With age comes resilience: how mitochondrial modulation drives age-associated fluconazole tolerance in Cryptococcus neoformans.

Cryptococcus neoformans (Cn) is an opportunistic fungal microorganism that causes life-threatening meningoencephalitis. During the infection, the microbial population is heterogeneously composed of cells with varying generational ages, with older cells accumulating during chronic infections. This is attributed to their enhanced resistance to phagocytic killing and tolerance of antifungals like fluconazole (FLC). In this study, we investigated the role of ergosterol synthesis, ATP-binding cassette (ABC) transporters, and mitochondrial metabolism in the regulation of age-dependent FLC tolerance. We find that old Cn cells increase the production of ergosterol and exhibit upregulation of ABC transporters. Old cells also show transcriptional and phenotypic characteristics consistent with increased metabolic activity, leading to increased ATP production. This is accompanied by increased production of reactive oxygen species, which results in mitochondrial fragmentation. This study demonstrates that the metabolic changes occurring in the mitochondria of old cells drive the increase in ergosterol synthesis and the upregulation of ABC transporters, leading to FLC tolerance. IMPORTANCE: Infections caused by Cryptococcus neoformans cause more than 180,000 deaths annually. Estimated 1-year mortality for patients receiving care ranges from 20% in developed countries to 70% in developing countries, suggesting that current treatments are inadequate. Some fungal cells can persist and replicate despite the usage of current antifungal regimens, leading to death or treatment failure. Aging in fungi is associated with enhanced tolerance against antifungals and resistance to killing by host cells. This study shows that age-dependent increase in mitochondrial reactive oxygen species drive changes in the regulation of membrane transporters and ergosterol synthesis, ultimately leading to the heightened tolerance against fluconazole in old C. neoformans cells. Understanding the underlying molecular mechanisms of this age-associated antifungal tolerance will enable more targeted antifungal therapies for cryptococcal infections.

Exploring the biological activities and potential therapeutic applications of agro-industrial waste products through non-clinical studies: A systematic review.

The latent potential of active ingredients derived from agro-industrial waste remains largely untapped and offers a wealth of unexplored resources. While these types of materials have applications in various fields, their ability to benefit human health needs to be further explored and investigated. This systematic review was conducted to systematically evaluate non-clinical studies that have investigated the biological effects of fractions, extracts and bioactive compounds from agro-industrial wastes and their potential therapeutic applications. Articles were selected via PubMed, Embase and Medline using the descriptors (by-products[title/abstract]) AND (agro-industrial[title/abstract]). The systematic review was registered in the International Prospective Register of Systematic Reviews (Prospero) under the number CRD42024491021. After a detailed analysis based on inclusion and exclusion criteria, a total of 38 articles were used for data extraction and discussion of the results. Information was found from in vitro and in vivo experiments investigating a variety of residues from the agro-industry. The studies investigated peels, pomace/bagasse, pulp, seeds, aerial parts, cereals/grains and other types of waste. The most studied activities include mainly antioxidant and anti-inflammatory effects, but other activities such as antimicrobial, cytotoxic, antiproliferative, antinociceptive, hypoglycemic, antihyperglycemic and anticoagulant effects have also been described. Finally, the studies included in this review demonstrate the potential of agro-industrial waste and can drive future research with a focus on clinical application.

Nonsurgical Endodontic Treatment of Type II Dens Invaginatus in A Maxillary Lateral Incisor: A Case Report.

Dens invaginatus (DI) is one of the developmental dental anomalies that results in an invagination of the enamel organ into the dental papila during odontogenesis. The purpose of this study is to report a case of nonsurgical endodontic treatment of an Oehlers type II DI in a right maxillary lateral incisor with an extensive periapical damage, along with the two-year clinical and tomographic follow-up. A 30-year-old patient was referred for endodontic treatment of tooth #12. On clinical examination, a change in the shape and color of the crown was observed. The tooth responded negative to pulp sensibility, percussion, palpation and mobility tests. After tomographic evaluation, an Oehlers type II DI was visualized, in addition to an extensive periradicular lesion. The diagnosis was asymptomatic apical periodontitis. The treatment was carried out in two sessions, through intense enhancement of the auxiliary chemical substance with passive ultrasonic irrigation, XP-Endo Finisher and the use of hydroxide-based intracanal medication. Appropriate treatment in cases with anatomic variations requires an accurate and early diagnosis based on clinical examination and radiographic images. A two-year follow-up of the present case showed that the correct diagnosis associated with appropriate instrumentation techniques, supplementary disinfection, and adequate three-dimensional sealing of the canal with filling material, resulted in regression of the periradicular lesion and bone repair.

