Effect of Jardiance on glucose uptake into astrocytomas.

PURPOSE: SGLT2, the sodium glucose cotransporter two, is expressed in human pancreatic, prostate and brain tumors, and in a mouse cancer model SGLT2 inhibitors reduce tumor glucose uptake and growth. In this study we have measured the effect of a specific SGLT2 inhibitor, Jardiance® (Empagliflozin), on glucose uptake into astrocytomas in patients. METHODS: We have used a specific SGLT glucose tracer, α-methyl-4-[18F]fluoro-4-deoxy-α-D-glucopyranoside (Me4FDG), and Positron Emission Tomography (PET) to measure glucose uptake. Four of five patients enrolled had WHO grade IV glioblastomas, and one had a low grade WHO Grade II astrocytoma. Two dynamic brain PET scans were conducted on each patient, one before and one after treatment with a single oral dose of Jardiance, a specific SGLT2 inhibitor. As a control, we also determined the effect of oral Jardiance on renal SGLT2 activity. RESULTS: In all five patients an oral dose (25 or 100 mg) of Jardiance reduced Me4FDG tumor accumulation, highly significant inhibition in four, and inhibited SGLT2 activity in the kidney. CONCLUSIONS: These initial experiments show that SGLT2 is a functional glucose transporter in astocytomas, and Jardiance inhibited glucose uptake, a drug approved by the FDA to treat type 2 diabetes mellitus (T2DM), heart failure, and renal failure. We suggest that clinical trials be initiated to determine whether Jardiance reduces astrocytoma growth in patients.

Hematopoietic Stem Cell Transplantation in Children with Sickle Cell Disease and Thalassemia Major: A National Database Study.

In patients with sickle cell disease (SCD) and beta-thalassemia major (TM), allogeneic hematopoietic stem cell transplantation (HSCT) was considered the only curative treatment option with a good survival rate. However, with the recent approval of gene therapies, more information is needed to understand the benefits and risks of these interventions. We performed a retrospective analysis of the Kids Inpatient Database to describe demographic features, short-term complications, and hospital charges of patients with SCD and TM treated with HSCT during 2006-2019 in the United States. The database was filtered using the International Classification of Diseases, 9th and 10th edition codes to identify children under 20 years of age with SCD or TM who underwent HSCT. A total of 513 children with SCD or TM who received HSCT were analyzed. The prevalence of HSCT per 1000,000 U.S. population increased from 0.31 in 2006 to 1.99 in 2019 (p < 0.001). The median age of children with SCD who underwent HSCT was 10 (6-15) years, and that for TM was 6 (3-11.5) years (p < 0.001). The combined mortality rate was 4% (2.4%-6.6%) but higher in the TM group. The length-of-stay and total charges were higher in the TM population (p < 0.01). This study provides national data on HSCT among hospitalized children with SCD and TM in the United States, demonstrating an increasing use of HSCT between 2006 and 2019. Although hospital mortality of HSCT in these conditions is low, it still represents a challenge, especially in TM patients.

A new 3D model of L929 fibroblasts microtissues uncovers the effects of Bothrops erythromelas venom and its antivenom.

In Brazil, around 80% of snakebites are caused by snakes of the genus Bothrops. A three-dimensional culture model was standardized and used to perform treatments with Bothrops erythromelas venom (BeV) and its antivenom (AV). The MRC-5 and L929 cell lines were cultured at increasing cell densities. Morphometric parameters were evaluated through images obtained from an inverted microscope: solidity, circularity, and Feret diameter. L929 microtissues (MT) showed better morphometric data, and thus they were used for further analysis. MT viability was assessed using the acridine orange and ethidium bromide staining method, which showed viable cells in the MT on days 5, 7, and 10 of cultivation. Histochemical and histological analyses were performed, including hematoxylin/eosin staining, which showed a good structure of the spheroids. Alcian blue staining revealed the presence of acid proteoglycans. Immunohistochemical analysis with ki-67 showed different patterns of cell proliferation. The MT were also subjected to pharmacological tests using the BeV, in the presence or absence of its AV. The results showed that the venom was not cytotoxic, but it caused morphological changes. The MT showed cell detachment, losing their structure. The antivenom was able to partially prevent the venom activities.

MHConstructor: A high-throughput, haplotype-informed solution to the MHC assembly challenge.

