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PURPOSE: The effect of orthodontic movement on the periodontal tissues of maxillary second pre-molars, after regenerative treatment for class II furcations, was evaluated in four mongrel dogs. MATERIAL AND METHODS: Class II furcation lesions were created. After 75 days they were treated with bovine bone mineral matrix and guided tissue regeneration with absorbable membrane. After 2 months of daily plaque control, each of the dog's furcation pre-molars was randomly assigned to a test or control group. Orthodontic appliances were placed on both sides of the maxilla using third pre-molars and canines as anchorages. In the test group, bodily orthodontic movement of the second pre-molars was performed in the mesial direction for 3 months while control pre-molars remained unmoved. The dogs were sacrificed for histometric and histologic analyses. RESULTS: There were no statistically significant differences between the two groups in total bone and biomaterial areas or linear extension of periodontal regeneration on the radicular surfaces. In the test group, however, there was a tendency to a greater quantity of bone and a lesser quantity of biomaterial. CONCLUSION: The orthodontic movement was not pre-judicial to the results obtained with the regenerative periodontal treatment. [ABSTRACT FROM AUTHOR]

Significance: This study reveals that Fc-enhanced anti-CTLA-4 harnesses novel mechanisms to overcome the limitations of conventional anti-CTLA-4, effectively treating poorly immunogenic and treatment-refractory cancers. Our findings support the development of a new class of immuno-oncology agents, capable of extending clinical benefit to patients with cancers resistant to current immunotherapies., (©2024 The Authors; Published by the American Association for Cancer Research.)

Background/objectives: KMT2B-related dystonia (DYT28, OMIM #617284) is a progressive neurological condition characterized by early onset movement disorders with autosomal dominant inheritance. In this study, we describe the use of a genome methylation episignature methodology to functionally validate two variants of uncertain significance (VUS) in the KMT2B gene., Methods: Genome-wide methylation status was assessed using the EPIC methylation assay in peripheral blood samples from two subjects with early onset movement disorder and missense variants of uncertain significance in the KMT2B gene (p.Leu1720Phe and p.Tyr2515Cys). After QC and normalization steps, we compared the M values for all 144 probes, previously described as an EpiSign for KMT2B-related dystonia, between the two subjects and 14 controls individuals., Results: The individual harboring the p.Tyr2515Cys variant exhibited a hypermethylation profile compatible with pathogenic/likely pathogenic variants in KMT2B, allowing for variant reclassification, conclusive genetic counseling, and patient stratification for deep brain stimulation. In contrast, the individual harboring the p.Leu1720Phe variant had a methylation status similar to controls, practically ruling out KMT2B-related dystonia., Conclusion: Investigation of methylation status can be a powerful tool to determine pathogenicity when facing KMT2B variants of uncertain significance. Methylation results may optimize genetic counseling and positively impact patient care., Competing Interests: Declarations. Ethics approval and consent to participate: The ethics committee of the University of São Paulo approved this study (HC-FMUSP—CAPPesq 4 0809520.3.0000.0068/2021). The patients or parents of the patients signed the consent form for participation in the study. Consent for publication: All authors have agreed to have this article published. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

The CRISPR interference (CRISPRi) system is a powerful tool for selectively and efficiently silencing genes in functional genomics research applications. However, its off-target activity has not been systematically investigated. Here, we utilized a genome-wide CRISPRi-Cas9 single-guide RNA (sgRNA) library to investigate the presence of off-target activity and its effects on gene expression. Our findings suggest that off-target effects in CRISPRi are quite pervasive and have direct and indirect impacts on gene expression. Most of the identified off-targets can be accounted for by complementarity of the protospacer adjacent motif (PAM)-proximal genomic sequence with the 3' half of the sgRNA spacer sequence, the seed sequence. We also report that while the stability of off-target binding is primarily driven by the PAM-proximal seed sequences, variations in the length of these seed sequences and the degree of mismatch tolerance at various positions can differ across different sgRNAs., Competing Interests: Declaration of interests N.R., J.-P.F., T.L., M.R.C., B.L.L., and R.R. are current employees of Roche/Genentech. Y.Z. is an employee of Scribe Therapeutics, and Y.Y. is an employee of Sana Biotechnology., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

