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Background Parasitic nematodes, including large roundworms colloquially known as ascarids, affect the health and well-being of livestock animals worldwide. The equine ascarids, Parascaris spp., are important parasites of juvenile horses and the first ascarids to develop widespread anthelmintic resistance. The microbiota has been shown to be an important factor in the fitness of many organisms, including parasitic nematodes, where endosymbiotic Wolbachia have been exploited for treatment of filariasis in humans. Methods This study used short-read 16S rRNA sequences and Illumina sequencing to characterize and compare microbiota of whole worm small intestinal stages and microbiota of male and female intestines and gonads. Diversity metrics including alpha and beta diversity, and the differential abundance analyses DESeq2, ANCOM-BC, corncob, and metagenomeSeq were used for comparisons. Results Alpha and beta diversity of whole worm microbiota did not differ significantly between groups, but Simpson alpha diversity was significantly different between female intestine (FI) and male gonad (MG) (P= 0.0018), and Shannon alpha diversity was significantly different between female and male gonads (P = 0.0130), FI and horse jejunum (HJ) (P = 0.0383), and FI and MG (P= 0.0001). Beta diversity (Fig. 2B) was significantly different between female and male gonads (P = 0.0006), male intestine (MI) and FG (P = 0.0093), and MG and FI (P = 0.0041). When comparing organs, Veillonella was differentially abundant for DESeq2 and ANCOM-BC (p P = 0.0008), and metagenomeSeq (P = 0.0118), and Sarcina was differentially abundant across four methods (P Parascaris spp. specimens were compared to establish shared microbiota between groups. Conclusions Overall, this study provided important information regarding the Parascaris spp. microbiota and provides a first step towards determining whether the microbiota may be a viable target for future parasite control options. Graphical abstract

BACKGROUND Strongylid and ascarid parasites are omnipresent in equine stud farms, and ever-increasing levels of anthelmintic resistance are challenging the industry with finding more sustainable and yet effective parasite control programs. OBJECTIVES To evaluate egg count levels, bodyweight and equine health under defined parasite control protocols in foals and mares at two Standardbred and two Thoroughbred stud farms. STUDY DESIGN Longitudinal randomised field trial. METHODS A total of 93 foals were enrolled and split into two treatment groups, and 99 mares were enrolled and assigned to three treatment groups. All horses underwent a health examination, and episodes of colic or diarrhoea were recorded at each faecal collection date. Bodyweights were assessed using a weight tape, and mares were body condition scored. Group A foals (FA) were dewormed at 2 and 5 months of age with a fenbendazole/ivermectin/praziquantel product, while group B foals (FB) were dewormed on a monthly basis, alternating between the above-mentioned product and an oxfendazole/pyrantel embonate product. Group A mares (MA) were dewormed twice with fenbendazole/ivermectin/praziquantel, group B mares (MB) were dewormed with the same product, when egg counts exceeded 300 strongylid eggs per gram, and group C mares (MC) were dewormed every 2 months, alternating between the two products. Health data were collected monthly for 6 months (foals) and bimonthly for 13 months (mares). Data were analysed with mixed linear models and interpreted at the α = 0.05 significance level. RESULTS There were no significant bodyweight differences between foal groups, but MA mares were significantly lighter than the other two groups. Very few health incidents were recorded. Foals in group FA had significantly higher ascarid and strongylid egg counts, whereas no significant differences were observed between mare groups. MAIN LIMITATIONS Study duration limited to one season. CONCLUSIONS Anthelmintic treatment intensity was lowered from the traditional intensive regimes without measurable negative health consequences for mares and foals.

Equine cyathostomins are ubiquitous in grazing horses around the world and a main target in parasite control programs. Anthelmintic resistance has been reported with increasing frequency in these parasites over the past decades, and recent findings of fulminant resistance to the macrocyclic lactone class have raised severe concerns. This study aimed to evaluate ivermectin efficacy in cohorts of yearlings and mares present on four different farms in Central Kentucky. Strongylid egg counts were determined with an automated egg counting system, and the percent fecal egg count reduction (FECR) was calculated using a hierarchical Bayesian analysis. Novel principles were used for classification of groups to either no signs of anthelmintic resistance, evidence of resistance, or inconclusive. Furthermore, an epidemiological analysis was conducted evaluating the possible influence of pregnancy status, time of foaling, and year of arrival on mare strongylid egg shedding levels. A total of 102 yearlings and 247 mares were enrolled in the study. Evidence of ivermectin resistance was documented in one group of yearlings with a mean FECR of 91.2% and a 95% credible interval of 84.0-95.8. The results from one mare group and one additional yearling group were deemed inconclusive, whereas the remaining five groups displayed no evidence of ivermectin resistance. Strongylid shedding in the mares was not positively associated with any of the evaluated factors. This study is the first to demonstrate ivermectin resistance in US bred horses, and the findings emphasize the need for routine monitoring of anthelmintic efficacy on horse farms.

Background Horses are host to a plethora of parasites. Knowledge of the seasonality of parasite egg shedding and transmission is important for constructing parasite control programs. However, studies describing these patterns are sparse, and have largely been conducted only in the United Kingdom. This study evaluated strongylid egg shedding patterns and transmission dynamics of Strongylus vulgaris in naturally infected and untreated mares and foals through one calendar year in Kentucky, USA. The study also investigated the existence of a peri-parturient rise (PPR) in strongylid egg counts in foaling mares and collected information about Strongyloides westeri and Parascaris spp. in the foals. Methods This study was conducted from January to December 2018. A herd of 18 mares, one stallion, and 14 foals born in 2018 were followed throughout the year. Sera and feces were collected biweekly from all horses, and worm burdens enumerated in 13 foals at necropsy. An S. vulgaris ELISA antibody test was run on all serum samples. Fecal egg counts were determined for all horses, and coproculture and qPCR assay were employed to test for the presence of S. vulgaris in the mature horses. Data were analyzed using the proc glimmix procedure in the SAS 9.4 software program. Results We found a general lack of seasonality in strongylid egg shedding throughout the year among the mature horses, and no PPR was demonstrated. Shedding of S. vulgaris eggs displayed a higher abundance during the spring, but findings were variable and not statistically significant. Anti-S. vulgaris antibody concentrations did not display significant fluctuations in the mature horses, but evidence of passive transfer of antibodies to the foals was demonstrated, and foals assumed their own production of antibodies starting at approximately 20 weeks of age. Overall, colts shed higher numbers of strongylid, ascarid, and S. westeri eggs than fillies. Conclusions This study demonstrated a lack of seasonality in strongylid egg shedding for the study population, which is in stark contrast to previous studies conducted elsewhere. This strongly suggests that more studies should be done investigating these patterns under different climatic conditions. Graphical Abstract

Drug-facilitated sexual assault (DFSA) is an act of sexual violence towards a victim who is incapacitated due to the voluntary or involuntary consumption of intoxicating substances. Sexual assaults are generally considered underreported and the toxicological analysis of DFSA cases is particularly challenging when there is a time delay from assault to medical examination. The aim of this review was to investigate typical toxicological findings in global DFSA cases and describe a typical DFSA case.A database search was conducted in PubMed using relevant search terms in order to identify studies reporting toxicological results in DFSA cases.In total, 22 studies were included, covering toxicological findings in DFSA cases in North America, Europe, Asia, South Africa and Australasia from 1996 to 2018. Biological matrices used for analysis included blood, urine and hair. Toxicological findings were comparable among countries, with ethanol, cocaine, cannabis, benzodiazepines, amphetamines and analgesics being among the most frequently detected substances. Ethanol was frequently detected in combination with one or more drugs. A variety of benzodiazepines were observed, with the most common being diazepam, clonazepam, alprazolam, and oxazepam. The majority of cases involved women (87%-100%).The findings suggest that a diverse range of substances are associated with DFSA and that victims are rendered vulnerable through recreational substance consumption at social events. As such, typical DFSA cases appear to be opportunistic in nature and primarily involves women in their mid-twenties and an acquaintance as the perpetrator.

Xia-Gibbs syndrome (XGS) is a neurodevelopmental disorder characterized by intellectual disability, developmental delay, seizures, hypotonia, obstructive sleep apnoea and mild facial dysmorphism. Heterozygosity for loss-of-function variants in AHDC1, encoding the AT-hook DNA binding motif containing protein 1, were discovered in 2014 as the likely genetic cause of Xia-Gibbs syndrome. We present five patients with Xia-Gibbs syndrome caused by previously unreported variants in AHDC1. Two of the patients share a frameshift variant: c.2849del (p.(Pro950Argfs*192)) in AHDC1. Despite sharing this variant, the two patients show remarkable phenotypic differences underscoring the clinical heterogeneity of Xia-Gibbs syndrome. In addition, we present a case of Xia-Gibbs syndrome caused by mosaicism for an AHDC1 variant.

