Microcosting Analysis of Advanced Ovarian Cancer: Real-World Evidence From the Perspective of a Reference Public Brazilian Hospital.

OBJECTIVES: Evaluate the cost of advanced ovarian cancer, using the microcosting technique, based on real-world evidence from the perspective of a reference Brazilian public hospital. METHODS: Retrospective cohort study of patients newly diagnosed with advanced ovarian cancer in 2017 and followed-up for up to 5 years. A bottom-up microcosting method was applied, using the activity-based cost approach, which evaluates service costs based on activity consumption throughout patients' journey. RESULTS: The results indicate a median overall survival of 35.3 months and a median age of 57 years (33-80 years old). The average cost per patient was USD 34 991.595 over a period of 35.3 months, with admissions because of the disease progression and end-of-life care being the most relevant. CONCLUSIONS: The results show that the costs of activities currently involved in the treatment of advanced ovarian cancer represent an important economic impact for the public health system. These data can support future analyses on the impact of incorporating new technologies for the treatment of ovarian cancer and on the financing and sustainability of the Brazilian public healthcare system.

Efficacy and Safety of Monoclonal Antibodies for the Treatment of Eosinophilic Esophagitis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND AND AIMS: Monoclonal antibodies (MAbs) have clinical benefits for treating several atopic diseases. However, consensus on its use for eosinophilic esophagitis (EoE) is lacking. The present meta-analysis aimed to compare the efficacy and safety of MAbs versus placebo for treating EoE. METHODS: We searched PubMed, Embase, and Cochrane Library for randomized controlled trials (RCTs). The primary outcomes were changes in peak esophageal eosinophils count/high power field (HPF) and mean esophageal eosinophils count/HPF. The secondary outcomes were changes in the EoE-Histology Scoring System (EoE-HSS), Endoscopic Reference Score (EREFS), dysphagia score, and adverse events (AEs). We compared binary outcomes using risk ratio (RR) and continuous outcomes using mean difference (MD) or standardized mean difference (SMD), with 95% confidence interval (CI). Considering the diversity of mechanistic properties of MAbs, a pre-specified subgroup analysis by MAb mechanism of action was performed for all outcomes, provided that at least two studies were in each subgroup. Heterogeneity was assessed using Cochran's Q test and I2 statistics. RESULTS: 6 RCTs were included (533 patients). Compared to placebo, MAbs led to a significant reduction in peak esophageal eosinophils count/HPF (MD -0.78; CI 95% -0.87, -0.6801) and mean esophageal eosinophils count/HPF (SMD -0.79; CI 95% -1.5, -0.08). Moreover, MAbs significantly reduced EoE-HSS scores (grade score: SMD -9.31; 95% CI -13.95, -4.6701; stage score: SMD -10.18; 95% CI -15.06, -5.31), EREFS (SMD -5.95; CI 95% -9.19, -2.71) and dysphagia score (SMD -1.79; CI 95% -3.36, -0.23) without increasing AEs compared to placebo. Among those MAbs whose mechanism of action includes the blockage of the receptor for IL-13 (Dupilumab, QAX576, and RPC4046), the scores of EoE-HSS grade, EoE-HSS stage, EREFS, and dysphagia were significantly reduced, and they presented a similar risk of overall and serious AEs compared to placebo. CONCLUSION: MAbs seem effective and safe in reducing esophageal eosinophil infiltrate, EoE-HSS score, EREFS score, and dysphagia symptoms in patients with EoE. However, further evidence is needed to establish its place in EoE management.

Paralympic Versus Olympic Canoe Sprint: Comprehension of the Development Trajectory of the Kayak 200 Meters.

