Trial Period Research Articles

Cortico-cancellous osseointegration into additively manufactured titanium implants using a load-bearing femoral ovine model.

Introduction: Titanium-based implants can be used to fill voids in bone reconstruction surgery. Through additive manufacturing (AM), it is possible to produce titanium implants with osteoconductive properties such as high porosity and low stiffness. AM facilitates a level of design flexibility and personalization that is not feasible with traditional techniques. Methods: In this study, osseointegration into titanium alloy (Ti-6Al-4V) lattices was investigated for 12weeks post-implantation using a novel bicortical load-bearing ovine model. The objective was to assess the safety and efficacy of AM-fabricated implants using two lattice structures of contrasting stiffness spanning the full width of the femoral condyle. Results: This was achieved by evaluating implant osseointegration and bone-implant contact properties by histomorphometry, scoring local implant tissue responses via histopathology, and micro-computed tomography reconstruction. Discussion: We found that Ti-6Al-4V implants facilitated widespread and extensive osseointegration, with bone maturation ongoing at the conclusion of the trial period. Following the implantation period, no adverse clinical indications that could be directly ascribed to the presence of the implanted device were identified, as determined by macroscopic and microscopic observation.

Effects of Tryptophan Supplementation in Diets with Different Protein Levels on the Production Performance of Broilers.

Tryptophan plays an important role in the pig industry but has the potential to improve performance in the poultry industry. The purpose of this study was to examine the effects of tryptophan supplementation in diets with different protein levels on the feed intake, average daily gain (ADG), and feed conversion ratio (F/G) of broilers. A total of 180 twenty-one-day-old broilers (half male and half female) were weighed and randomly allocated to twelve groups, with six male and six female groups. Each group consisted of 15 broilers. The broilers were fed low- (17.2%), medium- (19.2%), or high- (21.2%) protein diets with or without extra tryptophan (up to 0.25%) during the 28-day experiment. Food intake and body weight were measured weekly during the trial period. Male broilers fed a medium-protein diet containing more tryptophan showed a lower F/G. In the low-protein diet groups, additional tryptophan caused a significant reduction in the feed intake of female broilers during the first two weeks. Moreover, the serum GLP-1, cholesterol, and bile acid levels, as well as the expression of FXR mRNA in the ileum, were significantly increased. Additionally, the FXR mRNA in the hypothalamus and the GCG and GLP-1R mRNAs in the ileum tended to increase in these broilers. In summary, the tryptophan concentration in the diet can influence the feed intake and metabolism of broilers. Under a standard diet, an appropriate amount of tryptophan is beneficial to the F/G of male broilers, while under a low-protein diet, tryptophan supplementation may cause a short-term reduction in the feed intake of female broilers by increasing serum GLP-1 and bile acid signals.

Ningxiang pig-derived Enterococcus hirae HNAU0516 ameliorates postweaning diarrhoea by promoting intestinal health and modulating the gut microbiota in piglets

Early weaning-induced stress precipitates diarrhoea, significantly curtailing the growth performance of piglets. A pivotal contributor to this postweaning affliction is the emergence of gut bacterial dysbiosis. Enterococcus hirae, a promising probiotic, has indicated unclear effects and mechanisms on intestinal health. In this study, we investigated the effects and underlying mechanisms of oral supplementation with Ningxiang pig-derived Enterococcus hirae HNAU0516 orally supplementation on the gut bacterial community, immune response and gut barrier function in piglets. 21 d age Duroc × (Landrace × Yorkshire) piglets with a similar BW were randomly allocated to two groups. The Enterococcus hirae HNAU0516 administration group was inoculated orally with Ningxiang pig-derived Enterococcus hirae HNAU0516 throughout the trial period. Conversely, the control group received the same volume of physiological saline. Our findings revealed that Enterococcus hirae HNAU0516 supplementation effectively reduced diarrhoea rates of piglets (P = 0.010). Notably, this probiotic promoted intestinal development and enhanced intestinal barrier function. It also showed potential anti-inflammatory properties. Furthermore, Enterococcus hirae HNAU0516 supplementation significantly remodelled the colonic microbiota and increased the production of acetate (P = 0.007). In conclusion, our study highlights that Ningxiang pig-derived Enterococcus hirae HNAU0516 improves postweaning diarrhoea by promoting intestinal development, enhancing intestinal barrier function, decreasing intestinal permeability, modulating intestinal microbiota, and increasing short-chain fatty acids production.

