Repression of Irs2 by let-7 miRNAs is essential for homeostasis of the telencephalic neuroepithelium.

Structural integrity and cellular homeostasis of the embryonic stem cell niche are critical for normal tissue development. In the telencephalic neuroepithelium, this is controlled in part by cell adhesion molecules and regulators of progenitor cell lineage, but the specific orchestration of these processes remains unknown. Here, we studied the role of microRNAs in the embryonic telencephalon as key regulators of gene expression. By using the early recombiner Rx-Cre mouse, we identify novel and critical roles of miRNAs in early brain development, demonstrating they are essential to preserve the cellular homeostasis and structural integrity of the telencephalic neuroepithelium. We show that Rx-Cre;DicerF/F mouse embryos have a severe disruption of the telencephalic apical junction belt, followed by invagination of the ventricular surface and formation of hyperproliferative rosettes. Transcriptome analyses and functional experiments in vivo show that these defects result from upregulation of Irs2 upon loss of let-7 miRNAs in an apoptosis-independent manner. Our results reveal an unprecedented relevance of miRNAs in early forebrain development, with potential mechanistic implications in pediatric brain cancer.

First-in-human study of alpibectir (BVL-GSK098), a novel potent anti-TB drug.

BACKGROUND: The clinical candidate alpibectir augments the activity of, and overcomes resistance to, the anti-TB drug ethionamide in vitro and in vivo. OBJECTIVES: A Phase 1, double-blind, randomized, placebo-controlled study to investigate the safety, tolerability, pharmacokinetics (PK) and food effect of alpibectir administered as single and multiple oral doses in healthy volunteers (NCT04654143). METHODS: Eighty participants were randomized. In single ascending dose (SAD), a total of six dose levels of alpibectir (0.5 to 40 mg) were tested under fasted and fed (10 mg) conditions as single daily doses in sequential cohorts. In multiple ascending dose (MAD), repeat doses (5 to 30 mg) were administered once daily for 7 days in three sequential cohorts. RESULTS: No serious adverse event was reported. Thirteen participants across groups experienced a total of 13 mild or moderate treatment-emergent adverse events. Alpibectir showed rapid absorption after single dose (mean Tmax range of 0.88 to 1.53 h). Food affected the PK of alpibectir, characterized by a slower absorption (mean Tmax 3.87 h), a lower Cmax (-17.7%) and increased AUC0-t (+19.6%) compared with the fasted condition. Following repeat dosing, dose proportionality was shown for both Cmax and AUC0-tau. Accumulation of alpibectir was observed across all doses, with a more profound effect on AUC during a dosing interval (AUC0-tau) compared with Cmax (1.8- and 1.3-fold on average), respectively. Steady state was considered to have been achieved by Day 7 of dosing. CONCLUSIONS: Alpibectir was generally well tolerated, and no clinically relevant safety findings were identified in the participants treated during SAD or MAD. The PK is dose-proportional and affected by food.

COVID-19 infection and vaccination in 92 pediatric patients with cutaneous mastocytosis: A retrospective, cross-sectional study.

Mast cells (MCs) can release a variety of biologically active mediators under different circumstances, such as fever or vaccination. Our aim was to evaluate the incidence and severity of MC activation symptoms induced by SARS-CoV-2 virus (COVID-19) infection and vaccination in a cohort of 92 pediatric patients with cutaneous mastocytosis. Our findings support previous evidence on the safety of COVID-19 infection and vaccination in patients with MC disorders.

Integrated Discriminant Evaluation of Molecular Genetic Markers and Genetic Diversity Parameters of Endangered Balearic Dog Breeds.

