bluuebunny/crossref_metadata_2025 huggingface dataset:
The effect of medical and operative birth interventions on child health outcomes in the first 28 days and up to 5 years of age: A linked data population‐based cohort study
Authors: Peters Lilian L. , Thornton Charlene , de Jonge Ank , Khashan Ali , Tracy Mark , Downe Soo , Feijen‐de Jong Esther I. , Dahlen Hannah G.
Published: March 2018

Background

Spontaneous vaginal birth rates are decreasing worldwide, while cesarean delivery, instrumental births, and medical birth interventions are increasing. Emerging evidence suggests that birth interventions may have an effect on children's health. Therefore, the aim of our study was to examine the association between operative and medical birth interventions on the child's health during the first 28 days and up to 5 years of age.

Methods

In New South Wales (Australia), population‐linked data sets were analyzed, including data on maternal characteristics, child characteristics, mode of birth, interventions during labor and birth, and adverse health outcomes of the children (ie, jaundice, feeding problems, hypothermia, asthma, respiratory infections, gastrointestinal disorders, other infections, metabolic disorder, and eczema) registered with the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, Australian Modification codes. Logistic regression analyses were performed for each adverse health outcome.

Results

Our analyses included 491 590 women and their children; of those 38% experienced a spontaneous vaginal birth. Infants who experienced an instrumental birth after induction or augmentation had the highest risk of jaundice, adjusted odds ratio (aOR) 2.75 (95% confidence interval [CI] 2.61‐2.91) compared with spontaneous vaginal birth. Children born by cesarean delivery were particularly at statistically significantly increased risk for infections, eczema, and metabolic disorder, compared with spontaneous vaginal birth. Children born by emergency cesarean delivery showed the highest association for metabolic disorder, aOR 2.63 (95% CI 2.26‐3.07).

Conclusion

Children born by spontaneous vaginal birth had fewer short‐ and longer‐term health problems, compared with those born after birth interventions.
Late sodium current inhibitors to treat exercise‐induced obstruction in hypertrophic cardiomyopathy: an in vitro study in human myocardium
Authors: Ferrantini Cecilia , Pioner Josè Manuel , Mazzoni Luca , Gentile Francesca , Tosi Benedetta , Rossi Alessandra , Belardinelli Luiz , Tesi Chiara , Palandri Chiara , Matucci Rosanna , Cerbai Elisabetta , Olivotto Iacopo , Poggesi Corrado , Mugelli Alessandro , Coppini Raffaele
Published: March 2018

Background and Purpose

In 30–40% of hypertrophic cardiomyopathy (HCM) patients, symptomatic left ventricular (LV) outflow gradients develop only during exercise due to catecholamine‐induced LV hypercontractility (inducible obstruction). Negative inotropic pharmacological options are limited to β‐blockers or disopyramide, with low efficacy and tolerability. We assessed the potential of late sodium current (INaL)‐inhibitors to treat inducible obstruction in HCM.

Experimental Approach

The electrophysiological and mechanical responses to β‐adrenoceptor stimulation were studied in human myocardium from HCM and control patients. Effects of INaL‐inhibitors (ranolazine and GS‐967) in HCM samples were investigated under conditions simulating rest and exercise.

Key Results

In cardiomyocytes and trabeculae from 18 surgical septal samples of patients with obstruction, the selective INaL‐inhibitor GS‐967 (0.5 μM) hastened twitch kinetics, decreased diastolic [Ca2+] and shortened action potentials, matching the effects of ranolazine (10μM). Mechanical responses to isoprenaline (inotropic and lusitropic) were comparable in HCM and control myocardium. However, isoprenaline prolonged action potentials in HCM myocardium, while it shortened them in controls. Unlike disopyramide, neither GS‐967 nor ranolazine reduced force at rest. However, in the presence of isoprenaline, they reduced Ca2+‐transient amplitude and twitch tension, while the acceleration of relaxation was maintained. INaL‐inhibitors were more effective than disopyramide in reducing contractility during exercise. Finally, INaL‐inhibitors abolished arrhythmias induced by isoprenaline.

Conclusions and Implications

Ranolazine and GS‐967 reduced septal myocardium tension during simulated exercise in vitro and therefore have the potential to ameliorate symptoms caused by inducible obstruction in HCM patients, with some advantages over disopyramide and β‐blockers.
Cohort study with 4‐year follow‐up of myopia and refractive parameters in primary schoolchildren in Baoshan District, Shanghai
Authors: Ma Yingyan , Zou Haidong , Lin Senlin , Xu Xun , Zhao Rong , Lu Lina , Zhao Huijuan , Li Qiangqiang , Wang Ling , Zhu Jianfeng , He Xiangui
Published: March 2018

Importance

Cohort studies could not only reveal associations between change of refractive components and onset/progression of myopia, but also risk factors, which is important for understanding mechanism and providing strategies.

Background

Prevalence of myopia is high in Shanghai, being reported to be 52.2% in children aged 10 years old.

Design

Cohort study.

Participants

A total of 1856 students from six randomly selected primary schools in Baoshan District, Shanghai.

Methods

Children underwent comprehensive ocular measurement, including axial length (AL), corneal curvature radius and cycloplegic auto‐refraction. Questionnaires about eye usage time were collected. Grade 1 students were followed for 4 years, and grade 2 and 3 students for 2 years.

Main Outcome Measures

(i) Change of spherical equivalent (SE) and AL and (ii) risk factors for progression and incidence of myopia.

