Alveolar capillary dysplasia with misalignment of the pulmonary veins: A surgical lung biopsy and autopsy in a full-term newborn.

Alveolar capillary dysplasia with misalignment of the pulmonary veins (ACD/MPV) is a rare and lethal interstitial lung disorder, caused by a congenital abnormality affecting the development of the parenchyma and pulmonary vessels. We report the case of a newborn at the end of 40 weeks of pregnancy, who showed no cardiopulmonary anomalies in prenatal control ultrasounds. However, after delivery, pulmonary hypertension and hypoxemic respiratory failure became apparent. She died after 12 days from refractory hemodynamic and respiratory failure despite intensive therapy. A surgical lung biopsy and clinical autopsy were performed, both revealing the same histopathological signs consistent with this disorder. In our case, the findings of digestive and genital malformations, together with the genetic result of the alteration in the FOXF1 gene, led us to conclude the definitive diagnosis of alveolar capillary dysplasia.

Deep learning automatic semantic segmentation of glioblastoma multiforme regions on multimodal magnetic resonance images.

OBJECTIVES: In patients having naïve glioblastoma multiforme (GBM), this study aims to assess the efficacy of Deep Learning algorithms in automating the segmentation of brain magnetic resonance (MR) images to accurately determine 3D masks for 4 distinct regions: enhanced tumor, peritumoral edema, non-enhanced/necrotic tumor, and total tumor. MATERIAL AND METHODS: A 3D U-Net neural network algorithm was developed for semantic segmentation of GBM. The training dataset was manually delineated by a group of expert neuroradiologists on MR images from the Brain Tumor Segmentation Challenge 2021 (BraTS2021) image repository, as ground truth labels for diverse glioma (GBM and low-grade glioma) subregions across four MR sequences (T1w, T1w-contrast enhanced, T2w, and FLAIR) in 1251 patients. The in-house test was performed on 50 GBM patients from our cohort (PerProGlio project). By exploring various hyperparameters, the network's performance was optimized, and the most optimal parameter configuration was identified. The assessment of the optimized network's performance utilized Dice scores, precision, and sensitivity metrics. RESULTS: Our adaptation of the 3D U-net with additional residual blocks demonstrated reliable performance on both the BraTS2021 dataset and the in-house PerProGlio cohort, employing only T1w-ce sequences for enhancement and non-enhanced/necrotic tumor models and T1w-ce + T2w + FLAIR for peritumoral edema and total tumor. The mean Dice scores (training and test) were 0.89 and 0.75; 0.75 and 0.64; 0.79 and 0.71; and 0.60 and 0.55, for total tumor, edema, enhanced tumor, and non-enhanced/necrotic tumor, respectively. CONCLUSIONS: The results underscore the high precision with which our network can effectively segment GBM tumors and their distinct subregions. The level of accuracy achieved agrees with the coefficients recorded in previous GBM studies. In particular, our approach allows model specialization for each of the different tumor subregions employing only those MR sequences that provide value for segmentation.

BCAS1 defines a heterogeneous cell population in diffuse gliomas.

Oligodendrocyte precursor markers have become of great interest to identify new diagnostic and therapeutic targets for diffuse gliomas, since state-of-the-art studies point towards immature oligodendrocytes as a possible source of gliomagenesis. Brain enriched myelin associated protein 1 (BCAS1) is a novel marker of immature oligodendrocytes and was proposed to contribute to tumorigenesis in non-central nervous system tumors. However, BCAS1 role in diffuse glioma is still underexplored. This study analyzes the expression of BCAS1 in different tumor samples from patients with diffuse gliomas (17 oligodendrogliomas; 8 astrocytomas; 60 glioblastomas) and uncovers the molecular and ultrastructural features of BCAS1+ cells by immunostaining and electron microscopy. Our results show that BCAS1+ cells exhibit stellate or spherical morphology with similar ultrastructural features. Stellate and spherical cells were detected as isolated cells in all studied gliomas. Nevertheless, only stellate cells were found to be proliferative and formed tightly packed nodules with a highly proliferative rate in oligodendrogliomas. Our findings provide a comprehensive characterization of the BCAS1+ cell population within diffuse gliomas. The observed proliferative capacity and distribution of BCAS1+ stellate cells, particularly in oligodendrogliomas, highlight BCAS1 as an interesting marker, warranting further investigation into its role in tumor malignancy.

Endocardial substrate of ventricular tachycardia in an adult patient with congenitally corrected transposition of great arteries without surgical repair.

