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Thin-film nanocomposite (TFN) membranes with a polyamide (PA) active layer modified with carbon nanotubes (CNTs) hold promise for water desalination and wastewater reuse via forward osmosis (FO). We hypothesise that modifying the PA active layer with hydroxyl-functionalised multi-wall carbon nanotubes (f-MWCNTs) will enhance the water flux of the FO membrane while maximising salt rejection. TFN membranes were modified using in situ interfacial polymerisation, with varying f-MWCNT mass content to minimise agglomeration. These modified FO membranes are designated as CTFN-x, where x represents the mass content of f-MWCNTs, ranging from 0.001%, CTFN-1 to 0.008%, CTFN-8 (w/v). The surface properties of CTFN-x were characterised using electron microscopy, atomic force microscopy, and molecular spectroscopy. IR spectroscopic data confirm the successful adherence of f-MWCNTs as a bridging agent between the 1,3-phenylenediamine (MPD) and trimesoyl chloride (TMC) polymers, preserving FO membrane integrity. The CTFN-4 FO membrane shows the highest water flux (29 LMH) and the lowest reverse salt flux (2.90 gHM), attributed to preferential water flow channels in the f-MWCNTs. The integration of f-MWCNTs into the active layer improved water flux, reduced reverse salt flux, and enhanced the antifouling properties of FO membranes.

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Immune checkpoint inhibition (ICI) with chemotherapy is now the standard of care for stage II-III triple-negative breast cancer; however, it is largely unknown for which patients ICI without chemotherapy could be an option and what the benefit of combination ICI could be. The adaptive BELLINI trial explored whether short combination ICI induces immune activation (primary end point, twofold increase in CD8+ T cells or IFNG), providing a rationale for neoadjuvant ICI without chemotherapy. Here, in window-of-opportunity cohorts A (4 weeks of anti-PD-1) and B (4 weeks of anti-PD-1 + anti-CTLA4), we observed immune activation in 53% (8 of 15) and 60% (9 of 15) of patients, respectively. High levels of tumor-infiltrating lymphocytes correlated with response. Single-cell RNA sequencing revealed that higher pretreatment tumor-reactive CD8+ T cells, follicular helper T cells and shorter distances between tumor and CD8+ T cells correlated with response. Higher levels of regulatory T cells after treatment were associated with nonresponse. Based on these data, we opened cohort C for patients with high levels of tumor-infiltrating lymphocytes (≥50%) who received 6 weeks of neoadjuvant anti-PD-1 + anti-CTLA4 followed by surgery (primary end point, pathological complete response). Overall, 53% (8 of 15) of patients had a major pathological response (<10% viable tumor) at resection, with 33% (5 of 15) having a pathological complete response. All cohorts met Simon's two-stage threshold for expansion to stage II. We observed grade ≥3 adverse events for 17% of patients and a high rate (57%) of immune-mediated endocrinopathies. In conclusion, neoadjuvant immunotherapy without chemotherapy demonstrates potential efficacy and warrants further investigation in patients with early triple-negative breast cancer. ClinicalTrials.gov registration: NCT03815890 .

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As the pharmaceutical industry advances towards more patient-focused product development, it is well recognized that meaningful patient engagement is required for the authentic patient voice to inform research and regulatory decisions. However, for this to happen systematically and consistently across the industry, there is still a need to evaluate and communicate the value of patient engagement to all stakeholders. Evaluating engagement also informs process improvement, elevating the value further. We describe the development of a conceptual, yet practical, framework for measuring the impact of engagement to achieve this. The framework depicts how metrics can be used to capture and assess the inputs, outputs, and value of patient engagement across the medicines lifecycle. Although conceived in the context of systems and processes within one company, Novartis, the framework was co-created with patient advisors and designed to be both patient-relevant and adaptable for any pharmaceutical organization. The adoption and evolution of the framework will help to demonstrate the value-to patients, healthcare systems, and businesses-of integrating patient engagement into core activities across the medicines lifecycle. We encourage the pharmaceutical industry to apply impact measurement to build a robust evidence base, through measuring, publishing, and communicating the value of patient engagement.