The extremely high levels of genetic polymorphism within the human major histocompatibility complex (MHC) limit the usefulness of reference-based alignment methods for sequence assembly. We incorporate a short read de novo assembly algorithm into a workflow for novel application to the MHC. MHConstructor is a containerized pipeline designed for high-throughput, haplotype-informed, reproducible assembly of both whole genome sequencing and target-capture short read data in large, population cohorts. To-date, no other self-contained tool exists for the generation of de novo MHC assemblies from short read data. MHConstructor facilitates wide-spread access to high quality, alignment-free MHC sequence analysis.

Awareness, treatment, and control of hypertension among women at risk or living with HIV in the US South: a prospective study.

OBJECTIVES: Timely control of hypertension is vital to prevent comorbidities. We evaluated the association of race/ethnicity and HIV infection with incident hypertension outcomes, including awareness, treatment, and control. DESIGN: We evaluated cisgender women living with HIV and sociodemographically matched women living without HIV recruited into four Southern sites of the Women's Interagency HIV Study (2013-2019). METHODS: We calculated measurements of the time to four events or censoring: incident hypertension, hypertension awareness, hypertension treatment, and hypertension control. Hazard ratios for race/ethnicity and HIV status were calculated for each outcome using Cox proportional-hazards models adjusted for sociodemographic, behavioral, and clinical risk factors. RESULTS: Among 712 women, 56% were hypertensive at baseline. Forty-five percent of the remaining women who were normotensive at baseline developed incident hypertension during follow-up. Non-Hispanic White and Hispanic women had faster time to hypertension control compared to non-Hispanic Black women (p = 0.01). In fully adjusted models, women living with HIV who were normotensive at baseline had faster time to treatment compared to normotensive women living without HIV (p = 0.04). CONCLUSIONS: In our study of women in the US South, non-Hispanic Black women became aware of their hypertension diagnosis more quickly than non-Hispanic White and Hispanic women but were slower to control their hypertension. Additionally, women living with HIV more quickly treated and controlled their hypertension compared to women living without HIV.

Donanemab, another anti-Alzheimer's drug with risk and uncertain benefit.

Based on "reducing amyloid plaques in the brain", the U.S. Food and Drug Administration has granted accelerated and full approval for two monoclonal anti-Alzheimer's antibodies, aducanumab and lecanemab, respectively. Approval of a third antibody, donanemab, is pending. Moreover, lecanemab and donanemab are claimed to cause delay in the cognitive decline that characterizes the disease. We believe that these findings are subject to misinterpretation and statistical bias. Donanemab is claimed to cause removal of up to 86 % of cerebral amyloid and 36 % delay in cognitive decline compared to placebo. In reality, these are very small changes on an absolute scale and arguably less than what can be achieved with cholinesterase inhibitor/memantine therapy. Moreover, the "removal" of amyloid, based on the reduced accumulation of amyloid-PET tracer, most likely also reflects therapy-related tissue damage. This would also correlate with the minimal clinical effect, the increased frequency of amyloid-related imaging abnormalities, and the accelerated loss of brain volume in treated compared to placebo patients observed with these antibodies. We recommend halting approvals of anti-AD antibodies until these issues are fully understood to ensure that antibody treatment does not cause more harm than benefit to patients.

Pandemic preparedness improves national-level SARS-CoV-2 infection and mortality data completeness: a cross-country ecologic analysis.

