Objectives
To examine the diagnostic yield of trio exome sequencing in fetuses with multiple structural defects with no pathogenic findings in cytogenetic and microarray analyses.
Methods
We ...recruited 51 fetuses with two or more defects, non‐immune fetal hydrops or fetal akinesia deformation syndrome|or fetal akinesia deformation sequence (FADS). Trio exome sequencing was performed on DNA from chorionic villi samples and parental blood. Detection of genomic variation and prioritization of clinically relevant variants was performed according to in‐house standard operating procedures.
Results
Median maternal and gestational age was 32.0 years and 21.0 weeks, respectively. Forty‐three (84.3%) fetuses had two or more affected organ systems. The remaining fetuses had isolated fetal hydrops or FADS. In total, the exome analysis established the genetic cause for the clinical abnormalities in 22 (43.1%, 95% CI 29.4%–57.8%) pregnancies.
Conclusions
In fetuses with multiple defects, hydrops or FADS and normal standard genetic results, trio exome sequencing has the potential to identify genetic anomalies in more than 40% of cases.
Key points
What's already known about this topic?
Genome‐wide sequencing for unspecific heterogeneous syndromic and non‐syndromic congenital conditions increases the diagnostic yield compared with standard genetic testing in both the pre‐ and postnatal settings. The diagnostic yield prenatally varies depending on selection criteria and number of anomalies present.
What does this study add?
Trio exome sequencing should be considered for fetuses with normal cytogenetic and micro‐array analysis and two or more organ defects, fetal hydrops or fetal akinesia syndromes. Selection of cases for exome sequencing should be based on expert prenatal imaging.
Rivers are a major supplier of particulate and dissolved material to the ocean, but their role as sources of bio-essential dissolved iron (dFe) is thought to be limited due to rapid, efficient Fe ...removal during estuarine mixing. Here, we use trace element and radium isotope data to show that the influence of the Congo River margin on surface Fe concentrations is evident over 1000 km from the Congo outflow. Due to an unusual combination of high Fe input into the Congo-shelf-zone and rapid lateral transport, the Congo plume constitutes an exceptionally large offshore dFe flux of 6.8 ± 2.3 × 10
mol year
. This corresponds to 40 ± 15% of atmospheric dFe input into the South Atlantic Ocean and makes a higher contribution to offshore Fe availability than any other river globally. The Congo River therefore contributes significantly to relieving Fe limitation of phytoplankton growth across much of the South Atlantic.
The 26S proteasome operates at the executive end of the ubiquitinproteasome pathway. Here, we present a cryo-EM structure of the Saccharomyces cerevisiae 26S proteasome at a resolution of 7.4 Å or ...6.7 Å (Fourier-Shell Correlation of 0.5 or 0.3, respectively). We used this map in conjunction with molecular dynamics-based flexible fitting to build a near-atomic resolution model of the holocomplex. The quality of the map allowed us to assign α-helices, the predominant secondary structure element of the regulatory particle subunits, throughout the entire map. We were able to determine the architecture of the Rpn8/Rpn11 heterodimer, which had hitherto remained elusive. The MPN domain of Rpn11 is positioned directly above the AAA-ATPase N-ring suggesting that Rpn11 deubiquitylates substrates immediately following commitment and prior to their unfolding by the AAA-ATPase module. The MPN domain of Rpn11 dimerizes with that of Rpn8 and the C-termini of both subunits form long helices, which are integral parts of a coiled-coil module. Together with the C-terminal helices of the six PCI-domain subunits they form a very large coiled-coil bundle, which appears to serve as a flexible anchoring device for all the lid subunits.
