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Introduction Globally, chronic HBV infection is the leading cause of hepatocellular carcinoma and cirrhosis. (1) In 2022, an estimated 5 million people in the AMR (2) had chronic HBV infection, [...], In 2022, an estimated 5 million persons in the WHO Region of the Americas (AMR) were living with chronic hepatitis B virus (HBV) infection, the leading cause of hepatocellular carcinoma and cirrhosis worldwide. Most chronic infections are acquired through mother-to-child transmission (MTCT) or horizontal transmission during childhood and are preventable with HBV vaccination, including a birth dose (HepB-BD), followed by 2-3 additional doses (HepB3) in infancy. The aim of the Pan American Health Organization (PAHO) Elimination of MTCT of HBV strategy (EMTCT Plus) is intented to reduce the prevalence of chronic HBV infection (measured as hepatitis B surface antigen [HBsAg]) among children to [less than or equal to]0.1% by achieving 1) [greater than or equal to]95% coverage with HepB-BD and HepB3 and 2) increasing HBsAg testing among pregnant women and provision of hepatitis B immunoglobulin to HBV-exposed neonates to [greater than or equal to]80%. By 2012, all 51 countries and territories (countries) in the AMR had provided HepB3 nationwide; and, by 2021, 34 (67%) had provided HepB-BD nationwide. Mathematical models were used to estimate that the HBsAg prevalence in children is [less than or equal to] 0.1% in 14 (28%) countries and at regional level. Three (6%) of 51 countries met the 95% coverage targets for both HepB3 and HepB-BD during both 2021 and 2022. Of these, 2 have probably met the criteria for EMTCT of HBV infection. In 2022, however, HepB3 coverage was [greater than or equal to] 10 percentage points lower in 15 (37%) of 41 countries with 2012 coverage data for comparison. These decreases in HepB3 coverage and the absence of HepB-BD from the routine immunization schedules in 17 countries threaten the Region&apos;s progress towards the EMTCT of HBV infection. Efforts to introduce HepB-BD and to maintain high HepB3 and HepB-BD coverage are necessary. En 2022, on estimait a 5 millions le nombre de personnes vivant avec une infection chronique par le virus de l&apos;hepatite B (VHB) dans la Region OMS des Ameriques, principale cause de carcinome hepatocellulaire et de cirrhose dans le monde. La plupart des infections chroniques sont contractees par transmission mere-enfant (TME) ou par transmission horizontale pendant l&apos;enfance et peuvent etre evitees grace a la vaccination contre le VHB, notamment par l&apos;administration d&apos;une dose a la naissance (DN-HepB), suivie de 2 a 3 doses supplementaires (HepB3) dans la petite enfance. La strategie d&apos;elimination de la transmission mere-enfant du VHB (EMTCT Plus) de l&apos;Organisation panamericaine de la Sante (OPS) vise a reduire la prevalence de l&apos;infection chronique par le VHB (mesuree par une prevalence de l&apos;antigene de surface du virus de l&apos;hepatite B [AgHBs]) [less than or equal to]0,1% chez les enfants) en parvenant a: 1) une couverture [greater than or equal to]95% par la DN-HepB et la HepB3 et 2) une couverture [greater than or equal to]80% du depistage a la recherche de l&apos;AgHBs chez les femmes enceintes et de l&apos;administration d&apos;immunoglobulines antihepatite B aux nouveau-nes exposes au VHB. En 2012, les 51 pays et territoires (ci-apres <>) de la Region des Ameriques administraient la HepB3 a l&apos;echelle nationale; en 2021, 34 pays (67%) administraient la DN-HepB a l&apos;echelle nationale. Des modeles mathematiques ont permis d&apos;estimer que la prevalence de l&apos;AgHBs chez les enfants etait [less than or equal to] 0,1% dans 14 pays (28%) et au niveau regional. Trois des 51 pays (6%) avaient atteint la cible d&apos;une couverture de 95% par la HepB3 et la DN-HepB en 2021 et en 2022, dont 2 remplissaient probablement les criteres de l&apos;elimination de la TME de l&apos;infection par le VHB. En 2022, cependant, la couverture par la HepB3 etait inferieure de [greater than or equal to] 10 points de pourcentage dans 15 des 41 pays (37%) pour lesquels les donnees de couverture de 2012 etaient disponibles a des fins de comparaison. Cette diminution de la couverture par la HepB3 et l&apos;absence de la DN-HepB dans les calendriers de vaccination systematique dans 17 pays menacent les progres de la Region vers l&apos;elimination de la TME de l&apos;infection par le VHB. Il est necessaire de deployer des efforts pour introduire la DN-HepB et maintenir une couverture elevee par la HepB3 et la DN-HepB.

