrimination. The study used secondary data from the Vietnam Access to Resources Household Survey (VARHS) published in 2013–14, and analysis was undertaken by econometric approaches such as logistic and multiple linear regression models and propensity score matching methods. The results show that among those participants who successfully obtained credit, approximately 85 per cent of women obtained less credit than men; and the amount of credit that women obtained was also less (on average, approximately 1.8 per cent less). Gender, number of years of schooling, marital status, participation in agricultural activities, off‐farm employment, and ownership of agricultural land for a male‐headed household positively influenced discrimination in obtaining credit and the amount of credit obtained. Moreover, the propensity score matching results found that the average increase in the credit obtained by males was 220,000 Vietnamese Dong (VND) and this is mainly due to discrimination in favour of men. The results suggest that policy action is needed to avoid discrimination in credit disbursement on the basis of gender.
Exercise on‐transition uncoupling of ventilatory, gas exchange and cardiac hemodynamic kinetics accompany pulmonary oxygen stores depletion to impact exercise intolerance in human heart failure
Authors: Van Iterson E. H. , Smith J. R. , Olson T. P.
Published: March 2018

Aim

In contrast to knowledge that heart failure (HF) patients demonstrate peak exercise uncoupling across ventilation, gas exchange and cardiac haemodynamics, whether this dyssynchrony follows that at the exercise on‐transition is unclear. This study tested whether exercise on‐transition temporal lag for ventilation relative to gas exchange and oxygen pulse (O2pulse) couples with effects from abnormal pulmonary gaseous oxygen store (O2store) contributions to O2 to interdependently precipitate persistently elevated ventilatory demand and low oxidative metabolic capacity in HF.

Methods

Beat‐to‐beat HR and breath‐to‐breath ventilation and gas exchange were continuously acquired in HF (N = 9, ejection fraction = 30 ± 9%) and matched controls (N = 10) during square‐wave ergometry at 60% O2peak (46 ± 14 vs 125 ± 54‐W, P < .001). Temporal responses across E, O2 and O2pulse were assessed for the exercise on‐transition using single exponential model Phase II on‐kinetic time constants (τ = time to reach 63% steady‐state rise). Breath‐to‐breath gas fractions and respiratory flows were used to determine O2stores.

Results

HF vs controls: τ for E (137 ± 93 vs 74 ± 40‐seconds, P = .03), O2 (60 ± 40 vs 23 ± 5‐seconds, P = .03) and O2pulse (28 ± 18 vs 23 ± 15‐seconds, P = .59). Within HF, τ for E differed from O2pulse (P < .02), but not O2. Exercise E rise (workload indexed) differed in HF vs controls (545 ± 139 vs 309 ± 88‐mL min−1 W−1, P < .001). Exercise on‐transition O2store depletion in HF exceeded controls, generally persisting to end‐exercise.

Conclusion

These data suggest HF demonstrated exercise on‐transition O2store depletion (high O2store contribution to O2) coupled with dyssynchronous E, O2 and O2pulse kinetics—not attributable to prolonged cardiac haemodynamics. Persistent high ventilatory demand and low oxidative metabolic capacity in HF may be precipitated by physiological uncoupling occurring within the exercise on‐transition.
Recurrent inhibition is higher in eccentric compared to isometric and concentric maximal voluntary contractions
Authors: Barrué‐Belou S. , Marque P. , Duclay J.
Published: March 2018

Aim

This study was designed to investigate the influence of muscle contraction type on spinal recurrent inhibition during maximal voluntary contractions (MVC) of the plantar flexor muscles.

Methods

To that purpose, the paired Hoffmann‐reflex (H‐reflex) technique permitted to assess changes in recurrent pathway by comparing the modulations of test, reference and conditioning H‐reflexes (H’, Href and H1 respectively) in the soleus muscle during isometric, concentric and eccentric MVC. Twenty‐five subjects participated in an experimental session designed to assess the activity of the recurrent inhibition pathway.

Results

The results indicate that both the electromyographic activity and the amplitude of H1 normalized to the maximal M‐wave (Mmax) were similar regardless of the muscle contraction type while the ratio between H’ and H1 amplitudes was significantly smaller during eccentric compared with isometric and concentric MVC. Furthermore, Href and H’ amplitudes did not differ significantly during both isometric and concentric MVCs while H’ amplitude was significantly lower than Href amplitude during eccentric MVC. In addition, the V/Mmax ratio was similar for all muscle contraction type and greater H’ amplitude was significantly correlated with greater V‐wave amplitude regardless of the muscle contraction type.