Lessons learned from the trial operation of an autonomous urban passenger ferry

Cities worldwide consider autonomous passenger ferries a sustainable way of transporting passengers across and along waterways. Since 2016, a university-led effort to develop autonomous urban passenger ferry prototypes has been underway in Trondheim, Norway. The work culminated in what is considered the world’s first trial operations of an autonomous urban passenger ferry open to the public, where the ferry milliAmpere2, over three weeks, completed almost 500 trips and transported more than 1500 passengers over a 100-meter crossing. During the trial period in September and October 2022, several quantitative and qualitative data samples were collected to understand passengers’ and safety operators’ perceptions of trust and safety onboard autonomous ferries. This article briefly presents the autonomous ferry and its autonomy system and provides details about the trial operation, the area of operation, and the data samples collected. It concludes with lessons learned from the trial operation that can be useful for other researchers who study autonomous ferries and their interplay with operators, passengers, and other stakeholders.

Pathological and biochemical investigation of the effects of Silybum marianum against Methomyl damage in broiler liver

This study was aimed to investigate the protective/preventive and/or curative effects of Silybum marianum seed powder against Methomyl toxication by examining some biochemical parameters and pathological changes hepatic in broiler chicks fed with feeds supplemented with Methomyl and S. marianum seed powder. For this purpose, 4 different groups, each containing 32 animals, were used; Control group (CONT), Methomyl group (MET), S. marianum seed powder group (SMT) and Methomyl + S. marianum seed powder group (MET+SMT). In the study, Methomyl was added to the feeds as 20 ppm and S. marianum seed powder as 10 g·kg-1. The trial period was planned as 28 days, and necropsies of animals from each group were performed daily, and samples were taken for histopathology and biochemistry. In the study, liver enzyme activities and liver tissue oxidative stress markers GPx, MDA and SOD values were found to be similar in the CONT and SMT groups, but statistically higher in the MET group. In the MET+SMT group, the increased parameters were lower than the MET group. The histopathological examinations of liver sections, hyperemia, hemorrhage, hydropic degeneration and fatty changes of hepatocytes, focal necrosis, dissociation of remark cords, mononuclear cell infiltration in the portal area and bile ducts hyperplasia were detected. It has been observed that S. marianum given for preventive/healing purposes reduces histopathological damage and contributes positively in all groups. It has been concluded that S. marianum can be added to poultry diets against Methomyl residues or contamınatıons according to thıs study.

Reasons and experience for patients with amyotrophic lateral sclerosis using traditional Chinese medicine: a CARE-TCM based mixed method study

Background and aimTraditional Chinese medicine (TCM) is widely used by patients with amyotrophic lateral sclerosis (ALS). However, their reasons and experience in using TCM have received insufficient attention. Therefore, we conducted a mixed method study to gain insights into this issue.Materials and methodsThis study was conducted on the basis of the China Amyotrophic Lateral Sclerosis Registry of Patients with Traditional Chinese Medicine (CARE-TCM). Data were collected from Dongzhimen Hospital through a mixed method approach, including a questionnaire and a semi-structured interview. Patients with ALS who were using TCM when they were initially registered with CARE-TCM and who had been followed-up for over six months were recruited. The questionnaires’ outcomes were statistically outlined, and the interview transcripts were thematically analysed to identify themes and sub-themes.ResultsFifty-two and sixteen patients were included in the questionnaire and semi-structured interview groups, respectively. Patients used TCM with the hope of regulating their body holistically to improve nonmotor symptoms and quality of life (QOL). Those who recognised TCM as ineffective tended to discontinue it after a three-month trial period. Although quality was a major concern, herbal medicine (HM) was the most frequently used modality among all participants (n = 52), with the majority (n = 44, 84.6%) continuing to use it. Patients emphasised in-person consultations as a crucial part of TCM treatment. However, the disability caused by disease often made this interaction unattainable.ConclusionNonmotor symptoms and QOL hold substantial importance for patients with ALS using TCM. HM is a more suitable modality than other TCM treatment modalities, but patients are facing challenges in seeking HM treatment. It is necessary to promote the implementation of hierarchical diagnosis and treatment, thus making TCM more accessible.Trial registrationClinicalTrials.gov identifier: NCT04885374 (registered on May 13, 2021).

