Fetal growth restriction and related placental pathologies such as preeclampsia, stillbirth, and placental abruption are believed to arise in early pregnancy when inadequate remodeling of the ...maternal spiral arteries leads to persistent high-resistance and low-flow uteroplacental circulation. The consequent placental ischaemia, reperfusion injury, and oxidative stress are associated with an imbalance in angiogenic/antiangiogenic factors. Many interventions have centered on the prevention and/or treatment of preeclampsia with results pertaining to fetal growth restriction and small-for-gestational-age pregnancy often included as secondary outcomes because of the common pathophysiology. This renders the study findings less reliable for determining clinical significance. For the prevention of fetal growth restriction, a recent large-study level meta-analysis and individual patient data meta-analysis confirm that aspirin modestly reduces small-for-gestational-age pregnancy in women at high risk (relative risk, 0.90, 95% confidence interval, 0.81–1.00) and that a dose of ≥100 mg should be recommended and to start at or before 16 weeks of gestation. These findings support national clinical practice guidelines. In vitro and in vivo studies suggest that low-molecular-weight heparin may prevent fetal growth restriction; however, evidence from randomized control trials is inconsistent. A meta-analysis of multicenter trial data does not demonstrate any positive preventative effect of low-molecular-weight heparin on a primary composite outcome of placenta-mediated complications including fetal growth restriction (18% vs 18%; absolute risk difference, 0.6%; 95% confidence interval, 10.4–9.2); use of low-molecular-weight heparin for the prevention of fetal growth restriction should remain in the research setting. There are even fewer treatment options once fetal growth restriction is diagnosed. At present the only management option if the risk of hypoxia, acidosis, and intrauterine death is high is iatrogenic preterm birth, with the use of peripartum maternal administration of magnesium sulphate for neuroprotection and corticosteroids for fetal lung maturity, to prevent adverse neonatal outcomes. The pipeline of potential therapies use different strategies, many aiming to increase fetal growth by improving poor placentation and uterine blood flow. Phosphodiesterase type 5 inhibitors that potentiate nitric oxide availability such as sildenafil citrate have been extensively researched both in preclinical and clinical studies; results from the Sildenafil Therapy In Dismal Prognosis Early-Onset Intrauterine Growth Restriction consortium of randomized control clinical trials are keenly awaited. Targeting the uteroplacental circulation with novel therapeutics is another approach, the most advanced being maternal vascular endothelial growth factor gene therapy, which is being translated into the clinic via the doEs Vascular endothelial growth factor gene therapy safEly impRove outcome in seveRe Early-onset fetal growth reSTriction consortium. Other targeting approaches include nanoparticles and microRNAs to deliver drugs locally to the uterine arterial endothelium or trophoblast. In vitro and in vivo studies and animal models have demonstrated effects of nitric oxide donors, dietary nitrate, hydrogen sulphide donors, statins, and proton pump inhibitors on maternal blood pressure, uteroplacental resistance indices, and angiogenic/antiangiogenic factors. Data from human pregnancies and, in particular, pregnancies with fetal growth restriction remain very limited. Early research into melatonin, creatine, and N-acetyl cysteine supplementation in pregnancy suggests they may have potential as neuro- and cardioprotective agents in fetal growth restriction.
The Pfizer-BioNTech (BNT162b2) and the Oxford-AstraZeneca (ChAdOx1 nCoV-19) COVID-19 vaccines have shown excellent safety and efficacy in phase 3 trials. We aimed to investigate the safety and ...effectiveness of these vaccines in a UK community setting.
In this prospective observational study, we examined the proportion and probability of self-reported systemic and local side-effects within 8 days of vaccination in individuals using the COVID Symptom Study app who received one or two doses of the BNT162b2 vaccine or one dose of the ChAdOx1 nCoV-19 vaccine. We also compared infection rates in a subset of vaccinated individuals subsequently tested for SARS-CoV-2 with PCR or lateral flow tests with infection rates in unvaccinated controls. All analyses were adjusted by age (≤55 years vs >55 years), sex, health-care worker status (binary variable), obesity (BMI <30 kg/m2vs ≥30 kg/m2), and comorbidities (binary variable, with or without comorbidities).