Distinct effect of calorie restriction between congenic mating types of Cryptococcus neoformans.

Cryptococcus neoformans (Cn) is an opportunistic yeast that causes meningoencephalitis in immunocompromised individuals. Calorie restriction (CR) prolongs Cn replicative lifespan (RLS) and mimics low-glucose environments in which Cn resides during infection. The effects of CR-mediated stress can differ among strains and have only been studied in MATα cells. Cn replicates sexually, generating two mating types, MATα and MATa. MATα strains are more dominant in clinical and environmental isolates. We sought to compare the effects of CR stress and longevity regulation between congenic MATα and MATa. Although MATα and MATa cells extended their RLS in response to CR, they engaged different pathways. The sirtuins were upregulated in MATα cells under CR, but not in MATa cells. RLS extension was SIR2-dependent in KN99α, but not in KN99a. The TOR nutrient-sensing pathway was downregulated in MATa strains under CR, while MATα strains demonstrated no difference. Lower oxidative stress and higher ATP production were observed in KN99α cells, possibly due to higher SOD expression. SIR2 was important for mitochondrial morphology and function in both mating types. Increased ATP production during CR powered the upregulated ABC transporters, increasing efflux in MATα cells. This led to enhanced fluconazole tolerance, while MATa cells remained sensitive to fluconazole. Our investigation highlights differences in the response of the mating types to CR.

Oral Treatment with the Pectin Fibre Obtained from Yellow Passion Fruit Peels Worsens Sepsis Outcome in Mice by Affecting the Intestinal Barrier.

The biological activities of plant-derived soluble dietary fibres (SDFs) have been widely investigated. Pectin from yellow passion fruit (YPF-peSDF) peels was suggested as a protective macromolecule in ulcers and colitis due to its antioxidant and anti-inflammatory properties. Sepsis has high mortality and morbidity and is characterised by inflammatory and oxidative stress imbalances. Evidence suggests that pectins may aid sepsis treatment; however, the effects of YPF-peSDF on sepsis remain unclear. Herein, polymicrobial sepsis was induced by cecal-ligation and puncture in mice treated with YPF-peSDF (1 and 10 mg/kg; gavage). YPF-peSDF accelerated mortality, reaching 100% in 24 h. Inflammation was present in the colons and small intestines (SI) of both vehicle- and fibre-treated mice. Although crypt depth and width, and villus height were preserved in the SI of septic mice administered YPF-peSDF, they exhibited exacerbated muscle layer atrophy and mucosa and submucosa hypertrophy, along with shortened enterocytes. Larger crypts and shorter enterocytes were noted in their colons in comparison with vehicle-controls. YPF-peSDF also reduced inflammatory cell numbers and exacerbated IL-6 levels in peritoneal lavage fluid (PELF) samples. YPF-peSDF modulated SI but not colon cytokines. Lipoperoxidation and antioxidant capacity levels were attenuated in PELF samples. Overall, in contrast to previous evidence, YPF-peSDF worsened polymicrobial sepsis outcomes in mice.

Association of body image perception and (dis)satisfaction with adiposity in adults: The Pró-Saúde study.

