Acute activation of hemichannels by ethanol leads to Ca2+-dependent gliotransmitter release in astrocytes.

Multiple studies have demonstrated that acute ethanol consumption alters brain function and cognition. Nevertheless, the mechanisms underlying this phenomenon remain poorly understood. Astrocyte-mediated gliotransmission is crucial for hippocampal plasticity, and recently, the opening of hemichannels has been found to play a relevant role in this process. Hemichannels are plasma membrane channels composed of six connexins or seven pannexins, respectively, that oligomerize around a central pore. They serve as ionic and molecular exchange conduits between the cytoplasm and extracellular milieu, allowing the release of various paracrine substances, such as ATP, D-serine, and glutamate, and the entry of ions and other substances, such as Ca2+ and glucose. The persistent and exacerbated opening of hemichannels has been associated with the pathogenesis and progression of several brain diseases for at least three mechanisms. The uncontrolled activity of these channels could favor the collapse of ionic gradients and osmotic balance, the release of toxic levels of ATP or glutamate, cell swelling and plasma membrane breakdown and intracellular Ca2+ overload. Here, we evaluated whether acute ethanol exposure affects the activity of astrocyte hemichannels and the possible repercussions of this phenomenon on cytoplasmatic Ca2+ signaling and gliotransmitter release. Acute ethanol exposure triggered the rapid activation of connexin43 and pannexin1 hemichannels in astrocytes, as measured by time-lapse recordings of ethidium uptake. This heightened activity derived from a rapid rise in [Ca2+]i linked to extracellular Ca2+ influx and IP3-evoked Ca2+ release from intracellular Ca2+ stores. Relevantly, the acute ethanol-induced activation of hemichannels contributed to a persistent secondary increase in [Ca2+]i. The [Ca2+]i-dependent activation of hemichannels elicited by ethanol caused the increased release of ATP and glutamate in astroglial cultures and brain slices. Our findings offer fresh perspectives on the potential mechanisms behind acute alcohol-induced brain abnormalities and propose targeting connexin43 and pannexin1 hemichannels in astrocytes as a promising avenue to prevent deleterious consequences of alcohol consumption.

Overcoming Pitfalls in Breast FNAC: A Practical Review.

BACKGROUND: Fine-needle aspiration cytology (FNAC) is a cornerstone technique for the initial assessment of breast lesions, offering a rapid and minimally invasive option for cytological evaluation. While FNACs can forego the need for core needle biopsies (CNB), variations in technique, subjective interpretation, and intrinsic limitations present diagnostic challenges. The International Academy of Cytology (IAC) established the Yokohama system and is developing the WHO Reporting System for Breast Cytopathology jointly with IARC, to standardize diagnostic criteria, aiming to enhance diagnostic precision and consistency. Due to the preference for CNBs, expertise in breast FNAC is low in the developed world. SUMMARY: This review assesses common pitfalls in breast cytopathology. These common and uncommon entities may easily lead to false negative or false positive diagnoses, due to morphological overlap or misleading clinical and radiological contexts. For instance, pauci-cellular lesions, such as lobular carcinomas, often lead to false negative diagnoses, whereas complex sclerosing lesions, fibroadenomas and papillary lesions may show concerning features, resulting in a false positive. The same is true for some benign inflammatory pathologies, such as steatonecrosis, and uncommon lesions, such as collagenous spherulosis. Ductal carcinoma in situ (DCIS) can lead to both false negative and false positive diagnoses and high-grade lesions are impossible to tell apart from invasive carcinomas. These are discussed in detail. Procedural and preanalytical conditions, and the role of ancillary testing, are also briefly addressed. KEY MESSAGES: Breast FNAB is a powerful diagnostic technique, fast and minimally invasive. Even in contexts which lack expertise, this technique can be successfully adopted with a cautious approach and as long as pitfalls are kept in mind, benefiting patients and healthcare systems.

Evaluating Diagnostic Clarity: The Comparative Efficacy of BlueStain in Serous Effusion Cytology under the International System for Reporting Serous Fluid Cytopathology Reporting Framework.