Between Dec 8, and March 10, 2021, 627 383 individuals reported being vaccinated with 655 590 doses: 282 103 received one dose of BNT162b2, of whom 28 207 received a second dose, and 345 280 received one dose of ChAdOx1 nCoV-19. Systemic side-effects were reported by 13·5% (38 155 of 282 103) of individuals after the first dose of BNT162b2, by 22·0% (6216 of 28 207) after the second dose of BNT162b2, and by 33·7% (116 473 of 345 280) after the first dose of ChAdOx1 nCoV-19. Local side-effects were reported by 71·9% (150 023 of 208 767) of individuals after the first dose of BNT162b2, by 68·5% (9025 of 13 179) after the second dose of BNT162b2, and by 58·7% (104 282 of 177 655) after the first dose of ChAdOx1 nCoV-19. Systemic side-effects were more common (1·6 times after the first dose of ChAdOx1 nCoV-19 and 2·9 times after the first dose of BNT162b2) among individuals with previous SARS-CoV-2 infection than among those without known past infection. Local effects were similarly higher in individuals previously infected than in those without known past infection (1·4 times after the first dose of ChAdOx1 nCoV-19 and 1·2 times after the first dose of BNT162b2). 3106 of 103 622 vaccinated individuals and 50 340 of 464 356 unvaccinated controls tested positive for SARS-CoV-2 infection. Significant reductions in infection risk were seen starting at 12 days after the first dose, reaching 60% (95% CI 49–68) for ChAdOx1 nCoV-19 and 69% (66–72) for BNT162b2 at 21–44 days and 72% (63–79) for BNT162b2 after 45–59 days.
Systemic and local side-effects after BNT162b2 and ChAdOx1 nCoV-19 vaccination occur at frequencies lower than reported in phase 3 trials. Both vaccines decrease the risk of SARS-CoV-2 infection after 12 days.
ZOE Global, National Institute for Health Research, Chronic Disease Research Foundation, National Institutes of Health, UK Medical Research Council, Wellcome Trust, UK Research and Innovation, American Gastroenterological Association.
Linked article: This is a mini commentary on Athiel et al, pp. 759‐767 in this issue. To view this article visit https://doi.org/10.1111/1471‐0528.17624.
Development of potentially life-threatening enterocolitis is the most frequent complication in children with Hirschsprung disease (HSCR), even after definitive corrective surgery. Intestinal ...microbiota likely contribute to the etiology of enterocolitis, so the aim of this study was to compare the fecal bacterial and fungal communities of children who developed Hirschsprung-associated enterocolitis (HAEC) with HSCR patients who had never had enterocolitis. Eighteen Hirschsprung patients who had completed definitive surgery were enrolled: 9 had a history of HAEC and 9 did not. Fecal DNA was isolated and 16S and ITS-1 regions sequenced using Next Generation Sequencing and data analysis for species identification. The HAEC group bacterial composition showed a modest reduction in Firmicutes and Verrucomicrobia with increased Bacteroidetes and Proteobacteria compared with the HSCR group. In contrast, the fecal fungi composition of the HAEC group showed marked reduction in diversity with increased Candida sp., and reduced Malassezia and Saccharomyces sp. compared with the HSCR group. The most striking finding within the HAEC group is that the Candida genus segregated into "high burden" patients with 97.8% C. albicans and 2.2% C. tropicalis compared with "low burden" patients 26.8% C. albicans and 73% C. tropicalis. Interestingly even the low burden HAEC group had altered Candida community structure with just two species compared to more diverse Candida populations in the HSCR patients. This is the first study to identify Candida sp. as potentially playing a role in HAEC either as expanded commensal species as a consequence of enterocolitis (or treatment), or possibly as pathobioants contributing to the pathogenesis of HAEC. These findings suggest a dysbiosis in the gut microbial ecosystem of HAEC patients, such that there may be dominance of fungi and bacteria predisposing patients to development of HAEC.
