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The inner surfaces of the human heart are covered by a complex network of muscular strands that is thought to be a remnant of embryonic development 1 , 2 . The function of these trabeculae in adults and their genetic architecture are unknown. Here we performed a genome-wide association study to investigate image-derived phenotypes of trabeculae using the fractal analysis of trabecular morphology in 18,096 participants of the UK Biobank. We identified 16 significant loci that contain genes associated with haemodynamic phenotypes and regulation of cytoskeletal arborization 3 , 4 . Using biomechanical simulations and observational data from human participants, we demonstrate that trabecular morphology is an important determinant of cardiac performance. Through genetic association studies with cardiac disease phenotypes and Mendelian randomization, we find a causal relationship between trabecular morphology and risk of cardiovascular disease. These findings suggest a previously unknown role for myocardial trabeculae in the function of the adult heart, identify conserved pathways that regulate structural complexity and reveal the influence of the myocardial trabeculae on susceptibility to cardiovascular disease. A genome-wide association study shows that myocardial trabeculae are an important determinant of cardiac performance in the adult heart, identifies conserved pathways that regulate structural complexity and reveals the influence of trabeculae on the susceptibility to cardiovascular disease.

Background This simulation study investigated potential modulations of total peripheral resistance (TPR), due to distributed peripheral vascular activity, by means of a lumped model of the arterial tree and a non linear model of microcirculation, inclusive of local controls of blood flow and tissue-capillary fluid exchange. Results Numerical simulations of circulation were carried out to compute TPR under different conditions of blood flow pulsatility, and to extract the pressure-flow characteristics of the cardiovascular system. Simulations showed that TPR seen by the large arteries was increased in absence of pulsatility, while it decreased with an augmented harmonic content. This is a typically non linear effect due to the contribution of active, non linear autoregulation of the peripheral microvascular beds, which also generated a nonlinear relationship between arterial blood pressure and cardiac output. Conclusion This simulation study, though focused on a simple effect attaining TPR modulation due to pulsatility, suggests that non-linear autoregulation mechanisms cannot be overlooked while studying the integrated behavior of the global cardiovascular system, including the arterial tree and the peripheral vascular bed.

Since being first described by Leonardo da Vinci in 1513 it has remained an enigma why the endocardial surfaces of the adult heart retain a complex network of muscular trabeculae - with their persistence thought to be a vestige of embryonic development. For causative physiological inference we harness population genomics, image-based intermediate phenotyping and in silico modelling to determine the effect of this complex cardiovascular trait on function. Using deep learning-based image analysis we identified genetic associations with trabecular complexity in 18,097 UK Biobank participants which were replicated in an independently measured cohort of 1,129 healthy adults. Genes in these associated regions are significantly enriched for expression in the fetal heart or vasculature and implicate loci associated with haemodynamic phenotypes and developmental pathways. A causal relationship between increasing trabecular complexity and both ventricular performance and electrical activity are supported by complementary biomechanical simulations and Mendelian randomisation studies. These findings show that myocardial trabeculae are a previously-unrecognised determinant of cardiovascular physiology in adult humans. Footnotes * https://doi.org/10.5281/zenodo.2571996

ObjectiveTo produce European League Against Rheumatism (EULAR) recommendations for the reporting of ultrasound studies in rheumatic and musculoskeletal diseases (RMDs).MethodsBased on the literature reviews and expert opinion (through Delphi surveys), a taskforce of 23 members (12 experts in ultrasound in RMDs, 9 in methodology and biostatistics together with a patient research partner and a health professional in rheumatology) developed a checklist of items to be reported in every RMD study using ultrasound. This checklist was further refined by involving a panel of 79 external experts (musculoskeletal imaging experts, methodologists, journal editors), who evaluated its comprehensibility, feasibility and comprehensiveness. Agreement on each proposed item was assessed with an 11-point Likert scale, grading from 0 (total disagreement) to 10 (full agreement).ResultsTwo face-to-face meetings, as well as two Delphi rounds of voting, resulted in a final checklist of 23 items, including a glossary of terminology. Twenty-one of these were considered ‘mandatory’ items to be reported in every study (such as blinding, development of scoring systems, definition of target pathologies) and 2 ‘optional’ to be reported only if applicable, such as possible confounding factors (ie, ambient conditions) or experience of the sonographers.ConclusionAn EULAR taskforce developed a checklist to ensure transparent and comprehensive reporting of aspects concerning research and procedures that need to be presented in studies using ultrasound in RMDs. This checklist, if widely adopted by authors and editors, will greatly improve the interpretability of study development and results, including the assessment of validity, generalisability and applicability.