Impact of the ARRIVE Trial in Nulliparous Individuals with Morbid Obesity: Interrupted Time Series Analysis

Objective We aimed to examine rates of induction of labor at 39 weeks and cesarean delivery before and after the ARRIVE (A Randomized Trial of Induction Versus Expectant Management) trial stratified by body mass index (BMI; kg/m2) category. Study Design This was a repeated cross-sectional analysis of publicly available U.S. birth certificate data from 2015 to 2021. We limited analyses to nulliparous individuals with a singleton pregnancy, cephalic presentation, without chronic hypertension, diabetes (gestational or pregestational), and fetal anomaly who delivered between 39 and 42 weeks' gestation. The pre-ARRIVE period spanned from August 2016 to July 2018 and the post-ARRIVE period spanned from January 2019 to December 2020. The dissemination period of the ARRIVE trial was from August 2018 to December 2018. Our co-primary outcomes were induction at 39 weeks and cesarean delivery. Our secondary outcomes were overall induction of labor and preeclampsia. We conducted an interrupted time series analysis after stratifying by prepregnancy BMI (<40 or ≥40). Negative binomial regression was used to calculate adjusted incident rate ratios with 95% confidence intervals. Results Of 2,122,267 individuals that were included, 2,051,050 had BMI <40 and 71,217 had BMI ≥40. In individuals with BMI <40, the post-ARRIVE period compared to the pre-ARRIVE period was associated with an increased rate of induction of labor at 39 weeks, a decreased rate of cesarean delivery, and an increased rate of overall induction of labor. In individuals with BMI ≥40, the post-ARRIVE period compared to the pre-ARRIVE period was associated with an increased rate of induction of labor at 39 weeks, an increased rate of overall induction of labor and a decreased rate of preeclampsia; however, the decrease in the rate of cesarean delivery was not significant. Conclusion An increase in induction of labor at 39 weeks' gestation in individuals with BMI ≥40 was not associated with a decrease in the cesarean delivery rate. Key Points

Supporting young women’s health through girl-friendly drug vendors in Lake Zone, Tanzania: protocol for the AmbassADDOrs for Health cluster-randomised controlled trial

IntroductionAdverse sexual and reproductive health (SRH) outcomes, such as unplanned pregnancies and HIV infection, disproportionately affect adolescent girls and young women (AGYW; aged 15–24 years) in east Africa. Increasing uptake...

Why did I participate in an HIV vaccine study? Experiences of participation in the first phase II HIV vaccine trial in Mozambique: An ancillary study using a mixed-method approach

IntroductionThis study recognized the lack of information regarding recruitment and retention factors associated with implementing HIV vaccine trials from the perspective of de facto participants. It aimed to describe the motives and experiences of 31 young adults who participated in a phase II HIV vaccine clinical trial conducted in Maputo, Mozambique. MethodsThis was an ancillary study with a mixed-method approach that employed a convergent design, combining both quantitative and qualitative methodologies. Data collection involved questionnaire surveys, in-depth interviews, and focus group discussions. Participants were assessed before and after learning whether they received the experimental vaccine or placebo. Thematic analysis was used for qualitative data, while descriptive analysis and statistical tests such as Fischer’s test and McNemar’s exact test were applied to quantitative data. The study also utilized the Health Belief Model to understand the decision-making process of participating in an HIV vaccine study. ResultsMost of our participants were young females, single, with limited financial resources. Participants joined the trial with the belief that they had a unique opportunity to help the fight against HIV and contribute to the research for the discovery of an HIV vaccine. Positive experiences related to trial participation include gaining knowledge about HIV and personal health and receiving risk reduction counseling. Participants reported blood collection as a negative experience and that they suffered social harm because of trial participation. Participants felt abandoned after the trial ended. ConclusionPreventive HIV vaccine trials should integrate a social-behavioral component to assess reasons for participation and refusal in real-time. Providing ongoing personal attention is crucial for young individuals who have committed 1–2 years to trial participation, extending beyond the trial period. Implementing tailored strategies for HIV risk assessment and reduction during and after the trial is essential. Addressing these factors can enhance preventive HIV vaccine trial implementation.

