bluuebunny/crossref_metadata_2025 huggingface dataset:
Longitudinal assessment of utilities in patients with migraine: an analysis of erenumab randomized controlled trials
Authors: Di Tanna Gian Luca , Porter Joshua K. , Lipton Richard B. , Hatswell Anthony J. , Sapra Sandhya , Villa Guillermo
Published: November 2019

Background

Cost-effectiveness analyses in patients with migraine require estimates of patients’ utility values and how these relate to monthly migraine days (MMDs). This analysis examined four different modelling approaches to assess utility values as a function of MMDs.

Methods

Disease-specific patient-reported outcomes from three erenumab clinical studies (two in episodic migraine [NCT02456740 and NCT02483585] and one in chronic migraine [NCT02066415]) were mapped to the 5-dimension EuroQol questionnaire (EQ-5D) as a function of the Migraine-Specific Quality of Life Questionnaire (MSQ) and the Headache Impact Test (HIT-6™) using published algorithms. The mapped utility values were used to estimate generic, preference-based utility values suitable for use in economic models. Four models were assessed to explain utility values as a function of MMDs: a linear mixed effects model with restricted maximum likelihood (REML), a fractional response model with logit link, a fractional response model with probit link and a beta regression model.

Results

All models tested showed very similar fittings. Root mean squared errors were similar in the four models assessed (0.115, 0.114, 0.114 and 0.114, for the linear mixed effect model with REML, fractional response model with logit link, fractional response model with probit link and beta regression model respectively), when mapped from MSQ. Mean absolute errors for the four models tested were also similar when mapped from MSQ (0.085, 0.086, 0.085 and 0.085) and HIT-6 and (0.087, 0.088, 0.088 and 0.089) for the linear mixed effect model with REML, fractional response model with logit link, fractional response model with probit link and beta regression model, respectively.

Conclusions

This analysis describes the assessment of longitudinal approaches in modelling utility values and the four models proposed fitted the observed data well. Mapped utility values for patients treated with erenumab were generally higher than those for individuals treated with placebo with equivalent number of MMDs. Linking patient utility values to MMDs allows utility estimates for different levels of MMD to be predicted, for use in economic evaluations of preventive therapies.

Trial registration

ClinicalTrials.gov numbers of the trials used in this study: STRIVE, NCT02456740 (registered May 14, 2015), ARISE, NCT02483585 (registered June 12, 2015) and NCT02066415 (registered Feb 17, 2014).
In vitro effect of nerve growth factor on the main traits of rabbit sperm
Authors: Castellini Cesare , Mattioli Simona , Dal Bosco Alessandro , Collodel Giulia , Pistilli Alessandra , Stabile Anna Maria , Macchioni Lara , Mancuso Francesca , Luca Giovanni , Rende Mario
Published: November 2019

Background

The nerve growth factor (NGF), a member of the neurotrophins family, plays an important role not only in the nervous but also in other non-nervous systems such as the reproductive system. The aim of the paper is to study the in vitro effect of NGF on rabbit sperm functions.

Methods

Ten adult rabbit bucks were collected five times, and pooled semen samples have been analysed. NGF was quantified in seminal plasma, and the distribution of NGF receptors (TrKA and p75NTR) in sperm was established. Moreover, the dose-effect of NGF on motility rate and track speed was evaluated. Successively, the effect of the neutralisation of NGF receptors was assessed to verify the specific role of each receptor. Untreated sperm were used as control.

Results

Our study identified several interesting results: i) We detected NGF in seminal plasma and TrKA and p75NTR in sperm surface. In particular, TrKA is localised in the head and p75NTR in the midpiece and tail of rabbit sperm. ii) Once the optimal dose of NGF (100 ng/mL) was established, its addition affected both kinetics and other physiological traits (capacitation, apoptosis and necrosis) of rabbit sperm. (iii) The neutralisation of TrKA and p75NTR receptors affected sperm traits differently. In particular, sperm speed, apoptosis and capacitation seemed mainly modulated via p75NTR receptor, whereas motile, live cells, necrosis and acrosome reaction were modulated via TrKA.

Conclusion

For the first time, we showed the presence of p75NTR in rabbit sperm. NGF affects kinetic and other physiological traits of rabbit sperm. Most of these changes are modulated by the receptors involved (TrKA or p75NTR). Considering that some seminal disorders in human have been correlated with a lower NGF concentration and no studies have been done on the possible involvement of NGF receptors, these findings also provide new insights on human fertility.
Debridement, antibiotics, and implant retention for periprosthetic knee infections: a pooling analysis of 1266 cases
Authors: Qu Guo-Xin , Zhang Cai-Hua , Yan Shi-Gui , Cai Xun-Zi
Published: November 2019

Background

The debridement, antibiotics, and implant retention (DAIR) procedure is an established therapeutic option for periprosthetic knee infections (PKI). However, the efficacy and the indication for this procedure are still controversial.

Methods

All the relevant literatures were systematically reviewed and analyzed. The present study aimed to assess the success rate of DAIR in the management of PKI, identify the factors associated with prognosis of DAIR, and establish a simple algorithm for predicting a high success rate of DAIR.

Results

Totally, 33 studies with 1266 cases were included. The overall success rate following DAIR in the management of PKI was 57.11%. In the subgroup analyses, the factors of “the time from symptoms to debridement was < 3 weeks” and “the bacterial species other than methicillin-resistant Staphylococcus aureus” significantly improved the success rate of DAIR and thus were defined as the major criteria. The statistically insignificant factors of “the open debridement and liner exchange” and “the comorbidity of rheumatoid arthritis” were set as the minor criteria. The success rate of DAIR for PKI meeting all the major criteria and no less than one minor criterion was 80.98%, which was significantly higher than the overall success rate of DAIR (p < 0.05).