Serous effusion cytology is a pivotal diagnostic and staging tool in clinical pathology, valued for its simplicity and cost-effectiveness. Staining techniques such as Giemsa and Papanicolaou are foundational, yet the search for rapid and efficient alternatives continues. Our study assesses the efficacy of an in-house-developed BlueStain, a toluidine blue variant, within the International System for Reporting Serous Fluid Cytopathology (TIS), aiming to optimize diagnostic clarity and resource use. MATERIALS AND METHODS: This section provides details on the cohort of 237 patients with serous effusions, the ethical approval process, sample collection, and staining procedures with BlueStain, Papanicolaou, and Giemsa. It also describes the microscopic evaluation criteria, scoring system, and statistical methods used to compare the stains. RESULTS: BlueStain demonstrated notable performance, particularly in identifying malignant cells, presenting a competitive alternative to the Papanicolaou stain, which, despite higher quality indices in other categories, requires more resources and time. The study revealed that BlueStain might offer a valuable balance between quality and efficiency, especially in cases where rapid diagnostic turnaround is essential. CONCLUSIONS: Our findings suggest that BlueStain is a viable staining method in the context of serous effusions, capable of providing detailed cytomorphological analysis. While traditional stains hold their place for their established diagnostic clarity, BlueStain offers a rapid and resource-optimized alternative. The absence of definitive diagnostic criteria in the atypical category and the inherent sample heterogeneity underscores the necessity for adaptable staining methods like BlueStain. The study highlights the potential trade-offs between detail and practicality in staining techniques, advocating for further research into innovative methods that do not compromise diagnostic precision for cost and time efficiency.

A phase I/II study of valemetostat (DS-3201b), an EZH1/2 inhibitor, in combination with irinotecan in patients with recurrent small cell lung cancer.

PURPOSE: Recurrent small cell lung cancer (SCLC) has few effective treatments. The EZH2-SLFN11 pathway is a driver of acquired chemoresistance that may be targeted. PATIENTS AND METHODS: This phase I/II trial investigated valemetostat, an EZH1/2 inhibitor, with fixed-dose irinotecan in patients with recurrent SCLC. Phase I primary objectives were to assess safety and a recommended phase II dose (RP2D). The phase II primary objective was to determine overall response rate (ORR), with secondary objectives of duration of response (DoR), progression-free survival (PFS) and overall survival (OS). Immunohistochemistry of pre- and on-treatment tumor biopsies and pharmacokinetics analysis were performed. RESULTS: Twenty-two patients enrolled (phase I, n=12; phase II n=10); one withdrew consent prior to treatment. Three dose-limiting toxicities (DLTs) in dose-escalation resulted in valemetostat 100 mg orally daily selected as RP2D. Among 21 toxicity-evaluable patients, the most frequent (≥20%) treatment-related adverse events were diarrhea, fatigue, nausea, and rash; 3 patients discontinued treatment for toxicity. In phase II, 3/10 patients experienced DLTs triggering a stopping rule. The ORR was 4/19 (21%, 95% CI 6 to 46%). The median DoR, PFS and OS were 4.6 mo, 2.2 mo (95% CI 1.3 to 7.6 mo) and 6.6 mo (95% CI 4.3 to not reached). SLFN11, EZH2 and SCLC subtyping markers did not correlate with response. MHC-I protein expression increased in 4/4 patients with paired biopsies, including 3/3 responders; two responders demonstrated subtype switching on treatment. CONCLUSIONS: Valemetostat and irinotecan was not tolerated but demonstrated efficacy in recurrent SCLC. Valemetostat may warrant further investigation in SCLC.

Etiologically Based Functional Taxonomy of the Preterm Birth Syndrome.

Preterm birth (PTB) is a complex syndrome traditionally defined by a single parameter, namely, gestational age at birth (ie, ˂37 weeks). This approach has limitations for clinical usefulness and may explain the lack of progress in identifying cause-specific effective interventions. The authors offer a framework for a functional taxonomy of PTB based on (1) conceptual principles established a priori; (2) known etiologic factors; (3) specific, prospectively identified obstetric and neonatal clinical phenotypes; and (4) postnatal follow-up of growth and development up to 2 years of age. This taxonomy includes maternal, placental, and fetal conditions routinely recorded in data collection systems.

Impact of Glucocorticoid Dose on Complete Response, Serious Infections, and Mortality During the Initial Therapy of Lupus Nephritis: A Systematic Review and Meta-Analysis of the Control Arms of Randomized Controlled Trials.

