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Abstract It is critical to understand the impact of significant physiological changes during pregnancy on the extent of maternal and fetal drug exposure. Fostemsavir (FTR) is a prodrug of temsavir (TMR) and is approved in combination with other antiretrovirals for multi‐drug‐resistant human immunodeficiency virus (HIV) infections. This physiologically based pharmacokinetic model (PBPK) study was used to estimate TMR PK in pregnant populations during each trimester of pregnancy to inform FTR dosing. A PBPK model was developed and validated for TMR using PK data collected following intravenous TMR and oral FTR dosing (immediate‐release and extended‐release tablets) in healthy volunteers. Predicted TMR concentration–time profiles accurately predicted the reported clinical data and variability in healthy (dense data) and pregnant (sparse data) populations. Predicted versus observed TMR geometric mean (CV%) clearance following intravenous administration was 18.01 (29) versus 17 (21) (L/h). Predicted versus observed TMR AUC0–inf (ng.h/mL) in healthy volunteers following FTR administration of the extended‐release tablet were 9542 (66) versus 7339 (33). The validated TMR PBPK model was then applied to predict TMR PK in a population of pregnant individuals during each trimester. Simulations showed TMR AUC in pregnant individuals receiving FTR 600 mg twice daily was decreased by 25% and 38% in the second and third trimesters, respectively. However, TMR exposure remained within the range observed in nonpregnant adults with no need for dose adjustment. The current PBPK model can also be applied for the prediction of local tissue concentrations and drug–drug interactions in pregnancy.

BackgroundKnowledge, attitude, and practice of Adverse Drug Reactions (ADRs) and ADRs reporting among healthcare workers were related to the quality and ADRs reporting rate. The aim of this study was to evaluate the effectiveness of the multifaceted interventions on knowledge, attitude, and practice (KAP) of healthcare workers and to compare the proportion of spontaneous ADRs reports at the study center, before and after instituting multifaceted interventions.MethodsA comparative intervention study was conducted among healthcare workers at the hospital. The participants were asked to complete a questionnaire before and after instituting the multifaceted interventions to assess the KAP of ADRs and their reporting. The impact of the multifaceted interventions was assessed by comparing their correct responses to the KAP questions and the proportion of spontaneous ADRs reports before and after the interventions. The pre- and post-intervention scores for KAP questions were compared usingMcNemar test by R Language.Results388 healthcare workers completed the study. The proportion of participants qualified for ADRs reporting increased significantly, from 73.5% (pre–intervention) to 99.2% (post–intervention) for knowledge scores, from 70.6% to 91.8% for attitude scores, and from 81.4% to 97.2% for practice scores (p < 0.001). Similarly, the number of spontaneous ADRs reports increased by 31% after 3 months of interventions.ConclusionMultifaceted interventions instituted at the study center improved the knowledge, attitude, and practice of health workers towards ADRs and spontaneous reporting. It would be beneficial to implement such interventions in other hospitals in Vietnam.

Abstract Fostemsavir is an approved gp120‐directed attachment inhibitor and prodrug for the treatment of human immunodeficiency virus type 1 infection in combination with other antiretrovirals (ARVs) in heavily treatment‐experienced adults with multi‐drug resistance, intolerance, or safety concerns with their current ARV regimen. Initial in vitro studies indicated that temsavir, the active moiety of fostemsavir, and its metabolites, inhibited organic cation transporter (OCT)1, OCT2, and multidrug and toxin extrusion transporters (MATEs) at tested concentration of 100 uM, although risk assessment based on the current Food and Drug Administration in vitro drug–drug interaction (DDI) guidance using the mechanistic static model did not reveal any clinically relevant inhibition on OCTs and MATEs. However, a DDI risk was flagged with EMA static model predictions. Hence, a physiologically based pharmacokinetic (PBPK) model of fostemsavir/temsavir was developed to further assess the DDI risk potential of OCT and MATEs inhibition by temsavir and predict changes in metformin (a sensitive OCT and MATEs substrate) exposure. No clinically relevant impact on metformin concentrations across a wide range of temsavir concentrations was predicted; therefore, no dose adjustment is recommended for metformin when co‐administered with fostemsavir.

The article deals with the motion of the breech block carrier and the weapon casing of an automatic weapon mounted on a flexible carriage and the base of the weapon. Earlier works, which did not consider the dynamic properties of the base of the weapon, did not allow to reconcile the calculated and experimental results of the weapon casing displacement when shooting from firing rests. For the analysis of the motion of individual parts, the methods of mathematical modelling and firing experiments using a high-speed camera were chosen. Calculations show the best accord with experiment when modelling the system with 4 degrees of freedom. The oscillation of the system regarding the movement of the breech block carrier and the weapon casing was investigated under changed conditions of rate of fire, the use of a muzzle brake and different types of shock absorbers. The velocities and displacements of the weapon casing and the breech block carrier at different values of the impulse of the gases to the breech block carrier were determined.

Abstract This paper presents a unique 15-year dataset of Incident Management Situation Reports (IMSR), which document daily wildland fire situations across ten geographical regions in the United States. The IMSR dataset includes summaries for each reported day on national and regional wildfire activities, wildfire-specific activities, and committed fire suppression resources (i.e., personnel and equipment). This dataset is distinct from other wildfire data sources as it provides daily information on national fire suppression resource utilization, national and regional preparedness levels, and management priority for each region and fire. We developed an open-source Java program, IMSR-Tool, to process 3,124 IMSR reports available from 2007 to 2021 to generate this structured IMSR dataset, which can be updated when future reports become available. The dataset presented here and its future extension enable researchers and practitioners to study historical wildfire activity and resource use across regions and time, examine fire management perceptions, evaluate strategies for fire prioritization and fire resource allocation, and exploit other broader usage to improve wildfire management and response in the United States.

Water pollution remains a significant global challenge, with dye contamination from industrial activities being particularly problematic. Adsorption is widely recognized as an efficient, rapid, and cost-effective method for pollutant removal. To enhance adsorption efficiency, researchers have increasingly focused on the development of reusable adsorbent materials. Magnetic materials, in particular, have garnered attention due to their ability to be easily recovered through the application of an external magnetic field. In this study, ferrite spinel adsorbents were synthesized by substituting Co(ii) into the FeFe2O4 spinel structure using a coprecipitation method. The random distribution of a Co cation into host FeFe2O4 compounds, Fe1–x CoxFe2O4 (x = 0–1), strongly influenced optical and magnetic properties. Nanoparticle sizes varying within 10–17 nm were obtained in Fe1−x CoxFe2O4 compounds. X-ray diffraction and Fourier transform infrared spectroscopy analyses revealed a single-crystal phase that was well fabricated. The optical bandgap energy decreased from 2.27 to 1.89 eV, together with a reduction of magnetic moment from 93.5 to 43.1 emu/g. The Fe1−x CoxFe2O4 materials demonstrated significant adsorption performance for Direct Red 79 (DR79), particularly at low pH levels, with optimal results observed at x = 0.5 (FC3). The adsorption behavior was effectively described by the Langmuir and Redlich–Peterson models. Kinetic analysis revealed that the pseudo-second-order and intragranular diffusion models provided the best fit. Thermodynamic analysis indicated an endothermic process (ΔH = 74.947 kJ/mol), suggesting that the adsorption mechanism is primarily physical. This study underscores the potential of Fe1−x CoxFe2O4 materials for the effective removal of Direct Red 79 (DR79), offering valuable insights into their synthesis, characterization, and application for environmental remediation. After four cycles of recovery and reuse, the FC3 magnetic nanomaterial was able to remove 42% of the DR79 pollutant while maintaining good chemical stability. The adsorption efficiency of the material for the actual textile wastewater sample reached 57% for color removal and 54.5% for chemical oxygen demand reduction.