Conclusion

PKI cases meeting two major criteria and no less than one minor criterion may confer a high success rate of DAIR. This simple algorithm may contribute to identifying the appropriate PKI patient for DAIR treatment and predicting the prognosis of DAIR.
Acceleration of cellodextrin phosphorolysis for bioelectricity generation from cellulosic biomass by integrating a synthetic two-enzyme complex into an in vitro synthetic enzymatic biosystem
Authors: Meng Dongdong , Wu Ranran , Wang Juan , Zhu Zhiguang , You Chun
Published: November 2019

Background

Cellulosic biomass, the earth’s most abundant renewable resource, can be used as substrates for biomanufacturing biofuels or biochemicals via in vitro synthetic enzymatic biosystems in which the first step is the enzymatic phosphorolysis of cellodextrin to glucose 1-phosphate (G1P) by cellodextrin phosphorylase (CDP). However, almost all the CDPs prefer cellodextrin synthesis to phosphorolysis, resulting in the low reaction rate of cellodextrin phosphorolysis for biomanufacturing.

Results

To increase the reaction rate of cellodextrin phosphorolysis, synthetic enzyme complexes containing CDP and phosphoglucomutase (PGM) were constructed to convert G1P to glucose 6-phosphate (G6P) rapidly, which is an important intermediate for biomanufacturing. Four self-assembled synthetic enzyme complexes were constructed with different spatial organizations based on the high-affinity and high-specific interaction between cohesins and dockerins from natural cellulosomes. Thus, the CDP–PGM enzyme complex with the highest enhancement of initial reaction rate was integrated into an in vitro synthetic enzymatic biosystem for generating bioelectricity from cellodextrin. The in vitro biosystem containing the best CDP–PGM enzyme complex exhibited a much higher current density (3.35-fold) and power density (2.14-fold) than its counterpart biosystem containing free CDP and PGM mixture.

Conclusions

Hereby, we first reported bioelectricity generation from cellulosic biomass via in vitro synthetic enzymatic biosystems. This work provided a strategy of how to link non-energetically favorable reaction (cellodextrin phosphorolysis) and energetically favorable reaction (G1P to G6P) together to circumvent unfavorable reaction equilibrium and shed light on improving the reaction efficiency of in vitro synthetic enzymatic biosystems through the construction of synthetic enzyme complexes.
Radiographic progression can still occur in individual patients with low or moderate disease activity in the current treat-to-target paradigm: real-world data from the Dutch Rheumatoid Arthritis Monitoring (DREAM) registry
Authors: ten Klooster Peter M. , Versteeg Letty G. A. , Oude Voshaar Martijn A. H. , de la Torre Inmaculada , De Leonardis Francesco , Fakhouri Walid , Zaremba-Pechmann Liliana , van de Laar Mart
Published: November 2019

Background

The aim of this retrospective study was to examine the longitudinal association between disease activity and radiographic damage in a cohort of patients with early RA (symptom onset < 1 year) treated according to treat-to-target (T2T) therapy.

Methods

Baseline to 3-year follow-up data were used from patients included in the DREAM remission induction cohort. Patients received protocolized T2T treatment, aimed at 28-joint disease activity score-erythrocyte sedimentation rate (DAS28-ESR) remission. Disease activity (DAS28-ESR and C-reactive protein, CRP) were assessed at least every 3 months; X-rays of the hand and feet at inclusion, 6 months, and 1, 2, and 3 years were scored using modified Sharp/van der Heijde scoring (SHS). Between and within-person associations between time-integrated disease activity and radiographic progression over time were examined.

Results

A subset of 229 out of 534 included patients were available for analysis. At the between-patient level, time-integrated DAS28-ESR scores were not significantly correlated with progression at the 6 month and 2-year follow-up and only weakly at the 1-year (Pearson’s correlation coefficient r = 0.17, P < 0.05) and 3-year follow-up (r = 0.21, P < 0.05). Individual slopes of the relationship between DAS28-ESR and progression scores in each time interval were significantly correlated over time and the slope of the first 6 months was moderately associated with this slope at later time points (r between 0.39 and 0.59; P values < 0.001). Between 15.9 to 22.7% and 16.7 to 38.5% of patients with low and moderate time-integrated disease activity, respectively, experienced relevant (ΔSHS ≥ 3) radiographic progression at the different time intervals. Analyses using CRP showed similar results.

Conclusions

In early RA patients treated according to T2T, radiographic progression appears to be an individually determined disease process, driven by factors other than consistent high disease activity. For individual patients, the intra-patient relation between disease activity and cumulative radiographic damage during the first 6 months is a good indicator for this relation in later years.

Trial registration

Netherlands Trial Register NTR578, 12 January 2006.
Neglected intrauterine fetal demise for more than two decades leading to the development of a lithopedion: a case report
Authors: Gebresenbet Fitsum Fikru , Mulat Abdu Mengesha , Nur Namus Muhajir , Getaneh Ferehiwot Bekele
Published: November 2019

Background

Lithopedion is a word derived from the Greek words lithos, meaning stone, and paidion, meaning child, to describe a fetus that has become stony or petrified. Lithopedion is a rare complication of pregnancy which occurs when a fetus dies and becomes too large to be reabsorbed by the body. This entity in rare circumstances can be challenging for physicians to diagnose since it has a range of clinical manifestations.