Accurate medical image segmentation is essential for diagnosis, surgical planning and many other applications. Convolutional Neural Networks (CNNs) have become the state-of-the-art automatic ...segmentation methods. However, fully automatic results may still need to be refined to become accurate and robust enough for clinical use. We propose a deep learning-based interactive segmentation method to improve the results obtained by an automatic CNN and to reduce user interactions during refinement for higher accuracy. We use one CNN to obtain an initial automatic segmentation, on which user interactions are added to indicate mis-segmentations. Another CNN takes as input the user interactions with the initial segmentation and gives a refined result. We propose to combine user interactions with CNNs through geodesic distance transforms, and propose a resolution-preserving network that gives a better dense prediction. In addition, we integrate user interactions as hard constraints into a back-propagatable Conditional Random Field. We validated the proposed framework in the context of 2D placenta segmentation from fetal MRI and 3D brain tumor segmentation from FLAIR images. Experimental results show our method achieves a large improvement from automatic CNNs, and obtains comparable and even higher accuracy with fewer user interventions and less time compared with traditional interactive methods.
Microfluidics, a technology characterized by the engineered manipulation of fluids at the submillimetre scale, has shown considerable promise for improving diagnostics and biology research. Certain ...properties of microfluidic technologies, such as rapid sample processing and the precise control of fluids in an assay, have made them attractive candidates to replace traditional experimental approaches. Here we analyse the progress made by lab-on-a-chip microtechnologies in recent years, and discuss the clinical and research areas in which they have made the greatest impact. We also suggest directions that biologists, engineers and clinicians can take to help this technology live up to its potential.
Sex differences in heart failure Lam, Carolyn S P; Arnott, Clare; Beale, Anna L ...
European heart journal,
12/2019, Letnik:
40, Številka:
47
Journal Article
Recenzirano
Odprti dostop
Abstract
The overall lifetime risk of heart failure (HF) is similar between men and women, however, there are marked sex differences in the landscape of this condition that are both important and ...under-recognized. Men are predisposed to HF with reduced ejection fraction (HFrEF), whereas women predominate in HF with preserved ejection fraction (HFpEF). Sex differences are also notable in the penetrance of genetic cardiomyopathies, risk factors, e.g. breast cancer which may be associated with cancer treatment-induced cardiomyopathy, as well as sex-specific conditions such as peripartum cardiomyopathy (PPCM). This review outlines the key sex differences with respect to clinical characteristics, pathophysiology, and therapeutic responses to HF treatments. Finally, we address important differences in the prognosis of HF. A central hypothesis is that the higher risk of HFrEF in men compared to women may be attributable to their predisposition to macrovascular coronary artery disease and myocardial infarction, whereas coronary microvascular dysfunction/endothelial inflammation has been postulated to play a key role in HFpEF and maybe the common link among HF syndromes that women are predisposed to Takotsubo cardiomyopathy, PPCM, and breast cancer radiotherapy-induced cardiomyopathy. Under-pinning current sex disparities in HF, there is a paucity of women recruited to HF clinical trials (20–25% of cohorts) and thus treatment guidelines are predominantly based on male-derived data. Large gaps in knowledge exist in sex-specific mechanisms, optimal drug doses for women and sex-specific criteria for device therapy.
Aim
These international clinical practice recommendations (CPR) for developmental coordination disorder (DCD), initiated by the European Academy of Childhood Disability (EACD), aim to address key ...questions on the definition, diagnosis, assessment, intervention, and psychosocial aspects of DCD relevant for clinical practice.
Method
Key questions in five areas were considered through literature reviews and formal expert consensus. For recommendations based on evidence, literature searches on ‘mechanisms’, ‘assessment’, and ‘intervention’ were updated since the last recommendations in 2012. New searches were conducted for ‘psychosocial issues’ and ‘adolescents/adults’. Evidence was rated according to the Oxford Centre for Evidence‐Based Medicine (level of evidence LOE 1–4) and transferred into recommendations. For recommendations based on formal consensus, two meetings of an international, multidisciplinary expert panel were conducted with a further five Delphi rounds to develop good clinical practice (GCP) recommendations.
