Explore the vast range of titles available.

Haematology and biochemistry safety monitoring blood results are also reported from the immunology cohort (100 participants with additional visits), at baseline (before the prime dose), at day 28 (before the boost dose) and 7 days post-boost, graded according to a modified US Food and Drug Administration toxicity scale (appendix). In this interim safety analysis, we found an increase in systemic reactogenicity after the boost dose reported by participants in heterologous vaccine schedules in comparison to homologous vaccine schedules, and this was accompanied by increased paracetamol usage. Of note, these data were obtained in participants aged 50 years and older, and reactogenicity might be higher in younger age groups4,5 for whom a mixed vaccination schedule is being advocated in Germany, France, Sweden, Norway, and Denmark among those who have received a ChAd prime dose, in light of concerns regarding thrombotic thrombocytopenia after the first dose of ChAd.6 Pending availability of a more complete safety dataset and immunogenicity results for heterologous prime-boost schedules (to be reported shortly), these data suggest that the two heterologous vaccine schedules in this trial might have some short-term disadvantages.

Typhoid remains a major cause of illness and death globally. In this trial, the efficacy of a typhoid conjugate vaccine was assessed in children in Nepal. A total of 20,019 children were randomly assigned to receive either a TCV or a meningococcal A vaccine. The TCV was associated with a decrease of 81.6% in Salmonella Typhi bacteremia.

This study investigates water inrush mechanisms in goaf roof strata through multi-scale analysis of fracture network evolution and seepage dynamics. A three-zone overburden model was established via PFC3D simulation and validated with experimental data. Coupled PFC-CFD simulations reveal that seepage is governed by the interplay of pressure gradients, fracture pathways, and flow rates. Key findings include: nonlinear attenuation of pressure gradients amplifies flow velocities in dominant channels; increased injection rates widen effective channels by 86%; and high-velocity flow enhances permeability through erosion, resulting in significant directional anisotropy. These results provide insight into the positive feedback mechanisms controlling dynamic seepage in fractured rock masses.

In a randomized trial, 450 patients with venous leg ulcers were assigned to early endovenous ablation within 2 weeks after randomization or to deferred ablation after ulcer healing. The time to ulcer healing was shorter with early ablation than with deferred ablation.

Given the limited fuel capacity of an on-orbit service vehicle (OSV), proper OSV allocation to satellites during each service mission is critical for economic fuel consumption. This allocation problem can be formulated as an optimization problem with many continuous and discrete design variables of wide domains. This problem can be effectively handled through the proposed approach that combines the tabu search with the discrete particle swarm optimization algorithm (DPSO-TS). First of all, Pontryagin’s minimum principle and genetic algorithm (GA) are exploited to find the most fuel-efficient transfer trajectory. This fuel efficiency maximization can then serve as the performance index of the OSV allocation optimization model problem. In particular, the maximization of the minimum residual fuel over individual OSVs is proposed as a performance index for OSV allocation optimization. The optimization problem is numerically solved through the proposed DPSO-TS algorithm. Finally, the simulation results demonstrate that the DPSO-TS algorithm has a higher accuracy compared to the DPSO, the DPSO-PDM and the DPSO-CSA algorithms in the premise that these four algorithms have the basically same computational time. The DPSO-TS algorithm can effectively solve the OSV allocation optimization problem.