OBJECTIVE: Our objective was to evaluate the effect of glucocorticoid regimens on renal response, infections, and mortality among patients with lupus nephritis (LN). METHODS: We performed a systematic review and meta-analysis of the control arms of randomized clinical trials (RCTs). We included RCTs of biopsy-proven LN that used a protocolized regimen of glucocorticoids in combination with mycophenolic acid analogs or cyclophosphamide and reported the outcomes of complete response (CR), serious infections, and death. The starting dosage of glucocorticoids, tapering method, and administration of glucocorticoid pulses were abstracted. Meta-analysis of proportions, meta-regression, and subgroup meta-analysis were performed at 6 and 12 months for all outcomes. RESULTS: Fifty RCT arms (3,231 patients with LN) were included. The predicted rates of CR, serious infections, and death when starting on oral prednisone at 25 mg/day without pulses were 19.5% (95% confidence interval [CI] 7.3-31.5), 3.2% (95% CI 2.4-4.0), and 0.2% (95% CI 0.0-0.4), respectively. Starting on prednisone at 60 mg/day (without pulses) increased the rates to 34.6% (95% CI 16.9-52.3), 12.1% (95% CI 9.3-14.9), and 2.7% (95% CI 0.0-5.3), respectively. Adding glucocorticoid pulses increased the rates of CR and death but not serious infections. We observed a dose-response gradient between the initial glucocorticoid dosage and all the outcomes at six months after accounting for the administration of glucocorticoid pulses, underlying immunosuppressant, and baseline proteinuria. CONCLUSION: A higher exposure to glucocorticoids during the initial therapy of LN was associated with better renal outcomes at the cost of increased infections and death.

The International System for Reporting Serous Fluid Cytopathology: A Systematic Review and Meta-Analysis of Diagnostic Test Accuracy Studies.

This is the first systematic review and meta-analysis of The International System (TIS) for reporting serous fluid cytopathology. Our aims were to present the pooled malignancy rate of each TIS reporting category and the diagnostic accuracy of cytology using this system. Database search using a predefined strategy was followed by study selection, data extraction, study quality assessment, and statistical analysis. Data derived from 16 eligible studies were pooled. The pooled rates of malignancy were as follows: 27% (95% CI; 16%-41%) for "nondiagnostic" (ND), 11% (95% CI; 7%-18%) for negative for malignancy" (NFM), 49% (95% CI; 37%-61%) for "atypia of undetermined significance" (AUS), 90% (95% CI; 81%-95%) for "suspicious for malignancy" (SFM), and 100% (95% CI; 98%-100%) for "positive for malignancy" (MAL). Studies performed exclusively in cancer hospitals showed higher pooled malignancy rates, compared with academic and community hospitals serving the general population, in the ND [40% (95% CI; 21%-62%) vs. 22% (95% CI; 11%-39%)], NFM [20% (95% CI; 13%-30%) vs. 9% (95% CI; 5%-17%)], and AUS categories [55% (95% CI; 47%-63%) vs. 46% (95% CI; 31%-62%)]. Notably, the difference was significant in the NFM category ( P =0.04). When both SFM and MAL cytology interpretations were considered as malignant outcomes, the pooled sensitivity and specificity were 68.74% (95% CI; 59.90%-76.39%) and 98.81% (95% CI; 98.18%-99.22%), respectively. In addition, the diagnostic odds ratio (DOR) was found to be 170.7 (95% CI; 96.2-303.3). Despite its strengths, our study also had some limitations. Therefore, future large-scale longitudinal studies could strengthen the findings of this review.

Evaluation of polymersome permeability as a fundamental aspect towards the development of artificial cells and nanofactories.