Reproductive and Physiological Responses and Egg Quality Traits of Isa Brown Chickens fed Diets fed Ginger or Turmeric Powder under Tropical Hot Environments

The increasing demand for healthy and low-fat poultry products by consumers has necessitated the use of natural growth promoters to enhance hens’ laying performance. This study investigated the reproductive response and egg quality traits of pullet chickens fed dietary turmeric (Curcuma longa) and ginger (Zingiber officinale) powder. Four hundred and twenty egg-type chicks of Isa Brown at three weeks old were assigned to 5 treatments: basal diet (G0); basal diet supplemented with 1.5 % (G1.5) or 3% (G3) ginger or 1.5(T1.5) or 3% (T3) turmeric during a 60 week trial period. A complete randomized design arrangement was applied. The results showed that the best (p<0.05) hen-day production, hen-housed production, egg mass, feed conversion ratio (FCR), age at first lay and weight at first lay were obtained for birds receiving the 1.5% ginger ration. A higher mortality rate was experienced among the control groups (9.82%), while egg traits revealed significantly higher values of albumen height in hens placed on 1.5 and 3% turmeric powder compared to the other treatment groups. The study concluded that dietary ginger and turmeric enhanced the reproductive performance and egg quality of egg-type chickens over their commercial production lifespan without impairing their overall well-being.

Safety and efficacy of inebilizumab for the treatment of neuromyelitis optica spectrum disorder: end-of-study results from the open-label period of the N-MOmentum trial