Results
Thirty‐five recommendations were made. Eight were based on the evidence from literature reviews (three on ‘assessment’, five on ‘intervention’). Twenty‐two were updated from the 2012 recommendations. New recommendations relate to diagnosis and assessment (two GCPs) and psychosocial issues (three GCPs). Additionally, one new recommendation (LOE) reflects active video games as adjuncts to more traditional activity‐oriented and participation‐oriented interventions, and two new recommendations (one GCP, one LOE) were made for adolescents and adults with DCD.
Interpretation
The CPR–DCD is a comprehensive overview of DCD and current understanding based on research evidence and expert consensus. It reflects the state of the art for clinicians and scientists of varied disciplines. The international CPR–DCD may serve as a basis for national guidelines.
What this paper adds
Updated international clinical practice guidelines on developmental coordination disorder (DCD).
Refined and extended recommendations on clinical assessment and intervention for DCD.
A critical synopsis of current research on mechanisms of DCD.
A critical synopsis of psychosocial issues in DCD, with implications for clinical practice.
The first international recommendations to consider adolescents and adults with DCD.
Resumen
Recomendaciones internacionales para la práctica clínica sobre la definición, diagnóstico, evaluación, intervención y aspectos psicosociales del trastorno del desarrollo de la coordinación
Objetivo
Estas recomendaciones internacionales para la práctica clínica (RPC) sobre el trastorno del desarrollo de la coordinación (TDC), iniciadas por la Academia Europea de Discapacidad Infantil (EACD), tienen como objetivo abordar preguntas clave sobre la definición, diagnóstico, evaluación, intervención y aspectos psicosociales de TDC relevantes para la práctica clínica.
Método
Las preguntas clave en cinco áreas fueron tratadas a través de revisiones bibliográficas y consenso formal de expertos. Para las recomendaciones basadas en la evidencia, las búsquedas en la literatura sobre “mecanismos”, “evaluación” e “intervención” se actualizaron desde las últimas recomendaciones en 2012. Se realizaron nuevas búsquedas para “problemas psicosociales” y “adolescentes / adultos”. La evidencia se calificó de acuerdo con la gradación del Centro de Oxford para Medicina Basada en la Evidencia (nivel de evidencia LOE 1–4) y en ello se basaron las recomendaciones. Para recomendaciones basadas en el consenso formal, se llevaron a cabo dos reuniones de un panel multidisciplinario internacional de expertos con cinco rondas Delphi adicionales para desarrollar recomendaciones de buena práctica clínica (BPC).
Resultados
Se realizaron 35 recomendaciones. Ocho de ellas se basaron en la evidencia de las revisiones de la literatura (tres en “evaluación”, cinco en “intervención”). Veintidós fueron actualizadas a partir de las recomendaciones de 2012. Las nuevas recomendaciones se relacionan con el diagnóstico y la evaluación (dos BPC) y las cuestiones psicosociales (tres BPC). Además, una nueva recomendación (LOE) trata acerca de los videojuegos activos como complemento de las intervenciones más tradicionales orientadas a la actividad y la participación, y se hicieron dos nuevas recomendaciones (una BCP, una LOE) para adolescentes y adultos con TDC.
Interpretación
Estas recomendaciones internacionales para la práctica clínica sobre TDC aportan una visión general completa sobre TDC y el conocimiento actual basado en evidencia de investigación y consenso de expertos. Brinda actualización para clínicos y científicos de diversas disciplinas. Las recomendaciones internacionales para la práctica clínica TDC pueden servir como base para recomendaciones nacionales.
Recomendações internacionais para a prática clínica na definição, diagnóstico, avaliação, intervenção e aspectos psicossociais do transtorno do desenvolvimento da coordenação
Objetivo
Essas recomendações internacionais para a prática clínica (RPC) no transtorno do desenvolvimento da coordenação (TDC), iniciadas pela Academia Européia de Deficiência Infantil (EACD), objetiva direcionar questões chave na definição, diagnóstico, avaliação, intervenção e aspectos psicossociais do TDC relevantes para a prática clínica.