Drug companies often talk to patients about making new medicines. This is called patient engagement. It helps to ensure that new medicines are right for the patients who will take them. Patient engagement is useful, but it does not always happen. Sometimes, companies make important decisions without involving patients. All drug companies need to understand why it is important to listen and learn what patients need. We made a practical way to measure this value. Our team included people from Novartis (a drug company), and patient groups. We developed a structure called the 'framework'. It measures: How we involve patients ('Inputs') What we learn from patients ('Outputs') How this benefits patients, healthcare systems, and companies ('Value') It can measure all steps from the start to the end of drug development. We invite other companies to use a similar approach and share what they measure. Doing this will show the value of patient engagement, to make it more standard practice.

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Objective: Antimicrobial resistance is an emerging problem and multi-drug resistant (MDR) Klebsiella pneumoniae (K. pneumoniae) represents an enormous risk of failing therapy in hospital-acquired pneumonia. The current study aimed to determine the immunomodulatory effect of topical flagellin in addition to antibiotic treatment during respiratory infection evoked by hypervirulent antibiotic-susceptible and antibiotic-resistant K. pneumoniae in mice. Methods: C57BL6 mice were inoculated intranasally with hypervirulent K. pneumoniae (K2:O1) which was either antibiotic-susceptible or multi-drug resistant. Six hours after infection, mice were treated with antibiotics intraperitoneally and flagellin or vehicle intranasally. Mice were sacrificed 24 hours after infection. Samples were analyzed for bacterial loads and for inflammatory and coagulation markers. Results: Flagellin therapy induced neutrophil influx in the lung during antibiotic-treated pneumonia evoked by either antibiotic-susceptible or -resistant K. pneumoniae. The pulmonary neutrophil response was matched by elevated levels of neutrophil-attracting chemokines, neutrophil degranulation products, and local coagulation activation. The combined therapy of effective antibiotics and flagellin did not impact K. pneumoniae outgrowth in the lung, but decreased bacterial counts in distant organs. Neutrophil depletion abrogated the flagellin-mediated effect on bacterial dissemination and local coagulation responses. Conclusion: Topical flagellin administration as an adjunctive to antibiotic treatment augments neutrophil responses during pneumonia evoked by MDR-K. pneumoniae, thereby reducing bacterial dissemination to distant organs.

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Coral reefs support an incredible abundance and diversity of fish species, with reef-associated fisheries providing important sources of income, food, and dietary micronutrients to millions of people across the tropics. However, the rapid degradation of the world's coral reefs and the decline in their biodiversity may limit their capacity to supply nutritious and affordable seafood while meeting conservation goals for sustainability. Here, we conduct a global-scale analysis of how the nutritional quality of reef fish assemblages (nutritional contribution to the recommended daily intake of calcium, iron, and zinc contained in an average 100 g fish on the reef) relates to key environmental, socioeconomic, and ecological conditions, including two key metrics of fish biodiversity. Our global analysis of more than 1,600 tropical reefs reveals that fish trophic composition is a more important driver of micronutrient concentrations than socioeconomic and environmental conditions. Specifically, micronutrient density increases as the relative biomass of herbivores and detritivores increases at lower overall biomass or under high human pressure. This suggests that the provision of essential micronutrients can be maintained or even increase where fish biomass decreases, reinforcing the need for policies that ensure sustainable fishing, and that these micronutrients are retained locally for nutrition. Furthermore, we found a negative association between micronutrient density and two metrics of fish biodiversity, revealing an important nutrition-biodiversity trade-off. Protecting reefs with high levels of biodiversity maintains key ecosystem functions, whereas sustainable fisheries management in locations with high micronutrient density could sustain the essential supply of micronutrients to coastal human communities.

