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Research question Do cumulative live birth rates (CLBR) differ between polycystic ovary syndrome (PCOS) phenotypes when a freeze-all strategy is used to prevent ovarian hyperstimulation syndrome (OHSS) after ovarian stimulation (OS)? Design This is a single-centre, retrospective cohort study including 422 women with PCOS as defined by Rotterdam criteria or with PCO-like ovarian morphology-only (PCOM) in whom, between January 2015 and December 2019, a freeze-all strategy was applied after GnRH agonist triggering in the context of hyper-response defined as ≥18 follicles of ≥11 mm in their first or second IVF/ICSI cycle in a tertiary referral hospital. The primary outcome was CLBR resulting from the transfer of all cryopreserved embryos from the same IVF/ICSI cycle. Analysis was performed by multivariate logistic regression analysis adjusting for confounders. Results In total, 91/422 (21.6%) patients had PCOS phenotype A (hyperandrogenism + ovulation disorder + PCOM = HOP), 33/422 (7.8%) had phenotype C (hyperandrogenism + PCOM = HP), 161/422 (38.2%) had phenotype D (ovulation disorder + PCOM = OP) and 137/422 (32.5%) had PCOM. Unadjusted CLBR was similar among the groups (69.2%, 69.7%, 79.5% and 67.9%, respectively; p= 0.11). The multivariate logistic regression model adjusting for age, BMI, number of oocytes, fertilization rate and embryo stage at vitrification confirmed that the PCOS/PCOM phenotype did not have any impact on CLBR [OR 0.72, CI 0.24-2.14 (phenotype C); OR 1.55, CI 0.71-3.36 (phenotype D); OR 0.84, CI 0.39-1.83 (PCOM); p= 0.2, with phenotype A as reference]. Conclusions In subfertile women with PCOS eligible for ART, hyper-response after OS confers excellent cumulative live birth rates of ∼70%, irrespective of the phenotype, when a freeze-all strategy is used. This contrasts with the unfavourable clinical outcomes that have previously been observed in hyperandrogenic PCOS women who underwent mild OS targeting normal ovarian response and fresh embryo transfer. The data should however be interpreted with caution as the retrospective nature of the study holds the possibility of unmeasured confounding factors. The results cannot be generalized to all ART cycles in women with polycystic ovaries as they pertain to those cycles in which hyper-response is observed after OS.

Two brothers, completely asymptomatic until their first year of life, started to complain from gingival hypertrophy, progressive development of painful soft tissue masses on the fingers and toes, on the face and on the scalp. There were no neurological symptoms or mental delay for both brothers.

BACKGROUND: Magnetic resonance imaging (MRI) has become important in the diagnostic work-up of neurodegenerative diseases. icobrain dm, a CE-labeled and FDA-cleared automated brain volumetry software, has shown potential in differentiating cognitively healthy controls (HC) from Alzheimer's disease (AD) dementia (ADD) patients in selected research cohorts. OBJECTIVE: This study examines the diagnostic value of icobrain dm for AD in routine clinical practice, including a comparison to the widely used FreeSurfer software, and investigates if combined brain volumes contribute to establish an AD diagnosis. METHODS: The study population included HC (n = 90), subjective cognitive decline (SCD, n = 93), mild cognitive impairment (MCI, n = 357), and ADD (n = 280) patients. Through automated volumetric analyses of global, cortical, and subcortical brain structures on clinical brain MRI T1w (n = 820) images from a retrospective, multi-center study (REMEMBER), icobrain dm's (v.4.4.0) ability to differentiate disease stages via ROC analysis was compared to FreeSurfer (v.6.0). Stepwise backward regression models were constructed to investigate if combined brain volumes can differentiate between AD stages. RESULTS: icobrain dm outperformed FreeSurfer in processing time (15-30 min versus 9-32 h), robustness (0 versus 67 failures), and diagnostic performance for whole brain, hippocampal volumes, and lateral ventricles between HC and ADD patients. Stepwise backward regression showed improved diagnostic accuracy for pairwise group differentiations, with highest performance obtained for distinguishing HC from ADD (AUC = 0.914; Specificity 83.0%; Sensitivity 86.3%). CONCLUSION: Automated volumetry has a diagnostic value for ADD diagnosis in routine clinical practice. Our findings indicate that combined brain volumes improve diagnostic accuracy, using real-world imaging data from a clinical setting. ispartof: JOURNAL OF ALZHEIMERS DISEASE vol:83 issue:2 pages:623-639 ispartof: location:Netherlands status: published

Summary Background Two main trends are described for the treatment of diastasis recti: plication versus midline mesh reinforcement. Indications for these procedures have not been clearly described. This study reviewed the outcomes in the treatment of rectus diastasis with plication versus mesh by the assessment of durability, complications, and patient-reported outcomes. Materials and methods A systematic review of literature on the treatment of diastasis recti was performed searching through PubMed, Embase, Web of Science, and Cochrane databases. This resulted in 53 eligible articles and predefined inclusion criteria led to the selection of 24 articles. Primary outcomes included recurrence and perioperative complications and secondary outcomes were defined as patient satisfaction, chronic pain, and quality of life. Results A total of 931 patients were surgically treated for rectus divarication (age range: 18 - 70 years). The most frequently noted comorbidity was obesity and 10.6 percent were smokers. Recurrence was reported in 5 percent of the patients. The most frequent complication was seroma (7 percent), followed by abdominal hypoesthesia (6 percent), and surgical site infection (2 percent). Chronic pain was reported in 4 percent of the patients. Satisfaction was assessed subjectively in the majority of patients and was generally rated as high. Follow-up period ranged from 3 weeks to 20 years. Conclusions Durability, safety, and high patient satisfaction support surgical correction of rectus diastasis and could not favor a treatment method. Inter-rectus distance could not be identified as the indicator for technique, which emphasizes that other factors might add to the entity of abdominal wall protrusion more than previously thought.

Contains fulltext : 234372.pdf (Publisher’s version ) (Open Access) We examined the response to a phonics through spelling intervention in 52 children with dyslexia by analyzing their phonological, morphological, and orthographical spelling errors both before and after the intervention whereas their spelling errors before the intervention were compared with those of 105 typically developing spellers. A possible compensatory role of semantics on the intervention effects was also investigated. Results showed that before the intervention, children with dyslexia and the typically developing children both made most morphological errors, followed by orthographic and phonological errors. Within each category, children with dyslexia made more errors than the typically developing children, with differences being largest for phonological errors. Children with dyslexia with better developed semantic representations turned out to make less phonological, morphological, and orthographic errors compared with children with dyslexia with less developed semantic representations. The intervention for children with dyslexia led to a reduction of all error types, mostly of the orthographic errors. In addition, semantics was related to the decline in phonological, morphological, and orthographic spelling errors. This study implicates that semantic stimulation could benefit the spelling development of children at risk for or with dyslexia. 20 p.

Endothelial cells (ECs) secrete different paracrine signals that modulate the function of adjacent cells; two examples of these paracrine signals are nitric oxide (NO) and neuregulin-1 (NRG1), a cardioprotective growth factor. Currently, it is undetermined whether one paracrine factor can compensate for the loss of another. Herein, we hypothesized that NRG1 can compensate for endothelial NO synthase (eNOS) deficiency. We characterized eNOS null and wild-type (WT) mice by cardiac ultrasound and histology and we determined circulating NRG1 levels. In a separate experiment, eight groups of mice were divided into four groups of eNOS null mice and WT mice; half of the mice received angiotensin II (ANG II) to induce a more severe phenotype. Mice were randomized to daily injections with NRG1 or vehicle for 28 days. eNOS deficiency increased NRG1 plasma levels, indicating that ECs increase their NRG1 expression when NO production is deleted. eNOS deficiency also increased blood pressure, lowered heart rate, induced cardiac fibrosis, and affected diastolic function. In eNOS null mice, ANG II administration not only increased cardiac fibrosis but also induced cardiac hypertrophy and renal fibrosis. NRG1 administration prevented cardiac and renal hypertrophy and fibrosis caused by ANG II infusion and eNOS deficiency. Moreover, Nrg1 expression in the myocardium is shown to be regulated by miR-134. This study indicates that administration of endothelium-derived NRG1 can compensate for eNOS deficiency in the heart and kidneys. NEW & NOTEWORTHY ECs compensate for eNOS deficiency by increasing the secretion of NRG1. NRG1 administration prevents cardiac and renal hypertrophy and fibrosis caused by ANG II infusion and eNOS deficiency. NRG1 expression is regulated by miR-134.

