Regulation of Age-Related Lipid Metabolism in Ovarian Cancer.

Although a lot of effort has been dedicated to ovarian cancer (OC) research, the mortality rate is still among the highest in female gynecologic malignancies. The effects of the aged tumor microenvironment are still being undermined despite age being the highest risk factor in ovarian cancer development and progression. In this study, we have conducted RNA sequencing and lipidomics analysis of gonadal adipose tissues from young and aged rat xenografts before and after ovarian cancer formation. We have found significantly higher tumor formation rates and volumes in aged OC xenograft rat models compared to their young counterparts (p<0.05), suggesting the aged adipose microenvironment (AME) is more susceptible to OC outgrowth. We have revealed significant shifts in the gene expression enrichment from groups of young vs. aged rats before tumor formation, groups of young vs. aged rats when the tumor formed, and groups of aged rats before and after tumor formation. We also observed shifts in the lipid components of the gonadal adipose tissues between young and aged rat xenografts when tumors were generated. Additionally, we found that the aged AME was associated with age-related changes in the immune cell composition, especially inflammation-related cells. The top hits showing the most differences between aged and young adipose tissues were eight genes including S100a8, S100a9, Il1rl1, Lcn2, C3, Hba-a1, Fcna, and Pnpla3, 22 lipids including multiple isoforms of free fatty acids (FFA) and triglyceride (TG), as well as four immune cells including neutrophil, myeloid dendritic cell, T cell CD4+ (non-regulatory), and mast cell activation. The functional correlation among S100a8, S100a9, neutrophil, and FFA (18:3) was also determined. Furthermore, FFA (18:3), which was shown to be downregulated in aged xenograft rats, was capable of inhibiting OC cell proliferation. In conclusion, our study suggested that aging promoted OC proliferation through changes in genes/pathways, lipid metabolism, and immune cells. Targeting the aging adipose microenvironment, particularly lipid metabolism reprogramming, holds promise as a therapeutic strategy for OC, which warrants further investigation. Significance: Aging microenvironment of OC may be regulated by S100a8 and S100a9 secreted by adipocytes, preadipocytes, or neutrophils through affecting the lipid metabolism, such as FFA (18:3).

Optimizing ß-lactam-containing antibiotic combination therapy for the treatment of Buruli ulcer.

AIMS: The current treatment for Buruli ulcer is based on empirical evidence of efficacy. However, there is an opportunity for shortening its duration and improving response rates. Evolving understanding of the pharmacokinetic-pharmacodynamic relationships provides the basis for a stronger dose rationale for antibiotics. In conjunction with modelling and simulation, it is possible to identify dosing regimens with the highest probability of target attainment (PTA). This investigation aims to: (i) assess the dose rationale for a new combination therapy including amoxicillin/clavulanic acid (AMX/CLV) currently in clinical trials; and (ii) compare its performance with alternative dosing regimens including rifampicin, clarithromycin and AMX/CLV. METHODS: In vitro estimates of the minimum inhibitory (MIC) concentration were selected as a measure of the antibacterial activity of different drug combinations. Clinical trial simulations were used to characterize the concentration vs. time profiles of rifampicin, clarithromycin and amoxicillin in a virtual cohort of adult and paediatric patients, considering the effect of baseline covariates on disposition parameters and interindividual variability in exposure. The PTA of each regimen was then assessed using different thresholds of the time above MIC. RESULTS: A weight-banded dosing regimen including 150-600 mg rifampicin once daily, 250-1000 mg clarithromycin and AMX/CLV 22.5 mg/kg /1000 mg twice daily ensures higher PTA than the standard of care with AMX/CLV 45 mg/kg/2000 mg once daily. CONCLUSION: The higher PTA values support the proposed 4-drug combination (rifampicin, clarithromycin, AMX/CLV) currently under clinical investigation. Our findings also suggest that higher rifampicin doses might contribute to enhanced treatment efficacy.

Corrigendum to "An early economic evaluation of Kooth, a web-based mental health platform for children and young people with emerging mental health needs" [Internet Interv. 36 (2024) 100748 10.1016/j.invent.2024.100748 (Published online 2024 May 11)].

[This corrects the article DOI: 10.1016/j.invent.2024.100748.].

SCAI Manual of Standard Operating Procedures for Performing Scientific Surveys.

