bluuebunny/crossref_metadata_2025 huggingface dataset:
The impact of CYP2D6 mediated drug–drug interaction: a systematic review on a combination of metoprolol and paroxetine/fluoxetine
Authors: Bahar Muh. Akbar , Kamp Jasper , Borgsteede Sander D. , Hak Eelko , Wilffert Bob
Published: September 2018

Aim

Metoprolol (a CYP2D6 substrate) is often co‐prescribed with paroxetine/fluoxetine (a CYP2D6 inhibitor) because the clinical relevance of this drug–drug interaction (DDI) is still unclear. This review aimed to systematically evaluate the available evidence and quantify the clinical impact of the DDI.

Method

Pubmed, Web of Science, Cochrane Library and Embase were searched for studies reporting on the effect of the DDI among adults published until April 2018. Data on pharmacokinetics, pharmacodynamics and clinical outcomes from experimental, observational and case report studies were retrieved. The protocol of this study was registered in PROSPERO (CRD42018093087).

Results

We found nine eligible articles that consisted of four experimental and two observational studies as well as three case reports. Experimental studies reported that paroxetine increased the AUC of metoprolol three to five times, and significantly decreased systolic blood pressure and heart rate of patients. Case reports concerned bradycardia and atrioventricular block due to the DDI. Results from observational studies were conflicting. A cohort study indicated that the DDI was significantly associated with the incidence of early discontinuation of metoprolol as an indicator of the emergence of metoprolol‐related side effects. In a case–control study, the DDI was not significantly associated with bradycardia.

Conclusion

Despite the contradictory conclusions from the current literature, the majority of studies suggest that the DDI can lead to adverse clinical consequences. Since alternative antidepressants and beta‐blockers with comparable efficacy are available, such DDIs can be avoided. Nonetheless, if prescribing the combination is unavoidable, a dose adjustment or close monitoring of the metoprolol‐related side effects is necessary.
Late biochemical recurrence after radical prostatectomy is associated with a slower rate of progression
Authors: Chow Ken , Herrera Pia , Stuchbery Ryan , Peters Justin S. , Costello Anthony J. , Hovens Christopher M. , Corcoran Niall M.
Published: September 2018

Objective

To characterise the pattern of late biochemical recurrence (BCR) in the largest contemporary cohort of patients with localised prostate cancer treated with radical prostatectomy (RP) in the active surveillance era.

Patients and methods

Consecutive patients who underwent RP for localised prostate cancer between 2003 and 2017 were identified from a prospectively recorded, dedicated prostate cancer database. Patients who received neoadjuvant androgen‐deprivation therapy were excluded. These patients were categorised into the following groups: no BCR, BCR at <12 months (early), BCR at 12–60 months (intermediate), and BCR at >60 months (late), after RP. Clinicopathological characteristics were analysed using the Student's t‐test, Mann–Whitney U‐test, or chi‐squared test where appropriate. Multivariable binomial logistic regression models were used to assess predictors of BCR at various time‐points.

Results

In all, 2312 patients were included in the final analysis with up to 12 years of follow‐up data. The average patient had clinically localised prostate cancer, an elevated PSA level, and International Society of Urological Pathology (ISUP) Grade Group 2 on biopsy. In all, 88.7% of patients had ISUP Grade Group ≥2 at RP. A subgroup of 446 patients had undetectable PSA levels at 5 years after RP; 11.7% of them progressed to experience BCR. In this subgroup, late recurrers had significantly higher‐grade tumours on ISUP and Gleason sum (P <0.001 and P = 0.001, respectively), higher rates of extraprostatic extension (P = 0.022), and larger tumour volumes (P = 0.032). Logistic regression showed that RP ISUP Grade Group was a significant predictor of BCR (odds ratio 2.14, 95% confidence interval 1.43–3.20; P <0.001).

Conclusion

This study characterises the pattern of late BCR in the largest contemporary active surveillance era cohort. We have identified that RP ISUP Grade Group is a strong predictive indicator for late BCR. We also propose that timing of BCR resides on a continuum of risk and that the potential concept of dormant micrometastatic involvement requires further research and evaluation.
Characterization of eomesodermin and T-bet expression by allostimulated CD8+ T cells of healthy volunteers and kidney transplant patients in relation to graft outcome
Authors: Perez-Gutierrez A , Metes D M , Lu L , Hariharan S , Thomson A W , Ezzelarab M B
Published: September 2018