INTRODUCTION: Body image distortion and/or dissatisfaction may occur primarily due to body fat accumulation and/or distribution. The aim of this study was to evaluate the frequency of body image perception and (dis)satisfaction categories in adult men and women according to the adiposity classification. METHODS: This is a cross-sectional study (n = 514; 33-79 years; 265 women) that is part of a prospective cohort (Pró-Saúde study). Adiposity measurements were determined by two methods: anthropometry, used to calculate the body mass index (BMI) and dual-energy X-ray absorptiometry (DXA), to estimate body fat percentage. Participants were grouped as "no excess adiposity" and "excess adiposity", considering BMI and body fat percentage (>30% for men, >40% for women). Perception and (dis)satisfaction with body image were evaluated using the Kakeshita scale, composed by 15 silhouettes, developed for the Brazilian population. Degree of distortion (perceived BMI - real BMI) and dissatisfaction (perceived BMI - desired BMI) were calculated. RESULTS: A high proportion of men (58.6%; 74.3%), and especially of women (82.6%; 86.8%), presented body size overestimation and dissatisfaction due to excess weight, respectively. A relevant fraction of the women (32.6%) and men (30.8%) who were dissatisfied due to excess weight did not present excess adiposity, especially if classified by DXA. Variability in degree of distortion was hardly explained by anthropometric and DXA variables in women (<5%) and men (∼22%). Both anthropometric and DXA measurements accounted for ∼30% and ∼50% of the variability in degree of dissatisfaction among women and men, respectively. CONCLUSION: Our results suggest a high frequency of body image distortion in Brazilian adult individuals, as well as dissatisfaction with excess weight, especially among women with excess adiposity. The findings indicate that anthropometric measurements explain much of the variability in degree of body image dissatisfaction in men, with no apparent advantage of the use of more refined DXA measurements.

Measuring Replicative Lifespan in Cryptococcus neoformans.

Advances in understanding cellular aging research have been possible due to the analysis of the replicative lifespan of yeast cells. Studying longevity in the pathogenic yeast Cryptococcus neoformans is essential because old yeast cells with age-related phenotypes accumulate during infection and are associated with increased virulence and antifungal tolerance. Microdissection and microfluidic devices are valuable tools for continuously tracking cells at the single-cell level. In this chapter, we describe the features of these two platforms and outline technical limitations and information to study aging mechanisms while assessing the lifespan of yeast cells.

Pemigatinib in previously treated solid tumors with activating FGFR1-FGFR3 alterations: phase 2 FIGHT-207 basket trial.

Fibroblast growth factor receptor (FGFR) alterations drive oncogenesis in multiple tumor types. Here we studied pemigatinib, a selective, potent, oral FGFR1-FGFR3 inhibitor, in the phase 2 FIGHT-207 basket study of FGFR-altered advanced solid tumors. Primary end points were objective response rate (ORR) in cohorts A (fusions/rearrangements, n = 49) and B (activating non-kinase domain mutations, n = 32). Secondary end points were progression-free survival, duration of response and overall survival in cohorts A and B, and safety. Exploratory end points included ORR of cohort C (kinase domain mutations, potentially pathogenic variants of unknown significance, n = 26) and analysis of co-alterations associated with resistance and response. ORRs for cohorts A, B and C were 26.5% (13/49), 9.4% (3/32) and 3.8% (1/26), respectively. Tumors with no approved FGFR inhibitors or those with alterations not previously confirmed to be sensitive to FGFR inhibition had objective responses. In cohorts A and B, the median progression-free survival was 4.5 and 3.7 months, median duration of response was 7.8 and 6.9 months and median overall survival was 17.5 and 11.4 months, respectively. Safety was consistent with previous reports. The most common any-grade treatment-emergent adverse events were hyperphosphatemia (84%) and stomatitis (53%). TP53 co-mutations were associated with lack of response and BAP1 alterations with higher response rates. FGFR1-FGFR3 gatekeeper and molecular brake mutations led to acquired resistance. New therapeutic areas for FGFR inhibition and drug failure mechanisms were identified across tumor types. ClinicalTrials.gov identifier: NCT03822117 .

Interphase nuclei, karyotypes and nuclear DNA amounts in five species of Oenocarpus (Arecaceae).

The genus Oenocarpus Martius, 1823 (Arecaceae) includes five species commonly used in Amazonia, especially for their fruits. Little is known about the cytogenetic characteristics and DNA amounts of these species, except for O.bataua (Martius, 1823). This study characterized and compared the types of interphase nuclei, the chromosome sets, and estimated the nuclear DNA amounts of Oenocarpusbacaba (Martius, 1823), O.bataua, O.distichus (Martius, 1823), O.mapora (H. Karsten, 1857) and O.minor (Martius, 1823). Standard cytogenetic analyses and estimates of the nuclear DNA amount by flow cytometry were carried out. These are the first reports of chromosome numbers and DNA amounts, except for O.bataua, as is the description of the chromatin distribution in interphase nuclei and karyotype for all species. All species presented 2n = 36, confirming the previous report for O.bataua. Differences between karyotype formulas and the positioning of secondary constrictions were observed. There were no significant differences for the nuclear DNA amounts among species. The constancy in chromosome number and variations in karyotype formulas suggest the occurrence of chromosome rearrangement as an important mechanism in Oenocarpus speciation.