CDK4/6 inhibition in combination with endocrine therapy is the standard of care for estrogen receptor (ER+) breast cancer, and although cytostasis is frequently observed, new treatment strategies that enhance efficacy are required. Here, we perform two independent genome-wide CRISPR screens to identify genetic determinants of CDK4/6 and endocrine therapy sensitivity. Genes involved in oxidative stress and ferroptosis modulate sensitivity, with GPX4 as the top sensitiser in both screens. Depletion or inhibition of GPX4 increases sensitivity to palbociclib and giredestrant, and their combination, in ER+ breast cancer models, with GPX4 null xenografts being highly sensitive to palbociclib. GPX4 perturbation additionally sensitises triple negative breast cancer (TNBC) models to palbociclib. Palbociclib and giredestrant induced oxidative stress and disordered lipid metabolism, leading to a ferroptosis-sensitive state. Lipid peroxidation is promoted by a peroxisome AGPAT3-dependent pathway in ER+ breast cancer models, rather than the classical ACSL4 pathway. Our data demonstrate that CDK4/6 and ER inhibition creates vulnerability to ferroptosis induction, that could be exploited through combination with GPX4 inhibitors, to enhance sensitivity to the current therapies in breast cancer., (© 2024. The Author(s).)

The aim of this paper is to summarize the available evidence in the literature regarding the effects generated by exposure to an enriched environment (EE) on the modulation of epigenetic processes in the central nervous system under adverse environmental conditions. Searches were conducted in three databases: PubMed/Medline (1053 articles), Scopus (121 articles), and Embase (52 articles), which were subjected to eligibility criteria. Of the 1226 articles found, 173 duplicates were removed. After evaluating titles/abstracts, 904 studies were excluded, resulting in 49 articles, of which 14 were included in this systematic review. EE was performed using different inanimate objects. Adverse environmental conditions included CUMS, sepsis, nicotine exposure, PCP exposure, early stress, WAS, high fructose intake, TBI, and sevoflurane exposure. Regarding microRNA expression, after exposure to EE, an increase in the expression of miR-221 and miR-483 was observed in the prefrontal cortex, and a reduction in the expression of miR-92a-3p and miR-134 in the hippocampus. Regarding histone modifications, in the hippocampus, there was a reduction of HAT, HDAC/HDAC4, H3 (acetyl K14), H4 (acetyl K15), H3K4me3, K3k27me3, and HDAC2/3/5. In the cortex, there was a reduction of HDAC2, and in the prefrontal cortex, there was an increase in acetylated H3. Regarding DNA modifications, there was a reduction of DNMT in the hippocampus. This systematic review concludes that the benefits of EE on the brain and behavior of animals are directly related to different epigenetic mechanisms, reflecting in cell growth and neuroplasticity. EE may be a non-pharmacological and easy-to-apply alternative to prevent symptoms in disorders affecting brain tissue., (© 2024. The Author(s).)

The development of hydroxyapatite (HAp) and polyether ether ketone (PEEK) biocomposites has been extensively studied for bone repair applications due to the synergistic properties of the involved materials. In this study, we aimed to develop HAp/PEEK biocomposites using high-energy ball milling, with HAp concentrations (20%, 40%, and 60% w / v ) in PEEK, to evaluate their physicochemical, mechanical, cytotoxicity, and antimicrobial properties for potential applications in Tissue Engineering (TE). The biocomposites were characterized by structure, morphology, apparent porosity, diametral compression strength, cytotoxicity, and antimicrobial activity. The study results demonstrated that the HAp/PEEK biocomposites were successfully synthesized. The C2 biocomposite, containing 40% HAp, stood out due to the optimal distribution of HAp particles in the PEEK matrix, resulting in higher compression strength (246 MPa) and a homogeneous microstructure. It exhibited antimicrobial activity against Staphylococcus aureus , Pseudomonas aeruginosa , and Escherichia coli , with no cytotoxicity observed. These properties make the C2 biocomposite promising for regenerative medicine applications, combining mechanical strength, bioactivity, and biocompatibility.

