Platelet Biorheology and Mechanobiology in Thrombosis and Hemostasis: Perspectives from Multiscale Computation.

Thrombosis is the pathological clot formation under abnormal hemodynamic conditions, which can result in vascular obstruction, causing ischemic strokes and myocardial infarction. Thrombus growth under moderate to low shear (<1000 s-1) relies on platelet activation and coagulation. Thrombosis at elevated high shear rates (>10,000 s-1) is predominantly driven by unactivated platelet binding and aggregating mediated by von Willebrand factor (VWF), while platelet activation and coagulation are secondary in supporting and reinforcing the thrombus. Given the molecular and cellular level information it can access, multiscale computational modeling informed by biology can provide new pathophysiological mechanisms that are otherwise not accessible experimentally, holding promise for novel first-principle-based therapeutics. In this review, we summarize the key aspects of platelet biorheology and mechanobiology, focusing on the molecular and cellular scale events and how they build up to thrombosis through platelet adhesion and aggregation in the presence or absence of platelet activation. In particular, we highlight recent advancements in multiscale modeling of platelet biorheology and mechanobiology and how they can lead to the better prediction and quantification of thrombus formation, exemplifying the exciting paradigm of digital medicine.

Isolation and Antitumoral Effect of a New Siphonochilone Derivative from African Ginger.

A new eusdesmane sesquiterpenoid, characterized as 3,5,8a-trimethyl-8-oxo-4,4a,5,6,7,8,8a,9-octahydronaphtho[2,3-b]furan-5-yl acetate (1), has been isolated from the rhizomes of the South African variety of wild ginger (Siphonochilus aethiopicus (Schweinf) B. L. Burtt). The compound was obtained by silica gel column chromatography. Its structure was elucidated by nuclear magnetic resonance spectroscopy (NMR) and mass-spectrometric (MS) analyses, including 1D-, 2D-NMR, and HR-LCMS. We also investigated the cytotoxic effect of 1 on a panel of cancer cell lines, human breast, pancreas, lung, colon, and central nervous system cancer lines. The data are not encouraging since its antitumor effect is poor. Nonetheless, the discovery of new molecules may provide a source of new compounds with important biological effects applicable to the field of medicine.

Low rCBV values in glioblastoma tumor progression under chemoradiotherapy.

PURPOSE: After standard treatment for glioblastoma, perfusion MRI remains challenging for differentiating tumor progression from post-treatment changes. Our objectives were (1) to correlate rCBV values at diagnosis and at first tumor progression and (2) to analyze the relationship of rCBV values at tumor recurrence with enhancing volume, localization of tumor progression, and time elapsed since the end of radiotherapy in tumor recurrence. METHODS: Inclusion criteria were (1) age > 18 years, (2) histologically confirmed glioblastoma treated with STUPP regimen, and (3) tumor progression according to RANO criteria > 12 weeks after radiotherapy. Co-registration of segmented enhancing tumor VOIs with dynamic susceptibility contrast perfusion MRI was performed using Olea Sphere software. For tumor recurrence, we correlated rCBV values with enhancing tumor volume, with recurrence localization, and with time elapsed from the end of radiotherapy to progression. Analyses were performed with SPSS software. RESULTS: Sixty-four patients with glioblastoma were included in the study. Changes in rCBV values between diagnosis and first tumor progression were significant (p < 0.001), with a mean and median decreases of 32% and 46%, respectively. Mean rCBV values were also different (p < 0.01) when tumors progressed distally (radiation field rCBV values of 1.679 versus 3.409 distally). However, changes and, therefore, low rCBV values after radiotherapy in tumor recurrence were independent of time. CONCLUSION: Chemoradiation alters tumor perfusion and rCBV values may be decreased in the setting of tumor progression. Changes in rCBV values with respect to diagnosis, with low rCBV in tumor progression, are independent of time but related to the site of recurrence.

Advancing the assessment of pacifier effects with a novel computational method.