Achieving Resilience in Aging: How Mitochondrial Modulation Drives Age-associated Fluconazole Tolerance in Cryptococcus neoformans.

Cryptococcus neoformans ( Cn ) is an opportunistic fungal microorganism that causes life-threatening meningoencephalitis. During the infection, the microbial population is heterogeneously composed of cells with varying generational ages, with older cells accumulating during chronic infections. This is attributed to their enhanced resistance to phagocytic killing and tolerance of antifungals like fluconazole (FLC). In this study, we investigated the role of ergosterol synthesis, ATP-binding cassette (ABC) transporters, and mitochondrial metabolism in the regulation of age-dependent FLC tolerance. We find that old Cn cells increase the production of ergosterol and exhibit upregulation of ABC transporters. Old cells also show transcriptional and phenotypic characteristics consistent with increased metabolic activity, leading to increased ATP production. This is accompanied by increased production of reactive oxygen species (ROS), which results in mitochondrial fragmentation. This study demonstrates that the metabolic changes occurring in the mitochondria of old cells drive the increase in ergosterol synthesis and the upregulation of ABC transporters, leading to FLC tolerance. IMPORTANCE: Infections caused by Cryptococcus neoformans cause more than 180,000 deaths annually. Estimated one-year mortality for patients receiving care ranges from 20% in developed countries to 70% in developing countries, suggesting that current treatments are inadequate. Some fungal cells can persist and replicate despite the usage of current antifungal regimens, leading to death or treatment failure. In replicative aging, older cells display a resilient phenotype, characterized by their enhanced tolerance against antifungals and resistance to killing by host cells. This study shows that age-dependent increase in mitochondrial reactive oxygen species drive changes in ABC transporters and ergosterol synthesis, ultimately leading to the heightened tolerance against fluconazole in old C. neoformans cells. Understanding the underlying molecular mechanisms of this age-associated antifungal tolerance will enable more targeted antifungal therapies for cryptococcal infections.

Evolution of household availability of added sugars and their sources in Brazil: analysis of Household Budget Surveys from 2002 to 2017.

The objective of this study was to describe the evolution of household purchase of added sugars and their main food sources in Brazil. Nationally representative data from the Household Budget Surveys from 2002-2003, 2008-2009 and 2017-2018 were used. Energy and added sugar quantities were estimated by means of per capita food quantities. The items considered as food sources were: (1) table sugar: refined sugar and other energetic sweeteners and (2) processed and ultra-processed foods with added sugar: soft drinks; other drinks; sweets, candies and chocolates; cookies; cakes and pies and other foods. The parameters estimated were: mean share of added sugar in total energy and, for food sources, the share of added sugar in total sugar intake and the impact of variations in sources of added sugar between 2008 and 2017. There was a regular share of energy from added sugar to total energy intake between 2002 and 2008 but a reduced share in 2017. Between 2008 and 2017, there was a decrease in the share of refined sugar and other sweeteners and soft drinks to total sugar intake and an increased share of all other items. High-income households had a lower share of refined sugar and other energetic sweeteners, but a higher share of soft drinks, sweets, candies and chocolates. The decrease in added sugar in 2017 was mainly due to the lower share of soft drinks. In conclusion, Brazilians' total intake of added sugar was decreased, mostly owing to reduced consumption of sugar from soft drinks.

Urinary symptoms and sexual function after hysterectomy secondary to cervical cancer: A prospective, cohort study.