Purpose: The early phase of the COVID-19 pandemic affected cancer care globally. Evaluating the impact of the pandemic on the quality of cancer care delivery is crucial for understanding how changes in care delivery may influence outcomes. Our study compared care delivered during the early phase of the pandemic with the same period in the previous year at two institutions across continents (Princess Margaret Cancer Center [PM] in Canada and A.C. Camargo Cancer Center [AC] in Brazil)., Methods: Patients newly diagnosed with colorectal or anal cancer between February and December 2019 and the same period in 2020 were analyzed. Sociodemographic and clinical characteristics and performance of individual indicators within and between centers and between the peri-COVID-19 and control cohorts were tested using Cohen's h test to assess the standardized differences between the two groups., Results: Among 925 patients, distinct effects of the early COVID-19 pandemic on oncology services were observed. AC experienced a 50% reduction in patient consultations (98 v 197) versus a 12.5% reduction at PM (294 v 336). Similarly, AC experienced a higher proportion of stage IV disease presentations (42.9% v 29.9%; P = .015) and an increase in treatment delay (61.9% v 9.7%; P < .001) compared with prepandemic. At PM, a 10% increase in treatment interruption (32.4% v 22.3%; P < .001) and a higher rate of discontinuation of radiotherapy (9.4% v 1.1%; P < .001) were observed during the pandemic. Postsurgical readmission rates increased in both AC (20.9% v 2.6%; P < .001) and PM (10.5% v 3.6%; P < .01)., Conclusion: The early phase of the COVID-19 pandemic affected the quality of care delivery for colorectal and anal cancers at both centers. However, the magnitude of this impact was greater in Brazil.

Bridging Integrator 1 (BIN1) is the second most important Alzheimer's disease (AD) risk gene, but its physiological roles in neurons and its contribution to brain pathology remain largely elusive. In this work, we show that BIN1 plays a critical role in the regulation of calcium homeostasis, electrical activity, and gene expression of glutamatergic neurons. Using single-cell RNA-sequencing on cerebral organoids generated from isogenic BIN1 wild type (WT), heterozygous (HET) and homozygous knockout (KO) human-induced pluripotent stem cells (hiPSCs), we show that BIN1 is mainly expressed by oligodendrocytes and glutamatergic neurons, like in the human brain. Both BIN1 HET and KO cerebral organoids show specific transcriptional alterations, mainly associated with ion transport and synapses in glutamatergic neurons. We then demonstrate that BIN1 cell-autonomously regulates gene expression in glutamatergic neurons by using a novel protocol to generate pure culture of hiPSC-derived induced neurons (hiNs). Using this system, we also show that BIN1 plays a key role in the regulation of neuronal calcium transients and electrical activity via its interaction with the L-type voltage-gated calcium channel Cav 1.2 . BIN1 KO hiNs show reduced activity-dependent internalization and higher Cav 1.2 expression compared to WT hiNs. Pharmacological blocking of this channel with clinically relevant doses of nifedipine, a calcium channel blocker, partly rescues electrical and gene expression alterations in BIN1 KO glutamatergic neurons. Further, we show that transcriptional alterations in BIN1 KO hiNs that affect biological processes related to calcium homeostasis are also present in glutamatergic neurons of the human brain at late stages of AD pathology. Together, these findings suggest that BIN1-dependent alterations in neuronal properties could contribute to AD pathophysiology and that treatment with low doses of clinically approved calcium blockers should be considered as an option to slow disease-onset and progression., (© 2024. The Author(s).)

Despite advances in the study of rheumatoid arthritis-associated interstitial lung disease (RA-ILD), the pulmonary manifestation remains an important cause of morbidity and mortality. However, there is a lack of biochemical markers for this manifestation in the literature. Therefore, the objective of this study was to carry out a qualitative systematic review on biochemical markers associated with RA-ILD in the PubMed, Web of Science, Embase, Cochrane Library, and Virtual Health Library (VHL) between January 2015 and July 2024, using the following descriptors: #1 "biomarkers" (MeSH) AND #2 "rheumatoid arthritis" (MeSH) AND #3 "Lung Diseases, Interstitial" (MeSH). Of the 1497 articles found, 27 presented eligibility criteria. The findings were divided into three sessions: "Main biomarkers for RA-ILD," "Other biomarkers for RA-ILD activity," and "Other biomarkers for RA-ILD prognosis." Among the evaluated markers, KL-6, RF, ACPA, ESR, and CRP appear to have prognostic value and association with damage in patients with RA-ILD. The association of some molecules such as sPD-1, sCD25, VCAM-1, MCP-1, and ADMA with tissue damage is intriguing. Longitudinal and randomized studies are imperative to comprehensively delineate the history of RA-ILD and evaluate potential serum biomarkers., Competing Interests: Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Lira et al.)

