bluuebunny/crossref_metadata_2025 huggingface dataset:
Loss of the homologous recombination generad51leads to Fanconi anemia-like symptoms in zebrafish
Authors: Botthof Jan Gregor , Bielczyk-Maczyńska Ewa , Ferreira Lauren , Cvejic Ana
Published: December 2016

RAD51is an indispensable homologous recombination protein, necessary for strand invasion and crossing over. It has recently been designated as a Fanconi anemia (FA) gene, following the discovery of two patients carrying dominant negative mutations. FA is a hereditary DNA repair disorder characterized by various congenital abnormalities, progressive bone marrow failure and cancer predisposition. In this paper, we describe the first viable vertebrate model ofRAD51loss. Zebrafishrad51loss-of-function mutants developed key features of FA, including hypocellular kidney marrow, sensitivity to crosslinking agents and decreased size. We show that some of these symptoms stem from both decreased proliferation and increased apoptosis of embryonic hematopoietic stem and progenitor cells. Co-mutation ofp53was able to rescue the hematopoietic defects seen in the single mutants, but led to tumor development. We further demonstrate that prolonged inflammatory stress can exacerbate the hematological impairment, leading to an additional decrease in kidney marrow cell numbers. These findings strengthen the assignment ofRAD51as a Fanconi gene and provide more evidence for the notion that aberrant p53 signaling during embryogenesis leads to the hematological defects seen later in life in FA. Further research on this novel zebrafish FA model will lead to a deeper understanding of the molecular basis of bone marrow failure in FA and the cellular role of RAD51.

Significance statement

The homologous recombination protein RAD51 has been extensively studied in prokaryotes and lower eukaryotes. However, there is a significant lack of knowledge of the role of this protein and its regulation in anin-vivocontext in vertebrates. Here we report the first viable vertebrate mutant model ofrad51in zebrafish. These mutant fish enabled us to confirm for the first time the recently discovered role ofRAD51in Fanconi anemia pathogenesis. We report that p53 linked embryonic stem cell defects directly lead to hematological impairments later in life. Co-mutation ofrad51withp53rescues the observed hematological defects, but predisposes the fish to early tumor development. The application of this model opens new possibilities to advance Fanconi anemia drug discovery.
Researching fractured (information) landscapes
Authors: Lloyd Annemaree
Published: December 2016

Purpose

The purpose of this paper is to introduce a range of sensitising themes that may help to frame the emerging concept of fractured landscapes.

Design/methodology/approach

Key concepts are drawn from the forced migration field, from social theory and from Library and information science research to frame the concept of fractured landscape research. Methodological and ethical aspects that influence research are also introduced.

Findings

The importance of nomenclature is identified in relation to designations of refugee and migrant. The concept of a fractured landscape provides a suitable way of describing the disruption that is caused to refugees’ information landscapes in the process of transition and resettlement. The sensitising themes such as the exilic journey, liminality, integration, bonding and bridging capital are introduced to provide a way of framing a deeper analysis of the information experience of people who must reconcile previously established ways of knowing with the new landscapes related to transition and resettlement.

Originality/value

Original paper that introduces an emerging conceptual framework and a range of questions that may be useful to library and information science researchers who wish to pursue research that contributes to the humanitarian area or library services.
Methodology‐as‐Technique and the Meaning of Rigour in Globalized Management Research
Authors: Bell Emma , Kothiyal Nivedita , Willmott Hugh
Published: December 2016

This paper analyses the genre of ‘methodology‐as‐technique’, which we suggest provides the underpinning logic for a particular conception of scientific rigour that is increasingly regarded as normal in globalized management research. Based on a qualitative interview study of management researchers in the peripheral context of India, we associate the methodology‐as‐technique genre with social scientific methods of organizing, conducting and disseminating knowledge founded on Western neo‐imperialism and colonialism. Our analysis draws attention to the consequences of the genre of methodology‐as‐technique which relate to a narrowing and displacement of research goals, erasure of context, and devaluation and marginalization of alternatives. By providing insight into how methodology‐as‐technique comes to dominate in peripheral locations such as India, we suggest that these normative constraints also present an opportunity for denaturalization, by making what is increasingly seen as normal appear alien or strange. We conclude by arguing that countering restrictive definitions of rigour in management research relies on development of a more expansive and inclusive conception of the global that fosters indigenous ways of knowing and promotes decolonizing methodologies.
Modeling landscape connectivity for bobcats using expert‐opinion and empirically derived models: how well do they work?
Authors: Reed G. C. , Litvaitis J. A. , Callahan C. , Carroll R. P. , Litvaitis M. K. , Broman D. J. A.
Published: December 2016