Background and aims: Atherogenesis involves a complex interaction between immune cells and lipids, processes greatly influenced by the vascular smooth muscle cell (VSMC) phenotype. The DNA glycosylase NEIL3 has previously been shown to have a role in atherogenesis, though whether this is due to its ability to repair DNA damage or to other non-canonical functions is not yet clear. Hereby, we investigate the role of NEIL3 in atherogenesis, specifically in VSMC phenotypic modulation, which is critical in plaque formation and stability.Methods: Chow diet-fed atherosclerosis-prone Apoe(-/-) mice deficient in Neil3, and NEIL3-abrogated human primary aortic VSMCs were characterized by qPCR, and immunohistochemical and enzymatic-based assays; moreover, single-cell RNA sequencing, mRNA sequencing, and proteomics were used to map the molecular effects of Neil3/NEIL3 deficiency in the aortic VSMC phenotype. Furthermore, BrdU-based proliferation assays and Western blot were performed to elucidate the involvement of the Akt signaling pathway in the transdifferentiation of aortic VSMCs lacking Neil3/NEIL3.Results: We show that Neil3 deficiency increases atherosclerotic plaque development without affecting systemic lipids. This observation was associated with a shift in VSMC phenotype towards a proliferating, lipid-accumulating and secretory macrophage-like cell phenotype, without changes in DNA damage. VSMC transdifferentiation in Neil3-deficient mice encompassed increased activity of the Akt signaling pathway, supported by cell experiments showing Akt-dependent proliferation in NEIL3-abrogated human primary aortic VSMCs.Conclusions: Our findings show that Neil3 deficiency promotes atherosclerosis development through non-canonical mechanisms affecting VSMC phenotype involving activation of the Akt signaling pathway.

PURPOSE: To report the first successful application of in vitro maturation (IVM) of oocytes resulting in live births in two anovulatory women who had suffered oophorectomy following ovarian torsion after stimulation with gonadotropins. METHODS: Data abstraction was performed from medical records of two subfertile women with excessive functional ovarian reserve. Both women had previously received gonadotropins for ovulation induction or ovarian stimulation, resulting in ovarian torsion. They were offered IVM of oocytes retrieved from antral follicles after mild ovarian stimulation, insemination of mature oocytes using ICSI, and embryo transfer. Outcome measures were the incidence of complications and live birth after fertility treatment. RESULTS: Transvaginal retrieval of cumulus-oocyte complexes from a unique ovary was conducted. One patient had a singleton live birth after vitrified-warmed embryo transfer in the second IVM cycle. The other patient had a singleton live birth after transfer of a fresh blastocyst in her first IVM cycle. CONCLUSIONS: Although approaches have been developed to prevent ovarian hyperstimulation syndrome (OHSS) and to increase the safety profile of fertility treatment in predicted high responders, women with an excessive functional ovarian reserve may have a non-negligible risk of ovarian torsion. For these patients, IVM should be considered as a safer alternative approach.

The changes experienced by the arterial system due to the aging process have been extensively studied but are incompletely understood. Within-subject patterns of changes in regards to input impedance and wave reflection parameters have not been assessed. The Asklepios study is a longitudinal population study including healthy (at onset) middle-aged subjects, with 974 males and 1052 females undergoing 2 rounds of measurements of applanation tonometry and ultrasound, 10.15±1.40 years apart. Carotid-femoral pulse wave velocity, aortic input impedance, and wave reflection parameters were assessed, and linear mixed-effects models were used to evaluate their longitudinal trajectories and determinants. Overall, the effective 10-year increase in pulse wave velocity was less than expected from first round cross-sectional data, and pulse wave velocity was found to accelerate more in women than in men. Interestingly, the increase in pulse wave velocity was not paralleled by a decrease in arterial volume compliance, particularly in younger males. Aortic root characteristic impedance decreased with age in younger subjects while it increased for the older subjects in the study. These changes suggest that aortic dilation and elongation may play an important role determining the longitudinal age-related changes in impedance parameters in middle-age. Wave reflection decreased with aging, whereas resistance increased in women and decreased in men. We conclude that the effective impact of aging on arterial system properties, in a middle-aged population, is not well reflected by cross-sectional studies. Future studies should assess the interaction between geometric remodeling and wall stiffening as determinants of pulsatile hemodynamics.

During the first half of the 20th century, extraordinary high jumping performances of East-African athletes were observed. These athletes used a specific native jumping style called Gusimbuka Urukiramende. Eye-witnesses believed that these performances could have been world-records and that these athletes could have competed at the Olympics. However, these athletes never participated in international competitions and there is no other proof to support these performance claims. We have analysed historical photos and cine sequences of these jumps, documented the movement analysis of this technique, quantified performance and compared it to contemporaneous elite performances. Our analyses demonstrate that Gusimbuka Urukiramende athletes did not jump as high as the world record. Nevertheless, even though they used a suboptimal jump technique (because they had to lift their bodies higher to cross the bar) they could cross bar heights of 188 cm or 135% body height and as such their performance still was worthy of participation to the Olympics.

High dose methotrexate (HDMTX) acute kidney injury (AKI) results in prolonged hospitalization and treatment delays. Using a pharmacologically-based approach, HDMTX was administered with standard combination therapy to patients with osteosarcoma; nephrotoxicity was assessed. Patients were randomized by cycle to 4 h or 12 h HDMTX (12 g/m2) infusions administered with hydration, alkalization and leucovorin rescue. Urinalysis, AKI biomarkers, and estimated glomerular filtration rate using serum creatinine or cystatin C (GFRCr or GFRcysC) were obtained. Serum and urine methotrexate concentrations [MTX] were measured. Patients (n = 12), median (range) age 12.4 (5.7–19.2) years were enrolled; 73 MTX infusions were analyzed. Median (95% Confidence Interval) serum and urine [MTX] were 1309 (1190, 1400) µM and 16.4 (14.7, 19.4) mM at the end of 4 h infusion and 557 (493, 586) µM and 11.1 (9.9, 21.1) mM at the end of 12 h infusion. Time to serum [MTX] 95%. Reducing peak serum and urine MTX concentration by prolonging the infusion duration did not alter risk of acute kidney injury. GFRcysC was decreased at the end of therapy. Proteinuria and elevations in AKI biomarkers indicate that direct tubular damage contributes to HDMTX nephrotoxicity. NCT01848457.

Atypical sensory processing one of the more ubiquitous symptoms in autism spectrum disorder, the exact nature of these sensory issues remains unclear, with different studies showing either enhanced or deficient sensory processing. Using a well-established continuous free-recall task that assesses visual working memory, the current study provides novel evidence reconciling these apparently discrepant findings by showing both enhanced and impaired sensory processing in the same individuals on distinct aspects of the same task and stimuli. Autistic children exhibited perceptual advantages in both likelihood of recall and recall precision relative to their typically-developed peers. When autistic children did make errors, however, they showed a higher probability of erroneously binding a given colour with the incorrect spatial location. These data indicate that although the initial perceptual representations of sensory inputs were maintained with enhanced fidelity, the subsequent cognitive process of binding multiple features of sensory information into one percept was impaired. These data align with neural-architecture models for feature binding in visual working memory, suggesting that atypical population-level neural noise in the report dimension (colour) and cue dimension (spatial location) may drive both the increase in probability of recall and precision of colour recall as well as the increase in proportion of binding errors, respectively. These changes are likely to impact core symptomatology associated with autism, as perceptual binding and working memory play significant roles in higher-order tasks, such as communication.