Introduction Anxiety is one of the most prevalent mental health conditions worldwide, and psychotherapeutic techniques can be employed to help manage and mitigate symptoms. While the available ...therapies are numerous, key strategies often involve cognitive and/or embodiment techniques. Within body-centered methods, breathing-oriented approaches are particularly prevalent, using either attention towards or active control of breathing. As the perception of body states (i.e., interoception) is thought to be an integral component of emotion generation, these embodiment and breathing techniques may be key in addressing the miscommunication between the brain and body that is thought to exist with anxiety. Therefore, we conducted a systematic review and meta-analysis to assess the effects of acute administration of psychological interventions for state anxiety. Results This systematic review was conducted in accordance with the PRISMA statement and registered prospectively in PROSPERO. A literature search for randomized controlled trials was conducted in PubMed, PsycINFO, and Scopus. We considered interventions that focused on cognitive, embodiment or breathing strategies, or a combination of these techniques. Twelve studies met our inclusion criteria, and study characteristics, quality and effect sizes were assessed. A single cognitive study was found to produce a moderate reduction in state anxiety, while moderate to large effects were found across studies assessing embodiment practices. In contrast, studies which utilized breathing-based interventions alone produced inconsistent results, with both attention towards and active control of breathing producing large to no effects depending on the technique employed. Finally, consistent moderate effects were found with combination techniques that involved passive attention (e.g., towards cognitions, body and/or breathing), with active combination techniques producing inconsistent results. Discussion While study numbers are limited regarding brief interventions, cognitive and embodiment techniques are consistently helpful for reducing state anxiety, while breathing-based exercises need to consider the specific technique employed, and how successful this may be for each individual. Furthermore, combined practices such as mindfulness can also be successful, although care must be taken when introducing an active change to one or more elements. PROSPERO Systematic Review Registration Number CRD42024507585 Available from: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024507585 .
Non-coding RNAs have emerged as crucial regulators of gene expression and cell fate decisions. However, their expression patterns and regulatory functions during normal and malignant human ...hematopoiesis are incompletely understood. Here we present a comprehensive resource defining the non-coding RNA landscape of the human hematopoietic system. Based on highly specific non-coding RNA expression portraits per blood cell population, we identify unique fingerprint non-coding RNAs-such as LINC00173 in granulocytes-and assign these to critical regulatory circuits involved in blood homeostasis. Following the incorporation of acute myeloid leukemia samples into the landscape, we further uncover prognostically relevant non-coding RNA stem cell signatures shared between acute myeloid leukemia blasts and healthy hematopoietic stem cells. Our findings highlight the importance of the non-coding transcriptome in the formation and maintenance of the human blood hierarchy.While micro-RNAs are known regulators of haematopoiesis and leukemogenesis, the role of long non-coding RNAs is less clear. Here the authors provide a non-coding RNA expression landscape of the human hematopoietic system, highlighting their role in the formation and maintenance of the human blood hierarchy.
Malnutrition and dehydration are widespread in older people, and obesity is an increasing problem. In clinical practice, it is often unclear which strategies are suitable and effective in ...counteracting these key health threats.
To provide evidence-based recommendations for clinical nutrition and hydration in older persons in order to prevent and/or treat malnutrition and dehydration. Further, to address whether weight-reducing interventions are appropriate for overweight or obese older persons.
This guideline was developed according to the standard operating procedure for ESPEN guidelines and consensus papers. A systematic literature search for systematic reviews and primary studies was performed based on 33 clinical questions in PICO format. Existing evidence was graded according to the SIGN grading system. Recommendations were developed and agreed in a multistage consensus process.
We provide eighty-two evidence-based recommendations for nutritional care in older persons, covering four main topics: Basic questions and general principles, recommendations for older persons with malnutrition or at risk of malnutrition, recommendations for older patients with specific diseases, and recommendations to prevent, identify and treat dehydration. Overall, we recommend that all older persons shall routinely be screened for malnutrition in order to identify an existing risk early. Oral nutrition can be supported by nursing interventions, education, nutritional counselling, food modification and oral nutritional supplements. Enteral nutrition should be initiated if oral, and parenteral if enteral nutrition is insufficient or impossible and the general prognosis is altogether favorable. Dietary restrictions should generally be avoided, and weight-reducing diets shall only be considered in obese older persons with weight-related health problems and combined with physical exercise. All older persons should be considered to be at risk of low-intake dehydration and encouraged to consume adequate amounts of drinks. Generally, interventions shall be individualized, comprehensive and part of a multimodal and multidisciplinary team approach.
