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Caused by the Gram-positive bacteria Clostridium perfringens, necrotic enteritis (NE) is an enteric disease with significant economic implications in broiler production. This study employed an experimental NE model involving co-infection with Eimeria maxima and C. perfringens to assess whether sulfate polysaccharides extracted from marine macroalgae could mitigate the adverse effects of NE in broilers. A total of 600 day (d)-old Ross 708 male broilers were randomly assigned to one of four treatment groups: NC (negative control, fed a corn-soybean meal diet); PC (positive control, NC + 15 ppm Avilamycin and 125 ppm Amprolium); AGS (Algimun® Standard, NC + Algimun added at 0.1 % of the diet); and AGH (Algimun High, NC + Algimun added at 0.2 % of the diet). Average daily feed intake and weight gain were calculated and adjusted for daily mortality on d 14, 21, 28, and 42. On d 21, four birds/pen were examined for intestinal NE lesions. On d 14, 21, and 42, serum and jejunum samples from one bird/pen were collected to measure the concentration of the biomarker calprotectin and mRNA abundance of cytokines and tight junction proteins. Data were analyzed using JMP and significance between treatments identified by LSD (P ≤ 0.05). NE lesion scores on d 21, and mortality and FCR during d 0 to 42 were lower in PC, AGS, and AGH compared to NC birds. AGS birds had the lowest levels for serum calprotectin on d 21 while PC, AGS, and AGH had lower levels than the NC group on d 42. On d 14 and d 42, mRNA abundance of CLDN1, 3, ZO1, IL1β, IFNγ, IL10, and IL12B was greater in AGS and AGH birds compared to NC. Also, AGH had a greater abundance of TNFα on d 14 and d 42 compared to NC. Further, mRNA abundance of CLDN3, ZO1, 2, OCLDN, IL1β, IL10, IL12B, IFNγ, and ANXA1 was greater in PC on d 21 compared to NC and AGS. Based on these findings, dietary supplementation of this macroalgae-derived sulfated polysaccharides yielded a similar response to an antibiotic growth promoter presenting potential as an alternative additive., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest. The funders had no role in the collection, analyses, or interpretation of the data., (Copyright © 2024. Published by Elsevier Inc.)

In many regions, nitrogen (N) deficiency limits pepper cultivation, presenting significant cultivation challenges. This study investigates the impact of N deficiency and silicon (Si) supplementation on physiological responses and antioxidant modulation in pepper plants, focusing particularly on the homeostasis of carbon (C), nitrogen, and phosphorus (P), and their effects on growth and biomass production. Conducted in a factorial design, the experiment examined pepper plants under conditions of N sufficiency and deficiency, with and without Si supplementation (0.0 mM and 2.0 mM). Results showed that N deficiency sensitizes pepper plants, leading to increased electrolyte leakage (39.59%) and disrupted C, N, and P homeostasis. This disruption manifests as reductions in photosynthetic pigments (-64.53%), photochemical efficiency (-14.92%), and the synthesis of key metabolites such as total free amino acids (-86.97%), sucrose (-53.88%), and soluble sugars (-39.96%), ultimately impairing plant growth. However, Si supplementation was found to alleviate these stresses. It modulated the antioxidant system, enhanced the synthesis of ascorbic acid (+30.23), phenolic compounds (+33.19%), and flavonoids (+7.52%), and reduced cellular electrolyte leakage (-25.02%). Moreover, Si helped establish a new homeostasis of C, N, and P, optimizing photosynthetic and nutritional efficiency by improving the utilization of C (+17.46%) and N (+13.20%). These Si-induced modifications in plant physiology led to increased synthesis of amino acids (+362.20%), soluble sugars (+51.34%), and sucrose (77.42%), thereby supporting enhanced growth of pepper plants. These findings elucidate the multifaceted biological roles of Si in mitigating N deficiency effects, offering valuable insights for more sustainable horticultural practices., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Bacterial peritonitis infections comprise a life-threatening clinical condition in domestic animals that commonly lead to sepsis and high mortality. A set of bacterial pathogens have been identified in septic peritonitis in livestock and companion animals. Nonetheless, most descriptions are restricted to case reports or limited to only one domestic species, and a restrict number of comprehensive studies involving this infection has focused on a great number of domestic animals. Here, we retrospectively investigated selected epidemiological data (with an emphasis in outcome), clinical signs, bacteriological culturing, and in vitro antimicrobial susceptibility patterns of microorganisms isolated of peritoneal fluid from 160 domestic animals (2009-2023) compatible with septic peritonitis. Bacteria were isolated from 71.9% (115/160) of the peritoneal fluid from 75 dogs (75/115 = 65.2%), 22 cats (22/115 = 19.1%), 14 horses (14/115 = 12.2%), and 4 cattle (4/115 = 3.5%). Among animals with bacterial isolation, Escherichia coli (34/115 = 29.6%), alfa-hemolytic Streptococcus (12/115 = 10.4%), Staphylococcus aureus (8/115 = 6.9%), beta-hemolytic Streptococcus (7/115 = 6.1%), and Pasteurella multocida (6/115 = 5.2%) were predominant in pure culture, in addition to a miscellaneous of other bacteria isolated in minor frequency, e.g., Pseudomonas sp., Trueperella pyogenes, Klebsiella pneumoniae, and Salmonella sp. In general, in vitro susceptibility tests of isolates revealed that florfenicol, chloramphenicol, and amoxicillin/clavulanic acid showed moderate effectivity (≥ 60%). Conversely, most of isolates exhibited resistance mainly to trimethoprim/sulfamethoxazole, enrofloxacin, and penicillin (> 60%). Additionally, multidrug resistance was found in 42.6% (49/115) of the isolates. Data related to the outcome were available in 37.4% (43/115) of animals that had bacterial isolation and, from these, the mortality rate was 79.1% (34/43), with a significant association (p < 0.036) between mortality and septic peritonitis by gram-negative bacteria. Neoplasia (7/43 = 16.3%), pneumonia/pulmonary abscess (5/43 = 11.6%), hepatitis (5/43 = 11.6%), metritis/pyometra (4/43 = 9.3%), and gall bladder rupture (3/43 = 7%) represented the probable main sources of septic peritonitis. Anorexia (34/115 = 29.6%), emesis (29/115 = 25.2%), lethargy (26/115 = 22.6%), respiratory distress (25/115 = 21.7%), ascites (20/115 = 17.4%), and fever (19/115 = 16.5%) were the most frequent clinical signs among animals with bacterial isolation. A variety of bacteria were isolated in the peritoneal fluid of animals, with a predominance of Enterobacteriaceae, streptococci, and staphylococci, highlighting the opportunistic nature of the pathogens in septic peritonitis. High in vitro multidrug resistance of isolates and high mortality of animals reinforce the need for early diagnosis and therapy based on the in vitro antimicrobial profile of the pathogens involved in septic peritonitis. Our results contribute to the etiological characterization, clinical-epidemiological findings, and vigilance of multidrug-resistant bacteria in septic peritonitis among livestock and companion animals., (© 2024. The Author(s) under exclusive licence to Sociedade Brasileira de Microbiologia.)

Background: Peripheral nodal B-cell lymphomas (PNBCL) represent the most common presentation of lymphomas in dogs. Multiagent CHOP (C = cyclophosphamide, H = hydroxydaunorubicin [Doxorubicin], O = Oncovin, P = prednisolone)-based chemotherapy protocols have been widely accepted as gold standard 1st-line treatment. CHOP-25 and CHOP-19 are most commonly prescribed but have never been directly compared., Objectives: Our primary aim was to compare outcomes of dogs diagnosed with PNBCL, treated using a 1st-line CHOP-19 or CHOP-25 protocol. A secondary objective was to determine the impact of protocol-related variables on outcomes., Animals: Five hundred two dogs from 16 European oncology referral centers. One hundred fifty-five dogs were treated with CHOP-19 and 347 dogs with CHOP-25., Methods: Retrospective, multicentric cohort study of dogs diagnosed with PNBCL between 2014 and 2021., Results: The 6-month, 1-year, and median progression-free survival (PFS) were 56.5% (95% confidence interval [CI], 49.2-65.0), 14.1% (95% CI, 9.4-21.0), and 196 days (95% CI, 176-233) with CHOP-19; and 56.4% (95% CI, 51.4-61.9), 17% (95% CI, 13.4-21.6), and 209 days (95% CI, 187-224) with CHOP-25. The 1-year, 2-year and median overall survival (OS) were 36.9% (95% CI, 29.7-46.0), 13.5% (95% CI, 8.6-21.1), and 302 days (95% CI, 249-338) with CHOP-19; and 42.8% (95% CI, 37.7-48.7), 15.4% (95% CI, 11.7-20.4), and 321 days (95% CI, 293-357) with CHOP-25. No significant difference in PFS and OS was found between the 2 protocols., Conclusions and Clinical Importance: Our study confirmed similar outcomes for dogs with PNBCL treated with 1st-line CHOP-19 or CHOP-25. Both protocols therefore could be used as a standard of care in future trials., (© 2024 The Author(s). Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.)