Contains fulltext : 226907.pdf (Publisher’s version ) (Open Access) Aim: To explore parents' experiences of parenting a child hospitalised with congenital heart disease (CHD) and undergoing surgery. Methods: Five electronic databases were systematically searched for articles describing the experiences of parents with a child with a CHD. A thematic analysis approach was used to identify the most common themes. Results: A total of 188 articles were identified. Eight studies were included in the review. Four themes emerged, including balancing the parental role, experiencing anticipatory grief, decreasing parental stress using coping strategies, and professional support. Conclusion: Having a child with CHD undergoing heart surgery is a stressful experience due to, among other things, the different situation-related parenting role during the hospital stay and feelings of anticipatory grief. Health care professionals in the PICU have an essential role in supporting parents and understanding the needs that are crucial for the parents in order to provide better support and reduce stress and anxiety. More qualitative research regarding the pathway from the prenatal diagnosis through the early childhood period is warranted. 11 p.

Gait retraining that stimulates impact reduction has resulted in fewer injuries in novice runners (Chan et al., 2018). However, feedback-driven retraining performed at a fixed running speed has bee...

This clinical review paper discusses the pathophysiology of the pulmonary and cardiovascular manifestations of a SARS-CoV-2 infection and the ensuing implications on acute cardiovascular care in patients presenting with a severe COVID-19 syndrome admitted to an intensive acute cardiac care unit. The high prevalence of old age, obesity, diabetes, hypertension, heart failure, and ischaemic heart disease in patients who develop a severe to critical COVID-19 syndrome suggests shared pathophysiological mechanisms. Pre-existing endothelial dysfunction and an impaired innate immune response promote the development by the viral infection of an acute endothelialitis in the pulmonary microcirculation complicated by abnormal vasoconstrictor responses, luminal plugging by inflammatory cells, and intravascular thrombosis. This endothelialitis extends into the systemic circulation what may lead to acute myocardial injury, myocarditis, and thromboembolic complications both in the arterial and venous circulation. Ever since the first case reports from the city of Wuhan in China in December of 2019, coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) continues as a raging pandemic causing significant morbidity and mortality [1]. In this paper we provide a review of the epidemiological characteristics and the pathophysiology of SARS-CoV-2 infection, and formulate the hypothesis that endothelialitis may play a key role in the pathogenesis of the pulmonary and cardiovascular complications of COVID-19.

Purpose This systematic review aimed to establish language and speech markers to support the clinical diagnosis of primary progressive aphasia (PPA) and its clinical phenotypes. Our first objective was to identify behavioral language and speech markers of early-stage PPA. Our second objective was to identify the electrophysiological correlates of the language and speech characteristics in PPA. Method The databases MEDLINE, Web of Science, and Embase were searched for relevant articles. To identify behavioral markers, the initial subjective complaints and the language and speech deficits detected during the initial diagnostic evaluation were summarized for PPA in general and each clinical variant according to the 2011 consensus diagnostic criteria (nonfluent variant [NFV], semantic variant, and logopenic variant [LV]). To identify electrophysiological markers, the studies in which event-related potentials (ERPs) were elicited by a language or speech paradigm in patients with PPA were included. Results In total, 114 relevant studies were identified, including 110 behavioral studies and only four electrophysiological studies. This review suggests that patients with the semantic variant could be accurately differentiated from the NFV and LV in the initial stages based on the consensus criteria. Nonetheless, the early differentiation between the NFV and LV is not straightforward. In the four electrophysiological studies, differences in the latency, amplitude, and topographical distribution of the semantic N400 component were found between patients with PPA and healthy controls. Conclusions To accurately differentiate the NFV from the LV, it could be important to assess the language and speech degeneration by more specific assessments and by more objective diagnostic methods that offer insights into the language-related processes. Electrophysiological markers of PPA were not identified in this review due to the low number of studies that investigated language-related ERPs. More controlled ERP studies in larger patient cohorts are needed to investigate the diagnostic applicability of language-related ERPs in PPA. Supplemental Material https://doi.org/10.23641/asha.12798080

Autism spectrum disorder is a neurodevelopmental disorder that is characterized by impairments in social communication, restricted interests, and repetitive behaviors. Many studies have demonstrated atypical responses to audiovisual sensory inputs, particularly those containing sociolinguistic information. It is currently unclear whether these atypical responses are due to the linguistic nature of the inputs or the social aspect itself. Further, it is unclear how atypical sensory responses to sociocommunicative stimuli intersect with autism symptomatology. The current study addressed these outstanding questions by using pupillometry in mental age-matched children with and without autism (N = 71) to examine physiological responses to dynamic, audiovisual stimuli including social, sociolinguistic, socioemotional, and nonsocial stimuli, as well as to temporally manipulated stimuli. Data revealed group differences in pupillary responses with social stimuli but not nonsocial stimuli and, importantly, showed no variation through the inclusion of linguistic or emotional information. This suggests that atypical sensory responses are driven primarily by the inclusion of social information broadly. Further, individual responses to social stimuli were significantly correlated with a wide range of autism spectrum disorder symptomatology, including social communication, restricted interests and repetitive behaviors, and sensory processing issues. Pupillary responses to social but not nonsocial presentation were also capable of predicting diagnosis with a high level of selectivity, but only with marginal sensitivity. Finally, responses to the temporal manipulation did not yield any group differences, suggesting that while atypical multisensory temporal processing has been well documented in autism at the level of behavior and perception, these issues may be intact at the physiological level. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Contains fulltext : 245171.pdf (Publisher’s version ) (Open Access) Background and purpose - A guideline committee of medical specialists and a physiotherapist was formed on the initiative of the Dutch Orthopedic Association (NOV) to update the guideline Arthroscopy of the Knee: Indications and Treatment 2010. This next guideline was developed between June 2017 and December 2019. In this Part 1 we focus on the meniscus, in Part 2 on all other aspects of knee arthroscopy.Methods - The guideline was developed in accordance with the criteria of the AGREE instrument (AGREE II: Appraisal of Guidelines for Research and Evaluation II) with support of a professional methodologist from the Dutch Knowledge Institute of Medical Specialists. The scientific literature was searched and systematically analyzed. Conclusions and recommendations were formulated according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) method. Recommendations were developed considering the balance of benefits and harms, the type and quality of evidence, the values and preferences of the people involved, and the costs.