Conclusion

Together, the current results indicate that recurrent inhibition is elevated for the soleus muscle during eccentric compared to isometric and concentric MVC. Data further suggest that the Renshaw cell activity is specifically controlled by the descending neural drive and/or peripheral neural mechanisms during eccentric MVC.
The stressed brain of humans and rodents
Authors: Joëls M. , Karst H. , Sarabdjitsingh R. A.
Published: March 2018

After stress, the brain is exposed to waves of stress mediators, including corticosterone (in rodents) and cortisol (in humans). Corticosteroid hormones affect neuronal physiology in two time‐domains: rapid, non‐genomic actions primarily via mineralocorticoid receptors; and delayed genomic effects via glucocorticoid receptors. In parallel, cognitive processing is affected by stress hormones. Directly after stress, emotional behaviour involving the amygdala is strongly facilitated with cognitively a strong emphasis on the “now” and “self,” at the cost of higher cognitive processing. This enables the organism to quickly and adequately respond to the situation at hand. Several hours later, emotional circuits are dampened while functions related to the prefrontal cortex and hippocampus are promoted. This allows the individual to rationalize the stressful event and place it in the right context, which is beneficial in the long run. The brain's response to stress depends on an individual's genetic background in interaction with life events. Studies in rodents point to the possibility to prevent or reverse long‐term consequences of early life adversity on cognitive processing, by normalizing the balance between the two receptor types for corticosteroid hormones at a critical moment just before the onset of puberty.
A selenoprotein T‐derived peptide protects the heart against ischaemia/reperfusion injury through inhibition of apoptosis and oxidative stress
Authors: Rocca C. , Boukhzar L. , Granieri M. C. , Alsharif I. , Mazza R. , Lefranc B. , Tota B. , Leprince J. , Cerra M. C. , Anouar Y. , Angelone T.
Published: March 2018

Aim

Selenoprotein T (SelT or SELENOT) is a novel thioredoxin‐like enzyme whose genetic ablation in mice results in early embryonic lethality. SelT exerts an essential cytoprotective action during development and after injury through its redox‐active catalytic site. This study aimed to determine the expression and regulation of SelT in the mammalian heart in normal and pathological conditions and to evaluate the cardioprotective effect of a SelT‐derived peptide, SelT43‐52(PSELT) encompassing the redox motif which is key to its function, against ischaemia/reperfusion(I/R) injury.

Methods

We used the isolated Langendorff rat heart model and different analyses by immunohistochemistry, Western blot and ELISA.

Results

We found that SelT expression is very abundant in embryo but is undetectable in adult heart. However, SelT expression was tremendously increased after I/R. PSELT (5 nmol/L) was able to induce pharmacological post‐conditioning cardioprotection as evidenced by a significant recovery of contractility (dLVP) and reduction of infarct size (IS), without changes in cardiac contracture (LVEDP). In contrast, a control peptide lacking the redox site did not confer cardioprotection. Immunoblot analysis showed that PSELT‐dependent cardioprotection is accompanied by a significant increase in phosphorylated Akt, Erk‐1/2 and Gsk3α‐β, and a decrement of p38MAPK. PSELT inhibited the pro‐apoptotic factors Bax, caspase 3 and cytochrome c and stimulated the anti‐apoptotic factor Bcl‐2. Furthermore, PSELT significantly reduced several markers of I/R‐induced oxidative and nitrosative stress.

Conclusion

These results unravel the role of SelT as a cardiac modulator and identify PSELT as an effective pharmacological post‐conditioning agent able to protect the heart after ischaemic injury.
Roles of pH in control of cell proliferation
Authors: Flinck M. , Kramer S. H. , Pedersen S. F.
Published: March 2018

Precise spatiotemporal regulation of intracellular pH (pHi) is a prerequisite for normal cell function, and changes in pHi or pericellular pH (pHe) exert important signalling functions. It is well established that proliferation of mammalian cells is dependent on a permissive pHi in the slightly alkaline range (7.0‐7.2). It is also clear that mitogen signalling in nominal absence of is associated with an intracellular alkalinization (~0.3 pH unit above steady‐state pHi), which is secondary to activation of Na+/H+ exchange. However, it remains controversial whether this increase in pHi is part of the mitogenic signal cascade leading to cell cycle entry and progression, and whether it is relevant under physiological conditions. Furthermore, essentially all studies of pHi in mammalian cell proliferation have focused on the mitogen‐induced G0‐G1 transition, and the regulation and roles of pHi during the cell cycle remain poorly understood. The aim of this review is to summarize and critically discuss the possible roles of pHi and pHe in cell cycle progression. While the focus is on the mammalian cell cycle, important insights from studies in lower eukaryotes are also discussed. We summarize current evidence of links between cell cycle progression and pHi and discuss possible pHi‐ and pHe sensors and signalling pathways relevant to mammalian proliferation control. The possibility that changes in pHi during cell cycle progression may be an integral part of the checkpoint control machinery is explored. Finally, we discuss the relevance of links between pH and proliferation in the context of the perturbed pH homoeostasis and acidic microenvironment of solid tumours.
Assessing Surface Correspondence and Trade of Maya Figurines and Moulds Using Multi‐Stripe Laser Technology and Metrology*
Authors: Winemiller T. L. , Ochoa‐Winemiller V. , Ludwig J.
Published: March 2018