Polymersomes are synthetic vesicles with potential use in healthcare, chemical transformations in confined environment (nanofactories), and in the construction of artificial cells and organelles. In this framework, one of the most important features of such supramolecular structures is the permeability behavior allowing for selective control of mass exchange between the inner and outer compartments. The use of biological and synthetic nanopores in this regard is the most common strategy to impart permeability nevertheless, this typically requires fairly complex strategies to enable porosity. Yet, investigations concerning the permeability of polymer vesicles to different analytes still requires further exploration and, taking these considerations into account, we have detailed investigated the permeability behavior of a variety of polymersomes with regard to different analytes (water, protons, and rhodamine B) which were selected as models for solvents, ions, and small molecules. Polymersomes based on hydrophilic blocks of poly[N-(2-hydroxypropyl)methacrylamide] (PHPMA) or PEO (poly(ethylene oxide)) linked to the non-responsive blocks poly[N-(4-isopropylphenylacetamide)ethyl methacrylate] (PPPhA) or poly(methyl methacrylate) (PMMA), or to the stimuli pH-responsive block poly[2-(diisopropylamino)ethyl methacrylate] (PDPA) have been investigated. Interestingly, the produced PEO-based vesicles are notably larger than the ones produced using PHPMA-containing block copolymers. The experimental results reveal that all the vesicles are inherently permeable to some extent with permeability behavior following exponential profiles. Nevertheless, polymersomes based on PMMA as the hydrophobic component were demonstrated to be the least permeable to the small molecule rhodamine B as well as to water. The synthetic vesicles based on the pH-responsive PDPA block exhibited restrictive and notably slow proton permeability as attributed to partial chain protonation upon acidification of the medium. The dye permeability was evidenced to be much slower than ion or solvent diffusion, and in the case of pH-responsive assemblies, it was demonstrated to also depend on the ionic strength of the environment. These findings are understood to be highly relevant towards polymer selection for the production of synthetic vesicles with selective and time-dependent permeability, and it may thus contribute in advancing biomimicry and nanomedicine.

Erosion of the Capital City Advantage in Child Survival and Reproductive, Maternal, Newborn, and Child Health Intervention Coverage in Sub-Saharan Africa.

The place of residence is a major determinant of RMNCH outcomes, with rural areas often lagging in sub-Saharan Africa. This long-held pattern may be changing given differential progress across areas and increasing urbanization. We assessed inequalities in child mortality and RMNCH coverage across capital cities and other urban and rural areas. We analyzed mortality data from 163 DHS and MICS in 39 countries with the most recent survey conducted between 1990 and 2020 and RMNCH coverage data from 39 countries. We assessed inequality trends in neonatal and under-five mortality and in RMNCH coverage using multilevel linear regression models. Under-five mortality rates and RMNCH service coverage inequalities by place of residence have reduced substantially in sub-Saharan Africa, with rural areas experiencing faster progress than other areas. The absolute gap in child mortality between rural areas and capital cities and that between rural and other urban areas reduced respectively from 41 and 26 deaths per 1000 live births in 2000 to 23 and 15 by 2015. Capital cities are losing their primacy in child survival and RMNCH coverage over other urban areas and rural areas, especially in Eastern Africa where under-five mortality gap between capital cities and rural areas closed almost completely by 2015. While child mortality and RMNCH coverage inequalities are closing rapidly by place of residence, slower trends in capital cities and urban areas suggest gradual erosion of capital city and urban health advantage. Monitoring child mortality and RMNCH coverage trends in urban areas, especially among the urban poor, and addressing factors of within urban inequalities are urgently needed.

Predictive Factors of Renal Recovery and Progression to End-Stage Kidney Disease in Patients With Antineutrophil Cytoplasmic Autoantibody-Associated Vasculitis With Severe Kidney Disease.