The genetic diversity analysis of six dog breeds, including Ca de Bestiar (CB), Ca de Bou (CBOU), Podenco Ibicenco (PI), Ca Rater (CR), Ca Mè (CM), and Ca de Conills (CC), reveals insightful findings. CB showcases the highest mean number of alleles (6.17) and heterozygosity values, with significant deviations from Hardy-Weinberg equilibrium (HWE) observed in five markers, indicating high intra-racial genetic diversity (average observed heterozygosity (Ho) = 0.754, expected heterozygosity (He) = 0.761). In contrast, CBOU presents the lowest mean number of alleles (5.05) and heterozygosity values, coupled with moderate polymorphic information content (PIC) values and a moderate level of intra-racial genetic diversity (average Ho = 0.313, He = 0.394). PI demonstrates moderate genetic diversity with an average of 5.75 alleles and highly informative PIC values, while CR displays robust genetic diversity with an average of 6.61 alleles and deviations from equilibrium, indicating potential risks of inbreeding (average Ho = 0.563, He = 0.658). CM exhibits moderate genetic diversity and deviations from equilibrium, similar to CBOU, with an average of 6.5 alleles and moderate PIC values (average Ho = 0.598, He = 0.676). Conversely, CC shows a wider range of allelic diversity and deviations from equilibrium (average Ho = 0.611, He = 0.706), suggesting a more diverse genetic background. Inter-racial analysis underscores distinct genetic differentiation between breeds, emphasizing the importance of informed breeding decisions and proactive genetic management strategies to preserve diversity, promote breed health, and ensure long-term sustainability across all breeds studied.

Fulminant myocarditis following SARS-CoV-2 mRNA vaccination rescued with venoarterial ECMO: A report of two cases.

INTRODUCTION: Cases of myocarditis after COVID-19 messenger RNA (mRNA) vaccines administration have been reported. Although the majority follow a mild course, fulminant presentations may occur. In these cases, cardiopulmonary support with venoarterial extracorporeal membrane oxygenation (V-A ECMO) may be needed. RESULTS: We present two cases supported with V-A ECMO for refractory cardiogenic shock due to myocarditis secondary to a mRNA SARS-CoV2 vaccine. One of the cases was admitted for out-of-hospital cardiac arrest. In both, a peripheral V-A ECMO was implanted in the cath lab using the Seldinger technique. An intra-aortic balloon pump was needed in one case for left ventricle unloading. Support could be successfully withdrawn in a mean of five days. No major bleeding or thrombosis complications occurred. Whereas an endomyocardial biopsy was performed in both, a definite microscopic diagnosis just could be reached in one of them. Treatment was the same, using 1000mg of methylprednisolone/day for three days. A cardiac magnetic resonance was performed ten days after admission, showing a significant improvement of the left ventricular ejection fraction and diffuse oedema and subepicardial contrast intake in different segments. Both cases were discharged fully recovered, with CPC 1. CONCLUSIONS: COVID-19 vaccine-associated fulminant myocarditis has a high morbidity and mortality but presents a high potential for recovery. V-A ECMO should be established in cases with refractory cardiogenic shock during the acute phase.

GSK2556286 Is a Novel Antitubercular Drug Candidate Effective In Vivo with the Potential To Shorten Tuberculosis Treatment.

As a result of a high-throughput compound screening campaign using Mycobacterium tuberculosis-infected macrophages, a new drug candidate for the treatment of tuberculosis has been identified. GSK2556286 inhibits growth within human macrophages (50% inhibitory concentration [IC50] = 0.07 µM), is active against extracellular bacteria in cholesterol-containing culture medium, and exhibits no cross-resistance with known antitubercular drugs. In addition, it has shown efficacy in different mouse models of tuberculosis (TB) and has an adequate safety profile in two preclinical species. These features indicate a compound with a novel mode of action, although still not fully defined, that is effective against both multidrug-resistant (MDR) or extensively drug-resistant (XDR) and drug-sensitive (DS) M. tuberculosis with the potential to shorten the duration of treatment in novel combination drug regimens. (This study has been registered at ClinicalTrials.gov under identifier NCT04472897).

Nosocomial infections during extracorporeal membrane oxygenation.

PURPOSE OF THE REVIEW: The aim of this review is to present the latest evidence regarding the prevention, diagnosis and treatment of nosocomial infections during extracorporeal membrane oxygenation (ECMO) support. RECENT FINDINGS: New descriptive data from the Extracorporeal Life Support Organisation (ELSO) registry and single centre studies have been published. In parallel, there is an increase in the availability of evidence about the diagnostic accuracy of infection markers, yield of routine cultures, effectivity of antibiotic prophylaxis and other preventive measures. SUMMARY: ECMO is a rescue therapy for severe hemodynamic or respiratory failure. Nosocomial infections on ECMO support are frequent (infection rate ranging between 20.5% to more than 50% of ECMO runs) and have impact in survival, with reported increases in the risk of death up to 63% in infected patients. However, diagnosis and treatment are challenging, as the unique relationship between patient and circuit may act as a confounder for infection and exacerbate the variability of antibiotic pharmacokinetics in critical illness. Clinical practice regarding antibiotic treatment and infection prevention is not yet supported by high-quality evidence.