Results

The average 2‐year progress of SE was 0.91D, 0.91D and 1.11D for grade 1, 2 and 3, respectively, and the average elongation of AL was 0.70 mm, 0.64 mm and 0.71 mm, respectively. Only parental myopia, but not near work time, near work diopter time, outdoor activity time or attending tutoring classes, was associated with myopia incidence and progression in the present population. Using baseline SE could be a simple and effective indicator for myopia prediction.

Conclusions and Relevance

Incidence and progression of myopia is relatively high in schoolchildren in Shanghai compared with children of Western countries, East Asia and other parts of China. Effective strategies to control myopia prevalence are in urgent need.
A golden thread? The relationship between supervision, practice, and family engagement in child and family social work
Authors: Wilkins David , Lynch Amy , Antonopoulou Vivi
Published: March 2018

Within the social work profession, supervision is highly valued. Yet it is not clear how supervision supports good practice or how supervision makes a difference for children and families. In this study, using paired observations of group supervision and family meetings alongside interviews with parents, we explored the link between supervision, practice, and engagement. Considering each data set separately, we found a range of skill levels within the supervision discussions and in the meetings with families. Parents reported generally high levels of satisfaction with the service and in relation to their individual worker. But more importantly, we found a “golden thread” between certain elements of supervision, more skilful practice, and improved parental engagement. We discuss these key elements in detail and consider what these findings tell us about good supervision and what difference it can make for families and children.
Community contextual effects on at‐risk mothers' engagement in Georgia's Maternal, Infant, and Early Childhood Home Visiting programme
Authors: Cho Junhan , Bae Dayoung , Terris Darcey D. , Glisson Rachael E. , Brown Anita
Published: March 2018

The current study examined family and community factors related to home visiting programme engagement in a sample of 1,024 mothers (primary caregivers, mean age 22.89 years) who participated in family support programmes funded through Georgia's Maternal, Infant, and Early Childhood Home Visiting programme. Using 2‐level hierarchical linear modelling, we examined the relationships between mothers' home visiting programme engagement and mothers' sociodemographic and community‐level risk factors. Higher sociodemographic risks, characterized by unstable romantic relationships, employment, low educational, and economic resources, were associated with less active home visiting engagement. Mothers who lived in communities with more challenging socio‐economic contexts, such as communities that had a higher proportion of divorced/separated households, poor quality housing conditions, and residential mobility, demonstrated lower programme engagement. Meanwhile, mothers who lived in communities that had a higher proportion of residents that did not finish high school demonstrated relatively higher programme engagement. The observed influence of community‐level factors remained significant after we controlled for mothers' sociodemographic characteristics. Although community‐level risks may appear outside the locus of control of home visiting, flexible programming and strategic partnerships with other community‐based resources, ones that explicitly take into account community‐level risks, may support improved home visiting engagement outcomes.
Quantifying species recovery and conservation success to develop an IUCN Green List of Species
Authors: Akçakaya H. Resit , Bennett Elizabeth L. , Brooks Thomas M. , Grace Molly K. , Heath Anna , Hedges Simon , Hilton‐Taylor Craig , Hoffmann Michael , Keith David A. , Long Barney , Mallon David P. , Meijaard Erik , Milner‐Gulland E.J. , Rodrigues Ana S.L. , Rodriguez Jon Paul , Stephenson P.J. , Stuart Simon N. , Young Richard P.
Published: March 2018

Stopping declines in biodiversity is critically important, but it is only a first step toward achieving more ambitious conservation goals. The absence of an objective and practical definition of species recovery that is applicable across taxonomic groups leads to inconsistent targets in recovery plans and frustrates reporting and maximization of conservation impact. We devised a framework for comprehensively assessing species recovery and conservation success. We propose a definition of a fully recovered species that emphasizes viability, ecological functionality, and representation; and use counterfactual approaches to quantify degree of recovery. This allowed us to calculate a set of 4 conservation metrics that demonstrate impacts of conservation efforts to date (conservation legacy); identify dependence of a species on conservation actions (conservation dependence); quantify expected gains resulting from conservation action in the medium term (conservation gain); and specify requirements to achieve maximum plausible recovery over the long term (recovery potential). These metrics can incentivize the establishment and achievement of ambitious conservation targets. We illustrate their use by applying the framework to a vertebrate, an invertebrate, and a woody and an herbaceous plant. Our approach is a preliminary framework for an International Union for Conservation of Nature (IUCN) Green List of Species, which was mandated by a resolution of IUCN members in 2012. Although there are several challenges in applying our proposed framework to a wide range of species, we believe its further development, implementation, and integration with the IUCN Red List of Threatened Species will help catalyze a positive and ambitious vision for conservation that will drive sustained conservation action.
Delayed‐type allergy to cobalt—comparison of a flow cytometric lymphocyte proliferation test with patch testing
Authors: Spoerri Iris , Bircher Andreas J. , Link Susanne , Heijnen Ingmar A. F. M. , Scherer Hofmeier Kathrin
Published: March 2018

Background

The patch test is the standard procedure for diagnosing delayed‐type sensitization. If a patch test is not possible, the flow cytometric lymphocyte proliferation test (LPT), which determines the number and type of cells responding to a specific antigen in vitro, might be considered as an alternative.

Objectives

Our aim was to establish a flow cytometric LPT for the detection of delayed‐type allergic responses to cobalt, and to determine the correlation between stimulation indices (SIs) in LPT and the grade of patch test reactions. With the patch test as a diagnostic reference, we also assessed the sensitivity and specificity of the LPT.

Methods

Fifty‐four patients patch tested with the baseline series including cobalt (CoCl2) were additionally tested with the flow cytometric LPT with CoCl2.