Efforts to retain ecological connectivity have become a conservation priority to permit animal movements within home ranges, allow dispersal between populations and provide opportunities for animals to respond to climate change. We used expert‐opinion and empirically derived models to investigate landscape connectivity at two spatial scales among bobcats Lynx rufus in New Hampshire, USA. Paths of marked bobcats were compared to random movements in the context of program CircuitScape. At the local scale (within home ranges), the empirical model (based on observations and telemetry locations) performed better than the expert‐opinion model. At the regional scale (state of New Hampshire), both models identified urban development as a potential barrier; however, the models differed in predicting how specific natural features (e.g. mountains and large water bodies) and some roads affected bobcat movements. When compared with bobcat population structure based on genetic information, the expert‐opinion model overestimated the influence of roads. Alternatively, the empirical model overestimated the influence of snow. Our findings indicate that the empirically based resistance model was better at describing landscape‐scale effects, whereas the expert‐opinion model provided a good understanding of gene flow at a regional scale. As such, both models may be considered complementary. Bobcats were sensitive to disruptions imposed by habitat fragmentation and thus may be a suitable focal species for evaluating the consequences of land‐use changes on the regional suite of mesocarnivores.
Performance of adjustable pressure‐limiting (APL) valves in two different modern anaesthesia machines
Authors: Thomas J. , Weiss M. , Schmidt A. R. , Buehler P. K.
Published: December 2016

The ability to gently ventilate a patient's lungs using a self‐inflating bag requires a properly working adjustable pressure‐limiting (APL) valve. We compared the performance of the APL valves of the GE Aisys CS2 and the Draeger Fabius anaesthetic machines during closure and opening from 1‐20 and from 20‐1 cmH2O, using standardised experimental baby and adolescent patient lung models. Airway pressures and inspiratory tidal volumes were measured using an ASL‐5000 test lung and a GE Aisys CS2 near‐patient spirometry sensors. In both lung models, the GE Aisys CS2 APL valves demonstrated non‐linear behaviours for airway pressures and for inspiratory tidal volumes, with a sharp increase at set APL pressure levels of 8–10 cmH2O. With further closure of the GE Aisys CS2 APL valves up to 20 cmH2O, inspiratory tidal volumes decreased to ~50% of the highest values measured. Airway pressures in the Draeger Fabius APL valves demonstrated a near linear increase and decrease. Airway pressure values measured in the Draeger Fabius were never higher than those set by the APL valves, whereas in the GE Aisys CS2, they considerably exceeded set pressures (by up to 27 cmH2O). We conclude that the performance of the GE Aisys CS2 APL valve does not allow safe bag‐assisted ventilation of a patient's lungs.
AAGBI: Consent for anaesthesia 2017
Authors: Yentis S. M. , Hartle A. J. , Barker I. R. , Barker P. , Bogod D. G. , Clutton‐Brock T. H. , Ruck Keene A. , Leifer S. , Naughton A. , Plunkett E.
Published: December 2016

Previous guidelines on consent for anaesthesia were issued by the Association of Anaesthetists of Great Britain and Ireland in 1999 and revised in 2006. The following guidelines have been produced in response to the changing ethical and legal background against which anaesthetists, and also intensivists and pain specialists, currently work, while retaining the key principles of respect for patients’ autonomy and the need to provide adequate information. The main points of difference between the relevant legal frameworks in England and Wales and Scotland, Northern Ireland and the Republic of Ireland are also highlighted.
Sexual functioning mirrors overall men's health status, even irrespective of cardiovascular risk factors
Authors: Capogrosso P. , Ventimiglia E. , Boeri L. , Capitanio U. , Gandaglia G. , Dehò F. , Pederzoli F. , Cazzaniga W. , Scano R. , Montorsi F. , Salonia A.
Published: December 2016

Erectile dysfunction has been described as a sentinel marker of co‐existing and undetected cardiovascular disease. Beside cardiovascular diseases, a correlation between erectile dysfunction and other major comorbidities has been also reported. The study was aimed to analyze the association between sexual functioning and overall men's health in sexually active, Caucasian‐European men with new‐onset sexual dysfunction. Data from the last 881 consecutive patients seeking first medical help for sexual dysfunction were cross‐sectionally analyzed. The International Classification of Diseases, 9th revision, Clinical Modification was used to classify health‐significant comorbidities, which were scored with the Charlson Comorbidity Index (CCI). A modified CCI score from which all potential cardiovascular risk factors (CCI‐CV) were subtracted was then calculated for every patient. Patients were requested to complete the International Index of Erectile Function (IIEF). The main outcome of the study was the association between the IIEF domain scores and CCI, which scored health‐significant comorbidities even irrespective of cardiovascular risk factors (CCI‐CV). The final sample included 757 patients (85.9%) (Median age: 48 years; IQ range: 37–59). Overall, erectile dysfunction was found in 540 (71.4%) patients. Of these, 164 (21.6%) had a CCI ≥ 1 and 138 (18.2%) had a CCI‐CV ≥ 1, respectively. At the analysis of variance, IIEF‐Erectile Function (EF) scores significantly decreased as a function of incremental CCI and CCI‐CV scores (all p < 0.01). At multivariable logistic regression analysis, both IIEF‐EF and IIEF‐total score achieved independent predictor status for either CCI ≥ 1 or CCI‐CV ≥ 1, after accounting for potential confounders (p < 0.01). We report novel findings of a significant association between erectile dysfunction severity and overall men's health, even irrespective of cardiovascular risk factors. Thereof, erectile dysfunction severity could serve as a proxy for general men's health, thus encouraging physicians to comprehensively assess patients complaining of sexual dysfunction in the real‐life everyday clinical practice.
Can mesenchymal stem cells improve spermatogonial stem cell transplantation efficiency?
Authors: Kadam P. , Van Saen D. , Goossens E.
Published: December 2016