Background: Evidence suggests that the phenotypic expression of substance use disorders (SUD) may be influenced by exposure to childhood maltreatment (CM)., Objective: To assess how CM could impact severity (relapse, treatment dropout, withdrawal), age of substance use onset, psychiatric dual diagnosis (depression, anxiety, PTSD, distress), and self-harm behavior/suicide attempts in adults with SUD, we performed a systematic review and meta-analyses., Methods: We searched PubMed, Web of Science, PsycINFO, and Embase to identify articles examining the association of maltreatment (physical, sexual, or emotional abuse or neglect) before age 18 years with clinical features and course of illness SUD. Multilevel random effects models were performed. Heterogeneity was quantified using the I 2 statistic. Subgroup/meta-regression analyses were employed to investigate sources of heterogeneity. Risk of bias was assessed using an adapted version of the Newcastle-Ottawa Quality Assessment Scale., Results: Forty-five studies were included. CM was associated with all tested outcomes, such as anxiety (OR = 1.52; 95 % CI = 1.39, 1.65), depression (OR = 1.57; 95 % CI = 1.40, 1.77), PTSD (OR = 1.67; 95 % CI = 1.40, 1.99), psychological distress (OR = 1.49; 95 % CI = 1.24, 1.78), self-harm behavior and suicidal attempts (OR = 1.70; 95 % CI = 1.47, 1.96), SUD severity (OR = 1.15; 95 % CI = 1.04, 1.26), and younger age of onset use (OR = 0.76; 95 % CI = 0.69, 0.84). However, comparisons between outcomes revealed that the association was stronger for dual diagnosis symptoms/conditions than for measures of SUD severity itself. Meta-analyses for some outcomes had large statistical heterogeneity, though these were partly addressed through additional analyses. Gender, mean age of participants, polysubstance use pattern, substance of preference, and CM subtype were found to be moderators of these associations., Conclusions: The consequences of CM on individuals with SUD are more closely linked to co-occurring psychiatric manifestations than to the severity of common clinical indicators (relapse, treatment dropout, withdrawal), and this finding has important implications., Funding: None., Systematic Review Registration: PROSPERO (CRD42021245936)., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier Ltd.)

Introduction: Chronic kidney disease (CKD) is related to high morbidity and mortality and loss of quality of life. Likewise, hyperparathyroidism is associated to progressive loss of renal function, with increased phosphate and decrease calcium levels, which induce the secretion of parathyroid hormone., Objectives: To translate into Portuguese (Brazil), culturally adapt and validate the questionnaire Parathyroid Symptoms Assessment (PAS), following reliability and validity criteria in patients with chronic kidney disease and hyperparathyroidism., Methods: Methodological and cross-sectional study, carried out at São Lucas Hospital/PUCRS, Porto Alegre, Brazil. The PAS questionnaire validation process followed protocols from previous studies. After translating into Portuguese, it was applied to 100 patients with secondary (SHPT) and tertiary or persistent (THPT) hyperparathyroidism. For PAS validation data, patients responded to the Short Form Health 36 (SF-36) questionnaire. Reliability criteria were evaluated using intraclass correlation coefficient (ICC) and Cronbach's alpha (α-C). Validity was assessed by Spearman's correlation coefficient between PAS and SF-36 values., Results: Participant's mean age was 55.6 ± 15.6 years, 61% was male, and 68% was diagnosed with SHPT. Among 100 patients, 53% performed a PAS retest (ICC = 0.83). The internal reliability by α-C was 0.86. Negative correlations were observed between PAS questions and SF-36 physical and mental domains, which ranged from 0.3 to 0.7., Conclusion: The Brazilian version of the PAS questionnaire was found to be valid and reliable. The PAS questionnaire can be used to evaluate quality of life in Brazilian patients with hyperparathyroidism who speak Portuguese.

This study investigated the impact of ocean acidification on the photodegradation of three microplastics (MPs): polypropylene (PP), expanded polystyrene (EPS), and ethylene-vinyl acetate (EVA), under accelerated UV radiation at three pH levels (i.e., 8.1, 7.8, and 7.5), simulating marine conditions. The acidification system simulated current and projected future environmental conditions. As expected, an increase in partial pressure of CO2, total inorganic carbon, bicarbonate ion, and CO2 resulted in more acidic pH levels, with the reverse being true for the carbonate ion. Structural changes of MPs were evaluated, revealing that all weathered samples underwent higher degradation rate compared to the virgin samples. The oxidation state and crystallinity of PP and EVA MPs were higher in samples exposed to the lowest pH, whereas no significant increase in the degradation rate of EPS samples was observed. Saltwater acidification in this study contributed to enhance the photo-oxidation of MPs depending on their polymeric composition., Competing Interests: Declaration of competing interest The authors have no relevant financial or non-financial interests to disclose. Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Sexual dysfunction (SD) has been associated with worse quality of life and higher disease activity in patients with rheumatic diseases, yet it is still not regularly addressed during routine rheumatologic evaluations. This study aimed to determine the prevalence of sexual dysfunction in patients with rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE) and evaluate their perception of their sexual health. We performed a retrospective study in an outpatient rheumatology clinic to evaluate patients over 18 years old with a diagnosis of RA or SLE through the Spanish version of the Arizona Sexual Experiences Scale (ASEX) and the Sexual Health Perception Survey (SHEPS), a questionnaire of 6 items designed in our clinic. Additionally, we applied the Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F version 4) and the Hospital Anxiety and Depression Scale (HADS). A total of 567 patients were evaluated with SHEPS, most of whom were women with a median age of 50 years (IQR: 34) and a median disease duration of 5 years (IQR: 9). Through the ASEX, we found that 67% of the patients with RA and 60% of the patients with SLE experienced SD. Patients reported the level of sex drive, arousal, and the ability to achieve orgasms as the areas with the most difficulties. Most patients did not know their disease could affect their sexuality and had never addressed these issues with their rheumatologists, but almost all of them were willing to. Our findings highlight the importance of addressing sexual health issues regularly during rheumatologic evaluations., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Alzheimer's disease (AD) is associated with the cerebral deposition of Amyloid-β (Aβ) peptide, which leads to NLRP3 inflammasome activation and subsequent release of interleukin-1β (IL-1β) and interleukin-18 (IL-18). NLRP3 reduction has been found to increase microglial clearance, protect from synapse loss, and suppress both the changes to synaptic plasticity and spatial memory dysfunction observed in murine AD models. Here, we test whether NLRP3-directed antisense oligonucleotides (ASOs) can be harnessed as immune modulators in primary murine microglia and human THP-1 cells. NLRP3 mRNA degradation was achieved at 72 h of ASO treatment in primary murine microglia. Consequently, NLRP3-directed ASOs significantly reduced the levels of cleaved caspase-1 and mature IL-1β when microglia were either activated by LPS and nigericin or LPS and Aβ. In human THP-1 cells NLRP3-targeted ASOs also significantly reduced the LPS plus nigericin- or LPS plus Aβ-induced release of mature IL-1β. Together, NLRP3-directed ASOs can suppress NLRP3 inflammasome activity and subsequent release of IL-1β in primary murine microglia and THP-1 cells. ASOs may represent a new and alternative approach to modulate NLRP3 inflammasome activation in neurodegenerative diseases, in addition to attempts to inhibit the complex pharmacologically., (© 2023 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry.)

Introduction: Patients with Antiphospholipid Syndrome (APS) undergoing cardiopulmonary bypass (CPB) surgery are at increased risk for thrombotic and hemorrhagic complications. Anticoagulation during CPB is typically monitored with activated clotting time (ACT) which may be falsely prolonged in patients with APS. The Hepcon Hemostasis Management System quantitatively determines the whole blood heparin concentration through heparin/protamine titration., Methods: This was a retrospective study of APS patients who underwent cardiac surgery requiring CPB at the Cleveland Clinic between April 2013, and July 2020. The primary endpoint was the composite rate of hemorrhagic or thromboembolic complications per surgical case in patients monitored by Hepcon versus patients monitored by ACT. Secondary endpoints were median volume of chest tube output and packed red blood cell (PRBC) transfusion within the first three post-operative days., Results: 43 patients were included. 20 (47%) patients were monitored using Hepcon while 23 (53%) were monitored using ACT. For the primary endpoint of rate of thromboembolic or hemorrhagic complications per surgical case, there was no statistically significant difference between the Hepcon and ACT groups (HMS, 6/20 [30%]; ACT, 7/23 [30%]; p = >0.99). For the secondary endpoints, there was no statistically significant difference in median post-operative chest tube output (780 mL vs. 850 mL; p = 0.88) and median post-operative PRBC transfusion (1 unit vs. 0 unit; p = 0.28) between the Hepcon and ACT groups, respectively., Conclusion: There was no difference in the composite outcome of thrombotic or hemorrhagic complications in patients monitored by Hepcon versus those monitored by ACT., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Patrick Grady: Consultancy for Medtronic.