Results

There was a significant correlation between the results of both tests: rs = 0.43; P = .001. The LPT with CoCl2 showed a sensitivity of 52.6% and a specificity of 85.7%. Corresponding to the low sensitivity of the LPT, high likelihood ratios for a positive patch test reaction were reached only in cases of strong lymphocyte proliferation (SI ≥ 10).

Conclusions

In cases of clearly increased SIs, the flow cytometric LPT with CoCl2 gives relevant diagnostic information, and represents a valuable alternative to patch testing.
The effect of increasing body mass index on laparoscopic surgery for colon and rectal cancer
Authors: Bell S. , Kong J. C. , Wale R. , Staples M. , Oliva K. , Wilkins S. , Mc Murrick P. , Warrier S. K.
Published: March 2018

Aim

Obesity is common in Western countries and its prevalence is increasing. Colorectal cancer is common, and surgery for colorectal cancer is technically more challenging in obese patients. Laparoscopic surgery for colon cancer has been shown to be oncologically equivalent, with improved short‐ term outcomes. Laparoscopic surgery for rectal cancer has proven technically challenging, and recent results have raised concerns about oncological equivalence. Our aim was to evaluate the effect of body mass index (BMI) on the clinical and oncological outcomes of surgery for colorectal cancer, including the rate at which laparoscopic surgery is attempted and the rate at which laparoscopic surgery is converted to open surgery.

Method

A retrospective analysis of prospectively collected data from two tertiary institutions was performed. Data were obtained from the Cabrini Monash University colorectal neoplasia database for patients having surgical resection for colon and rectal cancers between 1 January 2010 and 30 June 2015. Surgical and medical complications, tumour recurrence and overall survival and laparoscopic surgery and conversion rates were investigated.

Results

This large case series of 1464 patients undergoing elective surgery for colorectal cancer has demonstrated that an elevated BMI is associated with a lower likelihood of attempting laparoscopic surgery and a higher conversion rate to open surgery when laparoscopy is attempted. Conversion was 1.9 times more likely in obese patients with colon cancer and 4.1 times more likely in obese patients with rectal cancer. The critical BMI for colon cancer patients was > 35 kg/m2, and for rectal cancer patients > 30 kg/m2. Obesity is also associated with increased rates of surgical complications, including anastomotic leakage and wound complications. Pathological parameters, tumour recurrence and survival were not affected by elevated BMI.

Conclusion

In the surgical management of colorectal cancer, obesity is associated with a lower likelihood of laparoscopic surgery being attempted, a higher likelihood of conversion to open surgery when laparoscopic surgery is attempted, and a higher rate of surgical complications.
Transanal endoscopic surgery is effective and safe after endoscopic polypectomy of potentially malignant rectal polyps with questionable margins
Authors: Serra‐Aracil X. , Pallisera‐Lloveras A. , Mora‐Lopez L. , Serra‐Pla S. , Puig‐Diví V. , Casalots À. , Martínez‐Bauer E. , Navarro‐Soto S.
Published: March 2018

Aim

To determine the percentage of residual lesion observed in the pathology study of transanal endoscopic surgery (TEM) specimens after endoscopic polypectomy of malignant rectal polyps with questionable margins, and the need for further surgery. Secondary aims: to determine the morbidity and mortality associated with this procedure and to identify the percentage of recurrence after excision by TEM.

Methods

Observational study with prospective data collection of all patients undergoing TEM after endoscopic polypectomy for malignant rectal polyps or non‐invasive high‐grade neoplasia, from January 2004 to December 2016. An en bloc full‐thickness wall excision of the scar was performed. Variables recorded: histology of TEM specimen, 30‐day morbidity and mortality according to the Clavien‐Dindo classification, need for salvage surgery and recurrence.

Results

Fifty out of 690 patients undergoing TEM during the study period (36 adenocarcinomas, five non‐invasive high‐grade neoplasias and 9 neuroendocrine tumors) were included. Post‐surgery histology showed residual lesion in 21 (42%) patients: 7 neuroendocrine tumors, 10 adenomas and 4 adenocarcinomas (two pT1, one pT2 and one pT3). The pT2 and pT3 patients (4%) underwent salvage surgery. No recurrence was observed, and mean follow‐up was 29.1Â ± 21.6 months. The 30‐day morbidity rate was 14%, but 4/7 with Clavien‐Dindo grade I.

Conclusions

After endoscopic polypectomy of malignant rectal polyps with questionable margins, the presence of residual lesion in the pathology study of transanal resection specimens is high. TEM with full‐thickness resection of these lesions is an appropriate treatment, allowing disease control and achieving minimal morbidity
Preformed donor‐specific antibodies do not affect the 1‐year allograft survival in living donor liver transplantation
Authors: Kim Hyeyoung , Yi Nam‐Joon , Song Eun Young , Lee Kyoungbun , Lee Kwang‐Woong , Lee Hae Won , Ahn Hye Young , Yoon Kyung Chul , Hong Suk Kyun , Suh Kyung‐Suk
Published: March 2018