This study presents a detailed analysis of the thermal degradation and kinetic behavior of two Amazonian wood species, Goupia glabra (cupiúba) and Manilkara huberi (maçaranduba), using thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), Fourier-transform infrared spectroscopy (FTIR-ATR), and direct infusion mass spectrometry (DIMS). Wood samples were subjected to controlled heating rates of 20, 40, and 60 °C/min from 25 to 800 °C under an argon atmosphere. TGA revealed moisture evaporation below 120 °C, with hemicellulose degradation occurring between 220 and 315 °C, cellulose decomposition between 315 and 400 °C, and lignin breakdown over a broader range from 180 to 900 °C. The highest rate of mass loss occurred at 363.99 °C for G. glabra and 360.27 °C for M. huberi at a heating rate of 20 °C/min, with shifts to higher temperatures at faster heating rates. Activation energies were calculated using Arrhenius and Kissinger models, yielding values between 53.46–61.45 kJ/mol for G. glabra and 58.18–62.77 kJ/mol for M. huberi, confirming their stable thermal profiles. DSC analysis identified a significant endothermic peak related to moisture evaporation below 100 °C, followed by two exothermic peaks. For G. glabra, the first exothermic peak appeared at 331.45 °C and the second at 466.08 °C, while for M. huberi, these occurred at 366.41 °C and 466.08 °C, indicating the decomposition of hemicellulose, cellulose, and lignin. Enthalpy values for G. glabra were 12,633.37 mJ and 18,652.66 mJ for the first and second peaks, respectively, while M. huberi showed lower enthalpies of 9648.04 mJ and 14,417.68 mJ, suggesting a higher energy release in G. glabra. FTIR-ATR analysis highlighted the presence of key functional groups in both species, with strong absorption bands in the 3330–3500 cm−1 region corresponding to O-H stretching vibrations, indicative of hydroxyl groups in cellulose and hemicellulose. The 1500–1600 cm−1 region, representing aromatic C=C vibrations, confirmed the presence of lignin. Quantitatively, these results suggest a high content of cellulose and lignin in both species. DIMS analysis further identified polyphenolic compounds and triterpenoids in M. huberi, with major ions at m/z 289 and 409, while G. glabra showed steroidal and polyphenolic compounds with a base peak at m/z 395. These findings indicate the significant presence of bioactive compounds, contributing to the wood’s resistance to microbial degradation. This comprehensive thermal and chemical characterization suggests that both species have potential industrial applications in environments requiring high thermal stability.

Extreme spread events (ESEs), often characterized by high intensity and rapid rates of spread, can overwhelm fire suppression and emergency response capacity, threaten responder and public safety, damage landscapes and communities, and result in high socioeconomic costs and losses. Advances in remote sensing and geospatial analysis provide an improved understanding of observed ESEs and their contributing factors; however, there is a need to improve anticipatory and predictive capabilities to better prepare, mitigate, and respond. Here, leveraging individual-fire day-of-arrival raster outputs from the FSim fire modeling system, we prototype and evaluate methods for the simulation and categorization of ESEs. We describe the analysis of simulation outputs on a case study landscape in Colorado, USA, summarize daily spread event characteristics, threshold and probabilistically benchmark ESEs, spatially depict ESE potential, and describe limitations, extensions, and potential applications of this work. Simulation results generally showed strong alignment with historical patterns of daily growth and the proportion of cumulative area burned in the western US and identified hotspots of high ESE potential. Continued analysis and simulation of ESEs will likely expand the horizon of uses and grow in salience as ESEs become more common.

BackgroundThe etiology of ischemic stroke is multifactorial. Several gene mutations have been identified as leading causes of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a hereditary disease that causes stroke and other neurological symptoms. ObjectiveWe aimed to identify the variants of NOTCH3 and thrombophilia genes, and their complex interactions with other factors. MethodsWe conducted a hierarchical cluster analysis (HCA) on the data of 100 patients diagnosed with ischemic stroke. The variants of NOTCH3 and thrombophilia genes were identified by polymerase chain reaction with confronting 2-pair primers and real-time polymerase chain reaction. The overall preclinical characteristics, cumulative cutpoint values, and factors associated with these somatic mutations were analyzed in unidimensional and multidimensional scaling models. ResultsWe identified the following optimal cutpoints: creatinine, 83.67 (SD 9.19) µmol/L; age, 54 (SD 5) years; prothrombin (PT) time, 13.25 (SD 0.17) seconds; and international normalized ratio (INR), 1.02 (SD 0.03). Using the Nagelkerke method, cutpoint 50% values of the Glasgow Coma Scale score; modified Rankin scale score; and National Institutes of Health Stroke Scale scores at admission, after 24 hours, and at discharge were 12.77, 2.86 (SD 1.21), 9.83 (SD 2.85), 7.29 (SD 2.04), and 6.85 (SD 2.90), respectively. ConclusionsThe variants of MTHFR (C677T and A1298C) and NOTCH3 p.R544C may influence the stroke severity under specific conditions of PT, creatinine, INR, and BMI, with risk ratios of 4.8 (95% CI 1.53-15.04) and 3.13 (95% CI 1.60-6.11), respectively (Pfisher

Abstract Background Healthcare utilization is typically adversely affected when the treatment is expensive and requires multiple visits. We examined the determinants of healthcare-seeking for Hepatitis C virus (HCV) infection which is asymptomatic, chronic, and requires costly treatment in an urban tertiary care referral hospital in Vietnam. Methods We conducted a secondary analysis of hospital data for patients attending the Hospital for Tropical Diseases in Ho Chi Minh City, Vietnam between 2017 and 2020 specifically for HCV infection treatment. Poisson regression was used to determine the effect of personal factors (age, sex, comorbidities) and structural factors (health insurance, proximity to the facility, seasonality, year of visit) on the number of hospital visits. Results From 2017 to 2020 a total of 22,052 eligible patients sought treatment in the hospital. Among the patients, 50.4% were males and 58.7% were > 50 years of age. The mean number of visits per person was 2.17. In the multivariate analysis compared to 2017, the number of hospital visits increased by 4% in 2018 and then significantly decreased in 2019 and 2020. Visit numbers were significantly lower (6%) among South East region residents compared to those from Central Highlands and for those who lived further away from the hospital. The visit numbers were significantly higher among older age groups (5–11%), those with health insurance (6%), and those with comorbidities (5%) compared to others. Although the number of hospital visits by females was higher (7%) than males in 2017, it significantly decreased in subsequent years. Conclusions Our study indicated that there are both structural and individual factors affecting the number of visits for HCV treatment. To meet the global strategy for elimination of HCV, Vietnam Government needs to address the structural and personal barriers to healthcare seeking, with a special focus on women.