This study assessed the impact of phytoremediation on reducing the residual concentration of metolachlor in soil treated with doses of 530.7 and 1061.4 g/ha and its effect on microbial biodiversity in contaminated areas. For the plant species Avena sativa and Medicago sativa , a significant efficacy of 54.5 and 36.4% was observed in the dissipation of the herbicide, especially at higher doses. Although metolachlor application reduced soil microbial biodiversity, phytoremediating plants, especially M. sativa , promoted greater richness and distribution of microbial species, mitigating the negative effects of the herbicide. Principal component analysis revealed the influence of these plants and metolachlor on the composition of the microbial community. These results highlight the importance of phytoremediation in promoting soil biodiversity and reducing herbicide contamination, providing crucial insights for remediation strategies in contaminated areas.

The concept of uncertainty in an isotopic analysis is not uniform in the scientific community worldwide and can compromise the risk of false compliance assessment applied to carbon isotopic analyses in natural gas exploratory evaluation. In this work, we demonstrated a way to calculate one of the main sources of this uncertainty, which is underestimated in most studies focusing on gas analysis: the δ 13 C calculation itself is primarily based on the raw analytical data. The carbon isotopic composition of methane, ethane, propane, and CO 2 was measured. After a detailed mathematical treatment, the corresponding expanded uncertainties for each analyte were calculated. Next, for the systematic isotopic characterization of the two gas standards, we calculated the standard uncertainty, intermediary precision, combined standard uncertainty, and finally, the expanded uncertainty for methane, ethane, propane, and CO 2 . We have found an expanded uncertainty value of 1.8‰ for all compounds, except for propane, where a value of 1.6‰ was obtained. The expanded uncertainty values calculated with the approach shown in this study reveal that the error arising from the application of delta calculation algorithms cannot be neglected, and the obtained values are higher than 0.5‰, usually considered as the accepted uncertainty associated with the GC-IRMS analyses. Finally, based on the use of uncertainty information to evaluate the risk of false compliance, the lower and upper acceptance limits for the carbon isotopic analysis of methane in natural gas are calculated, considering the exploratory limits between -55‰ and -50‰: (i) for the underestimated current uncertainty of 0.5‰, the lower and upper acceptance limits, respectively, are -54.6‰ and -50.4‰; and (ii) for the proposed realistic uncertainty of 1.8‰, the lower and upper acceptance limits would be more restrictive; i.e., -53.5‰ and -51.5‰, respectively.

Ferroptosis is an iron-dependent cell death mechanism characterized by the accumulation of toxic lipid peroxides and cell membrane rupture. GPX4 (glutathione peroxidase 4) prevents ferroptosis by reducing these lipid peroxides into lipid alcohols. Ferroptosis induction by GPX4 inhibition has emerged as a vulnerability of cancer cells, highlighting the need to identify ferroptosis regulators that may be exploited therapeutically. Through genome-wide CRISPR activation screens, we identify the SWI/SNF (switch/sucrose non-fermentable) ATPases BRM (SMARCA2) and BRG1 (SMARCA4) as ferroptosis suppressors. Mechanistically, they bind to and increase chromatin accessibility at NRF2 target loci, thus boosting NRF2 transcriptional output to counter lipid peroxidation and confer resistance to GPX4 inhibition. We further demonstrate that the BRM/BRG1 ferroptosis connection can be leveraged to enhance the paralog dependency of BRG1 mutant cancer cells on BRM. Our data reveal ferroptosis induction as a potential avenue for broadening the efficacy of BRM degraders/inhibitors and define a specific genetic context for exploiting GPX4 dependency., Competing Interests: Declaration of interests All of the authors of the paper were employees of Genentech/Roche during the execution of this work., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Testosterone (T), estrogen receptor alpha (ERα), and androgen receptor (AR) play a significant role in the regulation of paternal behavior. We determined the effects of deprivation of paternal care on alterations in paternal behavior, T concentrations in plasma, and the presence of ERα and AR in the medial preoptic area (mPOA), bed nucleus of the stria terminalis (BNST), medial amygdala (MeA), and olfactory bulb (OB), as well as the corticosterone (CORT) concentrations in plasma caused by deprivation of paternal care in the Mongolian gerbil (Meriones unguiculatus). Twenty pairs of gerbils were formed; the pups were deprived of paternal care (DPC) in 10 pairs. In another 10 pairs, the pups received paternal care (PC). Ten males raised in DPC condition and 10 males raised in PC conditions were mated with virgin females. When they became fathers, each DPC male and PC male was subjected to tests of paternal behavior on day three postpartum. Blood samples were obtained to quantify T and CORT concentrations, and the brains were removed for ERα and AR immunohistochemistry analyses. DPC males gave less care to their pups than PC males, and they had significantly lower T concentrations and levels of ERα and AR in the mPOA and BNST than PC males. DPC males also had higher CORT concentrations than PC males. These results suggest that in the Mongolian gerbil father's absence causes a decrease in paternal care in the offspring, which is associated with alterations in the neuroendocrine mechanisms that regulate it., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease associated with obesity and diabetes prevalence. The use of natural compounds has become an attractive approach to prevent NAFLD and its progression. Gamma-oryzanol (Orz) is a natural compound whose beneficial effects on chronic metabolic diseases have been reported. Therefore, we aimed to investigate the preventive effect of Orz on the hepatic proteome in a diet induced NAFLD model. Wistar rats were randomly distributed into three experimental groups (n=6/group) according to the diet received for 30 weeks: Control group, high sugar-fat (HSF) group, and HSF+Orz group. The isolated Orz was added to the chow at the dose of 0.5% (w/w). We evaluated the nutritional profile, characterized the presence of steatosis through histological analysis, triglyceride content in liver tissue and hepatic inflammation. Next, we performed label-free quantitative proteomics of hepatic tissue. Network analysis was performed to describe involved protein pathways. NAFLD induction was characterized by the presence of hepatic steatosis. Orz prevented lipid accumulation. The compound prevented alterations of the hepatic proteome, highlighted by the modulation of lipid metabolism, inflammation, oxidative stress, xenobiotic metabolism, and the sirtuin signaling pathway. It was possible to identify key altered pathways of NAFLD pathophysiology modulated by Orz which may provide insights into NAFLD treatment targets., Competing Interests: Declaration of Competing Interest The authors declare no conflicts., (Copyright © 2024 Elsevier Inc. All rights reserved.)