Improved treatments have led to an increased survival rate in cancer patients. However, in pre‐pubertal boys, these gonadotoxic treatments can result in the depletion of the spermatogonial stem cell (SSC) pool causing lifelong infertility. SSC transplantation has been proposed as a promising technique to preserve the fertility of these patients. In mice, this technique has resulted in live‐born offspring, but the efficiency of colonization remained low. This could be because of a deficient microenvironment, leading to apoptosis of the transplanted SSCs. Interestingly, mesenchymal stem cells (MSCs), being multipotent and easy to isolate and multiply in vitro, are nowadays successfully and widely used in regenerative medicine. Here, we shortly review the current understanding of MSC and SSC biology, and we hypothesize that a combined MSC‐SSC transplantation might improve the efficiency of SSC colonization and differentiation as paracrine factors from MSCs may contribute to the SSC niche.
Macular thickness in healthy eyes of adults (N = 4508) and relation to sex, age and refraction: the Tromsø Eye Study (2007–2008)
Authors: von Hanno Therese , Lade Anette C. , Mathiesen Ellisiv B. , Peto Tunde , Njølstad Inger , Bertelsen Geir
Published: December 2016

Purpose

To provide sex‐stratified normative data on retinal thickness and study the relationship with sex, age and refractive status.

Methods

Population‐based study including 2617 women and 1891 men, aged 38–87 (mean 61 ± 8) years, without diabetes, glaucoma and retinal diseases, and spherical equivalent refraction (SER) within ±6 dioptres. Retinal thickness was measured with optical coherence tomography (spectral domain Cirrus HD‐OCT).

Results

Women had thinner retina than men. Retinal thickness was significantly associated with refraction, where mean change in retinal thickness per 1 D increase in SER was −1.3 (0.2) μm in the fovea, 0.7 (0.1) μm in the pericentral ring and 1.4 (0.1) μm in the peripheral ring. In the fovea, there was a non‐monotonic curved relationship between retinal thickness and age in both sexes with a maximum at about 60 years (p < 0.001). In the pericentral ring, the mean reduction in retinal thickness per 10‐year increase was 2.7 (0.3) μm in women and 4.0 (0.4) μm in men and corresponding results in the peripheral ring were 2.3 (0.3) μm in women and 2.6 (0.4) μm in men. In both regions, there was evidence for a nonlinear pattern with an increased rate of change with higher age. There was a significant interaction between sex and age for retinal thickness of the pericentral ring (p = 0.041).

Conclusion

Women had thinner retina than men, and thickness varied with refractive status. Retinal thickness was associated with age in all macular regions, and the rate of change in retinal thickness varied at different ages.
Photobiomodulation reduces drusen volume and improves visual acuity and contrast sensitivity in dry age‐related macular degeneration
Authors: Merry Graham F. , Munk Marion R. , Dotson Robert S. , Walker Michael G. , Devenyi Robert G.
Published: December 2016

Purpose

To evaluate the efficacy of photobiomodulation (PBM) treatment for patients with dry age‐related macular degeneration (AMD).

Methods

Assessments on 42 eyes with dry AMD (age related eye disease study (AREDS) 2–4) were conducted. Multiwavelength light emitting diode (LED) light comprising of yellow (590 nm), red (670 nm) and near‐infrared (790 nm) bandwidths was applied to subjects’ eyes for a treatment course of 3 weeks. Outcome measures were changes in best‐corrected visual acuity (BCVA), contrast sensitivity (CS), drusen volume and central drusen thickness.

Results

Significant improvement in mean BCVA of 5.90 letters (p < 0.001) was seen on completion of the 3‐week treatment and 5.14 letters (p < 0.001) after 3 months. Contrast sensitivity improved significantly (log unit improvement of 0.11 (p = 0.02) at 3 weeks and 3 months (log unit improvement of 0.16 (p = 0.02) at three cycles per degree. Drusen volume decreased by 0.024 mm3 (p < 0.001) and central drusen thickness was significantly reduced by a mean of 3.78 μm (p < 0.001), while overall central retinal thickness and retinal volume remained stable.

Conclusion

This is the first study demonstrating improvements in functional and anatomical outcomes in dry AMD subjects with PBM therapy. These findings corroborate an earlier pilot study that looked at functional outcome measures. The addition of anatomical evidence contributes to the basis for further development of a non‐invasive PBM treatment for dry AMD.
Re‐visiting historical semi‐natural grasslands in the Apennines to assess patterns of changes in species composition and functional traits
Authors: Giarrizzo Eleonora , Burrascano Sabina , Chiti Tommaso , de Bello Francesco , Lepš Jan , Zavattero Laura , Blasi Carlo
Published: December 2016

Questions

To what extent have semi‐natural grassland plant species composition and functional traits changed during the past five decades? Which are the main directions of change? Which environmental, management and landscape factors have determined these changes?

Location

Central and southern Apennines of Italy.

Methods

In 2013–2014, we used a stratified random sampling design to revisit 132 semi‐natural grasslands originally sampled between 1966 and 1992. The exact locations of the historical plots were not available but they were associated with detailed vegetation maps. Plots were divided in 17 groups based on study area and original community type. To assess changes in species composition we ran PERMANOVA and RDA. The extent of change was estimated by comparing each new plot with the quantitative species pool of the corresponding historical group; species composition changes were calculated using Bray‐Curtis coefficient, and shifts in functional traits were quantified as differences in community‐weighted means. These measures of change were used as response variables in mixed effects models including climate, topography, management and landscape metrics as explanatory variables.