Data sharing holds promise to accelerate innovative discoveries through artificial intelligence (AI) and traditional analytics. However, it remains unclear whether these prospects translate into tangible benefits in improving health care and scientific progress. In this cross-sectional study, we investigate current data reuse practices and explore ways to enhance the use of existing data in clinical research, focusing on low- and middle-income countries. 643 clinical researchers and data professionals participated in the study. 55.5% analysed clinical trial data. 75.3% of data users analysed data from observational studies obtained mainly through personal requests or downloads from publicly available sources. Data was mainly used to influence the design of new studies or in pooled and individual patient-level data meta-analyses. Key benefits realised were career progression and academic qualification, with more gains reported by users affiliated with high-income and upper-middle-income countries (p = 0.046, chi = 8.0). Scientific progress through publications and collaborations was associated with gender (p = 0.012, chi = 10.9), with males more likely to contribute. Benefits to the public although minimal, were associated with career seniority (p = 0.001, chi = 18.8), with works by senior researchers being more likely to influence health policy or treatment guidelines. Although 54% of the respondents accessed at least 3 datasets in the past 5 years, 79.4% of data users encountered difficulty finding relevant data for planned analyses. Researchers affiliated with low and middle income institutions reported more difficulty interpreting data (p = 0.012, chi = 25.7), while challenges with language were regionally influenced (p = 0.000, chi = 51.3) and more commonly reported by researchers in Latin America and South and East Asia institutions. While the utilisation of shared data is lower than expected, focused efforts to enrich existing data with extensive metadata using standard terminologies can enhance data findability. Investment in training programmes, building professional networks, and mentorship in data science may improve the quality of data generated and increase researchers' ability to use existing datasets.

Abstract Gepotidacin is a novel triazaacenaphthylene antibiotic in phase III development. Based on nonclinical in vitro characterization of gepotidacin metabolism, two phase I studies were conducted in healthy participants to investigate clinical drug–drug interactions (DDIs). We assessed gepotidacin as a DDI victim with a potent cytochrome P450 (CYP) 3A4/P‐glycoprotein (P‐gp) inhibitor (itraconazole), potent CYP3A4 inducer (rifampicin), and nonspecific organic cation transporter (OCT)/multidrug and toxic extrusion transporter (MATE) renal transport inhibitor (cimetidine) via single doses of gepotidacin before and after co‐administration with multiple doses of the modulator drugs. Gepotidacin DDI perpetrator potential for P‐gp inhibition (digoxin) and CYP3A4 inhibition (midazolam) was evaluated via single doses of the two‐drug cocktail without and with gepotidacin. The DDI magnitudes were interpreted based on area under the concentration‐time curve (AUC). A weak DDI (AUC increase 48%–50%) was observed for gepotidacin co‐administered with itraconazole. A clinically significant decrease in gepotidacin plasma AUC (52%) was observed with rifampicin coadministration, indicating a moderate DDI. There was no DDI for gepotidacin with cimetidine; a unique biomarker approach showed increased serum creatinine (24%), decreased renal clearance of creatinine (21%), and N1‐methylnicotinamide (39%), which confirmed extensive MATE inhibition and partial OCT2 inhibition. Gepotidacin was not a P‐gp DDI perpetrator, although the maximum plasma concentration of digoxin increased (53%) and is potentially clinically relevant given its narrow therapeutic index. Gepotidacin demonstrated weak CYP3A4 inhibition with midazolam (

Abstract Purpose To determine the rate of acute kidney injury (AKI) after laparoscopic colorectal cancer (CRC) surgery and the predictive value of urine neutrophil gelatinase‐associated lipocalin (uNGAL) for postoperative AKI and mortality during 3 years of follow‐up. Methods A total of 216 CRC patients who had undergone laparoscopic surgery were included in our study. We divided all patients into two groups, including group 1 (n = 31) with postoperative AKI and group 2 (n = 185) without postoperative AKI. Urine NGAL was measured using the ELISA technique. Clinical and laboratory data were collected the day before surgery. Postoperative AKI included events occurring within 7 days of the index operation, and mortality was obtained during 3 years of follow‐up. Results The ratio of postoperative AKI was 14.35% (31/216 patients). The urine NGAL level in group 1 was significantly higher than in group 2, p

Background: The B-type rafkinase (BRAF) V600E gene mutation plays an important role in the pathogenesis, diagnosis, and prognosis of thyroid carcinoma. This study was conducted to investigate the rate of the BRAF V600E mutation, the relationships between the BRAF V600E gene mutation and some immunohistochemical markers, and recurrence rate in patients with differentiated thyroid cancer. Method: The study was conducted by a descriptive and longitudinal follow-up method on 102 thyroid carcinoma patients at 103 Military Hospital, Hanoi, Vietnam. All patients were identified with the BRAF V600E gene mutation by real-time polymerase chain reaction. Results: The rate of BRAF V600E gene mutation in patients with thyroid cancer was 60.8%. Patients with BRAF V600E gene mutation had a significantly higher rate of positive cyclooxygenase 2 (COX-2) and Ki67 markers than those without the mutation (COX-2: odds ratio [OR] = 2.93; 95% confidence interval [CI] = 1.27-6.74, P = .011; Ki67: OR = 3.41; 95% CI = 1.31-8.88, P = .01). A statistically significant relationship was identified between the rate of BRAF V600E mutation and the rate of positive Hector Battifora mesothelial 1 (HBME-1) (B = −1.040; P = .037) and COX-2 (B = −1.123; P = .023) markers. The recurrence rate in patients with BRAF V600E gene mutation was significantly higher than that in those without the mutation ( P = .007). The mean of the recurrence time of patients with BRAF V600E mutation was significantly lower than that in those without the mutation ( P = .011). Conclusions: A high prevalence of BRAF V600E gene mutation was found in thyroid carcinoma patients. The rates of positive HBME-1, COX-2, and Ki67 markers were significantly correlated to BRAF V600E gene mutation. Patients with BRAF V600E gene mutation showed a significantly higher relapse rate and earlier relapse time than those without the mutation.

Collagen provides tissue strength and structural integrity. Quantification of the orientated dispersion of collagen fibers is an important factor when studying the mechanical properties of the cervix. In this study, for the first time, a new method for rapid characterization of the collagen fiber orientations of the cervix using linearly polarized light colposcopy is presented. A total of 24 colposcopic images were captured using a cross-polarized imaging system with white LED light sources. In the preprocessing stage, the Red channel of the RGB image was chosen, which contains no information of the blood vessels because of the low-absorption of blood cells in the red region. OrientationJ, which is an ImageJ plug-in, was used to estimate the local orientation of the collagen fibers. The result shows that in the nonpregnant cervix, the middle zone (Zone 2) has circumferentially aligned collagen fibers while the inner zone (Zone 1) has randomly arranged. The collagen fiber dispersion in Zone 2 is much smaller than that in Zone 1 at all four quadrants region (anterior, posterior, left, and right quadrant). This new analysis technique could potentially combine with diagnostic tools to provide a quantitative platform of collagen fibers in the clinic.