Congenitally corrected transposition of the great arteries (CCTGA) is a rare congenital heart disease which may present sudden cardiac death presumably due to malignant ventricular tachycardia (VT). In patients with congenital heart disease, knowledge of arrhythmogenic substrate is crucial for planning an ablation procedure. We present the first description of the arrhythmogenic endocardial substrate of a non-iatrogenic scar-related VT in a patient with CCTGA.

Proteometabolomics of initial and recurrent glioblastoma highlights an increased immune cell signature with altered lipid metabolism.

BACKGROUND: There is an urgent need to better understand the mechanisms associated with the development, progression, and onset of recurrence after initial surgery in glioblastoma (GBM). The use of integrative phenotype-focused -omics technologies such as proteomics and lipidomics provides an unbiased approach to explore the molecular evolution of the tumor and its associated environment. METHODS: We assembled a cohort of patient-matched initial (iGBM) and recurrent (rGBM) specimens of resected GBM. Proteome and metabolome composition were determined by mass spectrometry-based techniques. We performed neutrophil-GBM cell coculture experiments to evaluate the behavior of rGBM-enriched proteins in the tumor microenvironment. ELISA-based quantitation of candidate proteins was performed to test the association of their plasma concentrations in iGBM with the onset of recurrence. RESULTS: Proteomic profiles reflect increased immune cell infiltration and extracellular matrix reorganization in rGBM. ASAH1, SYMN, and GPNMB were highly enriched proteins in rGBM. Lipidomics indicates the downregulation of ceramides in rGBM. Cell analyses suggest a role for ASAH1 in neutrophils and its localization in extracellular traps. Plasma concentrations of ASAH1 and SYNM show an association with time to recurrence. CONCLUSIONS: We describe the potential importance of ASAH1 in tumor progression and development of rGBM via metabolic rearrangement and showcase the feedback from the tumor microenvironment to plasma proteome profiles. We report the potential of ASAH1 and SYNM as plasma markers of rGBM progression. The published datasets can be considered as a resource for further functional and biomarker studies involving additional -omics technologies.

Soluble factors in COVID-19 mRNA vaccine-induced myocarditis causes cardiomyoblast hypertrophy and cell injury: a case report.

BACKGROUND: Inflammation affecting the heart and surrounding tissues is a clinical condition recently reported following COVID-19 mRNA vaccination. Assessing trends of these events related to immunization will improve vaccine safety surveillance and best practices for forthcoming vaccine campaigns. However, the causality is unknown, and the mechanisms associated with cardiac myocarditis are not understood. CASE PRESENTATION: After the first dose, we reported an mRNA vaccine-induced perimyocarditis in a young patient with a history of recurrent myocardial inflammation episodes and progressive loss of cardiac performance. We tested this possible inflammatory cytokine-mediated cardiotoxicity after vaccination in the acute phase (ten days), and we found a significant elevation of MCP-1, IL-18, and IL-8 inflammatory mediators. Still, these cytokines decreased considerably at the recovery phase (42 days later). We used the cardiomyoblasts cell line to test the effect of serum on cell viability, observing that serum from the acute phase reduced the cell viability to 75%. We did not detect this toxicity in cells when we tested serum from the patient in the recovery phase. We also tested serum-induced hypertrophy, a phenomenon in myocarditis and heart failure. We found that acute phase-serum has hypertrophy effects, increasing 25% of the treated cardiac cells' surface and significantly increasing B-type natriuretic peptide. However, we did not observe the hypertrophic effect in the recovery phase or sera from healthy controls. CONCLUSION: Our results opened the possibility of the inflammatory cytokines or serum soluble mediators as key factors for vaccine-associated myocarditis. In this regard, identifying anti-inflammatory molecules that reduce inflammatory cytokines could help avoid vaccine-induced myocardial inflammation.

Pediatric chronic urticaria: Clinical and laboratory characteristics and factors linked to remission.