Improvements in race times for male and female Para canoe athletes across different sports classes have led to a reduction in relative differences between classes over time. However, there is a lack of research examining the comparative developmental trajectories between high-performance Paralympic (PCS) and Olympic (OCS) canoe sprint. In this study, we compared the developmental trajectories of 200-meter kayak performances among PCS and OCS athletes. In total, we analyzed 628 race results obtained from public online databases, for nine competitions between 2015 and 2023. Race times were reduced over the years except in specific sports classes (KL3-M, K1-M, and K1-F; KL: Kayak Level, M: male, F: female), with a poor positive correlation (r = 0.17 to 0.33) between time and the years. For the remaining sports classes, these correlations ranged from poor to fair (r = -0.58 to -0.13). OCS K1 athletes outperformed their Paralympic counterparts. Among Paralympic classes, KL1 had slower times than KL2 and KL3 (p ≤ .05), with KL2 times significantly lower than KL3 in the female category. OCS athletes exhibited less variability in race times compared to PCS athletes. In the male category, there were no significant differences in the coefficients of variation (CV) and amplitude of race times between sport classes, except for KL1-M, which had a larger CV than K1 (p ≤ .05). In the female category, the CV and amplitude of race times were significantly higher in KL1-F compared to KL3-F and K1-F. OCS times remained stable from 2015, with KL3-M following a similar trend. PCS displayed greater race time variability, particularly in higher impairment classes, notably KL1. This underscores the existence of distinct developmental stages within the canoe sprint modality, particularly emphasizing the early developmental phase of KL1. It also provides valuable insights for coaches and sports selection, especially concerning athletes with more severe impairments, including those in Rehabilitation Centers and during athlete recruitment.

Robotics-Driven Manufacturing of Cartilaginous Microtissues for Skeletal Tissue Engineering Applications.

Automated technologies are attractive for enhancing the robust manufacturing of tissue-engineered products for clinical translation. In this work, we present an automation strategy using a robotics platform for media changes, and imaging of cartilaginous microtissues cultured in static microwell platforms. We use an automated image analysis pipeline to extract microtissue displacements and morphological features as noninvasive quality attributes. As a result, empty microwells were identified with a 96% accuracy, and dice coefficient of 0.84 for segmentation. Design of experiment are used for the optimization of liquid handling parameters to minimize empty microwells during long-term differentiation protocols. We found no significant effect of aspiration or dispension speeds at and beyond manual speed. Instead, repeated media changes and time in culture were the driving force or microtissue displacements. As the ovine model is the preclinical model of choice for large skeletal defects, we used ovine periosteum-derived cells to form cartilage-intermediate microtissues. Increased expression of COL2A1 confirms chondrogenic differentiation and RUNX2 shows no osteogenic specification. Histological analysis shows an increased secretion of cartilaginous extracellular matrix and glycosaminoglycans in larger microtissues. Furthermore, microtissue-based implants are capable of forming mineralized tissues and bone after 4 weeks of ectopic implantation in nude mice. We demonstrate the development of an integrated bioprocess for culturing and manipulation of cartilaginous microtissues and anticipate the progressive substitution of manual operations with automated solutions for the manufacturing of microtissue-based living implants.

Effects of different training methods in tele-exercise on acute performance decrement in adults with disability and wheelchair users.

PURPOSE: Wheelchair users and people with disabilities have limited access to physical exercise due to various factors, including medical follow-up and training facilities. Although tele-exercise guided by experts has become a viable option, there is limited knowledge about the acute performance decrement (APD) resulting from remote training methods. The current cross-sectional study aimed to: (1) assess the APD of muscle resistance strength after three synchronous tele-exercise training methods in wheelchair users and (2) compare the training loads associated with each training method. MATERIALS AND METHODS: Eighteen male and female wheelchair users who participated in tele-exercise strength practices were recruited. The participants performed a maximum resistance strength test by synchronous tele-assessment (push-up test, PUT) at baseline and immediately after three training methods: high-intensity interval training (HIIT), moderate-intensity continuous training (MICT) and sprint interval training (SIT). The primary outcome was the APD, which was measured by the percentage decrease in the number of repetitions of the PUT immediately after the training methods. RESULTS: APD was observed for all three training methods, with no significant differences between them (-34.8%, -29.9% and -38.0% for MICT, SIT and HII, respectively), and presented a non-significant correlation with the training loads. HIIT had a significantly higher training load than MICT and SIT. CONCLUSIONS: APD occurred in all training sessions, but did not correlate with training load, indicating that it is not an appropriate metric for comparison. Findings provide insight into APD response and highlight the need to consider multiple metrics when comparing training protocols.