Secondary lymphedema is a common condition among cancer survivors, and treatment strategies to prevent or treat lymphedema are in high demand. The development of novel strategies to diagnose or treat lymphedema would benefit from a robust experimental animal model of secondary lymphedema. The purpose of this methods paper is to describe and summarize our experience in developing and characterizing a rat hindlimb model of lymphedema. Here we describe a protocol to induce secondary lymphedema that takes advantage of micro computed tomography imaging for limb volume measurements and visualization of lymph drainage with near infrared imaging. To demonstrate the utility of this preclinical model for studying the therapeutic benefit of novel devices, we apply this animal model to test the efficacy of a biomaterials-based implantable medical device.

High-speed rail (HSR) is considered as one of the breakthrough technologies in the field of passenger transport in the second half of the 20th century, however, the construction, maintenance and operation are very expensive, involving huge amounts of costs. In Vietnam, the Ministry of Transport has submitted to the Politburo to consider the investment policy of the North-South high-speed railway project with a total length of 1,508 km, with an estimated total investment of 58.71 billion [1]. This is the first project deployed in Vietnam, with the largest total investment in Vietnam's history, so it is necessary to carefully study in order to choose the method and source of investment capital, technical factors and suitable models with international development trends and conditions in Vietnam. The article studies the experience of mobilizing financial resources for the development of the HSR system in the form of a public-private partnership (PPP) in some typical countries in the world; based on the actual conditions of Vietnam to draw important lessons in choosing investment forms in line with development policies and actual resources, ensuring strategic and long-term vision.

Abstract Background Early recognition and call for help, fast initiation of chest compressions, and early defibrillation are key elements to improve survival after cardiac arrest but are often not achieved. We aimed to investigate what occurs during the initial treatment of unannounced in situ simulated inhospital cardiac arrests and reasons for successful or inadequate initial resuscitation efforts. Methods We conducted unannounced full-scale in situ simulated inhospital cardiac arrest followed by a debriefing. Simulations and debriefings were video recorded for subsequent analysis. We analyzed quantitative data on actions performed and time measurements to key actions from simulations and qualitative data from transcribed debriefings. Results We conducted 36 simulations. Time to diagnosis of cardiac arrest was 37 (27; 55) s. Time to first chest compression from diagnosis of cardiac arrest was 37 (18; 74) s, time to calling the cardiac arrest team was 144 (71; 180) s, and time to first shock was 221 (181; 301) s. We observed participants perform several actions after diagnosing the cardiac arrest and before initiating chest compressions. Domains emerging from the debriefings were teaming and resources. Teaming included the themes communication, role allocation, leadership, and shared knowledge, which all included facilitators and barriers. Resources included the themes knowledge, technical issues, and organizational resources, of which all included barriers, and knowledge also included facilitators. Conclusion Using unannounced in situ simulated cardiac arrests, we found that key elements such as chest compressions, calling the cardiac arrest team, and defibrillation were delayed. Perceived barriers to resuscitation performance were leadership and teaming, whereas experience, clear leadership, and recent training were perceived as important facilitators for treatment progress.

This paper uses Molecular Dynamics (MD) method to study the influence of high temperature (T) and high pressure (P) on the structure and phase transition of Fe2O3 materials. The results show that, when increasing the temperature from T = 300 K to T = 7000 K, P = 0.0 GPa, the size (1) of the Fe2O3 materials increases, the energy (E) increases, the length link (r) decreased, the number of structural units FeO4, FeO5 increased, and FeO6 decreased. Similarly, as the pressure (P) is increased, from P = 0 GPa to P = 360 GPa at temperatures T, l decreases, E increases, r decreases, FeO4 decreases and disappears, FeO5 decreases, and FeO6 increases at high P with P ≥ 150 GPa, FeO5 disappeared at P ≥ 250 GPa and only FeO6 appeared at T = 2300, 7000 K. In addition, when increasing T, P, the bond angle of Fe–O–Fe, O–Fe–O decreases, E increases, r decreases, l increases when T increases and l decreases when P increases, leading to the number of structural units FeO4, FeO5 increasing and FeO6 decreasing when T increases and vice versa when P increases. In addition, the phase transition temperature (Tm), Tm = 2300 K was determined. All the obtained results will be the basis for future experimental studies of amorphous Fe2O3 materials

Innovative people are desperately wanted in nowadays world, wherefore tools to measure individual innovativeness are needed. This work reviews the commonly used metrics to gauge innovativeness, such as the Individual Innovativeness Scale (IIS). Hereby, it demonstrates via a survey that often a simple self-evaluation question contains the same information as conventional psychological surveys. As an alternative, another survey investigates whether bibliographical information can predict innovativeness. Finally, a new type of experiments to measure innovativeness is proposed, enabled by recent progress in neuroscience, that will not rely on classical self-report questions but on empirical data on the candidate’s brain activity in response to external stimuli.

Ertesvåg, Xiao et al. describe a method to evaluate neutralising antibodies to SARS-CoV-2 infection or vaccination, including variants of concern. A second mRNA-vaccine dose results in a broader antibody repertoire in adults, although with reduced cross-reactivity to beta and gamma compared to alpha and delta, particularly in the elderly.

The hepatitis C virus (HCV) epidemic in Western countries is primarily perpetuated by the sub-populations of men who have sex with men (MSM) and people who inject drugs (PWID). Understanding the dynamics of transmission in these communities is crucial for removing the remaining hurdles towards HCV elimination. We sequenced 269 annotated HCV plasma samples using probe enrichment and next-generation sequencing, obtaining 224 open reading frames of HCV (OR497849-OR498072). Maximum likelihood phylogenies were generated on the four most prevalent subtypes in this study (HCV1a, 1b, 3a, 4d) with a subsequent transmission cluster analysis. The highest rate of clustering was observed for HCV4d samples (13/17 (76.47%)). The second highest rate of clustering was observed in HCV1a samples (42/78 (53.85%)) with significant association with HIV-positive MSM. HCV1b and HCV3a had very low rates of clustering (2/83 (2.41%) and (0/29)). The spread of the prevalent subtype HCV1b appears to have been largely curtailed, and we demonstrate the onwards transmission of HCV1a and HCV4d in the HIV-positive MSM population across municipal borders. More systematic data collection and sequencing is needed to allow a better understanding of the HCV transmission among the community of PWID and overcome the remaining barriers for HCV elimination in Belgium.