Mounting evidence suggests that patterns of local relatedness can change over time in predictable ways, a process termed kinship dynamics. Kinship dynamics may occur at the level of the population or social group, where the mean relatedness across all members of the population or group changes over time, or at the level of the individual, where an individual's relatedness to its local group changes with age. Kinship dynamics are likely to have fundamental consequences for the evolution of social behaviour and life history because they alter the inclusive fitness payoffs to actions taken at different points in time. For instance, growing evidence suggests that individual kinship dynamics have shaped the evolution of menopause and age-specific patterns of helping and harming. To date, however, the consequences of kinship dynamics for social evolution have not been widely explored. Here we review the patterns of kinship dynamics that can occur in natural populations and highlight how taking a kinship dynamics approach has yielded new insights into behaviour and life-history evolution. We discuss areas where analysing kinship dynamics could provide new insight into social evolution, and we outline some of the challenges in predicting and quantifying kinship dynamics in natural populations.

Objective Timely evaluation and initiation of treatment is the key for improving stroke outcomes, although minimizing the time from symptom onset to the first contact with healthcare professionals remains a challenge. We aimed to identify patient‐related factors associated with early hospital arrival. Materials and methods In this cross‐sectional survey, we included patients with stroke or transient ischemic attack admitted directly to one of two noncomprehensive stroke units or transferred to the units from comprehensive stroke centers in the Capital Region of Denmark. Patient‐reported factors associated with early hospital arrival were analyzed using multivariable logistic regression analysis adjusted for age, sex, education, living arrangement, brain location of the stroke, stroke severity, patient‐perceived symptom severity, history of prior stroke, stroke risk factors, and knowledge of stroke symptoms. Results In total, 479 patients with acute stroke were included (median age 74 (25th–75th percentile, 64–80), 40% women), of whom 46.4% arrived within 180 min of symptom onset. Factors associated with early hospital arrival were patients or bystanders choosing emergency medical service (EMS) for the first contact with a medical professional (adjusted odds ratio (OR), 3.41; 95% confidence interval, CI [1.57, 7.35]) or the patient's perceived symptom severity above the median score of 25 on a 100‐point verbal scale (adjusted OR, 2.44; 95% CI [1.57, 3.82]). Living alone reduced the likelihood of early arrival (adjusted OR, 0.53; 95% CI [0.33, 0.86]). Conclusions Only when patients perceived symptoms as severe or when EMS was selected as the first contact, early arrival for stroke treatment was ensured., Patient‐related factors associated with hospital arrival within 180 minutes

Selective anthelmintic therapy has been recommended as a sustainable strategy for cyathostomin control in horse populations for several decades. The traditional approach has been to determine strongyle fecal egg counts (FEC) for all horses, with treatment only recommended for those exceeding a predetermined threshold. The aims are to achieve a reduction of overall egg shedding, while leaving a proportion of the herd untreated, which lowers anthelmintic treatment intensity and reduces selection pressure for development of anthelmintic resistance. This study made use of the cyathostomin model to evaluate the influence of treatment strategies with between 1 and 8 yearly treatment occasions, where either 1) all horses were treated, 2) a predetermined proportion of the herd remained untreated, or 3) horses were treated if their FEC exceeded thresholds between 100 and 600 strongyle eggs per gram. Weather data representing four different climatic zones was used and three different herd age structures were compared; 1) all yearlings, 2) all mature horses 10–20 years old, and 3) a mixed age structure of 1–20 years of age. Results indicated a consistent effect of age structure, with anthelmintic resistance developing quickest in the yearling group and slowest among the mature horses. Development of anthelmintic resistance was affected by treatment intensity and selective therapy generally delayed resistance. Importantly, the results suggest that the effects of selective therapy on resistance development are likely to vary between climatic zones and herd age structures. Overall, a substantial delaying of resistance development requires that the average number of treatments administered annually across a herd of horses needs to be about two or less. However, results also indicate that an age-structured prioritisation of treatment to younger horses should still be effective. It appears that a ‘one-size-fits-all’ approach to the management of anthelmintic resistance in cyathostomins is unlikely to be optimal., Graphical abstract Image 1

Bronchopulmonary neuroendocrine tumours are divided into typical carcinoid (TC), atypical carcinoid (AC), large cell neuroendocrine carcinoma (LCNEC), and small cell lung cancer (SCLC).To thoroughly describe a cohort of 252 patients with TC, AC and LCNEC (SCLC excluded).Collection of data from 252 patients referred to and treated at Rigshospitalet 2008-2016. Data was collected from electronic patient files and our prospective NET database. Statistics were performed in SPSS.162 (64%) had TC, 29 (12%) had AC and 61 (24%) had LCNEC. Median age at diagnosis was 69 years (range: 19-89) with no difference between genders. Thoraco-abdominal CT was performed in all patients at diagnosis. FDG-PET/CT was performed in 207 (82%) at diagnosis and was positive in 95% of the entire cohort, with no difference between tumour types. Synaptophysin was positive in 98%, chromogranin A in 92% and CD56 in 97%. Mean Ki67 index was 5% in TC, 16% in AC and 69% in LCNEC (p 0.001). Metastatic disease was found in 4% of TC, 27% of AC and 58% of LCNEC at time of initial diagnosis (p 0.001). In total 179 patients (71%) underwent surgical resection; TC: 87%, AC: 72% and LCNEC: 28% (p 0.001). Of the resected patients, 11 (6%) had recurrence. Five-year survival rate was 88% for TC, 63% for AC and 20% for LCNEC.In this comprehensive study of a cohort of 252 patients, one of the largest until date, with TC, AC and LCNEC, the gender distribution showed female predominance with 68%. FDG-PET/CT was positive in 95% of the patients independent of tumour type, which confirms that FDG-PET/CT should be a part of the preoperative work-up for TC, AC and LCNEC. Tumour type was the single most potent independent prognostic factor.

A model was developed to reproduce the dynamics of the parasitic stages of equine cyathostomins. Based on a detailed review of published literature, a deterministic simulation model was constructed using the escalator boxcar-train approach, which allows for fully-overlapping cohorts of worms and approximately normally distributed variations in age/size classes. Key biological features include a declining establishment of ingested infective stage larvae as horses age. Development rates are constant for all the parasitic stages except the encysted early third stage larvae, for which development rates are variable to reflect the sometimes extended arrestment of this stage. For these, development is slowed in the presence of adult worms in the intestinal lumen, and when ingestion of infective larvae on herbage is high or extended. In the absence of anthelmintic treatments, the life span of adult worms is approximately 12 months, and the presence of an established adult worm burden largely blocks the transition of luminal fourth stage larvae to the adult stage, resulting in mortality of the larvae. This inhibition is removed by effective anthelmintic treatment allowing the rapid replacement of adult worms from the pool of mucosal stages. Within the model, the rate and seasonality at which infective stage larvae are ingested strongly influences the dynamics of the pre-adult stages. While the adult worm burden remains relatively stable within a year, due to the negative feedback they have on developing stages, the numbers and proportions of larval stages relative to the total worm burden increase with the numbers of infective larvae ingested. Further, within the model, the seasonal rise and fall of encysted stages is largely driven by the seasonal pattern of infective larvae on pasture. Because of this, the model reproduces the contrasting seasonal patterns of mucosal larvae, typical of temperate and tropical environments, using only the appropriate seasonality of larvae on pasture. Thus, the model reproduces output typical of different climatic regions and suggests that observed patterns of arrested development may simply reflect the numbers and seasonality of free-living stages on pasture as determined by different management practices and weather patterns.

With the exception of a few master transcription factors, regulators of neutrophil maturation are poorly annotated in the intermediate phenotypes between the granulocyte-macrophage progenitor (GMP) and the mature neutrophil phenotype. Additional challenges in identifying gene expression regulators in differentiation pathways relate to challenges wherein starting cell populations are heterogeneous in lineage potential and development, are spread across various states of quiescence, as well as sample quality and input limitations. These factors contribute to data variability make it difficult to draw simple regulatory inferences. In response we have applied a multi-omics approach using primary blood progenitor cells primed for homogeneous proliferation and granulocyte differentiation states which combines whole transcriptome resequencing (Ampliseq RNA) supported by droplet digital PCR (ddPCR) validation and mass spectrometry-based proteomics in a hypothesis-generation study of neutrophil differentiation pathways. Primary CD34+ cells isolated from human cord blood were first precultured in non-lineage driving medium to achieve an active, proliferating phenotype from which a neutrophil primed progenitor was isolated and cultured in neutrophil lineage supportive medium. Samples were then taken at 24-hour intervals over 9 days and analysed by Ampliseq RNA and mass spectrometry. The Ampliseq dataset depth, breadth and quality allowed for several unexplored transcriptional regulators and ncRNAs to be identified using a combinatorial approach of hierarchical clustering, enriched transcription factor binding motifs, and network mapping. Network mapping in particular increased comprehension of neutrophil differentiation regulatory relationships by implicating ARNT, NHLH1, PLAG1, and 6 non-coding RNAs associated with PU.1 regulation as cell-engineering targets with the potential to increase total neutrophil culture output. Overall, this study develops and demonstrates an effective new hypothesis generation methodology for transcriptome profiling during differentiation, thereby enabling identification of novel gene targets for editing interventions.