BACKGROUND: Heterogeneity in national SARS-CoV-2 infection surveillance capabilities may compromise global enumeration and tracking of COVID-19 cases and deaths and bias analyses of the pandemic's tolls. Taking account of heterogeneity in data completeness may thus help clarify analyses of the relationship between COVID-19 outcomes and standard preparedness measures. METHODS: We examined country-level associations of pandemic preparedness capacities inventories, from the Global Health Security (GHS) Index and Joint External Evaluation (JEE), on SARS-CoV-2 infection and COVID-19 death data completion rates adjusted for income. Analyses were stratified by 100, 100-300, 300-500, and 500-700 days after the first reported case in each country. We subsequently reevaluated the relationship of pandemic preparedness on SARS-CoV-2 infection and age-standardized COVID-19 death rates adjusted for cross-country differentials in data completeness during the pre-vaccine era. RESULTS: Every 10% increase in the GHS Index was associated with a 14.9% (95% confidence interval 8.34-21.8%) increase in SARS-CoV-2 infection completion rate and a 10.6% (5.91-15.4%) increase in the death completion rate during the entire observation period. Disease prevention (infections: ß = 1.08 [1.05-1.10], deaths: ß = 1.05 [1.04-1.07]), detection (infections: ß = 1.04 [1.01-1.06], deaths: ß = 1.03 [1.01-1.05]), response (infections: ß = 1.06 [1.00-1.13], deaths: ß = 1.05 [1.00-1.10]), health system (infections: ß = 1.06 [1.03-1.10], deaths: ß = 1.05 [1.03-1.07]), and risk environment (infections: ß = 1.27 [1.15-1.41], deaths: ß = 1.15 [1.08-1.23]) were associated with both data completeness outcomes. Effect sizes of GHS Index on infection completion (Low income: ß = 1.18 [1.04-1.34], Lower Middle income: ß = 1.41 [1.16-1.71]) and death completion rates (Low income: ß = 1.19 [1.09-1.31], Lower Middle income: ß = 1.25 [1.10-1.43]) were largest in LMICs. After adjustment for cross-country differences in data completeness, each 10% increase in the GHS Index was associated with a 13.5% (4.80-21.4%) decrease in SARS-CoV-2 infection rate at 100 days and a 9.10 (1.07-16.5%) decrease at 300 days. For age-standardized COVID-19 death rates, each 10% increase in the GHS Index was with a 15.7% (5.19-25.0%) decrease at 100 days and a 10.3% (- 0.00-19.5%) decrease at 300 days. CONCLUSIONS: Results support the pre-pandemic hypothesis that countries with greater pandemic preparedness capacities have larger SARS-CoV-2 infection and mortality data completeness rates and lower COVID-19 disease burdens. More high-quality data of COVID-19 impact based on direct measurement are needed.

Development and characterization of a novel variant of long-acting bovine follicle-stimulating hormone (brscFSH).

Assisted reproduction is a key aspect of modern animal breeding, providing valuable assistance in improving breeding programs. In this field, the administration of exogenous hormones, such as follicle-stimulating hormone (FSH), plays a crucial role in the induction of multiple ovulations. However, commercial FSH used in veterinary practice has been derived primarily from pituitary glands, obtained mostly from pigs for nearly four decades. Although these hormones have contributed significantly to the advancement of assisted reproductive techniques, they have certain limitations that warrant further improvements. These limitations include contamination with luteinizing hormone (LH), the potential risk of pathogen contamination, the potential to trigger an immune response in non-pig species, and the short half-life in circulation, requiring the implementation of complex 8-dose superovulation schedules. Our research team has developed and characterized a new variant of bovine follicle-stimulating hormone (bscrFSH) to address these limitations. The new hormone is produced recombinantly in CHO cell cultures, with a specific productivity of about 30 pg/cell/day. The bscrFSH can be purified to a high purity of 97 % using a single step of immobilized metal affinity chromatography (IMAC). N-glycan analysis of bscrFSH showed that approximately 74 % of the glycans corresponded to charged structures, including mono-, di-, tri-, and tetra-sialylated glycans. Superovulation trials conducted in cattle revealed that bscrFSH, administered at a total dose of about 0.5 µg per kg of body weight, using a decrescent schedule of 4 doses with 24-h intervals, resulted in an average yield of 8-12 transferable embryos per animal. Further research is required; however, the preliminary findings indicate that bscrFSH, currently packaged under the provisional brand name of Cebitropin B, holds potential as a commercial product for assisted reproduction in ruminants.

Variational umbrella seeding for calculating nucleation barriers.

In this work, we introduce variational umbrella seeding, a novel technique for computing nucleation barriers. This new method, a refinement of the original seeding approach, is far less sensitive to the choice of order parameter for measuring the size of a nucleus. Consequently, it surpasses seeding in accuracy and umbrella sampling in computational speed. We test the method extensively and demonstrate excellent accuracy for crystal nucleation of nearly hard spheres and two distinct models of water: mW and TIP4P/ICE. This method can easily be extended to calculate nucleation barriers for homogeneous melting, condensation, and cavitation.