In this paper, we studied the effect of the 2D epoxy thin films’ shape with equilateral triangle and square structures, and matrix size Lx × Ly of (10 × 9), (20 × 19), (30 × 29), and (40 × 39) with equilateral triangle structure and (10 × 10), (20 × 20), (30 × 30), and (40 × 40) with the square structure on their mechanical properties [such as strain (ɛ), stress (σ), Young stress (E), and shear strain (G)] by using the Monte Carlo simulation method. The results show that when the shape of the 2D epoxy thin film is changed from an equilateral triangle structure to a square structure, the values of σ, E, and G decreased sharply. In addition, when the matrix size is increased from (10 × 9) to (20 × 19), (30 × 29), and (40 × 39) with an equilateral triangle structure and from (10 × 10) to (20 × 20), (30 × 30), and (40 × 40) with a square structure, σ slightly increased, but E and G decreased slightly. These results prove that the influence of structure shape on the mechanical properties of the 2D epoxy thin film is very large. The strain stress on the epoxy 2D thin film with an equilateral triangle structure and with a matrix size of (30 × 29) has a value of σ = 63.3 MPa. This result is consistent with the experimental result that σ of bulk epoxy has the maximum value of σmax = 64.76 MPa. The results are the basis for experimental research in future studies on practical applications of epoxy-thin films. In these cases, when thin films with equilateral triangle structures are used in biomedical fields, high stresses are required (such as replacement material for adaxial onion epidermis and fibrin and collagen with low stress).

Abstract Background and Aim A low serum prealbumin concentration is common in maintenance hemodialysis patients with hepatitis B and C and may be associated with mortality. In this study, we assessed Department of Nephrology and Hemodialysis predictive value of a low serum prealbumin concentration on mortality in HD patients using reused low‐flux dialyzers who were infected with hepatitis B and/or C virus. Methods We used serum prealbumin levels to predict the long‐term mortality of 326 hemodialysis patients. The patients were divided into two groups: group 1 (n = 140, with hepatitis B and/or C virus infections), and group 2 (n = 186, without hepatitis virus infections). Results During a 5‐year follow‐up, there were 75 deaths due to all‐cause mortality (23.0%). Mortality was significantly higher (P

Canine parvovirus (CPV) is one of the most important pathogens causing enteritis in dogs. Although there have been a few reports of CPV in Vietnam, recent information on CPV infection in domestic dogs in Vietnam is limited. Faecal samples collected from 30 diarrheic and 50 healthy dogs were examined by PCR for detection of CPV DNA. The prevalence of CPV in diarrheic dogs (43.3%, 13/30) was significantly higher than in healthy dogs (4.0%, 2/50), indicating that CPV was a major cause of diarrhoea in domestic dogs. Genotyping of 15 CPV strains showed that both CPV‑2a and CPV‑2c were circulating and that CPV‑2c was a dominant CPV variant in Vietnam. Virus isolation was performed from faecal samples using A72/cSLAM cells, and nine CPV strains were successfully isolated. The dominant genotype spreading among Vietnamese dogs has changed from CPV‑2b to CPV‑2c.

Enterovirus A71 (EV-A71) and coxsackievirus A6 (CVA6) cause hand, foot and mouth disease (HFMD) and are occasionally linked to severe neurologic complications and large outbreaks worldwide. We estimated EV-A71 and CVA6 seroprevalence using cross-sectional age-stratified samples collected in 2006, 2011, and 2017. Seroprevalences of EV-A71 and CVA6 increased from 32% and 54% at 6–11 months to >75% by 10 years of age. Antibody titers declined after 20 years, which could indicate infrequent re-exposure in older populations. Age profiles for acquiring infections and mean titers were comparable in the 3 testing years, despite the marked increase in incidence of CVA6-related HFMD from 2010. The uncoupling of changes in disease severity from the infection kinetics of CVA6 as we inferred from the seroprevalence data, rather than incidence of infection over the 11-year study period, provides further evidence for a change in its pathogenicity.

SUMMARY: Background: Lateral intercostal artery perforator (LICAP) flap for breast volume augmentation provides the benefits of addressing axillary tissue excess and avoiding intramuscular dissection. Previous experience with the LICAP flap in patients with prior breast conservation therapy (BCT) has led to the development of an extended version for massive weight loss (MWL) patients as well. Methods: A retrospective review of all cases of LICAP flaps was performed by a single surgeon. Data were subsequently extracted and analyzed including patient demographics, indication and timing of volume augmentation, complications, and follow-up length. Results: From 2016 to 2020, 12 patients underwent 16 LICAP flaps for volume augmentation. Indications for volume augmentation included deficits from prior oncologic surgery (ten patients) and loss of volume due to MWL (two patients). The average BMI was 29.9 kg/m2. Among the oncologic group, eight patients had delayed reconstruction, while two were immediate. Nine patients underwent radiation prior to volume augmentation. Eight of the 14 patients simultaneously received fat grafting. There were 4 cases of delayed wound healing that improved with local wound care. There were no statistically significant differences in complication rates between the oncologic and MWL groups. The average length of follow-up was 11.4 months. Conclusions: This study supports that the application of the LICAP flap can be effectively broadened from the oncologic population to the MWL population. If needed, extending the flap provides an option to simultaneously address excess axillary and back tissue.

Abstract Privacy protection is paramount in conducting health research. However, studies often rely on data stored in a centralized repository, where analysis is done with full access to the sensitive underlying content. Recent advances in federated learning enable building complex machine-learned models that are trained in a distributed fashion. These techniques facilitate the calculation of research study endpoints such that private data never leaves a given device or healthcare system. We show—on a diverse set of single and multi-site health studies—that federated models can achieve similar accuracy, precision, and generalizability, and lead to the same interpretation as standard centralized statistical models while achieving considerably stronger privacy protections and without significantly raising computational costs. This work is the first to apply modern and general federated learning methods that explicitly incorporate differential privacy to clinical and epidemiological research—across a spectrum of units of federation, model architectures, complexity of learning tasks and diseases. As a result, it enables health research participants to remain in control of their data and still contribute to advancing science—aspects that used to be at odds with each other.

Pancreatic cancer is known for its tumor microenvironment (TME), which is rich in stromal and immune cells supporting cancer growth and therapy resistance. In particular, tumor-associated macrophages (TAMs) are known for their angiogenesis- and metastasis-promoting properties, which lead to the failure of conventional therapies for pancreatic cancer. Hence, treatment options targeting TAMs are needed. The C-C chemokine receptor type 4 (CCR4) is critical for immune cell recruitment into the TME, and in this paper we explore the effects of its genetic or immunotherapeutic blockade in pancreatic-cancer-bearing mice. Murine PDA6606 pancreatic cancer cells and murine peritoneal macrophages were used for in vitro migration assays. In vivo, a syngeneic, orthotropic pancreatic cancer model was established. Tumor growth and survival were monitored under prophylactic and therapeutic application of a CCR4 antagonist (AF-399/420/18025) in wildtype (CCR4wt) and CCR4-knockout (CCR4−/−) mice. Immune infiltration was monitored in tumor tissue sections and via flow cytometry of lysed tumors. PDA6606 cells induced less migration in CCR4−/− than in CCR4wt macrophages in vitro. Pancreatic TAM infiltration was higher, and survival was reduced in CCR4wt mice compared to CCR4−/− mice. Antagonizing CCR4 in wildtype mice revealed similar results as in CCR4−/− mice without antagonization. Prophylactic CCR4 antagonist application in wildtype mice was more efficient than therapeutic antagonization. CCR4 seems to be critically involved in TAM generation and tumor progression in pancreatic cancer. CCR4 blockade may help prolong the relapse-free period after curative surgery in pancreatic cancer and improve prognosis.