Aims: To evaluate how common radiation therapy techniques perform in the setting of the new European Society for Radiotherapy and Oncology-Advisory Committee in Radiation Oncology Practice (ESTRO-ACROP) delineation recommendations for immediate breast reconstruction (IBR). Materials and methods: Seven Danish radiation therapy centres and six international European centres participated in this project. Two breast cancer cases (one left-sided and one right-sided) with a retropectoral implant were chosen for radiation therapy planning using deep-inspiration breath-hold. Target volumes were delineated according to ESTRO-ACROP delineation recommendations. The centres were asked to plan the cases using any radiation therapy technique according to the Danish Breast Cancer Group plan objectives. Results: In total, 35 treatment plans were collected. Half of the submitted plans, for both the left-sided and the right-sided case, used the field-in-field (FiF) technique (nine for each), a quarter used volumetric arc radiation therapy (VMAT; five for right-sided, four for left-sided) and the remaining quarter was a mix of inverse intensity-modulated radiation therapy (IMRT), helicoidal therapy and hybrid (combined open fields and VMAT) techniques. Mean clinical target volume doses were in the range 99-102% of the prescribed dose. The median FiF mean heart dose (MHD) for right-sided radiation therapy was 1 Gy (range 0.8-3.7) and 5.2 Gy for left-sided radiation therapy (range 2.2-6.5). For right-sided radiation therapy, the median VMAT MHD was 3.42 Gy, for IMRT was 2.3 Gy and for helicoidal therapy was 5.1 Gy. For left-sided radiation therapy, the median VMAT MHD was 6.3 Gy, for IMRT was 7.8 Gy and for helicoidal therapy was 7.3 Gy. Conclusions: Different radiation therapy techniques could be used to plan radiation therapy in the setting of IBR. FiF provided good coverage with acceptable organ at risk doses. The best dose distribution results as a trade-off between the objectives of target volume coverage and high-dose organ at risk inclusion. The radiation therapy technique affects the interplay between these objectives. (C) 2020 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

Peripheral nerve blocks (PNBs) are increasingly popular in acute ankle fracture surgery but rebound pain may outweigh the benefits. The AnAnkle Trial was designed to assess the postoperative pain profile of PNB anaesthesia compared with spinal anaesthesia (SA).The AnAnkle Trial was a randomised, two-centre, blinded outcome analysis trial. Eligible adults booked for primary ankle fracture surgery were randomised to PNB or SA. The PNBs were ultrasound-guided popliteal sciatic and saphenous blocks with ropivacaine and SAs were with hyperbaric bupivacaine. Postoperatively, all subjects received paracetamol, ibuprofen, and patient-controlled i.v. morphine for pain. The primary endpoint was 27 h Pain Intensity and Opioid Consumption (PIOC) score. Secondary endpoints included longitudinal pain scores and morphine consumption separately, and questionnaires on quality of recovery.This study enrolled 150 subjects, and the PNB success rate was94%. PIOC was lower with PNB anaesthesia (median, -26.5% vs +54.3%; P0.001) and the probability of a better PIOC score with PNB than with SA was 74.8% (95% confidence interval, 67.0-82.6). Pain scores and morphine consumption analysed separately also yielded a clear benefit with PNB, despite substantial rebound pain when PNBs subsided. Quality of recovery scores were similar between groups, but 99% having PNB vs 90% having SA would choose the same anaesthesia form again (P=0.03).PNB anaesthesia was efficient and provided a superior postoperative pain profile compared with SA for acute ankle fracture surgery, despite potentially intense rebound pain after PNB.Clinicaltrialsregister.eu, EudraCT number: 2015-001108-76.

Background: It was the aim to investigate the frequency and genetic basis of dilated cardiomyopathy (DCM) among relatives of index patients with unexplained heart failure at a tertiary referral center. Methods: Clinical investigations were performed in 109 DCM index patients and 445 of their relatives. All index patients underwent genetic investigations of 76 disease-associated DCM genes. A family history of DCM occurred in 11% (n=12) while clinical investigations identified familial DCM in a total of 32% (n=35). One-fifth of all relatives (n=95) had DCM of whom 60% (n=57) had symptoms of heart failure at diagnosis, whereas 40% (n=38) were asymptomatic. Symptomatic relatives had a shorter event-free survival than asymptomatic DCM relatives ( P Results: Genetic investigations identified 43 pathogenic (n=27) or likely pathogenic (n=16) variants according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology criteria. Forty-four percent (n=48/109) of index patients carried a pathogenic/likely pathogenic variant of whom 36% (n=27/74) had sporadic DCM, whereas 60% (21/35) were familial cases. Thirteen of the pathogenic/likely pathogenic variants were also present in ≥7 affected individuals and thereby considered to be of sufficient high confidence for use in predictive genetic testing. Conclusions: A family history of DCM identified only 34% (n=12/35) of hereditary DCM, whereas systematic clinical screening identified the remaining 66% (n=23) of DCM families. This emphasized the importance of clinical investigations to identify familial DCM. The high number of pathogenic/likely pathogenic variants identified in familial DCM provides a firm basis for offering genetic investigations in affected families. This should also be considered in sporadic cases since adequate family evaluation may not always be possible and the results of the genetic investigations may carry prognostic information with an impact on individual management.

Purpose We investigated the feasibility of the Actiheart monitor to determine total daily energy expenditure and the validity of the Actiheart step test as an accurate estimate of peak oxygen uptake. Methods (Equation is included in full-text article.)O2 peak was estimated with the Actiheart step test and compared with a cardiopulmonary exercise test. Total daily energy expenditure was measured using the Actiheart monitor on days with and without classmate coadmission. Results Of 26 eligible measurement periods (15 children), 89% participated and 91% could participate safely; however, 35% fulfilled demands for valid monitoring. The percentage of children not completing the monitoring period was 10% (attrition) and adherence to classmate visits was 84%. Forty-eight percent of the measurement periods provided data, and only 27% was calibrated data. Actiheart step test significantly overestimated (Equation is included in full-text article.)O2 peak compared with the Cardio Pulmonary Exercise Test. Conclusion Measuring total daily energy expenditure using Actiheart is not feasible, nor implementable in children with cancer. Furthermore, the Actiheart step test is not a valid test to estimate (Equation is included in full-text article.)O2 peak in children with cancer.

Background Musculocontractural Ehlers–Danlos Syndrome (mcEDS) is a rare connective tissue disorder caused by biallelic loss‐of‐function variants in CHST14 (mcEDS‐CHST14) or DSE (mcEDS‐DSE), both of which result in defective dermatan sulfate biosynthesis. Forty‐one patients with mcEDS‐CHST14 and three patients with mcEDS‐DSE have been described in the literature. Methods Clinical, molecular, and glycobiological findings in three additional patients with mcEDS‐DSE were investigated. Results Three patients from two families shared craniofacial characteristics (hypertelorism, blue sclera, midfacial hypoplasia), skeletal features (pectus and spinal deformities, characteristic finger shapes, progressive talipes deformities), skin features (fine or acrogeria‐like palmar creases), and ocular refractive errors. Homozygous pathogenic variants in DSE were found: c.960T>A/p.Tyr320* in patient 1 and c.996dupT/p.Val333Cysfs*4 in patients 2 and 3. No dermatan sulfate was detected in the urine sample from patient 1, suggesting a complete depletion of DS. Conclusion McEDS‐DSE is a congenital multisystem disorder with progressive symptoms involving craniofacial, skeletal, cutaneous, and cardiovascular systems, similar to the symptoms of mcEDS‐CHST14. However, the burden of symptoms seems lower in patients with mcEDS‐DSE., Clinical, molecular, and glycobiological findings in three additional patients from two families with musculocontractural Ehlers–Danlos syndrome (mcEDS‐DSE) are described. McEDS‐DSE is a congenital multisystem disorder with progressive symptoms involving craniofacial, skeletal, cutaneous, and cardiovascular systems, similar to the symptoms of mcEDS‐CHST14. However, the burden of symptoms seems lower in patients with mcEDS‐DSE.

