Comparison of the collagen haemostat Sangustop(R) versus a carrier-bound fibrin sealant during liver resection; ESSCALIVER-study

Background: Haemostasis in liver surgery remains a challenge despite improved resection techniques. Oozing from blood vessels too small to be ligated necessitate a treatment with haemostats in order to prevent complications attributed to bleeding. There is good evidence from randomised trials for the efficacy of fibrin sealants, on their own or in combination with a carrier material. A new haemostatic device is Sangustop(R). It is a collagen based material without any coagulation factors. Pre-clinical data for Sangustop(R) showed superior haemostatic effect. This present study aims to show that in the clinical situation Sangustop(R) is not inferior to a carrier-bound fibrin sealant (Tachosil(R)) as a haemostatic treatment in hepatic resection. Methods: This is a multi-centre, patient-blinded, intra-operatively randomised controlled trial. A total of 126 patients planned for an elective liver resection will be enrolled in eight surgical centres. The primary objective of this study is to show the non-inferiority of Sangustop(R) versus a carrier-bound fibrin sealant (Tachosil(R)) in achieving haemostasis after hepatic resection. The surgical intervention is standardised with regard to devices and techniques used for resection and primary haemostasis. Patients will be followed-up for three months for complications and adverse events. Discussion: This randomised controlled trial (ESSCALIVER) aims to compare the new collagen haemostat Sangustop(R) with a carrier-bound fibrin sealant which can be seen as a "gold standard" in hepatic and other visceral organ surgery. If non-inferiority is shown other criteria than the haemostatic efficacy (e.g. costs, adverse events rate) may be considered for the choice of the most appropriate treatment. Trial Registration: NCT0091861

Further investigation of confirmed urinary tract infection (UTI) in children under five years: a systematic review.

Background: Further investigation of confirmed UTI in children aims to prevent renal scarring and future complications. Methods: We conducted a systematic review to determine the most effective approach to the further investigation of confirmed urinary tract infection (UTI) in children under five years of age. Results: 73 studies were included. Many studies had methodological limitations or were poorly reported. Effectiveness of further investigations: One study found that routine imaging did not lead to a reduction in recurrent UTIs or renal scarring. Diagnostic accuracy: The studies do not support the use of less invasive tests such as ultrasound as an alternative to renal scintigraphy, either to rule out infection of the upper urinary tract (LR- = 0.57, 95%CI: 0.47, 0.68) and thus to exclude patients from further investigation or to detect renal scarring (LR+ = 3.5, 95% CI: 2.5, 4.8). None of the tests investigated can accurately predict the development of renal scarring. The available evidence supports the consideration of contrast-enhanced ultrasound techniques for detecting vesico-ureteric reflux (VUR), as an alternative to micturating cystourethrography (MCUG) (LR+ = 14.1, 95% CI: 9.5, 20.8; LR- = 0.20, 95%CI: 0.13, 0.29); these techniques have the advantage of not requiring exposure to ionising radiation. Conclusion: There is no evidence to support the clinical effectiveness of routine investigation of children with confirmed UTI. Primary research on the effectiveness, in terms of improved patient outcome, of testing at all stages in the investigation of confirmed urinary tract infection is urgently required

Mutations in DSTYK and dominant urinary tract malformations.

ABSTRACT Introduction Congenital abnormalities of the kidney of the urinary tract are the most common cause of pediatric kidney failure. These disorders are highly heterogeneous, and their etiology is poorly understood. Methods We performed genome-wide linkage analysis and whole-exome sequencing in a family with autosomal dominant congenital abnormalities of the kidney of the urinary tract (7 affected family members). We also performed sequence analysis in 311 unrelated patients, as well as histologic and functional studies. Results Linkage analysis identified five regions of the genome that were shared among all affected family members. Exome sequencing identified a single rare deleterious variant within these linkage intervals, a heterozygous splice-site mutation in dual serine/threonine and tyrosine protein kinase (DSTYK). This variant, which resulted in aberrant gene product splicing, was present in all affected family members. Additional independent DSTYK mutations, including nonsense and splice-site mutations, were detected among 7/311 unrelated patients. DSTYK is highly expressed in the maturing epithelia of all major organs, localizing to cell membranes. Knockdown in zebrafish resulted in multi-organ developmental defects, resembling loss of fibroblast growth factor (FGF) signaling. Consistent with this finding, DSTYK colocalizes with FGF receptors in the ureteric bud and metanephric mesenchyme. Finally, DSTYK knockdown in human embryonic kidney cells inhibited FGF-stimulated ERK-phosphorylation, the principal signal downstream of receptor tyrosine kinases. Conclusions We detected DSTYK mutations in 2.2% of patients with congenital abnormalities of the kidney and urinary tract whom we studied, suggesting that DSTYK is a major determinant of human urinary tract development, downstream of FGF signaling