Biodegradable Biocomposite of Starch Films Cross-Linked with Polyethylene Glycol Diglycidyl Ether and Reinforced by Microfibrillated Cellulose.

Biopolymers are biodegradable and renewable and can significantly reduce environmental impacts. For this reason, biocomposites based on a plasticized starch and cross-linker matrix and with a microfibrillated OCC cardboard cellulose reinforcement were developed. Biocomposites were prepared by suspension casting with varied amounts of microfibrillated cellulose: 0, 4, 8, and 12 wt%. Polyethylene glycol diglycidyl ether (PEGDE) was used as a cross-linking, water-soluble, and non-toxic agent. Microfibrillated cellulose (MFC) from OCC cardboard showed appropriate properties and potential for good performance as a reinforcement. In general, microfiber incorporation and matrix cross-linking increased crystallization, reduced water adsorption, and improved the physical and tensile properties of the plasticized starch. Biocomposites cross-linked with PEGDE and reinforced with 12 wt% MFC showed the best properties. The chemical and structural changes induced by the cross-linking of starch chains and MFC reinforcement were confirmed by FTIR, NMR, and XRD. Biodegradation higher than 80% was achieved for most biocomposites in 15 days of laboratory compost.

Signatures of epigenetic, biological and mitotic age acceleration and telomere shortening are associated with arsenic-induced skin lesions.

Chronic arsenic exposure is a global health hazard significantly associated with the development of deleterious cutaneous changes and increased keratinocyte cancer risk. Although arsenic exposure is associated with broad-scale cellular and molecular changes, gaps exist in understanding how these changes impact the skin and facilitate malignant transformation. Recently developed epigenetic "clocks" can accurately predict chronological, biological and mitotic age, as well as telomere length, on the basis of tissue DNA methylation state. Deviations of predicted from expected age (epigenetic age dysregulation) have been associated with numerous complex diseases, increased all-cause mortality and higher cancer risk. We investigated the ability of these algorithms to detect molecular changes associated with chronic arsenic exposure in the context of associated skin lesions. To accomplish this, we utilized a multi-algorithmic approach incorporating seven "clocks" (Horvath, Skin&Blood, PhenoAge, PCPhenoAge, GrimAge, DNAmTL and epiTOC2) to analyze peripheral blood of pediatric and adult cohorts of arsenic-exposed (n = 84) and arsenic-naïve (n = 33) individuals, among whom n = 18 were affected by skin lesions. Arsenic-exposed adults with skin lesions exhibited accelerated epigenetic (Skin&Blood: + 7.0 years [95% CI 3.7; 10.2], q = 6.8 × 10-4), biological (PhenoAge: + 5.8 years [95% CI 0.7; 11.0], q = 7.4 × 10-2, p = 2.8 × 10-2) and mitotic age (epiTOC2: + 19.7 annual cell divisions [95% CI 1.8; 37.7], q = 7.4 × 10-2, p = 3.2 × 10-2) compared to healthy arsenic-naïve individuals; and accelerated epigenetic age (Skin&Blood: + 2.8 years [95% CI 0.2; 5.3], q = 2.4 × 10-1, p = 3.4 × 10-2) compared to lesion-free arsenic-exposed individuals. Moreover, lesion-free exposed adults exhibited accelerated Skin&Blood age (+ 4.2 [95% CI 1.3; 7.1], q = 3.8 × 10-2) compared to their arsenic-naïve counterparts. Compared to the pediatric group, arsenic-exposed adults exhibited accelerated epigenetic (+ 3.1 to 4.4 years (95% CI 1.2; 6.4], q = 2.4 × 10-4-3.1 × 10-3), biological (+ 7.4 to 7.8 years [95% CI 3.0; 12.1] q = 1.6 × 10-3-2.8 × 10-3) and mitotic age (+ 50.0 annual cell divisions [95% CI 15.6; 84.5], q = 7.8 × 10-3), as well as shortened telomere length (- 0.23 kilobases [95% CI - 0.13; - 0.33], q = 2.4 × 10-4), across all seven algorithms. We demonstrate that lifetime arsenic exposure and presence of arsenic-associated skin lesions are associated with accelerated epigenetic, biological and mitotic age, and shortened telomere length, reflecting altered immune signaling and genomic regulation. Our findings highlight the usefulness of DNA methylation-based algorithms in identifying deleterious molecular changes associated with chronic exposure to the heavy metal, serving as potential prognosticators of arsenic-induced cutaneous malignancy.