Possible substantive improvements in the structure of the Quality of Life in Adult Cancer Survivors (QLACS) scale? A study based on its Spanish version.

PURPOSE: Quality of Life in Adult Cancer Survivors (QLACS) scale is one of the most commonly used and validated measures to assess the Health-Related Quality of Life (HRQoL) in this population. However, there are some aspects related to its structure that still deserve consideration. The aim of this study was to test the substantive improvement over the original QLACS structure resulting from several proposals reflected in the literature. METHOD: Using a cross-sectional design and Confirmatory Factorial Analysis, we explored those proposals. Reliability, convergent validity, and factor invariance across three cancer survivorships phases (re-entry, early, and long term) were also analyzed. 1.862 post-treatment survivors of diverse cancer types completed the Spanish versions of QLACS, Brief Symptom Inventory-18 (BSI-18), and Subjective Happiness Scale (SHS). RESULTS: The original model with twelve domains, grouped (with the exception of benefits) into a single total score, versus two subtotal (Generic and Cancer-specific) obtained a good fit. The values of Cronbach's alpha, Composite reliability, Average Variance Extracted indexes, and Pearson correlations supported the internal consistency and temporal stability (interval of 2-3 weeks) of the QLACS. Results also showed its adequate convergent validity and an invariant factor structure across survival periods (re-entry survivorship, early survivorship, long-term survivorship). CONCLUSION: In its original structure, albeit the replacement of the scores on the two subscales by a total score, our results support QLACS as a valid and useful tool for the assessment of HRQoL in post-treatment cancer survivors throughout the different survival phases.

Bayesian evaluation of the effect of non-genetic factors on the phenomics for quality-related milk nutrients and yield in Murciano-Granadina goats.

The aim of this study was to evaluate the effect of non-genetic factors on the variability of milk production and composition using Bayesian linear regression. We analyzed 2594 milk records from 159 dairy goats from the breeding nucleus of the Murciano-Granadina breed. Bayesian linear regression was used to determine the effects of non-genetic factors on the phenomics for quality-related milk nutrients and yield. Multivariate regression model significantly explained 21.5%, 40.0%, 41.5%, 44.3%, 44.6%, and 47.5% of the variability in somatic cell count (SCC, sc/mL), lactose (%), protein (%), milk yield (kg), fat (%), and dry matter (%), respectively. Although the aforementioned factor combination significantly conditions milk production and composition, SCC may be particularly affected by collateral factors. Milking routine and drying period factors are reference predictors to be considered in the evaluation of milk production and composition progression. Drying period extensions positively repercussed on milk yield and lactose content, but negatively affected fat, protein, dry matter contents, and somatic cell count. Variability across drying years may depend on the drying season rather than the drying month course, except for milk yield, for which an increasing trend was reported from winter to summer. Including drying period-related non-genetic factors in genetic evaluations improves the accuracy of the regression models and permits to boost the commercial possibilities and profitability of local breeds.

[Referral criteria to clinical genetics from primary care: Consensus document]. / Criterios de derivación a genética clínica desde Atención Primaria. Documento de consenso.

INTRODUCTION: Primary care (PC) is the first contact between the patient and the doctor, so it is essential to be clear about the criteria for suspecting a genetic disease and where it should be referred for study. MATERIAL AND METHODS: Four scientific societies: the Spanish Society of Family and Community Medicine (semFYC), the Spanish Association of Human Genetics (AEGH), the Spanish Association of Pediatrics (AEP) and the Spanish Society of Medical Oncology (SEOM), have reviewed the criteria for referral to the clinical genetics services of the different published guidelines with the purpose of define the recommendations for PC. CONCLUSIONS: With this consensus document, the PC doctor and pediatrician will know when, how and where to refer their patients with hereditary and/or genetic pathology to clinical genetics services.

Extracorporeal membrane oxygenation in Jehovah's Witness patients: Case report, literature review, and summary of recommendations.