One of the most intriguing questions for archaeologists studying clay artefacts concerns technologies employed in their manufacture and whether standardization can be demonstrated through traditional ceramic analysis. Visual comparisons and mechanical measurements have been used to determine correlations and infer standardization. Using a laser multi‐line scanner and software developed to quantify Hausdorff distances between vertices in 3D surfaces, we analysed sample collections of figurines and moulds from Belize, Mexico and Honduras. The results indicated that this procedure was a more precise indicator of common source and standardization in moulded clay artefacts. This method provided data relevant to assessing the scope of ancient trade networks and the nature of social and economic relationships that existed among the ancient inhabitants of Mesoamerica.
Preoperative weight loss program involving a 20‐day very low‐calorie diet for obesity before laparoscopic gastrectomy for gastric cancer
Authors: Inoue Kentaro , Yoshiuchi Sawako , Yoshida Mika , Nakamura Natsuko , Nakajima Sachiko , Kitamura Akiko , Mouri Keiko , Michiura Taku , Mukaide Hiromi , Ozaki Takashi , Miki Hirokazu , Yanagimoto Hiroaki , Satoi Sohei , Kaibori Masaki , Hamada Madoka , Kimura Yutaka , Kon Masanori
Published: March 2018

Introduction

The increased visceral fat in patients with obesity can increase the technical difficulty of surgery. This study was performed to evaluate a preoperative 20‐day very low‐calorie diet for obesity before laparoscopic gastrectomy for gastric cancer.

Methods

This prospective single‐center study involved patients with obesity who were planning to undergo laparoscopic gastrectomy for gastric cancer. Obesity was defined according to the Japanese criteria: BMI ≥25 kg/m2 or waist circumference ≥85 cm in men and ≥90 cm in women. The patients underwent a preoperative 20‐day very low‐calorie diet and received nutritional counseling. Weight loss, body composition, visceral fat mass, and operative outcomes were evaluated.

Results

Thirty‐three patients were enrolled from September 2013 to August 2015. Their median age was 71 years, and 78.8% were men. Their median bodyweight and BMI were 72.3 kg (range, 53.8–82.5 kg) and 26.0 kg/m2 (range, 23.5–31.0 kg/m2), respectively. The patients achieved a mean weight loss of 4.5% (95% confidence interval [CI]: 3.8–5.1), corresponding to 3.2 kg (95%CI: 2.7–3.7 kg). Body fat mass was significantly decreased by a mean of 2.5 kg (95%CI: 1.9–3.1), whereas skeletal muscle mass was unaffected (mean: −0.20 kg [95%CI: −0.55–0.15]). The visceral fat mass reduction rate was high as 16.8% (range, 11.6%–22.0%). All patients underwent laparoscopic gastrectomy as planned. Severe postoperative morbidity (Clavien–Dindo grade ≥III) was seen in only one patient (3.0%).

Conclusion

The preoperative 20‐day very low‐calorie diet weight loss program is promising for the treatment of obesity before laparoscopic gastrectomy for gastric cancer.
MiR‐330‐5p negatively regulates ovine preadipocyte differentiation by targeting branched‐chain aminotransferase 2
Authors: Shi Tao , Yan Xiaoru , Qiao Liying , Li Baojun , Cheng Lifen , Pan Yangyang , Jing Jiongjie , Cao Ningxian , Liu Wenzhong
Published: March 2018

The differentiation of preadipocytes into adipose tissues is tightly regulated by various factors including microRNAs and cytokines. This article aims to study the effect of miR‐330‐5p on expression of BCAT2 in ovine preadipocytes. Ovine preadipocytes were isolated, and we found that the miR‐330‐5p expression decreased gradually during the early differentiation of ovine preadipocytes, while BCAT2 expression increased. BCAT2 was identified as a direct target of miR‐330‐5p, ectopic expression of miR‐330‐5p could change the expression of both BCAT2 mRNA and protein. Silencing BCAT2 had the same inhibition effects as overexpressing miR‐330‐5p on the preadipocyte differentiation, but overexpressing BCAT2 had the converse effects. Taken together, we demonstrated that miR‐330‐5p is a negative regulator of differentiation by targeting BCAT2, and clarified the role of BCAT2 and miR‐330‐5p during preadipocyte differentiation.
Effects of polyphenolic extract from Eucommia ulmoides Oliver leaf on growth performance, digestibility, rumen fermentation and antioxidant status of fattening lambs
Authors: Liu Huawei , Li Ke , Zhao Jinshan , Deng Wen
Published: March 2018