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Certain species in the Brassicaceae family exhibit high photosynthesis rates, potentially providing a valuable route toward improving agricultural productivity. However, factors contributing to their high photosynthesis rates are still unknown. We compared Hirschfeldia incana, Brassica nigra, Brassica rapa and Arabidopsis thaliana, grown under two contrasting light intensities. Hirschfeldia incana matched B. nigra and B. rapa in achieving very high photosynthesis rates under high growth-light condition, outperforming A. thaliana. Photosynthesis was relatively more limited by maximum photosynthesis capacity in H. incana and B. rapa and by mesophyll conductance in A. thaliana and B. nigra. Leaf traits such as greater exposed mesophyll specific surface enabled by thicker leaf or high-density small palisade cells contributed to the variation in mesophyll conductance among the species. The species exhibited contrasting leaf construction strategies and acclimation responses to low light intensity. High-light plants distributed Chl deeper in leaf tissue, ensuring even distribution of photosynthesis capacity, unlike low-light plants. Leaf anatomy of H. incana, B. nigra and B. rapa facilitated effective CO2 diffusion, efficient light use and provided ample volume for their high maximum photosynthetic capacity, indicating that a combination of adaptations is required to increase CO2-assimilation rates in plants.

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Covalent Bruton's tyrosine kinase-inhibitors (cBTK-i) are highly active in MYD88-mutated (MYD88Mut) Waldenstrom's macroglobulinaemia and suppress nuclear factor kappa-light-chain-enhancer of activated B cells and extracellular signal-regulated kinases-1/2 (ERK1/2)-related signalling. BTKCys481 mutations are associated with cBTK-i acquired resistance and are accompanied by reactivation of ERK1/2 that promotes inflammatory cytokine secretion and paracrine-mediated resistance of BTK wild-type (BTKWT) tumour cells. Pirtobrutinib is a non-covalent BTK-inhibitor that binds at non-BTKCys481 sites. We show that pirtobrutinib blocked p-ERK1/2, ERK1/2-driven inflammatory cytokines, and overcame paracrine-mediated resistance in MYD88Mut lymphoma cells expressing mutated BTKCys481. Our results provide important mechanistic insights for the activity of pirtobrutinib in MYD88Mut lymphomas carrying BTKCys481 mutations.

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Salmonella enterica is a globally disseminated pathogen that is the cause of over 100 million infections per year. The resulting diseases are dependent upon host susceptibility and the infecting serovar. As S. enterica serovar Typhimurium induces a typhoid-like disease in mice, this model has been used extensively to illuminate various aspects of Salmonella infection and host responses. Due to the severity of infection in this model, researchers often use strains of mice resistant to infection or attenuated Salmonella. Despite decades of research, many aspects of Salmonella infection and fundamental biology remain poorly understood. Here, we use a transposon insertion sequencing technique to interrogate the essential genomes of widely used isogenic wild-type and attenuated S. Typhimurium strains. We reveal differential essential pathways between strains in vitro and provide a direct link between iron starvation, DNA synthesis, and bacterial membrane integrity.IMPORTANCESalmonella enterica is an important clinical pathogen that causes a high number of deaths and is increasingly resistant to antibiotics. Importantly, S. enterica is used widely as a model to understand host responses to infection. Understanding how Salmonella survives in vivo is important for the design of new vaccines to combat this pathogen. Live attenuated vaccines have been used clinically for decades. A widely used mutation, aroA, is thought to attenuate Salmonella by restricting the ability of the bacterium to access particular amino acids. Here we show that this mutation limits the ability of Salmonella to acquire iron. These observations have implications for the interpretation of many previous studies and for the use of aroA in vaccine development.