Case presentation

We present a case of a 55-year-old, gravida IV para III, Ethiopian woman from Ethiopia with a retained fetus and vesicovaginal fistula after an obstructed labor and a neglected intrauterine fetal demise of approximately 22 years. The diagnosis was confirmed by suggestive clinical history, physical examination findings, and an abdominopelvic computed tomography scan. Laparotomy and removal of the lithopedion was done and our patient was sent to a fistula hospital for vesicovaginal fistula repair.

Conclusion

This case is a rare phenomenon in which the dead fetus remained in the uterus for a long time after a neglected obstructed labor and uterine rupture.
Potential microRNA-related targets in clearance pathways of amyloid-β: novel therapeutic approach for the treatment of Alzheimer’s disease
Authors: Madadi Soheil , Schwarzenbach Heidi , Saidijam Massoud , Mahjub Reza , Soleimani Meysam
Published: November 2019

Imbalance between amyloid-beta (Aβ) peptide synthesis and clearance results in Aβ deregulation. Failure to clear these peptides appears to cause the development of Alzheimer’s disease (AD). In recent years, microRNAs have become established key regulators of biological processes that relate among others to the development and progression of neurodegenerative diseases, such as AD. This review article gives an overview on microRNAs that are involved in the Aβ cascade and discusses their inhibitory impact on their target mRNAs whose products participate in Aβ clearance. Understanding of the mechanism of microRNA in the associated signal pathways could identify novel therapeutic targets for the treatment of AD.
A note on generalized convex functions
Authors: Zaheer Ullah Syed , Adil Khan Muhammad , Chu Yu-Ming
Published: November 2019

In the article, we provide an example for a η-convex function defined on rectangle is not convex, prove that every η-convex function defined on rectangle is coordinate η-convex and its converse is not true in general, define the coordinate $(\eta _{1}, \eta _{2})$(η1,η2)-convex function and establish its Hermite–Hadamard type inequality.
APSIC guidelines for the prevention of surgical site infections
Authors: Ling Moi Lin , Apisarnthanarak Anucha , Abbas Azlina , Morikane Keita , Lee Kil Yeon , Warrier Anup , Yamada Koji
Published: November 2019

Background

The Asia Pacific Society of Infection Control (APSIC) launched the APSIC Guidelines for the Prevention of Surgical Site Infections in 2018. This document describes the guidelines and recommendations for the setting prevention of surgical site infections (SSIs). It aims to highlight practical recommendations in a concise format designed to assist healthcare facilities at Asia Pacific region in achieving high standards in preoperative, perioperative and postoperative practices.

Method

The guidelines were developed by an appointed workgroup comprising experts in the Asia Pacific region, following reviews of previously published guidelines and recommendations relevant to each section.

Results

It recommends that healthcare facilities review specific risk factors and develop effective prevention strategies, which would be cost effective at local levels. Gaps identified are best closed using a quality improvement process. Surveillance of SSIs is recommended using accepted international methodology. The timely feedback of the data analysed would help in the monitoring of effective implementation of interventions.

Conclusions

Healthcare facilities should aim for excellence in safe surgery practices. The implementation of evidence-based practices using a quality improvement process helps towards achieving effective and sustainable results.
Risk prediction for 30-day mortality among patients with Clostridium difficile infections: a retrospective cohort study
Authors: Chiang Hsiu-Yin , Huang Han-Chun , Chung Chih-Wei , Yeh Yi-Chun , Chen Yi-Chin , Tien Ni , Lin Hsiu-Shan , Ho Mao-Wang , Kuo Chin-Chi
Published: November 2019

Background

Current guidelines have unsatisfied performance in predicting severe outcomes after Clostridium difficile infection (CDI). Our objectives were to develop a risk prediction model for 30-day mortality and to examine its performance among inpatients with CDI.

Methods

This retrospective cohort study was conducted at China Medical University Hospital, a 2111-bed tertiary medical center in central Taiwan. We included adult inpatients who had a first positive C. difficile culture or toxin assay and had diarrhea as the study population. The main exposure of interest was the biochemical profiles of white blood cell count, serum creatinine (SCr), estimated glomerular filtration rate, blood urea nitrogen (BUN), serum albumin, and glucose. The primary outcome was the 30-day all-cause mortality and the secondary outcome was the length of stay in the intensive care units (ICU) following CDI. A multivariable Cox model and a logistic regression model were developed using clinically relevant and statistically significant variables for 30-day mortality and for length of ICU stay, respectively. A risk scoring system was established by standardizing the coefficients. We compared the performance of our models and the guidelines.

Results

Of 401 patients, 23.4% died within 30 days. In the multivariable model, malignancy (hazard ratio [HR] = 1.95), ≥ 1.5-fold rise in SCr (HR = 2.27), BUN-to-SCr ratio > 20 (HR = 2.04), and increased glucose (≥ 193 vs < 142 mg/dL, HR = 2.18) were significant predictors of 30-day mortality. For patients who survived the first 30 days of CDI, BUN-to-SCr ratio > 20 (Odds ratio [OR] = 4.01) was the only significant predictor for prolonged (> 9 days) length of ICU stay following CDI. The Harrell’s c statistic of our Cox model for 30-day mortality (0.727) was significantly superior to those of SHEA-IDSA 2010 (0.645), SHEA-IDSA 2018 (0.591), and ECSMID (0.650). Similarly, the conventional c statistic of our logistic regression model for prolonged ICU stay (0.737) was significantly superior to that of the guidelines (SHEA-IDSA 2010, c = 0.600; SHEA-IDSA 2018, c = 0.634; ESCMID, c = 0.645). Our risk prediction scoring system for 30-day mortality correctly reclassified 20.7, 32.1, and 47.9% of patients, respectively.