The subsurface is among Earth’s largest biomes, but the extent to which microbial communities vary across tectonic plate boundaries or interact with subduction-scale geological processes remains unknown. Here we compare bacterial community composition with deep-subsurface geochemistry from 21 hot springs across the Costa Rican convergent margin. We find that cation and anion compositions of the springs reflect the dip angle and position of the underlying tectonic structure and also correlate with the bacterial community. Co-occurring microbial cliques related to cultured chemolithoautotrophs that use the reverse tricarboxylic acid cycle (rTCA) as well as abundances of metagenomic rTCA genes correlate with concentrations of slab-volatilized carbon. This, combined with carbon isotope evidence, suggests that fixation of slab-derived CO 2 into biomass may support a chemolithoautotrophy-based subsurface ecosystem. We calculate that this forearc subsurface biosphere could sequester 1.4 × 10 9 to 1.4 × 10 10  mol of carbon per year, which would decrease estimates of the total carbon delivered to the mantle by 2 to 22%. Based on the observed correlations, we suggest that distribution and composition of the subsurface bacterial community are probably affected by deep tectonic processes across the Costa Rican convergent margin and that, by sequestering carbon volatilized during subduction, these chemolithoautotrophic communities could in turn impact the geosphere. The subsurface biosphere across a convergent margin may reflect tectonic processes and reduce carbon transfer to the mantle, according to bacterial and geochemical correlations from hot springs across the Costa Rican margin.

Mesenchymal Stromal/Stem Cells (MSCs) have attracted considerable attention in the field of regenerative medicine. Their unique properties make them suitable for various therapeutic applications. This article reviews accepted methods and guidelines for the isolation and characterization of MSCs from various sources. Common sources include bone marrow, adipose tissue, perinatal and umbilical cord tissue, dental pulp, etc. Naturally, the techniques used to isolate MSCs can vary depending on the source from which they are derived. However, several methods have been widely accepted by the scientific community. These include enzymatic digestion, density gradient centrifugation, the use of Percoll, adherence-based techniques and selective culture conditions. To characterize MSCs, basic criteria established by the International Society for Cell and Tissue Transplantation and the International Federation for Adipose Tissue are routinely used. These criteria include the ability of MSCs to adhere to plastic surfaces under standard culture conditions, the expression of specific membrane markers and their differentiation potential. Various techniques are used to assess these characteristics, including mixed lymphocyte reactions, flow cytometry and immunophenotyping profiles. These assessments aim to confirm the purity of the MSCs and validate their mesenchymal properties. In summary, the isolation and characterization of MSCs requires careful consideration of the different available methods. Each source presents unique challenges and advantages. By following established guidelines, researchers can ensure successful isolation and characterization of MSCs. This knowledge will ultimately improve their use in regenerative medicine.

Apelin is an adipokine that plays a role in the regulation of glucose homeostasis and in obesity. The relationship between apelin serum concentration and dysmetabolic conditions such as type 2 diabetes (T2D) is still controversial. Aims of our study are: 1) determine the circulating levels of apelin in a large cohort of Italian subjects with T2D, T1D and in non-diabetic controls; 2) identify putative metabolic determinants of modified apelin concentrations, in order to search possible mechanism of apelin control; 3) investigate changes in apelin levels in response to sharp modifications of glucose/insulin metabolism in T2D obese subjects before and 3 days after bariatric surgery. We recruited 369 subjects, 119 with T2D, 113 with T1D and 137 non-diabetic controls. All subjects underwent a complete clinical examination, including anthropometric and laboratory measurements. Serum apelin levels were determined by EIA (immunoenzyme assay). Patients with T2D had significantly higher serum apelin levels compared to controls (1.23 ± 1.1 ng/mL vs 0.91 ± 0.7 ng/mL, P<0.001) and to T1D subjects (0.73 ± 0.39 ng/mL, P<0.001). Controls and T1D subjects did not differ significantly in apelin levels. Apelin concentrations were directly associated with fasting blood glucose (FBG), body mass index (BMI), basal Disposition Index (DI-0), age, and diagnosis of T2D at bivariate correlation analysis. Multiple regression analysis confirmed that diagnosis of T2D, basal DI-0 and FBG were all determinants of serum apelin levels independently from age and BMI. Bariatric surgery performed in a subgroup of obese diabetic subjects (n = 12) resulted in a significant reduction of apelin concentrations compared to baseline levels (P = 0.01). Our study demonstrates that T2D, but not T1D, is associated with increased serum apelin levels compared to non-diabetic subjects. This association is dependent on impaired glucose homeostasis, and disappears after bariatric surgery, providing further evidence regarding the relationship between apelin and the regulation of glucose metabolism.