Memory T cell (Tmem) responses play a critical role in the outcome of allo-transplantation. While the role of the T-box transcription factor Eomesodermin (Eomes) in the maintenance of antigen-specific Tmem is well studied, little is known about Eomes+CD8+T cell responses after transplantation. We evaluated the phenotype and function of allo-reactive Eomes+CD8+T cells in healthy volunteers and kidney transplant patients and their relation to transplant outcome. High Eomes expression by steady-state CD8+T cells correlated with effector and memory phenotype. Following allo-stimulation, the expression of both the T-box proteins Eomes and T-bet by proliferating cells increased significantly, where high expression of Eomes and T-bet correlated with higher incidence of allo-stimulated IFNγ+TNFα+ CD8+T cells. In patients with no subsequent rejection, Eomes but not T-bet expression by donor-stimulated CD8+T cells, increased significantly after transplantation. This was characterized by increased EomeshiT-bet-/lo and decreased Eomes-/loT-bethi CD8+T cell subsets, with no significant changes in the EomeshiT-bethi CD8+T cell subset. No upregulation of exhaustion markers programmed-death-1 (PD-1) and cytotoxic-T-lymphocyte-associated-antigen-4 (CTLA4) by donor-stimulated Eomes+CD8+T cells was observed. Before transplantation, in patients without rejection, there were higher incidences of EomeshiT-bet-/lo, and lower incidences of EomeshiT-bethi and Eomes-/loT-bethi donor-stimulated CD8+T cell subsets, compared to those with subsequent rejection. Overall, our findings indicate that high Eomes expression by allo-stimulated T-bet+CD8+T cells is associated with enhanced effector function, and that an elevated incidence of donor-stimulated CD8+T cells co-expressing high levels of Eomes and T-bet before transplantation, may correlate with an increased incidence of acute cellular rejection.
Long term follow‐up of titanium implants installed in block‐grafted areas: A systematic review
Authors: Fuglsig João Marcus de Carvalho e Silva , Thorn Jens Jørgen , Ingerslev Janne , Wenzel Ann , Spin‐Neto Rubens
Published: September 2018

Background

An enduring clinical question concerns the outcome (ie, success) of implants placed in areas grafted with block‐grafts.

Objective

To undertake a systematic review of the literature on the long term results (≥5 years) of implants placed in maxillofacial areas grafted with any type of osseous block‐grafts in two‐stage surgeries. Further, the review addresses how available success criteria were used within the studies.

Materials and Methods

The MEDLINE (PubMed) and EMBASE bibliographic databases were searched up to March 2017 for studies evaluating the long term results of implants placed in grafted areas. The search strategy was restricted to English language publications using combined terms which referred to the treatment method (implants placed in areas grafted with bone blocks), and follow‐up characteristics (≥5 years and assessment of at least one parameter related to implant success criteria). To qualify for inclusion, studies should present outcome measurements indicating the success (or at least the survival) of the implants.

Results

The search strategy yielded 17 studies, which were included in this systematic review. These studies presented survival rates ranging from 88.7% (after 15 years follow‐up) to 98.7% (after 5 years follow‐up). Five studies presented data based on predefined success criteria with success rates ranging from 86.8% to 100%. In these studies, the term “success” was often not properly defined.

Conclusion

The long term survival (≥5 years) of implants placed into block‐grafted areas in two‐stage surgeries was not lower than 75%, while success rates ranged from 86.8% to 100%. Although it was possible to identify published success criteria for implant follow‐up, there is no broad consensus on how to report implant success in a consistent manner.
A novel methodological approach using superimposed Micro‐CT and STL images to analyze hard and soft tissue volume in immediate and delayed implants with different cervical designs
Authors: Sanz‐Martín Ignacio , Permuy María , Vignoletti Fabio , Nuñez Javier , Muñoz Fernando , Sanz Mariano
Published: September 2018

Objectives

To study the hard and soft tissue volume after placing immediate (IMI) or delayed implants (DLI) with a triangular coronal macro‐design (Test/T) or a conventional cylindrical design (Control/C).

Material and Methods

T/C implants were inserted in healed ridges or in fresh extraction sockets of eight beagle dogs. Biopsies were processed for Micro‐CT analysis and dental stone casts were optically scanned to obtain STL files revealing the soft tissue contours at 12 weeks. Image analysis software was utilized to match common landmarks superimposing the two sets of data. Three distinct volumes were calculated; buccal bone volume (B‐BV), soft tissue volume below the implant shoulder (EC‐STV), and the soft tissue volume above the implant shoulder (SC‐STV). Using linear measurements, the soft tissue height (STH), the mucosal thickness (MT‐IS), and the distance from the implant shoulder to the bone crest (I‐BC) were assessed in the digital images and in conventional histology to assess the concordance, reproducibility, and reliability.

Results

There were no significant differences between test and control implants regarding the buccal bone volume, although test implants had greater B‐BV in all locations except for PM2. The soft tissue volume was similar at T/C implants. The surgical approach influenced the distribution of the total tissue volume. In the IMI, a low position of the bone crest was correlated with low values of B‐BV, SC‐STV, MT‐IS, and STH. Linear measurements showed a high correlation between the histology and digital measurements and high inter and intra examiner agreement.

Conclusion

The superimposition of Micro‐CT/STL allowed the analysis of soft and hard tissue volumes. Reduction of the implant buccal aspect resulted in nonsignificant higher bone volume although similar soft tissue volume while the surgical approach influenced soft tissue response.
Histological and micro‐CT analysis of peri‐implant soft and hard tissue healing on implants with different healing abutments configurations
Authors: Souza André Barbisan , Alshihri AbdulMonem , Kämmerer Peer W. , Araújo Maurício G. , Gallucci German O.
Published: September 2018

Objective

The aim of this study was to assess the effect of different abutment configurations on peri‐implant soft and hard tissue healing.

Materials and Methods

Two‐piece dental implants, 3.5 mm in diameter and 8 mm in length, were placed in four beagle dogs. Two different transmucosal healing abutment configurations were randomly selected: one with a wide emergence profile (WE) (45° angulation with implant long axis) and the other with a narrow emergence profile (NE) (15° angulation with implant long axis). After four months of healing, the animals were sacrificed. Micro‐CT scans were taken for mesio‐distal analysis; subsequently, the biopsies were prepared for bucco–lingual histometric analyses. Several measurements were taken using the following reference points: marginal mucosal level (MML), apical barrier epithelium (aBE), implant shoulder (IS), marginal bone crest (BC), and first bone‐to‐implant contact (fBIC).