The ability to track disease without tissue biopsy in patients is a major goal in biology and medicine. Here, we identify and characterize cardiomyocyte-derived extracellular vesicles in circulation (EVs; "cardiovesicles") through comprehensive studies of induced pluripotent stem cell-derived cardiomyocytes, genetic mouse models, and state-of-the-art mass spectrometry and low-input transcriptomics. These studies identified two markers ( POPDC2 , CHRNE ) enriched on cardiovesicles for biotinylated antibody-based immunocapture. Captured cardiovesicles were enriched in canonical cardiomyocyte transcripts/pathways with distinct profiles based on human disease type (heart failure, myocardial infarction). In paired myocardial tissue-plasma from patients, highly expressed genes in cardiovesicles were largely cardiac-enriched (vs. "bulk" EVs, which were more organ non-specific) with high expression in myocardial tissue by single nuclear RNA-seq, largely in cardiomyocytes. These results demonstrate the first "liquid" biopsy discovery platform to interrogate cardiomyocyte states noninvasively in model systems and in human disease, allowing non-invasive characterization of cardiomyocyte biology for discovery and therapeutic applications.

In dogs, the risk of an acute hemolytic transfusion reaction at the first transfusion is negligible; however, mismatched transfusions may produce alloimmunization. To avoid fatal acute hemolytic reactions in subsequent blood transfusions, it is important to recognize blood groups and to blood type both the donor and the recipient. Prevalence of dog blood groups varies geographically and between breeds. Our aim was to determine DEA 1 prevalence in a canine population in Luanda (Angola) and to assess alloimmunization risk after a mismatched blood transfusion. Blood samples were typed using an immunochromatographic strip technique. Of the 112 dogs tested (59 males; 53 females), 52.68% were DEA 1 positive and 47.32% DEA 1 negative. Females tended to be DEA 1 positive, and males DEA 1 negative ( p = 0.0085). In a first-time mismatched blood transfusion, the calculated probability of a dog becoming sensitized was 24.9% and the probability of an acute hemolytic reaction following a second incompatible blood transfusion was 6.21%. DEA 1 prevalence obtained was similar to that reported worldwide, but differs from other African countries. The risk of alloimmunization and acute hemolytic transfusion reactions in mismatched blood transfusions is higher than that in other African regions. Blood typing is recommended prior to transfusion.

Objective: this study sought to evaluate the effect of isobornyl methacrylate (IBOMA) as a diluent monomer on the physicochemical properties of experimental flowable resin composites., Methodology: the organic resin matrix of a modal flowable resin composite was formulated with 50 wt.% of bisphenol-A-glycidyl methacrylate (Bis-GMA) and 50 wt.% of a diluent monomer, in which IBOMA was used as a combining or substituent diluent monomer to triethylene glycol dimethacrylate (TEGDMA). The resin matrices were filled with 55 wt.% particles, of which 10 wt.% was 0.05-μm fumed silica, and 45 wt.% was 0.7-μm BaBSiO2 glass. Polymerization shrinkage stress (PSS; n=10), degree of conversion (DC; n=3), maximum rate of polymerization (Rpmax; n=3), film thickness (FT; n=10), sorption (Wsp; n=10), solubility (Wsl; n=10), flexural strength (FS; n=10), flexural modulus (FM; n=10), Knoop microhardness (KH; n=10), and microhardness reduction after chemical softening (HR; n=10) were evaluated. Data were analyzed using one-way ANOVA, followed by Tukey's test (α=0.05; β=0.2)., Results: the results showed that the substitution or addition of IBOMA reduced FT (p=0.001), PSS (p=0.013), Rpmax (p=0.001), DC (p=0.001), FM (p=0.006) Wsp (p=0.032), and Wsl (p=0.021). However, when used as a complete substituent, IBOMA demonstrated significantly lower FS (p=0.017) and KH (p=0.008), while TEGDMA demonstrated significantly lower HR (p=0.022)., Conclusion: the flowable composite containing IBOMA combined with TEGDMA showed no effect in KH and FS and effectively reduced the PSS, RP, FT, Wsp, and Wsl. However, it showed a reduction in DC, FS, and an increase in HR.

Fava bean ( Vicia faba L.) is a protein-rich pulse with high nutritional value, but its functional and sensory characteristics limit its application in foods. Solid-state fermentation (SSF) can modify the composition of plant proteins, modulate its functionality, and enhance the sensory aspects. In this study, fava bean flour (FB) was fermented with Aspergillus oryzae and Rhizopus oligosporus to produce FBA and FBR, respectively, ingredients with distinct nutritional, functional, and aroma characteristics. The protein content increased by 20% in FBA and 8% in FBR, while fat levels rose more significantly in FBR (+40%). The overall content of fermentable oligo-, di-, mono-saccharides, and polyols (FODMAPs) decreased by 47% (FBA) and 57% (FBR), although polyol production by A. oryzae was observed. SSF improved the nutritional profile of FBA and FBR, with a notable increase in the concentration of essential amino acids observed, and a reduction in most antinutrients, with the exception of trypsin inhibitors. SSF resulted in the formation of aggregates, which increased the particle size and reduced protein solubility. Emulsions prepared with the fermented ingredients separated faster, and the foaming capacity of both FBA and FBR was decreased, but an increase in water-holding capacity was observed. SSF resulted in the production of predominantly savoury-associated aroma compounds, with compounds characteristic of metallic and mouldy aromas reduced. These results indicate the potential of SSF to transform FB with enhanced nutritional value and improved sensory and functional properties.

Chimeric antigen receptor T-cell therapy represents an innovative approach to immunotherapy and currently stands out, particularly for oncohematological patients refractory to traditional treatments. Ongoing trials are further expanding its clinical use for new oncological and non-oncological indications, potentially leading to newer treatment options soon. This new approach, however, also presents challenges, including cardiovascular toxicity. Little is reported in pivotal studies, and some recent retrospective observations suggest a non-negligible incidence of side effects with presentation ranging from mild adverse cardiovascular events to fatal complications in which, in most cases, there is a direct or indirect association with cytokine release syndrome. In this literature review, the hypotheses of an important interface between cytokine release syndrome and cardiotoxicity by chimeric antigen receptor T-cell therapy will be addressed, as will current knowledge about risk factors for cardiotoxicity and recommendations for pre-therapy evaluation, post-infusion monitoring and clinical management of these complications., Competing Interests: Conflicts of interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular. Published by Elsevier España, S.L.U. All rights reserved.)

Cervical cancer screening in Brazil is opportunistic, based on cytology and offered for women aged 25-64 years, with low coverage (30%) and 70% of cancer diagnoses done in advanced stages, without impact on mortality. The current study reports 5-year first-round results of a population-based DNA-HPV testing screening program in a Brazilian city, which intended to be a model for transition to a more efficient program. Program flowchart is simple and current, indicating repetition of a negative test after five years. The first-round (October 2017-September 2022) screened 20,551 women by DNA-HPV testing with 58.7% coverage and 99.4% compliance with the program's targeted age range. Coverage increases to 77.8% when excluding the 'pandemic period'. The DNA-HPV testing was 87.2% negative with 6.2% colposcopy referrals and 84.8% colposcopies performed. A total of 258 high-grade precursor lesions and 29 cervical cancers (mean age = 41.4 years, 83% Stage I) were detected. As a reference, 41,387 cytology tests from the previous program (2012-2016) detected 36 cervical cancers (mean age = 52.0 years, p = 0.0005), with 67% in advanced stages (p < 0.0001). Organizing cervical cancer screening using DNA-HPV testing demonstrated good coverage, high age and colposcopy compliance, and detection of more precancerous lesions and cervical cancers 10 years in advance., (© 2024. The Author(s).)