To investigate the effects of polyphenolic extract from Eucommia ulmoides Oliver leaf (PEEU) on growth performance, digestibility, rumen fermentation and antioxidant status of fattening lambs, 30 weaned male Huzhou lambs were equally divided into three treatments and fed the basal diet supplemented with 0 (CON), 5 (PEEU5) or 10 (PEEU10) g/kg PEEU. Dietary PEEU supplementation did not affect growth performance and apparent digestibility of nutrients. Compared with the CON group, lambs in the PEEU10 group had lower ammonia nitrogen concentration (p < .01) and acetic acid to propionic acid ratio (p < .05) and higher the molar proportion of propionate (p < .05) in rumen fluid. Ammonia nitrogen concentration (p < .01) and the molar proportion of propionate (p < .05) were affected by an interaction between PEEU and sampling day. Dietary PEEU supplementation at 10 g/kg increased total antioxidant capacity (p < .05), superoxide dismutase (p < .05) and glutathione peroxidase (p < .01) activities in serum and glutathione peroxidase activity (p < .05) in liver and decreased (p < .05) malondialdehyde content in serum and liver compared with the CON group. In conclusion, dietary PEEU supplementation affected rumen fermentation patterns and improved antioxidant status of fattening lambs.
Neuromuscular structure of the larva to early ancestrula stages of the cyclostome bryozoan Crisia eburnea
Authors: Nielsen Claus , Bekkouche Nicolas Tarik , Worsaae Katrine
Published: March 2018

For the first time, the development of a cyclostome bryozoan has been studied with immunochemistry and confocal laser scanning microscopy, with emphasis on nerves and muscles. The larva is covered by multiciliated cells, which are latitudinally strongly elongated and show phalloidin‐stained cell junctions. We hypothesize that these cells contract at metamorphosis and squeeze the apical invagination and the adhesive sac out. Ectodermal, longitudinal muscle cells extend from the cells of the inner, conical cuticularized part of the apical invagination to the lower part of the corona, around the adhesive sac pore. These muscles are retained in the ancestrula. Scattered monociliated nerve cells are interspersed between the coronal ciliary cells. An equatorial nerve in the larva disappears at metamorphosis. The central, conical part of the cuticle becomes the terminal membrane of the ancestrula, and the underlying ectodermal and mesodermal cell layers differentiate into the polypide bud, forming a deep narrow invagination, differentiating into vestibule–atrium, mouth ring and pharynx–stomach–rectum. Tentacles develop from the ring of cells around the mouth, and a small ganglion with four nerves innervating each of the tentacles develops at the anal side of the mouth. These new findings yield further support for previous homology statements of bryozoan larvae and development.
First‐in‐man–proof of concept study with molidustat: a novel selective oral HIF‐prolyl hydroxylase inhibitor for the treatment of renal anaemia
Authors: Böttcher M. , Lentini S. , Arens E. R. , Kaiser A. , van der Mey D. , Thuss U. , Kubitza D. , Wensing G.
Published: March 2018

Aims

Insufficient erythropoietin (EPO) synthesis is a relevant cause of renal anaemia in patients with chronic kidney disease. Molidustat, a selective hypoxia‐inducible factor prolyl hydroxylase (HIF‐PH) inhibitor, increases endogenous EPO levels dose dependently in preclinical models. We examined the pharmacokinetics, safety, tolerability and effect on EPO levels of single oral doses of molidustat in healthy male volunteers.

Methods

This was a single‐centre, randomized, single‐blind, placebo‐controlled, group‐comparison, dose‐escalation study. Molidustat was administered at doses of 5, 12.5, 25, 37.5 or 50 mg as a polyethylene glycol‐based solution.

Results

In total, 45 volunteers received molidustat and 14 received placebo. Molidustat was absorbed rapidly, and the mean maximum plasma concentration and area under the concentration–time curve increased dose dependently. The mean terminal half‐life was 4.64–10.40 h. A significant increase in endogenous EPO was observed following single oral doses of molidustat of 12.5 mg and above. Geometric mean peak EPO levels were 14.8 IU l–1 (90% confidence interval 13.0, 16.9) for volunteers who received placebo and 39.8 IU l–1 (90% confidence interval: 29.4, 53.8) for those who received molidustat 50 mg. The time course of EPO levels resembled the normal diurnal variation in EPO. Maximum EPO levels were observed approximately 12 h postdose and returned to baseline after approximately 24–48 h. All doses of molidustat were well tolerated and there were no significant changes in vital signs or laboratory safety parameters.