Synchronous moderate-intensity continuous training (MICT), sprint interval training (SIT) and high-intensity interval training tele-exercises provided similar acute performance decrement in wheelchair users and people with disabilities.High-intensity interval training showed a higher training load compared to MICT and SIT performed remotely.Acute performance decrement did not correlate with the training load.

Disruption of MAM integrity in mutant FUS oligodendroglial progenitors from hiPSCs.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neurodegenerative disorder, characterized by selective loss of motor neurons (MNs). A number of causative genetic mutations underlie the disease, including mutations in the fused in sarcoma (FUS) gene, which can lead to both juvenile and late-onset ALS. Although ALS results from MN death, there is evidence that dysfunctional glial cells, including oligodendroglia, contribute to neurodegeneration. Here, we used human induced pluripotent stem cells (hiPSCs) with a R521H or a P525L mutation in FUS and their isogenic controls to generate oligodendrocyte progenitor cells (OPCs) by inducing SOX10 expression from a TET-On SOX10 cassette. Mutant and control iPSCs differentiated efficiently into OPCs. RNA sequencing identified a myelin sheath-related phenotype in mutant OPCs. Lipidomic studies demonstrated defects in myelin-related lipids, with a reduction of glycerophospholipids in mutant OPCs. Interestingly, FUSR521H OPCs displayed a decrease in the phosphatidylcholine/phosphatidylethanolamine ratio, known to be associated with maintaining membrane integrity. A proximity ligation assay further indicated that mitochondria-associated endoplasmic reticulum membranes (MAM) were diminished in both mutant FUS OPCs. Moreover, both mutant FUS OPCs displayed increased susceptibility to ER stress when exposed to thapsigargin, and exhibited impaired mitochondrial respiration and reduced Ca2+ signaling from ER Ca2+ stores. Taken together, these results demonstrate a pathological role of mutant FUS in OPCs, causing defects in lipid metabolism associated with MAM disruption manifested by impaired mitochondrial metabolism with increased susceptibility to ER stress and with suppressed physiological Ca2+ signaling. As such, further exploration of the role of oligodendrocyte dysfunction in the demise of MNs is crucial and will provide new insights into the complex cellular mechanisms underlying ALS.

AGE-RELATED TRAJECTORY AND AGE AT PEAK COMPETITIVE PERFORMANCE IN WHEELCHAIR RUGBY PLAYERS AT THE PARALYMPIC GAMES.

OBJECTIVE: The first objective to examine the age-related trajectory of competitive performance and the age at peak competitive performance in wheelchair rugby (WR) players at the Paralympic Games. Another objective is to verify age correlations with performance over the years for each class. DESIGN: Retrospective cohort study. RESULTS: Data were collected from the official results books of the Paralympic games. The mean age (standard deviation) of the 267 players and 448 analyzed data from all Paralympic games (from Sidney 2004 to Tokyo 2020) across all classes was 32.8 (6.4) years, and the age at peak competitive performance was 30.6 (7.4) years. Each class had no statistical difference in age at peak competitive performance. Additionally, there was no significant correlation between age and performance within classes or across all Paralympic games. CONCLUSION: The findings indicate that WR players' age at peak competitive performance is 30.6 years, which remains consistent across all classes. There is no statistical correlation between age and performance in WR. These findings significantly affect effective talent identification and athlete development programs. This impact ensures that athletes receive the necessary support to reach their maximum potential while avoiding the pitfalls of underestimating or overestimating their stages of development.

Aquimarina aquimarini sp. nov. and Aquimarina spinulae sp. nov., novel bacterial species with versatile natural product biosynthesis potential isolated from marine sponges.