BACKGROUND: Numerous studies have demonstrated a high likelihood of malocclusions resulting from non-nutritive sucking. Consequently, quantifying the impact of pacifiers can potentially aid in preventing the development or exacerbation of malocclusions and guide the design of improved performance pacifiers. METHODS: This work proposes and assesses a computational methodology that can effectively gather crucial information and provide more precise data regarding the consequences of non-nutritive pacifier sucking. The computational framework utilized is based on solids4Foam [1, 2], a collection of numerical solvers developed within the OpenFOAM® computational library [3]. The computational model focuses on the palate of a six-month-old baby and incorporates various components such as palate tissues, pacifier and tongue, and considers the negative intraoral pressure generated and the tongue displacement. Different models were tested, each offering varying levels of detail in representing the palate structure. These models range from a simplified approach, with one tissue, to a more intricate representation, involving up to five different tissues, offering a more comprehensive palate model compared to existing literature. RESULTS: The analysis of results involved examining the distribution of stress on the palate surface, as well as the displacement and forces exerted on the dental crowns. By comparing the obtained results, it was possible to evaluate the precision of the approaches previously described in the literature. The findings revealed that the predictions were less accurate when using the simplified model with a single tissue for the palate, which is the most common approach proposed in the literature. In contrast, the results demonstrated that the palate model with the most intricate structure, incorporating five different tissues, yielded distinct outcomes compared to all other combinations. CONCLUSIONS: The computational methodology proposed, employing the most detailed palate model, has demonstrated its effectiveness and necessity in obtaining accurate data on the impact of non-nutritive sucking habits, which are recognized as a primary contributor to the development of dental malocclusions. In the future, this approach could be extended to conduct similar studies encompassing diverse pacifier designs, sizes, and age groups. This would foster the design of innovative pacifiers that mitigate the adverse effects of non-nutritive sucking on orofacial structures.

Informal sale of antibiotics in Guatemalan convenience stores before and after implementation of federal antibiotic dispensing legislation.

BACKGROUND: Convenience stores in Guatemala provide essential consumer goods in communities, but many dispense antibiotics illegally. Federal legislation, passed in August of 2019, requires prescriptions for antibiotic purchase at pharmacies but it is unclear if this legislation is enforced or if it has any impact on unlawful sales of antibiotics. METHODS: To determine if antibiotic availability changed in convenience stores, we carried out a repeated measures study collecting antibiotic availability data before and after implementation of the dispensing regulation. RESULTS: There was no statistical difference in the proportion of convenience stores that sold antibiotics before and after antibiotic regulations [66.6% (295/443) and 66.7% (323/484), respectively, P>0.96], nor in the number of stores selling amoxicillin [55.5% (246/443) and 52.3% (253/484), respectively, P>0.96], but fewer stores (20%) sold tetracycline capsules after regulation was passed (P<0.05). For stores visited both before and after passage of legislation (n=157), 15% stopped selling antibiotics while 25% started selling antibiotics. Antibiotics from convenience stores were reportedly sold for use in people and animals. CONCLUSIONS: Antibiotics remain widely available in convenience stores consistent with no significant change in the informal sector after implementation of prescription requirements for pharmacies. Importantly, effects from regulatory change could have been masked by potential changes in antibiotic use during the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic.

Association of tyrosine hydroxylase 01 (TH01) microsatellite and insulin gene (INS) variable number of tandem repeat (VNTR) with type 2 diabetes and fasting insulin secretion in Mexican population.

PURPOSE: A variable number of tandem repeats (VNTR) in the insulin gene (INS) control region may be involved in type 2 diabetes (T2D). The TH01 microsatellite is near INS and may regulate it. We investigated whether the TH01 microsatellite and INS VNTR, assessed via the surrogate marker single nucleotide polymorphism rs689, are associated with T2D and serum insulin levels in a Mexican population. METHODS: We analyzed a main case-control study (n = 1986) that used univariate and multivariate logistic regression models to calculate the risk conferred by TH01 and rs689 loci for T2D development; rs689 results were replicated in other case-control (n = 1188) and cross-sectional (n = 1914) studies. RESULTS: TH01 alleles 6, 8, 9, and 9.3 and allele A of rs689 were independently associated with T2D, with differences between sex and age at diagnosis. TH01 alleles with ≥ 8 repeats conferred an increased risk for T2D in males compared with ≤ 7 repeats (odds ratio, ≥ 1.46; 95% confidence interval, 1.1-1.95). In females, larger alleles conferred a 1.5-fold higher risk for T2D when diagnosed ≥ 46 years but conferred protection when diagnosed ≤ 45 years. Similarly, rs689 allele A was associated with T2D in these groups. In males, larger TH01 alleles and the rs689 A allele were associated with a significant decrease in median fasting plasma insulin concentration with age in T2D cases; the reverse occurred in controls. CONCLUSION: Larger TH01 alleles and rs689 A allele may potentiate insulin synthesis in males without T2D, a process disabled in those with T2D.