A range of effective interventions is available to support adequate nutrition and hydration in older persons in order to maintain or improve nutritional status and improve clinical course and quality of life. These interventions should be implemented in clinical practice and routinely used.
Not So Fast, All Devices and Their Materials Are Different Beck, Adam W.; Haulon, Stéphan; Ouriel, Kenneth
European journal of vascular and endovascular surgery,
April 2023, 2023-Apr, 2023-04-00, 20230401, 2023-04, Letnik:
65, Številka:
4
Journal Article
Mutations in
SCN1A
and other ion channel genes can cause different epileptic phenotypes, but the precise mechanisms underlying the development of hyperexcitable networks are largely unknown. Here, we ...present a multisystem analysis of an
SCN1A
mouse model carrying the Na
V
1.1-R1648H mutation, which causes febrile seizures and epilepsy in humans. We found a ubiquitous hypoexcitability of interneurons in thalamus, cortex, and hippocampus, without detectable changes in excitatory neurons. Interestingly, somatic Na
+
channels in interneurons and persistent Na
+
currents were not significantly changed. Instead, the key mechanism of interneuron dysfunction was a deficit of action potential initiation at the axon initial segment that was identified by analyzing action potential firing. This deficit increased with the duration of firing periods, suggesting that increased slow inactivation, as recorded for recombinant mutated channels, could play an important role. The deficit in interneuron firing caused reduced action potential-driven inhibition of excitatory neurons as revealed by less frequent spontaneous but not miniature IPSCs. Multiple approaches indicated increased spontaneous thalamocortical and hippocampal network activity in mutant mice, as follows: (1) more synchronous and higher-frequency firing was recorded in primary neuronal cultures plated on multielectrode arrays; (2) thalamocortical slices examined by field potential recordings revealed spontaneous activities and pathological high-frequency oscillations; and (3) multineuron Ca
2+
imaging in hippocampal slices showed increased spontaneous neuronal activity. Thus, an interneuron-specific generalized defect in action potential initiation causes multisystem disinhibition and network hyperexcitability, which can well explain the occurrence of seizures in the studied mouse model and in patients carrying this mutation.
Purpose: Hyperthermia has been shown to improve the effectiveness of chemotherapy and radiotherapy in the treatment of cancer. This paper summarises all recent clinical trials registered in the ...ClinicalTrials.gov registry. Materials and methods: The records of 175,538 clinical trials registered at ClinicalTrials.gov were downloaded on 29 September 2014 and a database was established. We searched this database for hyperthermia or equivalent words. Results: A total of 109 trials were identified in which hyperthermia was part of the treatment regimen. Of these, 49 trials (45%) had hyperthermic intraperitoneal chemotherapy after cytoreductive surgery (HIPEC) as the primary intervention, and 14 other trials (13%) were also testing some form of intraperitoneal hyperthermic chemoperfusion. Seven trials (6%) were testing perfusion attempts to other locations (thoracic/pleural n = 4, limb n = 2, hepatic n = 1). Sixteen trials (15%) were testing regional hyperthermia, 13 trials (12%) whole body hyperthermia, seven trials (6%) superficial hyperthermia and two trials (2%) interstitial hyperthermia. One remaining trial tested laser hyperthermia. Conclusions: In contrast to the general opinion, this analysis shows continuous interest and ongoing clinical research in the field of hyperthermia. Interestingly, the majority of trials focused on some form of intraperitoneal hyperthermic chemoperfusion. Despite the high number of active clinical studies, HIPEC is a topic with limited attention at the annual meetings of the European Society for Hyperthermic Oncology and the Society of Thermal Medicine. The registration of on-going clinical trials is of paramount importance for the achievement of a comprehensive overview of available clinical research activities involving hyperthermia.
Clearing of the dormant liver stage (the hypnozoite) of
P. vivax
malaria is important to prevent the relapse of infection. In this randomized clinical trial, a single dose of tafenoquine is shown to ...have significant activity against the hypnozoite form of
P. vivax
.
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