This study describes two Gram-negative, flexirubin-producing, biofilm-forming, motile-by-gliding and rod-shaped bacteria, isolated from the marine sponges Ircinia variabilis and Sarcotragus spinosulus collected off the coast of Algarve, Portugal. Both strains, designated Aq135T and Aq349T, were classified into the genus Aquimarina by means of 16S rRNA gene sequencing. We then performed phylogenetic, phylogenomic and biochemical analyses to determine whether these strains represent novel Aquimarina species. Whereas the closest 16S rRNA gene relatives to strain Aq135T were Aquimarina macrocephali JAMB N27T (97.8 %) and Aquimarina sediminis w01T (97.1 %), strain Aq349T was more closely related to Aquimarina megaterium XH134T (99.2 %) and Aquimarina atlantica 22II-S11-z7T (98.1 %). Both strains showed genome-wide average nucleotide identity scores below the species level cut-off (95 %) with all Aquimarina type strains with publicly available genomes, including their closest relatives. Digital DNA-DNA hybridization further suggested a novel species status for both strains since values lower than 70 % hybridization level with other Aquimarina type strains were obtained. Strains Aq135T and Aq349T grew from 4 to 30°C and with between 1-5 % (w/v) NaCl in marine broth. The most abundant fatty acids were iso-C17 : 03-OH and iso-C15 : 0 and the only respiratory quinone was MK-6. Strain Aq135T was catalase-positive and ß-galactosidase-negative, while Aq349T was catalase-negative and ß-galactosidase-positive. These strains hold unique sets of secondary metabolite biosynthetic gene clusters and are known to produce the peptide antibiotics aquimarins (Aq135T) and the trans-AT polyketide cuniculene (Aq349T), respectively. Based on the polyphasic approach employed in this study, we propose the novel species names Aquimarina aquimarini sp. nov. (type strain Aq135T=DSM 115833T=UCCCB 169T=ATCC TSD-360T) and Aquimarina spinulae sp. nov. (type strain Aq349T=DSM 115834T=UCCCB 170T=ATCC TSD-361T).

Performance Trajectory Related to Age, Classification, and Sex in Elite Kayak Para Canoe Athletes.

OBJECTIVE: The aim of the study is to verify the performance trajectory related to age, classification (KL: kayak level; M: male; F: female), and sex of elite kayak Para canoe athletes. DESIGN: This is a retrospective cohort study. RESULTS: Race results and athletes' data were retrieved from publicly available online databases for 17 competitions and 102 finals between 2015 and 2022. Race time reduced over the years except for KL3-M class. There was a reduction in the relative difference between KL2-M and KL3-M over the years ( r = -0.83, 95% confidence interval = -0.34 to -0.97, P ≤ 0.05). In addition, no significant differences were found in race times relative differences between KL2-F and KL3-F over the years. Although the correlation between age and performance was only found to be statistically significant in the KL3-F class, the ages of all classes (35.2, 32.6, 29.5, 34.6, 37.6, and 30.6 yrs for males and females KL1, KL2, and KL3, respectively) were higher than those in Olympic canoeing (27.8 yrs). CONCLUSIONS: Race times have improved overall since 2015, but not for the KL3-M class. Nevertheless, because of the stochastic ages of the finalist athletes, it was not possible to determine the age at which peak performance is achieved in all classes. Kayak Para canoe classes should be monitored in the coming years to determine whether interventions are necessary to improve differentiation.

Is the link between the Dark Tetrad and the acceptance of sexual violence mediated by sexual machismo?

Previous studies have established relationships between the Dark Tetrad traits and sexual violence and its acceptance through myths about this type of violence. Sexual violence is positively associated with machismo, with sexist beliefs having been found to be linked with the Dark Tetrad and with the acceptance of sexual violence. Using a community sample comprising 362 adults between the ages of 18 and 70 (M = 35.6, SD = 14.3) and three self-report measures, this cross-sectional study aimed to explore the mediating role of sexual machismo in the relationship between each of the Dark Tetrad traits and the acceptance of sexual violence, both in the overall sample and by gender, as well as whether a significant variance in this acceptance is explained by the "dark" traits, sexual machismo, and gender. In the regression, sexual machismo (the male) gender, and only Machiavellianism were uniquely associated with the acceptance of sexual violence, and sexual machismo partially mediated the associations between the Dark Tetrad and the acceptance of sexual violence. These findings indicate that being male and higher in sexism is more closely linked with the acceptance of sexual violence than most Dark Tetrad traits. Moreover, the associations between the Dark Tetrad, sexual machismo, and the acceptance of sexual violence were stronger in men, consistent with the notion that these traits facilitate a "male" exploitive mating strategy, which likely also extends to victim-blaming and positive attitudes about sexual violence more broadly. Lastly, the results emphasize the pervasiveness of beliefs about male superiority over women and its relationship with victim-blaming even in women.