Background WAGR syndrome (Wilms tumor, aniridia, genitourinary anomalies, and range of developmental delays) is a rare contiguous gene deletion syndrome with a 45% to 60% risk of developing Wilms tumor (WT). Currently, surveillance and treatment recommendations are based on limited evidence. Methods Clinical characteristics, treatments, and outcomes were analyzed for patients with WAGR and WT/nephroblastomatosis who were identified through International Society of Pediatric Oncology Renal Tumor Study Group (SIOP‐RTSG) registries and the SIOP‐RTSG network (1989‐2019). Events were defined as relapse, metachronous tumors, or death. Results Forty‐three patients were identified. The median age at WT/nephroblastomatosis diagnosis was 22 months (range, 6‐44 months). The overall stage was available for 40 patients, including 15 (37.5%) with bilateral disease and none with metastatic disease. Histology was available for 42 patients; 6 nephroblastomatosis without further WT and 36 WT, including 19 stromal WT (52.8%), 12 mixed WT (33.3%), 1 regressive WT (2.8%) and 2 other/indeterminable WT (5.6%). Blastemal type WT occurred in 2 patients (5.6%) after prolonged treatment for nephroblastomatosis; anaplasia was not reported. Nephrogenic rests were present in 78.9%. Among patients with WT, the 5‐year event‐free survival rate was 84.3% (95% confidence interval, 72.4%‐98.1%), and the overall survival rate was 91.2% (95% confidence interval, 82.1%‐100%). Events (n = 6) did not include relapse, but contralateral tumor development (n = 3) occurred up to 7 years after the initial diagnosis, and 3 deaths were related to hepatotoxicity (n = 2) and obstructive ileus (n = 1). Conclusions Patients with WAGR have a high rate of bilateral disease and no metastatic or anaplastic tumors. Although they can be treated according to existing WT protocols, intensive monitoring of toxicity and surveillance of the remaining kidney(s) are advised. Lay Summary WAGR syndrome (Wilms tumor, aniridia, genitourinary anomalies, and range of developmental delays) is a rare genetic condition with an increased risk of developing Wilms tumor.In this study, 43 patients with WAGR and Wilms tumor (or Wilms tumor precursor lesions/nephroblastomatosis) were identified through the international registry of the International Society of Pediatric Oncology Renal Tumor Study Group (SIOP‐RTSG) and the SIOP‐RTSG network. In many patients (37.5%), both kidneys were affected. Disease spread to other organs (metastases) did not occur.Overall, this study demonstrates that patients with WAGR syndrome and Wilms tumor can be treated according to existing protocols. However, intensive monitoring of treatment complications and surveillance of the remaining kidney(s) are advised., Patients with WAGR syndrome (Wilms tumor, aniridia, genitourinary anomalies, and range of developmental delays) and Wilms tumor/nephroblastomatosis, identified through the International Society of Pediatric Oncology Renal Tumor Study Group registries and network, have a high rate of bilateral disease and no metastatic or anaplastic tumors. Although they can be treated according to existing Wilms tumor protocols, intensive monitoring of toxicity and surveillance of the remaining kidney(s) are advised.

Background The efficacy of a novel inactivated intradermal Lawsonia intracellularis vaccine, Porcilis® Lawsonia ID, was evaluated in two experimental vaccination-challenge studies and under field conditions on a farm with a history of recurrent acute ileitis. In addition, the efficacy of the vaccine was compared to that of a commercially available live attenuated vaccine. The novel inactivated vaccine consists of a freeze-dried antigen fraction that is dissolved just prior to use in either the adjuvant or in Porcilis® PCV ID; an existing intradermal vaccine against porcine Circovirus type 2. In the two experimental vaccination-challenge studies, groups of 25 piglets were vaccinated once at 3 weeks of age or left unvaccinated as challenge control. Vaccines tested were Porcilis® Lawsonia ID as standalone (study 1) or in associated mixed use with Porcilis® PCV ID (study 2) and an orally administered commercially available live vaccine (study 1). The pigs were challenged with virulent L. intracellularis at 4 weeks (study 1) or 21 weeks (study 2) after vaccination. Post-challenge, the pigs were evaluated for clinical signs, average daily weight gain, shedding and macroscopic as well as microscopic immuno-histological ileum lesion scores. In the field study, the mortality and key performance parameters were evaluated over a period of 8 months. Results The results of the two experimental vaccination-challenge studies showed that Porcilis® Lawsonia ID as single vaccine or in associated mixed use with Porcilis® PCV ID, induced statistically significant protection against experimental L. intracellularis infection, 4 weeks or 21 weeks after vaccination. This was demonstrated by lower clinical scores, improved weight gain, reduction of L. intracellularis shedding and reduction of macroscopic as well as microscopic ileum lesion scores when compared to the controls. The protection induced was superior to that of the commercially available live vaccine. In the field study Porcilis® Lawsonia ID was highly efficacious in reducing L. intracellularis associated mortality and improving key production parameters. Conclusion The results support that this new intradermal vaccine is efficacious against L. intracellularis and may be used in associated mixed use with Porcilis® PCV ID.

OBJECTIVES The aim of this study was to investigate the effect of short- versus long-segment aortic stiffness and stenosis on ventriculo-arterial interaction in a porcine model of coarctation repair. METHODS Short–long aortic stiffness was created by transection/suture [coarctation (CoA) suture, n = 6] and stenting (stent, n = 5) of the proximal descending aorta. Short–long aortic stenosis was achieved by wrapping a prosthetic graft around the aorta to 1/3-circumference reduction, over a segment length of 1 cm (CoA suture stenosis, n = 5) and 4.5 cm (stent stenosis, n = 6). After 3 months, aortic pressure-flow haemodynamics, aortic distensibility by intravascular ultrasound and left ventricular performance by pressure–volume loops were compared to a Sham group (n = 5) at baseline and during dobutamine administration. RESULTS The aortic impedance increased with 30.3 (12.6%) and 41.3 (20.9%) (P CONCLUSIONS This animal study on the sequelae of coarctation repair demonstrated that aortic stiffness had little effect on aortic pressure-flow characteristics in the absence of stenosis. However, the negative chronic effect of stenosis on aortic haemodynamics—especially a longer segment—leads to the rapid impairment of ventriculo-arterial interaction, which is accentuated by inotropy. Therefore, therapeutical management needs to focus on improving aortic remodelling after coarctation repair, preferably by minimizing residual stenosis, even at the cost of inducing aortic stiffness.

Despite the wide recognition of larger artery stiffness as a highly clinically relevant and independent prognostic biomarker, it has yet be incorporated into routine clinical practice and to take a more prominent position in clinical guidelines. An important reason may be the plethora of methods and devices claiming to measure arterial stiffness in humans. This brief review provides a concise overview of methods in use, indicating strengths and weaknesses. We classified and graded methods, highly weighing their scrutiny and purity in quantifying arterial stiffness, rather than focusing on their ease of application or the level at which methods have demonstrated their prognostic and diagnostic potential.

Initial reports from the 1960s describing the observations of ultrasound contrast enhancement by tiny gaseous bubbles during echocardiographic examinations prompted the development of the first ultrasound contrast agent in the 1980s. Current commercial contrast agents for echography, such as Definity, Optison, Sonazoid and SonoVue, have proven to be successful in a variety of on- and off-label clinical indications. Whereas contrast-specific technology has seen dramatic progress after the introduction of the first approved agents in the 1990s, successful clinical translation of new developments has been limited during the same period, while understanding of microbubble physical, chemical and biologic behavior has improved substantially. It is expected that for a successful development of future opportunities, such as ultrasound molecular imaging and therapeutic applications using microbubbles, new creative developments in microbubble engineering and production dedicated to further optimizing microbubble performance are required, and that they cannot rely on bubble technology developed more than 3 decades ago.

The known crosstalk between short-chain fatty acids (SCFAs) and the circadian clock is tightly intertwined with feeding time. We aimed to investigate the role of the core clock gene Bmal1 and feeding time in the diurnal rhythms in plasma and caecal SCFA levels and in their effect on the release of the hunger hormone ghrelin in the stomach and colon. WT, Bmal1-/- (ad libitum fed) and night-time-restricted-fed (RF)-Bmal1-/- littermates were killed at zeitgeber time (ZT) 4 and 16. SCFA concentrations were measured by gas chromatography. To investigate the effect of SCFAs on ghrelin release, stomach and colonic full-thickness strips were incubated with Krebs or a SCFA mix mimicking plasma or caecal concentrations, after which octanoyl ghrelin release was measured by RIA. Diurnal rhythms in caecal and plasma SCFAs oscillated in phase but rhythmic changes were abolished in Bmal1-/- mice. RF of Bmal1-/- mice restored fluctuations in caecal SCFAs. Plasma SCFA concentrations failed to affect gastric ghrelin release. The effect of caecal SCFA concentrations on colonic ghrelin release was rhythmic (inhibition at ZT 4, no effect at ZT 16). In Bmal1-/- mice, the inhibitory effect of SCFAs at ZT 4 was abolished. RF Bmal1-/- mice restored the inhibitory effect and increased colonic Clock expression. To conclude, diurnal fluctuations in caecal SCFAs and the effect of SCFAs on colonic ghrelin release are regulated by feeding time, independent of the core clock gene Bmal1. However, local entrainment of other clock genes might contribute to the observed effects.