Results

In the micro‐CT analysis, the distance from IS‐fBIC was 1.11 ± 0.66 mm for WE and 0.12 ± 0.21 mm for NE (p = 0.004). The IS‐BC of WE was −0.54 ± 0.80 mm, whereas NE presented 0.76 ± 0.48 mm (p = 0.002). The histometric analysis showed that both groups presented comparable dimensions of peri‐implant biologic width (p > 0.05). However, in the distance from IS to BC, the WE showed a mean distance of −0.66 ± 0.78 mm while NE was 0.06 ± 0.42 mm (p = 0.039); the IS to fBIC was 0.89 ± 0.68 mm for WE while NE was 0.30 ± 0.30 mm (p = 0.041).

Conclusion

The design of the transmucosal component can influence the establishment of the peri‐implant biologic width. The flat and wide emergence profile induced an apical displacement of the peri‐implant biologic width and more bone loss.
Effectiveness of dorsal root ganglion stimulation and dorsal column spinal cord stimulation in a model of experimental painful diabetic polyneuropathy
Authors: Koetsier Eva , Franken Glenn , Debets Jacques , van Kuijk Sander M. J. , Perez Roberto S. G. M. , Linderoth Bengt , Joosten Elbert A. J. , Maino Paolo
Published: September 2018

Aims

Conventional dorsal root ganglion stimulation (DRGS) is known to achieve better pain‐paresthesia overlap of difficult‐to‐reach areas like the feet compared to dorsal column spinal cord stimulation (SCS). As in painful diabetic polyneuropathy (PDPN) pain is mostly present in the feet, we hypothesized that DRGS is more effective in relieving pain in PDPN when compared to SCS.

Methods

Diabetes was induced in female Sprague‐Dawley rats with an intraperitoneal injection of 65 mg/kg of streptozotocin (STZ; n = 48). Rats with a significant decrease in mechanical paw withdrawal response to von Frey filaments 4 weeks after injection were implanted with DRGS electrodes (n = 18). Rats were assigned to DRGS (n = 11) or sham‐DRGS (n = 7). Mechanical paw withdrawal thresholds (WT, measured in grams) in response to DRGS (50 Hz, 0.18 ± 0.05 mA) were assessed with von Frey testing. The results of the experiments on these animals were compared to the results of a previous study using exactly the same model on PDPN animals selected for SCS (n = 8) (40‐50 Hz, 0.19 ± 0.01 mA) and sham‐SCS (n = 3).

Results

In the SCS group, the log10 (10 000 × 50% WT) increased from 4910 to 5211 at t = 15 minutes (P < 0.05) and 5264 at t = 30 minutes (P = 0.11). In the DRGS group, the log10 (10,000 × 50% WT) increased from 4376 to 4809 at t = 15 minutes (P < 0.01) and 5042 at t = 30 minutes (P < 0.01). Both DRGS and SCS induced a similar and complete reversal of mechanical hypersensitivity. After cessation of stimulation (t = 60), the return of the log10 (10 000 × 50% WT) response was significantly faster with DRGS than that of SCS (P < 0.05).

Conclusions

We conclude that conventional DRGS is as effective as SCS in reduction of PDPN‐associated mechanical hypersensitivity in STZ‐induced diabetic rats. The wash‐in effect of DRGS and SCS was similar, but DRGS showed a faster washout course. Long‐term efficacy should be studied in future animal research.
Chronic hand eczema in Germany: 5‐year follow‐up data from the CARPE registry
Authors: Apfelbacher Christian J. , Ofenloch Robert F. , Weisshaar Elke , Molin Sonja , Bauer Andrea , Mahler Vera , Heinrich Andreas , von Kiedrowski Ralph , Schmitt Jochen , Elsner Peter , Diepgen Thomas L.
Published: September 2018

Background

The CARPE registry was set up in 2009 to prospectively investigate the management of patients with chronic hand eczema (CHE).

Objectives

To report comprehensive follow‐up data from the CARPE registry.

Patients and methods

We investigated sociodemographic and clinical characteristics, provision of medical care, physician‐assessed outcomes, and patient‐reported outcomes (PROs). Data were collected between 2009 and 2016, with up to 5 years of follow‐up, and are reported descriptively.

Results

Overall, 1281 patients were included in the registry (53.7% female). Mean age was 47.0 years. Of the patients, 793 and 231 completed the 2‐year follow‐up and 5‐year follow‐up, respectively. At baseline, 5.4% had changed or given up their job because of CHE, the average duration of CHE was 6.1 years, and, in 22.4%, the CHE was severe according to physician global assessment. Systemic treatment (alitretinoin, acitretin, and methotrexate) was prescribed at least once to 39.0% of the patients during the course of the follow‐up. Disease severity, quality of life and treatment satisfaction improved over time, and the proportion of patients receiving systemic treatments decreased.