Conclusions

Oral administration of molidustat to healthy volunteers elicited a dose‐dependent increase in endogenous EPO. These results support the ongoing development of molidustat as a potential new treatment for patients with renal anaemia.
An update on the clinical evidence that supports biosimilar approvals in Europe
Authors: Mielke Johanna , Jilma Bernd , Jones Byron , Koenig Franz
Published: March 2018

Aim

Sponsors and regulators have more than 10 years of experience with the development of biosimilars in Europe. However, the regulatory pathway is still evolving. The present article provides an update on biosimilar development in practice by reviewing the clinical development programmes of recently approved biosimilars in Europe.

Methods

We used the European public assessment reports (EPARs) which are published by the European Medicines Agency (EMA) for a comparison of the clinical development programmes of the 37 approved biosimilars in Europe. Here, we present novel strategies in the development of biosimilars by focusing specifically on the 17 biosimilars that have gained approval in the last year, but we also compare additional key characteristics for all approved biosimilars.

Results

The high variability of the clinical development strategies that we found previously was confirmed in the present analysis. Compared with earlier biosimilar applications, more nonstandard development strategies have been used recently. This includes, for example, applications without any studies in patients, and more complex study designs. During this study, we found that the EPARs for biosimilars seem to be improving; however, we identified important details which were still often missing. We provide a proposal for a checklist of the minimum information that should be included in biosimilar EPARs for giving the general public insights into the rationale for the approval of biosimilars.

Conclusions

European regulators still seem to be open to consider approaches that differ from the guidelines or previous applications, as long as justification is provided.
The relationship between frailty and polypharmacy in older people: A systematic review
Authors: Gutiérrez‐Valencia M. , Izquierdo M. , Cesari M. , Casas‐Herrero Á. , Inzitari M. , Martínez‐Velilla N.
Published: March 2018

Aims

Frailty is a complex geriatric syndrome resulting in decreased physiological reserves. Frailty and polypharmacy are common in older adults and the focus of extensive studies, although little is known about the impact they may have on each other. This is the first systematic review analysing the available evidence on the relationship between frailty and polypharmacy in older adults.

Methods

Systematic review of quantitative studies. A comprehensive literature search for publications in English or Spanish was performed on MEDLINE, CINAHL, the Cochrane Database and PsycINFO in September 2017 without applying restrictions on the date of publication. Studies reporting any relationship between frailty and polypharmacy in older adults were considered.

Results

A total of 25 publications were included, all of them observational studies. Evaluation of Fried's frailty criteria was the most common approach, followed by the Edmonton Frail Scale and FRAIL scale. Sixteen of 18 cross‐sectional analyses and five of seven longitudinal analyses demonstrated a significant association between an increased number of medications and frailty. The causal relationship is unclear and appears to be bidirectional. Our analysis of published data suggests that polypharmacy could be a major contributor to the development of frailty.

Conclusions

A reduction of polypharmacy could be a cautious strategy to prevent and manage frailty. Further research is needed to confirm the possible benefits of reducing polypharmacy in the development, reversion or delay of frailty.
Combination of RIZ1 Overexpression and Radiotherapy Contributes to Apoptosis and DNA Damage of HeLa and SiHa Cervical Cancer Cells
Authors: Yang Shanshan , Xing Linan , Gu Lina , Cheng Haiyan , Feng Yue , Zhang Yunyan
Published: March 2018

Although radiotherapy has been widely applied to treating cervical cancer in the clinic, its therapeutic efficacy is often restricted to the radioresistance of cancer cells. Retinoblastoma protein‐interacting zinc finger gene 1 (RIZ1) has been suggested as a tumour suppressor gene, whereas its role in cervical cancer with or without radiotherapy has been unclear. In this study, two cervical cancer cell lines, HeLa and SiHa cells, stably transfected with RIZ1 overexpression plasmid were subjected to ionizing radiation, and their survival fractions were calculated by assessing their clonogenic abilities. Our results showed that the forced overexpression of RIZ1 significantly reduced the clonogenic survival rates of both HeLa and SiHa cells exposed to ionizing radiation. By analysing the cell apoptotic status, we found that the RIZ1‐overexpressed cervical cancer cells under ionizing radiation were more vulnerable to damage, and more γ‐H2AX foci were found in these cells. Furthermore, the volumes of tumour xenografts formed by the RIZ1‐overexpressed cells in nude mice under ionizing radiation were smaller than those generated by the control cells. There were more morphological changes, apoptosis cells and lower expression of PCNA in RIZ1‐overexpressed tumour tissues of mice after exposure to ionizing radiation. Taken together, our study demonstrates that the overexpression of RIZ1 combined with radiotherapy facilitates apoptosis and DNA damage of cervical cancer cells.
Identifying Off‐Label Prescriptions Through Data Mining in Danish Community Pharmacy Servers: An Exploratory Study on Desmopressin, Diclofenac, Fucidin, Mirtazapine and Quetiapine
Authors: Andrulyte Monika , Bjerrum Ole Jannik
Published: March 2018