T cell epitopes are mostly nonmodified peptides, although posttranslationally modified peptide epitopes have been described, but they originated from viral or self-proteins. In this study, we provide evidence of a bacterial methylated T cell peptide epitope. The mycobacterial heparin-binding hemagglutinin (HBHA) is a protein Ag with a complex C-terminal methylation pattern and is recognized by T cells from humans latently infected with Mycobacterium tuberculosis. By comparing native HBHAwith recombinant HBHA produced in Mycobacterium smegmatis (rHBHA-Ms), we could link antigenic differences to differences in the methylation profile. Peptide scan analyses led to the discovery of a peptide containing methyl lysines recognized by a mAb that binds to native HBHA ∼100-fold better than to rHBHA-Ms. This peptide was also recognized by T cells from latently infected humans, as evidenced by IFN-g release upon peptide stimulation. The nonmethylated peptide did not induce IFN-g, arguing that the methyl lysines are part of the T cell epitope., SCOPUS: ar.j, info:eu-repo/semantics/published

Item does not contain fulltext The present study investigated responsiveness to intervention in children with an earlier versus later diagnosis of dyslexia. We examined differences between second (n = 122; early diagnosis) and third (n = 158; late diagnosis) graders with dyslexia on reading and spelling abilities before, during and after a dyslexia intervention as well as in precursor measures. Scores were also compared with those of typical reading peers at second (n = 108) and third (n = 119) grade. Finally, we examined the role of second versus third grade diagnosis in the prediction of variation in responsiveness to intervention. Before the intervention, the early diagnosed group was behind the late diagnosed group on almost all measures. During the intervention, the earlier diagnosed group made more progress on word decoding accuracy and showed comparable progress in skills otherwise. The effect of the intervention was indicated from the fact that later diagnosed children before the intervention were behind earlier diagnosed children after the intervention -when at a comparable age- on all reading and spelling measures. Finally, we showed that an early or later diagnosis of dyslexia similarly predicts the growth of reading and spelling outcomes with only a small benefit of early diagnosis for pseudoword reading efficiency. 21 p.

Background The safety and efficacy of edoxaban and dalteparin is unclear for several cancer groups. Methods We evaluated the occurrence of the primary outcome in large cancer groups. The primary outcome was the composite of recurrent VTE or major bleeding over 12 months. Results In patients with gastrointestinal cancer, the primary outcome occurred in 19.4% patients given edoxaban and in 15.0% given dalteparin (risk difference [RD], 4.4%; 95%-CI, −4.1% to 12.8%). The corresponding rates for edoxaban and dalteparin were 10.4% and 10.7% for lung cancer (RD, −0.3%; 95%-CI, −10.0% to 9.5%), 13.6% and 12.5% for urogenital cancer (RD, 1.1; 95%-CI, −10.1–12.4), 3.1% and 11.7% for breast cancer (RD, −8.6; 95%-CI, −19.3–2.2), 8.9% and 10.9% for hematological malignancies (RD, −2.0; 95%-CI, −13.1–9.1), and 10.4% and 17.4% for gynecological cancer (RD, −7.0; 95%-CI, −19.8–5.7). In the subgroup of gastrointestinal cancer, edoxaban was associated with a 3.5% lower absolute risk of recurrent VTE and a 7.9% higher risk of major bleeding. Conclusion Edoxaban has a similar risk-benefit ratio to dalteparin in most cancer groups. In those with gastrointestinal cancer, the lower risk of recurrent VTE and the advantages of oral therapy need to be balanced against the increased risk of major bleeding.

Denosumab is a fully human monoclonal anti-RANK-L antibody that is clinically used to counteract the bone loss induced by exacerbated osteoclast activity. Indeed, its binding to RANK-L prevents the interaction RANK-L/receptor RANK that is essential for osteoclastogenesis and bone resorbing activity. Although there are many medications available to treat bone loss diseases, including bisphosphonates, Denosumab is highly effective since it reduces the bone erosion. The use in pediatric patients is safe. However, some concerns are related to the interruption of the treatment. Indeed, in this study, we reported hypercalcemia in two pediatric patients and alterations of circulating osteoclast precursors. Peripheral Blood Mononuclear Cells (PBMC) were isolated from two pediatric patients with hypercalcemia after Denosumab interruption and from 10 controls. Cytofluorimetric analysis and in vitro osteoclastogenesis experiments were performed. Increase of CD16−CD14+CD11b+ cells was revealed in PBMC from patients reflecting the enhanced in vitro osteoclastogenesis. Our data suggest that precautions must be taken when Denosumab therapy is interrupted and gradual decrease of dose and/or timing of treatment should be performed. To prevent the onset of hypercalcemia that could be in the discontinuation phase, cytofluorimetric analysis of PBMC should be performed to evaluate osteoclast precursors.

Given the controversial nature of research into in-vitro gametogenesis (IVG), this study set out to investigate the current attitudes towards IVG in the general Belgian population in order to anticipate potential future barriers and misunderstandings. A questionnaire was developed and incorporated into a web-based online survey and sent out to Belgians aged ≥18 years in September 2018 until a representative sample (by age, gender and region) of 1000 participants was reached. Respondents expressed an overall positive attitude towards IVG and its possible future applications, with the exception of the use of IVG in postmenopausal women. They were ambivalent about the importance of genetic parenthood and about the necessary experiments on animals and embryos to bring IVG to the clinic. While the willingness to accept greater risks for IVG than for other assisted reproductive technology treatments was low (17.5%), the use of spare in-vitro fertilization embryos to study those risks was acceptable for 55.8% of participants; embryo creation was acceptable for 38.1%; and experiments on mice and monkeys were acceptable for 45.3% and 30.4%, respectively. Finally, 85.6% of participants agreed that the Belgian Government should strictly regulate IVG. In conclusion, preclinical research into IVG and other reproductive technologies elicits a great diversity of attitudes towards the importance of genetic parenthood and the acceptability of embryo and animal research. There is a need for public dialogue on these topics.

PURPOSE: To analyze the incidence and risk factors of posterior capsule rupture (PCR) in cataract surgery. SETTING: European clinics affiliated with the European Registry of Quality Outcomes for Cataract and Refractive Surgery (EUREQUO). DESIGN: Retrospective cross-sectional register-based study. METHODS: Data was obtained from the EUREQUO. The database contains data on demographics, comorbidities, and intraoperative complications, including PCR for the study period from January 1, 2008, to December 31, 2018. Univariable and multivariable logistic regression analyses were performed to estimate the (adjusted) odds ratio (OR) and 95% confidence intervals (CI). RESULTS: Data was available of 2,853,376 patients and 31,749 (1.1%) cataract surgeries were complicated by a PCR. The PCR rate ranged from 0.60 to 1.65 percent throughout the years, with a decreasing trend (p

Purpose: We compared the diagnostic yield of fetal clinical exome sequencing (fCES) in prospective and retrospective cohorts of pregnancies presenting with anomalies detected using ultrasound. We evaluated factors that led to a higher diagnostic efficiency, such as phenotypic category, clinical characterization, and variant analysis strategy. Methods: fCES was performed for 303 fetuses (183 ongoing and 120 ended pregnancies, in which chromosomal abnormalities had been excluded) using a trio/duo-based approach and a multistep variant analysis strategy. Results: fCES identified the underlying genetic cause in 13% (24/183) of prospective and 29% (35/120) of retrospective cases. In both cohorts, recessive heterozygous compound genotypes were not rare, and trio and simplex variant analysis strategies were complementary to achieve the highest possible diagnostic rate. Limited prenatal phenotypic information led to interpretation challenges. In 2 prospective cases, in-depth analysis allowed expansion of the spectrum of prenatal presentations for genetic syndromes associated with the SLC17A5 and CHAMP1 genes. Conclusion: fCES is diagnostically efficient in fetuses presenting with cerebral, skeletal, urinary, or multiple anomalies. The comparison between the 2 cohorts highlights the importance of providing detailed phenotypic information for better interpretation and prenatal reporting of genetic variants. (C) 2021 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.