Inebilizumab, an anti-CD19 B-cell-depleting antibody, demonstrated safety and efficacy in neuromyelitis optica spectrum disorder in the randomised controlled period of the N-MOmentum trial. Here, end-of-study data, including the randomised controlled period and open-label extension period, are reported. In the double-blind, randomised, placebo-controlled, phase 2/3 N-MOmentum trial, adults aged 18 years and older with an neuromyelitis optica spectrum disorder diagnosis, Expanded Disability Status Scale score of 8·0 or less, and history of either at least one acute inflammatory attack requiring rescue therapy in the past year or two attacks requiring rescue therapy in the past 2 years, were recruited from 81 outpatient specialty clinics or hospitals in 24 countries. Eligible participants were randomly assigned (3:1), using a central interactive voice system or interactive web response system, and a permuted block randomisation scheme (block size of 4), to receive intravenous inebilizumab (300 mg) or identical placebo on days 1 and 15 of the randomised period, which lasted up to 197 days. Participants and all study staff were masked to treatment assignment. The primary endpoint of the randomised period of the trial was time to onset of adjudicated neuromyelitis optica spectrum disorder attack on or before day 197. Participants in the randomised controlled period who had an adjudicated attack, completed 197 days in the study, or were in the randomised controlled period when enrolment stopped, could voluntarily enter the open-label period. In the open-label period, participants either initiated inebilizumab if assigned placebo (receiving 300 mg on days 1 and 15 of the open-label period) or continued treatment if assigned inebilizumab (receiving 300 mg on day 1 and placebo on day 15, to maintain B-cell depletion and masking of the randomised controlled period). All participants subsequently received inebilizumab 300 mg every 6 months for a minimum of 2 years. The end-of-study analysis endpoints were time to adjudicated attack and annualised attack rate (assessed in all participants who received inebilizumab at any point during the randomised controlled period or open-label period [any inebilizumab population] and the aquaporin-4 [AQP4]-IgG seropositive subgroup [any inebilizumab-AQP4-IgG seropositive population]) and safety outcomes (in all participants who were exposed to inebilizumab, analysed as-treated). This study is registered with ClinicalTrials.gov, NCT02200770, and is now complete. Between Jan 6, 2015, and Sept 24, 2018, 467 individuals were screened, 231 were randomly assigned, and 230 received at least one dose of inebilizumab (n=174) or placebo (n=56). Between May 19, 2015, and Nov 8, 2018, 165 (95%) of 174 participants in the inebilizumab group and 51 (91%) of 56 in the placebo group entered the open-label period (mean age 42·9 years [SD 12·4], 197 [91%] of 216 were female, 19 [9%] were male, 115 [53%] were White, 45 [21%] were Asian, 19 [9%] were American Indian or Alaskan Native, and 19 [9%] were Black or African American). As of data cutoff for this end of study analysis (Dec 18, 2020; median exposure 1178 days [IQR 856-1538], total exposure of 730 person-years) 225 participants formed the any inebilizumab population, and 208 (92%) participants were AQP4-IgG seropositive. Overall, 63 adjudicated neuromyelitis optica spectrum disorder attacks occurred in 47 (21%) of 225 treated participants (60 attacks occurred in 44 [21%] of 208 in the AQP4-IgG seropositive subgroup); 40 (63%) of 63 attacks occurred in 34 (15%) of 225 treated participants during the first year of treatment. Of individuals who had an adjudicated attack while receiving inebilizumab, 36 (77%) of 47 were subsequently attack-free at the end of 4 years. Annualised attack rates decreased year-on-year, with end-of-study adjusted annualised attack rates being similar in the any inebilizumab-AQP4-IgG seropositive subgroup (0·097 [95% CI 0·070-0·14]) and any inebilizumab populations (0·092 [0·067-0·13]). Overall, 208 (92%) of 225 participants who received any inebilizumab had at least one treatment-emergent adverse event, the most frequent of which were urinary tract infection (59 [26%]), nasopharyngitis (47 [21%]), and arthralgia (39 [17%]). Infection rates did not increase over 4 years. Three (1%) of 225 participants in the any inebilizumab population died during the open-label period (one each due to a CNS event of unknown cause and pneumonia, respiratory insufficiency resulting from an neuromyelitis optica spectrum disorder attack and viral pneumonia related to COVID-19), all of which were deemed to be unrelated to treatment. Data from the end-of-study analysis of the N-MOmentum trial showed continued and sustained clinical benefits of long-term inebilizumab treatment in individuals with neuromyelitis optica spectrum disorder, which supports the role of inebilizumab as a CD19+ B-cell-depleting therapy in neuromyelitis optica spectrum disorder. MedImmune and Viela Bio/Horizon Therapeutics, now part of Amgen.

Standardizing radiologic reporting of response to improve the patient experience: Comparing response categories of RECIST 1.1 and a novel, real-world, standardized, oncologic response lexicon derived from clinical radiology reports.