Extracorporeal Membrane Oxygenation (ECMO) is commonly associated with a high blood transfusion requirement. Jehovah's Witness patients present a particular challenge. The impossibility of transfusing blood cells and starting anticoagulation treatment are common contraindications for this supportive measure. Here we report the case of a Jehovah's Witness patient with refractory hypoxemia due to influenza A H1N1 pneumonia who required venovenous ECMO for 11 days. We describe the use of a bloodless approach to reduce the waste of blood, avoiding anticoagulation, and improving red blood cell production. We then summarize the current literature on the use of ECMO in Jehovah's Witness patients and, finally, we propose some recommendations for their management.

Development of a Highly Selective Plasmodium falciparum Proteasome Inhibitor with Anti-malaria Activity in Humanized Mice.

Plasmodium falciparum proteasome (Pf20S) inhibitors are active against Plasmodium at multiple stages-erythrocytic, gametocyte, liver, and gamete activation stages-indicating that selective Pf20S inhibitors possess the potential to be therapeutic, prophylactic, and transmission-blocking antimalarials. Starting from a reported compound, we developed a noncovalent, macrocyclic peptide inhibitor of the malarial proteasome with high species selectivity and improved pharmacokinetic properties. The compound demonstrates specific, time-dependent inhibition of the ß5 subunit of the Pf20S, kills artemisinin-sensitive and artemisinin-resistant P. falciparum isolates in vitro and reduces parasitemia in humanized, P. falciparum-infected mice.

Improving junior doctor medicine prescribing and patient safety: An intervention using personalised, structured, video-enhanced feedback and deliberate practice.

AIMS: This research investigated the effectiveness of an intervention for improving the prescribing and patient safety behaviour among Foundation Year doctors. The intervention consisted of simulated clinical encounters with subsequent personalised, structured, video-enhanced feedback and deliberate practice, undertaken at the start of four-month sub-specialty rotations. METHODS: Three prospective, non-randomised control intervention studies were conducted, within two secondary care NHS Trusts in England. The primary outcome measure, error rate per prescriber, was calculated using daily prescribing data. Prescribers were grouped to enable a comparison between experimental and control conditions using regression analysis. A break-even analysis evaluated cost-effectiveness. RESULTS: There was no significant difference in error rates of novice prescribers who received the intervention when compared with those of experienced prescribers. Novice prescribers not participating in the intervention had significantly higher error rates (P = .026, 95% confidence interval [CI] Wald 0.093 to 1.436; P = .026, 95% CI 0.031 to 0.397) and patients seen by them experienced significantly higher prescribing error rates (P = .007, 95% CI 0.025 to 0.157). Conversely, patients seen by the novice prescribers who received the intervention experienced a significantly lower rate of significant errors compared to patients seen by the experienced prescribers (P = .04, 95% CI -0.068 to -0.001). The break-even analysis demonstrates cost-effectiveness for the intervention. CONCLUSION: Simulated clinical encounters using personalised, structured, video-enhanced feedback and deliberate practice improves the prescribing and patient safety behaviour of Foundation Year doctors. The intervention is cost-effective with potential to reduce avoidable harm.

Non-parametric association analysis of additive and dominance effects of casein complex SNPs on milk content and quality in Murciano-Granadina goats.

Goat milk casein proteins (αS1, αS2, ß and κ) are encoded by four loci (CSN1S1, CSN1S2, CSN2 and CSN3, respectively) clustered within 250 kb in chromosome 6. In this study, 159 Murciano-Granadina goats were genotyped for 48 SNPs within the entire casein region. Phenotypes on milk yield and components were obtained from 2,594 dairy registries. Additive and dominance effects on milk composition and quality were studied using non-parametric tests and principal component analysis to prevent SNPs multicollinearity. Two deletions in exon 4 (CSN1S1 and CSN3), one in exon 7 (CSN2) and one in exon 15 (CSN1S2) have been found at frequencies ranging from 0.12 to 0.50. Bonferroni-corrected significant SNP additive and dominance effects were found for milk yield, fat, protein, dry matter and lactose, and somatic cells. Exons 15 and 7 were significantly associated with milk yield and components except for lactose and somatic cells, while exon 4 was significantly associated with milk yield and components except for protein and dry matter. SNPs' associations with somatic cells were less frequent and weaker than those with milk yield and components. As caseins increase, somatic cells decrease, reducing milk enzymatic activity and consumption suitability. Hence, including molecular information in breeding schemes may promote production efficiency, as selecting against undesirable alleles could prevent the compromises derived from their dominance effects.