BACKGROUND: Chronic urticaria (CU) is defined as the occurrence of wheals/angioedema for ≥6 consecutive weeks. Until now, guidelines and publications addressing CU have focused mainly on adults. As a result, evidence and guidance in the pediatric population are scarce. METHODS: This study aims to describe clinical and laboratory findings in pediatric CU and to determine factors associated with remission. RESULTS: 185 patients, 54% female, median age at onset of 8.8 years. Angioedema was present in almost half. The most common type of CU was chronic spontaneous urticaria (CSU) in 74%. At least one atopic comorbidity was found in almost a third (35%). In addition, 8% had an autoimmune disorder (exclusively in CSU) and 9% had a psychiatric condition. Basopenia was found in 67% and was more frequently associated with CSU. The basophil activation test (BAT) was positive in 40%. With regard to remission, being of male sex, angioedema absence, the absence of physical triggers, and eosinophil counts >0.51 × 109 /L were associated with shorter CU duration. CONCLUSION: Atopy is a common condition in pediatric CU. CSU is the most common type. Autoimmune comorbidities and basopenia were significantly more common in CSU. In addition, ours is one of the few studies, assessing BAT utility in the pediatric population, being positive in a relevant percentage (40%). BAT positivity was more frequent in CSU. Our results suggest that the absence of angioedema and physical triggers, male sex, and eosinophil counts >0.51 × 109 /L appear to be associated with a better prognosis in terms of remission.

Ensembles of endothelial and mural cells promote angiogenesis in prenatal human brain.

Interactions between angiogenesis and neurogenesis regulate embryonic brain development. However, a comprehensive understanding of the stages of vascular cell maturation is lacking, especially in the prenatal human brain. Using fluorescence-activated cell sorting, single-cell transcriptomics, and histological and ultrastructural analyses, we show that an ensemble of endothelial and mural cell subtypes tile the brain vasculature during the second trimester. These vascular cells follow distinct developmental trajectories and utilize diverse signaling mechanisms, including collagen, laminin, and midkine, to facilitate cell-cell communication and maturation. Interestingly, our results reveal that tip cells, a subtype of endothelial cells, are highly enriched near the ventricular zone, the site of active neurogenesis. Consistent with these observations, prenatal vascular cells transplanted into cortical organoids exhibit restricted lineage potential that favors tip cells, promotes neurogenesis, and reduces cellular stress. Together, our results uncover important mechanisms into vascular maturation during this critical period of human brain development.

Temperature pull-down of a retrofitted wine refrigerator cabinet cooled by a caloric system emulator.

The present study analyzes the time-dependent thermal behavior of a retrofitted wine refrigerator cabinet operated by a caloric system emulator. The presence of a full load of wine bottles enabled the assessment of the thermal stratification inside the cabinet. Further experimental tests have been performed to quantify the overall thermal conductance of the cabinet walls and the thermal conductance of the glass door. A detailed mathematical model was developed to predict the temperature pull down in the refrigerated compartment, considering the interaction between the cabinet air and the wine bottles. In addition to the air and bottle temperatures, a good agreement (lower than 15% relative error) was observed for the cooling capacity. The numerical simulations revealed that the cabinet door was responsible for approximately 60% of the thermal load (even though it corresponded to approximately 20% of the cabinet external area).

Combining familial hypercholesterolemia and statin genetic studies as a strategy for the implementation of pharmacogenomics. A multidisciplinary approach.

The diagnostic process of familial hypercholesterolemia frequently involves the use of genetic studies. Patients are treated with lipid-lowering drugs, frequently statins. Although pharmacogenomic clinical practice guidelines focusing on genotype-based statin prescription have been published, their use in routine clinical practice remains very modest.We have implemented a new NGS strategy that combines a panel of genes related to familial hypercholesterolemia with genomic regions related to the pharmacogenomics of lipid-lowering drugs described in clinical practice guidelines and in EMA and FDA drug labels. A multidisciplinary team of doctors, biologists, and pharmacists creates a clinical report that provides diagnostic and therapeutic findings using a knowledge management and clinical decision support system, as well as an algorithm for treatment selection.For 12 months, a total of 483 genetic diagnostic studies for familial hypercholesterolemia were carried out, of which 221 (45.8%) requested a complementary pharmacogenomic test. Of these 221 patients, 66.5% were carriers of actionable variants in any of the studied pharmacogenomic pathways: 46.6% of patients in one pathway, 19.0% in two pathways, and 0.9% in three pathways. 45.7% of patients could have a response to atorvastatin different from that of the reference population, 45.7% for simvastatin and lovastatin, 29.0% for fluvastatin, and 6.7% patients for pitavastatin.This implementation approach facilitates the incorporation of pharmacogenomic studies in clinical care practice, it does not add complexity nor additional steps to laboratory processes, and improves the pharmacotherapeutic process of patients.

Influence of Heat Exchanger Design on the Thermal Performance of a Domestic Wine Cooler Driven by a Magnetic Refrigeration System.