e13810 Background: With the 21st Century Cures Act of 2016, rapid and complete access to medical records including radiology reports is mandated. Patients have expressed that an unmet need is improving clarity in radiology results with more structured information that avoids technical jargon. RECIST is routinely applied in clinical trials to assess treatment response but is challenging to apply in routine practice. A standardized Oncologic Response (OR) lexicon was developed to categorize response and progression directly from clinical reports, using an ordinal scale. This study aims to compare the rates of response from OR categories to RECIST categories in the setting of three phase 2 trials. Methods: Patients from three phase 2 trials were retrospectively reviewed for real world response using OR categories by a radiologist blinded to RECIST data. Clinical radiology reports generated during the trial period were reviewed and response was categorized from the report impression text according to OR categories (OR-0: no evidence of disease, OR-1: unequivocal decrease, OR-2: slight decrease, OR-3: unchanged, OR-4: slight increase, and OR-5: unequivocal increase). Best RECIST response categories of complete response (CR) or partial response (PR), stable disease (SD), and progression of disease (PD) were compared to best OR response categories (OR-0/1, OR-2/3/4, and OR-5, respectively). Time to treatment failure (TTF) and overall survival (OS) for each category was calculated using Kaplan-Meier methodology. Results: Ninety-one patients were reviewed. Best response based on RECIST v1.1 was CR for 4 patients (4%), PR for 38 patients (42%), SD for 44 patients (48%), and PD for 5 patients (6%). Using OR-categories, 1 patient (1%) was categorized as OR-0, 46 (51%) as OR-1, 34 (37%) OR-2/3/4, and 10 (11%) OR-5. Concordance between the three response categories across RECIST (CR or PR; SD; PD) and OR-RADS (0-1; 2/3/4; 5) was 73.6%. The majority of discordant cases (50%, n=12/24) were patients with SD by RECIST but OR-1 using OR categories. Median TTF was similar between RECIST and OR categories: RECIST CR/PR: 21.8, SD: 6.9, and PD: 1.0 months (p<0.0001) and OR-0/1: 21.5, OR-2/3/4: 7.0, and OR-5 1.1 (p<0.0001). Median OS was similar between RECIST and OR-categories: RECIST CR/PR: 42.6, SD: 9.9, and PD: 8.2 months (p=0.005) and OR-0/1: 42.6, OR-2/3/4: 13.6, and OR-5 7.1 (p<0.0001). Conclusions: There was high concordance between RECIST and OR-categories. This study provides preliminary evidence for the use of standardized OR categories to identify real world responses, with outcomes similar to RECIST response categories. Use of OR can improve communication with patients and oncologists and allow for standardized data extraction of radiologic response for real-world studies.

For Debate: The 2023 European Society of Hypertension guidelines - cause for concern.

Originally, the beta-blockers were equally ranked alongside the other antihypertensive drug classes. Things changed when two major long-term randomized controlled trials, ASCOT-BPLA and LIFE showed that the patients receiving the beta-blockers based regimes suffered 25-30% more strokes than those receiving a calcium channel blocker based regime or an angiotensin receptor blocker based regime. The inferiority of the beta-blockers at stroke prevention was not due to differences in blood pressure control during the follow-up period in both trials. The 2023 European Society of Hypertension (ESH) guidelines still argue in favour of beta-blockers that their clinical inferiority was simply to lesser blood pressure reduction rather than class effect. The analysis argues that the return of beta-blockers as a first-line option for the management of uncomplicated hypertension by the ESH is a cause for concern and should be reconsidered.

Post-mortem intervals estimation by determination of insect diversity

ABSTRACT Dipteran flies have been employed to measure the post-mortem period examination with the help of decomposition of the carcasses. The current study attempted to update the baseline data of the insects to determine the post-mortem interval. Five decomposition stages were observed but the complete decomposition of (Oryctolagus cuniculus) rabbits in winter took place in 21 days and in spring in 12 to 15 days. Decomposition period in both trials varied due to temperature fluctuations. Odours were released at different stages of decay and blow flies were the first insect to come on carcasses. The species that identified were the blowfly (Calliphoridae) (34.4% | 49.12%), blue fly (Calliphora) (17.24% | 41.22%), flesh fly Sarcophagidae (20.68% | 5.26%), and house fly (Muscidae) (27.58% | 4.38%) in the first trial and second trial respectively. The timing of the various arthropod species’ arrivals and their correlation with various decompositional phases throughout both trials suggested that they could be useful for determining the PMI (post-mortem interval) in forensic investigations. This study showed that insect fauna on the corpse is a tool for estimating post-mortem interval and plays an important role in forensic entomology to analyse the suspicious suspect.