The Society for Cardiovascular Angiography & Interventions (SCAI) endeavors to serve the interventional cardiology community, including both clinicians and patients. The SCAI Scientific Oversight Committee is charged with annually reviewing the scientific needs of the membership at large, including survey-based research of the practice patterns and perspectives of SCAI members and stakeholders. This document is intended as a reference by the survey proponents, document writing groups, external collaborators, SCAI representatives, peer reviewers, and anyone seeking information about the SCAI surveys program. The aims of this SCAI document are to: (1) provide a framework for members to develop survey requests that are relevant, feasible, and align with the Society's missions and goals; (2) promote transparency and clarity for the process of performing a survey through SCAI; (3) establish the criteria for evaluating survey requests and provide input on reliable and meaningful design, data collection, and best practices; and (4) facilitate collaboration and communication between the survey committee and members of SCAI to maximize the impact of the findings to the interventional community at large.

Healable Supracolloidal Nanocomposite Water-Borne Coatings.

Water-borne coatings often contain nanofillers to enhance their mechanical or optical properties. The aggregation of these fillers may, however, lead to undesired effects such as brittle and opaque coatings, reducing their performance and lifetime. By controlling the distribution and structural arrangement of the nanofillers in the coatings and inserting reversible chemical bonds, both the elasticity and strength of the coatings may be effectively improved, while healing properties, via the reversible chemistry, extend the coating's lifetime. Aqueous dispersions of polymer-core/silica-corona supracolloidal particles were used to prepare water-borne coatings. Polymer and silica nanoparticles were prefunctionalized with thiol/disulfide groups during the supracolloid assembly. Disulfide bridges were further established between a cross-linker and the supracolloids during drying and coating formation. The supracolloidal nanocomposite coatings were submitted to intentional (physical) damages, i.e., blunt and sharp surface scratches or cut through into two pieces, and subsequently UV irradiated to induce the recovery of the damage(s). The viscoelasticity and healing properties of the coatings were examined by dynamic, static, and surface mechanical analyses. The nanocomposite coatings showed a great extent of interfacial restoration of cut damage and surface scratches. The healing properties are strongly related to the coating's viscoelasticity and interfacial (re)activation of the disulfide bridges. Nanocomposite coatings with silica concentrations below their critical volume fraction show higher in situ healing efficiency, as compared to coatings with higher silica concentration. This work provides insights into the control of nanofillers distribution in water-borne coatings and strategies to increase the coating lifetime via mechanical damage recovery.

Non-immune hydrops fetalis is associated with bi-allelic pathogenic variants in the MYB Binding Protein 1a (MYBBP1A) gene.

Non-immune hydrops fetalis (NIHF) is a rare entity characterized by excessive accumulation of fluid within the fetal extravascular compartments and body cavities. Here we present two intrauterine fetal demises with NIHF presenting with oligohydramnios, cystic hygroma, pleural effusion, and generalized hydrops with predominance of subcutaneous edema. The fetuses also presented with ascites, severe and precocious IUGR and skeletal anomalies. Whole exome sequencing was applied in order to screen for a possible genetic cause. The results identified biallelic variants in MYBBP1A in both fetuses. A previous report described another case with a similar phenotype having compound heterozygous variants in the same gene. The protein encoded by MYBBP1A is involved in several cellular processes including the synthesis of ribosomal DNA, the response to nucleolar stress, and tumor suppression. Our functional protein analysis through immunohistochemistry indicates that MYBBP1A is a gene expressed during fetal stages. Altogether, we concluded that MYBBP1A is associated with the development of hydrops fetalis. More cases and further studies are necessary to understand the role of this gene and the mechanism associated with NIHF.

The novel drug candidate VOMG kills Mycobacterium abscessus and other pathogens by inhibiting cell division.

AIMS: The incidence of lung infections is increasing worldwide in individuals suffering from cystic fibrosis and chronic obstructive pulmonary disease. Mycobacterium abscessus is associated with chronic lung deterioration in these populations. The intrinsic resistance of M. abscessus to most conventional antibiotics jeopardizes treatment success rates. To date, no single drug has been developed targeting M. abscessus specifically. The objective of this study was to characterize VOMG, a pyrithione-core drug-like small molecule, as a new compound active against M. abscessus and other pathogens. METHODS: A multi-disciplinary approach including microbiological, chemical, biochemical and transcriptomics procedures was used to validate VOMG as a promising anti-M. abscessus drug candidate. RESULTS: To the authors' knowledge, this is the first study to report the in-vitro and in-vivo bactericidal activity of VOMG against M. abscessus and other pathogens. Besides being active against M. abscessus biofilm, the compound showed a favourable pharmacological (ADME-Tox) profile. Frequency of resistance studies were unable to isolate resistant mutants. VOMG inhibits cell division, particularly the FtsZ enzyme. CONCLUSIONS: VOMG is a new drug-like molecule active against M. abscessus, inhibiting cell division with broad-spectrum activity against other microbial pathogens.