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Background: For adult patients with grade 1-3 gliomas, identifying patients with an indication for proton therapy (PT) can be challenging due to sparse evidence supporting its benefits. In this study, we aimed to ensure national consensus and develop a decision support tool to aid clinicians in identifying patients with grade 1-3 gliomas eligible for PT. Methods: Sixty-one historic patients referred for postoperative radiotherapy for glioma grade 1-3 were included in this study and had new photon therapy and PT plans calculated. These plans along with clinical parameters were presented to neurooncologists with experience in treating brain tumours. The patients were presented at three workshops (WSs), where each neurooncologist individually had to choose between photon and proton therapy. Important parameters were selected using cross validation. Multivariable logistic regression was used to predict the neurooncologists' treatment modality choice. Results: At the three WSs 23, 24 and 19 randomly selected patients were presented. Seventy-five percent of the neurooncologists agreed for 14 patients (61%), 16 patients (67%) and 15 patients (79%) at WS1, WS2 and WS3. Age at radiotherapy and difference in mean dose (ΔDmean) to the residual brain were significant predictors of the choice of treatment modality, p < 0.001. Model coefficients were: ßage = 0.07 per year (95% confidence interval [CI] = 0.05-0.09), and ßΔdose = -0.27 per Gy (95% CI=-0.36--0.18). Conclusion: Higher degree of agreement was reached. Age and ΔDmean to the residual brain significantly predicted the choice of radiation modality. We have developed a decision support model which may aid in the selection of patients with glioma grade 1-3 to PT.

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The eye has considerable chromatic aberration, meaning that the accommodative demand varies with wavelength. Given this, how does the eye accommodate to light of differing spectral content? Previous work is not conclusive but, in general, the eye focuses in the center of the visible spectrum for broadband light, and it focuses at a distance appropriate for individual wavelengths for narrowband light. For stimuli containing two colors, there are also mixed reports. This is the second of a series of two papers where we investigate accommodation in relation to chromatic aberration Fernandez-Alonso, Finch, Love, and Read (2024). In this paper, for the first time, we measure how the eye accommodates to images containing two narrowband wavelengths, with varying relative luminance under monocular conditions. We find that the eye tends to accommodate between the two extremes, weighted by the relative luminance. At first sight, this seems reasonable, but we show that image quality would be maximized if the eye instead accommodated on the more luminous wavelength. Next we explore several hypotheses as to what signal the eye might be using to drive accommodation and compare these with the experimental data. We show that the data is best explained if the eye seeks to maximize contrast at low spatial frequencies. We consider the implication of these results for both the mechanism behind accommodation, and for modern displays containing narrowband illuminants.

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BACKGROUND: The phase III PRIMA/ENGOT-OV26/GOG-3012 trial met its primary endpoint. Niraparib first-line maintenance significantly prolonged progression-free survival (PFS) among patients with newly diagnosed advanced ovarian cancer that responded to first-line platinum-based chemotherapy, regardless of homologous recombination deficiency (HRD) status. Final overall survival (OS) results are reported. PATIENTS AND METHODS: Patients were randomized 2:1 to niraparib or placebo, stratified by response to first-line treatment, receipt of neoadjuvant chemotherapy, and tumor HRD status. After reaching 60% target maturity, OS was evaluated via a stratified log-rank test using randomization stratification factors and summarized using Kaplan-Meier methodology. OS testing was hierarchical [overall population first, then the homologous recombination-deficient (HRd) population]. Other secondary outcomes and long-term safety were assessed; an updated, ad hoc analysis of investigator-assessed PFS was also conducted (cut-off date, 8 April 2024). RESULTS: The median follow-up was 73.9 months. In the overall population, the OS hazard ratio was 1.01 [95% confidence interval (CI) 0.84-1.23; P = 0.8834] for niraparib (n = 487) versus placebo (n = 246). In the HRd (n = 373) and homologous recombination-proficient (n = 249) populations, the OS hazard ratios were 0.95 (95% CI 0.70-1.29) and 0.93 (95% CI 0.69-1.26), respectively. Subsequent poly(ADP-ribose) polymerase inhibitor therapy was received by 11.7% and 15.8% of niraparib patients and 37.8% and 48.4% of placebo patients in the overall and HRd populations, respectively. The 5-year PFS rate numerically favored niraparib in the overall (niraparib, 22%; placebo, 12%) and HRd populations (niraparib, 35%; placebo, 16%). Myelodysplastic syndromes/acute myeloid leukemia incidence was <2.5% (niraparib, 2.3%; placebo, 1.6%). No new safety signals were observed. CONCLUSIONS: In patients with newly diagnosed advanced ovarian cancer at high risk of recurrence, there was no difference in OS between treatment arms. In the HRd population, patients alive at 5 years were two times as likely to be progression free with niraparib treatment than placebo. Long-term safety remained consistent with the established niraparib safety profile.