The term off‐label use describes the prescription and administration of medicines outside of the terms for which it officially has been approved, including age, dose and indication. Off‐label data can be generated from the Danish National Prescription Registry through combinations with diagnoses; however, the community pharmacy servers provide equal, local, albeit less data through a faster and less constrained collection process. The data collection for this exploratory study took place at five community pharmacies in Denmark. Five drugs were chosen for the investigation and collection of prescription data across a 2‐year period. Off‐label use by age was observed to be 1.9% for diclofenac, 1.7% for desmopressin and 2.3% for quetiapine. The percentages were based on total number of 3881, 925, 2712 prescriptions, respectively. Off‐label monitored by dosage appeared to be 75% for quetiapine; by box label text analysis, off‐label indication was found to be 10–15% and 15–23% for quetiapine and mirtazapine (from a total number of 3178 prescriptions), respectively. By route of administration where fucidin ointment was applied to the nose in 60 patients, 83% were prescribed off‐label (non‐dermatological). This exploratory study revealed that pharmacy servers represent a reliable and up‐to‐date source to collect a substantial amount of raw prescription data. The method gives straightforward and simple access to analysis of off‐label use by age and dose, whereas it is possible but difficult to interpret off‐label indications and route of administration from the box label text.
Inventing a new measurement for inhibitory control in preschoolers
Authors: Buttelmann David , Berger Philipp
Published: March 2018

One of the most prominent tasks to measure spatial‐conflict inhibitory control in preschoolers is the windows task (Russell et al., 1991, Br. J. Dev. Psychol., 9, 331). However, this task has been criticized given its high demands on abilities other than inhibition. The aim of the current set of studies was to establish the ‘car task’ as a novel instrument to assess conflict inhibition in children. In this task, children are asked to point at the current location of an occluded object. To do so, they have to inhibit a misleading colour cue in front of the locations in critical trials. In Study 1, we demonstrated that 3‐ to 6‐year‐old children's (N = 88) performance in the car task correlated positively with that in the windows task (even after controlling for age). Study 2 investigated whether children's failure in the car task might be caused by their inability to master the basic processes involved in the task rather than a lack of inhibition. We presented a new group of preschoolers (N = 85) with a modified version of the task without any misleading colour cues. Performance significantly improved, indicating that the difficulty of the car task lies in the necessity to inhibit the misleading colour cue leading towards the incorrect location. These findings suggest that the car task is a valid measurement of spatial‐conflict inhibition in children.

Statement of contribution

What is already known on this subject?

Inhibitory control (IC) is important for action planning and execution.

One of the most prominent measurements of spatial‐conflict IC is the windows task.

This task has been criticized for additionally requiring rule inference to succeed.

What does this study adds?

Performance in the novel car task correlates with that in the windows task.

Study 2 controls for demands other than IC such as memory or task difficulty.

This task can thus be used to measure IC more purely without demanding rule inference.
Quality of both parents’ cognitive guidance and quantity of early childhood education: Influences on pre‐mathematical development
Authors: Sorariutta Anne , Silvén Maarit
Published: March 2018

Background

Only a handful of longitudinal studies have explored the effects of both parents in early parenthood on children's cognitive development, and no study has controlled for simultaneous early childhood education and care (ECEC) experiences.

Aims

To examine the similarity of each parent's cognitive guidance and contribution to children's pre‐mathematical outcomes across parent gender while controlling for amount of ECEC.

Sample

A longitudinal study on 66 Finnish two‐parent families and their children.

Methods

Both parents’ autonomy support and scaffolding behaviour were observed during play interactions with the child at 2;0. Children's numerical and spatial skills were tested at 3;0 and 4;0. Parental reports on amount of ECEC in months were collected at 2;0, 3;0, and 4;0.