HBV/HCV co-infection is common in HIV-1-infected prisoners. To investigate the characteristics of HIV co-infections, and to evaluate the molecular heterogeneity of HIV, HBV and HCV in prisoners, we carried-out a multicenter cross-sectional study, including 65 HIV-1-infected inmates enrolled in 5 Italian detention centers during the period 2017–2019. HIV-1 subtyping showed that 77.1% of inmates were infected with B subtype and 22.9% with non-B subtypes. Italian nationals were all infected with subtype B (93.1%), except two individuals, one infected with the recombinant form CRF72_BF1, and the other with the HIV-1 sub-subtype A6, both previously not identified in inmates of Italian nationality. Non-Italian nationals were infected with subtype B (52.6%), CRFs (36.8%) and sub-subtypes A1 and A3 (5.2%). HIV variants carrying resistance mutations to NRTI, NNRTI, PI and InSTI were found in 7 inmates, 4 of which were never exposed to the relevant classes of drugs associated with these mutations. HBV and/or HCV co-infections markers were found in 49/65 (75.4%) inmates, while 27/65 (41.5%) showed markers of both HBV and HCV coinfection. Further, Italian nationals showed a significant higher presence of HCV markers as compared to non-Italian nationals ( p  = 0.0001). Finally, HCV phylogenetic analysis performed in 18 inmates revealed the presence of HCV subtypes 1a, 3a, 4d (66.6%, 16.7% and 16.7%, respectively). Our data suggest the need to monitor HIV, HBV and HCV infections in prisons in order to prevent spreading of these viruses both in jails and in the general population, and to implement effective public health programs that limit the circulation of different genetic forms as well as of viral variants with mutations conferring resistance to treatment.

COPD is a disease associated with significant economic burden. It was reported that Global initiative for chronic Obstructive Lung Disease (GOLD) guideline-oriented pharmacotherapy improves airflow limitation and reduces health care costs. However, several studies showed a significant dissociation between international recommendations and clinicians' practices. The consequent reduced diagnostic and therapeutic inappropriateness has proved to be associated with an increase in costs and a waste of economic resources in the health sector. The aim of the study was to evaluate COPD management in the Puglia region. The study was performed in collaboration with the pulmonology centers and the Regional Health Agency (AReS Puglia). An IT platform allowed the pulmonologists to enter data via the Internet. All COPD patients who visited a pneumological outpatient clinic for the first time or for regular follow-ups or were admitted to a pneumological department for an exacerbation were considered eligible for the study. COPD's diagnosis was confirmed by a pulmonologist at the moment of the visit. The project lasted 18 months and involved 17 centers located in the Puglia region. Six hundred ninety-three patients were enrolled, evenly distributed throughout the region. The mean age was 71±9 years, and 85% of them were males. Approximately 23% were current smokers, 63% former smokers and 13.5% never smokers. The mean post-bronchodilator forced expiratory volume in 1 second was 59%±20% predicted. The platform allowed the classification of patients according to the GOLD guidelines (Group A: 20.6%, Group B: 32.3%, Group C: 5.9% and Group D: 39.2%), assessed the presence and severity of exacerbations (20% of the patients had an exacerbation defined as mild [13%], moderate [37%] and severe [49%]) and evaluated the appropriateness of inhalation therapy at the time of the visit. Forty-nine percent of Group A patients were following inappropriate therapy; in Group B, 45.8% were following a therapy in contrast with the guidelines. Among Group C patients, 41.46% resulted in triple combination therapy, whilê14% of Group D patients did not have a therapy or were following an inappropriate therapy. In conclusion, 30% of all patients evaluated had been following an inadequate therapy. Subsequently, an online survey was developed to inquire about the reasons for the results obtained. In particular, we investigated the reasons why 30% of our population did not follow the therapy suggested by the GOLD guidelines: 1) why was there an excessive use of inhaled corticosteroids, 2) why a significantly high percentage was inappropriately treated with triple therapy and 3) why a consistent percentage (11%) of Group D patients were not treated at all. The data provides an overview on the management of COPD in the region of Puglia (Italy) and represents a resource in order to improve appropriateness and reduce the waste of health resources.

Childhood brain tumors have suspected prenatal origins. To identify vulnerable developmental states, we generated a single-cell transcriptome atlas of >65,000 cells from embryonal pons and forebrain, two major tumor locations. We derived signatures for 191 distinct cell populations and defined the regional cellular diversity and differentiation dynamics. Projection of bulk tumor transcriptomes onto this dataset shows that WNT medulloblastomas match the rhombic lip-derived mossy fiber neuronal lineage and embryonal tumors with multilayered rosettes fully recapitulate a neuronal lineage, while group 2a/b atypical teratoid/rhabdoid tumors may originate outside the neuroectoderm. Importantly, single-cell tumor profiles reveal highly defined cell hierarchies that mirror transcriptional programs of the corresponding normal lineages. Our findings identify impaired differentiation of specific neural progenitors as a common mechanism underlying these pediatric cancers and provide a rational framework for future modeling and therapeutic interventions. A single-cell transcriptomic atlas from embryonal pons and forebrain provides insights into the developmental origins of pediatric brain tumors. The study identifies impaired differentiation of specific neural progenitors as a common mechanism underlying these cancers.