Positioning of Tezepelumab in Severe Asthma.

Asthma is one of the most common chronic diseases and is estimated to be severe in 3%-10% of affected patients. There is a need for additional biologic treatments that are highly efficacious across the spectrum of severe uncontrolled asthma. Currently available drugs inhibit 1 or 2 specific cytokines or IgE antibodies and thus only partially suppress the complex type 2 (T2) inflammatory cascade. Biologics targeting more upstream molecules in the pathophysiological pathway of asthma could treat asthma more effectively. Tezepelumab is a human monoclonal immunoglobulin G2λ antibody that targets the cytokine thymic stromal lymphopoietin (TSLP). It is the first marketed biologic against an epithelial cell-derived cytokine, preventing binding of TSLP to its receptor and reducing the immune stimuli that TSLP can trigger in different asthma endotypes. Tezepelumab reduces downstream biomarkers of inflammation, such as blood and airway eosinophils, FeNO, IgE, IL-5, and IL-13. Tezepelumab provides a clinical benefit in severe asthma, reducing the annualized asthma exacerbation rate in patients with either high or low levels of biomarkers of T2 inflammation, although the effect is greater among those with high levels. The drug has been shown to improve asthma control, quality of life, and lung function and reduce airway hyperresponsiveness. Therefore, tezepelumab can be used across the spectrum of patients with severe uncontrolled asthma, especially in T2-high patients. This review includes a positioning statement by the authors, all of whom are members of the SEAIC Asthma Committee.

Positioning of Tezepelumab in Severe Asthma / Posicionamento do Tezepelumabe na Asma Grave

Asthma is one of the most common chronic diseases and is estimated to be severe in 3%-10% of affected patients. There is a need for additional biologic treatments that are highly efficacious across the spectrum of severe uncontrolled asthma. Currently available drugs inhibit 1 or 2 specific cytokines or IgE antibodies and thus only partially suppress the complex type 2 (T2) inflammatory cascade. Biologics targeting more upstream molecules in the pathophysiological pathway of asthma could treat asthma more effectively. Tezepelumab is a human monoclonal immunoglobulin G2λ antibody that targets the cytokine thymic stromal lymphopoietin (TSLP). It is the first marketed biologic against an epithelial cell–derived cytokine, preventing binding of TSLP to its receptor and reducing the immune stimuli that TSLP can trigger in different asthma endotypes. Tezepelumab reduces downstream biomarkers of inflammation, such as blood and airway eosinophils, FeNO, IgE, IL-5, and IL-13. Tezepelumab provides a clinical benefit in severe asthma, reducing the annualized asthma exacerbation rate in patients with either high or low levels of biomarkers of T2 inflammation, although the effect is greater among those with high levels. The drug has been shown to improve asthma control, quality of life, and lung function and reduce airway hyperresponsiveness. Therefore, tezepelumab can be used across the spectrum of patients with severe uncontrolled asthma, especially in T2-high patients. This review includes a positioning statement by the authors, all of whom are members of the SEAIC Asthma Committee (AU)