Contains fulltext : 240305.pdf (Publisher’s version ) (Open Access) The use of adequate reading comprehension strategies is important to read efficiently. Students with dyslexia not only read slower and less accurately, they also use fewer reading comprehension strategies. To compensate for their decoding problems, they often receive audio-support (narration written text). However, audio-support linearly guides readers from beginning to end through texts, possibly hindering the use of reading comprehension strategies in expository texts and negatively impacting reading time and reading comprehension performance. We examined to what extent audio-support affects reading comprehension strategies, reading times, and reading comprehension performance in 21 secondary school students with dyslexia and 22 typically developing controls. Participants were provided with three types of assignments (summarizing, open-ended questions, statement questions) in each condition (written text with and without audio-support). SMI RED-500 eye tracker captured eye movements during reading. The standard deviation of the weighted fixation duration times on the three paragraphs was considered indicative of the disparity of readers' attention within the text. Following a discrimination based on experts' reading behavior and hand-coded validation, these scores visualized whether students used the intensive reading strategy (reading whole text) or selective reading strategy (focusing on part of the text). In open-ended assignments, students divided their attention more over the whole text instead of focusing on one specific part when audio was added. In addition, audio-support increased reading time in students with and without dyslexia in most tasks, while in neither of the tasks audio-support affected reading comprehension performance. Audio-support impacts reading comprehension strategy and reading time in all students. 20 p.

Congenital melanocytic nevus syndrome (CMNS) is a rare condition characterized by pigmented skin lesions that is usually present at birth and is associated with an increased risk of neurological abnormalities and malignant melanoma. It mostly results from a post-zygotic NRAS mutation of neural-derived crest cells, leading to an uncontrolled cell growth. Due to the increased knowledge of the genetics underlying CMNS, targeted therapy becomes a promising treatment option. We present a case of CMNS in a newborn. Physical examination at birth showed a giant congenital melanocytic nevus, extending from the occipital to the lower lumbar region. An MRI-scan revealed multiple cerebral and cerebellar parenchymal lesions. Genetic analysis of the cutaneous lesions showed the presence of a NRAS Q61R mutation. The patient was treated with dermabrasion to reduce the color intensity of the nevus. However, this was complicated with recurrent wound infections and laborious wound healing. At the age of 1 year, the patient had an age-appropriate psychomotor development, without neurological deficits. This article is protected by copyright. All rights reserved. ispartof: Journal Of Cutaneous Pathology vol:48 issue:12 pages:1497-1503 ispartof: location:United States status: Published online

Malignant rhabdoid tumour (MRT) is an often lethal childhood cancer that, like many paediatric tumours, is thought to arise from aberrant fetal development. The embryonic root and differentiation pathways underpinning MRT are not firmly established. Here, we study the origin of MRT by combining phylogenetic analyses and single-cell mRNA studies in patient-derived organoids. Comparison of somatic mutations shared between cancer and surrounding normal tissues places MRT in a lineage with neural crest-derived Schwann cells. Single-cell mRNA readouts of MRT differentiation, which we examine by reverting the genetic driver mutation underpinning MRT, SMARCB1 loss, suggest that cells are blocked en route to differentiating into mesenchyme. Quantitative transcriptional predictions indicate that combined HDAC and mTOR inhibition mimic MRT differentiation, which we confirm experimentally. Our study defines the developmental block of MRT and reveals potential differentiation therapies., Malignant rhabdoid tumours (MRT) have been suggested to originate in the ectoderm-derived neural crest. Here, the authors analyse MRTs using phylogenetics, scRNA-seq, and patient-derived organoids; they find evidence for an MRT origin in the neural crest lineage and suggest differentiation treatment with HDAC/mTOR inhibitors.

Randomized clinical trials initially used heart failure (HF) patients with low left ventricular ejection fraction (LVEF) to select study populations with high risk to enhance statistical power. However, this use of LVEF in clinical trials has led to oversimplification of the scientific view of a complex syndrome. Descriptive terms such as ‘HFrEF’ (HF with reduced LVEF), ‘HFpEF’ (HF with preserved LVEF), and more recently ‘HFmrEF’ (HF with mid-range LVEF), assigned on arbitrary LVEF cut-off points, have gradually arisen as separate diseases, implying distinct pathophysiologies. In this article, based on pathophysiological reasoning, we challenge the paradigm of classifying HF according to LVEF. Instead, we propose that HF is a heterogeneous syndrome in which disease progression is associated with a dynamic evolution of functional and structural changes leading to unique disease trajectories creating a spectrum of phenotypes with overlapping and distinct characteristics. Moreover, we argue that by recognizing the spectral nature of the disease a novel stratification will arise from new technologies and scientific insights that will shape the design of future trials based on deeper understanding beyond the LVEF construct alone.

First cases that point at a correlation between SARS-CoV-2 infections and the development of Parkinson’s disease have been reported. Currently it is unclear if there also is a direct causal link between these diseases. To obtain first insights into a possible molecular relation between viral infections and the aggregation of α-synuclein protein into amyloid fibrils characteristic for Parkinson’s disease, we investigated the effect of the presence of SARS-CoV-2 proteins on α-synuclein aggregation. We show, in test tube experiments, that SARS-CoV-2 S-protein has no effect on α-synuclein aggregation while SARS-CoV-2 N-protein considerably speeds up the aggregation process. We observe the formation of multi-protein complexes, and eventually amyloid fibrils. Microinjection of N-protein in SHSY-5Y cells disturbed the α-synuclein proteostasis and increased cell death. Our results point toward direct interactions between the N-protein of SARS-CoV-2 and α-synuclein as molecular basis for the observed coincidence between SARS-CoV-2 infections and Parkinsonism.

Although concomitant coronary artery disease (CAD) is frequent in patients with severe aortic stenosis (AS), hemodynamic assessment of CAD severity in patients undergoing valve replacement for severe AS is challenging. Myocardial hypertrophic remodeling interferes with coronary blood flow and may influence the values of fractional flow reserve (FFR) and nonhyperemic pressure ratios (NHPRs). The aim of the current study is to investigate the effect of the AS and its treatment on current indices used for evaluation of CAD. We will compare intracoronary hemodynamics before, immediately after, and 6 mo after aortic valve replacement (AVR) when it is expected that microvascular function has improved. Furthermore, we will compare FFR and resting full-cycle ratio (RFR) with myocardial perfusion single-photon emission-computed tomography (SPECT) as indicators of myocardial ischemia in patients with AS and CAD. One-hundred consecutive patients with AS and intermediate CAD will be prospectively included. Patients will undergo pre-AVR SPECT and intracoronary hemodynamic assessment at baseline, immediately after valve replacement [if transcatheter AVR (TAVR) is chosen], and 6 mo after AVR. The primary end point is the change in FFR 6 mo after AVR. Secondary end points include the acute change of FFR after TAVR, the diagnostic accuracy of FFR versus RFR compared with SPECT for the assessment of ischemia, changes in microvascular function as assessed by the index of microcirculatory resistance (IMR), and the effect of these changes on FFR. The present study will evaluate intracoronary hemodynamic parameters before, immediately after, and 6 mo after AVR in patients with AS and intermediate coronary stenosis. The understanding of the impact of AVR on the assessment of FFR, NHPR, and microvascular function may help guide the need for revascularization in patients with AS and CAD planned for AVR. ispartof: AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY vol:321 issue:6 pages:H1106-H1116 ispartof: location:United States status: published