Results

The largest changes were related to successional dynamics, which occurred mainly in grasslands developing at low altitude and in the flattest sites where the soil organic horizon was relatively thick. Colonization by shrubs and trees was facilitated by high soil pH and amount of adjacent forests. Also, management factors affected the patterns of shifts in species composition and functional traits: grazing intensity was negatively related to the degree of compositional change as well as to the abundance of woody species, whereas the increase of species associated with frequent grazing disturbance was found at sites with higher values of soil salinity.

Conclusions

Apennine semi‐natural grasslands have undergone substantial changes in species composition and functional traits during recent decades. Compositional changes mainly indicated successional dynamics, likely following a decrease in grazing intensity, whereas some more accessible grasslands experienced an increase in disturbance‐tolerant species. The combination of the re‐visitation approach with functional traits allowed us to clarify different directions of changes in species composition, adding information on the ecological processes related to these changes.
Positive litter feedbacks of an introduced species reduce native diversity and promote invasion in Californian grasslands
Authors: Mariotte Pierre , Spotswood Erica N. , Farrer Emily C. , Suding Katharine N.
Published: December 2016

Questions

Californian grasslands have a long history of invasion, starting with the introduction of exotic forage species a century ago, and followed by newer waves of invaders. Both exotic and invasive species produce large amounts of litter, but the importance of litter accumulation on the growth and expansion of these species has not been rigorously assessed. We addressed the following questions: (1) do litter type (exotic or invasive species) and litter quantity affect exotic and invasive plant performance; (2) at which plant life stages does litter accumulation effects occur; and (3) is litter accumulation impacting native species recruitment and diversity?

Location

Semi‐natural grasslands, northern California.

Methods

We created litter quantity gradients (0, 62.5, 125, 250 or 500 g·m−2) of three litter types (exotic or invasive species litter or a mixture of both). We evaluated litter effects on the germination, recruitment, production of flowers and biomass production of the exotic Avena fatua, the invasive Elymus caput‐medusae and a mixture of native species. We used litter depth as a proxy for litter accumulation and measured litter impacts on light availability at ground level, soil moisture, soil and microbial C and N.

Results

We found a significant litter depth impact on all species, but no litter type effects. Litter accumulation principally reduced light availability at ground level and positively affected exotic and invasive species at different life‐history stages. Above‐ground biomass production of the exotic species Avena increased with increased litter depth, suggesting a litter accumulation feedback. The invasive species Elymus responded to increased litter with increased seed production, rather than biomass production. In contrast, litter negatively affected the recruitment and diversity of native species.

Conclusion

Overall, our findings point to cascading effects in invasion with positive litter accumulation feedbacks of an exotic species simultaneously reducing native diversity and promoting seed production of a more recent invasive arrival. These results have strong consequences for invasion management and suggest that litter removal practices, such as burning and grazing, would better succeed at limiting the growth and spread of invasive species than herbicide application or seeding.
Early surgical outcomes and oncological results of robot‐assisted partial nephrectomy: a multicentre study
Authors: Veeratterapillay Rajan , Addla Sanjai K. , Jelley Clare , Bailie John , Rix David , Bromage Steve , Oakley Neil , Weston Robin , Soomro Naeem A.
Published: December 2016

Objective

To describe a multicentre experience of robot‐assisted partial nephrectomy (RAPN) in northern England, with focus on early surgical outcomes and oncological results.

Patients and Methods

All consecutive patients undergoing RAPN at four tertiary referral centres in northern England in the period 2012–2015 were included for analysis. RAPN was performed via a transperitoneal approach using a standardized technique. Prospective data collection was performed to capture preoperative characteristics (including R.E.N.A.L. nephrometry score), and peri‐operative and postoperative data, including renal function. Correlations between warm ischaemia time (WIT), positive surgical margin (PSM) rate, complication rates, R.E.N.A.L. nephrometry scores and learning curve were assessed using univariate and multivariate analyses.

Results

A total of 250 patients (mean age 58.1 ± 13 years, mean ± sd body mass index 27.3 ± 7 kg/m2) were included, with a median (range) follow‐up of 12 (3–36) months. The mean ± sd tumour size was 30.6 ± 10 mm, mean R.E.N.A.L. nephrometry score was 6.1 ± 2 and 55% of tumours were left‐sided. Mean ± sd operating console time was 141 ± 38 min, WIT 16.7 ± 8 min and estimated blood loss 205 ± 145 mL. There were five conversions (2%) to open/radical nephrectomy. The overall complication rate was 16.4% (Clavien I, 1.6%; Clavien II, 8.8%; Clavien III, 6%; Clavien IV/V; 0%). Pathologically, 82.4% of tumours were malignant and the overall PSM rate was 7.3%. The mean ± sd preoperative and immediate postoperative estimated glomerular filtration rates were 92.8 ± 27 and 80.8 ± 27 mL/min/1.73 m2, respectively (P = 0.001). In all, 66% of patients remained in the same chronic kidney disease category postoperatively, and none of the patients required dialysis during the study period. ‘Trifecta’ (defined as WIT < 25 min, negative surgical margin status and no peri‐operative complications) was achieved in 68.4% of patients overall, but improved with surgeon experience. PSM status and long WIT were significantly associated with early learning curve.