INTRODUCTION AND HYPOTHESIS: The estimated worldwide incidence of cervical cancer (CC) is half a million cases per year. Surgical treatment is the mainstay approach for this condition. OBJECTIVES: To assess the effects of hysterectomy due to cervical cancer in urinary symptoms and sexual function and the disorder related impact on the quality of patients life. STUDY DESIGN: A cohort study was performed in Fortaleza/CE (Brazil) with 71 patients; of these, 31 were diagnosed with cervical cancer (G-CCU) and 40 with gynecological benign disease (G-PB). Sexual function (FSFI questionnaire), quality of life (SF-36 questionnaire) and urinary symptoms (KHQ instrument) were investigated in both groups at baseline (T0), one month (T1) and four months after surgery (T2). RESULTS: Both groups presented at baseline, similar urinary symptoms (p > 0.05), but this frequency doubled for the G-CCU group at T1 and remained unchanged at T2 (p = 0.012). G-PB's frequency of symptoms remained the same for 4 months after surgery. At baseline G-PB had higher risk for sexual dysfunction than G-CCU (82.5 % versus 54.8 %, p = 0.011). However for G-CCU, an increase of this percentage was perceived at T2.Women from the G-CCU group presented worse general and specific quality of life results. CONCLUSION: Women underwent to hysterectomy due to cervical cancer presented higher percentages of urinary symptoms, higher risk for sexual dysfunction and worse general and specific quality of life scores.

Potential Therapeutic Properties of Olea europaea Leaves from Selected Cultivars Based on Their Mineral and Organic Profiles.

Olive leaves are consumed as an extract or as a whole herbal powder with several potential therapeutic benefits attributed to polyphenols, tocopherol's isomers, and flavonoids, among others. This study assessed the potential variance in the functional features presented by olive leaves from three different Portuguese cultivars-Cobrançosa, Madural, and Verdeal-randomly mix-cultivated in the geographical area of Vale de Salgueiros. Inorganic analysis determined their mineral profiles while an organic analysis measured their total phenolic and flavonoid content, and scanned their phenolic and tocopherol and fatty acid composition. The extracts' biological activity was tested by determining their antimicrobial and antioxidant power as well as their ability to inhibit acetylcholinesterase, butyrylcholinesterase, MAO-A/B, and angiotensin-I-converting enzyme. The inorganic profiles showed them to be an inexpensive source able to address different mineral deficiencies. All cultivars appear to have potential for use as possible antioxidants and future alternative antibiotics against some multidrug-resistant microorganisms, with caution regarding the arsenic content in the Verdeal cultivar. Madural's extract displayed properties to be considered a natural multitarget treatment for Alzheimer's and Parkinson's diseases, depression, and cardiometabolic and dual activity for blood pressure modulation. This work indicates that randomly cultivating different cultivars significantly modifies the leaves' composition while keeping their multifaceted therapeutic value.

Serum Zinc Concentrations by Inflammation Status, Time of Day, and Fasting Status for Estimating Zinc Deficiency in 6-59-Mo-Old Children: Results from the Brazilian National Survey on Child Nutrition (ENANI-2019).

BACKGROUND: Serum zinc concentration (SZC) is considered the best biomarker of zinc status in population-level evaluations. However, zinc deficiency (ZD) estimations can be biased if they do not consider blood collection timing, inflammation, and fasting status. OBJECTIVES: The objectives of this study were to determine SZC without and with adjustment for inflammation, according to blood collection timing and fasting status, estimate ZD prevalence, and evaluate the associated factors with ZD in a representative sample of Brazilian children aged <5 y. METHODS: Population-based study with 7597 children aged 6-59 mo surveyed by the Brazilian National Survey on Child Nutrition. SZC was adjusted for inflammation using the Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia regression correction approach, with high-sensitive C-reactive protein, assessed according to blood collection timing (morning/afternoon) and fasting status (<8 and ≥8 h). SZC <65 µg/dL (morning collection) or SZC <57 µg/dL (afternoon collection) were classified as ZD. The analysis between associated factors and ZD used the adjusted prevalence ratio (PR). RESULTS: After adjusting for inflammation, SZC was higher in all percentiles and varied according to collection timing and fasting status. Children who had blood collected in the morning without fasting or in the afternoon had lower SZC than those assessed in the morning with fasting. The differences in adjusted SZC according to the timing of collection and fasting status were greater in the higher percentiles of the distribution, with the greatest absolute difference observed when comparing the 95th percentile of morning fasting compared with nonfasting (20.3 µg/dL). The prevalence of ZD estimated without and with adjusting SZC for inflammation was 17.8% and 13.8%, respectively. The occurrence of diarrhea, fever, or respiratory symptoms in the 15 d before blood collection was associated with a higher prevalence of ZD (PR: 1.42; 95% confidence interval: 1.04, 1.94). CONCLUSIONS: Adjusting SZC for inflammation and considering fasting status is important to avoid overestimating the prevalence of ZD.