BACKGROUND: In the Hokusai VTE Cancer study, the risk of major bleeding was 2.9% higher in the edoxaban group compared with the dalteparin group, mainly due to more gastrointestinal bleedings in patients with gastrointestinal cancer. The identification of risk factors for gastrointestinal bleeding may help to guide the use of DOACs in these patients. OBJECTIVES: To evaluate risk factors for gastrointestinal bleeding in patients with gastrointestinal cancer receiving edoxaban. PATIENTS/METHODS: In this nested case-control study in patients with gastrointestinal cancer randomized to edoxaban in the Hokusai VTE Cancer study, cases (patients with clinically relevant gastrointestinal bleeding during treatment) were randomly matched to three controls (patients who had no gastrointestinal bleeding). Data for the 4-week period prior to bleeding were retrospectively collected. Odds ratios (ORs) were calculated in a crude conditional logistic regression model and a multivariable model adjusted for age, sex, and cancer type. RESULTS: Twenty-four cases and 64 matched controls were included. In the multivariable analysis, advanced cancer, defined as regionally advanced or metastatic cancer (OR 3.6, 95% CI 1.01-12.6) and low hemoglobin levels (OR 4.8, 95% CI 1.5-16.0) were significantly associated with bleeding. There was no significant difference in patients with resected tumors (OR 0.4, 95% CI 0.1-1.4), or in patients on chemotherapy (OR 1.3, 95% CI 0.5-3.5). CONCLUSION: Advanced cancer and low hemoglobin levels were associated with an increased risk of gastrointestinal bleeding in patients with gastrointestinal cancer receiving edoxaban. We were unable to identify other risk factors, mainly due to limited statistical power. ispartof: JOURNAL OF THROMBOSIS AND HAEMOSTASIS vol:19 issue:12 pages:3008-3017 ispartof: location:England status: published

This study investigates the contribution of different CH4 sources to the seasonal cycle of 𝛿13C during years 2000–2012 using the TM5 atmospheric transport model. The seasonal cycles of anthropogenic emissions from two versions of the EDGAR inventories, v4.3.2 and v5.0 are examined. Those includes emissions from Enteric Fermentation and Manure Management (EFMM), rice cultivation and residential sources. Those from wetlands obtained from LPX-Bern v1.4 are also examined in addition to other sources such as fires and ocean sources. We use spatially varying isotopic source signatures for EFMM, coal, oil and gas, wetlands, fires and geological emission and for other sources a global uniform value. We analysed the results as zonal means for 30° latitudinal bands. Seasonal cycles of 𝛿13C are found to be an inverse of CH4 cycles in general, with a peak-to-peak amplitude of 0.07–0.26 ‰. However, due to emissions, the phase ellipses do not form straight lines, and the anti-correlations between CH4 and 𝛿13C are weaker (−0.35 to −0.91) in north of 30° S. We found that wetland emissions are the dominant driver in the 𝛿13C seasonal cycle in the Northern Hemisphere and Tropics, such that the timing of 𝛿13C seasonal minimum is shifted by ∼90 days in 60° N–90° N from the end of the year to the beginning of the year when seasonality of wetland emissions is removed. The results also showed that in the Southern Hemisphere Tropics, emissions from fires contribute to the enrichment of 𝛿13C in July–October. In addition, we also compared the results against observations from the South Pole, Antarctica, Alert, Nunavut, Canada and Niwot Ridge, Colorado, USA. In light of this research, comparison to the observation showed that the seasonal cycle of EFMM emissions in EDGAR v5.0 inventory is more realistic than in v4.3.2. In addition, the comparison at Alert showed that modelled 𝛿13C amplitude was approximately half of the observations, mainly because the model could not reproduce the strong depletion in autumn. This indicates that CH4 emission magnitude and seasonal cycle of wetlands may need to be revised. Results from Niwot Ridge indicate that in addition to biogenic emissions, the proportion of biogenic to fossil based emissions may need to be revised.

BACKGROUND: Factor XIa inhibitors for the prevention and treatment of venous and arterial thromboembolism may be more effective and result in less bleeding than conventional anticoagulants. Additional data are needed regarding the efficacy and safety of milvexian, an oral factor XIa inhibitor. METHODS: In this parallel-group, phase 2 trial, we randomly assigned 1242 patients undergoing knee arthroplasty to receive one of seven postoperative regimens of milvexian (25 mg, 50 mg, 100 mg, or 200 mg twice daily or 25 mg, 50 mg, or 200 mg once daily) or enoxaparin (40 mg once daily). The primary efficacy outcome was venous thromboembolism (which was a composite of asymptomatic deep-vein thrombosis, confirmed symptomatic venous thromboembolism, or death from any cause). The principal safety outcome was bleeding. RESULTS: Among the patients receiving milvexian twice daily, venous thromboembolism developed in 27 of 129 (21%) taking 25 mg, in 14 of 124 (11%) taking 50 mg, in 12 of 134 (9%) taking 100 mg, and in 10 of 131 (8%) taking 200 mg. Among those receiving milvexian once daily, venous thromboembolism developed in 7 of 28 (25%) taking 25 mg, in 30 of 127 (24%) taking 50 mg, and in 8 of 123 (7%) taking 200 mg, as compared with 54 of 252 patients (21%) taking enoxaparin. The dose–response relationship with twice-daily milvexian was significant (one-sided P

Purpose Vincristine (VCR) is a chemotherapeutic agent used in the treatment of pediatric oncology patients, but its main toxicity is VCR‐induced peripheral neuropathy (VIPN). However, whether VIPN has an effect on health‐related quality of life (HR‐QoL) in children during treatment is unknown. Therefore, the aim of our study was to investigate the association between VIPN and HR‐QoL in children starting treatment for cancer. Methods Measurements of VIPN were performed using two tools: Common Terminology Criteria for Adverse Events (CTCAE) and pediatric‐modified Total Neuropathy Score (ped‐mTNS). Assessment of HR‐QoL was done with self‐ and proxy assessment of the Cancer and Generic module of the Pediatric Cancer Quality of Life Inventory™ (PedsQL). Results In total, N = 86 children were included. HR‐QoL of children with VIPN (n = 67%, 76%) was significantly lower in comparison with children without VIPN: estimated Total score of PedsQL Generic (proxy) 84.57; β = −8.96 and 95% confidence interval (CI) −14.48 to −3.43; p = 0.002, estimated PedsQL Generic Total score (self‐reported): 85.16, β = −8.38 (95% CI: −13.76 to −3.00); p = 0.003. Similar results were found in the Pain and Hurt domain of the PedsQL Cancer (pain: estimated score [proxy]: 85.28, β = −9.94 [95%CI: −16.44 to −3.45], p = 0.003; hurt: estimated score [self‐report] 97.57, β = −19.15 [95%CI: −26.82 to −11.48], p, This article reports on the association between vincristine‐induced peripheral neuropathy and health‐related quality of life in pediatric oncology patients. Our data show that health‐related quality of life is significantly lower in children who experience vincristine‐induced peripheral neuropathy compared to pediatric oncology patients without vincristine‐induced peripheral neuropathy.

The case concerns a female presenting with dyspnoea resulting from recurrent hemopericardium. Pericardiocentesis, coronary angiography, and extensive laboratory and imaging studies did not reveal the underlying etiology of the hemopericardium. Only after repeat and exploratory surgery, diffuse venous pericardial hemorrhages with localized thrombi typical of angiosarcoma were discovered.

A 69-year-old patient underwent an urgent aortic valve replacement because of Streptococcus agalactiae endocarditis of his native aortic valve. Since a rapid progression of the former abscess cavity into an aortic root pseudoaneurysm with increasing paravalvular regurgitation during postoperative follow-up, reoperation was performed. In the preoperative transesophageal echocardiography (TEE) images the pseudoaneurysm completely surrounds the left coronary artery (LCA) without any signs of myocardial ischemia.