Abstract Recurrent breast cancers often develop resistance to standard-of-care therapies. Identifying targetable factors contributing to cancer recurrence remains the rate-limiting step in improving long-term outcomes. In this study, we identify tumor cell-derived osteopontin as an autocrine and paracrine driver of tumor recurrence. Osteopontin promotes tumor cell proliferation, recruits macrophages, and synergizes with IL-4 to further polarize them into a pro-tumorigenic state. Macrophage depletion and osteopontin inhibition decrease recurrent tumor growth. Furthermore, targeting osteopontin in primary tumor-bearing female mice prevents metastasis, permits T cell infiltration and activation, and improves anti-PD-1 immunotherapy response. Clinically, osteopontin expression is higher in recurrent metastatic tumors versus female patient-matched primary breast tumors. Osteopontin positively correlates with macrophage infiltration, increases with higher tumor grade, and its elevated pathway activity is associated with poor prognosis and long-term recurrence. Our findings suggest clinical implications and an alternative therapeutic strategy based on osteopontin’s multiaxial role in breast cancer progression and recurrence.

Objective This study identifies preoperative risk factors associated with blood transfusion in women undergoing surgery for ectopic pregnancy. A retrospective chart review of 252 cases was performed at a single academic-affiliated community hospital system between January 2014 and October 2017. Univariate analysis was performed using non-parametric testing where appropriate, and significant variables were incorporated in multivariate modelling.Methods In this cohort of 252 women, the overall transfusion rate was 8.7% (n=22). Increasing age (OR 1.12, 95% CI 1.03 to 1.22), lower systolic blood pressure (SBP) on presentation (OR 0.96, 95% CI 0.93 to 1.00), lower minimum systolic and diastolic blood pressure (DBP) (OR 0.92, 95% CI 0.89 to 1.95 and OR 0.9, 95% CI 0.84 to 0.93) and lower preoperative haemoglobin (g/L) (OR 0.46, 95% CI 0.33 to 0.62) were associated with higher rates of blood transfusion. Women who had prior care in their current pregnancy and women treated in a women’s specific emergency room (compared with a general emergency room) were less likely to be transfused (OR 0.16, 95% CI 0.05 to 0.51 and OR 0.09, 95% CI 0.03 to 0.30, respectively). Our study used a model in which variance in transfusion can reliably be explained by location of presentation to care, pain alone as a presenting complaint and haemoglobin level (Area under the curve (AUC) =0.87).Conclusion History of caesarean section and a presenting complaint of pain alone are newly identified indicators for women at higher risk of transfusion at the time of surgical management of ectopic pregnancy. Additionally, care provided in women’s specific emergency rooms may decrease the risk of blood transfusion in this population.

Noradrenaline (NA) regulates cold-stimulated adipocyte thermogenesis1. Aside from cAMP signalling downstream of β-adrenergic receptor activation, how NA promotes thermogenic output is still not fully understood. Here, we show that coordinated α1-adrenergic receptor (AR) and β3-AR signalling induces the expression of thermogenic genes of the futile creatine cycle2,3, and that early B cell factors, oestrogen-related receptors and PGC1α are required for this response in vivo. NA triggers physical and functional coupling between the α1-AR subtype (ADRA1A) and Gαq to promote adipocyte thermogenesis in a manner that is dependent on the effector proteins of the futile creatine cycle, creatine kinase B and tissue-non-specific alkaline phosphatase. Combined Gαq and Gαs signalling selectively in adipocytes promotes a continual rise in whole-body energy expenditure, and creatine kinase B is required for this effect. Thus, the ADRA1A-Gαq-futile creatine cycle axis is a key regulator of facultative and adaptive thermogenesis.