An efficient synthetic route for preparation of antimycobacterial wollamides and evaluation of their in vitro and in vivo efficacy.

A convenient solid phase peptide synthetic (SPPS) route is reported for the preparation of antimycobacterial wollamides. The method is based on on-resin head-to-tail cyclization and is fast, efficient and amenable to automation. The in vitro antimycobacterial activities of the newly synthesized wollamides were evaluated against M. tuberculosis H37Rv (Mtb H37Rv). To assess their drug-likeness, in vitro pharmacokinetic (ADME) profiling was also performed. For wollamides with potent extracellular potency, intracellular activities and in vivo efficacy were determined. The results disclose the potent antimycobacterial (MICMtb H37Rv = 1.1 µM) and suitable drug-like properties of wollamide A (4b). Out of the synthesized wollamides, four compounds (4b-e) exhibited potent intracellular activities against Mtb H37Rv infected human macrophages (IC50 = 0.2-1.3 µM). Results of in vivo blood exposure and efficacy assays for 4d and 4e are discussed.

A Complex Code of Extrinsic Influences on Cortical Progenitor Cells of Higher Mammals.

Development of the cerebral cortex depends critically on the regulation of progenitor cell proliferation and fate. Cortical progenitor cells are remarkably diverse with regard to their morphology as well as laminar and areal position. Extrinsic factors, such as thalamic axons, have been proposed to play key roles in progenitor cell regulation, but the diversity, extent and timing of interactions between extrinsic elements and each class of cortical progenitor cell in higher mammals remain undefined. Here we use the ferret to demonstrate the existence of a complex set of extrinsic elements that may interact, alone or in combination, with subpopulations of progenitor cells, defining a code of extrinsic influences. This code and its complexity vary significantly between developmental stages, layer of residence and morphology of progenitor cells. By analyzing the spatial-temporal overlap of progenitor cell subtypes with neuronal and axonal populations, we show that multiple sets of migrating neurons and axon tracts overlap extensively with subdivisions of the Subventricular Zones, in an exquisite lamina-specific pattern. Our findings provide a framework for understanding the feedback influence of both intra- and extra-cortical elements onto progenitor cells to modulate their dynamics and fate decisions in gyrencephalic brains.

Regulation of cerebral cortex size and folding by expansion of basal progenitors.

Size and folding of the cerebral cortex increased massively during mammalian evolution leading to the current diversity of brain morphologies. Various subtypes of neural stem and progenitor cells have been proposed to contribute differently in regulating thickness or folding of the cerebral cortex during development, but their specific roles have not been demonstrated. We report that the controlled expansion of unipotent basal progenitors in mouse embryos led to megalencephaly, with increased surface area of the cerebral cortex, but not to cortical folding. In contrast, expansion of multipotent basal progenitors in the naturally gyrencephalic ferret was sufficient to drive the formation of additional folds and fissures. In both models, changes occurred while preserving a structurally normal, six-layered cortex. Our results are the first experimental demonstration of specific and distinct roles for basal progenitor subtypes in regulating cerebral cortex size and folding during development underlying the superior intellectual capability acquired by higher mammals during evolution.

Anatomical variants and bilateral lacrimal pathways surgery: avoiding unnecessary surgery.

Success rates (SR) of transcanalicular diode laser-assisted dacryocystorhinostomy (TCL DCR) may be affected by the presence of nasal anatomical variations and additionally by whether or not the pathology is bilateral. The aim is to determine whether it is necessary to perform preliminary nasal anatomical variations surgery and to determine whether bilateral cases may be operated simultaneously. We extracted the patients undergoing simultaneous bilateral TCL DCR and we compared SR across the different groups using ANOVA, Chi-square testing and logistical regression. 159 Lacrimal pathways were operated: 89 unilateral and 35 bilateral. Non-nasal anatomical variations (non-NAV) unilateral surgery returned a success of 72.72%. The mean SR for nasal anatomical variations (NAV) unilateral surgery was 70.1%. The SR for non-NAV bilateral surgery was 60.86%. The mean SR for nasal anatomical variations bilateral surgery was 58.33%. As we identified no significant differences in the SR for NAV and non-NAV patients, we can avoid simultaneous corrective surgery.