Conclusions

Our model that included novel biomarkers of BUN-to-SCr ratio and glucose have a higher predictive performance of 30-day mortality and prolonged ICU stay following CDI than do the guidelines.
Correction to: Assessment of urban sprawl effects on regional climate change using a hybrid model of factor analysis and analytical network process in the Mashhad city, Iran
Authors: Mansouri Daneshvar Mohammad Reza , Rabbani Ghazaleh , Shirvani Susan
Published: November 2019

Following publication of the original article (Mansouri Daneshvar et al. 2019), the corrected text with the reference citations are given below:
Study protocol for PRISE: a longitudinal study of sexual harassment during the transition from childhood to adolescence
Authors: Skoog Therése , Holmqvist Gattario Kristina , Lunde Carolina
Published: November 2019

Background

Sexual harassment is a widespread problem with serious consequences for individuals and societies. It is likely that sexual harassment among peers has its main onset during the transition from late childhood to early adolescence, when young people enter puberty. However, there is a lack of systematic research on sexual harassment during this developmental period. Thus, there is very little information about the prevalence of sexual harassment during this important transition, its consequences, and how to effectively intervene against and prevent the problem. The primary objective of the described project, entitled Peer Relations In School from an Ecological perspective (PRISE), is to examine sexual harassment and its developmental correlates during the transition from late childhood to early adolescence.

Methods

The PRISE study has a longitudinal design over 3 years, in which a cohort of children (N = 1000) and their main teachers (N = 40) fill out questionnaires in grades 4, 5, and 6. The questionnaires assess aspects of peer sexual harassment and potential correlates including biological (e.g., pubertal development), psychosocial (e.g., self-assertiveness, self-image, peer relations), and contextual (e.g., classroom climate, norms) factors. In addition, we will examine school readiness and policies in relation to sexual harassment and collect register data to assess the number of reports of sexual harassment from the participating schools.

Discussion

The PRISE study will enable the researchers to answer fundamental, unresolved questions about the development of sexual harassment and thus advance the very limited understanding of sexual harassment during the transition from childhood to adolescence - a central period for physical, sexual, and social development. Due to the sensitive nature of the main research concepts, and the age of the participants, the ethical aspects of the research need particular attention. Ultimately, the hope is that the PRISE study will help researchers, policy makers, and practitioners develop, and implement, knowledge that may help in combating a major, current societal challenge and adverse aspect of young people’s developmental ecologies.
Relationship between adverse drug reactions to antibacterial agents and the Klebsiella pneumoniae carbapenemase-producing (KPC) Klebsiella pneumoniae outbreak: insight from a pharmacovigilance study
Authors: Gatti Milo , Raschi Emanuel , De Ponti Fabrizio
Published: November 2019

Background

The management of Klebsiella pneumoniae carbapenemase producing (KPC) infections represents a major challenge. Several safety and efficacy concerns are shared by available antibiotics used in KPC infections, leading to the occurrence of serious adverse drug reactions (ADRs), with ceftazidime-avibactam possibly showing a more favourable risk-benefit profile. We investigated the potential impact of resistance on ADR reports in countries with different prevalence of KPC isolates (Italy vs. United Kingdom [UK]), and described safety profile of newer and older antibiotics used in KPC infections.

Methods

Three spontaneous reporting systems (SRSs) with different features (Italy, UK and worldwide FAERS) were used to describe safety profiles of colistin, meropenem, tigecycline, gentamicin and ceftazidime-avibactam in terms of System Organ Class and Preferred Term level. ADRs were plotted with prevalence of KPC isolates in Italy and UK. A comparison between before-after the KPC outbreak period (1999–2008 vs. 2009–2018) of overall and serious ADRs for selected antibiotics in each SRS was performed. Relationship between total and serious number of ADR reports per year and KPC isolates per year after KPC outbreak (2009–2017) was investigated for both Italy and UK.

Results

A total of 16,329 ADR reports were collected in the three SRSs, with meropenem (42.6%) and gentamicin (36.9%) having the highest number of reports. Significant increase in total and serious ADR reports after the KPC outbreak compared to previous 10 years was found for colistin, meropenem and gentamicin (p < 0.01). No significant increase in tigecycline ADRs was reported in FAERS and UK database. Unexpected safety signals involving selected antibiotics were not detected. Significant positive relationship between overall and serious ADR reports and KPC isolates per year for both Italy (p < 0.01; p = 0.005) and UK (p = 0.032; p = 0.013) was found.

Conclusion

KPC outbreak led to significant increase in ADRs to selected antibiotics, and a close relationship with antimicrobial resistance was found, both in countries with high and low resistance rate. New safety signals were not detected for selected agents. Active surveillance should be maintained to promptly identify unexpected safety issues.
Tanshinone IIA attenuates Aβ-induced neurotoxicity by down-regulating COX-2 expression and PGE2 synthesis via inactivation of NF-κB pathway in SH-SY5Y cells
Authors: Geng Lijiao , Liu Wei , Chen Yong
Published: November 2019