Métodos
Questões chave em cinco áreas foram consideradas através de revisões da literatura e consensos formais de especialistas. Para recomendações baseadas em evidências, buscas na literatura em “mecanismos”, “avaliação” e “intervenção” foram atualizadas desde as últimas recomendações de 2012. Novas buscas foram conduzidas para “problemas psicossociais” e “adolescentes/adultos”. Evidências foram classificadas de acordo com o Centro Oxford para Medicina Baseada em Evidência (nível de evidência NE 1‐4) e transferidas em recomendações. Para recomendações baseadas em consensos formais, dois encontros de um painel de especialistas internacional e multidisciplinar foram conduzidos com posteriormente cinco sessões Delphi para desenvolver recomendações de boa prática clínica (BPC).
Resultados
Trinta e cinco recomendações foram feitas. Oito foram baseadas em evidências de revisões da literatura (três em “avaliação”, cinco em “intervenção). Vinte e duas foram atualizadas das recomendações de 2012. Novas recomendações são relacionadas com diagnóstico e avaliação (duas BPC) e problemas psicossociais (três BPCs). Adicionalmente, uma nova recomendação (NE) se refere a jogos de videogame ativos como adjuntos à mais tradicional terapia orientada à tarefa e intervenção orientada à participação, e duas novas recomendações (uma BPC, um NE) foram feitas para adolescentes e adultos com TDC.
Interpretação
A RPC‐TDC apresenta uma visão geral do TDC e o conhecimento atual baseado em evidências de pesquisas e consenso de especialistas. Reflete o estado de arte dos clínicos e cientistas de disciplinas variadas. A RPC‐TDC internacional deverá servir como uma base para as diretrizes nacionais.
What this paper adds
Updated international clinical practice guidelines on developmental coordination disorder (DCD).
Refined and extended recommendations on clinical assessment and intervention for DCD.
A critical synopsis of current research on mechanisms of DCD.
A critical synopsis of psychosocial issues in DCD, with implications for clinical practice.
The first international recommendations to consider adolescents and adults with DCD.
This article's has been translated into Spanish and Portuguese.
Follow the links from the to view the translations.
A pocket version of these guidelines is available as Appendix S1 (https://onlinelibrary.wiley.com/doi/full/10.1111/dmcn.14132#support-information-section)
Plasma levels of tau phosphorylated at threonine-217 (p-tau217) is a candidate tool to monitor Alzheimer's disease. We studied 150 cognitively unimpaired participants and 100 patients with mild ...cognitive impairment in the Swedish BioFINDER study. P-tau217 was measured repeatedly for up to 6 years (median three samples per person, median time from first to last sample, 4.3 years). Preclinical (amyloid-β-positive cognitively unimpaired, n = 62) and prodromal (amyloid-β-positive mild cognitive impairment, n = 49) Alzheimer's disease had accelerated p-tau217 compared to amyloid-β-negative cognitively unimpaired (β = 0.56, P < 0.001, using linear mixed effects models) and amyloid-β-negative mild cognitive impairment patients (β = 0.67, P < 0.001), respectively. Mild cognitive impairment patients who later converted to Alzheimer's disease dementia (n = 40) had accelerated p-tau217 compared to other mild cognitive impairment patients (β = 0.79, P < 0.001). P-tau217 did not change in amyloid-β-negative participants, or in patients with mild cognitive impairment who did not convert to Alzheimer's disease dementia. For 80% power, 109 participants per arm were required to observe a slope reduction in amyloid-β-positive cognitively unimpaired (71 participants per arm in amyloid-β-positive mild cognitive impairment). Longitudinal increases in p-tau217 correlated with longitudinal worsening of cognition and brain atrophy. In summary, plasma p-tau217 increases during early Alzheimer's disease and can be used to monitor disease progression.
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