The effect of preformed donor‐specific antibodies (DSAs) on liver transplantation (LT) remains unclear, especially in the field of living donor LT (LDLT). Herein, we evaluated the prevalence of preformed DSAs and their effect on graft outcome in LDLT in the first year following surgery. Using the Luminex® Single Antigen assay, we analyzed the preoperative sera of 61 adult LDLT recipients between 2014 and 2015. Clinical outcomes and pathologic findings including complement component 4d (C4d) expression in the first year after LT were retrospectively reviewed. Regardless of the class of DSA, DSAs with mean fluorescence intensity (MFI) ≥1000 were defined as positive and preformed DSA with MFI ≥5000 was defined as strongly positive. Fifteen patients (24.6%) had preformed DSAs, and 8 patients (13.1%) showed strongly positive preformed DSAs. Among 15 DSA positive patients, 2 (13.3%) showed persistent DSAs after LDLT. No de novo DSAs were noted in patients without preformed DSAs. Preformed DSAs were not related to graft dysfunction, laboratory values, or C4d expression or other pathologic findings in the first year of LDLT. In conclusion, preformed DSAs persisted during follow‐up in 13.3% of cases and did not have adverse effect on histologic or clinical outcomes in the first year of LDLT.
Surgical approach, cost, and complications of appendectomy in kidney transplant recipients
Authors: DiBrito Sandra R. , Olorundare Israel O. , Holscher Courtenay M. , Landazabal Claudia S. , Orandi Babak J. , Dagher Nabil N. , Segev Dorry L. , Garonzik‐Wang Jacqueline
Published: March 2018

Kidney transplant recipients (KTRs) have greater morbidity and length of stay (LOS) following certain surgical procedures than non‐KTR. Given that appendectomy is one of the most common surgical procedures, we investigated differences in outcomes between 1336 KTR and 2 640 247 non‐KTR postappendectomy at transplant and nontransplant centers in the United States from 2000 to 2011, using NIS data and adjusting for patient‐level and hospital‐level factors. Postoperative complications were identified using ICD‐9 codes. Among KTR, there were no post‐appendectomy in‐hospital deaths, compared to a 0.2% in non‐KTR (P = .5). Overall complications were similar among KTR and non‐KTR (17.0% vs 11.6%; aOR:0.77 1.121.61). LOS and costs were greater for KTR compared to non‐KTR (LOS ratio 1.191.311.45; cost ratio 1.111.171.26). Only 44.8% of KTR had laparoscopic approach compared to 54.5% of non‐KTR, but had similar complication rates (10.6 vs 8.7%, P = .5). When treated at transplant centers, KTR had similar complications (aOR 0.440.791.43), but longer LOS (ratio 1.211.371.55) and greater hospital‐associated costs (ratio 1.191.291.41) than non‐KTR. Conversely, at nontransplant centers, KTR and non‐KTR had similar complications (aOR 0.751.232.0), LOS (ratio 0.840.961.09), and cost (ratio 0.931.011.10). Contrary to other procedures, KTR did not constitute a high‐risk group for patients undergoing appendectomy.
An automated quantitativeDNAimage cytometry system detects abnormal cells in cervical cytology with high sensitivity
Authors: Wong O. G. , Ho M. W. , Tsun O. K. , Ng A. K. , Tsui E. Y. , Chow J. N. , Ip P. P. , Cheung A. N.
Published: March 2018

Objective

To evaluate the performance of an automatedDNA‐image‐cytometry system as a tool to detect cervical carcinoma.

Methods

Of 384 liquid‐based cervical cytology samples with available biopsy follow‐up were analyzed by both the Imager System and a high‐riskHPVtest (Cobas).

Results

The sensitivity and specificity of Imager System for detecting biopsy proven high‐grade squamous intraepithelial lesion (HSIL, cervical intraepithelial neoplasia [CIN]2‐3) and carcinoma were 89.58% and 56.25%, respectively, compared to 97.22% and 23.33% ofHPVtest but additionalHPV16/18 genotyping increased the specificity to 69.58%. The sensitivity and specificity of the Imager System for predictingHSIL+ (CIN2‐3+) lesions among atypical squamous cells of undetermined significance samples were 80.00% and 70.53%, respectively, compared to 100% and 11.58% ofHPVtest whilst theHPV16/18 genotyping increased the specificity to 77.89%. Among atypical squamous cells‐cannot excludeHSIL, the sensitivity and specificity of Imager System for predictingHSIL+ (CIN2‐3+) lesions upon follow up were 82.86% and 33.33%%, respectively, compared to 97.14% and 4.76% ofHPVtest and theHPV16/18 genotyping increased the specificity to 19.05%. Amonglow‐grade squamous intraepithelial lesioncases, the sensitivity and specificity of the Imager System for predictingHSIL+ (CIN2‐3+) lesions were 66.67% and 35.71%%, respectively, compared to 66.67% and 29.76% ofHPVtest whileHPV16/18 genotyping increased the specificity to 79.76%. The overall results of imager and high‐riskHPVtest agreed in 69.43% (268) of all samples.

Conclusions

The automated imager system andHPV16/18 genotyping can enhance the specificity of detectingHSIL+ (CIN2‐3+) lesions.
Universal prevention of alcohol and drug use: An overview of reviews in an Australian context
Authors: Mewton Louise , Visontay Rachel , Chapman Cath , Newton Nicola , Slade Tim , Kay‐Lambkin Frances , Teesson Maree
Published: March 2018

Issues

This overview of reviews will synthesise information from existing reviews to provide a summary of the evidence for universal alcohol and illicit drug prevention strategies across different intervention settings.

Approach

Academic databases, including Medline, EMBASE and PsycInfo were searched on 1 August 2016. All reviews and meta‐analyses of universal alcohol and drug prevention conducted since 2006 were included. The reviews included in this overview were grouped according to the different settings where prevention strategies have been applied (i.e. family, school, college, workplace, leisure, healthcare, community, media and policy).

Key Findings

Fifty‐two reviews met the inclusion criteria and were included in this report. There is sufficient evidence to support universal preventive interventions for alcohol in family and school settings. In terms of reducing drug use, there is sufficient evidence to support the use of school‐ and leisure‐based universal primary prevention strategies. Based on evidence published in the last 10 years, mass media campaigns to do not appear to be effective in reducing drug use. More evidence is needed to support preventive interventions in college, workplace, healthcare and community settings.