Amyloid-β (Aβ)-induced neurotoxicity is a major pathological mechanism of Alzheimer’s disease (AD). Tanshinone IIA (Tan IIA), extracted from traditional Chinese herb Radix salvia miltiorrhiza, possesses anti-oxidant and anti-inflammatory actions, as well as neuroprotective effects. The present study aims to explore the possible mechanism by which Tan IIA attenuated Aβ-induced neurotoxicity. Exposure of SH-SY5Y cells to different concentrations of Aβ led to neurotoxicity by reducing cell viability, inducing cell apoptosis and increasing neuroinflammation in a dose-dependent manner. Moreover, Aβ treatment promoted cyclooxygenase-2 (COX-2) expression and Prostaglandin E2 (PGE2) secretion, and activated nuclear transcription factor kappa (NF-κB) pathway in SH-SY5Y cells. However, pretreatment of SH-SY5Y cells with Tan IIA prior to Aβ prevented these Aβ-induced cellular events noticeably. These data suggested that Tan IIA exerted its neuroprotective action by alleviating Aβ-induced increase in COX-2 expression and PGE2 secretion via inactivation of NF-κB pathway.
Resistive index of central retinal artery is a bioimaging biomarker for severity of diabetic retinopathy
Authors: Khatri Manila , Saxena Sandeep , Kumar Manoj , Chabbra Apjit Kaur , Bhasker Shashi K. , Akduman Ece Isin , Pham Hang , Akduman Levent
Published: November 2019

Background

The present study was undertaken to assess the resistive index (RI) of central retinal artery (CRA) as a bioimaging biomarker for the severity of diabetic retinopathy (DR), for the first time.

Methods

Eighty-one consecutive patients of type 2 diabetes mellitus between the ages of 40 and 70 years were included in a tertiary care center-based cross sectional study. Severity of retinopathy was assessed according to Early Treatment Diabetic Retinopathy Study (ETDRS) classification: diabetes mellitus with no retinopathy (No DR) (n = 26); non-proliferative diabetic retinopathy (NPDR) (n = 29); and proliferative diabetic retinopathy (PDR) (n = 26). Twenty-six healthy controls of similar age were also included. Resistive index of CRA was studied using color Doppler and gray scale sonography. Central subfield thickness (CST), cube average thickness (CAT), retinal photoreceptor ellipsoid zone (EZ) disruption, and retinal nerve fiber layer (RNFL) thickness were evaluated using spectral domain optical coherence tomography. Sensitivity and specificity were assessed by receiver operating characteristic (ROC) curve.

Results

Mean RI of CRA for the study groups revealed significant increase with severity of diabetic retinopathy (F = 10.24, P < 0.001). The ROC curve analysis showed diagnostic accuracy of RI of CRA (area under curve = 0.841–0.999; sensitivity = 76–100%, specificity = 95.45–100%, P < 0.001) in discriminating controls and patients. Univariate regression analysis revealed significant association between the study groups and RI of CRA (P < 0.001). RI of CRA correlated positively with CST (r = 0.37), CAT (r = 0.45), EZ disruption (r = 0.43) and negatively with RNFL thickness (r = − 0.35) (P < 0.001).

Conclusions

Resistive index of CRA is a reliable bioimaging biomarker for the severity of DR.
Efficacy of α-Blockers on Hemodynamic Control during Pheochromocytoma Resection: A Randomized Controlled Trial
Authors: Buitenwerf Edward , Osinga Thamara E , Timmers Henri J L M , Lenders Jacques W M , Feelders Richard A , Eekhoff Elisabeth M W , Haak Harm R , Corssmit Eleonora P M , Bisschop Peter H L T , Valk Gerlof D , Veldman Ronald Groote , Dullaart Robin P F , Links Thera P , Voogd Magiel F , Wietasch Götz J K G , Kerstens Michiel N
Published: November 2019

Context

Pretreatment with α-adrenergic receptor blockers is recommended to prevent hemodynamic instability during resection of a pheochromocytoma or sympathetic paraganglioma (PPGL).

Objective

To determine which type of α-adrenergic receptor blocker provides the best efficacy.

Design

Randomized controlled open-label trial (PRESCRIPT; ClinicalTrials.gov NCT01379898)

Setting

Multicenter study including 9 centers in The Netherlands.

Patients

134 patients with nonmetastatic PPGL.

Intervention

Phenoxybenzamine or doxazosin starting 2 to 3 weeks before surgery using a blood pressure targeted titration schedule. Intraoperative hemodynamic management was standardized.

Main Outcome Measures

Primary efficacy endpoint was the cumulative intraoperative time outside the blood pressure target range (ie, SBP >160 mmHg or MAP <60 mmHg) expressed as a percentage of total surgical procedure time. Secondary efficacy endpoint was the value on a hemodynamic instability score.

Results

Median cumulative time outside blood pressure targets was 11.1% (interquartile range [IQR]: 4.3–20.6] in the phenoxybenzamine group compared to 12.2% (5.3–20.2)] in the doxazosin group (P = .75, r = 0.03). The hemodynamic instability score was 38.0 (28.8–58.0) and 50.0 (35.3–63.8) in the phenoxybenzamine and doxazosin group, respectively (P = .02, r = 0.20). The 30-day cardiovascular complication rate was 8.8% and 6.9% in the phenoxybenzamine and doxazosin group, respectively (P = .68). There was no mortality after 30 days.

Conclusions

The duration of blood pressure outside the target range during resection of a PPGL was not different after preoperative treatment with either phenoxybenzamine or doxazosin. Phenoxybenzamine was more effective in preventing intraoperative hemodynamic instability, but it could not be established whether this was associated with a better clinical outcome.
Classification of Type 2 Diabetes Genetic Variants and a Novel Genetic Risk Score Association With Insulin Clearance
Authors: Goodarzi Mark O , Palmer Nicholette D , Cui Jinrui , Guo Xiuqing , Chen Yii-Der I , Taylor Kent D , Raffel Leslie J , Wagenknecht Lynne E , Buchanan Thomas A , Hsueh Willa A , Rotter Jerome I
Published: November 2019

Context

Genome-wide association studies have identified more than 450 single nucleotide polymorphisms (SNPs) for type 2 diabetes (T2D).