Perceptions of interventional cardiologists on diversity and discrimination.

Background: There are limited data on diversity and discrimination against interventional cardiologists (ICs). Methods: We performed an online, anonymous, international survey of interventional cardiologists on their perceptions of diversity and discrimination in their field. Results: A total of 445 ICs participated in the survey. The median age of participants was 46 to 50 years and most (60%) practice in the United States. Among the respondents, 13% identified as women, while 31% identified as Asian, 10% as Latino, and 3.2% as Black/African American. Women ICs were less likely to be married (62% vs 92%; P < .001) or have children (48% vs 87%; P < .001). Women, non-native English speakers, and non-white individuals had a higher likelihood of reporting discrimination from patients/families, peers, supervisors, support staff, and nursing staff, compared with men, native English speakers, and non-Hispanic white individuals, respectively. Women were less satisfied with the level of gender diversity in their workplace (25% vs 45%; P = .015) and were more likely to believe that women physicians have fewer opportunities in the field of IC compared with men (69% vs 35%; P < .001). Non-white individuals were more likely to believe that their race/ethnicity may impede the progress of their career (54% vs 15%; P < .001), that their race/ethnicity negatively impacted their fellowship prospects/acceptance (35% vs 11%; P < .001), and that their religion negatively impacted their fellowship prospects/acceptance (17% vs 4%; P = .003). Several participants (41%) expressed concerns that diversity, equity, and inclusion initiatives might result in unintended consequences. Conclusions: Our survey suggests that ICs perceive high rates of discrimination in their field.

Enhancing computational thinking in early childhood education with educational robotics: A meta-analysis.

This paper deals within a context where technology plays a pivotal role in education. In this sense, it is essential to highlight the emergence of new competencies and skills in education due to technological advancements. Legislative frameworks have been developed to incorporate digital literacy, access to robotics, and computational thinking, between others. Hence, this review and meta-analysis aim at identifying the influence of robotics activities on computational thinking through a PRISMA-guided review. The findings reveal that interventions conducted in early childhood education significantly impact computational thinking. Results also showcase that, despite perceived barriers related to technology accessibility, the presence of legislation and contexts prioritizing these competencies is more relevant than the digital access gap.

Trends in the impact of suicide compared to other external causes of death: From 1995 to 2020.

BACKGROUND: Suicide is one of the world's greatest public health problems. More than 700,000 people lose their lives to suicide every year. While funding for mental health waits to be increased, thousands of suicides occur every day. MATERIAL AND METHODS: This study aims to quantify the global impact of suicide compared to other external causes of death in terms of years of potential life lost (YPLL), and how this will change between 1995 and 2020. Our source of information is the World Health Organization (WHO) mortality database. We then use YPLL, a standard measure of premature mortality and burden of disease that brings precision to the assessment of the impact of different causes of death. This, combined with the compound annual growth rate (CAGR) as a way of expressing increase, gives us a better understanding of the real situation and trends of suicide compared to other external causes of death in different countries worldwide. RESULTS: Based on the available sources of information and the selection criteria, we obtained a sample of 69 countries. The CAGR for all causes per capita decreased over the observed period in 65 countries, and it increases in 4 countries. In contrast, the CAGR specifically for suicide decreased in 49 countries, while an increase was observed in 20 countries. CONCLUSIONS: Prevention of most external causes of mortality shows promising data in most countries. However, this is not the case for suicide. Thus, YPLL due to suicide have decreased to a comparatively lesser extent and have even increased in some countries, a very worrying situation that poses many clinical and epidemiological challenges.

Role of Molecular Water Layer State on Freezing Front Propagation Rate and Mode Studied with Thermal Imaging.