A asma é uma das doenças crônicas mais comuns e estima-se que seja grave em 3% a 10% dos pacientes afetados. Há necessidade de tratamentos biológicos adicionais que sejam altamente eficazes em todo o espectro da asma grave não controlada. Os medicamentos atualmente disponíveis inibem 1 ou 2 citocinas específicas ou anticorpos IgE e, portanto, suprimem apenas parcialmente a cascata inflamatória complexa tipo 2 (T2). Os produtos biológicos que visam moléculas mais a montante na via fisiopatológica da asma poderiam tratar a asma de forma mais eficaz. Tezepelumab é um anticorpo monoclonal humano imunoglobulina G2λ que tem como alvo a citocina linfopoietina estromal tímica (TSLP). É o primeiro produto biológico comercializado contra uma citocina derivada de células epiteliais, impedindo a ligação da TSLP ao seu receptor e reduzindo os estímulos imunológicos que a TSLP pode desencadear em diferentes endótipos de asma. Tezepelumabe reduz biomarcadores de inflamação a jusante, como eosinófilos no sangue e nas vias aéreas, FeNO, IgE, IL-5 e IL-13. O tezepelumab proporciona um benefício clínico na asma grave, reduzindo a taxa anualizada de exacerbação da asma em pacientes com níveis elevados ou baixos de biomarcadores de inflamação T2, embora o efeito seja maior entre aqueles com níveis elevados. Foi demonstrado que o medicamento melhora o controle da asma, a qualidade de vida e a função pulmonar e reduz a hiperresponsividade das vias aéreas. Portanto, o tezepelumabe pode ser usado em todo o espectro de pacientes com asma grave não controlada, especialmente em pacientes com T2 elevado. Esta revisão inclui uma declaração de posicionamento dos autores, todos membros do Comitê de Asma da SEAIC (AU)

Power of the Disulfide Bond: An Ideal Random Copolymerization of Biodegradable Redox-Responsive Hyperbranched Polyglycerols.

The development of copolymerization techniques that can randomly incorporate biodegradable moieties into the hyperbranched polyglycerol backbone is an option to prevent its bioaccumulation in vivo. In this study, redox-responsive and biocompatible hyperbranched polyglycerol copolymers of glycidol and 1,4,5-oxadithiepan-2-one were synthesized with an adjustable molecular weight and a defined disulfide bond content through anionic and coordination-insertion ring-opening polymerization. A truly random incorporation of the monomers was achieved under both copolymerization mechanisms. The copolymers were further characterized in terms of their aggregation behavior in solution, degradability, in vitro cell viability, and blood compatibility for potential future biomedical applications. Transmission electron microscopy revealed that the copolymer assembled into nanoparticles with a size range of 20 nm. The copolymers underwent degradation when incubated with two different reducing agents, resulting in smaller fragments of the polymer with thiol end groups. The copolymers demonstrated good biocompatibility, making them suitable for further investigation in biomedical applications.

Nuclear Charge Radius of

Collinear laser spectroscopy was performed on the isomer of the aluminium isotope ^{26m}Al. The measured isotope shift to ^{27}Al in the 3s^{2}3p ^{2}P_{3/2}^{○}→3s^{2}4s ^{2}S_{1/2} atomic transition enabled the first experimental determination of the nuclear charge radius of ^{26m}Al, resulting in R_{c}=3.130(15) fm. This differs by 4.5 standard deviations from the extrapolated value used to calculate the isospin-symmetry breaking corrections in the superallowed ß decay of ^{26m}Al. Its corrected Ft value, important for the estimation of V_{ud} in the Cabibbo-Kobayashi-Maskawa matrix, is thus shifted by 1 standard deviation to 3071.4(1.0) s.

n-Tuples on Scaffold Diversity Inspired by Drug Hybridisation to Enhance Drugability: Application to Cytarabine.

A mathematical concept, n-tuples are originally applied to medicinal chemistry, especially with the creation of scaffold diversity inspired by the hybridisation of different commercial drugs with cytarabine, a synthetic arabinonucleoside derived from two marine natural products, spongouridine and spongothymidine. The new methodology explores the virtual chemical-factorial combination of different commercial drugs (immunosuppressant, antibiotic, antiemetic, anti-inflammatory, and anticancer) with the anticancer drug cytarabine. Real chemical combinations were designed and synthesised for 8-duples, obtaining a small representative library of interesting organic molecules to be biologically tested as proof of concept. The synthesised library contains classical molecular properties regarding the Lipinski rules and/or beyond rules of five (bRo5) and is represented by the covalent combination of the anticancer drug cytarabine with ibuprofen, flurbiprofen, folic acid, sulfasalazine, ciprofloxacin, bortezomib, and methotrexate. The insertion of specific nomenclature could be implemented into artificial intelligence algorithms in order to enhance the efficiency of drug-hunting programs. The novel methodology has proven useful for the straightforward synthesis of most of the theoretically proposed duples and, in principle, could be extended to any other central drug.