Purpose: Percutaneous thermal ablation is an effective treatment for primary and metastatic liver tumors and is a recommended local therapy for early-stage hepatocellular carcinoma (HCC). Reported evidence shows an increase in the ablation zone volume over the first 24-h post-liver ablation. This report compares ablation zone volumes immediately at the completion (T = 0) of 26 microwave ablations of liver tumors to 24-h post-procedure (T = 24) volumes., Materials and Methods: 20 patients, 13 (65%) males, underwent a total of 26 hepatic microwave ablations (MWA) under ultrasound guidance. Contrast-enhanced CT (CECT) or MRI was performed immediately and another CECT 24 h post operatively. Evaluation of the ablation zone and comparison of the two post-operative scans were done using BioTrace software. The expansion of ablation zones on post-op CECTs was matched point by point per direction. The distance between each 2 points was measured and grouped by distance. The incidence of each specific distance was then converted into a percentage, first for each case separately, then for all cases altogether. Data were tested by a matched paired one-sided t test., Results: The median lesion diameter was 1.5 cm (range 0.5-3.3) with 16 (62%) HCC cases and 9 hepatic metastases (4 neuroendocrine carcinoma, 4 colorectal carcinomas, 1 breast carcinoma, 1 pancreatic cancer). The data show a consistent volume expansion greater than 30% (p = 7.7e-5) 24-h post-ablation, where the median expansion is 57%. Distances between T = 0 and T = 24 equal to 3-7 mm occur in over 35% of the cases., Conclusion: The ablation zone expansion at 24-h post-op was not uniform. The final ablation zone is difficult to predict at the time of the procedure. The awareness of the ablation zone expansion is important when treating near-critical structures, managing the heat sink effect, and preserving liver parenchyma., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The present study examined different concentrations of the butylated hydroxytoluene (BHT) inhibitor on the kinetics of conversion, polymerization shrinkage stress, and other correlated physicochemical properties of experimental resin composites (ERC). A model composite was formulated with 75 wt% filler containing 0.5 wt% camphorquinone and 1 wt% amine with BHT concentrations of 0.01 wt% (BHT-0.01); 0.1 wt% (BHT-0.1); 0.25 wt% (BHT-0.25); 0.5 wt% (BHT-0.5); 1 wt% (BHT-1), and control (no BHT). They were tested on polymerization shrinkage stress (PSS; n = 5), degree of conversion (DC; n = 3), maximum polymerization rate (Rp MAX ; n = 5), water sorption (W sp ; n = 0), and solubility (W sl ; n = 10), flexural strength (FS; n = 10), flexural modulus (FM; n = 10), Knoop microhardness (KH; n = 10), and microhardness reduction (HR; n = 10). Data concerning these tests were submitted to one-way ANOVA and Tukey's test (α = 0.05; β = 0.2). BHT-0.25, BHT-0.5, and BHT-1 showed a gradually significant decrease in PSS (p = 0.037); however, BHT-1 demonstrated a decrease in the physicochemical properties tested. Thus, within the limitations of this study, it was possible to conclude that BHT concentrations between 0.25 and 0.5 wt% are optimal for reducing shrinkage stress without affecting other physicochemical properties of ERCs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this manuscript., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Various novel platform technologies have been used for the development of COVID-19 vaccines. In this nested cohort study among healthcare workers in Australia and Brazil who received three different COVID-19-specific vaccines, we (a) evaluated the incidence of adverse events following immunization (AEFI); (b) compared AEFI by vaccine type, dose and country; (c) identified factors influencing the incidence of AEFI; and (d) assessed the association between reactogenicity and vaccine anti-spike IgG antibody responses. Of 1302 participants who received homologous 2-dose regimens of ChAdOx1-S (Oxford-AstraZeneca), BNT162b2 (Pfizer-BioNTech) or CoronaVac (Sinovac), 1219 (94%) completed vaccine reaction questionnaires. Following the first vaccine dose, the incidence of any systemic reaction was higher in ChAdOx1-S recipients (374/806, 46%) compared with BNT162b2 (55/151, 36%; p  = 0.02) or CoronaVac (26/262, 10%; p  < 0.001) recipients. After the second vaccine dose, the incidence of any systemic reaction was higher in BNT162b2 recipients (66/151, 44%) compared with ChAdOx1-S (164/806, 20%; p  < 0.001) or CoronaVac (23/262, 9%; p  < 0.001) recipients. AEFI risk was higher in younger participants, females, participants in Australia, and varied by vaccine type and dose. Prior COVID-19 did not impact the risk of AEFI. Participants in Australia compared with Brazil reported a higher incidence of any local reaction (170/231, 74% vs 222/726, 31%, p  < 0.001) and any systemic reaction (171/231, 74% vs 328/726, 45%, p  < 0.001), regardless of vaccine type. Following a primary course of ChAdOx1-S or CoronaVac vaccination, participants who did not report AEFI seroconverted at a similar rate to those who reported local or systemic reactions. In conclusion, we found that the incidence of AEFI was influenced by participant age and COVID-19 vaccine type, and differed between participants in Australia and Brazil.

This study investigated the development of hybrid cheese analogues (HCA) made with fermented brewery side-stream ingredients (spent yeast and malt rootlets) and dairy milk. Different percentages of side-stream flours (3.5%, 5%, and 7.5%) were mixed with pasteurized milk, and the developed HCA were evaluated for their biochemical and textural properties. The addition of a fermentation step improved nutrient availability and led to pH (range 4.79-5.60) and moisture content (range 45.86%-61.29%) similar to traditional animal-based fresh cheeses (control). The inclusion of side-stream flours led to coagulation, even without rennet addition. The higher the concentration of the flour used, the faster the coagulation time, suggesting synergistic effect between the enzymes of the rennet and the enzymes present in the fermented side-stream flours. Nevertheless, textural properties were inferior compared to the control. Selected HCA formulations with added 3.5% flour exhibited increased counts of enterococci and enterobacteria cell densities, ranging from 7.28 ± 0.03 to 7.72 ± 0.09 log CFU/g and 4.90 ± 0.16 to 5.41 ± 0.01 log CFU/g, respectively. Compared to the control sample, HCA formulations exhibited higher concentrations of organic acids, peptides, and free amino acids (FAAs). Lactic acid reached up to 23.78 ± 0.94 g/kg of dry matter (DM), while the peptide area reached up to 22918.50 ± 2370.93 mL⋅AU. Additionally, the total concentration of individual FAAs reached up to 2809.74 ± 104.85 mg/kg of DM, contrasted with the control, which resulted in lower concentrations (847.65 ± 0.02 mg/kg of DM). The overall findings suggested that despite challenges in microbiological quality and textural properties, HCA produced with the inclusion of up to 3.5% brewery side-stream flours could be a sustainable solution to produce nutritious dairy alternatives., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier B.V.)

A metabolic theory is presented for predicting maximum growth rate, overflow metabolism, respiration efficiency, and maintenance energy flux based on the intersection of cell geometry, membrane protein crowding, and metabolism. The importance of cytosolic macromolecular crowding on phenotype has been established in the literature but the importance of surface area has been largely overlooked due to incomplete knowledge of membrane properties. We demonstrate that the capacity of the membrane to host proteins increases with growth rate offsetting decreases in surface area-to-volume ratios (SA:V). This increase in membrane protein is hypothesized to be essential to competitive Escherichia coli phenotypes. The presented membrane-centric theory uses biophysical properties and metabolic systems analysis to successfully predict the phenotypes of E. coli K-12 strains, MG1655 and NCM3722, which are genetically similar but have SA:V ratios that differ up to 30%, maximum growth rates on glucose media that differ by 40%, and overflow phenotypes that start at growth rates that differ by 80%. These analyses did not consider cytosolic macromolecular crowding, highlighting the distinct properties of the presented theory. Cell geometry and membrane protein crowding are significant biophysical constraints on phenotype and provide a theoretical framework for improved understanding and control of cell biology.

In classical cerebellar learning, Purkinje cells (PkCs) associate climbing fiber (CF) error signals with predictive granule cells (GrCs) that were active just prior (∼150 ms). The cerebellum also contributes to behaviors characterized by longer timescales. To investigate how GrC-CF-PkC circuits might learn seconds-long predictions, we imaged simultaneous GrC-CF activity over days of forelimb operant conditioning for delayed water reward. As mice learned reward timing, numerous GrCs developed anticipatory activity ramping at different rates until reward delivery, followed by widespread time-locked CF spiking. Relearning longer delays further lengthened GrC activations. We computed CF-dependent GrC→PkC plasticity rules, demonstrating that reward-evoked CF spikes sufficed to grade many GrC synapses by anticipatory timing. We predicted and confirmed that PkCs could thereby continuously ramp across seconds-long intervals from movement to reward. Learning thus leads to new GrC temporal bases linking predictors to remote CF reward signals-a strategy well suited for learning to track the long intervals common in cognitive domains., Competing Interests: Declaration of interests The authors declare no competing interests., (Published by Elsevier Inc.)