In this work, we study the relationship between the molecular water layer (MWL) and frost freezing onset and propagation. The progression of frost has been reported to be governed by various localized icing phenomena, including interdroplet ice bridging, dry zones, and frost halos. Reports studying the state of water on surfaces have revealed the presence of a thin nanometer water layer on a range of surfaces. Regardless of further investigations that show environmental humidity, temperature, and surface energy to affect the thickness of the MWL on surfaces, the influence of the MWL on frost nucleation and propagation has not yet been previously addressed in the literature. To study the effect of the MWL on surface freezing events, a range of surface-functionalized glass substrates were prepared. In situ monitoring of freezing events with thermal imaging allowed studying the effect of surface chemistry and environmental relative humidity (RH) on the thickness and continuity of the MWL. We argue that the observed icing nucleation and propagation kinetics are directly related to the presence and continuity of the MWL, which can be manipulated by controlling the environmental humidity and surface chemistry.

Guidelines for NGS procedures applied to prenatal diagnosis by the Spanish Society of Gynecology and Obstetrics and the Spanish Association of Prenatal Diagnosis.

OBJECTIVE: This document addresses the clinical application of next-generation sequencing (NGS) technologies for prenatal genetic diagnosis and aims to establish clinical practice recommendations in Spain to ensure uniformity in implementing these technologies into prenatal care. METHODS: A joint committee of expert obstetricians and geneticists was created to review the existing literature on fetal NGS for genetic diagnosis and to make recommendations for Spanish healthcare professionals. RESULTS: This guideline summarises technical aspects of NGS technologies, clinical indications in prenatal setting, considerations regarding findings to be reported, genetic counselling considerations as well as data storage and protection policies. CONCLUSIONS: This document provides updated recommendations for the use of NGS diagnostic tests in prenatal diagnosis. These recommendations should be periodically reviewed as our knowledge of the clinical utility of NGS technologies, applied during pregnancy, may advance.

An early economic evaluation of Kooth, a web-based mental health platform for children and young people with emerging mental health needs.

Background: "Kooth" is a web-based mental health platform commissioned by the National Health Service (NHS), local authorities, charities, and businesses in the UK. The platform gives children and young people (CYP) access to an online community of peers and a team of counsellors. This study reports an early economic evaluation of the potential benefits of Kooth in the UK. Methods: An early evidence cost calculator was built to estimate the potential costs and savings of implementing Kooth from a UK NHS and crime sector perspective. A decision tree structure was used to track the progress of CYP with emerging mental health needs (EMHN), comparing CYP with access to Kooth to CYP without access to Kooth. The model implemented a 12-month time horizon and followed a typical Kooth contract in relation to costing, engagement, and CYP demographics. Results: The base case results followed a cohort of 2160 CYP. The results of the cost calculator estimated that engagement with Kooth is associated with a cost saving of £469,237 to the NHS across a 12-month time horizon, or £236.15 per CYP with an EMHN. From a combined NHS and UK crime sector perspective, the cost savings increased to £489,897, or £246.54 per CYP with an EMHN. The largest cost savings were provided by an estimated reduction of 5346 GP appointments and 298 antidepressant prescriptions. For this cohort, the model predicted that engagement with Kooth averted 6 hospitalisations due to suicidal ideation and 13 hospitalisations due to self-harm. Furthermore, the number of smokers and binge drinkers was reduced by 20 and 24, respectively. When a crime sector perspective was taken, 3 crimes were averted. Discussion: This early model demonstrates that Kooth has the potential to be a cost-saving intervention from both an NHS and a combined NHS and UK crime sector perspective. Cost savings were provided through aversion in clinical and social outcomes. The model used a conservative approach to balance the uncertainty around assumptions of the intermediate outcomes (GP and medication use). However, it is limited by a paucity of costing data and published evidence relating to the impact of digital mental health platforms.

A Novel Missense Variant in the NKX2-1 Homeodomain Prevents Transcriptional Rescue by TAZ.

Background: Brain-lung-thyroid syndrome (BLTS) is caused by NKX2-1 haploinsufficiency, resulting in chorea/choreoathetosis, respiratory problems, and hypothyroidism. Genes interacting with NKX2-1 mutants influence its phenotypic variability. We report a novel NKX2-1 missense variant and the modifier function of TAZ/WWTR1 in BLTS. Methods: A child with BLTS underwent next-generation sequencing panel testing for thyroid disorders. His family was genotyped for NKX2-1 variants and screened for germline mosaicism. Mutant NKX2-1 was generated, and transactivation assays were performed on three NKX2-1 target gene promoters. DNA binding capacity and protein-protein interaction were analyzed. Results: The patient had severe BLTS and carried a novel missense variant c.632A>G (p.N211S) in NKX2-1, which failed to bind to specific DNA promoters, reducing their transactivation. TAZ cotransfection did not significantly increase transcription of these genes, although the variant retained its ability to bind to TAZ. Conclusions: We identify a novel pathogenic NKX2-1 variant that causes severe BLTS and is inherited through germline mosaicism. The mutant lacks DNA-binding capacity, impairing transactivation and suggesting that NKX2-1 binding to DNA is essential for TAZ-mediated transcriptional rescue.