Equine strongyle parasites are considered ubiquitous in grazing equids across the world, and cyathostomin parasites are known pathogens causing well-described disease complexes in horses. Decades of intensive anthelmintic treatments have led to anthelmintic resistance in cyathostomins, and current recommendations are to lower treatment intensity and base control strategies on fecal egg count surveillance. Little is known about risk factors associated with strongyle parasite egg shedding patterns in the United States equine population, as the most recent national survey was conducted 20 years ago. The present study was carried out as part of the National Animal Health Monitoring Systems (NAHMS) Equine 2015-2016 study. The aims were to describe strongyle parasite egg shedding patterns in the United States equine population and identify risk factors associated with prevalence and egg count magnitude. Data were collected from equine operations in 28 states via questionnaires and fecal samples submitted to a parasitology research laboratory for fecal egg count analysis and the data gathered underwent comprehensive statistical analyses. Though region and season were related, overall, the summer months and the fall in the southeast tended to have the greatest odds of presence of strongyles eggs on a FEC. Generally, equids resident in the Western region (Arizona, California, Colorado, Montana, Oregon, and Wyoming) had significantly lower strongyle prevalence, no matter the season, as well as a markedly different distribution between strongyle egg shedding levels (p = 0.0005). Overall, egg counts were over-dispersed with about 27% of equids (95% Confidence Interval (CI): 20-34%) contributing 80% of the egg output. Pasture history was significantly associated with strongyle egg prevalence (p = 0.0003) and egg shedding levels (p = 0.0063) with daily access in the previous 30 days being associated with higher odds of presence and greater median egg count levels. Equid gender was significantly associated with strongylid presence (p = 0.0081) and egg count level (p = 0.0008), with male equids having significantly lower odds and median egg counts than female equids, and age was significantly negatively associated with strongylid prevalence (p 0.0001). Time since last deworming was significantly positively associated with prevalence of strongyle eggs, and this was dependent on the class of dewormer used (p = 0.0086), with equids treated with macrocyclic lactone class of drugs having lower odds of strongyle egg presence at 120 days since the last deworming. These data provide useful insights into strongylid egg shedding patterns in the United States equine population, and they can help refine parasite control recommendations depending on region, pasture access, and age distribution.

Cyathostomins are ubiquitous in grazing horses across the world, and anthelmintic resistance has been reported with increasing levels over past decades. The aims of the present study were (i) to investigate the efficacy against encysted larval stages of moxidectin (0.4 mg/kg) and fenbendazole (10 mg/kg daily for five consecutive days) and compare these regimens at 2 and 5 weeks post-treatment, (ii) to investigate individual cyathostomin species associated with shortened egg reappearance periods, and (iii) to document species exhibiting decreased susceptibility to the evaluated compounds. Thirty-six ponies were allocated to treatment groups with half euthanatized 2 weeks post-treatment, and the remainder necropsied after 5 weeks. Luminal and mucosal worm counts were conducted and strongyle egg counts were determined at weekly intervals. At 2 weeks, mean reductions of early L3s were 50.4% and 73.8% for fenbendazole and moxidectin, respectively. At 5 weeks, the respective efficacies were 51.3% and 71.8%. Two week efficacies against late L3s and L4s (LL3s/L4s) were 70.8% and 74.6% for fenbendazole and moxidectin, respectively, whereas very low numbers were found in all three groups at 5 weeks. None of the mucosal counts were significantly different between treatment groups. Fenbendazole and moxidectin reduced luminal worm counts by 93.2% and 98.3% at 2 weeks following administration, with moxidectin group adult counts being significantly lower than the other two groups (P 0.0001). Both treatment groups had increased counts 3 weeks later (P = 0.0415). A moxidectin ERP of 4 weeks was associated with surviving luminal L4s, and adult species contributing to this were Cyathostomum catinatum, Cylicostephanus longibursatus, Cylicocyclus ashworthi and Cylicocyclus nassatus. This study documented (i) larvicidal efficacy of fenbendazole much lower than historical standards, (ii) survival of luminal immatures (L4) following moxidectin administration, and (iii) new information about cyathostomin species associated with these phenomena.

Importance: Truncating variants in the gene encoding filamin C (FLNCtv) are associated with arrhythmogenic and dilated cardiomyopathies with a reportedly high risk of ventricular arrhythmia.Objective: To determine the frequency of and risk factors associated with adverse events among FLNCtv carriers compared with individuals carrying TTN truncating variants (TTNtv).Design, Setting, and Participants: This cohort study recruited 167 consecutive FLNCtv carriers and a control cohort of 244 patients with TTNtv matched for left ventricular ejection fraction (LVEF) from 19 European cardiomyopathy referral units between 1990 and 2018. Data analyses were conducted between June and October, 2020.Main Outcomes and Measures: The primary end point was a composite of malignant ventricular arrhythmia (MVA) (sudden cardiac death, aborted sudden cardiac death, appropriate implantable cardioverter-defibrillator shock, and sustained ventricular tachycardia) and end-stage heart failure (heart transplant or mortality associated with end-stage heart failure). The secondary end point comprised MVA events only.Results: In total, 167 patients with FLNCtv were studied (55 probands [33%]; 89 men [53%]; mean [SD] age at baseline evaluation, 43 [18] years). For a median follow-up of 20 months (interquartile range, 7-60 months), 29 patients (17.4%) reached the primary end point (19 patients with MVA and 10 patients with end-stage heart failure). Eight (44%) arrhythmic events occurred among individuals with baseline mild to moderate left ventricular systolic dysfunction (LVSD) (LVEF = 36%-49%). Univariable risk factors associated with the primary end point included proband status, LVEF decrement per 10%, ventricular ectopy (≥500 in 24 hours) and myocardial fibrosis detected on cardiac magnetic resonance imaging. The LVEF decrement (hazard ratio [HR] per 10%, 1.83 [95% CI, 1.30-2.57]; P Conclusions and Relevance: The high frequency of MVA among patients with FLNCtv with mild to moderate LVSD suggests that higher LVEF values than those currently recommended should be considered for prophylactic implantable cardioverter-defibrillator therapy in FLNCtv carriers.

Cytauxzoon felis is an intraerythrocytic apicomplexan of felids enzootic in the southeastern United States. In domestic cats (Felis catus), this parasite can result in the highly fatal disease cytauxzoonosis or bobcat fever. Bobcats (Lynx rufus) are the wild animal reservoir host. To date, the characterization of prevalence of C. felis in bobcats is mostly based on broad-scale surveys from hunter-harvested specimens collected across large geographic areas, usually consisting of multiple states. Detailed studies on the development, transmission, distribution, effects, and prevalence of C. felis in the tick vectors are scarce. To fill some of these gaps in the literature, such as prevalence in ticks and bobcats in a discrete region, we examined bobcats and ticks in an 8,000-km2 portion of southern Illinois. We screened for C. felis using a nested polymerase chain reaction that amplifies a fragment of the nuclear small subunit (SSU) 18S rRNA. We screened 125 individual bobcats collected in southern ...

Increasing levels of anthelmintic resistance observed in equine cyathostomin parasites have led to recommendations of selective anthelmintic treatment strategies to lower the selection pressure favoring resistant populations. This principle is based on determining strongyle fecal egg counts from all herd members, and treating those exceeding a predetermined treatment cutoff. However, epidemiological information is lacking from horses kept under tropical conditions, where parasite burdens may be of a different composition and magnitude compared to those of horses kept under temperate climate conditions. The aim of the present work was to characterize the strongylid fauna in horses kept in tropical Camagüey, Cuba and identify risk factors associated with strongylid and ascarid egg counts. A total of 396 horses from eight different establishments were included in the study. Coprocultures revealed that Strongylus vulgaris and cyathostomins, sensu lato, were detected in all of those establishments. Prevalence and mean value of strongylid eggs per gram of feces were 97% and 1436, respectively. Eggs of Parascaris spp. were observed in 10% of horses. A multivariate mixed linear model identified sex (p=0.022), month (p=0.044), operation type (p=0.037) and time since last deworming (p0.001) to be significantly associated in with the magnitude of strongylid fecal egg counts. A multivariate logistic regression identified horses less than two years of age (p=0.010) and horses not receiving anthelmintic treatment (p0.001) to be significantly more likely to harbor Parascaris spp. parasites. The high magnitude and prevalence of strongylid fecal egg counts observed and the common occurrence of S. vulgaris suggest that strongylid parasite burdens are substantially different from those typically observed in managed equines kept under more temperate conditions.

The purpose of this study was to determine the detection rate of distant metastasis and synchronous cancer, comparing clinically used imaging strategies based on chest x-ray 1 head and neck MRI (CXR/MRI) and chest CT 1 head and neck MRI (CHCT/MRI) with 18F-FDG PET/CT upfront in the diagnostic workup of patients with oral, pharyngeal, or laryngeal cancer. Methods: This was a prospective cohort study based on paired data. Consecutive patients with histologically verified primary head and squamous cell carcinoma at Odense University Hospital from September 2013 to March 2016 were considered for the study. Included patients underwent CXR/MRI and CHCT/MRI as well as PET/CT on the same day and before biopsy. Scans were read masked by separate teams of experienced nuclear physicians or radiologists. The true detection rate of distant metastasis and synchronous cancer was assessed for CXR/MRI, CHCT/MRI, and PET/CT. Results: A total of 307 patients were included. CXR/MRI correctly detected 3 (1%) patients with distant metastasis, CHCT/MRI detected 11 (4%) patients, and PET/CT detected 18 (6%) patients. The absolute differences of 5% and 2%, respectively, were statistically significant in favor of PET/CT. Also, PET/CT correctly detected 25 (8%) synchronous cancers, which was significantly more than CXR/MRI (3 patients, 1%) and CHCT/MRI (6 patients, 2%). The true detection rate of distant metastasis or synchronous cancer with PET/CT was 13% (40 patients), which was significantly higher than 2% (6 patients) for CXR/ MRI and 6% (17 patients) for CHCT/MRI. Conclusion: A clinical imaging strategy based on PET/CT demonstrated a significantly higher detection rate of distant metastasis or synchronous cancer than strategies in current clinical imaging guidelines, of which European ones primarily recommend CXR/MRI, whereas U.S. guidelines preferably point to CHCT/MRI in patients with head and neck squamous cell carcinoma.