Introduction: A significant number of patients with antineutrophil cytoplasmic antibodies (ANCA)- associated vasculitis (AAV) with glomerulonephritis (AAV-GN) still progress to end-stage kidney disease (ESKD, estimated glomerular filtration rate [eGFR] <15 ml/min per 1.73 m2) despite advances in remission-induction treatment. Methods: This is a retrospective cohort study on myeloperoxidase (MPO)-ANCA or proteinase 3 (PR3)-ANCA positive patients with AAV (microscopic polyangiitis, MPA; or granulomatosis with polyangiitis, GPA) and eGFR <15 ml/min per 1.73 m2 or ESKD at presentation. Renal recovery, dialysis discontinuation, and persistence of ESKD after standard remission-induction, with or without the use of plasma exchange (PLEX) were analyzed. Results: We analyzed 166 patients with biopsy-proven active AAV-GN and eGFR <15 ml/min per 1.73 m2 at the time of diagnosis. Patients received glucocorticoids with cyclophosphamide (CYC) (n = 84) or with rituximab (RTX) (n = 72) for remission-induction, and 49 received PLEX. The predictors of renal recovery were erythrocyte sedimentation rate, serum creatinine (SCr) at diagnosis, and minimal or mild chronicity changes. We further analyzed 71 patients who started dialysis with or without PLEX within 4 weeks of AAV-GN diagnosis. The predictors of dialysis discontinuation were minimal chronicity changes in kidney biopsy at diagnosis (odds ratio = 6.138; 95% confidence interval [CI]: 1.389-27.118; P = 0.017). Predictors of persistence of ESKD within 12 months included higher SCr at diagnosis (incidence rate ratio [IRR] = 1.086; 95% CI: 1.005-1.173; P = 0.037), and moderate (IRR = 3.797; 95% CI: 1.090-13.225; P = 0.036), or severe chronicity changes in kidney biopsy (IRR = 5.883; 95% CI: 1.542-22.439; P =0.009). Conclusion: In our cohort, kidney recovery, dialysis discontinuation, and persistence of ESKD in patients with AAV-GN and eGFR <15 ml/min per 1.73 m2 depended on SCr and histologic findings on kidney biopsies at the time of diagnosis and was not affected by the addition of PLEX.

The current state of digital cytology and artificial intelligence (AI): global survey results from the American Society of Cytopathology Digital Cytology Task Force.

INTRODUCTION: The integration of whole slide imaging (WSI) and artificial intelligence (AI) with digital cytology has been growing gradually. Therefore, there is a need to evaluate the current state of digital cytology. This study aimed to determine the current landscape of digital cytology via a survey conducted as part of the American Society of Cytopathology (ASC) Digital Cytology White Paper Task Force. MATERIALS AND METHODS: A survey with 43 questions pertaining to the current practices and experiences of WSI and AI in both surgical pathology and cytology was created. The survey was sent to members of the ASC, the International Academy of Cytology (IAC), and the Papanicolaou Society of Cytopathology (PSC). Responses were recorded and analyzed. RESULTS: In total, 327 individuals participated in the survey, spanning a diverse array of practice settings, roles, and experiences around the globe. The majority of responses indicated there was routine scanning of surgical pathology slides (n = 134; 61%) with fewer respondents scanning cytology slides (n = 150; 46%). The primary challenge for surgical WSI is the need for faster scanning and cost minimization, whereas image quality is the top issue for cytology WSI. AI tools are not widely utilized, with only 16% of participants using AI for surgical pathology samples and 13% for cytology practice. CONCLUSIONS: Utilization of digital pathology is limited in cytology laboratories as compared to surgical pathology. However, as more laboratories are willing to implement digital cytology in the near future, the establishment of practical clinical guidelines is needed.

Geriatric Oncology: A 5-Year Strategic Plan.

The increasing rate of the older adult population across the world over the next 20 years along with significant developments in the treatment of oncology will require a more granular understanding of the older adult population with cancer. The ASCO Geriatric Oncology Community of Practice (COP) herein provides an outline for the field along three fundamental pillars: education, research, and implementation, inspired by ASCO's 5-Year Strategic Plan. Fundamental to improving the understanding of geriatric oncology is research that intentionally includes older adults with clinically meaningful data supported by grants across all career stages. The increased knowledge base that is developed should be conveyed among health care providers through core competencies for trainees and continuing education for practicing oncologists. ASCO's infrastructure can serve as a resource for fellowship programs interested in acquiring geriatric oncology content and provide recommendations on developing training pathways for fellows interested in pursuing formalized training in geriatrics. Incorporating geriatric oncology into everyday practice is challenging as each clinical setting has unique operational workflows with barriers that limit implementation of valuable geriatric tools such as Geriatric Assessment. Partnerships among experts in quality improvement from the ASCO Geriatric Oncology COP, the Cancer and Aging Research Group, and ASCO's Quality Training Program can provide one such venue for implementation of geriatric oncology through a structured support mechanism. The field of geriatric oncology must continue to find innovative strategies using existing resources and partnerships to address the pressing needs of the older adult population with cancer to improve patient outcomes.

Corrigendum: Evaluation of PIK3CA mutations in advanced ER+/HER2-breast cancer in Portugal - U-PIK Project.