Short-term Macrochloa tenacissima response understory Pinus halepensis Mill forest after early prescribed burns in a semi-arid landscape.

Climate change has led to altered fire patterns in the Mediterranean basin due to rising temperatures and greenhouse gas emissions, diminishing the resilience of forest ecosystems. To address this threat, forest management increasingly employs preventive measures like controlled burns, aiming to mitigate wildfire damage. However, understanding the impact of prescribed burns on vegetation remains crucial. Our study focuses on assessing the ecological effects of early-season prescribed burns on Macrochloa tenacissima communities within Pinus halepensis Mill forests on the Iberian Peninsula. These forests, with southeast-facing slopes and arid soils, heavily rely on alpha grass for post-fire recovery, acting as a shield against runoff and erosion. Yet, the presence of highly flammable resprouting species can lead to rapid combustible material accumulation. We evaluated parameters like coverage, floral diversity (α-diversity), aboveground plant biomass, photosynthetic activity, and chemical leaf properties of alpha grass, a year after a low-intensity controlled burn. Comparing burnt and unburnt areas revealed significant changes in α-diversity and ecophysiology of Macrochloa tenacissima due to early-season prescribed burns. These short-term shifts underscore the need for further exploration of underlying mechanisms. Our analysis also showed distinct shifts in alpha grass leaf chemical composition between the two plot types, potentially impacting post-fire recovery strategies. Although prescribed burning might not be optimal for reducing fire risk in resprouting species-dominated forests, it conserves native plants and enhances ecosystem diversity, providing valuable ecological benefits. In conclusion, our research deepens our understanding of early-season burning's repercussions on flammable vegetation dynamics and combustible material availability in semi-arid landscapes. It contributes to standardized management protocols, aiding effective forest service administration and wildfire risk reduction.

Sexually transmitted infections in Spain: Current status.

Sexually Transmitted Infections (STI) are a major public health problem. The problems inherent to their diagnosis, treatment and prevention have to do not only with their nature, but also with organizational issues and overlapping competencies of the different health authorities in Spain. The real situation of STI in Spain, at present, is poorly known. For this reason, the Scientific Committee on COVID and Emerging Pathogens of the Illustrious Official College of Physicians of Madrid (ICOMEM) has formulated a series of questions on this subject which were distributed, not only among the members of the Committee, but also among experts outside it. The central health authorities provide very high and increasing figures for gonococcal infection, syphilis, Chlamydia trachomatis infection and lymphogranuloma venereum (LGV). Both HIV infection and Monkeypox are two important STI caused by viruses in our environment, to which it should be added, mainly, Herpes simplex virus (HSV) and Human papillomavirus (HPV) infections. Emerging microorganisms such as Mycoplasma genitalium pose not only pathogenic challenges but also therapeutic problems, as in the case of N. gonohrroeae. The pathways that patients with suspected STI follow until they are adequately diagnosed and treated are not well known in Spain. Experts understand that this problem is fundamentally managed in public health institutions, and that Primary Care and Hospital Emergency Services, together with some institutions that deal monographically with this problem, are the recipients of most of these patients. One of the most serious difficulties of STI lies in the availability of the microbiological tests necessary for their diagnosis, particularly in this era of outsourcing of microbiology services. Added to this is the increased cost of implementing the latest generation of molecular techniques and the difficulties of transporting samples. It is clear that STI are not diseases to which the entire population is equally exposed and it is necessary to have a better knowledge of the risk groups where to focus the necessary interventions adapted to their characteristics. It should not be forgotten that STI are also a problem in the pediatric age group and that their presence can be a marker of sexual abuse with all that this implies in terms of health care and medicolegal activity. Finally, STI are infections that are associated with a high cost of care for which we have very little information. The possibility of expanding the automatic performance of laboratory tests for STI surveillance through laboratory routines is encountering ethical and legal problems that are not always easy to solve. Spain has created a ministerial area of specific attention to STI and there are plans to improve the diagnosis, treatment and prevention of these problems, but we still lack the necessary evidence on their impact. We cannot forget that these are diseases that transcend the individual and constitute a Public Health problem.

Simplified sewerage to prevent urban leptospirosis transmission: a cluster non-randomised controlled trial protocol in disadvantaged urban communities of Salvador, Brazil.