Conclusions

Under continued dermatological care, substantial improvements in disease severity and PROs over time was achieved during the course of the CARPE registry, even in patients with long‐standing and severe hand eczema.
Risk stratification of symptomatic patients suspected of colorectal cancer using faecal and urinary markers
Authors: Widlak M. M. , Neal M. , Daulton E. , Thomas C. L. , Tomkins C. , Singh B. , Harmston C. , Wicaksono A. , Evans C. , Smith S. , Savage R. S. , Covington J. A. , Arasaradnam R. P.
Published: September 2018

Aim

Faecal markers, such as the faecal immunochemical test for haemoglobin (FIT) and faecal calprotectin (FCP), have been increasingly used to exclude colorectal cancer (CRC) and colonic inflammation. However, in those with lower gastrointestinal symptoms there are considerable numbers who have cancer but have a negative FIT test (i.e. false negative), which has impeded its use in clinical practice. We undertook a study of diagnostic accuracy CRC using FIT, FCP and urinary volatile organic compounds (VOCs) in patients with lower gastrointestinal symptoms.

Method

One thousand and sixteen symptomatic patients with suspected CRC referred by family physicians were recruited prospectively in accordance with national referring protocol. A total of 562 patients who completed colonic investigations, in addition to providing stool for FIT and FCP as well as urine samples for urinary VOC measurements, were included in the final outcome measures.

Results

The sensitivity and specificity for CRC using FIT was 0.80 [95% confidence interval (CI) 0.66–0.93] and 0.93 (CI 0.91–0.95), respectively. For urinary VOCs, the sensitivity and specificity for CRC was 0.63 (CI 0.46–0.79) and 0.63 (CI 0.59–0.67), respectively. However, for those who were FIT‐negative CRC (i.e. false negatives), the addition of urinary VOCs resulted in a sensitivity of 0.97 (CI 0.90–1.0) and specificity of 0.72 (CI 0.68–0.76).

Conclusions

When applied to the FIT‐negative group, urinary VOCs improve CRC detection (sensitivity rises from 0.80 to 0.97), thus showing promise as a second‐stage test to complement FIT in the detection of CRC.
The extirpation of species outside protected areas
Authors: Boakes Elizabeth H. , Fuller Richard A. , McGowan Philip J.K.
Published: September 2018

Protected areas (PAs) are fundamental to conservation efforts but they are only part of a successful conservation strategy. We examine biodiversity outside PAs in Sundaland, one of the world's most biologically degraded regions. Using the avian order Galliformes as a case study, we identify species that have not been sighted outside PAs within the last 20 years on each individual landmass (i.e., Malay Peninsula, Borneo, Sumatra, Java, and Bali). We estimate these species’ extirpation dates outside PAs using optimal linear estimation and species’ sighting records.

We conclude there have been up to 13 extirpations of Galliformes from outside PAs in Sundaland. Three Sundaic endemics now occur only inside PAs. Sumatra has suffered the highest proportion of extirpations (50% of its galliform species). Effective management of Sundaland's PAs is thus critical to species’ persistence and the conservation strategy for species outside PAs must be improved.
When Ethnicity Beats Gender: Quotas and Political Representation in Rwanda and Burundi
Authors: Guariso Andrea , Ingelaere Bert , Verpoorten Marijke
Published: September 2018

This article examines the impact of electoral gender quotas in post‐war Burundi and Rwanda on women's political representation. First, it looks at the evolution in descriptive representation by studying the number of female representatives and the prestige of their positions in the legislative and executive branches of government. The results show that, in both Rwanda and Burundi, the number of female political representatives significantly increased with the introduction of gender quotas, with their presence in parliament and ministries consistently exceeding 30 per cent. While women disproportionally end up in ministries of relatively lower prestige, the gap with men has been closing over time, as more women have joined the executive branches of power. The study considers whether such an increase has been accompanied by a positive evolution in the way ordinary women perceive their political representation. Despite a general improvement in perceived political representation across the population, the article finds there is not a significant difference between women and men and the study explains this finding by analysing the intersectionality of ethnicity and gender.
Selective attention, filtering, and the development of working memory
Authors: Plebanek Daniel J , Sloutsky Vladimir M
Published: September 2018

Selective attention is fundamental for learning across many situations, yet it exhibits protracted development, with young children often failing to filter out distractors. In this research, we examine links between selective attention and working memory (WM) capacity across development. One possibility is that WM is resource‐limited, with development resulting in an increase in the amount of resources available for processing information. However, it is also possible that development results in greater efficiency of using available resources. In the current research, we explore the latter possibility by examining the developmental trajectory of selectivity and filtering in relation to WM capacity. We report that filtering efficiency of adults (N = 30), 7‐year‐olds (N = 29), and 4‐year‐olds (N = 28) was uniquely predictive of WM capacity. We also report that filtering efficiency continues to develop after 7 years of age, whereas WM capacity may reach an asymptote around 7 years of age. The latter finding suggests that selective attention plays a critical role in developmental and individual differences in visual working memory capacity.
The effect of hypoglycaemia on neurocognitive outcome in children and adolescents with transient or persistent congenital hyperinsulinism
Authors: Muukkonen Liisa , Männistö Jonna , Jääskeläinen Jarmo , Hannonen Riitta , Huopio Hanna
Published: September 2018

Aim

To examine the hypoglycaemic effect on neurodevelopmental outcome in patients with transient and persistent congenital hyperinsulinism (CHI) born in the 21st century.

Method

A cohort of 117 patients (66 males, 51 females) with CHI aged 5 to 16 years (mean age 8y 11mo, SD 2y 7mo) were selected from a Finnish nationwide registry to examine all the patients with similar methods. Neurodevelopment was first evaluated retrospectively. The 83 patients with no risk factors for neurological impairment other than hypoglycaemia were recruited and 44 participated (24 males, 20 females; mean age 9y 7mo, SD 3y 1mo) in neuropsychological assessment with the Wechsler Intelligence Scale for Children, Fourth Edition and the Finnish version of the Developmental Neuropsychological Assessment, Second Edition domains of attention, language, memory, sensorimotor, and visual functioning.