[This corrects the article DOI: 10.3389/fmolb.2023.1082915.].

Diagnostic yield of exome and genome sequencing after non-diagnostic multi-gene panels in patients with single-system diseases.

BACKGROUND: Though next-generation sequencing (NGS) tests like exome sequencing (ES), genome sequencing (GS), and panels derived from exome and genome data (EGBP) are effective for rare diseases, the ideal diagnostic approach is debated. Limited research has explored reanalyzing raw ES and GS data post-negative EGBP results for diagnostics. RESULTS: We analyzed complete ES/GS raw sequencing data from Mayo Clinic's Program for Rare and Undiagnosed Diseases (PRaUD) patients to assess whether supplementary findings could augment diagnostic yield. ES data from 80 patients (59 adults) and GS data from 20 patients (10 adults), averaging 43 years in age, were analyzed. Most patients had renal (n=44) and auto-inflammatory (n=29) phenotypes. Ninety-six cases had negative findings and in four cases additional genetic variants were found, including a variant related to a recently described disease (RRAGD-related hypomagnesemia), a variant missed due to discordant inheritance pattern (COL4A3), a variant with high allelic frequency (NPHS2) in the general population, and a variant associated with an initially untargeted phenotype (HNF1A). CONCLUSION: ES and GS show diagnostic yields comparable to EGBP for single-system diseases. However, EGBP's limitations in detecting new disease-associated genes underscore the necessity for periodic updates.

The World Health Organization Reporting System for Pancreaticobiliary Cytopathology: Overview and Summary.

The recently published WHO Reporting System for Pancreaticobiliary Cytopathology (World Health Organization [WHO] System) is an international approach to the standardized reporting of pancreaticobiliary cytopathology, updating the Papanicolaou Society of Cytopathology System for Reporting Pancreaticobiliary Cytology (PSC System). Significant changes were made to the categorization of benign neoplasms, intraductal neoplasms, mucinous cystic neoplasms, and malignant neoplasms considered low grade. Benign neoplasms, such as serous cystadenoma, categorized as Neoplastic: benign in the PSC system, are categorized as Benign/negative for malignancy in the WHO system. Pancreatic neuroendocrine tumor, solid-pseudopapillary neoplasm, and gastrointestinal stromal tumor, categorized as Neoplastic: other in the PSC system, are categorized as Malignant in the WHO System in accord with their classification in the 5th edition WHO Classification of Digestive System Tumours (2019). The two new categories of Pancreaticobiliary Neoplasm Low-risk/grade and Pancreaticobiliary Neoplasm High-risk/grade are mostly limited to intraductal neoplasms and mucinous cystic neoplasms. Low-risk/grade lesions are mucinous cysts, with or without low-grade epithelial atypia. High-risk/grade lesions contain neoplastic epithelium with high-grade epithelial atypia. Correlation with clinical, imaging, and ancillary studies remains a key tenet. The sections for each entity are written to highlight key cytopathological features and cytopathological differential diagnoses with the pathologist working in low resource setting in mind. Each section also includes the most pertinent ancillary studies useful for the differential diagnosis. Sample reports are provided for each category. Finally, the book provides a separate section with risk of malignancy and management recommendations for each category to facilitate decision-making for clinicians.

Rituximab or cyclosporine a for the treatment of membranous nephropathy: Economic evaluation of the MENTOR trial.

BACKGROUND AND HYPOTHESIS: The MENTOR trial (MEmbranous Nephropathy Trial Of Rituximab) showed that rituximab was noninferior to cyclosporine in inducing complete or partial remission of proteinuria and was superior in maintaining proteinuria remission. However, the cost of rituximab may prohibit first-line use for some patients and health care payers. METHODS: A Markov model was used to determine the incremental cost-effectiveness ratio (ICER) of rituximab compared with cyclosporine for the treatment membranous nephropathy from the perspective of a health care payer with a life-time time horizon. The model was informed by data from the MENTOR trial where possible; additional parameters including cost and utility inputs were obtained from the literature. Sensitivity analyses were performed to evaluate the impact of reduced cost biosimilar rituximab. RESULTS: Rituximab for the treatment of membranous nephropathy was cost-effective (assuming a willingness-to-pay threshold of ${\$}$50 000 per quality adjusted life year (QALY) gained; ${\$}$US 2021) compared with cyclosporine, with an ICER of ${\$}$8 373/QALY over a lifetime time horizon. The incremental cost of rituximab therapy was ${\$}$28 007 with an additional 3.34 QALYs compared with cyclosporine. Lower cost of rituximab biosimilars resulted in a more favourable ICER, and in some cases resulted in rituximab being dominant (lower cost and great benefit) compared to cyclosporine. CONCLUSIONS: Despite the greater cost of rituximab, it may be a cost-effective option for the treatment of membranous nephropathy when compared with cyclosporine. The cost-effectiveness of rituximab is further improved with the use of less expensive biosimilars.