Background The Intensive Care Delirium Screening Checklist (ICDSC) demonstrates good psychometric characteristics in research settings. However, evidence about these characteristics in pragmatic ICU settings is inconsistent. This study evaluated psychometric properties and user-friendliness of the ICDSC when administered by ICU nurses in daily practice. Methods This prospective study included 77 patients from a surgical intensive care unit. To examine the psychometric characteristics, the scores on the ICDSC (performed by bedside nurses) were compared with the scores on the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) (performed by researchers as gold standard). The user-friendliness was evaluated by 34 ICU nurses with a 20-item questionnaire. Results The ICDSC had an area under the curve of 0.843. It showed a good diagnostic accuracy with a sensitivity of 81.0%, a specificity of 87.7%, and a 53.1% positive and 96.4% negative predictive value. The overall Cronbach’s alpha coefficient for all ICDSC scores was high (0.839). Overall, ICU nurses experienced the ICDSC as easy-to-use. The scale was usable in most surgical ICU patients. Yet, some nurses (11.8%) had problems to score the items ‘inappropriate speech’ and ‘symptom fluctuation’ in intubated patients. Conclusions The ICDSC is a valid and user-friendly tool for delirium screening in daily ICU nursing practice. Yet, some problems were reported in intubated patients. Therefore, validation studies with specific focus on intubated patients are needed.

Various definitions of myocardial infarction type 5 after coronary artery bypass grafting (CABG) have been proposed (myocardial infarction [MI-5], also known as peri-procedural MI), using different biomarkers and different and arbitrary cut-off values. This meta-analysis aims to determine the expected release of high-sensitivity cardiac troponin T (hs-cTnT) after CABG in general and after uncomplicated surgery and off-pump CABG in particular. A systematic search was applied to 3 databases. Studies on CABG as a single intervention and reporting on postoperative hs-cTnT concentrations on at least 2 different time points were included. All data on hs-cTnT concentrations were extracted, and mean concentrations at various points in time were stratified. Eventually, 15 studies were included, encompassing 2,646 patients. Preoperative hs-cTnT was 17 ng/L (95% confidence interval [CI] 13 to 20 ng/L). Hs-cTnT peaked at 6 to 8 hours postoperatively (628 ng/L, 95% CI 400 to 856 ng/L; 45x upper reference limit [URL]) and was still increased after 48 hours. In addition, peak hs-cTnT concentration was 614 ng/L (95% CI 282 to 947 ng/L) in patients with a definite uncomplicated postoperative course (i.e., without MI). For patients after off-pump CABG compared to on-pump CABG, the mean peak hs-cTnT concentration was 186 ng/L (95% CI 172 to 200 ng/L, 13 x URL) versus 629 ng/L (95% CI 529 to 726 ng/L, 45 x URL), respectively. In conclusion, postoperative hs-cTnT concentrations surpass most of the currently defined cut-off values for MI-5, even in perceived uncomplicated surgery, suggesting thorough reassessment. Hs-cTnT release differences following on-pump CABG versus off-pump CABG were observed, implying the need for different cut-off values for different surgical strategies. (C) 2021 The Author(s). Published by Elsevier Inc.

OBJECTIVES Although in both the US and European guidelines the ‘heart team approach’ is a class I recommendation, supporting evidence is still lacking. Therefore, we sought to provide comparative survival data of patients with mitral valve disease referred to the general and the dedicated heart team. METHODS In this retrospective cohort, patients evaluated for mitral valve disease by a general heart team (2009–2014) and a dedicated mitral valve heart team (2014–2018) were included. Decision-making was recorded prospectively in heart team electronic forms. The end point was overall survival from decision of the heart team. RESULTS In total, 1145 patients were included of whom 641 (56%) were discussed by dedicated heart team and 504 (44%) by general heart team. At 5 years, survival probability was 0.74 [95% confidence interval (CI) 0.68–0.79] for the dedicated heart team group compared to 0.70 (95% CI 0.66–0.74, P = 0.040) for the general heart team. Relative risk of mortality adjusted for EuroSCORE II, treatment groups (surgical, transcatheter and non-intervention), mitral valve pathology (degenerative, functional, rheumatic and others) and 13 other baseline characteristics for patients in the dedicated heart team was 29% lower [hazard ratio (HR) 0.71, 95% CI 0.54–0.95; P = 0.019] than for the general heart team. The adjusted relative risk of mortality was 61% lower for patients following the advice of the heart team (HR 0.39, 95% CI 0.25–0.62; P CONCLUSIONS In this retrospective cohort, patients treated for mitral valve disease based on a dedicated heart team decision have significantly higher survival independent of the allocated treatment, mitral valve pathology and baseline characteristics.

Background The majority of childhood cancer survivors are at risk of treatment-related adverse health outcomes. Survivorship care to mitigate these late effects is endorsed, but it is not available for many adult survivors of childhood cancer in Europe. The PanCareFollowUp project was initiated to improve their health and quality of life (QoL) by facilitating person-centred survivorship care. Methods The PanCareFollowUp consortium was established in 2018, consisting of 14 project partners from ten European countries, including survivor representatives. The consortium will develop two PanCareFollowUp Interventions, including a person-centred guideline–based model of care (Care Intervention) and eHealth lifestyle coaching (Lifestyle Intervention). Their development will be informed by several qualitative studies and systematic reviews on barriers and facilitators for implementation and needs and preferences of healthcare providers (HCPs) and survivors. Implementation of the PanCareFollowUp Care Intervention as usual care will be evaluated prospectively among 800 survivors from Belgium, Czech Republic, Italy and Sweden for survivor empowerment, detection of adverse health conditions, satisfaction among survivors and HCPs, cost-effectiveness and feasibility. The feasibility of the PanCareFollowUp Lifestyle Intervention will be evaluated in the Netherlands among 60 survivors. Results Replication manuals, allowing for replication of the PanCareFollowUp Care and Lifestyle Intervention, will be published and made freely available after the project. Moreover, results of the corresponding studies are expected within the next five years. Conclusions The PanCareFollowUp project is a novel European collaboration aiming to improve the health and QoL of all survivors across Europe by developing and prospectively evaluating the person-centred PanCareFollowUp Care and Lifestyle Interventions.

The role of factor XI in the pathogenesis of postoperative venous thromboembolism is uncertain. Abelacimab is a monoclonal antibody that binds to factor XI and locks it in the zymogen (inactive precursor) conformation.In this open-label, parallel-group trial, we randomly assigned 412 patients who were undergoing total knee arthroplasty to receive one of three regimens of abelacimab (30 mg, 75 mg, or 150 mg) administered postoperatively in a single intravenous dose or to receive 40 mg of enoxaparin administered subcutaneously once daily. The primary efficacy outcome was venous thromboembolism, detected by mandatory venography of the leg involved in the operation or objective confirmation of symptomatic events. The principal safety outcome was a composite of major or clinically relevant nonmajor bleeding up to 30 days after surgery.Venous thromboembolism occurred in 13 of 102 patients (13%) in the 30-mg abelacimab group, 5 of 99 patients (5%) in the 75-mg abelacimab group, and 4 of 98 patients (4%) in the 150-mg abelacimab group, as compared with 22 of 101 patients (22%) in the enoxaparin group. The 30-mg abelacimab regimen was noninferior to enoxaparin, and the 75-mg and 150-mg abelacimab regimens were superior to enoxaparin (P0.001). Bleeding occurred in 2%, 2%, and none of the patients in the 30-mg, 75-mg, and 150-mg abelacimab groups, respectively, and in none of the patients in the enoxaparin group.This trial showed that factor XI is important for the development of postoperative venous thromboembolism. Factor XI inhibition with a single intravenous dose of abelacimab after total knee arthroplasty was effective for the prevention of venous thromboembolism and was associated with a low risk of bleeding. (Funded by Anthos Therapeutics; ANT-005 TKA EudraCT number, 2019-003756-37.).

While analyzing the persistence length of DNA atomistic simulations Wu et al. [J. Chem. Phys. 142, 125103 (2015)] introduced an empirical formula to account for the observed length-dependence. In particular they found that the persistence length increases with the distance. Here, we derive the formula by Wu et al. using a non-local twistable wormlike chain which introduces couplings between distal sites. Finally, we show that the same formula can account for the length-scale dependence of the torsional persistence length and is, in fact, applicable to any kind of polymer model with non-local couplings.