Key energy metabolisms in modern living microbialites from hypersaline Andean lagoons of the Salar de Atacama, Chile.

Microbialites are organosedimentary structures formed mainly due to the precipitation of carbonate minerals, although they can also incorporate siliceous, phosphate, ferric, and sulfate minerals. The minerals' precipitation occurs because of local chemical changes triggered by changes in pH and redox transformations catalyzed by the microbial energy metabolisms. Here, geochemistry, metagenomics, and bioinformatics tools reveal the key energy metabolisms of microbial mats, stromatolites and an endoevaporite distributed across four hypersaline lagoons from the Salar de Atacama. Chemoautotrophic and chemoheterotrophic microorganisms seem to coexist and influence microbialite formation. The microbialite types of each lagoon host unique microbial communities and metabolisms that influence their geochemistry. Among them, photosynthetic, carbon- and nitrogen- fixing and sulfate-reducing microorganisms appear to control the main biogeochemical cycles. Genes associated with non-conventional energy pathways identified in MAGs, such as hydrogen production/consumption, arsenic oxidation/reduction, manganese oxidation and selenium reduction, also contribute to support life in microbialites. The presence of genes encoding for enzymes associated with ureolytic processes in the Cyanobacteria phylum and Gammaproteobacteria class might induce carbonate precipitation in hypersaline environments, contributing to the microbialites formation. To the best of our knowledge, this is the first study characterizing metagenomically microbialites enriched in manganese and identifying metabolic pathways associated with manganese oxidation, selenium reduction, and ureolysis in this ecosystem, which suggests that the geochemistry and bioavailability of energy sources (As, Mn and Se) shapes the microbial metabolisms in the microbialites.

A plasma protein-based risk score to predict hip fractures.

As there are effective treatments to reduce hip fractures, identification of patients at high risk of hip fracture is important to inform efficient intervention strategies. To obtain a new tool for hip fracture prediction, we developed a protein-based risk score in the Cardiovascular Health Study using an aptamer-based proteomic platform. The proteomic risk score predicted incident hip fractures and improved hip fracture discrimination in two Trøndelag Health Study validation cohorts using the same aptamer-based platform. When transferred to an antibody-based proteomic platform in a UK Biobank validation cohort, the proteomic risk score was strongly associated with hip fractures (hazard ratio per s.d. increase, 1.64; 95% confidence interval 1.53-1.77). The proteomic risk score, but not available polygenic risk scores for fractures or bone mineral density, improved the C-index beyond the fracture risk assessment tool (FRAX), which integrates information from clinical risk factors (C-index, FRAX 0.735 versus FRAX + proteomic risk score 0.776). The developed proteomic risk score constitutes a new tool for stratifying patients according to hip fracture risk; however, its improvement in hip fracture discrimination is modest and its clinical utility beyond FRAX with information on femoral neck bone mineral density remains to be determined.

High Throughput Plasma Proteomics and Risk of Heart Failure and Frailty in Late Life.