Objective

To facilitate use of these SNPs in future genetic risk score (GRS)-based analyses, we aimed to classify the SNPs based on physiology. We also sought to validate GRS associations with insulin-related traits in deeply phenotyped Mexican Americans.

Design, Setting, and Participants

A total of 457 T2D SNPs from the literature were assigned physiologic function based on association studies and cluster analyses. All SNPs (All-GRS), beta-cell (BC-GRS), insulin resistance (IR-GRS), lipodystrophy (Lipo-GRS), and body mass index plus lipids (B + L–GRS) were evaluated for association with diabetes and indices of insulin secretion (from oral glucose tolerance test), insulin sensitivity and insulin clearance (from euglycemic clamp), and adiposity and lipid markers in 1587 Mexican Americans.

Results

Of the 457 SNPs, 52 were classified as BC, 30 as IR, 12 as Lipo, 12 as B + L, whereas physiologic function of 351 was undefined. All-GRS was strongly associated with T2D. Among nondiabetic Mexican Americans, BC-GRS was associated with reduced insulinogenic index, IR-GRS was associated with reduced insulin sensitivity, and Lipo-GRS was associated with reduced adiposity. B + L–GRS was associated with increased insulin clearance. The latter did not replicate in an independent cohort wherein insulin clearance was assessed by a different method.

Conclusions

Supporting their utility, BC-GRS, IR-GRS, and Lipo-GRS, based on SNPs discovered largely in Europeans, exhibited expected associations in Mexican Americans. The novel association of B + L–GRS with insulin clearance suggests that impaired ability to reduce insulin clearance in compensation for IR may play a role in the pathogenesis of T2D. Whether this applies to other ethnic groups remains to be determined.
Axo-glial interdependence in peripheral nerve development
Authors: Fledrich Robert , Kungl Theresa , Nave Klaus-Armin , Stassart Ruth M.
Published: November 2019

During the development of the peripheral nervous system, axons and myelinating Schwann cells form a unique symbiotic unit, which is realized by a finely tuned network of molecular signals and reciprocal interactions. The importance of this complex interplay becomes evident after injury or in diseases in which aspects of axo-glial interaction are perturbed. This Review focuses on the specific interdependence of axons and Schwann cells in peripheral nerve development that enables axonal outgrowth, Schwann cell lineage progression, radial sorting and, finally, formation and maintenance of the myelin sheath.
Temporospatial sonic hedgehog signalling is essential for neural crest-dependent patterning of the intrinsic tongue musculature
Authors: Okuhara Shigeru , Birjandi Anahid A. , Adel Al-Lami Hadeel , Sagai Tomoko , Amano Takanori , Shiroishi Toshihiko , Xavier Guilherme M. , Liu Karen J. , Cobourne Martyn T. , Iseki Sachiko
Published: November 2019

The tongue is a highly specialised muscular organ with a complex anatomy required for normal function. We have utilised multiple genetic approaches to investigate local temporospatial requirements for sonic hedgehog (SHH) signalling during tongue development. Mice lacking a Shh cis-enhancer, MFCS4 (ShhMFCS4/−), with reduced SHH in dorsal tongue epithelium have perturbed lingual septum tendon formation and disrupted intrinsic muscle patterning, with these defects reproduced following global Shh deletion from E10.5 in pCag-CreERTM; Shhflox/flox embryos. SHH responsiveness was diminished in local cranial neural crest cell (CNCC) populations in both mutants, with SHH targeting these cells through the primary cilium. CNCC-specific deletion of orofaciodigital syndrome 1 (Ofd1), which encodes a ciliary protein, in Wnt1-Cre; Ofdfl/Y mice led to a complete loss of normal myotube arrangement and hypoglossia. In contrast, mesoderm-specific deletion of Ofd1 in Mesp1-Cre; Ofdfl/Y embryos resulted in normal intrinsic muscle arrangement. Collectively, these findings suggest key temporospatial requirements for local SHH signalling in tongue development (specifically, lingual tendon differentiation and intrinsic muscle patterning through signalling to CNCCs) and provide further mechanistic insight into the tongue anomalies seen in patients with disrupted hedgehog signalling.
Dynamics of Spaetzle morphogen shuttling in the Drosophila embryo shapes gastrulation patterning
Authors: Rahimi Neta , Averbukh Inna , Carmon Shari , Schejter Eyal D. , Barkai Naama , Shilo Ben-Zion
Published: November 2019

Establishment of morphogen gradients in the early Drosophila embryo is challenged by a diffusible extracellular milieu, and by rapid nuclear divisions that occur at the same time. To understand how a sharp gradient is formed within this dynamic environment, we followed the generation of graded nuclear Dorsal protein, the hallmark of pattern formation along the dorso-ventral axis, in live embryos. The dynamics indicate that a sharp extracellular gradient is formed through diffusion-based shuttling of the Spaetzle (Spz) morphogen that progresses through several nuclear divisions. Perturbed shuttling in wntD mutant embryos results in a flat activation peak and aberrant gastrulation. Re-entry of Dorsal into the nuclei at the final division cycle plays an instructive role, as the residence time of Dorsal in each nucleus is translated to the amount of zygotic transcript that will be produced, thereby guiding graded accumulation of specific zygotic transcripts that drive patterned gastrulation. We conclude that diffusion-based ligand shuttling, coupled with dynamic readout, establishes a refined pattern within the diffusible environment of early embryos.
Dorsal convergence of gastrula cells requires a Vangl2 and adhesion protein-dependent change in protrusive activity
Authors: Prince Dianna J. , Jessen Jason R.
Published: November 2019