Cyathostomins (small strongyles) are ubiquitous in grazing horses and are known pathogens as cause of larval cyathostominosis. As part of their life cycle, cyathostomin larvae invade the mucosal walls of the large intestines and undergo encystment. Newly ingested third stage larvae are known to undergo arrested development and this can lead to an accumulation of encysted burdens over the course of a grazing season. It is believed that the host immune system plays a significant role in triggering this arrestment. Little is known about the development and progression of larval stages in foals that are not expected to mount a pronounced immune response to ingested cyathostomin larvae. This study evaluated counts of encysted larvae measured in 37 foals. The foals were born in 2013, 2014, and 2015 into a parasitology research herd kept without anthelmintic intervention and were humanely euthanatized between 50 and 293 days of age as part of an ongoing parasite transmission study. A mucosal digestion technique was performed to enumerate encysted early third stage (EL3) and late third stage/fourth stage (LL3/L4) larvae in the cecum, ventral colon and dorsal colon. Counts were analyzed statistically to evaluate the influence of foal age, sex, and seasonality on the counts. Total counts as well as LL3/L4 counts were significantly higher during the grazing season (March–November). Three defined age groups (>100, 100–200, >200 days) did not have statistically different counts. Male foals had significantly higher total counts compared to females, and this has not been reported before. The study found that 41% of the recovered larvae were EL3s, but no indication of arrested development of these was observed. This indicates that cyathostomin infection in foals progresses in a manner substantially different from mature horses.

Macrocyclic lactones are the most widely used drugs for the control of gastrointestinal nematodes of horses in Argentina. Ivermectin and moxidectin are used as broad spectrum anthelmintics and although there are several international reports on the resistance of Parascaris spp., the resistance status of the local nematode population is largely unknow. This report informs a case of suboptimal efficacy to both drugs to control Parascaris spp in foals in central Argentina. In February 2018, routine fecal parasite egg counts showed a moderate-high number of Parascaris spp eggs (mean = 680 eggs per gram of feces) in foals treated approximately one month before with moxidectin. Upon suspicion of resistance of this parasite to the macrocyclic lactones, 24 of these animals were selected for a fecal egg count reduction test (FECRT). Twelve foals were treated with ivermectin and the remaining 12 animals with moxidectin. Two weeks after treatment, the FECRT was 48.1% and 34.8% for moxidectin and ivermectin respectively (25% of the animals increased the number of eggs in feces after treatment). Five days later, the administration of fenbendazole resulted in a FECRT = 100%. The monitoring of the status of susceptibility or resistance in each establishment is critical for the design of control programs based on rational and sustainable use of anthelmintics.

A total of 1209 ptarmigan were examined for Mironovia lagopus, including 721 juvenile birds (ca. 3 months old) and 488 adult birds (15 months or older). A total of 88 birds or 7.3% (n = 1209, 95% cl 5.9–8.9%) were infested with M. lagopus. There was an age difference in prevalence of infection, and more adults (10.7%, n = 488, 95% cl 8.2–13.7%) than juveniles (5.0%, n = 721, 95% cl 3.6–6.8%) were infested. There was a significant age effect in the mean intensity index, and adult birds had more advanced infestations compared with juvenile birds. There were no significant changes in either the interannual prevalence of infection or the mean intensity index of infection. Of the feather types inspected, there was no age-related difference in selection of feathers, nor was there any preference of mites for any one of the inspected feather types. Body dispersants were all adult females. There was an age-related difference in mean intensities of infection of body dispersants; it was higher in adult birds. The methods used to determine presence or absence of M. lagopus were not 100% accurate especially for juvenile hosts, and this at least partly explains the difference in prevalence among age groups. There was no relationship between host body condition or host density and infection by M. lagopus.

Objective: To investigate whether a 18F-FDG PET/CT (PET/CT)-based diagnostic strategy adds decisive new information compared to conventional imaging in the evaluation of salivary gland tumours and the detection of cervical lymph node metastases, distant metastases, and synchronous cancer in patients with salivary gland carcinoma. Methods: The study was a blinded prospective cohort study. Data were collected consecutively through almost 3 years. All patients underwent conventional imaging—magnetic resonance imaging (MRI) and chest X-ray (CXR)—in addition to PET/CT prior to surgery. Final diagnosis was obtained by histopathology. MRI/CXR and PET/CT were interpreted separately by experienced radiologists and nuclear medicine physicians. Interpretation included evaluation of tumour site, cervical lymph node metastases, distant metastases, and synchronous cancer. Results: Ninety-one patients were included in the study. Thirty-three patients had primary salivary gland carcinoma and eight had cervical lymph node metastases. With PET/CT, the sensitivity was 92% and specificity 29% regarding tumour site. With MRI/CXR, the sensitivity and specificity were 90% and 26%, respectively. Regarding cervical lymph node metastases in patients with salivary gland carcinoma, the sensitivity with PET/CT was 100% and with MRI/CXR 50%. PET/CT diagnosed distant metastases in five patients, while MRI/CXR detected these in two patients. Finally, PET/CT diagnosed two synchronous cancers, whereas MRI/CXR did not detect any synchronous cancers. Conclusions: Compared with MRI/CXR PET/CT did not improve discrimination of benign from malignant salivary gland lesions. However, PET/CT may be advantageous in primary staging and in the detection of distant metastases and synchronous cancers.

BACKGROUND AND OBJECTIVES: Patients undergoing major elective ankle surgery often experience pain from the saphenous nerve territory persisting beyond the duration of a single-injection saphenous nerve block. We hypothesized that perineural dexamethasone as an adjuvant for the saphenous nerve block prolongs the duration of analgesia and postpones as well as reduces opioid-requiring pain.METHODS: Forty patients were included in this prospective, randomized, controlled study. All patients received a continuous sciatic catheter and were randomized to receive a single-injection saphenous nerve block with 10 mL of 0.5% bupivacaine with 1:200,000 epinephrine with addition of 1 mL of saline or 1 mL of 0.4% (ie, 4 mg) dexamethasone. The primary outcome was duration of saphenous nerve block estimated as the time until the first opioid request. Secondary outcomes were opioid consumption and pain.RESULTS: The mean (SD) duration of the saphenous nerve block until first opioid request was 29.4 (8.4) hours in the dexamethasone group and 23.2 (10.3) hours in the control group (P = 0.048). The median opioid consumption [interquartile range] during the first 24 hours was 0 mg [0-0] versus 1.5 mg [0-14.2] in the dexamethasone and control groups, respectively. Nonparametric comparison of opioid consumption from 0 to 24 hours was statistically significant. The opioid consumption was similar in the two groups in the time interval 24 to 48 postoperative hours.CONCLUSION: Perineural dexamethasone as an adjuvant for the single-injection subsartorial saphenous nerve block can prolong analgesia and reduce opioid-requiring pain after major ankle surgery.

To investigate the impact of common anesthetic techniques on postoperative opioid consumption in ankle fracture surgery.We performed a retrospective cohort study on 622 patients with isolated ankle fractures undergoing primary reconstructive surgery. Patients were identified by consecutive screening in the years 2008 to 2011. Our primary endpoint was the difference in the 24-hour postoperative opioid consumption after general anesthesia (GA) compared with different regional anesthesia modalities. Secondary endpoints were length of stay in the postanesthesia care unit, risk of postoperative nausea and vomiting, and postoperative length of hospital stay.Opioid consumption in 4 anesthesia groups (equipotent doses of IV morphine) was as follows: GA: 21.9 mg (95% confidence interval [CI]±1.2), GA+peripheral nerve block (PNB): 16.3 mg (95% CI±1.1), spinal anesthesia (SA): 17.1 mg (95% CI±0.9), and SA+PNB: 14.6 mg (95% CI±1.0). We found significant differences between "GA" and all other groups (P≤0.01). The most pronounced difference is seen when GA is compared with SA+PNB, with a 33.4% opioid reduction in the latter group.Regional anesthesia modalities reduce postoperative opioid consumption in ankle fracture surgery in comparison with GA. A benefit of PNBs is possibly due to an improved pain profile. Our study is retrospective and cannot predict the exact magnitude of this benefit.