Metabolic rewiring is essential for tumor growth and progression to metastatic disease, yet little is known regarding how cancer cells modify their acquired metabolic programs in response to different metastatic microenvironments. We have previously shown that liver-metastatic breast cancer cells adopt an intrinsic metabolic program characterized by increased HIF-1α activity and dependence on glycolysis. Here, we confirm by in vivo stable isotope tracing analysis (SITA) that liver-metastatic breast cancer cells retain a glycolytic profile when grown as mammary tumors or liver metastases. However, hepatic metastases exhibit unique metabolic adaptations including elevated expression of genes involved in glutathione (GSH) biosynthesis and reactive oxygen species (ROS) detoxification when compared to mammary tumors. Accordingly, breast-cancer-liver-metastases exhibited enhanced de novo GSH synthesis. Confirming their increased capacity to mitigate ROS-mediated damage, liver metastases display reduced levels of 8-Oxo-2′-deoxyguanosine. Depletion of the catalytic subunit of the rate-limiting enzyme in glutathione biosynthesis, glutamate-cysteine ligase (GCLC), strongly reduced the capacity of breast cancer cells to form liver metastases, supporting the importance of these distinct metabolic adaptations.Loss of GCLC also affected the early steps of the metastatic cascade, leading to decreased numbers of circulating tumor cells (CTCs) and impaired metastasis to the liver and the lungs. Altogether, our results indicate that GSH metabolism could be targeted to prevent the dissemination of breast cancer cells.

BackgroundSex differences in human immunodeficiency virus (HIV) reservoir dynamics remain underexplored.MethodsLongitudinal samples from virally suppressed midlife women (n = 59, median age 45 years) and age-matched men (n = 31) were analyzed retrospectively. At each time point, we measured sex hormones (by means of enzyme-linked immunosorbent assay) and cellular HIV DNA and RNA (by means of digital droplet polymerase chain reaction). Number of inducible HIV RNA+ cells, which provides an upper estimate of the replication-competent reservoir, was quantified longitudinally in a different subset of 14 women, across well-defined reproductive stages. Mixed-effects models included normalized reservoir outcomes and sex, time since antiretroviral therapy (ART) initiation, and the sex-by-time interaction as predictors.ResultsAt ART initiation, women and men had median (interquartile range [IQR]) CD4+ T-cell counts of 204/μL (83-306/μL) versus 238/μL (120-284/μL), respectively; median ages of 45 (42-48) versus 47 (43-51) years; and median follow-up times of 79.2/μL (60.5-121.1/μL) versus 66.2/μL (43.2-80.6/μL) months. We observed a significant decline of total HIV DNA over time in both men and women (P

Abstract Immune checkpoint inhibitors (ICI) are highly effective in specific cancers where canonical markers of antitumor immunity are used for patient selection. Improved predictors of T cell-inflammation are needed to identify ICI-responsive tumor subsets in additional cancer types. We investigated associations of a 4-chemokine expression signature (c-Score: CCL4, CCL5, CXCL9, CXCL10) with metrics of antitumor immunity across tumor types. Across cancer entities from The Cancer Genome Atlas, subgroups of tumors displayed high expression of the c-Score (c-Scorehi) with increased expression of immune checkpoint (IC) genes and transcriptional hallmarks of the cancer-immunity cycle. There was an incomplete association of the c-Score with high tumor mutation burden (TMB), with only 15% of c-Scorehi tumors displaying ≥10 mutations per megabase. In a heterogeneous pan-cancer cohort of 82 patients, with advanced and previously treated solid cancers, c-Scorehi tumors had a longer median time to progression (103 versus 72 days, P = 0.012) and overall survival (382 versus 196 days, P = 0.038) following ICI therapy initiation, compared to patients with low c-Score expression. We also found c-Score stratification to outperform TMB assignment for overall survival prediction (HR = 0.42 [0.22–0.79], P = 0.008 versus HR = 0.60 [0.29-1.27], P = 0.18, respectively). Assessment of the c-Score using the TIDE and PredictIO databases, which include ICI treatment outcomes from 10 tumor types, provided further support for the c-Score as a predictive ICI therapeutic biomarker. In summary, the c-Score identifies patients with hallmarks of T cell-inflammation and potential response to ICI treatment across cancer types, which is missed by TMB assignment.