Implications

Through the identification of settings where preventive interventions are effective, this overview can be used to guide alcohol and drug policy and the allocation of resources.

Conclusion

The evidence base for universal prevention in several settings could be strengthened, guiding priorities for future research.
Snare with endoclips to assist in endoscopic submucosal dissection with mucosal internal traction for a gastric neoplasia involving pyloric ring
Authors: Zhang Qiang , Wang Zhen
Published: March 2018

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Hypoglycaemia incidence and recovery during home use of hybrid closed‐loop insulin delivery in adults with type 1 diabetes
Authors: Ruan Yue , Bally Lia , Thabit Hood , Leelarathna Lalantha , Hartnell Sara , Tauschmann Martin , Wilinska Malgorzata E. , Evans Mark L. , Mader Julia K. , Kojzar Harald , Dellweg Sibylle , Benesch Carsten , Arnolds Sabine , Pieber Thomas R. , Hovorka Roman
Published: March 2018

Glucose excursion was assessed prior to and post hypoglycaemia to increase understanding of hypoglycaemia incidence and recovery during hybrid closed‐loop insulin delivery. We retrospectively analysed data from 60 adults with type 1 diabetes who received, in a crossover randomized design, day‐and‐night hybrid closed‐loop insulin delivery and insulin pump therapy, the latter with or without real‐time continuous glucose monitoring. Over 4‐week study periods, we identified hypoglycaemic episodes, defined as sensor glucose <3.0 mmol/L, and analysed sensor glucose relative to the onset of hypoglycaemia. We identified 377 hypoglycaemic episodes during hybrid closed‐loop intervention vs 662 during control intervention (P < .001), with a predominant reduction of nocturnal hypoglycaemia. The slope of sensor glucose prior to hypoglycaemia was steeper during closed‐loop intervention than during control intervention (P < .01), while insulin delivery was reduced (P < .01). During both day and night, participants recovered from hypoglycaemia faster when treated by closed‐loop intervention. At 120 minutes post hypoglycaemia, sensor glucose levels were higher during closed‐loop intervention compared to the control period (P < .05).

In conclusion, closed‐loop intervention reduces the risk of hypoglycaemia, particularly overnight, with swift recovery from hypoglycaemia leading to higher 2‐hour post‐hypoglycaemia glucose levels.
Single and multiple dose evaluation of a novel MetAP2 inhibitor: Results of a randomized, double‐blind, placebo‐controlled clinical trial
Authors: Malloy Jaret , Zhuang Dongliang , Kim Terri , Inskeep Phil , Kim Dennis , Taylor Kristin
Published: March 2018

Aims

Methionine aminopeptidase 2 (MetAP2) inhibition has been shown to result in significant weight loss and improved glucose control. This Phase 1 clinical trial assessed the safety and tolerability, pharmacokinetics and preliminary efficacy of a novel MetAP2 inhibitor, ZGN‐1061.

Methods

This clinical trial included a single ascending dose (SAD) phase in healthy subjects (BMI, 23 to <30 kg/m2) and a multiple ascending dose (MAD) phase in otherwise healthy subjects (BMI, 27 to 40 kg/m2). SAD phase doses, administered subcutaneously (SC), were 0.2, 0.6, 1.2, 2.4, 3.6 and 4.8 mg and the MAD phase evaluated doses of 0.2, 0.6 and 1.8 mg twice weekly SC for 4 weeks.

Results

The SAD phase included 39 subjects (ZGN‐1061, N = 28; placebo, N = 11); 90% were male and BMI was 26.4 kg/m2. ZGN‐1061 was well tolerated across all doses, with the most frequent adverse events being mild headache and procedural‐related irritation. There were no severe or serious adverse events. All doses of ZGN‐1061 were rapidly absorbed and cleared, resulting in short duration of exposure that is anticipated to minimize potential off‐drug target risks. The MAD phase included 29 subjects (ZGN‐1061, N = 22; placebo, N = 7); 76% were male and BMI was 33.5 kg/m2. Safety observations were consistent with SAD findings. Efficacy measures in the MAD phase indicated trends for weight change (−1.5 kg total ZGN‐1061 vs −0.2 kg placebo) and other biomarker changes.

Conclusions

ZGN‐1061 was well tolerated with no safety signals in all doses tested. In addition, the desired pharmacokinetic profile and preliminary efficacy observations with ZGN‐1061 support evaluation in larger and longer clinical trials.
Clock genes alterations and endocrine disorders
Authors: Angelousi Anna , Kassi Eva , Nasiri‐Ansari Narjes , Weickert Martin O. , Randeva Harpal , Kaltsas Gregory
Published: March 2018

Background

Various endocrine signals oscillate over the 24‐hour period and so does the responsiveness of target tissues. These daily oscillations do not occur solely in response to external stimuli but are also under the control of an intrinsic circadian clock.

Design

We searched the PubMed database to identify studies describing the associations of clock genes with endocrine diseases.