New Insights and Perspective on Bioprosthetic Valve Fracture From Bench Testing and Computed Tomography Analysis.

Background: Bioprosthetic valve fracture (BVF) during valve-in-valve TAVR (transcatheter aortic valve replacement) is a procedural adjunct designed to optimize the expansion of the transcatheter heart valve and reduce patient-prosthesis mismatch by using a high-pressure balloon to intentionally fracture the surgical heart valve (SHV). Methods: We performed bench testing on 15 bioprosthetic SHV to examine the optimal balloon size and pressure for BVF. We assessed morphological changes and expansion of SHV by computed tomography angiography. Successful BVF was defined as balloon waist disappearance on fluoroscopy and/or sudden pressure drop during balloon inflation. Results: Nine valves met the definition of BVF, 3 of which were confirmed by disruption of the stent frame. We classified surgical valves into 3 subsets: 1) fracturable with metal stent frame (MSF), 2) fracturable with polymer stent frame (PSF) and 3) nonfracturable. In general, valves with MSF were fractured using a balloon size = true internal diameter plus 3-5 mm inflated at high pressure (16-20 ATM) whereas valves with PSF could be fractured with a balloon size = true internal diameter plus 3-5 mm and lower balloon pressure (6-14 ATM). Gains in computed tomography angiography derived inflow area after BVF were 12.3% for MSF and 3.6% for PSF SHV. Conclusions: Gains in CT-determined valve area after BVF depend on the physical properties of the SHV, which in turn influences pressure thresholds and balloon sizing strategy for optimal BVF. Elastic recoil of PSF valves limits the gains in inflow area after BVF.

Sex-Related Differences in the Phenotype and Course of Inflammatory Bowel Disease: SEXEII Study of ENEIDA.

BACKGROUND & AIMS: The impact of patient sex on the presentation of inflammatory bowel disease (IBD) has been poorly evaluated. Our aims were to assess potential disparities in IBD phenotype and progression between sexes. METHODS: We performed an observational multicenter study that included patients with Crohn's disease (CD) or ulcerative colitis from the Spanish Estudio Nacional en Enfermedad Inflamatoria intestinal sobre Determinantes genéticos y Ambientales registry. Data extraction was conducted in July 2021. RESULTS: A total of 51,595 patients with IBD were included, 52% were males and 25,947 had CD. The median follow-up period after diagnosis was 9 years in males and 10 years in females. In CD, female sex was an independent risk factor for medium disease onset (age, 17-40 y) (relative risk ratio, 1.45; 95% CI, 1.31-1.62), later disease onset (age, >40 y) (relative risk ratio, 1.55; 95% CI, 1.38-1.73), exclusive colonic involvement (odds ratio, 1.24; 95% CI, 1.14-1.34), inflammatory behavior (odds ratio, 1.14; 95% CI, 1.07-1.21), and extraintestinal manifestations (odds ratio, 1.48; 95% CI, 1.38-1.59). However, female sex was a protective factor for upper gastrointestinal involvement (odds ratio, 0.84; 95% CI, 0.79-0.90), penetrating behavior (odds ratio, 0.76; 95% CI, 0.70-0.82), perianal disease (odds ratio, 0.77; 95% CI, 0.71-0.82), and complications (odds ratio, 0.73; 95% CI, 0.66-0.80). In ulcerative colitis, female sex was an independent risk factor for extraintestinal manifestations (odds ratio, 1.48; 95% CI, 1.26-1.61). However, female sex was an independent protective factor for disease onset from age 40 onward (relative risk ratio, 0.76; 95% CI, 0.66-0.87), left-sided colonic involvement (relative risk ratio, 0.72; 95% CI, 0.67-0.78), extensive colonic involvement (relative risk ratio, 0.59; 95% CI, 0.55-0.64), and abdominal surgery (odds ratio, 0.78; 95% CI, 0.69-0.88). CONCLUSIONS: There is sexual dimorphism in IBD. The patient's sex should be taken into account in the clinical management of the disease.