Lateral zebrafish hypoblast cells initiate dorsal convergence near mid-gastrulation and exhibit non-polarized morphologies, limited cell-cell contact, and indirect migration trajectories. By late gastrulation mesodermal cells become packed as they engage in planar cell polarity (PCP)-dependent movement. Here, we aimed to understand this transition in cell behavior by examining the relationship between protrusion dynamics and establishment of PCP and directed migration. We found that wild-type cells undergo a reduction in bleb protrusions near late gastrulation accompanied by a VANGL planar cell polarity protein 2 (Vangl2) regulated increase in filopodia number and polarization. Manipulation of blebs is sufficient to interfere with PCP and directed migration. We show that Vangl2, fibronectin, and Cadherin 2 function to suppress blebbing. Vangl2 maintains Ezrin b (Ezrb) protein levels and higher Ezrb activation rescues defective mediolateral cell alignment and migration paths in vangl2 mutant embryos. Transplantation experiments show that loss of vangl2 disrupts protrusion formation cell-autonomously while fibronectin acts non-autonomously. We propose that dorsal convergence requires the coordinated action of Vangl2, Ezrb, and cell adhesion proteins to inhibit blebs and promote polarized actin-rich protrusive activity and PCP.
Hmgcr promotes a long-range signal to attract Drosophila germ cells independently of Hedgehog
Authors: Kenwrick Kim , Mukherjee Amrita , Renault Andrew D.
Published: November 2019

During development, many cell types migrate along stereotyped routes determined through deployment of cell surface or secreted guidance molecules. Although we know the identity of many of these molecules, the distances over which they natively operate can be difficult to determine. Here, we have quantified the range of an attractive signal for the migration of Drosophila germ cells. Their migration is guided by an attractive signal generated by the expression of genes in the 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (Hmgcr) pathway, and by a repulsive signal generated by the expression of Wunens. We demonstrate that the attractive signal downstream of Hmgcr is cell-contact independent and acts at long range, the extent of which depends on Hmgcr levels. This range would be sufficient to reach all of the germ cells for their entire migration. Furthermore, Hmgcr-mediated attraction does not require Wunens but can operate simultaneously with Wunen-mediated repulsion. Finally, several papers posit Hedgehog (Hh) as being the germ cell attractant downstream of Hmgcr. Here, we provide evidence that this is not the case.
Recent advances in the prevention and management of infections in children undergoing treatment for cancer
Authors: Phillips Bob
Published: November 2019

A major consequence of the intensive multi-modal chemotherapy commonly used to treat malignancies in childhood is life-threatening infection, frequently during periods of profound neutropenia. Recent advances have been made in all areas of management, from trying to prevent infection to getting patients off antimicrobials and home again in the shortest, safest way. Potential avenues of further research are outlined for readers to be aware of in the next few years.
Methods of stent placement in patients with upper-third and middle-third esophageal cancer
Authors: Kirkilevsky S. I. , Krahmalyov P. S. , Frydel R. I. , Dobrzhanskyi O. Y.
Published: November 2019

Relevance. At that moment of diagnosis patients with esophageal cancer (EC) are often inoperable due to locally advanced disease. Life expectancy in such cases augmented with dysphagia comprises 90 days in average. Curative treatment can be performed only in 20-30 % of patients with a 5-year survival rate varying from 10,3 to 35%.Objective. Assessing short-term and long-term outcomes of patients with stents with EC depending on the localization of the primary tumor.Materials and methods. We analyzed our experience of using intraesophageal self-expanding stents in ЕС patients. 49 of patients them had tumor in upper-third of esophagus and 73 patients had middle-third esophageal tumor location as compared to those who underwent stoma formation (53 patients) in EC patients.Results. All patients who were stented had significantly lower grade of dysphagia and could eat in the ordinary way. It also improved quality of life, and many of such patients had an opportunity to continue treatment. It has been revealed that stenting of inoperable cancer patients with upper and middle-third esophageal cancer gives benefit to patients as it allows to continue to eat naturally and thereby significantly improves the quality of life in contrast to stoma placement. Patients with upper-third esophageal cancer who were not stented because of fistula formation had significantly better long-term survival than EC patients with stoma and similar cancer patients with middle-third esophageal tumors. Survival rate of patients with cancer of upper-third of esophagus after stenting not because of fistula was significantly better. Patients with cancer of the middle esophagus, who experienced stent placement because of fistulae, had the same long-term survival rate as cancer patients with middle esophageal tumors  and with fistula who were not stented. It shows high efficacy of stenting in cancer of the middle-third esophagus with presence of fistula.Conclusion. Stent placement in case of inoperable cancer of upper and middle-third of esophagus shows significant benefit. It allows patients to eat in an ordinary was, and thereby significantly improves the quality of life in comparison with stoma formation.
Influenza vaccinations: Ten years on from swine flu
Authors: Greener Mark
Published: November 2019

Mark Greener details the progress made on vaccination since the 2009 pandemic
Causality in life course research: the potential use of ‘natural experiments’ for causal inference
Authors: Macmillan Ross , Hannan Carmel
Published: November 2019