Results

The two parenting constructs were conceptually similar across parent gender as demonstrated by fairly strong measurement equivalence. While mothers on average showed more scaffolding and equal amounts of autonomy support compared to fathers during play interaction, they displayed less variability in the former and more variability in the latter behaviour. The contribution of mothers’ and fathers’ cognitive guidance was more similar for children's numerical than spatial development. Both parents’ education positively predicted autonomy support but not amount of ECEC exposure, which was positively related to numerical development. As expected, parents’ education did not predict ECEC exposure, and child gender was not related to child outcomes.

Conclusions

The findings are discussed in relation to measurement invariance and gender‐neutral parenting in the context of early childhood.
Shared decision‐making in tinnitus care – An exploration of clinical encounters
Authors: Pryce Helen , Hall Amanda , Marks Elizabeth , Culhane Beth‐Anne , Swift Sarah , Straus Jean , Shaw Rachel L.
Published: March 2018

Objectives

This study examined clinical encounters between clinicians and patients to determine current practice for the diagnosis and treatment of tinnitus. The objective was to develop an understanding of the ideal clinical encounter that would facilitate genuine shared decision‐making.

Design

Video ethnography was used to examine clinical encounters for the diagnosis and treatment of tinnitus.

Methods

Clinical encounters were video‐recorded. Patients were interviewed individually following their clinic appointment. Data were analysed using constant comparison techniques from Grounded Theory. Initial inductive analyses were then considered against theoretical conceptualizations of the clinician–patient relationship and of the clinical encounter.

Results

Alignment between clinician and patient was found to be essential to a collaborative consultation and to shared decision‐making. Clinician groups demonstrated variation in behaviour in the encounter; some asked closed questions and directed the majority of the consultation; others asked open questions and allowed patients to lead the consultation.

Conclusions

A shift away from aetiology and physiological tests is needed so that tinnitus is managed as a persistent unexplained set of symptoms. This uncertainty is challenging for the medical professionals; lessons could be learned from the use of therapeutic skills. Further research is required to test techniques, such as the use of decision aids, to determine how we might create the ideal clinical encounter.

Statement of contribution

What is already known on this subject?

Tinnitus is a condition in which sound is heard in the absence of an external source. Current approaches to managing tinnitus vary depending on clinical site (Hoare & Hall, 2011).

In most instances, tinnitus does not have a straightforward medical cause. Tinnitus care is challenging to traditional biomedical encounters because the process of diagnosis may not lead to a defined treatment.

Clinicians are required to consider not only what the tinnitus sounds like but more importantly, what it means for the affected individual. This requires a careful and skilled approach to eliciting a patient's current behaviour, coping, and preferences for both outcomes and treatment approaches.

What does this study add?

We provide the first in‐depth description of decision‐making in clinical services for tinnitus.

Findings suggest a shift in focus is required to move away from the current prioritization of the biomedical treatment of tinnitus.

There is variation to the extent different clinicians were able to deal with the uncertainty presented by the symptoms of tinnitus.
Economic Integration and State Responses: Change in European Industrial Relations since Maastricht
Authors: Meardi Guglielmo
Published: March 2018

The article analyses industrial relations change in the six largest EU countries since 1992 in relation to increased internationalization pressures. Based on qualitative and quantitative analysis, it distinguishes between associational and state governance, and detects that despite a predominant, but not universal, trend of weakening trade unions and collective bargaining, no overall liberalization has occurred in the political regulation of employment (employment policies, welfare state, labour law, state support to collective bargaining, public sector). Rather than converging towards neoliberalism, industrial relations emerge as more politically contingent and dependent on multiple forms of power, which are affected by internationalization in different ways.
Stratigraphical signatures of glacier activity, marine processes and a possible tsunami in the Leirfjorden fjord‐valley system, north Norway
Authors: Hansen Louise , Bøe Reidulv , Sveian Harald , Husum Katrine
Published: March 2018

An integrated interpretation of on‐ and offshore stratigraphical records at Leirfjorden, north Norway, reveals new aspects of the area's palaeoenvironmental history. The study is based on marine sparker data and well‐exposed sections on land that were analysed for their sediment facies, mineralogy and fossil assemblages. Existing research and new radiocarbon dates provide a chronological framework for the interpretation. The late Younger Dryas Nordli substage type locality in the Leirfjorden catchment is revised and found to reflect local glacial activity, maybe a collapse of stagnant ice rather than glacier advance, while late Younger Dryas to Preboreal glacier re‐advances south of Leirfjorden and near Ranfjorden are here named the Bardal substage. The stratigraphical record includes pre‐Younger Dryas, valley‐crossing, glacial striae and old till with provenance of resistant bedrock typical of more elevated mountain areas. It differs from younger till units representing topographically controlled glacier movement. Part of the Leirfjorden fjord‐valley system is located between the main glacial and fluvial drainage paths affecting the sediment supply. As a result, highstand deposits are indistinct and fluvial sediments form only a minor part of the forced‐regressive systems tract. Instead, the valley fill overlying till and subtill sediments is dominated by the deglacial transgressive tract and a forced‐regressive systems tract with composite marine deposits and various marine erosion surfaces. A special event bed is interpreted as a possible tsunami deposit caused by seismicity and/or mass‐wasting in the fjord following glacier retreat. The study highlights the stratigraphical complexity of interconnected fjord and sound systems in a low accretion setting.
Inhibition of human prostate smooth muscle contraction by the LIM kinase inhibitors, SR7826 and LIMKi3
Authors: Yu Qingfeng , Gratzke Christian , Wang Yiming , Herlemann Annika , Sterr Christian Maximilian , Rutz Beata , Ciotkowska Anna , Wang Xiaolong , Strittmatter Frank , Stief Christian G , Hennenberg Martin
Published: March 2018