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Hypothermia is a relatively rare condition in pregnancy and has been associated with fetal bradycardia. The management of maternal hypothermia resulting in fetal bradycardia presents a challenging dilemma for healthcare professionals. Currently, no evidence exists to advise on the duration of this condition before obstetric interventions are necessary for a safe outcome for both mother and infant. We discuss a case of a 26-year old primigravida with a gestational age of 32 weeks, who presented with clinical urosepsis, resulting in severe hypothermia up to 32 degrees Celsius. Active warming measures were taken and intravenous antibiotic treatment was started. Fetal evaluation on the cardiotocogram showed prolonged bradycardia (90 BPM) prompting consideration of a cesarean section. However, after multidisciplinary consultation, conservative treatment was proposed since there were no other signs of fetal hypoxia; no decelerations, good variability and accelerations. The patient started to show clinical improvement and had a body core temperature of 36 degrees Celsius after approximately 60 h of active rewarming measures. Fetal heartrate baseline normalized as the maternal temperature raised. Subsequently the patient was discharged in good clinical condition and had an uncomplicated vaginal delivery of a healthy newborn at term. In conclusion, when fetal bradycardia occurs due to maternal hypothermia, in the absence of signs for fetal hypoxia on the cardiotocogram, treatment of the underlying maternal condition instead of immediate obstetrics intervention is the best clinical option. This strategy aims to address the underlying cause of maternal hypothermia and consequently fetal bradycardia while ensuring the well-being of both mother and fetus and preventing unnecessary premature delivery.

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This paper demonstrates the potential of Raman spectroscopy for differentiating neoplastic from non-neoplastic colon tumors, obtained with the CAM (chicken chorioallantoic membrane) model. For the CAM model two human cell lines were used to generate two types of tumors, the RKO cell line for neoplastic colon tumors and the NCM460 cell line for non-neoplastic colon tumors. The Raman spectra were acquired with a 785 nm excitation laser. The measured Raman spectra from the CAM samples (n = 14) were processed with several methods for baseline correction and to remove artifacts. The corrected spectra were analyzed with PCA (principal component analysis). Additionally, machine learning based algorithms were used to create a model capable of classifying neoplastic and non-neoplastic tumors. The principal component scores showed a clear differentiation between neoplastic and non-neoplastic colon tumors. The classification model had an accuracy of 93 %. Thus, a complete methodology to process and analyze Raman spectra was validated, using a rapid, accessible, and well-established tumor model that mimics the human tumor pathology with minor ethical concerns.