Objectives Congestive heart failure secondary to cardiomyopathy is a common manifestation of cardiac disease in cats, carrying a variable prognosis. The objective of this retrospective study was to evaluate the relationship between red blood cell distribution width (RDW) and survival time in feline patients with acquired heart disease with and without congestive heart failure (CHF). Methods Three hundred and forty-nine client-owned cats with echocardiograms and complete blood count, including RDW measurement, performed between March 2006 and December 2011, were included in the study. Patient characteristics, including signalment, hematocrit, RDW, echocardiographic parameters and survival, were recorded. Comparisons between RDW in cats with asymptomatic acquired heart disease and those with CHF were made. Survival was documented and compared at 30 days and 6 months. Results CHF was present in 80 cats and absent in 269 cats. Cats with CHF had an increase in mortality compared with cats without CHF at 30 days and 6 months ( P = 0.007 and P = 0.04, respectively). RDW was not significantly associated with survival in cats with or without CHF at 30 days or 6 months. A significant difference was found between median RDW values in cats with CHF vs cats without CHF (16.3% vs 15.8%; P = 0.02). The median RDW value was significantly higher in cats with unclassified cardiomyopathy compared with cats with other types of cardiomyopathy (16.3% vs 15.8%; P = 0.03). Conclusions and relevance Single RDW values did not predict mortality in cats with acquired heart disease but may be useful in determining if cats have decompensated heart disease and CHF. Human studies indicate that incremental increases in serial RDW measurements are associated with decreased survival; serial RDW measurements in cats may be an area of future study.

Strongyloides westeri is a threadworm parasite found in the small intestine mainly in foals at up to about 4 months of age. This parasite is associated with small intestinal enteritis and diarrhea as well as skin irritation and a clinical syndrome called "frenzied behavior" due to percutaneous invasion. The aim of this study was to investigate S. westeri parasite burdens in age groups older than the initial lactogenic transmission phase. Secondary aims were to examine the impact of host age and gender on worm burden and egg output in naturally infected foals. Thirteen foals were enrolled in the study, exposed to natural infection with S. westeri and were humanely euthanized at ages ranging from 89 to 221days old. Egg counts per gram of feces were determined using the Mini-FLOTAC method. Worms were retrieved from the mucosa of the anterior half of the small intestine using a digestion method and enumerated. The foals were all observed to be healthy with no signs of parasitic disease. Foals at 4-5 months of age had significantly higher S. westeri worm and egg counts compared to those aged 6-8 months (p

Previously described models for the free-living and parasitic phases of the cyathostomin life-cycle were combined into a single model for the complete life-cycle. The model simulates a single free-living population on pasture utilising parasite egg output from the horses and localised temperature and rainfall data to estimate infective larval density on herbage. Multiple horses of different ages are possible, each with an individualised anthelmintic treatment programme. Genotypes for anthelmintic resistance are included allowing for up to three resistance genes with 2 alleles each. Because little is known of the genetics of resistance to anthelmintics in cyathostomins, the first use of this model was to compare the effect of different assumptions regarding the inheritance of resistance on model outputs. Comparisons were made between single and two-gene inheritance, where the heterozygote survival was dominant, intermediate or recessive under treatment, and with or without a fitness disadvantage associated with the resistance mechanism. Resistance developed fastest when the heterozygotes survived anthelmintic treatment (i.e., were dominant) and slowest when they did not (i.e., were recessive). Resistance was slower to develop when inheritance was poly-genic compared to a single gene, and when there was a fitness cost associated with the resistance mechanism, although the latter variable was the least influential. Importantly, while these genetic factors sometimes had a large influence on the rate at which resistant genotypes built up in the model populations, their order of ranking was always the same, when different anthelmintic use strategies were compared. Therefore, the described model is a useful tool for evaluating different treatment and management strategies on their potential to select for resistance.

BACKGROUND: Previous studies have suggested that sigmoidectomy with primary anastomosis is superior to Hartmann's procedure. The likelihood of stoma reversal after primary anastomosis has been reported to be higher and reversal seems to be associated with lower morbidity and mortality. Although promising, results from these previous studies remain uncertain because of potential selection bias. Therefore, this study aimed to assess outcomes after Hartmann's procedure versus sigmoidectomy with primary anastomosis, with or without defunctioning ileostomy, for perforated diverticulitis with purulent or faecal peritonitis (Hinchey III or IV disease) in a randomised trial. METHODS: A multicentre, randomised, open-label, superiority trial was done in eight academic hospitals and 34 teaching hospitals in Belgium, Italy, and the Netherlands. Patients aged between 18 and 85 years who presented with clinical signs of general peritonitis and suspected perforated diverticulitis were eligible for inclusion if plain abdominal radiography or CT scan showed diffuse free air or fluid. Patients with Hinchey I or II diverticulitis were not eligible for inclusion. Patients were allocated (1:1) to Hartmann's procedure or sigmoidectomy with primary anastomosis, with or without defunctioning ileostomy. Patients were enrolled by the surgeon or surgical resident involved, and secure online randomisation software was used in the operating room or by the trial coordinator on the phone. Random and concealed block sizes of two, four, or six were used, and randomisation was stratified by age (

INTRODUCTION Much of behavioral health care takes place within primary care settings rather than in specialty mental health settings. Access to specialty mental health care can be difficult due to limited access to mental health providers and wait times to receive mental health care. The purpose of this study is to determine patient satisfaction with behavioral health consultation visits that take place within the context of the primary care behavioral health consultation model. Patient likelihood to seek out specialty mental health care services if behavioral health consultation services were not provided was also examined. METHOD Two primary care clinic systems were examined in this study. The first was a primary care clinic predominately serving low-income patients: 100 individuals participated. The second was primary care in the context of military treatment centers: 539 individuals participated. RESULTS Results show that 61% of the patients in the low-income primary care clinic would not attend a specialty mental health appointment versus 30% in the military population. DISCUSSION This study suggests that primary care behavioral health is a patient-centered approach to care and reaches populations that otherwise may not receive behavioral health services. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

The present work represents a comprehensive study of in utero maternal transfer of legacy and emerging flame retardants (FRs) in marine predators. We analyzed liver tissues from pregnant sharks of five viviparous species, including blacknose shark ( Carcharhinus acronotus; n = 12), blacktip shark ( Carcharhinus limbatus; n = 2), bonnethead ( Sphyrna tiburo; n = 2), Atlantic sharpnose shark ( Rhizoprionodon terraenovae; n = 2), and spinner shark ( Carcharhinus brevipinna; n = 2), as well as their embryos ( n = 84 in total from five species), collected from the western North Atlantic Ocean. Concentrations of frequently detected emerging FRs in adult female blacknose sharks were determined to be 6.1-83.3 ng/g lipid weight (lw) for dechlorane analogues, 2.5-29.8 ng/g lw for tetrabromo- o-chlorotoluene, and nondetection -32.6 ng/g lw for hexabromobenzene. These concentrations were 1-2 orders of magnitude lower than those of legacy polybrominated diphenyl ether flame retardants (85.7-398 ng/g lw). Similar contamination profiles were also found in the other four species, although FR concentrations varied in different species. A total of 21 FRs were commonly found in developing embryos of female sharks from five species, demonstrating maternal transfer in utero. The maternal transfer ratio (i.e., ratio of the mean litter concentration to their mother's concentration) determined in blacknose shark mother/embryo groups for each FR chemical was negatively associated with its octanol-water partition coefficient. Our work lays a solid foundation for future investigation of the underlying mechanisms of in utero transfer and additional physical or chemical factors that affect maternal transfer.

Southern right whales (Eubalaena australis) invest substantial amounts of energy in their calves, while facing the risk of having them predated upon by eavesdropping killer whales (Orcinus orca). We tested the hypothesis that southern right whale mother–calf pairs employ acoustic crypsis to reduce acoustic detectability by such predators. Specifically, we deployed multi-sensor DTAGs on nine lactating whales for a total of 62.9 h in a Western Australian breeding ground, and used a SoundTrap to estimate the concomitant acoustic background noise. Vocalisations were recorded at low rates of

The Danish Adult Diabetes Database (DADD) annually reports a quality indicator for lipid-lowering treatment of type 2 diabetes mellitus (T2DM) patients. This retrospective cohort study aims to A) investigate the reasons for inadequate or lacking lipid-lowering treatment and to B) assess the validity of the DADD indicator as a measure of quality of care.A) A pop-up questionnaire enquiring about reasons for lack of treatment was added to the clinicians' data entry tool in the Central Denmark Region. B) The DADD indicator was compared on a per-clinic basis with the achieved median low-density lipoprotein (LDL) cholesterol level and with an internationally widely used indicator of lipid-lowering treatment quality.A) A total of 3,491 patients were registered from 1 January 2013 to 28 February 2015. For 170 (62%) of 309 patients with an LDL level2.5 mmol/l who were not receiving lipid-lowering treatment, there was no "good" explanation for lacking treatment. Among 518 patients with an LDL level2.5 mmol/l despite lipid-lowering treatment, 259 (50%) did not receive high-intensity treatment. B) The DADD quality indicator was neither associated with the international quality indicator nor with the median per-clinic LDL level for T2DM patients.A) We found substantial potential for improvement of lipid management among T2DM patients in Denmark by initiating and/or intensifying lipid-lowering treatment. B) The current DADD indicator is not a valid measure of lipid-lowering quality of care.supported by the Rosa and Asta Jensen Foundation.not relevant.