This paper explores the theoretical economic outcome of management changes that result in different levels of antimicrobial use (AMU) in two types of UK pig farm. A static farm economic pig production model (FEPM) was used on a representative 'Top-third' most profitable farm and a representative 'Mid-range' profitable farm. Three AMU theoretical management scenarios were investigated; (a) management changes leading to a reduction of AMU by 35% (AMU35); (b) more extensive management changes leading to a reduction of AMU by 95% (AMU95); and (c) implementing depopulation of the herd (AMU Depop). A sensitivity analysis was conducted to determine the effect of increases or decreases in pig revenue and feed price on farm gross margin under these scenarios. Over a single year, the AMU35 scenario was estimated to have a small positive impact (+3%) on both farm types. The other two AMU reduction scenarios had higher AMU reduction on farms but required higher variable cost and hence they resulted in lower farm profitability. There was a substantial reduction (up to -50%) in farm gross margin under these two AMU reduction scenarios in the modeled short-term time-period. The impact of the alternative AMU scenarios was slightly higher on a farm representing the 'Top-third' farm type, reducing farm gross margin further by 7% compared to the 'Mid-range' farm. Nevertheless, both farm types stay profitable under all three AMU scenarios. The results showed that in the modeled short-term implementing management changes that result in a reduction of on-farm AMU by 35% had a good economic outcome. In practice, the other two scenarios would be considered as longer-term strategies. Although both require higher initial costs to implement, the improved biosecurity and hygiene will benefit from lower disease occurrence for a longer term. Farm gross margins were, however, found to be highly sensitive to changes on market prices especially increasing feed prices. An increase of more than 15% in feed price moved a profitable farm into a loss-making farm. It will be economically challenging for uptakes of these, or similar, AMU reduction scenarios on farms if the market prices become un-favorable to pig farmers., Competing Interests: AM was employed by the Wholesome Pigs (Scotland) Ltd. The remaining 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 Shrestha, da Costa, Correia-Gomes, Nevel, McGowan and Tongue.)

Neuroinflammation is a key feature of Alzheimer's disease (AD). In this work, analysis of single- cell RNA-sequencing (scRNA-seq) data obtained from the brain of patients with AD provides evidence supporting a switch from an innate to an adaptative immune response during tauopathy progression, with both disease-associated microglia (DAM) and CD8+ T cells becoming more frequent at advanced Braak stages., (© 2024. The Author(s).)