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Arsenic is a ubiquitous metalloid and heavy metal that contributes to the global decline in human fertility. Humans are constantly exposed to arsenic through biotic and abiotic sources, especially ingestion of arsenic-contaminated food and water. Its exposure is associated with several adverse health challenges, including reproductive toxicity. In spite of its reported adverse effects, arsenic exposure remains a global challenge. Hence, this study provides a comprehensive review of the literature on the impact and mechanism of arsenic on male and female reproductive function. Additionally, a review of the potential therapeutic strategies is presented. Evidence from the literature reveals that arsenic upregulates reactive oxygen species (ROS) generation which mediates arsenic-induced suppression of the hypothalamic-pituitary-gonadal axis and inactivation of 3ß-HSD and 17ß-HSD activities, leading to reduced gonadal steroidogenesis. Through several oxidative stress-dependent signaling, arsenic induces the apoptosis of the germ cells, thus contributing to the development of infertility. At the moment, there is no specific treatment for arsenic-induced reproductive toxicity. However, increasing data form the scientific literature reveals the benefits of antioxidants in ameliorating arsenic-induced reproductive toxicity. These molecules suppress ROS generation and maintain optimal activities of the hypothalamic-pituitary-gonadal axis, leading to optimal steroidogenesis and gametogenesis as well as improved germ cells. Overall, this study revealed the impact and associated mechanism of arsenic-induced reproductive toxicity. It also provides evidence from the literature demonstrating potential therapeutic measures in managing arsenic-induced reproductive toxicity.

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INTRODUCTION: Pressurized intraperitoneal aerosol chemotherapy-oxaliplatin (PIPAC-OX) induces direct DNA damage and immunogenic cell death in patients with gastric cancer peritoneal metastases (GCPM). Combining PIPAC-OX with immune checkpoint inhibition remains untested. We conducted a phase I first-in-human trial evaluating the safety and efficacy of PIPAC-OX combined with systemic nivolumab (NCT03172416). METHODS: Patients with GCPM who experienced disease progression on at least first-line systemic therapy were recruited across three centers in Singapore and Belgium. Patients received PIPAC-OX at 90 mg/m2 every 6 weeks and i.v. nivolumab 240 mg every 2 weeks. Translational studies were carried out on GCPM samples acquired during PIPAC-OX procedures. RESULTS: In total, 18 patients with GCPM were prospectively recruited. The PIPAC-OX and nivolumab combination was well tolerated with manageable treatment-related adverse events, although one patient suffered from grade 4 vomiting. At second and third PIPAC-OX, respectively, the median decrease in peritoneal cancer index (PCI) was -5 (interquartile range: -12 to +1) and -7 (interquartile range: -6 to -20) and peritoneal regression grade 1 or 2 was observed in 66.7% (6/9) and 100% (3/3). Translational analyses of 43 GCPM samples revealed enrichment of immune/stromal infiltration and inflammatory signatures in peritoneal tumors after PIPAC-OX and nivolumab. M2 macrophages were reduced in treated peritoneal tumor samples while memory CD4+, CD8+ central memory and naive CD8+ T-cells were increased. CONCLUSIONS: The first-in-human trial combining PIPAC-OX and nivolumab demonstrated safety and tolerability, coupled with enhanced T-cell infiltration within peritoneal tumors. This trial sets the stage for future combinations of systemic immunotherapy with locoregional intraperitoneal treatments.

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INTRODUCTION: Addressing the public health problem of physical inactivity, this study evaluates "SNapp", a just-in-time adaptive app intervention to promote walking through dynamically tailored coaching content. It assesses SNapp's impact on daily steps and how users' perceptions regarding ease of use and usefulness moderated its effectiveness. STUDY DESIGN: SNapp was evaluated in an RCT from February 2021 to May 2022. Analyses were conducted in November 2022. SETTING/PARTICIPANTS: 176 adults (76% female, mean age of 56 years) were randomized to a control group receiving a step counter app (n = 89) or an intervention group receiving the app plus coaching content (n = 87). INTERVENTION: SNapp's coaching content encompasses individually tailored feedback on step counts and advice to engage in more walking, taking preferences regarding behavior change techniques into account. Additionally, SNapp provides contextualized content calling attention to suitable walking locations in the user's environment. MAIN OUTCOME MEASURES: The primary outcome was daily step count as recorded by the step counter app. User perceptions regarding ease of use and usefulness were assessed via survey at 3-month follow-up. RESULTS: Mixed models indicated that the intervention did not significantly impact step counts on average over time (B = -202.30, 95% CI = -889.7, 485.1), with the coefficient indicating that the intervention group walked fewer steps per day on average, though this difference was not statistically significant. Perceived ease of use did not moderate the intervention effect (B group x perceived ease of use = 38.60, 90% CI = -276.5, 353.7). Perceived usefulness significantly moderated the intervention effect (B group x perceived usefulness = 344.38, 90% CI = 40.4, 648.3). CONCLUSIONS: SNapp increased steps only in users who deemed the app useful, underscoring the importance of user perceptions in app-based interventions. TRIAL REGISTRATION: This trial was preregistered in the Dutch Trial Register (NL7064).