Results

Various human single nucleotide polymorphisms of brain and muscle ARNT‐like 1 (BMAL1) and Circadian Locomotor Output Cycles Kaput (CLOCK) genes exhibited significant associations with type 2 diabetes mellitus. ARNTL2 gene expression and upregulation of BMAL1 and PER1 were associated with the development of type 1 diabetes mellitus. Thyroid hormones modulated PER2 expression in a tissue‐specific way, whereas BMAL1 regulated the expression of type 2 iodothyronine deiodinase in specific tissues. Adrenal gland and adrenal adenoma expressed PER1, PER2, CRY2, CLOCK and BMAL1 genes. Adrenal sensitivity to adrenocorticotrophin was also affected by circadian oscillations. A significant correlation between the expression of propio‐melanocorticotrophin and PER 2, as well as between prolactin and CLOCK, was found in corticotroph and lactosomatotroph cells, respectively, in the pituitary. Clock genes and especially BMAL1 showed an important role in fertility, whereas oestradiol and androgens exhibited tissue‐specific effects on clock gene expression. Metabolic disorders were also associated with circadian dysregulation according to studies in shift workers.

Conclusions

Clock genes are associated with various endocrine disorders through complex mechanisms. However, data on humans are scarce. Moreover, clock genes exhibit a tissue‐specific expression representing an additional level of regulation. Their specific role in endocrine disorders and their potential implications remain to be further clarified.
Pharmacogenetics of vitamin K antagonists and bleeding risk prediction in atrial fibrillation
Authors: Serna María José , Rivera‐Caravaca José Miguel , Gonzalez‐Conejero Rocío , Esteve‐Pastor María Asunción , Valdés Mariano , Vicente Vicente , Lip Gregory Y.H. , Roldán Vanessa , Marín Francisco
Published: March 2018

Background

Polymorphisms in the vitamin K epoxide reductase complex 1 (VKORC1) and cytochrome P450 2C9 (CYP2C9) genes increase the bleeding risk in anticoagulated atrial fibrillation (AF) patients. Here, we aimed to investigate whether VKORC1 and CYP2C9 polymorphisms improved the predictive performance for major bleeding using the HAS‐BLED score.

Material and methods

We recruited 652 consecutive AF patients stable on vitamin K antagonist (INR 2.0‐3.0) during at least the previous 6 months. A baseline venous blood sample was obtained for DNA extraction. We gave an extra point to the HAS‐BLED score if the patient was a simultaneous carrier of the VKORC1 and CYP2C9 polymorphisms related to bleeding, and we called this modified score “GEN|HAS‐BLED.” During a median follow‐up of 7.6 years (IQR 5.6‐8.0), all major bleeding events were recorded.

Results

During follow‐up, 106 (16.2%) patients experienced a major bleeding (2.81%/y; 42 intracranial haemorrhages and 44 gastrointestinal bleeding) and 24 (3.7%) died from major bleeding (0.48%/y). Cox regression analyses demonstrated a significant association between HAS‐BLED or GEN|HAS‐BLED and major bleeds, both as continuous or categorical scores. Comparison of receiver operating characteristic (ROC) curves shows that original HAS‐BLED clinical score had better predictive ability than GEN|HAS‐BLED (0.660, 95% CI 0.622‐0.696 vs 0.645, 95% CI 0.607‐0.682; P = .030). Discrimination and reclassification analyses showed that GEN|HAS‐BLED did not improve sensitivity compared with the original score and even showed significant negative reclassification.

Conclusion

Adding pharmacogenetic factors (ie polymorphisms of the VKORC1 and CYP2C9 genes) to the HAS‐BLED score does not improve the prediction or discrimination performance for major bleeding.
Elevated high‐sensitive troponin T in negative stress test individuals
Authors: Brzezinski Rafael Y. , Fisher Eyal , Ehrenwald Michal , Shefer Gabi , Stern Naftali , Shapira Itzhak , Zeltser David , Berliner Shlomo , Shenhar‐Tsarfaty Shani , Milwidsky Assi , Rogowski Ori
Published: March 2018

Background

The exercise ECG stress test (EST) is still the first step of work‐up in intermediate risk patients in many clinical scenarios. High‐sensitive cardiac troponin T (hs‐cTnT) elevation is related to future cardiovascular events in the general population and in patients with ischaemic heart disease. The relation between these 2 tests is not well described.

Materials and methods

A total of 2780 participants from the Tel‐Aviv Medical Center Inflammation Survey cohort (mean age 49 years, 79% men) were analysed. Multiple physiologic and metabolic parameters including hs‐cTnT were collected. All participants completed an EST manually reviewed by a cardiologist.

Results

A positive EST was documented in 224 subjects (8%). The majority (91%) of participants with hs‐cTnT levels of 5‐14 ng/L had a negative EST as well as 89.3% of subjects with levels >14 ng/L. The proportion of subjects with a positive EST and detectable hs‐cTnT levels (>5 ng/L) was not significantly greater compared to those with a negative EST (53.1% vs 46.2%, respectively, P = .09).

Conclusion

Among subjects referred for EST as part of an annual health survey, we found no significant association between EST results to hs‐cTnT detection.
Asterina arxii‐batistae sp. nov. (Asterinaceae) on fabaceous hosts in Brazil
Authors: Firmino A. L. , Bezerra J. L. , Pereira O. L.
Published: March 2018

A new species of Asterina, A. arxii‐batistae was found on living leaves of Inga sp. and Tachigali multijuga, collected in the Reserva Ecológica Michelin and Parque Estadual da Serra do Conduru, municipality of Igrapiúna and Uruçuca, respectively, in Bahia state, Brazil. Description, illustrations and comments on the taxonomic and morphological characteristics are presented. This is the first species of Asterina found on fabaceous hosts in Brazil and the first species on these host genera.
Responses of soil bacterial community and enzyme activity to experimental warming of an alpine meadow
Authors: Zi H. B. , Hu L. , Wang C. T. , Wang G. X. , Wu P. F. , Lerdau M. , Ade L. J.
Published: March 2018