Conclusion

This is the largest multicentre RAPN study in the UK. Initial results show that RAPN is safe and can be performed with minimal morbidity. Early oncological outcomes and renal function preservation data are encouraging.
Efficacy and safety of tadalafil 5 mg once daily in the treatment of lower urinary tract symptoms associated with benign prostatic hyperplasia in men aged ≥75 years: integrated analyses of pooled data from multinational, randomized, placebo‐controlled clinical studies
Authors: Oelke Matthias , Wagg Adrian , Takita Yasushi , Büttner Hartwig , Viktrup Lars
Published: December 2016

Objective

To assess efficacy and safety of tadalafil in men aged ≥75 years with lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH) and additional safety in men aged ≥75 years with erectile dysfunction (ED).

Patients and Methods

We conducted an integrated analysis of 12 phase II–III randomized, double‐blind and/or open‐label extension studies to evaluate short‐term (12–26 weeks) efficacy and short‐ and longer‐term (42–52 weeks) safety in men aged <75 years vs men aged ≥75 years. All men received once‐daily tadalafil 5 mg or placebo. The efficacy outcome was International Prostate Symptom Score (IPSS). Safety measurements included treatment‐emergent adverse events (TEAEs), adverse events (AEs) leading to discontinuation, serious AEs (SAEs), and cardiovascular AEs. All analyses were intention‐to‐treat. Changes from baseline to efficacy endpoint and differences in changes between treatment groups were estimated as least‐squares means using analysis of covariance models.

Results

Change in the mean IPSS was significantly different in men aged <75 years vs those aged ≥75 years across tadalafil and placebo groups (treatment‐by‐age interaction P = 0.034). Tadalafil was not statistically significantly better than placebo in men aged ≥75 years, but effect size varied between studies. Maintenance of efficacy with tadalafil was observed across age groups. Short‐term tadalafil safety findings for men aged <75 vs ≥75 years included: TEAEs (52 [33.8%] vs 503 [30.1%]), AEs leading to discontinuation (3 [1.9%] vs 50 [3.0%]), SAEs (4 [2.6%] vs 15 [0.9%]) and cardiovascular AEs (4 [2.6%] vs 30 [1.8%]). Long‐term tadalafil safety data did not reveal clinically relevant differences between age groups. Limitations include exclusion of men with serious co‐existing conditions and limited sample sizes of men aged ≥75 years.

Conclusions

Efficacy with once‐daily tadalafil 5 mg in the treatment of LUTS/BPH differed between men aged <75 vs ≥75 years, with significant efficacy in the <75‐year age group. The older age group had more concomitant diseases and used more drugs, which may have reduced efficacy. The small sample size precluded uni‐/multivariate analyses to assess plausible interference from confounding factors. Tadalafil had a reassuring safety profile and no evidence of increased cardiovascular AEs in aging men.
Verteporfin suppresses cell survival, angiogenesis and vasculogenic mimicry of pancreatic ductal adenocarcinoma via disrupting the YAP‐TEAD complex
Authors: Wei Honglong , Wang Fuhai , Wang Yong , Li Tao , Xiu Peng , Zhong Jingtao , Sun Xueying , Li Jie
Published: December 2016

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive human malignancies. The Yes‐associated protein‐1 (YAP) plays a critical role in cell proliferation, apoptosis and angiogenesis. Verteporfin is a photosensitizer used in photodynamic therapy and also a small molecular inhibitor of the Hippo‐YAP pathway. However, little is known about whether verteporfin could inhibit YAP activity in PDAC cells. Our present results showed that verteporfin suppressed the proliferation of human PDAC PANC‐1 and SW1990 cells by arresting cells at the G1 phase, and inducing apoptosis in dose‐ and time‐dependent manners. Verteporfin also inhibited the tumor growth on the PDAC xenograft model. Treatment with verteporfin led to downregulation of cyclinD1 and cyclinE1, modulation of Bcl‐2 family proteins and activation of PARP. In addition, verteporfin exhibited an inhibitory effect on angiogenesis and vasculogenic mimicry via suppressing Ang2, MMP2, VE‐cadherin, and α‐SMA expression in vitro and in vivo. Mechanism studies demonstrated that verteporfin impaired YAP and TEAD interaction to suppress the expression of targeted genes. Our results provide a foundation for repurposing verteporfin as a promising anti‐tumor drug in the treatment of pancreatic cancer by targeting the Hippo pathway.
Young Children's Reliance on Information From Inaccurate Informants
Authors: Kim Sunae , Paulus Markus , Kalish Chuck
Published: December 2016

Prior work shows that children selectively learn from credible speakers. Yet little is known how they treat information from non‐credible speakers. This research examined to what extent and under what conditions children may or may not learn from problematic sources. In three studies, we found that children displayed trust toward previously inaccurate speakers. Children were equally likely to extend labels from previously accurate and inaccurate speakers to novel objects. Moreover, they expected third parties to share labels provided by previously inaccurate speakers. Only when there was clear evidence that the speakers' information was wrong (as in the case when speakers' perceptual access to the information was blocked), did young children reject the label. Together, the findings provide evidence that young children do not completely ignore the labels supplied by non‐credible speakers unless there is strong reason to do so.
Antibody depletion strategy for the treatment of suspected antibody‐mediated rejection in lung transplant recipients: Does it work?
Authors: Vacha Mary , Chery Godefroy , Hulbert Amanda , Byrns Jennifer , Benedetti Clark , Finlen Copeland Catherine Ashley , Gray Alice , Onwuemene Oluwatoyosi , Palmer Scott M. , Snyder Laurie D.
Published: December 2016

Background

Donor‐specific antibodies (DSAs) after lung transplantation correlate with poor outcomes. The ideal treatment strategy for antibody‐mediated rejection AMR is not defined. Our institution implemented an aggressive multimodality protocol for the treatment of suspected AMR.