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Hepatitis D virus (HDV) is currently classified into 8 genotypes (1 to 8) and several subgenotypes, with distinct distribution worldwide. However, due to the scarcity of complete genome sequences in databases, this classification is constantly being updated and tends to be regularly revisited in upcoming years as more sequence data becomes available. Aiming to increase knowledge about the genetic variability of HDV, this study presents the full-length genomes of 11 HDV samples collected in Brazil in endemic and non-endemic regions, including the first complete genomes of the genotypes 5 and 8 obtained outside Africa. We also determined the co-infecting HBV genotypes to investigate their prevalence among the HDV-infected individuals throughout the country. Whole genome sequencing confirmed our previous findings based on a partial fragment of the HDV genome, in which HDV subgenoypes 3c (9/11; 81.8 %), 5b (1/11; 9.1 %) and one HDV-8 sequence (1/11; 9.1 %) were detected. As previously observed, HDV-8 formed a distinct branch apart from subgenotypes 8a and 8b, a monophyletic clade representing a novel HDV-8 subgenotype, designated as 8c. Among HDV-3 samples, the main co-infecting HBV genotype found was HBV-F (4/8; 50 %), reflecting the higher incidence of this native South American genotype in the endemic Amazon Basin. Both samples infected with HDV-5 and HDV-8 were coinfected with HBV genotype E, also a genotype with African origin. Our findings based on complete genome sequence of HDV corroborated our results based on a partial region of the HDV genome of a novel HDV-8 subgenotype and reinforced the need to use full-length genomes to properly subdivide genotypes with very low intragroup genetic variability, such as HDV-3. The provision of these complete genomes is expected to contribute to the enrichment of sequence databases for future molecular and evolutionary investigations of HDV.

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PURPOSE: The purpose of our study was to determine the minimum effective dose of oxytocin maintenance infusion required to maintain adequate uterine tone in 90% of patients (ED90) after administration of the initial bolus at elective Cesarean delivery (CD) under spinal anesthesia. METHODS: We conducted a prospective, double-blind dose-finding study with biased coin up-down design. Immediately after delivery, a 1-IU oxytocin bolus was administered, followed by a maintenance infusion. The obstetrician assessed the uterine tone by palpation as satisfactory or unsatisfactory. In case of unsatisfactory response, the dose for the next patient was increased by 2 IU·hr-1. For satisfactory response, the dose for the next patient was either decreased by 2 IU·hr-1 with a probability of 1/9, or remained unchanged. The primary outcome was a satisfactory uterine tone from five minutes after delivery until discharge from postanesthesia care unit. The secondary outcomes were blood loss, need for additional uterotonics, and side effects. RESULTS: We analyzed data for 40 patients. The ED90 of oxytocin maintenance infusion was 4.5 IU·hr-1 (95% confidence interval, 3.3 to 5.5) based on the isotonic regression estimator. The median [interquartile range] blood loss was 861 [553-1,181] mL; 18% received additional uterotonics, and 38% developed hypotension post delivery. CONCLUSION: Based on the results of this dose-finding study, we recommend a maintenance infusion rate of 4.5 IU·hr-1 following an oxytocin bolus of 1 IU for adequate uterine tone in pregnant patients undergoing elective CDs. This infusion rate is four-fold lower than that required without an initial bolus. STUDY REGISTRATION: ClinicalTrials.gov ( NCT04946006 ); first submitted 25 June 2021.