The ability of the HIV-1 accessory proteins Nef and Vpu to decrease CD4 levels contributes to the protection of infected cells from antibody-dependent cellular cytotoxicity (ADCC) by preventing the exposure of Env vulnerable epitopes. Small-molecule CD4 mimetics (CD4mc) based on the indane and piperidine scaffolds such as (+)-BNM-III-170 and (S)-MCG-IV-210 sensitize HIV-1-infected cells to ADCC by exposing CD4-induced (CD4i) epitopes recognized by non-neutralizing antibodies that are abundantly present in plasma from people living with HIV. Here, we characterize a new family of CD4mc, (S)-MCG-IV-210 derivatives, based on the piperidine scaffold which engages the gp120 within the Phe43 cavity by targeting the highly conserved Asp368 Env residue. We utilized structure-based approaches and developed a series of piperidine analogs with improved activity to inhibit the infection of difficult-to-neutralize tier-2 viruses and sensitize infected cells to ADCC mediated by HIV+ plasma. Moreover, the new analogs formed an H-bond with the α-carboxylic acid group of Asp368, opening a new avenue to enlarge the breadth of this family of anti-Env small molecules. Overall, the new structural and biological attributes of these molecules make them good candidates for strategies aimed at the elimination of HIV-1-infected cells.

Structural features such as the shape, the lattice constant, the bond length, the total energy per cell, and the energy bandgap (Eg) of C13H8OS-X are studied by the calculating Partial Density Of States (PDOS), and DOS package of the Material Studio (MS) software. Calculations show that the bond length and the bond angle between atoms insignificant change as 1.316 Å to 1.514 Å for C-C, 1.211 Å for C-O, 1.077 Å to 1.105 Å for C-H; bond angle of round one changes from 118.883° to 121.107° for C-C-C, from 117.199° to 122.635° for H-C-C, from 119.554° to 123.147° for C-C-O and from 109.956° to 117.537° for C-C-H. When C13H8OS-X doped in the order of -Br, -Cu, -Kr, -Ge, -As, and -Fe then bond lengths, bond angles between atoms have a nearly constant value. Particularly for links C-X, there is a huge change in value, respectively 1.876, 1.909, 10.675, 2.025, 2.016, 2.014 Å; the total energy change from Etot = −121,794 eV to Etot = −202,859 eV, and the energy band gap decreases from Eg = 2.001 eV to Eg = 0.915 eV. The obtained results are useful and serve as a basis for future experimental research.

The content of this paper focuses/shed light on the effects of X (X = S in P1 and X = O in P2) in C11H7NSX and R (R = H in P3, R = OCH3 in P4, and R = Cl in P5) in C18H9ON2S2-R on structural features and band gaps of the polythiophenes containing benzo[d]thiazole and benzo[d]oxazole by the Density Function Theory (DFT) method/calculation. The structural features including the electronic structure lattice constant (a), shape, total energy (Etot) per cell, and link length (r), are measured via band gap (Eg) prediction with the package of country density (PDOS) and total country density (DOS) of material studio software. The results obtained showed that the link angle and the link length between atoms were not changed significantly while the Etot was decreased from Etot = – 1904 eV (in P1) to Etot = – 2548 eV (in P2) when replacing O with S; and the Etot of P3 was decreased from Etot = – 3348 eV (in P3) when replacing OCH3, Cl on H of P3 corresponding to Etot = – 3575 eV (P4), – 4264 eV (P5). Similarly, when replacing O in P1 with – S to form P2, the Eg of P1 was dropped from Eg = 0.621 eV to Eg = 0.239 eV for P2. The Eg of P3, P4, and P5 is Eg = 0.006 eV, 0.064 eV, and 0.0645 eV, respectively. When a benzo[d]thiazole was added in P1 (changing into P3), the Eg was extremely strongly decreased, nearly 100 times (from Eg = 0.621 eV to Eg = 0.006 eV). The obtained results serve as a basis for future experimental work and used to fabricate smart electronic device.

This study aims to provide new insights into the influencing factors of the Earth (low temperature, depth, and annealing time) on the heterogeneous kinetics of bulk Fe2O3 by the molecular dynamics simulation method. The obtained results show that there is an influence of the low temperature corresponding to the temperature of liquefied gases, such as helium (4.212 K), nitrogen (77 K), argon (83.8058 K), oxygen (90 K), and carbon (194.5 K), the depth (h) of the Earth’s surface from h0 = 0 km to h5* = 6370 km that corresponds to the temperature (T) from T = 300 K to T = 7000 K and the pressure (P) from P = 0 GPa to P = 360 GPa, and then annealing time (t) (120 ps) on the heterogeneous kinetics of bulk Fe2O3, such as the Radial Distribution Function (RDF), Coordination Number (CN), angular distribution, number of structural units, size (l), and energy (E). When the temperature increases in the low temperature (T) region at zero pressure (P), the link length (r), RDF height, size, CN, and the number of structural units FeO4, FeO5, and FeO6 do not change significantly, but only the very large change in E serves as the basis for future research on the mechanical properties and electrical conductivity of semiconductor materials. When the depth (h) of the Earth’s surface and the thermal annealing time at different locations are increased, the characteristic quantities of dynamic dynamics change greatly, including the disappearance of FeO4 at depth h1 ≥ 17.5 km and the appearance of additional structural units FeO7, FeO8, and FeO9 at h3 ≥ 1742 km and FeO10 at h5 ≥ 5562.5 km.

Abstract Fat grafting can reduce radiation‐induced fibrosis. Improved outcomes are found when fat grafts are enriched with adipose‐derived stromal cells (ASCs), implicating ASCs as key drivers of soft tissue regeneration. We have identified a subpopulation of ASCs positive for CD74 with enhanced antifibrotic effects. Compared to CD74− and unsorted (US) ASCs, CD74+ ASCs have increased expression of hepatocyte growth factor, fibroblast growth factor 2, and transforming growth factor β3 (TGF‐β3) and decreased levels of TGF‐β1. Dermal fibroblasts incubated with conditioned media from CD74+ ASCs produced less collagen upon stimulation, compared to fibroblasts incubated with media from CD74− or US ASCs. Upon transplantation, fat grafts enriched with CD74+ ASCs reduced the stiffness, dermal thickness, and collagen content of overlying skin, and decreased the relative proportions of more fibrotic dermal fibroblasts. Improvements in several extracellular matrix components were also appreciated on immunofluorescent staining. Together these findings indicate CD74+ ASCs have antifibrotic qualities and may play an important role in future strategies to address fibrotic remodeling following radiation‐induced fibrosis.