Methods

Lung transplant recipients with suspected AMR were treated with a standardized protocol of plasma exchange, steroids, bortezomib, rituximab, and intravenous immune globulin. Primary outcome was DSA clearance at 6 months in those alive. Secondary endpoints included preserved allograft function at 6 months, survival at 6 and 12 months and complications due to the protocol.

Results

Sixteen lung transplant recipients with documented DSA and allograft dysfunction were included in the analysis. Of the 16 patients, 11 survived to 6 months. Three of those 11 patients (27%) cleared all DSAs within 6 months of the protocol. Four of the 11 patients (36%) had preserved allograft function at 6 months. Overall 12‐month patient survival was 56%. Complications included thrombocytopenia (50%) and abdominal pain or gastrointestinal discomfort (18.7%).

Conclusions

This multimodality protocol resulted in clearance of DSAs and preserved lung function in a minority of lung transplant recipients with suspected AMR surviving to 6 months after therapy. There were significant side effects of the protocol.
Single‐center outcomes of combined heart and liver transplantation in the failing Fontan
Authors: D'Souza Benjamin A. , Fuller Stephanie , Gleason Lacey P. , Hornsby Nicole , Wald Joyce , Krok Karen , Shaked Abraham , Goldberg Lee R. , Pochettino Alberto , Olthoff Kim M. , Kim Yuli Y.
Published: December 2016

Long‐term outcomes of the Fontan operation include Fontan failure and liver disease. Combined heart‐liver transplantation (CHLT) is an option for select patients although limited data exist on this strategy. A retrospective review of Fontan patients 18 years or older referred for cardiac transplant evaluation between 2000 and 2013 at the Hospital of the University of Pennsylvania was performed. All patients were considered for potential CHLT. Clinical variables such as demographics, perioperative factors, and short‐term outcomes were reviewed. Of 17 referrals for cardiac transplantation, seven Fontan patients underwent CHLT. All patients who underwent CHLT had either advanced fibrosis or cirrhosis on liver biopsy. There were no perioperative deaths. The most common postoperative morbidity was acute kidney injury. Short‐term complications include one episode of acute liver rejection but no cardiac rejection greater than 1R. CHLT is an acceptable therapeutic option for patients with failing Fontan physiology who exhibit concomitant advanced liver fibrosis. However, optimal patient selection is currently undefined, and long‐term outcomes are not known.
Pruritus and quality of life in renal transplant patients
Authors: Panuccio Vincenzo , Tripepi Rocco , Bellantoni Marianna , Saporito Licia , Quattrone Serena , Lacava Viviana , Parlongo Giovanna , Tripepi Giovanni , Mallamaci Francesca , Zoccali Carmine
Published: December 2016

Background

Pruritus has a negative impact on quality of life (QoL) in dialysis patients. The reversibility of this symptom after renal transplantation and its impact upon QoL has scarcely been studied in these patients.

Methods

Pruritus was evaluated by the Visual Analogue Scale (VAS), the Visual Rating Scale (VRS), and the Numerical Rating Scale (NRS) in 133 unselected renal transplant patients, 62 healthy subjects, and 29 hemodialysis patients. QoL was assessed by KDQOL‐SF™1.3. The reversibility of pruritus was studied by applying retrospectively the VRS.

Results

The prevalence of pruritus by the VRS was 62% in hemodialysis patients, 32% in renal transplant patients, and 11% in healthy subjects (P<.001). The prevalence of pruritus among transplant patients was 32% by VRS and 38% by VAS and NRS. The prevalence of pretransplantation pruritus (68%) by the VRS recall questionnaire was higher than the prevalence of pruritus in the same patients after renal transplantation (32%, P<.01). Pruritus in transplant patients was associated with important dimensions of QoL, including social, emotional, and working limitations (P<.05 for the three comparisons).

Conclusions

The prevalence of pruritus markedly reduces after renal transplantation but remains substantially higher than in the general population and impacts upon quality of life in these patients.
Environmental impact on young children's participation in home‐based activities
Authors: Albrecht Erin C , Khetani Mary A
Published: December 2016

Aim

To test the effect of child, family, and environmental factors on young children's participation in home‐based activities.

Method

Caregivers of young children were recruited using convenience and snowball sampling. Participants were 395 caregivers of children (222 males, 173 females) aged from 1 month to 5 years and 11 months. Demographic items and the home section of the Young Children's Participation and Environment Measure were administered online, followed by completion of the daily activities, mobility, and social/cognitive domains of the Pediatric Evaluation of Disability Inventory Computer Adaptive Test by telephone interview.