Results

In retrospective analysis, transient and persistent CHI groups had similar prevalences of mild (22% and 18% respectively) or severe (5% and 7% respectively) neurodevelopmental difficulties. In clinical assessment, the neurocognitive profile was within the average range in both groups, but children with persistent CHI showed significant but restricted deficits in attention, memory, visual, and sensorimotor functions compared with the general population. The transient CHI group did not differ from the standardization samples.

Interpretation

Besides the more apparent broader neurological deficits, children with persistent CHI have an increased risk for milder specific neurocognitive problems, which should be considered in the follow‐up.

What this paper adds

Children with persistent congenital hyperinsulinism showed deficits in attention, memory, visual, and sensorimotor functions.

The deficits were potentially of hypoglycaemic origin.

Children with transient hyperinsulinism did not differ from the general population.
Optical coherence tomography and magnetic resonance imaging visual pathway evaluation in Wolfram syndrome
Authors: Zmyslowska Agnieszka , Waszczykowska Arleta , Baranska Dobromila , Stawiski Konrad , Borowiec Maciej , Jurowski Piotr , Fendler Wojciech , Mlynarski Wojciech
Published: September 2018

Aim

The aim of this study was to assess parameters of retinal morphology by using high‐definition optical coherence tomography (OCT) in patients with Wolfram syndrome (WFS) and their relation to optic tract atrophy in magnetic resonance imaging (MRI).

Method

High‐definition OCT and MRI parameters were evaluated in 12 patients with WFS (three males, nine females; median age at examination 12y 8mo, range 10y 2mo–15y 11mo) and referred to 30 individuals with type 1 diabetes (T1D) (12 males, 18 females; median age at examination 20y 5mo, range 16y 8mo–21y 4mo) and 33 typically developing comparison participants (10 males, 23 females; median age at examination 20y 7mo, range 13y–22y 4mo).

Results

Total thickness and quadrant thickness of the retinal nerve fibre layer (RNFL), macular full‐thickness parameters and macular ganglion cell layer/inner plexiform layer, intraorbital and intracranial thickness of the optical nerve, as well as the optic chiasm and visual tracts were significantly reduced in patients with WFS compared with those having T1D and the typically developing comparison participants. Optic chiasm thickness correlated negatively in patients with WFS with both age (r=−0.79; p=0.002) and duration of diabetes (r=−0.62; p=0.032). Thickness of the intraorbital parts of the optic nerves in patients with WFS correlated positively with thickness of the superior RNFL (r=0.73; p=0.006).

Interpretation

High‐definition OCT in combination with MRI could become an important tool for evaluating the effectiveness of therapeutic trials in patients with WFS.

What this paper adds

Provides evidence of significant reduction of retinal parameters and optic nerves in patients with Wolfram syndrome (WFS).

Shows correlations between magnetic resonance imaging parameters and retinal morphology parameters in patients with WFS.
Comparative use of the Ages and Stages Questionnaires in the USA and Scandinavia: a systematic review
Authors: Marks Kevin P , Madsen Sjö Nina , Wilson Philip
Published: September 2018

Aim

The aim of this systematic review was to investigate screening practices with the Ages and Stages Questionnaires (ASQ) and the Ages and Stages Questionnaires: Social‐Emotional (ASQ:SE) in the USA and Scandinavia and to identify practical lessons and research opportunities.

Method

The review was performed for ASQ‐ and ASQ:SE‐related studies in children from birth to 5 years. From nine databases and 1689 references (published from 1988–2018), 127 articles were included and categorized using Covidence online software. The Critical Appraisal Skills Programme Checklists were used before data synthesis.

Results

US studies primarily use the ASQ/ASQ:SE to detect delays in general and at‐risk populations in medical settings, which increases early detection, clinician‐referral, and intervention rates. Scandinavian studies commonly use the ASQ/ASQ:SE to monitor developmental–behavioural differences in intervention/exposure‐based cohorts. Pre‐visit screening yields completion/return rates of 83% to more than 90% and fosters same‐day interpretation. When referrals are indicated, systemwide care coordination or colocation with a developmental–behavioural specialist is beneficial.

Interpretation

Practical implementation lessons are reviewed. Research opportunities include investigating and measuring the ASQ/ASQ:SE's ‘overall’ sections. Danish, Norwegian, and Swedish translations are available but up‐to‐date norming and validation studies are needed throughout Scandinavia. Randomized controlled trials are needed to investigate outcomes in screened versus unscreened cohorts.

What this paper adds

General and at‐risk populations broadly benefited from periodic Ages and Stages Questionnaires (ASQ) and/or Ages and Stages Questionnaires: Social‐Emotional (ASQ:SE) screening.

Pre‐visit ASQ and/or ASQ:SE screenining implementation systems work best.

The ASQ and ASQ:SE ‘overall’ sections are not quantifiable and under‐researched.
International tax planning within the structure of corporate entities owned by the shareholder‐individuals through Panama Papers destinations
Authors: Nerudova Danuse , Solilova Veronika , Litzman Marek , Janský Petr
Published: September 2018

Motivation

The Panama Papers scandal highlighted the scale of financial secrecy, anonymous ownership and shell companies and their role in profit shifting and tax avoidance. We show the importance of international tax planning within the structure of corporate entities owned by shareholder‐individuals through Panama Papers destinations.