Importance: Heart failure (HF) and frailty frequently coexist and may share a common pathobiology, although the underlying mechanisms remain unclear. Understanding these mechanisms may provide guidance for preventing and treating both conditions. Objective: To identify shared pathways between incident HF and frailty in late life using large-scale proteomics. Design, Setting, and Participants: In this cohort study, 4877 aptamers (Somascan v4) were measured among participants in the community-based longitudinal Atherosclerosis Risk In Communities (ARIC) cohort study at visit 3 (V3; 1993-1995; n = 10 638) and at visit 5 (V5; 2011-2013; n = 3908). Analyses were externally replicated among 3189 participants in the Cardiovascular Health Study (CHS). Data analysis was conducted from February 2022 to June 2023. Exposures: Protein aptamers, measured at study V3 and V5. Main Outcomes and Measures: Outcomes assessed included incident HF hospitalization after V3 and after V5, prevalent frailty at V5, and incident frailty between V5 and visit 6 (V6; 2016-2017; n = 4131). Frailty was assessed using the Fried criteria. Analyses were adjusted for age, gender, race, field center, hypertension, diabetes, smoking status, body mass index, estimated glomerular filtration rate, prevalent coronary heart disease, prevalent atrial fibrillation, and history of myocardial infarction. Mendelian randomization (MR) analysis was performed to assess potential causal effects of candidate proteins on HF and frailty. Results: A total of 4877 protein aptamers were measured among 10 638 participants at V3 (mean [SD] age, 60 [6] years; 4886 [46%] men). Overall, 286 proteins were associated with incident HF after V3 (822 events; P < 1.0 × 10-5), 83 of which were also associated with incident after V5 (336 events; P < 1.7 × 10-4). Among HF-free participants at V5 (n = 3908; mean [SD] age, 75 [5] years; 1861 [42%] men), 48 of 83 HF-associated proteins were associated with prevalent frailty (223 cases; P < 6.0 × 10-4), 18 of which were also associated with incident frailty at V6 (152 cases; P < 1.0 × 10-3). These proteins enriched fibrosis and inflammation pathways and demonstrated stronger associations with incident HF with preserved ejection fraction (HFpEF) than HF with reduced ejection fraction. All 18 proteins were associated with both prevalent frailty and incident HF in CHS. MR identified potential causal effects of several proteins on frailty and HF. Conclusions and Relevance: In this study, the proteins associated with risk of HF and frailty enrich for pathways related to inflammation and fibrosis as well as risk of HFpEF. Several of these proteins could potentially contribute to the shared pathophysiology of frailty and HF.

Between conflict and reciprocal habituation: Human-wild boar coexistence in urban areas.

Urbanization is an ongoing global environmental change. Wildlife may respond using anthropized environments and resources, which is known as synurbization, creating human-wildlife interactions. Wild boar (Sus scrofa) populations have become common in urban areas, including the metropolitan area of Barcelona. Humans respond to wild boars in urban environments either habituating, with lower conflict perception and higher wild boar acceptance, or sensitizing, with reduced tolerance towards wild boars. Since citizen response influences conflict management, this study analysed the drivers of human responses, which should allow adopting socially-accepted measures to manage synurbic wild boar populations. Interviews to 1956 Barcelona citizens were performed, grouping the response variables to score citizen and urban characteristics, as well as citizen lay-knowledge, emotions, experiences, and perception of wild boar. Five citizen clusters were identified: cluster 1 (3.3 %), highly habituated and active wild boar feeder; cluster 2 (11.3 %), habituated to wild boars with positive feelings; cluster 3 (19.8 %), not habituated nor sensitized, willing to maintain urban wild boar populations; cluster 4 (29.1 %), sensitized and concerned, defending to reduce wild boar; and cluster 5 (40.1 %), highly sensitized and proposing to reduce or even eliminate wild boar. Positive attitudes associated wild boar to aesthetic value, closeness to nature and sympathy, and were more frequent in young citizens with urban background and high education, animal lovers habituated to wild boar through contact without negative experiences. Conversely, negative attitudes were concerned about city fouling, safety or health, accepted lethal management measures, and were more frequent in older citizens with rural background, lower education, low contact with wild boar or sensitized through negative experiences. We document for the first time the sensitization and reciprocal habituation of humans to wild boar in urban areas. The identification of the drivers of citizen attitudes towards urban wildlife should be useful to design socially-accepted management measures.

Alzheimer's Amyloid Hypothesis and Antibody Therapy: Melting Glaciers?

The amyloid cascade hypothesis for Alzheimer's disease is still alive, although heavily challenged. Effective anti-amyloid immunotherapy would confirm the hypothesis' claim that the protein amyloid-beta is the cause of the disease. Two antibodies, aducanumab and lecanemab, have been approved by the U.S. Food and Drug Administration, while a third, donanemab, is under review. The main argument for the FDA approvals is a presumed therapy-induced removal of cerebral amyloid deposits. Lecanemab and donanemab are also thought to cause some statistical delay in the determination of cognitive decline. However, clinical efficacy that is less than with conventional treatment, selection of amyloid-positive trial patients with non-specific amyloid-PET imaging, and uncertain therapy-induced removal of cerebral amyloids in clinical trials cast doubt on this anti-Alzheimer's antibody therapy and hence on the amyloid hypothesis, calling for a more thorough investigation of the negative impact of this type of therapy on the brain.