Results

A structural equation model fitted the data well (comparative fit index=0.91) and explained 31.2% of the variance in perceived environmental support and 42.5% of the variance in home involvement. Functional limitations and performance had an indirect effect on young children's participation through their effect on perceived environmental support. Specifically, fewer functional limitations and higher task performance were associated with greater environmental support, which in turn predicted higher levels of home involvement.

Interpretation

Results suggest the importance of a young child's functional abilities and task performance on caregiver perceptions of environmental support at home, and the impact of environmental support on a child's participation in home‐based activities during the early childhood period. Results warrant replication with more diverse samples to evaluate model generalizability.
Behaviour in Cornelia de Lange syndrome: a systematic review
Authors: Mulder Paul A , Huisman Sylvia A , Hennekam Raoul C , Oliver Chris , van Balkom Ingrid D C , Piening Sigrid
Published: December 2016

Aim

Careful study and accurate description of behaviour are important to understand developmental challenges for individuals with Cornelia de Lange syndrome (CdLS). Here we present a systematic review of current understanding of behaviour in CdLS.

Method

A systematic search was performed for articles published between January 1946 and December 2015 evaluating autism, self‐injury, and/or cognition in CdLS. After study‐selection, 43 papers were included. The Cochrane quality criteria were adjusted to assign quality scores to the included studies.

Results

Participants were mostly categorized in the severe/profound developmental level. Methodology and quality were very heterogeneous, as well as reporting occurrence of autism. Self‐injurious behaviour was reported in 15 papers. Physical conditions were reported in 21 studies, mostly related to hearing and vision. Only nine studies mentioned details about medication.

Interpretation

Comparison of presented results was hindered by heterogeneous assessment methods. Improving our understanding of behavioural characteristics in CdLS requires more uniform methodology. We propose a criterion standard of instruments that can ideally be used in assessment of behaviour and development. This will improve understanding of behaviour in the context of developmental level and daily functioning.
Can a Two‐Question Test Be Reliable and Valid for Predicting Academic Outcomes?
Authors: Bridgeman Brent
Published: December 2016

Scores on essay‐based assessments that are part of standardized admissions tests are typically given relatively little weight in admissions decisions compared to the weight given to scores from multiple‐choice assessments. Evidence is presented to suggest that more weight should be given to these assessments. The reliability of the writing scores from two of the large volume admissions tests, the GRE General Test (GRE) and the Test of English as a Foreign Language Internet‐based test (TOEFL iBT), based on retesting with a parallel form, is comparable to the reliability of the multiple‐choice Verbal or Reading scores from those tests. Furthermore, and even more important, the writing scores from both tests are as effective as the multiple‐choice scores in predicting academic success and could contribute to fairer admissions decisions.
Premature mortality of epilepsy in low‐ and middle‐income countries: A systematic review from the Mortality Task Force of the International League Against Epilepsy
Authors: Levira Francis , Thurman David J. , Sander Josemir W. , Hauser W. Allen , Hesdorffer Dale C. , Masanja Honorati , Odermatt Peter , Logroscino Giancarlo , Newton Charles R. ,   the Epidemiology Commission of the International League Against Epilepsy
Published: December 2016

To determine the magnitude of risk factors and causes of premature mortality associated with epilepsy in low‐ and middle‐income countries (LMICs). We conducted a systematic search of the literature reporting mortality and epilepsy in the World Bank‐defined LMICs. We assessed the quality of the studies based on representativeness; ascertainment of cases, diagnosis, and mortality; and extracted data on standardized mortality ratios (SMRs) and mortality rates in people with epilepsy. We examined risk factors and causes of death. The annual mortality rate was estimated at 19.8 (range 9.7–45.1) deaths per 1,000 people with epilepsy with a weighted median SMR of 2.6 (range 1.3–7.2) among higher‐quality population‐based studies. Clinical cohort studies yielded 7.1 (range 1.6–25.1) deaths per 1,000 people. The weighted median SMRs were 5.0 in male and 4.5 in female patients; relatively higher SMRs within studies were measured in children and adolescents, those with symptomatic epilepsies, and those reporting less adherence to treatment. The main causes of death in people with epilepsy living in LMICs include those directly attributable to epilepsy, which yield a mean proportional mortality ratio (PMR) of 27.3% (range 5–75.5%) derived from population‐based studies. These direct causes comprise status epilepticus, with reported PMRs ranging from 5 to 56.6%, and sudden unexpected death in epilepsy (SUDEP), with reported PMRs ranging from 1 to 18.9%. Important causes of mortality indirectly related to epilepsy include drowning, head injury, and burns. Epilepsy in LMICs has a significantly greater premature mortality, as in high‐income countries, but in LMICs the excess mortality is more likely to be associated with causes attributable to lack of access to medical facilities such as status epilepticus, and preventable causes such as drowning, head injuries, and burns. This excess premature mortality could be substantially reduced with education about the risk of death and improved access to treatments, including AEDs.
Perampanel effects in the WAG/Rij rat model of epileptogenesis, absence epilepsy, and comorbid depressive‐like behavior
Authors: Citraro Rita , Leo Antonio , Franco Valentina , Marchiselli Roberto , Perucca Emilio , De Sarro Giovambattista , Russo Emilio
Published: December 2016

Objective

Perampanel (PER), a selective non‐competitive α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA)‐receptor antagonist, exhibits broad‐spectrum anticonvulsant activity in several seizure models, but its potential disease‐modifying effects have not been investigated. Because of the relevance of AMPA receptors in epileptogenesis and psychiatric comorbidities, we studied the effects of PER in the WAG/Rij rat model of epileptogenesis, absence epilepsy, and depressive‐like comorbidity.