Purpose

To identify profit‐shifting channels and to estimate related government revenue losses to European Union Member States.

Methods

Using company data from the Amadeus/Orbis database (Bureau Van Dijk, n.d.a, n.d.b), we applied micro‐data analysis to the financial statements of multinational companies (MNEs) owned by shareholder‐individuals. Two groups—one with and the other without links to Panama Papers tax havens—alongside an analysis of profit‐shifting indicators.

Findings

Profit is generally shifted by moving operating revenues or costs, though the use of debt channels is also important. Also, groups linked to tax havens pay significantly less tax per unit of profit before tax, and require less operating revenue to achieve higher profits. Finally, related government revenue losses were assessed at EUR 8.67 billion.

Policy implication

Our results are relevant to the European Commission’s Comprehensive Common Consolidated Corporate Tax Base (CCCCTB) as it aims to counter profit shifting out of the European Union (EU) into tax havens. Further, our research highlights the importance of setting up registries of ultimate beneficiary owners in EU Member States.
Aβ and the dementia syndrome: Simple versus complex perspectives
Authors: Hunter Sally , Smailagic Nadja , Brayne Carol
Published: September 2018

Background

The amyloid cascade hypothesis (ACH) has dominated strategy in dementia research for decades despite evidence of its limitations including known heterogeneity of the dementia syndrome in the population and the narrow focus on a single molecule – the amyloid beta protein (Aβ) as causal for all Alzheimer‐type dementia. Other hypotheses relevant to Aβ are the presenilin (PS) hypothesis (PSH) relating to the involvement of PS in the generation of Aβ, and the amyloid precursor protein (APP) matrix approach (AMA), relating to the complex and dynamic breakdown of APP, from which Aβ derives.

Materials and methods

In this article we explore perspectives relating to complex disorders occurring mainly in older populations through a detailed case study of the role of Aβ in AD.

Results

Scrutiny of the evidence generated so far reveals and a lack of understanding of the wider APP proteolytic system and how narrow research into the dementia syndrome has been to date. Confounding factors add significant limitations to the understanding of the current evidence base.

Conclusions

A better characterisation of the entire APP proteolytic system in the human brain is urgently required to place Aβ in its complex physiological context. From a molecular perspective, a combination of the alternative hypotheses, the PSH and the AMA may better describe the complexity of the APP proteolytic system leading to new therapeutic approaches. The reductionist approach is widespread throughout biomedical research and this example highlights how neglect of complexity can undermine investigations of complex disorders, particularly those arising in the oldest in our populations.
Coronary stent implantation and adverse cardiac events after surgery
Authors: Thim Troels , Egholm Gro , Olesen Kevin Kris Warnakula , Madsen Morten , Jensen Svend Eggert , Jensen Lisette Okkels , Bøtker Hans Erik , Kristensen Steen Dalby , Maeng Michael
Published: September 2018

Background

In the risk assessment of patients considered for non‐cardiac surgery and with recent coronary stent implantation, coronary drug‐eluting stent implantation procedure characteristics may be taken into account. We aimed to evaluate associations between coronary drug‐eluting stent implantation procedure characteristics and the risk of myocardial infarction and all‐cause death within 30 days after non‐cardiac surgery.

Design

Patients with coronary drug‐eluting stents were identified using the Western Denmark Heart Registry. Surgical procedures performed after stent implantation were detected using the Danish National Patient Registry. We used registry‐based detection of myocardial infarction and all‐cause death.

Results

Of 22 590 patients treated with drug‐eluting stents between 2005 and 2012, 4046 underwent non‐cardiac surgery within 1 and 12 months after stent implantation. We found no significant association between the risk of myocardial infarction or all‐cause death within 30 days after surgery and number of arteries treated (1 [reference] vs more), number of lesions treated (1 [reference] vs more), segments treated (left main and proximal left anterior descending artery vs other [reference]), total stent length (<20 mm [reference] vs ≥20 mm), number of stents (1 [reference] vs >1) and largest balloon diameter (≥3 mm [reference] vs <3 mm). All‐cause death, but not myocardial infarction, risk was lower among patients treated with first‐generation vs second‐generation stents (odds ratio 0.58).

Conclusions

We identified no significant associations between stent implantation procedure characteristics and risk of myocardial infarction or all‐cause death among patients undergoing non‐cardiac surgery. All‐cause death was lower with first‐ vs second‐generation drug‐eluting stents.
Obstructive sleep apnea in refractory epilepsy: A pilot study investigating frequency, clinical features, and association with risk of sudden unexpected death in epilepsy
Authors: McCarter Allison R. , Timm Paul C. , Shepard Paul W. , Sandness David J. , Luu Thao , McCarter Stuart J. , Dueffert Lucas , Dresow Max , Feemster John C. , Cascino Gregory D. , So Elson L. , Worrell Gregory A. , Britton Jeffrey W. , Sherif Akil , Jaliparthy Keerthi , Chahal Anwar A. , Somers Virend K. , St. Louis Erik K.
Published: September 2018

Objective

We aimed to determine the frequency of probable obstructive sleep apnea (pOSA) in refractory epilepsy monitoring unit inpatients and clinical features associated with pOSA, including risk for sudden unexpected death in epilepsy (SUDEP).