Analysis of Mitochondrial DNA Sequence Data Demonstrates That Monophyly of \u3ci\u3eMyotis occultus\u3c/i\u3e Is Complicated by Greater Sampling of \u3ci\u3eMyotis lucifugus\u3c/i\u3e

Abstract The validity of Myotis occultus as a species unique from Myotis lucifugus has been a source of debate. Most recently, many authorities treat M. occultus as a distinct species, at least in part because a previous study showed that M. occultus and M. l. carissima (the subspecies that occurs in closest geographic proximity to M. occultus) form separate monophyletic clades based on sequences of two mitochondrial genes (cytochrome-b [cytb] and cytochrome oxidase subunit II [COII]). We re-evaluated the phylogenetic relationship between M. occultus and M. lucifugus based on mitochondrial sequences using an expanded dataset of cytb and COII sequences that originated from more genetically diverse specimens of M. lucifugus collected across a broader geographic area. Based on a phylogenetic analysis, we found that M. occultus sublineages embedded within a well-supported clade that included some specimens of M. lucifugus. These results indicate that the previous genetic analysis demonstrating that M. occultus and M. lucifugus form distinct monophyletic groups is unsupported by our larger dataset. Future research will likely need to focus on genetic work involving whole-genome sequencing of nuclear DNA to better resolve the true taxonomic relationship between M. occultus and M. lucifugus. Resumen La valides de Myotis occultus como una especie distinta a Myotis lucifugus ha sido fuente de debate. Recientemente, muchas autoridades han considerado M. occultus como una especie diferente, en parte porque un estudio anterior mostró que M. occultus y M. l. carissima (la subespecie con la mayor proximidad geográfica a M. occultus) forman clados monofiléticos separados basados en secuencias de dos genes mitocondriales (el citocromo-b [cytb] y la subunidad II de citocromo oxidasa [COII]). Nosotros hemos reevaluado la relación filogenética entre M. occultus y M. lucifugus usando una ampliada colección de datos que contiene secuencias de los genes mitocondriales cytb y COII de especímenes de M. lucifugus genéticamente más diversos que fueron muestreados en un área geográfica más extensa. Nuestro análisis filogenético muestra que los sublinajes de M. occultus están incrustados dentro de un clado bien respaldado que incluye algunos especímenes de M. lucifugus. Estos resultados indican que el análisis genético anterior que demostró que M. occultus y M. lucifugus forman grupos monofiléticos distintos no está respaldado por nuestra más amplia colección de datos. Es probable que para resolver mejor la verdadera relación taxonómica entre M. occultus y M. lucifugus sea necesario el uso de secuenciación del genoma completo del ADN nuclear

How does study quality affect the results of a diagnostic meta-analysis?

Background: The use of systematic literature review to inform evidence based practice in diagnostics is rapidly expanding. Although the primary diagnostic literature is extensive, studies are often of low methodological quality or poorly reported. There has been no rigorously evaluated, evidence based tool to assess the methodological quality of diagnostic studies. The primary objective of this study was to determine the extent to which variations in the quality of primary studies impact the results of a diagnostic meta-analysis and whether this differs with diagnostic test type. A secondary objective was to contribute to the evaluation of QUADAS, an evidence-based tool for the assessment of quality in diagnostic accuracy studies. Methods: This study was conducted as part of large systematic review of tests used in the diagnosis and further investigation of urinary tract infection (UTI) in children. All studies included in this review were assessed using QUADAS, an evidence-based tool for the assessment of quality in systematic reviews of diagnostic accuracy studies. The impact of individual components of QUADAS on a summary measure of diagnostic accuracy was investigated using regression analysis. The review divided the diagnosis and further investigation of UTI into the following three clinical stages: diagnosis of UTI, localisation of infection, and further investigation of the UTI. Each stage used different types of diagnostic test, which were considered to involve different quality concerns. Results: Many of the studies included in our review were poorly reported. The proportion of QUADAS items fulfilled was similar for studies in different sections of the review. However, as might be expected, the individual items fulfilled differed between the three clinical stages. Regression analysis found that different items showed a strong association with test performance for the different tests evaluated. These differences were observed both within and between the three clinical stages assessed by the review. The results of regression analyses were also affected by whether or not a weighting (by sample size) was applied. Our analysis was severely limited by the completeness of reporting and the differences between the index tests evaluated and the reference standards used to confirm diagnoses in the primary studies. Few tests were evaluated by sufficient studies to allow meaningful use of meta-analytic pooling and investigation of heterogeneity. This meant that further analysis to investigate heterogeneity could only be undertaken using a subset of studies, and that the findings are open to various interpretations. Conclusion: Further work is needed to investigate the influence of methodological quality on the results of diagnostic meta-analyses. Large data sets of well-reported primary studies are needed to address this question. Without significant improvements in the completeness of reporting of primary studies, progress in this area will be limited