Are pvcrt-o and pvmdr1 Gene Mutations Associated with Plasmodium vivax Chloroquine-Resistant Parasites?

(1) Background: Malaria remains a significant global public health issue. Since parasites quickly became resistant to most of the available antimalarial drugs, treatment effectiveness must be constantly monitored. In Brazil, up to 10% of cases of vivax malaria resistant to chloroquine (CQ) have been registered. Unlike P. falciparum, there are no definitive molecular markers for the chemoresistance of P. vivax to CQ. This work aimed to investigate whether polymorphisms in the pvcrt-o and pvmdr1 genes could be used as markers for assessing its resistance to CQ. (2) Methods: A total of 130 samples from P. vivax malaria cases with no clinical and/or parasitological evidence of CQ resistance were studied through polymerase chain reaction for gene amplification followed by target DNA sequencing. (3) Results: In the pvcrt-o exons, the K10 insert was present in 14% of the isolates. Regarding pvmdr1, T958M and F1076L haplotypes showed frequencies of 95% and 3%, respectively, while the SNP Y976F was not detected. (4) Conclusions: Since K10-pvcrt-o and F1076L/T958M-pvmdr1 polymorphisms were detected in samples from patients who responded well to CQ treatment, it can be concluded that mutations in these genes do not seem to have a potential for association with the phenotype of CQ resistance.

CPW partially attenuates DSS-induced ulcerative colitis in mice.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) of the gastrointestinal tract. The etiology is not fully understood, but environmental, microbial, and immunologic factors, as well as a genetic predisposition, play a role. UC is characterized by episodes of abdominal pain, diarrhea, bloody stools, weight loss, severe colonic inflammation, and ulceration. Despite the increase in the frequency of UC and the deterioration of the quality of life, there are still patients who do not respond well to available treatment options. Against this background, natural products such as polysaccharides are becoming increasingly important as they protect the intestinal mucosa, promote wound healing, relieve inflammation and pain, and restore intestinal motility. In this study, we investigated the effect of a polysaccharide isolated from the biomass of Campomanesia adamantium and Campomanesia pubescens (here referred to as CPW) in an experimental model of acute and chronic ulcerative colitis induced by dextran sulfate sodium (DSS). CPW reversed weight loss, increased disease activity index (DAI), bloody diarrhea, and colon shortening. In addition, CPW reduced visceral mechanical hypersensitivity, controlled oxidative stress and inflammation, and protected the mucosal barrier. CPW is not absorbed in the intestine, does not inhibit cytochrome P450 proteins, and does not exhibit AMES toxicity. These results suggest that CPW attenuates DSS-induced acute and chronic colitis in mice and may be a potential alternative treatment for UC.

Factors determining safety culture in hospitals: a scoping review.

OBJECTIVE: To evaluate and synthesise the factors determining patient safety culture in hospitals. METHODS: The scoping review protocol was based on the criteria of the Joanna Briggs Institute. Eligibility criteria were as follows: (1) empirical study published in a peer-reviewed journal; (2) used methods or tools to assess, study or measure safety culture or climate; (3) data collected in the hospital setting and (4) studies published in English. Relevant literature was located using PubMed, CINAHL, Web of Science and PsycINFO databases. Quantitative and qualitative analyses were performed using RStudio and the R interface for multidimensional analysis of texts and questionnaires (IRaMuTeQ). RESULTS: A total of 248 primary studies were included. The most used instruments for assessing safety culture were the Hospital Survey on Patient Safety Culture (n=104) and the Safety Attitudes Questionnaire (n=63). The Maslach Burnout Inventory (n=13) and Culture Assessment Scales based on patient perception (n=9) were used in association with cultural instruments. Sixty-six articles were included in the qualitative analysis. In word cloud and similarity analyses, the words 'communication' and 'leadership' were most prominent. Regarding the descending hierarchical classification analysis, the content was categorised into two main classes, one of which was subdivided into five subclasses: class 1a: job satisfaction and leadership (15.56%), class 1b: error response (22.22%), class 1c: psychological and empowerment nurses (20.00%), class 1d: trust culture (22.22%) and class 2: innovation worker (20.00%). CONCLUSION: The instruments presented elements that remained indispensable for assessing the safety culture, such as leadership commitment, open communication and learning from mistakes. There was also a tendency for research to assess patient and family engagement, psychological safety, nurses' engagement in decision-making and innovation.