Purpose: To compare the injection of small amounts of undiluted C3F8 with the traditional gas injection in vitrectomy for macular hole treatment., Methods: This clinical trial included 26 individuals divided into two groups. Group 1 received an intravitreal injection of 0.9-1.0 mL of 100% C3F8, and Group 2 received 15-20 mL of 20% C3F8., Results: The median intraocular gas duration was 31 days in Group 1 and 34 in Group 2. The median letter gains in corrected distance visual acuity for the 26th postoperative week were 20 letters in Group 1 and 12.5 in Group 2. The median intraocular pressure was normal in both groups. Primary anatomical success was 11/13 in both groups., Conclusions: The use of C3F8 gas in a small undiluted volume is an alternative that slightly reduces the duration of the gas without negatively affecting the anatomical and visual response.

Objectives: The aim of this study is to conduct a cost-utility analysis of the use of the antiviral nirmatrelvir/ritonavir, applied to a vaccinated Brazilian population against COVID-19, from the perspective of the Brazilian Public Health System (SUS)., Methods: A microsimulation model was created with individual-level data and daily cycles, with a 1-year time horizon, to compare the current scenario of standard care with a scenario in which nirmatrelvir/ritonavir is offered to the population. Adults of any age group that received ≥2 doses of the COVID-19 vaccine formed the investigated population. Direct medical costs of the outpatients and inpatients admitted to the ward or intensive care unit were included. The effectiveness of the model was measured in quality-adjusted life-years (QALYs)., Results: In all simulations, the use of nirmatrelvir/ritonavir resulted in incremental costs per patient of US dollar (USD)245.86 and incremental effectiveness of 0.009 QALY, over a year. The incremental cost-utility ratio was USD27 220.70/QALY. The relative risk of the vaccinated population was the factor that affected the outcome most, according to the univariate sensitivity analysis. The probabilistic sensitivity analysis resulted in 100% of the simulations being more costly and effective, but that only 4% of them were below the established cost-effectiveness threshold of USD24 000.00/QALY. In the scenario considering only the population over 60 years old and immunosuppressed (of any age), the incremental cost-utility ratio was USD7589.37/QALY., Conclusions: The use of nirmatrelvir/ritonavir in the treatment of COVID-19 in a vaccinated population was cost-effective only for immunosuppressed individuals and people over 60 years of age., Competing Interests: Author Disclosures Links to the individual disclosure forms provided by the authors are available here., (Copyright © 2023 International Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

Consumption of diets high in sugar and fat is related to the development of Metabolic dysfunction-associated steatotic liver disease (MASLD). Carnosine (CAR) is a dipeptide with antioxidant and anti-inflammatory action and has been studied for treating diseases. This work aimed to evaluate the effects of CAR on diet-induced MASLD in rats. Male Wistar rats were distributed into 2 groups (17 weeks): normocaloric (Co, n = 12), and hypercaloric diet rich in lipids and simple carbohydrates (MASLD, n = 12). After, the animals were redistributed to begin the treatment with CAR (4 weeks): Co (n = 6), Co + CAR (n = 6), MASLD (n = 6), and MASLD + CAR (n = 6), administered intraperitoneally (250 mg/kg). Evaluations included nutritional, hormonal and metabolic parameters; hepatic steatosis, inflammatory and oxidative markers. MASLD group had a higher adiposity index, systolic blood pressure, glucose, plasma and liver triglycerides and cholesterol, insulin, hepatic steatosis, oxidative markers, and lower PPAR-α (Peroxisome Proliferator-activated receptor α), compared to the Co. CAR attenuated plasma and hepatic triglyceride and cholesterol levels, hepatic steatosis, CD68 + macrophages, and hepatic oxidative markers, in addition to increasing HDL cholesterol levels and PPAR-α, compared to the untreated MASLD group. CAR acts in importants pathophysiological processes of MASLD and may be a therapeutic compound to control the disease., 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 © 2023 Elsevier B.V. All rights reserved.)