Soil microbes and enzymes play vital roles in the decomposition and transformation of soil material, nutrient cycling, energy flow and physicochemical properties. However, the responses of soil microbes and enzymes to warming remains poorly understood, which limits our ability to predict the consequences of future climate warming. To understand better how climate warming will alter the activity of soil microbes and enzymes, we established a field experiment to manipulate temperature in an alpine meadow in northwestern Sichuan, China. After 5 years of experimental warming, soil bacterial communities were assessed by MiSeq sequencing of 16S rRNA gene amplicons. The results showed that the experimental warming treatments increased the soil acid phosphatase, invertase and urease activity, and available nutrients, but decreased the catalase activity and soil organic matter (SOM) at the 0–10‐cm soil depth. However, the warming treatment increased catalase activity, SOM, available nitrogen (AN) and available potassium (AK), but decreased invertase activity at the 10–20‐cm soil depth. Warming significantly increased the relative abundance of Chloroflexi at the 0–10‐cm depth, whereas it significantly increased the relative abundance of Cyanobacteria and decreased the relative abundance of Firmicutes at the 10–20‐cm depth. Similarly, warming altered the relative abundance of bacterial genera, for example Candidatus Solibacter increased, whereas Pseudomonas and Janthinobacterium decreased. Warming did not significantly affect diversity or structure of the soil bacterial community. The soil acid phosphatase and urease activity, and SOM, total potassium (TK), AK and total phosphorus (TP) contents were strongly correlated with the soil bacterial community. Overall, despite the pronounced changes in soil enzyme activity and plant nutrient contents under warming, composition and diversity of the soil bacterial community were not changed. This study helps to elucidate soil responses in grasslands to climate warming.

Highlights

Warming promoted nutrient mineralization and altered soil enzyme activity.

Warming decreased diversity of the soil bacterial community.

Specific taxa responded differentially to experimental warming.

Soil microorganisms regulated plant nutrient cycling under continuous climate warming.
Modelling heterogeneous phosphate sorption kinetics on iron oxyhydroxides and soil with a continuous distribution approach
Authors: Warrinnier R. , Goossens T. , Braun S. , Gustafsson J. P. , Smolders E.
Published: March 2018

The kinetics of orthophosphate (PO4) sorption in soil has far reaching consequences on its long‐term fate. Traditionally, a distinction is made between fast, reversible adsorption and slow fixation. The kinetics are commonly described by compartmental models (CMs) assuming kinetically distinct homogeneous pools (e.g. a rapid‐ and slow‐sorbing pool), with phenomenological equations or with complex diffusion‐based models. Alternatively, this process can be described by assuming frequency distributions of both adsorption and desorption rate constants and, thereby, enabling better description of experimental data with fewer adjustable parameters. Here, we developed such a rate constant distribution (RCD) model and compared it with CMs and other commonly used rate equations. Batch 33PO4 sorption was measured in agitated suspensions between 2 minutes and 20 days after spiking in 13 contrasting types of soil and two iron oxyhydroxides. Overall, the RCD model, with three adjustable parameters, describes the data better than the other models tested. The so‐called slow reactions, denoted as the factor change in soluble 33PO4 between 1 and 20 days after spiking, were described better by the RCD model and ranged from 1.0 (i.e. no change) to 6.9. The extent of slow reactions increased with the increase in the fraction of poorly crystalline iron in the soil (r = 0.69; P = 0.0088). Equilibrium was elusive up to 20 days for PO4 sorption on ferrihydrite and on soil samples with a large fraction of poorly crystalline iron oxyhydroxides. The RCD model code is available as freeware from the first author.

Highlights

A new rate constant distribution (RCD) model for PO4 sorption kinetics was developed.

The RCD model offers a simple approach to take surface heterogeneity into account.

The RCD model fitted PO4 sorption kinetics better than commonly used equations.

Equilibrium was elusive for PO4 sorption on ferrihydrite and soil with poorly crystalline iron.
Nitrogen loss through anaerobic ammonium oxidation coupled with iron reduction in a mangrove wetland
Authors: Guan Q. S. , Cao W. Z. , Wang M. , Wu G. J. , Wang F. F. , Jiang C. , Tao Y. R. , Gao Y.
Published: March 2018

Anaerobic ammonium oxidation coupled with iron(III) reduction (Feammox) with dinitrogen, nitrite or nitrate as end‐products is the most recently discovered nitrogen cycling process. This reaction has been observed in tropical forest soils, paddy soils and intertidal wetlands. However, Feammox has not been measured in mangrove wetlands. In this study, sediment slurry incubation experiments were combined with isotope tracing and acetylene inhibition techniques. Feammox was detected in mangrove sediments and ‘bare flats’ (mud flats without mangrove), with potential rates of 0.48 (±0.03 SE) mg N kg−1 day−1 (accounting for 6.4% of the total nitrogen loss through N2) and 0.38 (±0.02 SE) mg N kg−1 day−1 (accounting for 6.7% of the total nitrogen loss through N2), respectively. Microbially reducible iron(III) was added, which significantly (P < 0.01) increased the Feammox rate in contrast to no addition of iron(III). It was estimated that a loss of 12.33 t N year−1 was associated with Feammox in mangrove sediments of the Jiulong River Estuary, accounting for 0.04% of the total external inorganic nitrogen transported into the estuary. Overall, these findings demonstrate that Feammox can act as a nitrogen loss mechanism in mangroves.

Highlights

Feammox was investigated by ammonium 15N labelled isotopic tracing technique.

Feammox rates in mangrove were larger than those in mud flats without mangrove.