Background and Purpose

In men with benign prostatic hyperplasia, increased smooth muscle tone in the prostate may lead to bladder outlet obstruction and subsequent lower urinary tract symptoms. Consequently, medical treatment aims to inhibit prostate smooth muscle contraction. However, the efficacy of the treatment options available is limited, and improved understanding of mechanisms of prostate smooth muscle contraction and identification of new targets for medical intervention are mandatory. Several studies suggest that LIM kinases (LIMKs) promote smooth muscle contraction; however, this has not yet been examined. Here, we studied effects of the LIMK inhibitors on prostate smooth muscle contraction.

Experimental Approach

Human prostate tissues were obtained from radical prostatectomy. Phosphorylation of cofilin, a LIMK substrate, was examined using a phospho‐specific antibody. Smooth muscle contractions were studied in organ bath experiments.

Key Results

Real‐time PCR, Western blot and immunofluorescence suggested LIMKs are expressed in smooth muscle cells of prostate tissues. Two different LIMK inhibitors, SR7826 (1 μM) and LIMKi3 (1 μM), inhibited contractions of prostate strips, which were induced by electrical field stimulation, α1‐adrenoceptor agonists phenylephrine and methoxamine and the TXA2 analogue, U46619. LIMK inhibition in prostate tissues and cultured stromal cells (WPMY‐1) was confirmed by cofilin phosphorylation, which was reduced by SR7826 and LIMKi3. In WPMY‐1 cells, SR7826 and LIMKi3 caused breakdown of actin filaments and reduced viability.

Conclusions and Implications

Smooth muscle tone in the hyperplastic human prostate may underlie the effects of LIMKs, which promote contraction. Contraction of prostate strips can be inhibited by small molecule LIMK inhibitors.
Cannabidiol exerts antiepileptic effects by restoring hippocampal interneuron functions in a temporal lobe epilepsy model
Authors: Khan Archie A , Shekh‐Ahmad Tawfeeq , Khalil Ayatakin , Walker Matthew C , Ali Afia B
Published: March 2018

Background and Purpose

A non‐psychoactive phytocannabinoid, cannabidiol (CBD), shows promising results as an effective potential antiepileptic drug in some forms of refractory epilepsy. To elucidate the mechanisms by which CBD exerts its anti‐seizure effects, we investigated its effects at synaptic connections and on the intrinsic membrane properties of hippocampal CA1 pyramidal cells and two major inhibitory interneurons: fast spiking, parvalbumin (PV)‐expressing and adapting, cholecystokinin (CCK)‐expressing interneurons. We also investigated whether in vivo treatment with CBD altered the fate of CCK and PV interneurons using immunohistochemistry.

Experimental Approach

Electrophysiological intracellular whole‐cell recordings combined with neuroanatomy were performed in acute brain slices of rat temporal lobe epilepsy in in vivo (induced by kainic acid) and in vitro (induced by Mg2+‐free solution) epileptic seizure models. For immunohistochemistry experiments, CBD was administered in vivo (100 mg·kg−1) at zero time and 90 min post status epilepticus, induced with kainic acid.

Key Results

Bath application of CBD (10 μM) dampened excitability at unitary synapses between pyramidal cells but enhanced inhibitory synaptic potentials elicited by fast spiking and adapting interneurons at postsynaptic pyramidal cells. Furthermore, CBD restored impaired membrane excitability of PV, CCK and pyramidal cells in a cell type‐specific manner. These neuroprotective effects of CBD were corroborated by immunohistochemistry experiments that revealed a significant reduction in atrophy and death of PV‐ and CCK‐expressing interneurons after CBD treatment.

Conclusions and Implications

Our data suggest that CBD restores excitability and morphological impairments in epileptic models to pre‐epilepsy control levels through multiple mechanisms to reinstate normal network function.