Methods

We prospectively recruited 49 consecutive adult patients admitted to the Mayo Clinic Epilepsy Monitoring Unit with focal, generalized, or unclassified epilepsy syndromes. pOSA was identified using oximetric oxyhemoglobin desaturation index (ODI) and the Sleep Apnea–Sleep Disorders Questionnaire (SA‐SDQ) and STOP‐BAG screening tools. Revised SUDEP Risk Inventory (rSUDEP‐7) scores were calculated, and epilepsy patients with and without pOSA were compared with Wilcoxon signed‐rank tests. Correlation and regression analyses were utilized to determine relationships between pOSA and rSUDEP‐7 scores.

Results

Thirty‐five percent of patients had pOSA, with a mean ODI of 11.3 ± 5.1/h (range = 5.1‐22.8). Patients with pOSA were older and heavier, and more frequently had a focal epilepsy syndrome and longer epilepsy duration, with higher SA‐SDQ and STOP‐BAG scores (all P < 0.05). Median rSUDEP‐7 score was 3 ± 1.4 (range = 0‐6). Higher rSUDEP‐7 scores were positively correlated with higher ODI (P = 0.036). rSUDEP‐7 score ≥ 5 was associated with pOSA by ODI, SA‐SDQ, and STOP‐BAG questionnaire criteria (P < 0.05).

Significance

Our pilot study identified a high frequency of pOSA in refractory epilepsy monitoring patients, finding that pOSA patients were older and heavier, with higher screening symptoms for sleep apnea and more frequent focal seizures with a longer epilepsy duration. We also found a possible association between OSA and SUDEP risk. Identification and treatment of OSA in patients with epilepsy could conceivably provide a novel approach toward preventing the risk of SUDEP. Future studies with polysomnography are needed to confirm predictive features for OSA in epilepsy populations, and to determine whether OSA is associated with SUDEP risk.
Response to treatment schedules after the first antiepileptic drug failed
Authors: Chi Xiaosa , Li Rui , Hao Xiaoting , Chen Jiani , Xiong Weixi , Xu Hao , He Yazhou , Liu Wenyu , Tong Xin , Zhang Le , Jiang Xinyue , Gao Hui , Zhou Dong
Published: September 2018

Objective

After the failure of the first antiepileptic drug (AED) at doses > 50% defined daily dose (DDD), there are three options for patients with epilepsy: combination therapy, alternative therapy, and increased dosage of the first AED. However, present studies have not provided evidence for which option is best. Therefore, we conducted this retrospective observational cohort study to compare the effects of three treatment schedules.

Methods

Patients diagnosed with newly diagnosed epilepsy at the epilepsy clinic of West China Hospital between August 2006 and February 2016 were evaluated for eligibility for this study. Patients who failed to respond to the first AED at doses > 50% DDD were included, and divided into three cohorts: increased dosage, combination therapy, and alternative therapy. Cumulative incidence curves for time to seizure freedom were compared for different cohorts by Gray test. Competing risk regression was conducted to evaluate the association of clinical predictors with seizure freedom.

Results

Altogether, 502 patients (277 male, 55.2%) were included for further analysis, and the median duration of follow‐up was 32 months (range = 8‐127). The probability of seizure freedom was significantly higher in patients receiving combination therapy (n = 323) compared to the alternative therapy cohort (n = 76, P < 0.001) and increased dosage cohort (n = 103, P = 0.025). Competing risk regression analysis showed that combination therapy significantly increased the probability of seizure freedom (hazard ratio [HR] = 2.423, 95% confidence interval [CI] = 1.529‐3.841, P < 0.001). In addition, male sex and generalized seizure were significantly associated with increased probability of seizure freedom (male sex: HR = 1.440, 95% CI = 1.106‐1.880, P = 0.007; generalized seizure: HR = 1.543, 95% CI = 1.176‐2.020, P = 0.002).

Significance

Combination therapy may increase the probability of seizure freedom for patients with first AED failure due to lack of efficacy.
Maternal stress and fish reproduction: The role of cortisol revisited
Authors: Faught Erin , Vijayan Mathilakath M.
Published: September 2018

Stressor‐induced elevation of circulating cortisol levels is generally considered to have an inhibitory effect on reproduction in teleosts. However, mature female fish have higher levels of circulating cortisol levels, and this is particularly telling in salmonids during their spawning migration. This raises the possibility that a cortisol buffering capacity is active at the level of the gonad. This is particularly important given the recent findings in zebrafish (Danio rerio, Cyprinidae) that zygotic cortisol content, either high or low, can alter developmental programming. Therefore, a tight regulation of corticosteroid during oogenesis may be essential for proper ovarian development. Here, we focus on the temporal dynamics of cortisol in the ovary and its role in regulating the different processes related to oogenesis. Maternally deposited cortisol along with the local production of this steroid by the ovary may be involved in the regulation of oogenesis. We propose two critical stages when cortisol may exert a modulatory effect on oogenesis. The first stage occurs during vitellogenesis when maternal cortisol is incorporated into the yolk, and the second is during maturation and ovulation when cortisol may have a regulatory role on the action of maturation‐inducing hormones. A key protective mechanism to prevent excess cortisol deposition appears to be the upregulation of 11β‐hydroxysteroid dehydrogenase 2 in the theca and/or granulosa cells of the developing oocyte in response to excess maternal cortisol stimulation. Taken together, cortisol dynamics during oogenesis is complex, but maintaining a “Goldilocks” concentration of this steroid may be a critical process governing successful spawning and progeny development.
Combined effects of warming and nutrients on marine communities are moderated by predators and vary across functional groups
Authors: White Lydia , Donohue Ian , Emmerson Mark C. , O’Connor Nessa E.
Published: September 2018