Abstract Fat grafting is a surgical technique able to reconstruct and regenerate soft tissue. The adipose‐derived stromal cells (ASCs) within the stromal vascular fraction are believed to drive these beneficial effects. ASCs are increasingly recognized to be a heterogeneous group, comprised of multiple stem and progenitor subpopulations with distinct functions. We hypothesized the existence of an ASC subpopulation with enhanced angiogenic potential. Human ASCs that were CD34+CD146+, CD34+CD146−, or CD34+ unfractionated (UF) were isolated by flow cytometry for comparison of expression of proangiogenic factors and endothelial tube‐forming potential. Next, lipoaspirate was enriched with either CD34+CD146+, CD34+CD146−, CD34+ UF ASCs, or was not enriched, and grafted beneath the scalp skin of immunodeficient CD‐1 Nude mice (10 000 cells/200 μL/graft). Fat retention was monitored radiographically more than 8 weeks and fat grafts were harvested for histological assessment of quality and vascularization. The CD34+CD146+ subpopulation comprised ~30% of ASCs, and exhibited increased expression of vascular endothelial growth factor and angiopoietin‐1 compared to CD34+CD146− and CD34+ UF ASCs, and increased expression of fibroblast growth factor‐2 compared to CD34+CD146− ASCs. The CD34+CD146+ subpopulation exhibited enhanced induction of tube‐formation compared to CD34+CD146− ASCs. Upon transplantation, fat enriched CD34+CD146+ ASCs underwent less resorption and had improved histologic quality and vascularization. We have identified a subpopulation of CD34+ ASCs with enhanced angiogenic effects in vitro and in vivo, likely mediated by increased expression of potent proangiogenic factors. These findings suggest that enriching lipoaspirate with CD34+CD146+ ASCs may enhance fat graft vascularization and retention in the clinical setting.

This paper proposes a system to effectively identify brain tumors on MRI images using artificial intelligence algorithms and ADAS optimization function. This system is developed with the aim of assisting doctors in diagnosing one of the most dangerous diseases for humans. The data used in the study is patient image data collected from Bach Mai Hospital, Vietnam. The proposed approach includes two main steps. First, we propose the normalization method for brain MRI images to remove unnecessary components without affecting their information content. In the next step, Deep Convolutional Neural Networks are used and then we propose to apply ADAS optimization function to build predictive models based on that normalized dataset. From there, the results will be compared to choose the most optimal method. Those results of the evaluated algorithms through the coefficient F1-score are greater than 94% and the highest value is 97.65%.

Antibiotics like rifampicin are often persistent in the environment. When entering the water, it causes antimicrobial resistance that affects the ecosystem and accumulates in the aquatic organisms and affects human health through the food chain. In this study, titanium dioxide was doped with neodymium (0.01 to 0.8%) using the sol-gel hydrothermal method. TiO2/Nd was then coated on rice husk ash to produce a modified TiO2/Nd/rice husk ash material containing 0.36% (w/w) Nd. The structural characteristics and photocatalytic properties of the materials were analyzed by X-ray diffraction, energy dispersive X-ray, transmission electron microscopy, scanning electron microscopy, forbidden zone energy, and specific surface area. The TiO2/Nd material exhibited a higher photocatalytic decomposition capacity than TiO2 and depended on the Nd content. The rifampicin removal efficiency of TiO2/Nd materials with 0.36 to 0.80% Nd contents was approximately 40% higher than that of TiO2/Nd containing 0.01 to 0.28% Nd. A new photocatalytic TiO2/Nd/rice husk ash material was developed to decompose rifampicin. The rifampicin-degrading efficiency of TiO2/Nd and TiO2/Nd/rice husk ash material reached approximately 86 and 75%, respectively, within 90 min under sunlight. Although a lower efficiency was obtained, the TiO2/Nd/rice husk ash material was selected to degrade rifampicin residue in water via the photocatalytic process (under sunlight) because of its advantages such as requirement of a small amount and easy recovery. In the rifampicin removal process, k values were found to match the zero- and first-order kinetics. In particular, for TiO2/Nd and TiO2/Nd/rice husk ash under solar irradiation, R2 values reached approximately 0.98. These results have been previously published as a preprint.

Herein, we carefully investigated the Fe3+ doping effects on the structure and electron distribution of Cr2O3 nanoparticles using X-ray diffraction analysis (XRD), maximum entropy method (MEM), and density functional theory (DFT) calculations. We showed that increasing the Fe doping induces an enlargement in the axial ratio of c/a, which is associated with an anisotropic expansion of the unit cell. We found that as Fe3+ replaces Cr in the Cr2O3 lattice, it caused a higher interaction between the metal 3d states and the oxygen 2p states, which led to a slight increase in the Cr/Fe–O1 bond length followed by an opposite effect for the Cr/Fe–O2 bonds. Our results also suggest that the excitations characterize a well-localized bandgap region from occupied Cr d to unoccupied Fe d states. The Cr2O3 and Fe-doped Cr2O3 nanoparticles behave as Mott–Hubbard insulators due to their band gap being in the d−d gap, and Cr 3d orbitals dominate the conduction band. These findings suggest that the magnitude and the character of the electronic density near the O atom bonds in Cr2O3 nanoparticles are modulated by the Cr–Cr distances until its stabilization at the induced quasi-equilibrium of the Cr2O3 lattice when the Fe3+ doping values reaches the saturation level range.

A strategy followed to integrate in vitro solubility and permeability data into a PBBM model to predict the food effect of a BCS IV zwitterionic drug (GSK3640254) observed in clinical studies is described. The PBBM model was developed, qualified and verified using clinical data of an immediate release (IR)-tablet (10–320 mg) obtained in healthy volunteers under fasted and fed conditions. The solubility of GSK3640254 was a function of its ionization state, the media composition and pH, whereas its permeability determined using MDCK cell lines was enhanced by the presence of mixed micelles. In vitro data alongside PBBM modelling suggested that the positive food effect observed in the clinical studies was attributed to micelle-mediated enhanced solubility and permeability. The biorelevant media containing oleic acid and cholesterol in fasted and fed levels enabled the model to appropriately capture the magnitude of the food effect. Thus, by using Simcyp® v20 software, the PBBM model accurately predicted the results of the food effect and predicted data were within a two-fold error with 70% being within 1.25-fold. The developed model strategy can be effectively adopted to increase the confidence of using PBBM models to predict the food effect of BCS class IV drugs.