Autosomal dominant polycystic kidney disease (ADPKD) causes renal cysts and leads to end-stage renal disease in midlife due mainly to PKD1 gene mutations. Virtually no studies have explored gene therapeutic strategies for long-term effective treatment of PKD. Toward this aim, the severely cystic Pkd1-null mouse model was targeted with a series of transgene transfers using genomic Pkd1 under its regulatory elements (Pkd1wt), a kidney-targeted Pkd1 gene (SBPkd1), or Pkd1Minigene. The introduced Pkd1wt gene constructs with ∼8-fold overexpression display similar endogenous cellular profiles and full complementation of Pkd1−/− phenotype and establish the referral Pkd1 genomic length for proper regulation. SBPkd1 transgene transfer expressing 0.6- or 7-fold Pkd1 endogenous levels is sufficient to correct glomerular and proximal tubular cysts and to markedly postpone cysts in other tubular segments as well, showing that the small SB elements appreciably overlap with Pkd1 promoter/5′ UTR regulation. Renal-targeted Pkd1Minigene at high copy numbers conveys an expression level similar to that of the endogenous Pkd1 gene, with widespread and homogeneous weak Pkd1 cellular signal, partially rescuing all cystic tubular segments. These transgene transfers determine that Pkd1 intragenic sequences regulate not only expression levels but also spatiotemporal patterns. Importantly, our study demonstrates that Pkd1 re-expression from hybrid therapeutic constructs can ameliorate, with considerably extended lifespan, or eliminate PKD.

This report reviews national data from all Member States on measles, rubella, and congenital rubella syndrome (CRS) elimination in the Region of the Americas during 2019–2023. It includes an analysis of compliance with vaccination coverage, surveillance indicators, and measles outbreaks, as well as an analysis of the response capacity of the laboratory network and a country case study that meets all indicators. The sources of information were the integrated epidemiological surveillance system for measles and rubella of the Pan American Health Organization (PAHO)/World Health Organization (WHO) and the Joint Reporting Form (eJRF), among others. From 2020 to 2022, regional coverage with first (MMR-1) and second doses (MMR-2) decreased to rates below 90%. The regional suspected case notification rate was maintained above the minimum expected 2.0 suspect cases per 100,000 population, except in 2021. During 2019 to 2023, 18 countries experienced outbreaks, with two of the outbreaks resulting in re-established endemic transmission. In conclusion, two countries in the Americas have not maintained measles elimination, but by the end of 2023 no country showed endemic measles transmission. One of the countries that lost its certification of elimination in 2018 managed to be reverified in 2023; the other is pending reverification. All countries maintained rubella elimination. Despite these challenges, the sustainability of the elimination of these diseases remains a health priority in the Region.

If we realized that we are not alone when we design, would it help us to approach the possibility of a wider Sacred Pedagogy? The contemporary world poses some significant challenges to the realization of a sacred pedagogy. Some of them have been theorized as The Secular Age, The Disenchanted World and the Technologic Time. “To throw the baby out with the bathwater” is an idiomatic expression that adequately represents the state of the art on this subject: something valuable – the sacred – has almost been eliminated while trying to get rid of something deemed to be worthless. But if the sacred is – broadly speaking – about transcendence, then sacred pedagogy should be less about easiness and more about resilience. Through this paper, we will try to work through a small exercise together: we will provide a picture as an inspiration to cross the levels of Creation step by step, from the most evident for an architect to the most subtle. With this goal in mind, we hope to take a small step towards a fraternal pedagogy of sacred imagination. And finally, to try and question the unrecognizable role of the pedagogue within this context.