The nitrogen loss contribution of Feammox in mangrove was less than in other ecosystems.

Tidal fluctuations and the large TOC would accelerate the Feammox process.
Assessment of bulbar function in amyotrophic lateral sclerosis: validation of a self‐report scale (Center for Neurologic Study Bulbar Function Scale)
Authors: Smith R. A. , Macklin E. A. , Myers K. J. , Pattee G. L. , Goslin K. L. , Meekins G. D. , Green J. R. , Shefner J. M. , Pioro E. P.
Published: March 2018

Background and purpose

Impaired bulbar functions of speech and swallowing are among the most serious consequences of amyotrophic lateral sclerosis (ALS). Despite this, clinical trials in ALS have rarely emphasized bulbar function as an endpoint. The rater‐administered Amyotrophic Lateral Sclerosis Functional Rating Scale‐Revised (ALSFRS‐R) or various quality‐of‐life measures are commonly used to measure symptomatic benefit. Accordingly, we sought to evaluate the utility of measures specific to bulbar function in ALS.

Methods

We assessed bulbar functions in 120 patients with ALS, with clinicians first making direct observations of the degree of speech, swallowing and salivation impairment in these subjects. Clinical diagnosis of bulbar impairment was then compared with ALSFRS‐R scores, speech rate, time to swallow liquids and solids, and scores obtained when patients completed visual analog scales (VASs) and the newly‐developed 21‐question self‐administered Center for Neurologic Study Bulbar Function Scale (CNS‐BFS).

Results

The CNS‐BFS, ALSFRS‐R, VAS and timed speech and swallowing were all concordant with clinician diagnosis. The self‐report CNS‐BFS and ALSFRS‐R bulbar subscale best predicted clinician diagnosis with misclassification rates of 8% and 14% at the optimal cut‐offs, respectively. In addition, the CNS‐BFS speech and swallowing subscales outperformed both the bulbar component of the ALSFRS‐R and speech and swallowing VASs when correlations were made between these scales and objective measures of timed reading and swallowing.

Conclusions

Based on these findings and its relative ease of administration, we conclude that the CNS‐BFS is a useful metric for assessing bulbar function in patients with ALS.
Muscle function deterioration in patients with haemophilia: Prospective experience from Costa Rica
Authors: Seuser A. , Navarrete‐Duran M. , Auerswald G. , Mancuso M. E.
Published: March 2018

Introduction

In haemophilia, recurrent joint bleeds are responsible for the development of chronic joint damage, because blood induces biochemical changes in joint structures. Joint degeneration is a long process, and structural damage is often preceded by joint dysfunction, which is represented by quantitative and qualitative changes in the contraction pattern of muscles around the joints. Muscle function in patients with haemophilia is still poorly investigated.

Aim

The aim of this 2‐year prospective study was to assess the changes in muscle function of lower limbs in a group of patients affected with haemophilia in San José, Costa Rica.

Methods

Muscle function of lower limbs was assessed by means of surface electromyography (sEMG) accomplished at study enrolment and after 2 years of follow‐up. Gluteus medius, vastus medialis, biceps femoris, gastrocnemius and tibialis anterior were examined. All patients underwent concurrent clinical examination using Haemophilia Joint Health Score (HJHS).

Results

Sixty patients aged 2‐43 years with severe haemophilia underwent clinical and sEMG evaluation. Thirty‐two patients (53%) had target joints. sEMG parameters were altered in all patients and were not correlated to the presence of target joints and/or an abnormal HJHS. Muscle function deterioration was observed after 2 years of follow‐up despite an unmodified HJHS.

Conclusions

Muscle function of lower limbs as detected by means of sEMG was impaired in patients with haemophilia irrespective of the presence of overt joint damage. sEMG is a simple and sensitive assessment tool able to detect muscle dysfunction and so favouring the implementation of early rehabilitation therapy.
“In vitro” correction of the severe factor V deficiency‐related coagulopathy by a novel plasma‐derived factor V concentrate
Authors: Bulato C. , Novembrino C. , Anzoletti M. Boscolo , Spiezia L. , Gavasso S. , Berbenni C. , Tagariello G. , Farina C. , Nardini I. , Campello E. , Peyvandi F. , Simioni P.
Published: March 2018

Introduction

Severe congenital factor V (FV) deficiency is a rare bleeding disorder characterized by very low/undetectable levels of FV. Fresh frozen plasma is the standard treatment for bleeding manifestations. Recently, a novel plasma‐derived FV concentrate has been developed.

Aim

To evaluate the “in vitro” ability of the novel FV concentrate to normalize clotting times and generate normal amount of thrombin in plasma collected from patients with severe FV deficiency.

Methods

Prothrombin time (PT), activated partial thromboplastin time (aPTT), FV activity and antigen levels and thrombin generation were measured pre‐ and postspiking of plasma samples of 10 patients with increasing doses of FV concentrate (from 0 to 100 IU/dL).

Results

Prothrombin time and activated partial thromboplastin time ratios as well as all thrombin generation parameters were fully corrected by the addition of FV concentrate at a final concentration of 25 IU/dL. However, the addition of FV at a concentration of 1‐3 IU/dL was already sufficient to correct peak height and endogenous thrombin potential (but not lag time and time to peak) after activation with 5 pmol/L tissue factor. FV activity and antigen levels showed a linear response to supplementation with the novel FV concentrate.

Conclusion

The novel plasma‐derived FV concentrate was effective to correct “in vitro” severe FV deficiency in patients. The optimal FV concentration to fully normalize both global clotting times and thrombin generation parameters using the novel plasma‐derived FV concentrate was 25 IU/dL.