The current research proposes an innovative strategy for the facile preparation of magnetic activated carbon (MAC) from rosemary distillation residues (RDR). As a magnetic precursor, FeCl _3 was impregnated into RDR before KOH was added as an activating agent. One-pot pyrolysis was then conducted to produce zero-valent iron nanoparticles (14.4 wt%) embedded in the activated carbon matrix. Moreover, KOH activation yielded MAC with a large total pore volume of 0.27 cm ^3 g ^−1 , a high specific surface area of 459 m ^2 g ^−1 , and hierarchical porosity. With a large porous system and different polar functional groups, MAC was subsequently investigated for malachite green (MG) removal in aqueous media. At pH 6.0, the adsorption process was consistent with the pseudo-second-order kinetic model and the Langmuir isotherm, with a maximum adsorption capacity of 82.6 mg g ^−1 . Additionally, MAC demonstrated effective reusability after five consecutive cycles, when MG removal slightly decreased from 96.4 ± 0.6 to 91.8 ± 2.3%. Notably, MAC with a strong saturation magnetization of 18.4 emu g ^−1 could be conveniently recovered from treated media through magnetic fields. Overall, rosemary distillation residue-derived magnetic activated carbon can be a potential adsorbent for malachite green remediation thanks to its cost-effectiveness, eco-friendliness, and magnetic separability.

Background: Typhoid and paratyphoid fever (enteric fever) is a common cause of non-specific febrile infection in adults and children presenting to health care facilities in low resource settings such as the South Asia. A 7-day course of a single oral antimicrobial such as ciprofloxacin, cefixime, or azithromycin is commonly used for its treatment. Increasing antimicrobial resistance threatens the effectiveness of these treatment choices. We hypothesize that combined treatment with azithromycin (active mainly intracellularly) and cefixime (active mainly extracellularly) will be a better option for the treatment of clinically suspected and culture-confirmed typhoid fever in South Asia. Methods: This is a phase IV, international multi-center, multi-country, comparative participant-and observer-blind, 1:1 randomised clinical trial. Patients with suspected uncomplicated typhoid fever will be randomized to one of the two interventions: Arm A: azithromycin 20mg/kg/day oral dose once daily (maximum 1gm/day) and cefixime 20mg/kg/day oral dose in two divided doses (maximum 400mg bd) for 7 days, Arm B: azithromycin 20mg/kg/day oral dose once daily (max 1gm/day) for 7 days AND cefixime-matched placebo for 7 days. We will recruit 1500 patients across sites in Bangladesh, India, Nepal, and Pakistan. We will assess whether treatment outcomes are better with the combination after one week of treatment and at one- and three-months follow-up. Discussion: Combined treatment may limit the emergence of resistance if one of the components is active against resistant sub-populations not covered by the other antimicrobial activity. If the combined treatment is better than the single antimicrobial treatment, this will be an important result for patients across South Asia and other typhoid endemic areas. Clinicaltrials.gov registration: NCT04349826 (16/04/2020)

Background: High cure rates with licensed durations of therapy for chronic hepatitis C virus suggest that many patients are overtreated. New strategies in individuals who find it challenging to adhere to standard treatment courses could significantly contribute to the elimination agenda. Objectives: To compare cure rates using variable ultrashort first-line treatment stratified by baseline viral load followed by retreatment, with a fixed 8-week first-line treatment with retreatment with or without adjunctive ribavirin. Design: An open-label, multicentre, factorial randomised controlled trial. Randomisation: Randomisation was computer generated, with patients allocated in a 1 : 1 ratio using a factorial design to each of biomarker-stratified variable ultrashort strategy or fixed duration and adjunctive ribavirin (or not), using a minimisation algorithm with a probabilistic element. Setting: NHS. Participants: A total of 202 adults (aged ≥ 18 years) infected with chronic hepatitis C virus genotype 1a/1b or 4 for ≥ 6 months, with a detectable plasma hepatitis C viral load and no significant fibrosis [FibroScan® (Echosens, Paris, France) score F0–F1 or biopsy-proven minimal fibrosis], a hepatitis C virus viral load 24 weeks on anti-human immunodeficiency virus drugs. Interventions: Fixed-duration 8-week first-line therapy compared with variable ultrashort first-line therapy, initially for 4–6 weeks (continuous scale) stratified by screening viral load (variable ultrashort strategy 1, mean 32 days of treatment) and then, subsequently, for 4–7 weeks (variable ultrashort strategy 2 mean 39 days of duration), predominantly with ombitasvir, paritaprevir, ritonavir (Viekirax®; AbbVie, Chicago, IL, USA), and dasabuvir (Exviera®; AbbVie, Chicago, IL, USA) or ritonavir. All patients in whom first-line treatment was unsuccessful were immediately retreated with 12 weeks’ sofosbuvir, ledipasvir (Harvoni®, Gilead Sciences, Inc., Foster City, CA, USA) and ribavirin. Main outcome measure: The primary outcome was overall sustained virological response (persistently undetectable) 12 weeks after the end of therapy (SVR12). Results: A total of 202 patients were analysed. All patients in whom the primary outcome was evaluable achieved SVR12 overall [100% (197/197), 95% confidence interval 86% to 100%], demonstrating non-inferiority between fixed- and variable-duration strategies (difference 0%, 95% confidence interval –3.8% to 3.7%, prespecified non-inferiority margin 4%). A SVR12 following first-line treatment was achieved in 91% (92/101; 95% confidence interval 86% to 97%) of participants randomised to the fixed-duration strategy and by 48% (47/98; 95% confidence interval 39% to 57%) allocated to the variable-duration strategy. However, the proportion achieving SVR12 was significantly higher among those allocated to variable ultrashort strategy 2 [72% (23/32), 95% confidence interval 56% to 87%] than among those allocated to variable ultrashort strategy 1 [36% (24/66), 95% confidence interval 25% to 48%]. Overall, a SVR12 following first-line treatment was achieved by 72% (70/101) (95% confidence interval 65% to 78%) of patients treated with ribavirin and by 68% (69/98) (95% confidence interval 61% to 76%) of those not treated with ribavirin. A SVR12 with variable ultrashort strategies 1 and 2 was 52% (25/48) (95% confidence interval 38% to 65%) with ribavirin, compared with 44% (22/50) (95% confidence interval 31% to 56) without. However, at treatment failure, the emergence of viral resistance was lower with ribavirin [12% (3/26), 95% confidence interval 2% to 30%] than without [38% (11/29), 95% confidence interval 21% to 58%; p = 0.01]. All 10 individuals who became undetectable at day 3 of treatment achieved first-line SVR12 regardless of treatment duration. Five participants in the variable-duration arm and five in the fixed-duration arm experienced serious adverse events (p = 0.69), as did five participants receiving ribavirin and five participants receiving no ribavirin. Conclusions: SVR12 rates were significantly higher when ultrashort treatment varied between 4 and 7 weeks, rather than between 4 and 6 weeks. We found no evidence of ribavirin significantly affecting first-line SVR12, with unsuccessful first-line short-course therapy also not compromising subsequent retreatment with sofosbuvir, ledipasvir and ribavirin. Future work: A priority for future work needs to be the development and evaluation of robust predictive measures to identify those patients who can be cured with ultrashort courses of therapy. Trial registration: Current Controlled Trials ISRCTN37915093, EudraCT 2015-005004-28 and CTA 19174/0370/001-0001. Funding: This project was funded by the Efficacy and Mechanism Evaluation programme, a MRC and National Institute for Health Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 8, No. 17. See the NIHR Journals Library website for further project information.