Abstract PD-1 immune checkpoint blockade against inhibitory receptors such as receptor programmed cell death-1 (PD-1), has revolutionized cancer treatment. Effective immune reactivity against tumour antigens requires the infiltration and activation of tumour-infiltrating T-cells (TILs). In this context, ligation of the antigen-receptor complex (TCR) in combination with the co-receptor CD28 activates the intracellular mediator AKT (or PKB, protein kinase B) and its downstream targets. PD-1 inhibits the activation of AKT/PKB. Given this, we assessed whether the direct activation of AKT might be effective in activating the immune system to limit the growth of tumors that are resistant to PD-1 checkpoint blockade. We found that the small molecule activator of AKT (SC79) limited growth of a B16 tumor and an EMT-6 syngeneic breast tumor model that are poorly responsive to PD-1 immunotherapy. In the case of B16 tumors, direct AKT activation induced (i) a reduction of suppressor regulatory (Treg) TILs and (ii) an increase in effector CD8+ TILs. SC79 in vivo therapy caused a major increase in the numbers of CD4+ and CD8+ TILs to express interferon-γ (IFN-γ). This effect on IFN-γ expression distinguished responsive from non-responsive anti-tumor responses and could be recapitulated ex vivo with human T-cells. In CD4+FoxP3+Treg TILs, AKT induced IFN-γ expression was accompanied by a loss of suppressor activity, the conversation to CD4+ helper Th1-like TILs and a marked reduction in phospho-SHP2. In CD8+ TILs, we observed an increase in the phospho-activation of PLC-γ. Further, the genetic deletion of the transcription factor T-bet (Tbx21) blocked the increased IFN-γ expression on all subsets while ablating the therapeutic benefits of SC79 on tumor growth. Our study shows that AKT activation therapy acts to induce IFN-γ on CD4 and CD8 TILs that is accompanied by the intra-tumoral conversation of suppressive Tregs into CD4+Th1-like T-cells and augmented CD8 responses.

Activation of the tyrosine kinase c-Src promotes breast cancer progression and poor outcomes, yet the underlying mechanisms are incompletely understood. Here, we have shown that deletion of c-Src in a genetically engineered model mimicking the luminal B molecular subtype of breast cancer abrogated the activity of forkhead box M1 (FOXM1), a master transcriptional regulator of the cell cycle. We determined that c-Src phosphorylated FOXM1 on 2 tyrosine residues to stimulate its nuclear localization and target gene expression. These included key regulators of G2/M cell-cycle progression as well as c-Src itself, forming a positive feedback loop that drove proliferation in genetically engineered and patient-derived models of luminal B–like breast cancer. Using genetic approaches and small molecules that destabilize the FOXM1 protein, we found that targeting this mechanism induced G2/M cell-cycle arrest and apoptosis, blocked tumor progression, and impaired metastasis. We identified a positive correlation between FOXM1 and c-Src expression in human breast cancer and show that the expression of FOXM1 target genes predicts poor outcomes and associates with the luminal B subtype, which responds poorly to currently approved therapies. These findings revealed a regulatory network centered on c-Src and FOXM1 that is a targetable vulnerability in aggressive luminal breast cancers.

Microglia subpopulations may differentially contribute to pain. Here, the authors show that peripheral nerve injury induces time- and sex-specific transcriptional changes in mouse spinal cord microglia subpopulations and that ApoE is linked to neuropathic pain hypersensitivity in mice and humans.