Warming, nutrient enrichment and biodiversity modification are among the most pervasive components of human‐induced global environmental change. We know little about their cumulative effects on ecosystems; however, even though this knowledge is fundamental to predicting and managing their consequences in a changing world. Here, we show that shifts in predator species composition can moderate both the individual and combined effects of warming and nutrient enrichment in marine systems. However, all three aspects of global change also acted independently to alter different functional groups in our flow‐through marine rock‐pool mesocosms. Specifically, warming reduced macroalgal biomass and assemblage productivity, whereas enrichment led to increased abundance of meso‐invertebrate consumers, and loss of predator species led to increased gastropod grazer biomass. This disparity in responses, both across trophic levels (macroalgae and intermediate consumers), and between detecting additive effects on aggregate measures of ecosystem functioning, yet interactive effects on community composition, illustrates that our forecasting ability depends strongly on the level of ecological complexity incorporated within global change experiments. We conclude that biodiversity change—and loss of predator species in particular—plays a critical and overarching role in determining how ecological communities respond to stressors.
Hydrogeochemical Evolution Along Groundwater Flow Paths in the Manas River Basin, Northwest China
Authors: Wang Jianjun , Liang Xing , Liu Yanfeng , Jin Menggui , Knappett Peter S.K. , Liu Yalei
Published: September 2018

The impacts of long‐term pumping on groundwater chemistry remain unclear in the Manas River Basin, Northwest China. In this study, major ions within five surface water and 105 groundwater samples were analyzed to identify hydrogeochemical processes affecting groundwater composition and evolution along the regional‐scale groundwater flow paths using the multivariate techniques of hierarchical cluster analysis (HCA) and principal components analysis (PCA) and traditional graphical methods for analyzing groundwater geochemistry. HCA classified the groundwater samples into four clusters (C1 to C4). PCA reduced the dimensionality of geochemical data into three PCs, which explained 86% of the total variance. The results of HCA and PCA were used to identify three zones: “recharge,” “transition,” and “discharge.” In the recharge zone the groundwater type is Ca‐HCO3‐SO4 and is primarily impacted by the dissolution of calcite and silicate weathering. In the transition zone the groundwater type is Ca‐HCO3‐SO4‐Cl and is impacted by rock dissolution and reverse ion exchange. In the discharge zone the groundwater type is Na‐Cl and is impacted by evaporation and reverse ion exchange. In addition, anthropogenic activities impact the groundwater chemistry in the study area. The groundwater type generally changes from Ca‐HCO3‐SO4 in the recharge area to Na‐Cl in the discharge area along the regional‐scale groundwater flow paths. This study provides a process‐based knowledge for understanding the interaction of groundwater flow patterns and geochemical evolution within the Manas River Basin.
Helicobacter pylori and non‐alcoholic fatty liver disease: A new enigma?
Authors: Abdel‐Razik Ahmed , Mousa Nasser , Shabana Walaa , Refaey Mohamed , Elhelaly Rania , Elzehery Rasha , Abdelsalam Mostafa , Elgamal Ayman , Nassar Mervat R. , Abu El‐Soud Atef , Seif Ahmed S. , Tawfik Ahmed M. , El‐Wakeel Niveen , Eldars Waleed
Published: September 2018

Background and Aim

The relationship between Helicobacter pylori (H. pylori) and nonalcoholic fatty liver disease (NAFLD) is a matter of debate. We achieved this prospective work to study whether H. pylori infection is a risk factor for NAFLD.

Methods

A cohort multicenter pilot study of 369 adults without NAFLD at baseline was followed up for 2 years. Serum leptin, insulin, tumor necrosis factor‐α, adiponectin, and interleukin‐6 were measured using an enzyme‐linked immunosorbent assay (ELISA). Homeostasis model assessment of insulin resistance (HOMA‐IR) and leptin/adiponectin ratio (LAR) were calculated. Fecal H. pylori antigen was measured by ELISA. A total of 127 participants with H. pylori positive were treated and then followed up for 3 months.

Results

Helicobacter pylori‐positive patients (46.3%) were associated with an increase in IR, proinflammatory cytokines, C‐reactive protein (CRP), LAR, NAFLD‐liver fat score (NAFLD‐LFS), and hepatic steatosis index (HSI) (all P < 0.01). Multivariate analysis of NAFLD according to HSI and NAFLD‐LFS reported that presence of H. pylori, LAR, CRP, IL‐6, smoking, and age (all P < 0.01) were independent risk factors for the presence of NAFLD. Multiple models adjusted for potential mediators or confounders such as metabolic, inflammatory, and biochemical factors were constructed. After therapy of H. pylori infection, there was a significant reduction in lipogenic profile, IR, leptin, LAR, CRP, proinflammatory cytokines, HSI, and NAFLD‐LFS, as well as, increasing HDL.

Conclusion

Helicobacter pylori infection was related to an increased risk of NAFLD development, through increased markers of IR, inflammatory mediators, and lipid metabolism. Moreover, its eradication can recover these NAFLD risk factors.