RéSUMé: OBJECTIF: L'objectif de notre étude était de déterminer la dose minimale efficace de perfusion d'entretien d'ocytocine nécessaire pour maintenir un tonus utérin adéquat chez 90 % des personnes parturientes (DE90) après l'administration du bolus initial lors d'une césarienne programmée sous rachianesthésie. MéTHODE: Nous avons réalisé une étude prospective et en double aveugle de détermination de la dose avec une méthodologie de conception biaisée type « up-and down ¼. Immédiatement après l'accouchement, un bolus d'ocytocine de 1 UI a été administré, suivi d'une perfusion d'entretien. L'obstétricien·ne a évalué le tonus utérin par palpation comme satisfaisant ou insatisfaisant. En cas de réponse insatisfaisante, la dose pour la personne suivante a été augmentée de 2 UI·h−1. Lors d'une réponse satisfaisante, la dose pour la personne suivante a été diminuée de 2 UI·h−1 avec une probabilité de 1/9, ou est restée inchangée. Le critère d'évaluation principal était un tonus utérin satisfaisant de cinq minutes après l'accouchement jusqu'à la sortie de la salle de réveil. Les critères d'évaluation secondaires étaient la perte de sang, la nécessité d'utérotoniques supplémentaires et les effets secondaires. RéSULTATS: Nous avons analysé les données de 40 patient·es. La DE90 de perfusion d'entretien d'ocytocine était de 4,5 UI·h−1 (intervalle de confiance à 95 %, 3,3 à 5,5) basé sur l'estimateur de régression isotonique. La perte de sang médiane [écart interquartile] était de 861 [553-1 181] mL; 18 % ont reçu des utérotoniques supplémentaires et 38 % ont développé une hypotension après l'accouchement. CONCLUSION: D'après les résultats de cette étude de détermination de la dose, nous recommandons un débit de perfusion d'entretien de 4,5 UI·h−1 après un bolus d'ocytocine de 1 UI pour un tonus utérin adéquat chez les personnes parturientes bénéficiant d'une césarienne programmée. Ce débit de perfusion est quatre fois inférieur à celui requis sans bolus initial. ENREGISTREMENT DE L'éTUDE: ClinicalTrials.gov ( NCT04946006 ); première soumission le 25 juin 2021.

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INTRODUCTION: In vitro methods have been widely used to assess adverse effects. Reconstructed Human Epidermis (RHE) poses as a fascinating test system employed to assess the dermal irritation hazard potential of chemicals. Although several RHE models are reported in the OECD Test Guideline No. 439, the OECD Document No. 220 encourages the scientific community to develop and validate new RHE test systems due to its relevance for socio-economic advancement. METHODS: Following the criteria documented in the OECD No. 220, a blind study for skin irritation (OECD 439) was conducted employing the Minimum List of Reference Chemicals for Determination of Reproducibility and Predictive Capacity using ES®-RHE. Structural and functional characteristics were assessed alongside the prediction model. RESULTS: The model has shown reproducibility of optical density and barrier function, similarly to internationally validated methods. Furthermore, it shows the cell layers' development and differentiation ability due to Cytokeratin14, Cytokeratin10, and filaggrin expression. The prediction model resulted in sensitivity, specificity and accuracy rates of 100, 70, and 77 %, respectively. CONCLUSIONS: The ES®-RHE demonstrated reliability and relevance, with similar structural and functional characteristics comparable to internationally validated models, in addition to the accepted predictive capacity according to OECD required minimum criteria, thus confirming the suitability of the national ES®-RHE in the hazard prediction of dermal irritation based on OECD Test Guideline No. 439.