Objective Preterm delivery for preeclampsia or placental insufficiency (PREPI) is a clinical criterion for antiphospholipid syndrome (APS), but no prior prospective studies have used the international classification criteria for APS. Our objective is to determine the proportion of women with PREPI who test positive for aPL using international criteria for antiphospholipid antibody (aPL) assays. Methods We conducted a prospective, case-control study of 148 women delivered Results Controls were more likely to be Caucasian (87% vs 70%, p = 0.006) and had lower BMIs (BMI 26 vs 33, p Conclusion Women requiring early delivery for PREPI are more likely to have aPL (and thus APS) than controls. This is the first prospective study using both obstetric definitions and laboratory criteria in accordance with APS international criteria.

The purpose of this study was to examine whether staging with 18F-FDG PET/CT better predicts survival in patients with recurrent head and neck squamous cell carcinoma (HNSCC) than chest x-ray (CXR) plus head and neck MRI or chest CT (CCT) plus head and neck MRI. Methods: This was a prospective cohort study based on paired data. Consecutive patients with histologically verified HNSCC recurrence were enrolled from September 2013 to March 2016. All patients underwent CXR/MRI, CCT/MRI, and PET/CT on the same day and before biopsy. All imaging studies underwent masked interpretation by separate teams of experienced nuclear physicians or radiologists. Recurrent carcinomas were categorized as localized (equivalent to primary stages I–II), locally advanced (equivalent to primary stages III–IVB), or metastatic (equivalent to primary stage IVC). Discriminative abilities for each imaging strategy with respect to cancer-specific and stage-based survival were compared using Kaplan–Meier analysis, Cox proportional-hazards regression with the Harrell concordance index (C-index), and net reclassification improvement. Results: In total, 110 patients (90 men and 20 women; median age, 66 y; range, 40–87 y) were included. PET/CT significantly changed the assigned tumor stage when compared with imaging strategies based on CXR/MRI or CCT/MRI (P, 0.001 for both). Kaplan–Meier analysis of PET/CT-based staging showed progressively worsened prognosis with localized, locally advanced, or metastatic disease (log-rank test, P, 0.001), whereas CXR/MRI and CCT/MRI were unable to distinguish between these groups in terms of survival (log-rank test, P 5 0.18 and P 5 0.58, respectively). Overall discriminative ability in predicting cancer-specific mortality was significantly greater for PET/CT (C-index, 0.72) than for CXR/MRI (C-index, 0.55) (P 5 0.001) and CCT/MRI (C-index, 0.55)(P, 0.001). The addition of PET/CT to either CXR/MRI or CCT/MRI was associated with a significantly positive net reclassification improvement (P, 0.001 for both). Conclusion: Contrary to standard imaging strategies, PET/CT-based staging in recurrent HNSCC was able to significantly discriminate among the survival courses of patients with local, locally advanced, or metastatic disease and predict their respective survival probability.

BACKGROUND AND OBJECTIVES: Major ankle surgery causes intense postoperative pain, and whereas the importance of a sciatic nerve block is well established, the clinical significance of a supplemental saphenous nerve block has never been determined in a prospective, randomized, double-blind, placebo-controlled trial. We hypothesized that a saphenous nerve block reduces the proportion of patients experiencing significant clinical pain after major ankle surgery.METHODS: Eighteen patients were enrolled and received a popliteal sciatic nerve block. Patients were randomized to single-injection saphenous nerve block with 10 mL 0.5% bupivacaine with 1:200,000 epinephrine or 10 mL saline (Fig. 1). Primary outcome was the proportion of patients reporting significant clinical pain, defined as a score greater than 3 on the numerical rating scale. Secondary outcomes were maximal pain and analgesia of the cutaneous territory of the infrapatellar branch of the saphenous nerve.RESULTS: Eight of 9 patients in the placebo group reported significant clinical pain versus 1 of 9 patients in the bupivacaine-epinephrine group (P = 0.003). Maximal pain was significantly lower in the active compared with the placebo group (median, 0 [0-0] vs 5 [4-6]; P = 0.001). Breakthrough pain from the saphenous territory began within 30 minutes after surgery in all cases. Sensory testing of the cutaneous territory of the infrapatellar branch of the saphenous nerve showed correlation between pain reported in the anteromedial ankle region and the intensity of cutaneous sensory block in the anteromedial knee region.CONCLUSIONS: The saphenous nerve is an important contributor to postoperative pain after major ankle surgery, with significant clinical pain appearing within 30 minutes after surgery.CLINICAL TRIALS REGISTRATION: This study has been registered at ClinicalTrials.gov, identifier NCT02697955.

International audience; The SPECC1L protein plays a role in adherens junctions involved in cell adhesion, actin cytoskeleton organization, microtubule stabilization, spindle organization and cytokinesis. It modulates PI3K-AKT signaling and controls cranial neural crest cell delamination during facial morphogenesis. SPECC1L causative variants were first identified in individuals with oblique facial clefts. Recently, causative variants in SPECC1L were reported in a pedigree reported in 1988 as atypical Opitz GBBB syndrome. Six families with SPECC1L variants have been reported thus far. We report here eight further pedigrees with SPECC1L variants, including a three-generation family, and a further individual of a previously published family. We discuss the nosology of Teebi and GBBB, and the syndromes related to SPECC1L variants. Although the phenotype of individuals with SPECC1L mutations shows overlap with Opitz syndrome in its craniofacial anomalies, the canonical laryngeal malformations and male genital anomalies are not observed. Instead, individuals with SPECCL1 variants have branchial fistulae, omphalocele, diaphragmatic hernias, and uterus didelphis. We also point to the clinical overlap of SPECC1L syndrome with mild Baraitser-Winter craniofrontofacial syndrome: they share similar dysmorphic features (wide, short nose with a large tip, cleft lip and palate, blepharoptosis, retrognathia, and craniosynostosis), although intellectual disability, neuronal migration defect, and muscular problems remain largely specific to Baraitser-Winter syndrome. In conclusion, we suggest that patients with pathogenic variants in SPECC1L should not be described as "dominant (or type 2) Opitz GBBB syndrome", and instead should be referred to as "SPECC1L syndrome" as both disorders show distinctive, non overlapping developmental anomalies beyond facial communalities.

Anthelmintic resistance among cyathostomin parasites is a wide-spread problem. The parasite control guidelines written by the American Association of Equine Practitioners (AAEP) encourages the preservation of anthelmintic efficacy by reducing treatment frequency, using targeted deworming, and implementing environmental management practices. While there is knowledge regarding parasite management practices of affluent horse farms in the United States, surveys rarely explore the rural and underserved regions. The purpose of this study was to observe the management practices of horse farms in rural regions Kentucky, including working Amish farms, and determine factors associated with strongyle prevalence. A total of 160 horses among 38 owners from 28 different farms were enrolled in this study. A questionnaire survey regarding equine information, farm management, and deworming history was performed with each owner. Fecal samples were collected to determine fecal egg counts, perform coprocultures for subsequent strongyle larvae identification, and Strongylus vulgaris specific PCR. Serum samples were collected for the S. vulgaris antibody specific ELISA. The mean number of deworming treatments given in the last year was 2.1 with a 95% confidence interval of 1.9–2.3 with ivermectin being the most common active used. Statistical analysis showed horses treated within the last three months with a macrocylic lactone (ML) drug had significantly lower egg counts than horses treated with a ML 7–9 months ago (p = .0005). Despite the AAEP recommendations to reduce the overall number of treatments by using a surveillance-based approach and to no longer rotate treatments, only 17 horses reportedly had a fecal sample submitted for a fecal egg count and 65 horses were dewormed in a rotational manner. Horses whose owners utilized an informative deworming source (i.e., veterinarian, internet, magazine, local feed store) also had significantly lower counts (p = .0026). All coprocultures were negative for S. vulgaris while five horses were PCR positive. Interestingly, 95 horses tested ELISA positive for S. vulgaris. The strongyle egg counts of the working Amish horses were not significantly different from the other horses in this study and deworming practices including the use of efficacious drugs and low treatment frequencies were in accordance with the AAEP guidelines. This study was the first to summarize deworming management practices of rural regions in Kentucky, including a working Amish community. Overall, horse owners employed deworming practices recommended by the AAEP, however rotational deworming is still commonly implemented and fecal egg counts are rarely used.