Conventional and not-in-kind refrigerators require heat exchangers for their operation. Yet, most magnetic cooling studies do not take full account of those components despite their importance in defining the cooling capacity and temperature span. To investigate the influence of heat exchanger design parameters on the performance of magnetic refrigerators, a model was developed to integrate the heat exchangers, regenerators and thermal reservoirs. The results were compared with data generated in an apparatus that emulates the conditions of the thermal fluid supplied by the regenerators to a cold heat exchanger positioned inside the cabinet of a retrofitted 130-liter wine cooler. Six tube-fin heat exchangers were evaluated to identify the most suitable geometry (number of tube rows and fin density) for the compact magnetic refrigerator. Numerical simulations described the influence of the heat exchanger on the regenerator performance in terms of the liquid stream effectiveness. For a temperature span of 20°C between the external environment and the refrigerated compartment, the best heat exchanger/fan assembly resulted in a cooling capacity reduction of 37\% and a temperature span increase of 32\%, in comparison with an idealized system. The expected system coefficient of performance (COP) and second-law efficiency were 1.8\% and 13\%, respectively.

Nests of dividing neuroblasts sustain interneuron production for the developing human brain.

The human cortex contains inhibitory interneurons derived from the medial ganglionic eminence (MGE), a germinal zone in the embryonic ventral forebrain. How this germinal zone generates sufficient interneurons for the human brain remains unclear. We found that the human MGE (hMGE) contains nests of proliferative neuroblasts with ultrastructural and transcriptomic features that distinguish them from other progenitors in the hMGE. When dissociated hMGE cells are transplanted into the neonatal mouse brain, they reform into nests containing proliferating neuroblasts that generate young neurons that migrate extensively into the mouse forebrain and mature into different subtypes of functional interneurons. Together, these results indicate that the nest organization and sustained proliferation of neuroblasts in the hMGE provide a mechanism for the extended production of interneurons for the human forebrain.

Local detection of microvessels in IDH-wildtype glioblastoma using relative cerebral blood volume: an imaging marker useful for astrocytoma grade 4 classification.

BACKGROUND: The microvessels area (MVA), derived from microvascular proliferation, is a biomarker useful for high-grade glioma classification. Nevertheless, its measurement is costly, labor-intense, and invasive. Finding radiologic correlations with MVA could provide a complementary non-invasive approach without an extra cost and labor intensity and from the first stage. This study aims to correlate imaging markers, such as relative cerebral blood volume (rCBV), and local MVA in IDH-wildtype glioblastoma, and to propose this imaging marker as useful for astrocytoma grade 4 classification. METHODS: Data from 73 tissue blocks belonging to 17 IDH-wildtype glioblastomas and 7 blocks from 2 IDH-mutant astrocytomas were compiled from the Ivy GAP database. MRI processing and rCBV quantification were carried out using ONCOhabitats methodology. Histologic and MRI co-registration was done manually with experts' supervision, achieving an accuracy of 88.8% of overlay. Spearman's correlation was used to analyze the association between rCBV and microvessel area. Mann-Whitney test was used to study differences of rCBV between blocks with presence or absence of microvessels in IDH-wildtype glioblastoma, as well as to find differences with IDH-mutant astrocytoma samples. RESULTS: Significant positive correlations were found between rCBV and microvessel area in the IDH-wildtype blocks (p < 0.001), as well as significant differences in rCBV were found between blocks with microvascular proliferation and blocks without it (p < 0.0001). In addition, significant differences in rCBV were found between IDH-wildtype glioblastoma and IDH-mutant astrocytoma samples, being 2-2.5 times higher rCBV values in IDH-wildtype glioblastoma samples. CONCLUSIONS: The proposed rCBV marker, calculated from diagnostic MRIs, can detect in IDH-wildtype glioblastoma those regions with microvessels from those without it, and it is significantly correlated with local microvessels area. In addition, the proposed rCBV marker can differentiate the IDH mutation status, providing a complementary non-invasive method for high-grade glioma classification.

Differences between surviving and non-surviving venous thromboembolism COVID-19 patients: a systematic review.