Ticks are obligate hematophagous arthropods that transmit a wide range of pathogens to humans as well as wild and domestic animals. They also harbor a non-pathogenic microbiota, although our previous study has shown that the diverse bacterial microbiome in the midgut of Ixodes ricinus is quantitatively poor and lacks a core. In artificial infections by capillary feeding of ticks with two model bacteria (Gram-positive Micrococcus luteus and Gram-negative Pantoea sp.), rapid clearance of these microbes from the midgut was observed, indicating the presence of active immune mechanisms in this organ. In the current study, RNA-seq analysis was performed on the midgut of I. ricinus females inoculated with either M. luteus or Pantoea sp. or with sterile water as a control. While no immune-related transcripts were upregulated by microbial inoculation compared to that of the sterile control, capillary feeding itself triggered dramatic transcriptional changes in the tick midgut. Manual curation of the transcriptome from the midgut of unfed I. ricinus females, complemented by the proteomic analysis, revealed the presence of several constitutively expressed putative antimicrobial peptides (AMPs) that are independent of microbial stimulation and are referred to here as 'guard' AMPs. These included two types of midgut-specific defensins, two different domesticated amidase effector 2 (Dae2), microplusin/ricinusin-related molecules, two lysozymes, and two gamma interferon-inducible lysosomal thiol reductases (GILTs). The in vitro antimicrobial activity assays of two synthetic mature defensins, defensin 1 and defensin 8, confirmed their specificity against Gram-positive bacteria showing exceptional potency to inhibit the growth of M. luteus at nanomolar concentrations. The antimicrobial activity of midgut defensins is likely part of a multicomponent system responsible for the rapid clearance of bacteria in the tick midgut. Further studies are needed to evaluate the role of other identified 'guard' AMPs in controlling microorganisms entering the tick midgut., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Guizzo, Frantová, Lu, Kozelková, Číhalová, Dyčka, Hrbatová, Tonk-Rügen, Perner, Ribeiro, Fogaça, Zurek and Kopáček.)

Adverse intrauterine conditions may cause fetal growth restriction (FGR), a pregnancy complication frequently linked to perinatal morbidity and mortality. Although many studies have focused on FGR, the pathophysiological processes underlying this disorder are complex and incompletely understood. We have recently determined that galectin-3 (gal-3), a β-galactoside-binding protein, regulates pregnancy-associated processes, including uterine receptibility, maternal vascular adaptation and placentation. Because gal-3 is expressed at both sides of the maternal-fetal interface, we unraveled the contribution of maternal- and paternal-derived gal-3 on fetal-placental development in the prenatal window and its effects on the post-natal period. Deficiency of maternal gal-3 induced maternal gut microbiome dysbiosis, resulting in a sex-specific fetal growth restriction mainly observed in female fetuses and offspring. In addition, poor placental metabolic adaptions (characterized by decreased trophoblast glycogen content and insulin-like growth factor 2 (Igf2) gene hypomethylation) were only associated with a lack of maternal-derived gal-3. Paternal gal-3 deficiency caused compromised vascularization in the placental labyrinth without affecting fetal growth trajectory. Thus, maternal-derived gal-3 may play a key role in fetal-placental development through the gut-placenta axis., (© 2024. The Author(s).)

Only a small number of studies have assessed structural differences between the two hemispheres during childhood and adolescence. However, the existing findings lack consistency or are restricted to a particular brain region, a specific brain feature, or a relatively narrow age range. Here, we investigated associations between brain asymmetry and age as well as sex in one of the largest pediatric samples to date (n = 4265), aged 1-18 years, scanned at 69 sites participating in the ENIGMA (Enhancing NeuroImaging Genetics through Meta-Analysis) consortium. Our study revealed that significant brain asymmetries already exist in childhood, but their magnitude and direction depend on the brain region examined and the morphometric measurement used (cortical volume or thickness, regional surface area, or subcortical volume). With respect to effects of age, some asymmetries became weaker over time while others became stronger; sometimes they even reversed direction. With respect to sex differences, the total number of regions exhibiting significant asymmetries was larger in females than in males, while the total number of measurements indicating significant asymmetries was larger in males (as we obtained more than one measurement per cortical region). The magnitude of the significant asymmetries was also greater in males. However, effect sizes for both age effects and sex differences were small. Taken together, these findings suggest that cerebral asymmetries are an inherent organizational pattern of the brain that manifests early in life. Overall, brain asymmetry appears to be relatively stable throughout childhood and adolescence, with some differential effects in males and females., (© 2024 The Author(s). Human Brain Mapping published by Wiley Periodicals LLC.)

The lack of effective treatments for dementia has led to explore the potential of antidiabetic agents as a possible approach. This cross-sectional and population-based study aimed to investigate the relationship between each antidiabetic drug and their defined daily doses (DDDs) and the use of anti-Alzheimer's disease (AD) drugs in order to establish new possible hypotheses about the role of antidiabetic drugs in AD. For that purpose, a database containing information on medications prescribed to 233183 patients aged 50 years or older between 2018 and 2020 was used. DDDs were calculated according to the ATC/DDD index 2023. Statistical analyses, with logistic regression, were carried out to assess antidiabetic and anti-AD drugs consumption. A total of 91836 patients who were prescribed at least one antihypertensive, antidiabetic, or lipid-modifying agent were included in the study; specifically, 29260 patients were prescribed antidiabetic medication. Among the antidiabetic agents, glucagon-like peptide-1 analogs (GLP-1) DDDs were likely to have a positive association with anti-AD drugs in people aged between 70 and 80 years. Additionally, sodium-glucose cotransporter 2 inhibitors (SGLT2i) were prone to have a positive association with anti-AD drug usage across almost every age. However, insulin usage was associated with an increased usage of anti-AD agents. In conclusion, there is evidence suggesting a correlation between certain antidiabetic agents and dementia. Specifically, GLP-1 and SGLT2i might be associated with lower odds of anti-AD drugs usage, while insulins might be linked to higher odds of using anti-AD drugs., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The atypia of undetermined significance (AUS) category is heterogeneous, leading to variations in its use. To prevent excessive usage, the AUS rate should be ≤10%. Although this recommendation aims to maintain diagnostic quality, it lacks supporting data. The AUS:Malignant (AUS:M) ratio has been proposed as a metric tool to evaluate AUS use. Furthermore, integrating ThyroSeq v3 (TSV3) positive call rate (PCR) and the molecular-derived risk of malignancy (MDROM) have been put forward as performance improvement tools. The authors reviewed their AUS:M ratios, TSV3 PCR, MDROM, and ROM., Methods: Thyroid aspirates evaluated in the laboratory (from August 2022 to September 2023) by seven cytopathologists (CPs) were identified. AUS:M ratio, MDROM, ROM, and TSV3 PCR results for the laboratory and each CP were recorded and analyzed., Results: A total of 2248 aspirates were identified (462 AUS and 80 malignant). The AUS:M ratio for the laboratory was 5.8 (CPs range, 2.8 to 7.3). The TSV3 PCR for the laboratory was 23% (CPs range, 11% to 41%). The MDROM for the laboratory was 19% (CPs range, 9% to 31%), whereas the ROM was 36% (CPs range, 29% to 50%). Linear regression analysis of AUS:M ratio versus TSV3 PCR and MDROM demonstrated a moderate positive correlation but a weak negative correlation to the ROM. Deviations from established targets were attributed to multiple factors., Conclusion: The findings of this study underscore the importance of using a combination of metrics to evaluate diagnostic practices. By dissecting the practice patterns of each CP, the authors can measure different aspects of their performance and provide individualized feedback., (© 2024 The Authors. Cancer Cytopathology published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Abnormal placental angiogenesis during gestation resulting from high levels of anti-angiogenic factors, soluble fms-like tyrosine kinase-1 (sFLT1) and soluble endoglin, has been implicated in the progression of preeclampsia (PE). This heterogeneous syndrome (defined by hypertension with or without proteinuria after 20 weeks of pregnancy) remains a major global health burden with long-term consequences for both mothers and child. Previously, we showed that in vivo systemic human (hsFLT1) overexpression led to reduced placental efficiency and PE-like syndrome in mice. Galectins (gal-1, -3 and -9) are critical determinants of vascular adaptation to pregnancy and dysregulation of the galectin-glycan circuits is associated with the development of this life-threatening disease. In this study, we assessed the galectin-glycan networks at the maternal-fetal interface associated with the hsFLT1-induced PE in mice. We observed an increase on the maternal gal-1 expression in the decidua and junctional zone layers of the placenta derived from hs FLT1 high pregnancies. In contrast, placental gal-3 and gal-9 expression were not sensitive to the hsFLT1 overexpression. In addition, O- and N-linked glycan expression, poly-LacNAc sequences and terminal sialylation were down-regulated in hsFLT1 high placentas. Thus, the gal-1-glycan axis appear to play an important role counteracting the anti-angiogenic status caused by sFLT1, becoming critical for vascular adaptation at the maternal-fetal interface., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Immune-surveillance depends in part on the recognition of peptide variants by T cell antigen receptors. Given that both normal B cells and malignant B cells accumulate mutations we chose a murine model of multiple myeloma to test conditions to induce cell-mediated immunity targeting malignant plasma cell (PC) clones but sparing of normal PCs. Revealing a novel function for intracellular C3d, we discovered that C3d engaged T cell responses against malignant plasma cells in the bone marrow of mice that had developed multiple myeloma spontaneously. Our results show that C3d internalized by cells augments immune surveillance by several mechanisms. In one, C3d induces a master transcription regulator, E2f1, to increase the expression of long non-coding (lnc) RNAs, to generate peptides for MHC-I presentation and increase MHC-I expression. In another, C3d increases expression of RNAs encoding ribosomal proteins linked to processing of defective ribosomal products (DRiPs) that arise from non-canonical translation and known to promote immunosurveillance. Cancer cells are uniquely susceptible to increased expression and presentation of mutant peptides given the extent of protein misfolding and accumulation of somatic mutations. Accordingly, although C3d can be internalized by any cell, C3d preferentially targets malignant clones by evoking specific T cell mediated immunity (CMI) and sparing most non-transformed polyclonal B cells and plasma cells with lower mutation loads. Malignant plasma cell deletion was blocked by cyclosporin or by CD8 depletion confirming that endogenous T cells mediated malignant clone clearance. Besides the potential for therapeutic application our results highlight how intracellular C3d modifies cellular metabolism to augment immune surveillance., One Sentence Summary: We show that intracellular soluble fragment 3d of complement (C3d) induces regression of spontaneous multiple myeloma in mice reducing tumor burden by 10 fold, after 8 weeks. C3d enables cell-mediated immunity to target multiple myeloma clones sparing non-transformed polyclonal B cells and plasma cells with lower mutation loads. We show that C3d increases the expression of ribosomal subunits associated with the translation of defective ribosomal products (DRiPs). C3d also decreases expression of protein arginine methyl transferase (PRMT) 5 which in turn relieves E2f1 repression increasing the expression of Lnc RNAs and derived peptides that evoke anti-tumor cellular immunity. The approach increases MHC-I expression by tumor cells and generates a CMI response that overcomes tumor immune-evasion strategies., Significance: Tumors are immunogenic in part because of somatic mutations that originate novel peptides that once presented on MHC engage cell-mediated immunity (CMI). However, in spite of the higher mutation load most tumors evade immunity. We discovered that a component of the complement system (C3d) overcomes tumor immune evasion by augmenting expression of ribosomal proteins and lncRNAs linked to the presentation of novel peptides by tumor cells. C3d induced CMI targets cancer cells sparing non transformed cells uncovering a novel function for complement in immune surveillance.