Background Peripheral nerve blocks (PNB) are increasingly used for anaesthesia and postoperative pain control in acute orthopaedic limb surgery but rebound pain upon cessation of PNBs may challenge the benefits on the pain profile. We aimed to explore the pain profile following acute ankle fracture surgery under PNB anaesthesia and investigate if rebound pain could pose a clinical problem. Methods Exploratory, observational study of adults scheduled for acute primary internal fixation of an ankle fracture under ultrasound-guided popliteal sciatic and saphenous ropivacaine block anaesthesia. Postoperatively, patients regularly registered pain scores while receiving a fixed analgesics regimen and patient controlled morphine on-demand. We analysed morphine consumption and depicted the detailed pain profiles as graphs allowing for visual analysis of pain courses, including rebound pain. Secondly, we compared the area under the curve and peak pain between relevant age-subgroups. Results We included 21 patients aged 20-83. Depicted pain profiles reveal that PNB supplied effective and long lasting postoperative pain control, but cessation of the PNB led to intense rises in pain scores with six out of nine 20-60-year-olds reaching severe pain levels. The rebound was less pronounced in patients >60 years old, but nearly all reached moderate pain levels. Morphine consumption rates were high during the rebound. Conclusions This study thoroughly analyses the post-PNB pain profile and suggests rebound pain is a clinically relevant and problematic issue with the potential to outweigh the PNB benefits, especially for younger patients. The conclusions are tentative, and a randomised study is pending.

Our purpose was to examine whether staging of head and neck squamous cell carcinoma (HNSCC) by upfront 18F-FDG PET/CT (i.e., on the day of biopsy and before the biopsy) discriminates survival better than the traditional imaging strategies based on chest x-ray plus head and neck MRI (CXR/MRI) or chest CT plus head and neck MRI (CCT/MRI). Methods: We performed a masked prospective cohort study based on paired data. Consecutive patients with histologically verified primary HNSCC were recruited from Odense University Hospital from September 2013 to March 2016. All patients underwent CXR/MRI, CCT/ MRI, and PET/CT on the same day. Tumors were categorized as localized (stages I and II), locally advanced (stages III and IVB), or metastatic (stage IVC). Discriminative ability for each imaging modality with respect to HNSCC staging were compared using Kaplan–Meier analysis, Cox proportional hazards regression with the Harrell C-index, and net reclassification improvement. Results: In total, 307 patients with histologically verified HNSCC were included. Use of PET/CT significantly altered the stratification of tumor stage when compared with either CXR/MRI or CCT/MRI (x 2, P, 0.001 for both). Cancer stages based on PET/CT, but not CXR/MRI or CCT/MRI, were associated with significant differences in mortality risk on Kaplan–Meier analyses (P # 0.002 for all PET/CT-based comparisons). Furthermore, overall discriminative ability was significantly greater for PET/ CT (C-index, 0.712) than for CXR/MRI (C-index, 0.675; P 5 0.04) or CCT/MRI (C-index, 0.657; P 5 0.02). Finally, PET/CT was significantly associated with a positive net reclassification improvement when compared with CXR/MRI (0.184, P 5 0.03) but not CCT/MRI (0.094%, P 5 0.31). Conclusion: Tumor stages determined by PET/CT were associated with more distinct prognostic properties in terms of survival than those determined by standard imaging strategies.

We examined variations within situational couple violence among 23 divorcing mothers and compared them with mothers with coercive controlling violence and no violence/no control. Situational couple violence had great variability in frequency and severity of violence, fear, harassment, and protective strategies. In some cases, situational couple violence was frequent and severe and resembled coercive controlling violence in its consequences. The dynamics of fear and harassment in situational couple violence and in the divorce process in general warrant attention. Finally, mothers reported mental health symptoms that did not differ by group, which is likely due to the stresses of divorce.

Chinese hamster ovary (CHO) cells are the preferred production host for therapeutic monoclonal antibodies (mAb) due to their ability to perform post-translational modifications and their successful approval history. The completion of the genome sequence for CHO cells has reignited interest in using quantitative proteomics to identify markers of good production lines. Here we applied two different proteomic techniques, iTRAQ and SWATH, for the identification of expression differences between a high- and low-antibody-producing CHO cell lines derived from the same transfection. More than 2000 proteins were quantified with 70 of them classified as differentially expressed in both techniques. Two biological processes were identified as differentially regulated by both methods: up-regulation of glutathione biosynthesis and down-regulation of DNA replication. Metabolomic analysis confirmed that the high producing cell line displayed higher intracellular levels of glutathione. SWATH further identified up-regulation of actin filament processes and intracellular transport and down regulation of several growth-related processes. These processes may be important for conferring high mAb production and as such are promising candidates for targeted engineering of high-expression cell lines.

Background To evaluate whether clinical, radiographic or MRI findings are associated with long term risk for total knee arthroplasty (TKA) in persons with knee osteoarthritis. Methods We performed a follow-up analysis of 100 persons with knee osteoarthritis who participated in a clinical trial between 2000 and 2002. Clinical data as well as radiography and MRI of the inclusion knee were obtained in all participants. Data on TKA procedures were extracted from The Danish National Patient Register. Clinical, radiographic and MRI findings were analyzed for associations with subsequent TKA. Results During a mean follow-up period of 15 years, 66% received a TKA in the included knee (target knee); 37% also received a TKA in the other knee. The degree of joint space narrowing was highly associated with subsequent TKA (adjusted odds ratio (OR) 5.0 (95% confidence interval (95% CI) 2.6 – 9.9)) as was a radiological sum score comprising joint space narrowing, osteophytes, subchondral sclerosis and cysts (adjusted OR 1.7 (95% CI 1.3 – 2.1)). MRI detected bone marrow lesions, synovitis and effusion were similarly associated with subsequent TKA with an adjusted OR of 2.3 (95% CI 1.3 – 4.0), 2.8 (95% CI 1.5 – 5.2) and 1.9 (95% CI 1.2 – 3.1), respectively. Increased body mass index (BMI) was not associated with subsequent TKA in the target knee but was associated with TKA in the other knee (OR 2.3 (95% CI 1.2 – 4.3). Conclusions Radiographic findings including joint space narrowing and MRI detected bone marrow lesions, synovitis and effusion were all significantly associated with the long term risk of TKA in persons with knee osteoarthritis. Electronic supplementary material The online version of this article (10.1186/s12891-017-1871-z) contains supplementary material, which is available to authorized users.

Anthelmintic resistance in equine cyathostomins has been described worldwide, with resistance to the benzimidazole class being particularly widespread. The status of anthelmintic efficacy in Cuba has been virtually unknown due to the lack of equine labelled products. One recent report documented suboptimal efficacy levels of extra-label albendazole products against cyathostomins, but it remains unknown to which extent benzimidazole resistance exists in the population. The aim of the present study was to evaluate the anthelmintic efficacy of two benzimidazole products labelled for equines, fenbendazole and oxibendazole. A fecal egg count reduction test (FECRT) was carried out on 132 horses aged 4 months to 18 years in 14 herds, belonging to six provinces. Ten herds exhibited signs of resistance to at least one of the benzimidazoles (mean FECRT90%). Overall, oxibendazole exhibited higher efficacy than fenbendazole (p = 0.0062), and higher efficacy levels were found in horses never dewormed before compared to those treated within 3-12 months prior to the study (p = 0.0015). Pre-treatment larval cultures revealed the presence of large strongyles and cyathostomin larvae in all herds, while only cyathostomin larvae were detected post treatment. The present work is the first report of anthelmintic resistance in equine cyathostomins in Cuba, and suggests pre-selection for resistant strains by extra-label use of albendazole on the studied farms.

Congenital or juvenile cataract is a disease condition in which opacification of the lenses is present at birth or manifests early in life. It has been attributed to different monogenic factors with a high degree of heterogeneity and is often studied using mouse models. A spontaneous mutation was identified in a mouse line selected for heat loss that influenced lens formation and resulted in juvenile cataracts in mice homozygous for the recessive allele. Genetic dissection of this selection line by combining high-density genotypes and homozygosity mapping uncovered a 906 kb fragment on MMU7 encompassing 21 SNPs split into two groups of consecutive, homozygous segments specific to the cataract phenotype. Haplotype analysis revealed a 197.5 kb segment unique to cataract-affected mice that included a single known transcript consisting of the first 14 exons of Sipa1l3. In this region, we discovered a deletion of 1114 bp at the mRNA level, spanning four coding exons, predicted to produce a truncated Sipa1l3 protein lacking a portion of a Rap-GAP domain and two other potentially vital domains. At the genome level, the deletion consisted of 16,733 bp. Genotyping across different samples confirmed that only affected mice were homozygous for the deletion and normal mice were either heterozygous or homozygous for the wild-type allele. Further studies will be required to determine the impact of the truncated Sipa1l3 domains on eye development.