Background: Multidimensional health-related quality of life (HRQOL) instruments, such as the EQ-5D, are increasingly used to assess inequalities in health. However, it is necessary to explore the ability of these instruments to capture differences between population groups, especially in low/middle-income countries. This study aimed to investigate whether the EQ-5D-3L instrument can detect differences in HRQOL between groups of different socioeconomic status (SES) in Brazil., Methods: Data collection occurred during the Brazilian EQ-5D-3L valuation study and included respondents aged 18 to 64 years enrolled in urban areas. SES was aggregated into three categories: "higher" (A and B), "intermediate" (C) and "lower" (D and E). EQ-5D-3L index was calculated considering the Brazilian value set. A mixed-effects regression model was estimated with random effects on individuals and marginal effects on SES, sex, and educational attainment. Odds ratios for the chance of reporting problems for each EQ-5D dimension were estimated by logistic regression., Results: A total of 9,148 respondents were included in the study. Mean age was 37.80 ± 13.13 years, 47.4% were men and the majority was ranked as classes B or C (38.4% and 50.7%, respectively). Participants in lower SES classes reported increasingly poorer health compared to individuals in higher classes. The mean EQ-5D-3L index decreased as SES deteriorates being significantly higher for classes A and B (0.874 ± 0.14) compared to class C (0.842 ± 0.15) and classes D and E (0.804 ± 0.17) (p < 0.001). The same was observed for the mean EQ-VAS scores (84.0 ± 13.8 in classes A and B, 81.0 ± 17 in class C and 78.3 ± 18.7 in class C [p < 0.001]). The multivariate analysis confirmed that SES is an independent factor that effects EQ-5D-3L index measures. Participants in intermediate and lower SES classes have a statistically significant lower EQ-5D-3L index compared to participants in classes A and B, regardless of age, sex, and educational attainment., Conclusion: In a Brazilian population sample, the EQ-5D-3L instrument was able to detect important differences between groups with distinct socioeconomic statuses (SES). The EQ-5D-3L is useful for exploring inequities in health., (© 2024. The Author(s).)

The nonalcoholic fatty liver disease (NAFLD), which is closely related to westernized dietary (WD) patterns, displays a rising epidemiological and economic burden. Since there is no pharmacological therapy approved for this disease, mechanistic studies are warranted. In this work, we investigated the action of carnosine (CAR), a natural dipeptide with several protection roles against oxidative stress in the liver of NAFLD rats. NAFLD was induced by WD-rich sugars and fat, verifying the histological evidence of steatosis. As intraperitoneal administration of CAR reversed liver steatosis, the protein profiles of NAFLD liver and CAR NAFLD liver were evaluated by label-free proteomics approach. A total of 2531 proteins were identified and the 230 and 276 were significantly up- and downregulated, respectively, by CAR treatment of NAFLD rats and involved in fundamental pathways such as oxidative stress and lipid metabolism. Perilipin 2 and apolipoprotein E, components of the plasma membrane of vesicle, resulted in highly downregulated in the CAR-treated NAFLD liver. The advanced bioanalytical approach demonstrated the efficacy of CAR in overcoming the main symptoms of NAFLD, ameliorating the steatosis in the liver., (© 2024 Wiley Periodicals LLC.)

Background: Previous work from our group has shown that chronic exposure to Vanadium pentoxide (V2O5) causes cytoskeletal alterations suggesting that V2O5 can interact with cytoskeletal proteins through polymerization and tyrosine phosphatases inhibition, causing Alzheimer's disease (AD)-like hippocampal cell death., Objective: This work aims to characterize an innovative AD experimental model through chronic V2O5 inhalation, analyzing the spatial memory alterations and the presence of neurofibrillary tangles (NFTs), amyloid-β (Aβ) senile plaques, cerebral amyloid angiopathy, and dendritic spine loss in AD-related brain structures., Methods: 20 male Wistar rats were divided into control (deionized water) and experimental (0.02 M V2O5 1 h, 3/week for 6 months) groups (n = 10). The T-maze test was used to assess spatial memory once a month. After 6 months, histological alterations of the frontal and entorhinal cortices, CA1, subiculum, and amygdala were analyzed by performing Congo red, Bielschowsky, and Golgi impregnation., Results: Cognitive results in the T-maze showed memory impairment from the third month of V2O5 inhalation. We also noted NFTs, Aβ plaque accumulation in the vascular endothelium and pyramidal neurons, dendritic spine, and neuronal loss in all the analyzed structures, CA1 being the most affected., Conclusions: This model characterizes neurodegenerative changes specific to AD. Our model is compatible with Braak AD stage IV, which represents a moment where it is feasible to propose therapies that have a positive impact on stopping neuronal damage.