Using multivariate analysis to predict carcass characteristics of lambs in grazing and supplemented with different levels of non-protein nitrogen

Abstract The aim of this study is to assess the effects of substituting soybean meal with extruded urea in the diet of crossbred Texel x no defined racial pattern lambs under continuous grazing on Brachiaria ssp., focusing on both their productive and nutritional performance. 60 Texel crossbred lambs (12 animals for each treatment) were used, with an average initial weight of 20.7 ± 0.87 kg and an average age of 2.5 ± 0.70 months, fed treatments with increasing levels of UE (Urea extruded Amireia® 200S): 0; 6; 12; 18 and 24 grams of EU 100/kg of body weight, with trial period was 5 months, using the multivariate technique. The data were subjected to principal component and canonical discriminant analysis to check possible differences between the evaluated treatments and identify the variables that best discriminate and use these variables to create a discriminant function that represents the differences between treatments. Of the 12 variables initially used, we observed that 9 were used by the main components, but 6 were those that presented the greatest discriminatory power for the study. Main component 1 was characterized by biometric measurements and showed the greatest power of variation in the study (60%), followed by main component 2, represented by slaughter weight and empty body weight (13%). These correlations indicate that biometric measurements can serve as reliable indirect indicators for estimating carcass traits in sheep, offering a practical alternative to visual assessments.

A Gender-Informed Smoking Cessation App for Women: A Protocol for an Acceptability and Feasibility Study.

Tobacco smoking remains the leading preventable cause of death and disease among women. Quitting smoking offers numerous health benefits; however, women tend to have less success than men when attempting to quit. This discrepancy is partly due to sex and/or gender-related factors, including the lower effectiveness of smoking cessation medication and the presence of unique motives for smoking and barriers to quitting among women. Despite the gendered nature of smoking, most smoking cessation apps are gender-neutral, and fail to address women's specific needs. To test the acceptability and feasibility of a smartphone app that delivers gender-informed content to support women in quitting smoking. We co-developed a smoking cessation app specifically tailored for women, named My Change Plan-Women (MCP-W). This app builds upon our previous gender-neutral app, MCP, by retaining its content grounded in behavioral change techniques aimed at supporting tobacco reduction and cessation. This includes quit goal setting, identifying triggers to smoking, creating coping strategies, tracking cigarettes and cravings, and assessing financial savings from quitting smoking. The MCP-W app contains additional gender-informed content that acknowledges barriers to quitting, such as coping with stress, having smokers in one's social circle, and managing unpleasant emotions. This content is delivered through testimonials and animated videos. This study is a prospective, single-group, mixed-methods investigation in which 30 women smokers will trial the app for a period of 28 days. Once participants provide informed consent, they will complete a baseline survey and download the app on their smartphones. After 28 days, participants will complete follow-up surveys. Acceptability will be assessed using the Theoretical Framework of Acceptability, which evaluates whether participants perceive the app as helpful in changing their smoking. The app will be deemed acceptable if the majority of participants rate it as such, and feasible if the majority of the participants use it for at least 7 days. Furthermore, after the 28-day trial period, participants will complete a semi-structured interview regarding their experience with the app and suggestions for improvement. Development of the MCP-W app was completed in September 2023. Participant recruitment for testing of the app commenced in February 2024. Offering smoking cessation support tailored specifically to address the unique needs of women through a smartphone app represents a novel approach. This study will test whether women who smoke perceive this approach to be acceptable and feasible in their journey towards smoking cessation.

Chinese herbal medicine Shufeng Jiedu capsule for mild to moderate COVID-19: a multicenter, randomized, double-blind, placebo-controlled phase II trial.