INTRODUCTION: Leptospirosis is a globally distributed zoonotic and environmentally mediated disease that has emerged as a major health problem in urban slums in developing countries. Its aetiological agent is bacteria of the genus Leptospira, which are mainly spread in the urine of infected rodents, especially in an environment where adequate sanitation facilities are lacking, and it is known that open sewers are key transmission sources of the disease. Therefore, we aim to evaluate the effectiveness of a simplified sewerage intervention in reducing the risk of exposure to contaminated environments and Leptospira infection and to characterise the transmission mechanisms involved. METHODS AND ANALYSIS: This matched quasi-experimental study design using non-randomised intervention and control clusters was designed to assess the effectiveness of an urban simplified sewerage intervention in the low-income communities of Salvador, Brazil. The intervention consists of household-level piped sewerage connections and community engagement and public involvement activities. A cohort of 1400 adult participants will be recruited and grouped into eight clusters consisting of four matched intervention-control pairs with approximately 175 individuals in each cluster in baseline. The primary outcome is the seroincidence of Leptospira infection assessed through five serological measurements: one preintervention (baseline) and four postintervention. As a secondary outcome, we will assess Leptospira load in soil, before and after the intervention. We will also assess Leptospira exposures before and after the intervention, through transmission modelling, accounting for residents' movement, contact with flooding, contaminated soil and water, and rat infestation, to examine whether and how routes of exposure for Leptospira change following the introduction of sanitation. ETHICS AND DISSEMINATION: This study protocol has been reviewed and approved by the ethics boards at the Federal University of Bahia and the Brazilian National Research Ethics Committee. Results will be disseminated through peer-reviewed publications and presentations to implementers, researchers and participating communities. TRIAL REGISTRATION NUMBER: Brazilian Clinical Trials Registry (RBR-8cjjpgm).

Density of Aedes aegypti (Diptera: Culicidae) in a low-income Brazilian urban community where dengue, Zika, and chikungunya viruses co-circulate.

BACKGROUND: Low-income urban communities in the tropics often lack sanitary infrastructure and are overcrowded, favoring Aedes aegypti proliferation and arboviral transmission. However, as Ae. aegypti density is not spatially homogeneous, understanding the role of specific environmental characteristics in determining vector distribution is critical for planning control interventions. The objectives of this study were to identify the main habitat types for Ae. Aegypti, assess their spatial densities to identify major hotspots of arbovirus transmission over time and investigate underlying factors in a low-income urban community in Salvador, Brazil. We also tested the field-collected mosquitoes for arboviruses. METHODS: A series of four entomological and socio-environmental surveys was conducted in a random sample of 149 households and their surroundings between September 2019 and April 2021. The surveys included searching for potential breeding sites (water-containing habitats) and for Ae. aegypti immatures in them, capturing adult mosquitoes and installing ovitraps. The spatial distribution of Ae. aegypti density indices were plotted using kernel density-ratio maps, and the spatial autocorrelation was assessed for each index. Visual differences on the spatial distribution of the Ae. aegypti hotspots were compared over time. The association of entomological findings with socio-ecological characteristics was examined. Pools of female Ae. aegypti were tested for dengue, Zika and chikungunya virus infection. RESULTS: Overall, 316 potential breeding sites were found within the study households and 186 in the surrounding public spaces. Of these, 18 (5.7%) and 7 (3.7%) harbored a total of 595 and 283 Ae. aegypti immatures, respectively. The most productive breeding sites were water storage containers within the households and puddles and waste materials in public areas. Potential breeding sites without cover, surrounded by vegetation and containing organic matter were significantly associated with the presence of immatures, as were households that had water storage containers. None of the entomological indices, whether based on immatures, eggs or adults, detected a consistent pattern of vector clustering in the same areas over time. All the mosquito pools were negative for the tested arboviruses. CONCLUSIONS: This low-income community displayed high diversity of Ae. aegypti habitats and a high degree of heterogeneity of vector abundance in both space and time, a scenario that likely reflects other low-income communities. Improving basic sanitation in low-income urban communities through the regular water supply, proper management of solid wastes and drainage may reduce water storage and the formation of puddles, minimizing opportunities for Ae. aegypti proliferation in such settings.