Currently, immunotherapy based on PD-1/PD-L1 pathway blockade has improved survival of non-small cell lung cancer (NSCLC) patients. However, differential responses have been observed by sex, where men appear to respond better than women. Additionally, adverse effects of immunotherapy are mainly observed in women. Studies in some types of hormone-dependent cancer have revealed a role of sex hormones in anti-tumor response, tumor microenvironment and immune evasion. Estrogens mainly promote immune tolerance regulating T-cell function and modifying tumor microenvironment, while androgens attenuate anti-tumor immune responses. The precise mechanism by which sex and sex hormones may modulate immune response to tumor, modify PD-L1 expression in cancer cells and promote immune escape in NSCLC is still unclear, but current data show how sexual differences affect immune therapy response and prognosis. This review provides update information regarding anti-PD-1/PD-L immunotherapeutic efficacy in NSCLC by sex, analyzing potential roles for sex hormones on PD-L1 expression, and discussing a plausible of sex and sex hormones as predictive response factors to immunotherapy., 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 © 2023 Rodriguez-Lara, Giovanny, Avila-Costa, Whaley, Rodriguez-Cid, Ordoñez-Librado, Rodriguez-Maldonado and Heredia-Jara.)

Alzheimer's disease (AD) is the most prevalent cause of dementia in the elderly, characterized by the presence of amyloid-beta (Aβ) plaques, neurofibrillary tangles, neuroinflammation, synapse loss and neurodegeneration in the brain. The amyloid cascade hypothesis postulates that deposition of Aβ peptides is the causative agent of AD pathology, but we still lack comprehensive understanding of the molecular mechanisms connecting Aβ peptides to neuronal dysfunctions in AD. In this work, we investigate the early effects of Aβ peptide accumulation on the functional properties and gene expression profiles of human-induced neurons (hiNs). We show that hiNs acutely exposed to low concentrations of both cell-secreted Aβ peptides or synthetic Aβ 1-42 exhibit alterations in the frequency of calcium transients suggestive of increased neuronal excitability. Using single-cell RNA sequencing, we also show that cell-secreted Aβ up-regulates the expression of several synapse-related genes and down-regulates the expression of genes associated with metabolic stress mainly in glutamatergic neurons and, to a lesser degree, in GABAergic neurons and astrocytes. These neuronal alterations correlate with activation of the SEMA5, EPHA and NECTIN signaling pathways, which are important regulators of synaptic plasticity. Altogether, our findings indicate that slight elevations in Aβ concentrations are sufficient to elicit transcriptional changes in human neurons, which can contribute to early alterations in neural network activity.

Implementation of evidence-based practice (EBP) is essential for ensuring high-quality nursing care. In Portugal, nurses are responsible for care delivery to patients who require peripheral intravenous access. However, recent authors emphasized the predominance of a culture based on outdated professional vascular access practices in Portuguese clinical settings. Thus, the aim of this study was to map the studies conducted in Portugal on peripheral intravenous catheterization. A scoping review was conducted based on the Joanna Briggs Institute recommendations, with a strategy adapted to different scientific databases/registers. Independent reviewers selected, extracted, and synthesized the data. Of the 2128 studies found, 26 were included in this review, published between 2010 and 2022. Previous research shows that Portuguese nurses' implementation of EBP was found to be relatively low overall, while most studies did not attempt to embed EBP change into routine care. Although nurses are responsible for implementing EBP at an individual patient level, the studies conducted in Portugal report nonstandardized practices among professionals, with significant deviations from recent evidence. This reality, combined with Portugal's absence of government-endorsed evidence-based standards for peripheral intravenous catheter (PIVC) insertion and treatment and vascular access teams, may explain the country's unacceptably high incidence of PIVC-related complications reported over the last decade., (Copyright © 2023 Infusion Nurses Society.)

Sonic Hedgehog (Shh) signaling plays a critical role during central nervous system (CNS) development, and its dysregulation leads to neurological disorders. Nevertheless, little is known about Shh signaling regulation in the adult brain. Here, we investigated the contribution of DNA methylation on the transcriptional control of Shh signaling pathway members and its basal distribution impact on the brain, as well as its modulation by inflammation. The methylation status of the promoter regions of these members and the transcriptional profile of DNA-modifying enzymes (DNA Methyltransferases - DNMTs and Tet Methylcytosine Dioxygenase - TETs) were investigated in a murine model of neuroinflammation by qPCR. We showed that, in the adult brain, methylation in the CpG promoter regions of the Shh signaling pathway members was critical to determine the endogenous differential transcriptional pattern observed between distinct brain regions. We also found that neuroinflammation differentially modulates gene expression of DNA-modifying enzymes. This study reveals the basal transcriptional profile of DNMTs and TETs enzymes in the CNS and demonstrates the effect of neuroinflammation on the transcriptional control of members of the Shh Signaling pathway in the adult brain., 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 © 2022 Elsevier B.V. All rights reserved.)