IntroductionStreptococcus pneumoniae serotype 3 (SPN3) remains a significant contributor to invasive pneumococcal disease globally, despite its inclusion in widely administered vaccines. The next generation of pneumococcal vaccines may confer better protection against this serotype, reducing disease burden. We describe an ethically approved protocol for a double-blind randomised controlled trial assessing the impact of VAXNEUVANCE (15-valent pneumococcal conjugated vaccine (PCV15)) and 0.9% saline (placebo) on the acquisition, density and duration of SPN3 carriage using a controlled human infection model.Methods and analysisHealthy adults aged 18–50 years will be randomised 1:1 to receive PCV15 or placebo. Participants will be considered enrolled on the trial at vaccination. One month following vaccination, all participants will be intranasally inoculated with SPN3. Following inoculation, participants will be followed up on days 2, 7, 14 and 28 to monitor safety, SPN3 colonisation status, density and duration, as well as immune responses. The primary endpoint of the study is to assess the rate of SPN3 acquisition between vaccinated and unvaccinated participants defined by classical microbiological methods. Secondary endpoints will determine the density and duration of SPN3 colonisation and compare the immune responses between study groups. An exploratory cohort of 5 participants will be asked to consent to a nasal biopsy procedure during a screening visit and a second nasal biopsy 28 days after PCV15 vaccination. This cohort will only receive PCV15 and will not be challenged. Through this exploratory cohort, we will explore gene expression changes induced by PCV15 vaccination and their visualisation (spatial location) within the nasal tissue.Ethics and disseminationThis protocol has been reviewed by the sponsor, funder and external peer reviewers. The study is approved by the NHS Research and Ethics Committee (Reference: 24/SC/0388) and by the Medicines and Healthcare Products Regulatory Agency (Reference: CTA 21584/0485/001-0001).Trial registration numberNCT06731374 – ISRCTN91656864.

Enteric fever remains a public health challenge. We analyzed data from a cluster-randomized Vi-tetanus toxoid conjugate vaccine trial to compare the epidemiology between Salmonella enterica serovars Paratyphi A, which causes paratyphoid fever, and Typhi, which causes typhoid fever. The overall incidence rate of paratyphoid fever was 27 (95% CI 23-32)/100,000 person-years (PY) and of typhoid fever was 216 (95% CI 198-236)/100,000 PY. We observed the highest incidence for both diseases in children 2-4 years of age: 72 (95% CI 41-117)/100,000 PY for paratyphoid and 887 (95% CI 715-1,088)/100,000 PY for typhoid. Lack of private toilets and safe drinking water were associated with both diseases. Prevalence of multidrug resistance was significantly higher in Salmonella Typhi (20.2%) than in Salmonella Paratyphi A (0.8%) (p<0.001). Our data suggest that integrated control measures targeting water, sanitation, and hygiene measures and bivalent vaccine targeting both pathogens are promising strategies to control both diseases.

Purpose Irosustat is a first-generation, orally active, irreversible steroid sulfatase inhibitor. We performed a multicentre, open label phase II trial of the addition of Irosustat to a first-line aromatase inhibitor (AI) in patients with advanced BC to evaluate the safety of the combination and to test the hypothesis that the addition of Irosustat to AI may further suppress estradiol levels and result in clinical benefit. Experimental design Postmenopausal women with ER-positive locally advanced or metastatic breast cancer who had derived clinical benefit from a first-line AI and who subsequently progressed were enrolled. The first-line AI was continued and Irosustat (40 mg orally daily) added. The primary endpoint was clinical benefit rate (CBR). Secondary endpoints included safety, tolerability, and pharmacodynamic end points. Results Twenty-seven women were recruited, four discontinued treatment without response assessment. Based on local reporting, the CBR was 18.5% (95% CI 6.3–38.1%) on an intent to treat basis, increasing to 21.7% (95% CI 7.4–43.7%) by per-protocol analysis. In those patients that achieved clinical benefit ( n  = 5), the median (interquartile range) duration was 9.4 months (8.1–11.3) months. The median progression-free survival time was 2.7 months (95% CI 2.5–4.6) in both the ITT and per-protocol analyses. The most frequently reported grade 3/4 toxicities were dry skin (28%), nausea (13%), fatigue (13%), diarrhoea (8%), headache (7%), anorexia (7%) and lethargy (7%). Conclusions The addition of Irosustat to aromatase inhibitor therapy resulted in clinical benefit with an acceptable safety profile. The study met its pre-defined success criterion by both local and central radiological assessments.