BACKGROUND: To our knowledge, the treatment, outcome, clinical presentation, risk stratification of patients with venous thromboembolism and COVID-19 have not been well characterized. METHODS: We searched for systematic reviews, cohorts, case series, case reports, editor letters, and venous thromboembolism COVID-19 patients' abstracts following PRISMA and PROSPERO statements. We analyzed therapeutic approaches and clinical outcomes of venous thromboembolism COVID-19 patients. Inclusion: COVID-19 patients with venous thromboembolism confirmed by an imaging method (venous doppler ultrasound, ventilation-perfusion lung scan, computed tomography pulmonary angiogram, pulmonary angiography). We assessed and reported the original Pulmonary Embolism Severity Index for each pulmonary embolism patient. In addition, we defined major bleedings according to the International Society of Thrombosis and Haemostasis criteria. RESULTS: We performed a systematic review from August 9 to August 30, 2020. We collected 1,535 papers from PubMed, Scopus, Web of Science, Wiley, and Opengrey. We extracted data from 89 studies that describe 143 patients. Unfractionated and low-molecular-weight heparin was used as parenteral anticoagulation in 85/143 (59%) cases. The Food and Drug Administration-approved alteplase regimen guided the advanced treatment in 39/143 (27%) patients. The mortality was high (21.6%, CI 95% 15.2-29.3). The incidence of major bleeding complications was 1 (0.9%) in the survival group and 1 (3.2%) in the death group. Pulmonary Embolism Severity Index was class I in 11.6% and II in 22.3% in survivors compared to 0% and 6.5% in non-survivors, respectively. Patients who experienced venous thromboembolism events at home were more likely to live than in-hospital events. CONCLUSIONS: We determined a high mortality incidence of pulmonary embolism and a low rate of bleeding. Unfractionated and low-molecular-weight heparin drove parenteral anticoagulation and alteplase the advanced treatment in both groups. The original Pulmonary Embolism Severity Index could be helpful in the risk stratification.

Deciphering Multiple Sclerosis Progression.

Multiple sclerosis (MS) is primarily an inflammatory and degenerative disease of the central nervous system, triggered by unknown environmental factors in patients with predisposing genetic risk profiles. The prevention of neurological disability is one of the essential goals to be achieved in a patient with MS. However, the pathogenic mechanisms driving the progressive phase of the disease remain unknown. It was described that the pathophysiological mechanisms associated with disease progression are present from disease onset. In daily practice, there is a lack of clinical, radiological, or biological markers that favor an early detection of the disease's progression. Different definitions of disability progression were used in clinical trials. According to the most descriptive, progression was defined as a minimum increase in the Expanded Disability Status Scale (EDSS) of 1.5, 1.0, or 0.5 from a baseline level of 0, 1.0-5.0, and 5.5, respectively. Nevertheless, the EDSS is not the most sensitive scale to assess progression, and there is no consensus regarding any specific diagnostic criteria for disability progression. This review document discusses the current pathophysiological concepts associated with MS progression, the different measurement strategies, the biomarkers associated with disability progression, and the available pharmacologic therapeutic approaches.

Evaluation of the optical criteria for sessile serrated lesions of the colon: A prospective study on a colorectal cancer screening population.

Background and study aims We aimed to describe the presence and combination of Hazewinkel's optical diagnosis (OD) criteria for sessile serrated lesions (SSL), determining which lesion characteristics increase the probability of a correct OD, with a focus on diminutive lesions. Patients and methods This was a prospective study describing the presence of Hazewinkel's OD criteria for SSL in lesions found in consecutive CRC screening colonoscopies. The presence of each OD criterion and their diagnostic combinations in SSL, related to the lesion's NBI International Colorectal Endoscopic (NICE) classification category, size, and location, were described. The presence of two or more optical criteria was considered diagnostic of SSL. The OD was compared to pathology as the gold standard. Results Seventy-nine SSLs (5.6 %) were diagnosed. Cloud-like appearance was the most prevalent OD criterion (35, 44.3 %). OD criteria were more frequently identified in NICE type 1, ≥ 10 mm, and proximal lesions. Only 26 SLLs fulfilled the OD criteria (sensitivity 32.9 %, 95 % CI 29.1 %-36.7 %). The sensitivity for diminutive SSL was 14.7 %, (95 % CI 11.9 %-17.6 %). Eighty-five lesions were optically diagnosed as SSL. However, only in 26 SSL was this the definitive diagnosis (positive predictive value 30.6 %, 95 % CI 26.9 %-34.3 %). Size > 5 mm and proximal location increased the probability of a correct diagnosis. The overall accuracy of the optical criteria was 92.0 % (95 % CI, 89.8 %-94.2 %). Conclusions The Hazewinkel's optical criteria are not reliable for a positive diagnosis of SSL, particularly for diminutive lesions.