A methodology to estimate postdisaster unmet housing needs using limited data: Application to the 2017 California wildfires.

In the United States, assistance from the Department of Housing and Urban Development (HUD) plays an essential role in supporting the postdisaster recovery of states with unmet housing needs. HUD requires data on unmet needs to appropriate recovery funds. Ground truth data are not available for months after a disaster, however, so HUD uses a simplified approach to estimate unmet housing needs. State authorities argue that HUD's simplified approach underestimates the state's needs. This article presents a methodology to estimate postdisaster unmet housing needs that is accurate and relies only on data obtained shortly after a disaster. Data on the number of damaged buildings are combined with models for expected repair costs. Statistical models for aid distributed by the Federal Emergency Management Agency (FEMA) and the Small Business Administration (SBA) are then developed and used to forecast funding provided by those agencies. With these forecasts, the unmet need to be funded by HUD is estimated. The approach can be used for multiple states and hazard types. As validation, the proposed methodology is used to estimate the unmet housing needs following disasters that struck California in 2017. California authorities suggest that HUD's methodology underestimated the state's needs by a factor of 20. Conversely, the proposed methodology can replicate the estimates by the state authorities and provide accounts of losses, the amount of funding from FEMA and SBA, and the total unmet housing needs without requiring data unavailable shortly after a disaster. Thus, the proposed methodology can help improve HUD's funding appropriation without delays.

Natural product biosynthetic potential reflects macroevolutionary diversification within a widely distributed bacterial taxon.

IMPORTANCE: This is the most comprehensive study performed thus far on the biosynthetic potential within the Flavobacteriaceae family. Our findings reveal intertwined taxonomic and natural product biosynthesis diversification within the family. We posit that the carbohydrate, peptide, and secondary metabolism triad synergistically shaped the evolution of this keystone bacterial taxon, acting as major forces underpinning the broad host range and opportunistic-to-pathogenic behavior encompassed by species in the family. This study further breaks new ground for future research on select Flavobacteriaceae spp. as reservoirs of novel drug leads.

Post-Transcriptional Gene Silencing of Glucanase Inhibitor Protein in Phytophthora cinnamomi.

Ink disease is considered one of the most significant causes contributing to the decline of chestnut orchards. The reduced yield of Castanea sativa Mill can be attributed to two main species: Phytophthora cinnamomi and Phytophthora cambivora, with the first being the main pathogen responsible for ink disease in Portugal. P. cinnamomi is a highly aggressive and widely distributed plant pathogen, capable of infecting nearly 1000 host species. This oomycete causes substantial economic losses and is accountable for the decline of numerous plant species in Europe and worldwide. To date, no effective treatments are available to combat these pathogens. Given chestnut's economic and ecological significance, particularly in Portugal, it is crucial to investigate the molecular mechanisms underlying the interaction between Phytophthora species and host plants. This can be achieved through the study of the glucanase inhibitor protein (GIP) produced by P. cinnamomi during infection. The technique of RNA interference (RNAi) was employed to suppress the GIP gene of P. cinnamomi. The resulting transformants, carrying the silenced gene, were used to infect C. sativa, allowing for the assessment of the effects of gene silencing on the plant's phenotype. Additionally, bioinformatics tools predicted the secretion of GIP protein. The obtained results validate RNAi as a potential alternative tool for studying molecular factors and for controlling and managing P. cinnamomi.

Widespread occurrence of chitinase-encoding genes suggests the Endozoicomonadaceae family as a key player in chitin processing in the marine benthos.