A 5-Lipoxygenase Inhibitor, Zileuton, Modulates Host Immune Responses and Improves Lung Function in a Model of Severe Acute Respiratory Syndrome (SARS) Induced by Betacoronavirus.

Exacerbated inflammatory responses are a hallmark of severe coronavirus disease 2019 (COVID-19). Zileuton (Zi) is a selective inhibitor of 5-lipoxygenase, an enzyme involved in the production of several inflammatory/pro-resolving lipid mediators. Herein, we investigated the effect of Zi treatment in a severe acute respiratory syndrome (SARS) model. Mouse hepatitis virus (MHV)3-infected mice treated with Zi significantly improved the clinical score, weight loss, cardiopulmonary function, and survival rates compared with infected untreated animals. The protection observed in Zi-treated mice was associated with a lower inflammatory score, reduced dendritic cell-producing tumor necrosis factor (TNF), and increased neutrophil-producing interleukin (IL)-10 in the lungs three days after infection (dpi). At 5 dpi, the lungs of treated mice showed an increase in Th2-, Treg CD4+-, and Treg CD8+-producing IL-10 and reduced Th1 infiltrating cells. Furthermore, similar results were found upon Zi treatment after SARS-CoV-2 infection in transgenic mice expressing the human angiotensin I-converting enzyme 2 (ACE2) receptor driven by the cytokeratin-18 (K18) gene promoter (K18-hACE2), significantly improving the clinical score, weight loss, and lung inflammatory score compared with untreated animals. Our data suggest that Zi protects against developing severe lung disease during SARS induced by betacoronavirus without affecting the host's capacity to deal with infection.

Trends of breastfeeding indicators in Brazil from 1996 to 2019 and the gaps to achieve the WHO/UNICEF 2030 targets.

BACKGROUND: The comprehension of breastfeeding patterns and trends through comparable indicators is essential to plan and implement public health policies. OBJECTIVE: To evaluate the trends of breastfeeding indicators in Brazil from 1996 to 2019 and estimate the gap to achieve the WHO/UNICEF 2030 targets in children under 5 years. METHODS: Microdata from two National Surveys on Demography and Health of Women and Children (PNDS-1996 and PNDS-2006) and the Brazilian National Survey on Child Nutrition-2019 were used. The indicators of early initiation of breastfeeding (EIBF), exclusive breastfeeding of infants 0-5 months of age (EBF<6 mo), continued breastfeeding at 1 year of age (CBF1yr) and CBF at 2 years of age (CBF2yr) were analysed using prevalence and 95% CI. The average annual variation and years to achieve the WHO/UNICEF 2030 targets were calculated for Brazil and the macroregions. Statistical analyses considered the survey's complex sample design for each database. RESULTS: EIBF increased from 36.3% (95% CI 33.6% to 39.0%) in 1996 to 60.9% (95% CI 56.5% to 65.3%) in 2006 (statistically significant) and 62.5% (95% CI 58.3% to 66.6%) in 2019. EBF<6 mo increased from 26.9% (95% CI 21.3% to 31.9%) in 1996 to 39.0% (95% CI 31.0% to 47.1%) in 2006 and 45.8% (95% CI 40.9% to 50.7%) in 2019 (significant increases for 1996-2019 for Brazil, Northeast and Midwest regions). CBF1yr rose from 36.6% (95% CI 30.8% to 42.4%) in 1996 to 48.7% (95% CI 38.3% to 59.0%) in 2006, and 52.1% (95% CI 45.4% to 58.9%) in 2019. CBF2yr increased from 24.7% (95% CI 19.5% to 29.9%) in 1996 to 24.6% (95% CI 15.7% to 33.5%) in 2006 and 35.5% (95% CI 30.4% to 40.6%) in 2019 (significant increase for 1996-2019). The South and Southeast regions need to double the 2019 prevalence to reach the target for the CBF1yr and CBF2yr; the Northeast and North need to increase 60% the current prevalence for the indicator of EBF<6 mo. CONCLUSION: A substantial improvement in breastfeeding indicators occurred in Brazil from 1996 to 2019, although at an insufficient rate to achieve the WHO/UNICEF 2030 targets.