Abstract Non-alcoholic fatty liver disease (NAFLD) is the most frequent liver disease worldwide and can progress to non-alcoholic steatohepatitis (NASH), which is characterized by triglyceride accumulation, inflammation, and fibrosis. No pharmacological agents are currently approved to treat these conditions, but it is clear now that modulation of lipid synthesis and autophagy are key biological mechanisms that could help reduce or prevent these liver diseases. The folliculin (FLCN) protein has been recently identified as a central regulatory node governing whole body energy homeostasis, and we hypothesized that FLCN regulates highly metabolic tissues like the liver. We thus generated a liver specific Flcn knockout mouse model to study its role in liver disease progression. Using the methionine- and choline-deficient diet to mimic liver fibrosis, we demonstrate that loss of Flcn reduced triglyceride accumulation, fibrosis, and inflammation in mice. In this aggressive liver disease setting, loss of Flcn led to activation of transcription factors TFEB and TFE3 to promote autophagy, promoting the degradation of intracellular lipid stores, ultimately resulting in reduced hepatocellular damage and inflammation. Hence, the activity of FLCN could be a promising target for small molecule drugs to treat liver fibrosis by specifically activating autophagy. Collectively, these results show an unexpected role for Flcn in fatty liver disease progression and highlight new potential treatment strategies.

In pursuit of energy self-sufficiency and meeting the growing energy demand, the Philippine government has formulated its Energy Road Map for the year 2040, aiming to strengthen, continue, and accelerate the adoption of renewable energy (RE) across the archipelago. This paper presents a proposed multiple microgrid system integrated into an existing distribution system, utilizing renewable energy sources. The proposed model involves the conversion of a section of the distribution system into a microgrid setup, comprising photovoltaic (PV) energy and fuel cell (FC) technologies connected to a 13.2 kV distribution grid. A modified three-phase three-level voltage-sourced converter (VSC) is employed to control the inverter. The proposed modifications result in improved operational efficiency compared to conventional approaches. Various operating cases are considered, each with a designated power source operating according to a predefined schedule. A unified controller is employed across all operating cases, ensuring system stability. Simulation and experimental results conducted through MATLAB/Simulink demonstrate the impact of VSC in terms of voltage regulation, frequency stability, and accumulated power losses. They revealed that voltage regulation for understudy cases ranged from 0.1 to 4.5%, microgrid frequencies were between 59.1 and 60.08 Hz, and power distribution losses were at 1.2–3.3% of the generated power.

Recurrent breast cancers often develop resistance to standard-of-care therapies. Identifying targetable factors contributing to cancer recurrence remains the rate-limiting step in improving long-term outcomes. In this study, we identify tumor cell-derived osteopontin as an autocrine and paracrine driver of tumor recurrence. Osteopontin promotes tumor cell proliferation, recruits macrophages, and synergizes with IL-4 to further polarize them into a pro-tumorigenic state. Macrophage depletion and osteopontin inhibition decrease recurrent tumor growth. Furthermore, targeting osteopontin in primary tumor-bearing female mice prevents metastasis, permits T cell infiltration and activation, and improves anti-PD-1 immunotherapy response. Clinically, osteopontin expression is higher in recurrent metastatic tumors versus female patient-matched primary breast tumors. Osteopontin positively correlates with macrophage infiltration, increases with higher tumor grade, and its elevated pathway activity is associated with poor prognosis and long-term recurrence. Our findings suggest clinical implications and an alternative therapeutic strategy based on osteopontin's multiaxial role in breast cancer progression and recurrence. Osteopontin promotes tumor growth in several cancer types. Here, in a preclinical model recapitulating features of human breast cancer recurrence, the authors report that osteopontin promotes the recruitment of immunosuppressive macrophages and its targeting reduces breast tumor growth and metastasis. [ABSTRACT FROM AUTHOR]

Nephric duct (ND)-derived ureteric buds (UB) form the kidney collecting duct system, while ureteric tips promote nephron formation. Here the authors use single-cell RNA-seq and introduce Cluster RNA-seq to identify four progenitor populations in developing ND/UB regulated by the transcription factors Tfap2a/b and Gata3.

Early-life adversity is thought to increase the risk of psychopathology through epigenetic mechanisms. Here, the authors profile 6 histone marks, chromatin states and DNA methylation in the lateral amygdala in subjects with a history of early-life adversity.