Chitin is the most abundant natural polymer in the oceans, where it is primarily recycled by chitin-degrading microorganisms. Endozoicomonadaceae (Oceanospirillales) bacteria are prominent symbionts of sessile marine animals, particularly corals, and presumably contribute to nutrient cycling in their hosts. To reveal the chitinolytic potential of this iconic, animal-dwelling bacterial family, we examined 42 publicly available genomes of cultured and uncultured Endozoicomonadaceae strains for the presence of chitinase-encoding genes. Thirty-two of 42 Endozoicomonadaceae genomes harbored endo-chitinase- (EC 3.2.1.14), 25 had exo-chitinase- (EC 3.2.1.52) and 23 polysaccharide deacetylase-encoding genes. Chitinases were present in cultured and uncultured Endozoicomonadaceae lineages associated with diverse marine animals, including the three formally described genera Endozoicomonas, Paraendozoicomonas and Kistimonas, the new genus Candidatus Gorgonimonas, and other, yet unclassified, groups of the family. Most endo-chitinases belonged to the glycoside hydrolase family GH18 but five GH19 endo-chitinases were also present. Many endo-chitinases harbored an active site and a signal peptide domain, indicating the enzymes are likely functional and exported to the extracellular environment where endo-chitinases usually act. Phylogenetic analysis revealed clade-specific diversification of endo-chitinases across the family. The presence of multiple, distinct endo-chitinases on the genomes of several Endozoicomonadaceae species hints at functional variation to secure effective chitin processing in diverse micro-niches and changing environmental conditions. We demonstrate that endo-chitinases and other genes involved in chitin degradation are widespread in the Endozoicomonadaceae family and posit that these symbionts play important roles in chitin turnover in filter- and suspension-feeding animals and in benthic, marine ecosystems at large.

Overall survival and associated factors in women with metastatic breast cancer treated with trastuzumab at a public referral institution.

OBJECTIVE: To characterize associated factors and overall survival of women with metastatic breast cancer treated with trastuzumab after its incorporation into the SUS, and additionally to present the direct costs of this technology. METHODS: This is a retrospective cohort, based on data from computerized medical records from one of the units of the National Cancer Institute (INCA), in Rio de Janeiro-RJ, Brazil. Women with HER-2 positive metastatic breast cancer undergoing trastuzumab treatment from September 2017 to August 2018 were included. Overall survival was estimated using the Kaplan-Meier method and compared between groups using the log-rank test. RESULTS: 136 women were selected, whose median age at diagnosis was 51 years (range: 21-81 years). The median OS was 43.63 months (95%CI 33.92-53.34). It is observed that the median OS for the population already diagnosed with metastatic disease (stage IV) was significantly lower than for patients diagnosed in stages I-III (37.43 months vs. 48.6 months, p<0, 01). Women without previous use of trastuzumab had a higher median OS than patients pretreated with trastuzumab (45.16 months vs. 40.73 months, p<0.01). CONCLUSION: Trastuzumab improves survival in HER-2 positive metastatic breast cancer. Brain and multiple metastases are associated with a worse prognosis. It is essential to avoid advanced staging and perform surgical treatment, with emphasis on radical mastectomy. The SUS must adopt policies and strategies for early diagnosis and guarantee access to trastuzumab, considering its high cost.

Sit to stand test and handgrip strength in men and women with post-COVID-19 syndrome without invasive ventilator support: insights from a Brazilian observational study.

Two valid tests have been used in patients with post-COVID-19 syndrome (coronavirus disease 2019) due to their fast application, feasibility, and accessible procedures, facilitating data collection in large groups: the 1-minute sit-to-stand test (STS) and handgrip strength (HGS) dynamometry. The present study aimed to: i) assess the STS and HGS in men and women with post-COVID-19 syndrome who did not require invasive ventilator support; ii) correlate STS repetitions and HGS with time since the COVID-19 diagnosis. Six hundred and twenty-two men and women with post-COVID-19 syndrome who did not require invasive ventilatory support performed the STS and HGS tests at the beginning of the rehabilitation process at a Reference Hospital Centre. Women over 55 years presented significantly lower results compared to participants under 55 years. For the HGS, the median ranged from 42 to 48 kg and 70 to 81 kg for the female and male groups, respectively. The correlations of time since COVID-19 diagnosis with STS and HGS ranged from -0.16 to 0.02 (p>0.05) for women and men, respectively.The test results could be used for the initial analysis of normality ranges and comparisons with other populations. Although STS repetitions and HGS presented low and non-significant correlations with time since the COVID-19 diagnosis, some COVID-19 sequelae were not measured, so these data should be interpreted with caution.