Cerebellum and neurodegenerative diseases: Beyond conventional magnetic resonance imaging

The cerebellum plays a key role in movement control and in cognition and cerebellar involvement is described in several neurodegenerative diseases. While conventional magnetic resonance imaging (MRI) is widely used for brain and cerebellar morphologic evaluation, advanced MRI techniques allow the investigation of cerebellar microstructural and functional characteristics. Volumetry, voxel-based morphometry, diffusion MRI based fiber tractography, resting state and task related functional MRI, perfusion, and proton MR spectroscopy are among the most common techniques applied to the study of cerebellum. In the present review, after providing a brief description of each technique's advantages and limitations, we focus on their application to the study of cerebellar injury in major neurodegenerative diseases, such as multiple sclerosis, Parkinson's and Alzheimer's disease and hereditary ataxia. A brief introduction to the pathological substrate of cerebellar involvement is provided for each disease, followed by the review of MRI studies exploring structural and functional cerebellar abnormalities and by a discussion of the clinical relevance of MRI measures of cerebellar damage in terms of both clinical status and cognitive performance

Increasing capacity for the treatment of common musculoskeletal problems: A non-inferiority RCT and economic analysis of corticosteroid injection for shoulder pain comparing a physiotherapist and orthopaedic surgeon

Background Role substitution is a strategy employed to assist health services manage the growing demand for musculoskeletal care. Corticosteroid injection is a common treatment in this population but the efficacy of its prescription and delivery by physiotherapists has not been established against orthopaedic standards. This paper investigates whether corticosteroid injection given by a physiotherapist for shoulder pain is as clinically and cost effective as that from an orthopaedic surgeon. Methods A double blind non-inferiority randomized controlled trial was conducted in an Australian public hospital orthopaedic outpatient service, from January 2013 to June 2014. Adults with a General Practitioner referral to Orthopaedics for shoulder pain received subacromial corticosteroid and local anaesthetic injection prescribed and delivered independently by a physiotherapist or a consultant orthopaedic surgeon. The main outcome measure was total Shoulder Pain and Disability Index (SPADI) score at baseline, six and 12 weeks, applying a non-inferiority margin of 15 points. Secondary outcomes tested for superiority included pain, shoulder movement, perceived improvement, adverse events, satisfaction, quality of life and costs. Results 278 participants were independently assessed by the physiotherapist and the orthopaedic surgeon, with 64 randomised (physiotherapist 33, orthopaedic surgeon 31). There were no significant differences in baseline characteristics between groups. Non-inferiority of injection by the physiotherapist was declared from total SPADI scores at 6 and 12 weeks (upper limit of the 95% one-sided confidence interval 13.34 and 7.17 at 6 and 12 weeks, respectively). There were no statistically significant differences between groups on any outcome measures at 6 or 12 weeks. From the perspective of the health funder, the physiotherapist was less expensive. Conclusions Corticosteroid injection for shoulder pain, provided by a suitably qualified physiotherapist is at least as clinically effective, and less expensive, compared with similar care delivered by an orthopaedic surgeon. Policy makers and service providers should consider implementing this model of care

Picky eaters are rare: DNA-based blood meal analysis of \u3ci\u3eCulicoides\u3c/i\u3e (Diptera: Ceratopogonidae) species from the United States