We describe an approach for designing high-affinity small molecule-binding proteins poised for downstream sensing. We use deep learning-generated pseudocycles with repeating structural units surrounding central binding pockets with widely varying shapes that depend on the geometry and number of the repeat units. We dock small molecules of interest into the most shape complementary of these pseudocycles, design the interaction surfaces for high binding affinity, and experimentally screen to identify designs with the highest affinity. We obtain binders to four diverse molecules, including the polar and flexible methotrexate and thyroxine. Taking advantage of the modular repeat structure and central binding pockets, we construct chemically induced dimerization systems and low-noise nanopore sensors by splitting designs into domains that reassemble upon ligand addition.

Brain abscesses in ruminants often arise from primary infection foci, leading to an unfavorable prognosis for affected animals. This highlights the need for comprehensive studies on brain abscesses across different ruminant species. We retrospectively investigated medical records of epidemiological, clinical, neuroimaging, anatomopathological, and bacteriological findings in six ruminants (three goats, two cows, and one sheep) diagnosed with brain abscesses. All animals studied were female. Apathy (50%), compulsive walking (33%), decreased facial sensitivity (33%), head pressing (33%), seizures (33%), semicomatous mental status (33%), strabismus (33%), unilateral blindness (33%), and circling (33%) represented the most common neurologic signs. Leukocytosis and neutrophilia were the main findings in the hematological evaluation. Cerebrospinal fluid (CSF) analysis revealed predominant hyperproteinorrachia and pleocytosis. In three cases, computed tomography or magnetic resonance imaging were used, enabling the identification of typical abscess lesions, which were subsequently confirmed during postmortem examination. Microbiological culture of the abscess samples and/or CSF revealed bacterial coinfections in most cases. Advanced imaging examinations, combined with CSF analysis, can aid in diagnosis, although confirmation typically relies on postmortem evaluation and isolation of the causative agent. This study contributes to clinicopathological aspects, neuroimages, and bacteriological diagnosis of brain abscesses in domestic ruminants.

Background: Despite growing interest in understanding the challenges faced by multidisciplinary health teams during the COVID-19 pandemic, there is a lack of studies specifically focusing on changes in pharmacist interventions and drug-related problems., Objectives: To analyze and compare the interventions performed by pharmacists during comprehensive medication management in the adult intensive care unit and general internal medicine ward of the University Hospital of the University of São Paulo, Brazil, for defined periods before the onset of the COVID-19 pandemic and during the pandemic itself., Methods: All pharmacist interventions performed in relation to inpatient prescriptions from March to December 2019 (before the pandemic) and from March to December 2021 (during the pandemic) were collected and tabulated. These interventions were then classified according to the Pharmaceutical Care Network Europe (PCNE) system, version 9.1, and categorized based on first-level codes of the Anatomical Therapeutic Chemical classification system., Results: The analysis revealed substantial changes in the patterns of pharmacist interventions and the therapeutic classes of drugs for COVID-19-positive and COVID-19-negative patients during the pandemic relative to patients in the pre-pandemic period. Among COVID-19-positive patients, interventions were predominantly related to enhancing patient safety (PCNE code P2), drug selection (C1), dose selection (C3), prescribing and dispensing processes (C5), the drug-use process (C6), and patient transfers between different levels of care (C8). The drug-related problems addressed by pharmacist interventions primarily involved COVID-19-positive patients in the pandemic period and were related to systemic hormonal preparations (excluding sex hormones and insulins), anti-infective agents for systemic use, nervous system and drugs for the blood and blood-forming organs., Conclusion: The results of this study highlight the adaptability and competence of pharmacists in responding to critical scenarios such as the COVID-19 pandemic. These scenarios are characterized by new work dynamics, the hiring of additional professionals, an increase in the number of beds, the rapid evolution of evidence-based information, and drug shortages that necessitate the use of alternative medications. Pharmacists play a crucial role in ensuring patient safety during these difficult times., Competing Interests: Competing interests: None declared., (2024 Canadian Society of Hospital Pharmacists. All content in the Canadian Journal of Hospital Pharmacy is copyrighted by the Canadian Society of Hospital Pharmacy. In submitting their manuscripts, the authors transfer, assign, and otherwise convey all copyright ownership to CSHP.)

Besides neutralizing antibodies, which are considered an important measure for vaccine immunogenicity, Fc-mediated antibody functions can contribute to antibody-mediated protection. They are strongly influenced by structural antibody properties such as subclass and Fc glycan composition. We here applied a systems serology approach to dissect humoral immune responses induced by MVA-MERS-S, an MVA-vectored vaccine against the Middle East respiratory syndrome coronavirus (MERS-CoV). Building on preceding studies reporting the safety and immunogenicity of MVA-MERS-S, our study highlights the potential of a late boost, administered one year after prime, to enhance both neutralizing and Fc-mediated antibody functionality compared to the primary vaccination series. Distinct characteristics were observed for antibodies specific to the MERS-CoV spike protein S1 and S2 subunits, regarding subclass and glycan compositions as well as Fc functionality. These findings highlight the benefit of a late homologous booster vaccination with MVA-MERS-S and may be of interest for the design of future coronavirus vaccines., Competing Interests: A.F. is an employee of BioNTech SE as of January 2024 (after the completion of this study). All other authors declare no competing interests., (© 2024 The Author(s).)