Association between breast feeding and food consumption according to the degree of processing in Brazil: a cohort study.

BACKGROUND: The benefits of breast feeding may be associated with better formation of eating habits beyond childhood. This study was designed to verify the association between breast feeding and food consumption according to the degree of processing in four Brazilian birth cohorts. METHODS: The duration of exclusive, predominant and total breast feeding was evaluated. The analysis of the energy contribution of fresh or minimally processed foods (FMPF) and ultra-processed foods (UPF) in the diet was evaluated during childhood (13-36 months), adolescence (11-18 years) and adulthood (22, 23 and 30 years). RESULTS: Those who were predominantly breastfed for less than 4 months had a higher UPF consumption (ß 3.14, 95% CI 0.82 to 5.47) and a lower FMPF consumption (ß -3.47, 95% CI -5.91 to -1.02) at age 22 years in the 1993 cohort. Exclusive breast feeding (EBF) for less than 6 months was associated with increased UPF consumption (ß 1.75, 95% CI 0.25 to 3.24) and reduced FMPF consumption (ß -1.49, 95% CI -2.93 to -0.04) at age 11 years in the 2004 cohort. In this same cohort, total breast feeding for less than 12 months was associated with increased UPF consumption (ß 1.12, 95% CI 0.24 to 2.19) and decreased FMPF consumption (ß -1.13, 95% CI -2 .07 to -0.19). Children who did not receive EBF for 6 months showed an increase in the energy contribution of UPF (ß 2.36, 95% CI 0.53 to 4.18) and a decrease in FMPF (ß -2.33, 95% CI -4 .19 to -0.48) in the diet at 13-36 months in the 2010 cohort. In this cohort, children who were breastfed for less than 12 months in total had higher UPF consumption (ß 2.16, 95% CI 0.81 to 3.51) and lower FMPF consumption (ß -1.79, 95% CI -3.09 to -0.48). CONCLUSION: Exposure to breast feeding is associated with lower UPF consumption and higher FMPF consumption in childhood, adolescence and adulthood.

Cx43 hemichannels and panx1 channels contribute to ethanol-induced astrocyte dysfunction and damage.

BACKGROUND: Alcohol, a widely abused drug, significantly diminishes life quality, causing chronic diseases and psychiatric issues, with severe health, societal, and economic repercussions. Previously, we demonstrated that non-voluntary alcohol consumption increases the opening of Cx43 hemichannels and Panx1 channels in astrocytes from adolescent rats. However, whether ethanol directly affects astroglial hemichannels and, if so, how this impacts the function and survival of astrocytes remains to be elucidated. RESULTS: Clinically relevant concentrations of ethanol boost the opening of Cx43 hemichannels and Panx1 channels in mouse cortical astrocytes, resulting in the release of ATP and glutamate. The activation of these large-pore channels is dependent on Toll-like receptor 4, P2X7 receptors, IL-1ß and TNF-α signaling, p38 mitogen-activated protein kinase, and inducible nitric oxide (NO) synthase. Notably, the ethanol-induced opening of Cx43 hemichannels and Panx1 channels leads to alterations in cytokine secretion, NO production, gliotransmitter release, and astrocyte reactivity, ultimately impacting survival. CONCLUSION: Our study reveals a new mechanism by which ethanol impairs astrocyte function, involving the sequential stimulation of inflammatory pathways that further increase the opening of Cx43 hemichannels and Panx1 channels. We hypothesize that targeting astroglial hemichannels could be a promising pharmacological approach to preserve astrocyte function and synaptic plasticity during the progression of various alcohol use disorders.