Methods

We investigated the effects of acute, subchronic, and chronic treatment with PER (0.25–3 mg/kg) on absence seizures, their development, and related psychiatric/neurologic comorbidity in WAG/Rij rats. Depression‐related behavior was studied by using the forced swimming and the sucrose preference test; anxiety‐related behavior by using the open field and elevated plus maze test; and memory by using the passive avoidance test.

Results

PER (3 mg/kg/day orally for 17 weeks starting from P30) significantly reduced the development of absence seizures at 6 months of age (1 month after treatment withdrawal), but this effect was not maintained when reassessed 4 months later. Attenuated absence seizure development was accompanied by reduced depressive‐like behavior in the forced swimming test (FST), whereas no effects were observed on anxiety‐related behavior and memory. Subchronic (1 and 3 mg/kg/day orally for 1 week) and acute PER (0.25–1 mg/kg, i.p.) dosing did not affect established absence seizures and behavior.

Significance

These results suggest that AMPA receptors are involved in mechanisms of epileptogenesis in an established model of absence epilepsy, and that these mechanisms differ from those responsible for seizure generation and spread when epilepsy has become established.
Time to onset of sustained ≥50% responder status in patients with focal (partial‐onset) seizures in three phase III studies of adjunctive brivaracetam treatment
Authors: Klein Pavel , Johnson Martin E. , Schiemann Jimmy , Whitesides John
Published: December 2016

Time to onset of sustained ≥50% responder status (SRS) was assessed for the pooled patient population receiving brivaracetam (BRV) 50, 100, or 200 mg/day or placebo in three randomized phase III studies (NCT00464269, NCT00490035, and NCT01261325). Patients were aged ≥16 years with well‐characterized focal (partial‐onset) seizures (FS) uncontrolled by 1–2 concomitant antiepileptic drugs. After an 8‐week baseline period, patients received study drug without up‐titration for a 12‐week (84‐day) treatment period. A patient was a sustained ≥50% responder on a particular day if they completed the entire treatment period through day 84 and was a ≥50% responder (based on percent reduction in FS frequency from baseline) both on that day and every successive day until day 84 (end of treatment period). In the pooled efficacy population (N = 1,160), 15.5%, 18.1%, and 19.4% of patients taking BRV 50, 100, or 200 mg/day, respectively, achieved SRS on day 1 versus 6.7% for placebo (p < 0.001). Statistically significant SRS was also achieved for most of the BRV‐treated groups in the three separate studies. This suggests that BRV has an early, sustained onset of action in a subset of responders. The incidence of adverse events during the first week was similar to that in the overall treatment period.
Ictal asystole: A systematic review
Authors: Tényi Dalma , Gyimesi Csilla , Kupó Péter , Horváth Réka , Bóné Beáta , Barsi Péter , Kovács Norbert , Simor Tamás , Siegler Zsuzsa , Környei László , Fogarasi András , Janszky József
Published: December 2016

Objective

To comprehensively analyze ictal asystole (IA) on a large number of subjects.

Methods

We performed a systematic review of case report studies of patients diagnosed with IA (1983–2016). Each included case was characterized with respect to patient history, IA seizure characteristics, diagnostic workup, and therapy. In addition, comparative analyses were also carried out: two alignments were developed based on the delay between epilepsy onset and IA onset (“new‐onset” if <1 year, “late‐onset” if ≥1 year) and asystole duration (asystole was “very prolonged” if lasted >30 s).

Results

One hundred fifty‐seven cases were included. All patients had focal epilepsy. In 7% of cases IA developed during a secondary generalized tonic–clonic seizure. Both the seizure‐onset zone and the focal seizure activity at asystole beginning were usually temporal (p < 0.001 and p = 0.001, respectively) and were lateralized to the left hemisphere in 62% (p = 0.005 and p = 0.05, respectively). Asystole duration was 18 ± 14 s (mean±SD) (range 3–96 s); 73% of patients had late‐onset, 27% had new‐onset IA. Compared to late‐onset IA, new‐onset IA was associated with female gender (p = 0.023), preexisting heart condition (p = 0.014), focal seizure activity at asystole beginning (p = 0.012), normal neuroimaging (p = 0.013), normal interictal EEG (p < 0.001), auditory aura (p = 0.012), and drug‐responsive epilepsy (p < 0.001). “Very prolonged” asystole was associated with secondary generalized tonic–clonic seizures (p = 0.003) and tended to occur in extratemporal lobe seizures (p = 0.074). No IA‐related death was reported.

Significance

Characteristics considered to be typical of IA (focal, left temporal seizures appearing on grounds of a long‐lasting, intractable epilepsy) seem only partially legitimate. We suggest that in new‐onset IA, female gender and a preexisting heart condition could serve as predispositions in an otherwise benign epilepsy. We speculate that in late‐onset IA, male‐predominant changes in neuronal networks in chronic, intractable epilepsy and an accompanying autonomic dysregulation serve as facilitating factors.