University students are vulnerable to mental health issues during their academic lives. During the COVID-19 pandemic, university students faced mental distress due to lockdowns and the transition to e-learning. However, it is not known whether these students were also affected specifically by COVID-19-related traumatic events. This study examined the impact of COVID-19-related traumatic events on 2277 university students from two federal institutions of higher education in Brazil. The university students completed an online questionnaire covering demographics, lifestyle habits, health characteristics, COVID-19-related traumatic events, and depression, anxiety, and stress symptoms. The results showed that an increased intensity of COVID-19-related traumatic events was positively associated with stress, anxiety, and depressive symptoms, and each specific type of event was associated with these symptoms. In addition, we found a negative association between these symptoms and male sex and age and a positive association with having or having had a history of cardiovascular, respiratory, neurological, or mental disorders or another disease diagnosed by a physician. In conclusion, this study emphasizes the heightened risk of mental health issues in university students in the face of COVID-19-related traumatic events. Women, young people and people who have or have had a history of disease were the most vulnerable to mental health issues during the COVID-19 pandemic., Competing Interests: Declaration of competing interest The Authors declare that there is no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

This study characterizes the chromosomal organization of DNA repetitive sequences and the karyotypic evolution in four representatives of the solitary wasp genus Trypoxylon using conventional and molecular cytogenetic techniques. Our findings present the first cytogenetic data for Trypoxylon rogenhoferi (2 n = 30) and Trypoxylon albonigrum (2 n = 32), while the karyotypes of Trypoxylon nitidum (2 n = 30) and Trypoxylon lactitarse (2 n = 30) were similar to those previously described. Fluorochrome staining and microsatellite distribution data revealed differences in the constitutive heterochromatin composition among species. Trypoxylon nitidum and T. albonigrum exhibited one major rDNA cluster, potentially representing an ancestral pattern for aculeate Hymenoptera, while T. rogenhoferi and T. lactitarse showed two pericentromeric rRNA gene sites, suggesting amplification events in their ancestral clade. The (TCAGG) n motif hybridized in the terminal regions of the chromosomes in all four Trypoxylon species, which may suggest that this sequence represents DNA telomeric repeat. Notably, the presence of this repetitive sequence in the centromeric regions of certain chromosome pairs in two species supports the hypothesis of chromosomal fusions or inversions in the ancestral karyotype of Trypoxylon . The study expands the chromosomal mapping data of repetitive sequences in wasps and offers insights into the dynamic evolutionary landscape of karyotypes in these insects., Competing Interests: The authors have no competing of interest to declare.

The antibiotic fusidic acid (FA) is used to treat Staphylococcus aureus infections. It inhibits protein synthesis by binding to elongation factor G (EF-G) and preventing its release from the ribosome after translocation. While FA, due to permeability issues, is only effective against gram-positive bacteria, the available structures of FA-inhibited complexes are from gram-negative model organisms. To fill this knowledge gap, we solved cryo-EM structures of the S. aureus ribosome in complex with mRNA, tRNA, EF-G and FA to 2.5 Å resolution and the corresponding complex structures with the recently developed FA derivative FA-cyclopentane (FA-CP) to 2.0 Å resolution. With both FA variants, the majority of the ribosomal particles are observed in chimeric state and only a minor population in post-translocational state. As expected, FA binds in a pocket between domains I, II and III of EF-G and the sarcin-ricin loop of 23S rRNA. FA-CP binds in an identical position, but its cyclopentane moiety provides additional contacts to EF-G and 23S rRNA, suggesting that its improved resistance profile towards mutations in EF-G is due to higher-affinity binding. These high-resolution structures reveal new details about the S. aureus ribosome, including confirmation of many rRNA modifications, and provide an optimal starting point for future structure-based drug discovery on an important clinical drug target., (© 2024. The Author(s).)

An accelerated local injection site reaction following Bacille Calmette-Guérin (BCG) vaccination has been associated with underlying active tuberculosis (TB) in high TB-prevalence settings. The clinical significance of this accelerated BCG reaction in individuals without TB symptoms, particularly in low TB-prevalence countries, is unclear. Using safety surveillance data and baseline interferon-gamma release assays (IGRA) within an international randomised trial of BCG vaccination in healthcare workers (the BRACE trial), we aimed to determine the incidence, and investigate for clinical implications, of an accelerated BCG reaction in asymptomatic adults in low and high TB-prevalence settings. An accelerated BCG reaction occurred in 755/1984 (38 %) of BCG-vaccinees. Although more frequently painful, tender, erythematous and/or swollen within the first fourteen days of vaccination, compared with non-accelerated reactions, the majority of injection site reactions were mild and did not meet criteria for an adverse event. Prior mycobacterial exposure, through prior BCG vaccination (OR 2.46, 95%CI 1.93-3.13, p < 0.001) or latent TB infection (OR 4.17, 95%CI 1.16-14.93, p = 0.03), and female sex (OR 1.27, 95%CI 1.03-1.57, p = 0.02), were key determinants for the occurrence of an accelerated BCG reaction. The development of an accelerated local reaction to BCG vaccination in an individual without prior history of BCG vaccination, should prompt consideration of further investigations for potential underlying TB infection., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 Published by Elsevier Ltd.)

Air pollution (AP) is one of the main recent concerns in reproductive healthy due to its potential to promote negative outcomes during pregnancy and male and female fertility. Several studies have demonstrated that AP exposure has been linked to increased embryonic implantation failures, alterations in embryonic, fetal and placental development. For a well-succeeded implantation, both competent blastocyst and receptive endometrium are required. Based on the lack of data about the effect of AP in endometrial receptivity, this study aimed to evaluate he particulate matter (PM) exposure impact on uterine receptive markers in mice and associate the alterations to increased implantation failures due to AP. For this study, ten dams per group were exposed for 39 days to either filter (F) or polluted air (CAP). At fourth gestational day (GD4), females were euthanized. Morphological, ultrastructural, immunohistochemical and molecular analysis of uterine and ovarian samples were performed. CAP-exposed females presented a reduced number of corpus luteum; glands and epithelial cells were increased with pinopodes formation impairment. Immunohistochemistry analysis revealed decreased LIF protein levels. These preliminary data suggests that PM exposure may exert negative effects on endometrial receptivity by affecting crucial parameters to embryonic implantation as uterine morphological differentiation, corpus luteum quantity and LIF expression during implantation window., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest associated with this study., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Although critical to the overall condition of animals under human care, there is still limited information about oral health in neotropical primates., Methods: We analyzed the main oral conditions and microbiota using mass spectrometry from 13 capuchin monkeys (Sapajus apella) under human care. The findings were registered on odontograms following the Triadan system., Results: The most prevalent conditions were dental fractures (n = 9), mainly enamel fractures, and periodontal disease (n = 8), mainly grade 1 calculi. When exanimating teeth, alterations were identified in 90 out of the 416 evaluated pieces, being periodontal disease the most common (n = 60), followed by enamel fracture (n = 15) and missing teeth (n = 10). In the oral microbiota analyses, Staphylococcus and Streptococcus species were the most prevalent, although no obvious association was observed between isolated organisms and oral conditions., Conclusions: These findings hold the potential to prevent oral disorders, including fractures and periodontal diseases, contribute to molecular identification of oral microbiota, and to improve the well-being of primates under human care., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: To evaluate the thermal insulation of protective liners and glass ionomer cement during light-curing procedures., Material and Methods: Human third molars underwent Class I preparations with dimensions 5 mm long × 4 mm wide × 4 mm deep in a standardized manner ensured a consistent ±0.5 mm dentin thickness at the pulpal floor. The teeth were attached to a customized oral cavity chamber simulator with a circulating bath at a standardized temperature of 34.2 ± 1oC. The temperature variations at the pulpal floor were captured in real-time by video using an infrared thermal camera (FLIR ONE Pro, FLIR Systems). The materials evaluated were: Dycal (Dentsply), TheraCal LC (Bisco), Activa (Pulpdent), and Fuji II LC (GC). All light-activation procedures were performed with the same light-curing unit (Valo Grand, Ultradent) in standard mode, 1000 mW/cm2, and time of exposure following manufacturer instructions. A power analysis was conducted to determine the sample size considering a minimal power of 0.8, with α=0.05. Statistical analyses were performed using ANOVA and Tukey's test for multiple comparisons., Results: The temperature at the pulpal floor increased above the 5.5 ºC safety threshold difference for clinical scenarios tested. None of the materials provided proper thermal insulation for light-curing procedures ( p = 0.25). The higher the number of light-cured steps, the longer the pulp remained above the 5.5 ºC temperature threshold., Conclusions: The materials tested provided improper thermal insulation (Δ > 5.5 ºC). Thus, prolonged or multiple light-curing exposures can be harmful to the pulp tissues. Therefore, for indirect pulpal capping procedures, self-cured materials or a reduced number of steps requiring light curing must be adopted to reduce the amount of time the pulp remains above the 5.5 ºC safety temperature threshold. Key words: Dental Pulp Capping, Calcium hydroxide, Bioactive, Thermal Damage., Competing Interests: Declared none., (Copyright: © 2024 Medicina Oral S.L.)