Multiattribute group decision-making (MAGDM) problems are characterized by the large number, uneven levels, and bounded rationality of decision-makers; multiple attributes and fuzziness of decision problems; and complex group behaviours. Considering these characteristics, we propose a MAGDM method using a genetic K-means clustering algorithm. First, we briefly review the traditional multiattribute decision-making method based on prospect theory (PT) and trapezoidal intuitionistic fuzzy numbers (TrIFNs) under the premise of human bounded rationality and uncertain decision environment. Then, the aggregation model of decision information given by decision-makers is established using the genetic K-means algorithm in order to determine optimal clustering results. Each clustering center represents decision information given by decision-makers in each cluster, and the weight of each clustering center is determined by considering the tightness of decision information within a cluster and the count of decision-makers in each cluster. Finally, the ranking of schemes is obtained according to the comparison rules of TrIFNs. We design comparison simulation experiments to test the proposed method and the simulation results demonstrate that the proposed method is apprehensible and feasible to solve MAGDM problems.

The treatment of enteric fever is complicated by the emergence of antimicrobial resistant Salmonella Typhi. Azithromycin is commonly used for first-line treatment of uncomplicated enteric fever, but the response to treatment may be sub-optimal in some patient groups when compared with fluoroquinolones. We performed an analysis of responses to treatment with azithromycin (500mg once-daily, 14 days) or ciprofloxacin (500mg twice-daily, 14 days) in healthy UK volunteers (18-60 years) enrolled into two Salmonella controlled human infection studies. Study A was a single-centre, open-label, randomised trial. Participants were randomised 1:1 to receive open-label oral ciprofloxacin or azithromycin, stratified by vaccine group (Vi-polysaccharide, Vi-conjugate or control Men-ACWY vaccine). Study B was an observational challenge/re-challenge study, where participants were randomised to challenge with Salmonella Typhi or Salmonella Paratyphi A. Outcome measures included fever clearance time, blood-culture clearance time and a composite measure of prolonged treatment response (persistent fever ≥38.0°C for ≥72 hours, persistently positive S. Typhi blood cultures for ≥72 hours, or change in antibiotic treatment). Both trials are registered with ClinicalTrials.gov (NCT02324751 and NCT02192008). In 81 participants diagnosed with S. Typhi in two studies, treatment with azithromycin was associated with prolonged bacteraemia (median 90.8 hours [95% CI: 65.9-93.8] vs. 20.1 hours [95% CI: 7.8-24.3], p<0.001) and prolonged fever clearance times <37.5°C (hazard ratio 2.4 [95%CI: 1.2-5.0]; p = 0.02). Results were consistent when studies were analysed independently and in a sub-group of participants with no history of vaccination or previous challenge. A prolonged treatment response was observed significantly more frequently in the azithromycin group (28/52 [54.9%]) compared with the ciprofloxacin group (1/29 [3.5%]; p<0.001). In participants treated with azithromycin, observed systemic plasma concentrations of azithromycin did not exceed the minimum inhibitory concentration (MIC), whilst predicted intracellular concentrations did exceed the MIC. In participants treated with ciprofloxacin, the observed systemic plasma concentrations and predicted intracellular concentrations of ciprofloxacin exceeded the MIC. Azithromycin at a dose of 500mg daily is an effective treatment for fully sensitive strains of S. Typhi but is associated with delayed treatment response and prolonged bacteraemia when compared with ciprofloxacin within the context of a human challenge model. Whilst the cellular accumulation of azithromycin is predicted to be sufficient to treat intracellular S. Typhi, systemic exposure may be sub-optimal for the elimination of extracellular circulating S. Typhi. In an era of increasing antimicrobial resistance, further studies are required to define appropriate azithromycin dosing regimens for enteric fever and to assess novel treatment strategies, including combination therapies. ClinicalTrials.gov (NCT02324751 and NCT02192008).