Recent decades have seen renewed attention to issues of causal inference in the social sciences, yet implications for life course research have not been spelled out nor is it clear what types of approaches are best suited for theoretical development on life course processes. We begin by evaluating a number of meta-theoretical perspectives, including critical realism, data mining and experimentation, and find them limited in their potential for causal claims in a life course context. From this, we initiate a discussion of the logic and practice of ‘natural experiments’ for life course research, highlighting issues of how to identify natural experiments, how to use cohort information and variation in the order and timing of life course transitions to isolate variation in exposure, how such events that alter social structures are the key to identification in causal processes of the life course and, finally, of analytic strategies for the extraction of causal conclusions from conventional statistical estimates. Through discussion of both positive and negative examples, we outline the key methodological issues in play and provide a road map of best practices. While we acknowledge that causal claims are not necessary for social explanation, our goal is to explain how causal inference can benefit life course scholarship and outline a set of practices that can complement conventional approaches in the pursuit of causal explanation in life course research.
Review
Authors: Chieffo Monica
Published: November 2019

Giving Voice: Mobile Communication, Disability and Inequality, Meryl Alper (2017) Cambridge, MA: MIT Press, 288 pp., ISBN 978-0-26203-558-3, h/bk; ISBN 978-0-26253-397-3, p/bk, £25
Ur hotzeko murgilketa kirol errekuperazioa metodo gisa
Authors: Duñabeitia Iratxe , Torres-Unda Jon , Gil Javier , Gil Susana Mª , Irazusta Jon , Bidaurrazaga-Letona Iraia
Published: November 2019

Kirolariengan entrenamenduen edota txapelketen osteko errekuperazio desegokiak estres fisiologiko handia, gainkarga sintomak eta nekea eragin ditzake, errendimendua gutxituz. Hori dela eta, eguneroko entrenamenduak ziurtatzeko eta lesionatzeko arriskuak murrizteko, fisioterapian hainbat agente fisiko erabiltzen dira errekuperazio metodo gisa, hala nola, hidroterapia. Hidroterapian hainbat modalitate erabili daitezke ur hotzeko murgilketak, besteak beste. kirol munduan ur hotzeko murgilketa errekuperazio metodo ezagunenetarikoa eta erabilienetakoa da eta denbora labur batez beheko gorputz-adarrak ur hotzean murgiltzean oinarritzen da. Ikerketa asko egon arren, bere efektuak ez daude argi eta kontraesanak daude. Lan honetan, lehenengo, hidroterapiaren printzipioen laburpen bat egiten da eta, ondoren, ur hotzeko murgilketaren kontraindikazioak, erabilpenak eta efektuak azaltzen dira, betiere kirol errekuperazioaren ikuspegitik.
La cultura del humor televisivo: El infoentretenimiento español desde su utilidad para las audiencias
Authors: Aguilera García Inmaculada Concepción
Published: November 2019

El panorama actual televisivo español muestra formatos que mezclan entretenimiento con información. Estas fórmulas permiten recursos como el empleo del humor, impropio para otros géneros más tradicionales, y que sin embargo pueden facilitar la comprensión de determinadas informaciones. Aplicando una metodología de naturaleza cualitativa realizamos tres grupos de discusión a dos generaciones de espectadores, una joven, de 18 a 35 años y otra madura, de 35 a 60. Las experiencias revelaron que el infoentretenimiento origina toda una cultura popular en torno a los programas, así como a sus presentadores, independientemente del visionado o del seguimiento de los mismos.
Long-Duration Oral Vancomycin to Treat Clostridioides difficile in Patients With Inflammatory Bowel Disease Is Associated With a Low Rate of Recurrence
Authors: Lei Donald K. , Ollech Jacob E. , Andersen Michael , Weisshof Roni , Zmeter Nada , Sossenheimer Philip , Rubin David T.
Published: November 2019

OBJECTIVES:

Patients with inflammatory bowel disease (IBD) are susceptible to Clostridioides difficile infections (CDIs), suffering from greater morbidity and mortality than the general population. Previous studies have proven the efficacy of oral vancomycin therapy in CDI, but there are no definitive guidelines to treat patients with IBD. We assessed the relationship between the length of vancomycin therapy and rates of CDI recurrence and reinfection in patients with IBD.

METHODS:

We compared rates of CDI recurrence and reinfection in Crohn's disease and ulcerative colitis (UC) patients receiving long-duration (LD) and short-duration (SD) oral vancomycin therapy, defined as 21–42 days and 10–14 days, respectively. Recurrence and reinfection were defined as positive C. difficile toxin assay by polymerase chain reaction within 8 weeks of the end of antibiotic therapy and after 8 weeks of the end of antibiotic therapy, respectively. The Fisher exact test was used to test for significance, and multivariate logistic regression models were constructed to control for other covariables.

RESULTS:

One hundred thirty-four patients with IBD (57 ulcerative colitis and 77 Crohn's disease) met inclusion criteria. LD vancomycin had a 1.8% incidence of CDI recurrence, compared with 11.7% in the SD vancomycin group (odds ratio = 0.13, P = 0.043). CDI reinfection rates and time to reinfection were not significantly different (LD 14.0% vs SD 16.9%, P = NS). Multivariate logistic regression models showed that treatment with LD vancomycin had lower odds for recurrence than SD vancomycin (odds ratio = 0.03, P = 0.021).

DISCUSSION:

LD vancomycin is associated with lower rates of CDI recurrence compared with SD vancomycin therapy. These results will help guide clinical decisions and the development of a prospective trial.