Postsynaptic scaffold proteins such as Shank, PSD-95, Homer and SAPAP/GKAP family members establish the postsynaptic density of glutamatergic synapses through a dense network of molecular interactions. Mutations in SHANK genes are associated with neurodevelopmental disorders including autism and intellectual disability. However, no SHANK missense mutations have been described which interfere with the key functions of Shank proteins believed to be central for synapse formation, such as GKAP binding via the PDZ domain, or Zn 2+ -dependent multimerization of the SAM domain. We identify two individuals with a neurodevelopmental disorder carrying de novo missense mutations in SHANK2. The p.G643R variant distorts the binding pocket for GKAP in the Shank2 PDZ domain and prevents interaction with Thr(-2) in the canonical PDZ ligand motif of GKAP. The p.L1800W variant severely delays the kinetics of Zn 2+ -dependent polymerization of the Shank2-SAM domain. Structural analysis shows that Trp1800 dislodges one histidine crucial for Zn 2+ binding. The resulting conformational changes block the stacking of helical polymers of SAM domains into sheets through side-by-side contacts, which is a hallmark of Shank proteins, thereby disrupting the highly cooperative assembly process induced by Zn 2+ . Both variants reduce the postsynaptic targeting of Shank2 in primary cultured neurons and alter glutamatergic synaptic transmission. Super-resolution microscopy shows that both mutants interfere with the formation of postsynaptic nanoclusters. Our data indicate that both the PDZ- and the SAM-mediated interactions of Shank2 contribute to the compaction of postsynaptic protein complexes into nanoclusters, and that deficiencies in this process interfere with normal brain development in humans., (© 2022. The Author(s).)

A new method has been introduced that is able to tackle the complexities of N-C(O) activation in amide moieties through utilization of pyrylium tetrafluoroborate in a mechanochemical setting, where amide bonds undergo activation and subsequent conversion to biaryl ketones. Due to the employment of a mechanochemical setting, the reaction conforms to green chemistry principles, offering an environmentally friendly approach to traditional amide derivatization techniques that rely on transition metals to achieve further functionalization., Competing Interests: The authors declare no competing financial interests., (This journal is © The Royal Society of Chemistry.)

The development of new molecules for the treatment of calmodulin related cardiovascular or neurodegenerative diseases is an interesting goal. In this work, we introduce a novel strategy with four main steps: (1) chemical synthesis of target molecules, (2) Förster Resonance Energy Transfer (FRET) biosensor development and in vitro biological assay of new derivatives, (3) Cheminformatics models development and in vivo activity prediction, and (4) Docking studies. This strategy is illustrated with a case study. Firstly, a series of 4-substituted Riluzole derivatives 1-3 were synthetized through a strategy that involves the construction of the 4-bromoriluzole framework and its further functionalization via palladium catalysis or organolithium chemistry. Next, a FRET biosensor for monitoring Ca 2+ -dependent CaM-ligands interactions has been developed and used for the in vitro assay of Riluzole derivatives. In particular, the best inhibition (80%) was observed for 4-methoxyphenylriluzole 2b. Besides, we trained and validated a new Networks Invariant, Information Fusion, Perturbation Theory, and Machine Learning (NIFPTML) model for predicting probability profiles of in vivo biological activity parameters in different regions of the brain. Next, we used this model to predict the in vivo activity of the compounds experimentally studied in vitro. Last, docking study conducted on Riluzole and its derivatives has provided valuable insights into their binding conformations with the target protein, involving calmodulin and the SK4 channel. This new combined strategy may be useful to reduce assay costs (animals, materials, time, and human resources) in the drug discovery process of calmodulin inhibitors., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Introduction: Infections in cardiac implantable electronic devices (CIED) are increasing over time and associated with substantially mortality and healthcare costs. The best approach is the complete removal of the system by transvenous lead extraction (TLE). However, when leads are more than 10 years old, this technique requires considerable expertise and failures with the result of abandoned leads or serious complications may occur. The aim of this study is to describe our experience using virtual and mixed reality in the preoperative planning of complex cases., Patients and Methods: Consecutive patients from a referral centre with CIED infections in which TLE was judged difficult. Synchronized computed tomography (CT) scan images were processed and transferred to a fully immersive virtual reality room and also to the operative room (mixed reality) for better guidance during the extracting procedure., Results: Ten patients (seven with local and three with systemic infections) were preoperative evaluated. Processed images and virtual reality showed intense adherences of the leads to the veins, right ventricle, and right atrium endocardium and between them that preclude a difficult extraction and required a carefully planning and sometimes a different technical approach. The anticipated difficulty was confirmed by the higher times of fluoroscopy. All leads were extracted and no complications were registered., Conclusions: Preoperative planning is essential for evaluation of TLE difficulty and prevention of unexpected situations. Virtual reality seems an estimable aid for operators in planning difficult cases and also an excellent tool for teaching., Supplementary Information: The online version contains supplementary material available at 10.1007/s12055-023-01663-9., Competing Interests: Conflict of interestThe authors have nothing to disclose, except Victor Herrera who works for the company Visuamed, Spain., (© Indian Association of Cardiovascular-Thoracic Surgeons 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Background: Serum transaminases, alkaline phosphatase and bilirubin are common parameters used for DILI diagnosis, classification, and prognosis. However, the relevance of clinical examination, histopathology and drug chemical properties have not been fully investigated. As cholestasis is a frequent and complex DILI manifestation, our goal was to investigate the relevance of clinical features and drug properties to stratify drug-induced cholestasis (DIC) patients, and to develop a prognosis model to identify patients at risk and high-concern drugs., Methods: DIC-related articles were searched by keywords and Boolean operators in seven databases. Relevant articles were uploaded onto Sysrev, a machine-learning based platform for article review and data extraction. Demographic, clinical, biochemical, and liver histopathological data were collected. Drug properties were obtained from databases or QSAR modelling. Statistical analyses and logistic regressions were performed., Results: Data from 432 DIC patients associated with 52 drugs were collected. Fibrosis strongly associated with fatality, whereas canalicular paucity and ALP associated with chronicity. Drugs causing cholestasis clustered in three major groups. The pure cholestatic pattern divided into two subphenotypes with differences in prognosis, canalicular paucity, fibrosis, ALP and bilirubin. A predictive model of DIC outcome based on non-invasive parameters and drug properties was developed. Results demonstrate that physicochemical (pKa-a) and pharmacokinetic (bioavailability, CYP2C9) attributes impinged on the DIC phenotype and allowed the identification of high-concern drugs., Conclusions: We identified novel associations among DIC manifestations and disclosed novel DIC subphenotypes with specific clinical and chemical traits. The developed predictive DIC outcome model could facilitate DIC prognosis in clinical practice and drug categorization., Competing Interests: Declaration of Competing Interest Authors declare no conflicts of interest that pertain to this work., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Introduction: SARS-CoV-2, the cause of the COVID pandemic, is an RNA virus with a high propensity to mutate. Successive virus variants, including variants of concern (VOC), have emerged with increased transmission or immune escape. The original pandemic virus and early variants replicated poorly, if at all, in mice at least partly due to a mismatch between the receptor binding domain on the viral spike protein and the murine angiotensin converting enzyme 2 (ACE2). Omicron VOC emerged in late 2021 harboring > 50 new mutations, 35 of them in the spike protein. This variant resulted in a very large wave of infections, even in the face of prior immunity, albeit being inherently less severe than earlier variants. Reflecting the lower severity reported in humans, Omicron displayed attenuated infection in hamsters and also in the K18- hACE2 mouse model. K18- hACE2 mice express both the human ACE2 as well as the endogenous mouse ACE2., Methods: Here we infected hACE2 knock-in mice that express only human ACE2 and no murine ACE2, or C57BL/6 wildtype mice with SARS-CoV-2 D614G (first-wave isolate), Delta or Omicron BA.1 variants and assessed infectivity and downstream innate immune responses., Results: While replication of SARS-CoV-2 Omicron was lower in the lungs of hACE2 knock-in mice compared with SARS-CoV-2 D614G and VOC Delta, it replicated more efficiently than the earlier variants in C57BL/6 wildtype mice. This opens the opportunity to test the effect of host genetics on SARS-CoV-2 infections in wildtype mice. As a proof of principle, we tested Omicron infection in mice lacking expression of the interferon-alpha receptor-1 (IFNAR1). In these mice we found that loss of type I IFN receptor signaling resulted in higher viral loads in the lungs were detected. Finally, using a chimeric virus of first wave SARS-CoV-2 harboring the Omicron spike protein, we show that Omicron spike increase infection of C57BL/6 wildtype mice, but non-spike genes of Omicron confer attenuation of viral replication., Discussion: Since this chimeric virus efficiently infected C57BL/6 wildtype mice, and replicated in their lungs, our findings illustrate a pathway for genetic mapping of virushost interactions during SARS-CoV-2 infection., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Ogger, Martín, Jang, Zhou, Brown, Sukhova, Furnon, Patel, Cowton, Palmarini, Barclay and Johansson.)