Background: Biting midges in the genus Culicoides (Diptera; Ceratopogonidae) have been implicated in the transmission of a number of parasites and highly pathogenic viruses. In North America, the complete transmission cycles of many of these pathogens need further elucidation. One way to increase our knowledge about the evolution and ecology of Culicoides species and the pathogens they transmit is to document the diversity of vertebrate hosts that Culicoides feed upon. Our objective was to identify the diversity of Culicoides hosts in the United States. Results: We sequenced two vertebrate mitochondrial genes (cytochrome c oxidase subunit 1 and cytochrome b) from blood-engorged Culicoides to identify Culicoides species and their blood meals. We detected the mitochondrial DNA of 12 host species from seven different Culicoides species from three states. The majority of the identified blood meals were from the C. variipennis species complex in California. The hosts included both mammals and birds. We documented new host records for some of the Culicoides species collected. The majority of the mammalian hosts were large ungulate species but we also detected a lagomorph and a carnivore. The bird species that were detected included house finch and emu; the latter is evidence that the species in the C. variipennis species complex are not strictly mammalophilic. Conclusions: These results demonstrate that Culicoides will feed on multiple classes of vertebrates and may be more opportunistic in regards to host choice than previously thought. This knowledge can help with identification of susceptible host species, pathogen reservoirs, and new vector species which, in turn, will improve disease outbreak risk assessments

Is medical device regulatory compliance growing as fast as extended reality to avoid misunderstandings in the future?

Purpose: European Extended Reality (XR) industry is expected to significantly increase by 2025 with an extreme impact on the Healthcare scenario. Considering that the transition period for the Medical Device Regulation 2017/745 (MDR 2017/745) will end in May 2024, purpose of this study is to assess whether the Medical Device Regulatory Compliance is ready to cope with the inclusion of XR and its possible social and economic impact in the world of medical device software (MDSW). Methods: XR publications patterns were evaluated since MDR 2017/745 release on different databases. European normative about MDSW are consulted, followed by the European Database of Medical Devices (EUDAMED). Results: The number of publications on XR have increased since 2017 and healthcare is the third highest-impacted subject area. Specific classes for software have been introduces in the European Nomenclature of Medical Devices (EMDN) and some XR applications have already been registered in EUDAMED classified as MDSW. Conclusions: XR will become intrinsic in everyday medical protocol and guidelines. The establishment of the IEEE Virtual Reality and Augmented Reality Working Group and the statement of VR for remoting surgery as a MDSW in MDCG 2019-11 are demonstration of the necessity of MD regulatory compliance in being able to keep up with the upcoming XR technologies. The Authors agree that the competent authorities should consider intervening in the European Regulative Compliance to cope with the revolution of Phygital in Healthcare and to regulate procedures involving the use of XR in medicine preventing future misunderstanding and criticalities especially for high risk situations

Can demographic histories explain long-term isolation and recent pulses of asymmetric gene flow between highly divergent grey fox lineages?

Secondary contact zones between deeply divergent, yet interfertile, lineages provide windows into the speciation process. North American grey foxes (Urocyon cinereoargenteus) are divided into western and eastern lineages that diverged approximately 1 million years ago. These ancient lineages currently hybridize in a relatively narrow zone of contact in the southern Great Plains, a pattern more commonly observed in smaller-bodied taxa, which suggests relatively recent contact after a long period of allopatry. Based on local ancestry inference with whole-genome sequencing (n = 43), we identified two distinct Holocene pulses of admixture. The older pulse (500–3500 YBP) reflected unidirectional gene flow from east to west, whereas the more recent pulse (70–200 YBP) of admixture was bi-directional. Augmented with genotyping-by-sequencing data from 216 additional foxes, demographic analyses indicated that the eastern lineage declined precipitously after divergence, remaining small throughout most of the late Pleistocene, and expanding only during the Holocene. Genetic diversity in the eastern lineage was highest in the southeast and lowest near the contact zone, consistent with a westward expansion. Concordantly, distribution modelling indicated that during their isolation, the most suitable habitat occurred far east of today\u27s contact zone or west of the Great Plains. Thus, long-term isolation was likely caused by the small, distant location of the eastern refugium, with recent contact reflecting a large increase in suitable habitat and corresponding demographic expansion from the eastern refugium. Ultimately, long-term isolation in grey foxes may reflect their specialized bio-climatic niche. This system presents an opportunity for future investigation of potential pre- and post-zygotic isolating mechanisms