Background: The COVID-19 pandemic has had a profound global impact, although the majority of recently infected cases have presented with mild to moderate symptoms. Previous clinical studies have demonstrated that Shufeng Jiedu (SFJD) capsule, a Chinese herbal patent medicine, effectively alleviates symptoms associated with the common cold, H1N1 influenza, and COVID-19. This study aimed to assess the efficacy and safety of SFJD capsules in managing symptoms of mild to moderate COVID-19 infection. Methods: A randomized, double-blind, placebo-controlled trial was conducted from May to December 2022 at two hospitals in China. Mild and moderate COVID-19-infected patients presenting respiratory symptoms within 3days from onset were randomly assigned to either the SFJD or placebo groups in a 1:1 ratio. Individuals received SFJD capsules or a placebo three times daily for five consecutive days. Participants were followed up for more than 14 days after their RT-PCR nucleoid acid test for SARS-CoV-2 turned negative. The primary outcome measure was time to alleviate COVID-19 symptoms from baseline until the end of follow-up. Results: A total of 478 participants were screened; ultimately, 407 completed the trial after randomization (SFJD, n = 203; placebo, n = 204). No statistically significant difference in baseline parameters was observed between the two groups. The median time to alleviate all symptoms was 7days in the SFJD group compared to 8days in the placebo group (p = 0.037). Notably, the SFJD group significantly attenuated fever/chills (p = 0.04) and headache (p = 0.016) compared to the placebo group. Furthermore, the median time taken to reach normal body temperature within 24h was reduced by 7hours in the SFJD group compared to the placebo group (p = 0.033). No deaths or instances of serious or critical conditions occurred during this trial period; moreover, no serious adverse events were reported. Conclusion: The trial was conducted in a unique controlled hospital setting, and the 5-day treatment with SFJD capsules resulted in a 1-day reduction in overall symptoms, particularly headache and fever/chills, among COVID-19-infected participants with mild or moderate symptoms. Compared to placebo, SFJD capsules were found to be safe with fewer side effects. SFJD capsules could potentially serve as an effective treatment for alleviating mild to moderate symptoms of COVID-19. Clinical Trial Registration: https://www.isrctn.com/, identifier ISRCTN14236594.

Effects of alpha-lipoic acid on the growth performance and serum biochemical index values of puppies

We investigated the effects of alpha-lipoic acid (α-LA) on the growth performance and health level of puppies. A total of 16 healthy Chinese rural dogs aged 30–45 days were randomly divided into four groups: control group (CG), low-dose group (LDG), middle-dose group (MDG) and high-dose group (HDG). The puppies were fed fresh food supplemented with 0, 0.2, 0.4 and 0.6 g/kg of α-LA, respectively. Average daily feed intake (ADFI), average daily gain (ADG), feed-to-gain ratio (F/G), faecal score, intestinal absorption function and serological indices on days 1, 14 and 28 were determined and analysed. The trial period was 28 days. The following results were obtained: (1) α-LA supplementation at 0.4 and 0.6 g/kg significantly increased the ADFI and ADG of the puppies (P < 0.05) but had no significant effect on the faecal score (P > 0.05); (2) α-LA in the fresh diet significantly increased crude fat (EE) digestibility (P< 0.05) but significantly decreased calcium (Ca) digestibility (P< 0.05), without significant impacts on the digestibility of nutrients such as crude protein (CP) and total phosphorus (P); (3) with increasing α-LA inclusion levels, the content of D-xylose in the blood serum increased, but there was no significant difference among groups (P = 0.097). Adding 0.6 mg/kg α-LA to the fresh diet significantly increased the content of IgG in the serum after 14 and 28 days (P < 0.05). At 28 days, adding 0.4 and 0.6 g/kg α-LA to the fresh diet could significantly increase the contents of albumin (ALB) and total protein (TP) in the blood serum (P < 0.05), and the addition of 0.6 g/kg α-LA could significantly increase the serum levels of IgA and IgG (P < 0.05). The addition of α-LA significantly increased the activities of total antioxidant capacity (T-AOC), glutathione peroxidase (GSH-Px) and total superoxide dismutase (T-SOD) (P < 0.05), decreased the content of malondialdehyde (MDA) (P < 0.05), decreased the levels of interleukin-1β (IL-1β) and interleukin-6 (IL-6) (P< 0.05) and increased the content of interleukin-10 (IL-10) in the blood serum (P < 0.05). In conclusion, the addition of α-LA at 0.6 g/kg to the fresh diet of puppies can improve the ADFI, ADG, serum immune capacity, antioxidant capacity and anti-inflammatory capacity of puppies.

Improvements in the spread–skill relationship of precipitation in a convective‐scale ensemble through blending

AbstractConvective‐scale ensembles are used routinely in operational centres around the world to produce probabilistic precipitation forecasts, but a lack of spread between members is providing forecasts that are frequently overconfident. This deficiency can be corrected by increasing spread, increasing forecast accuracy, or both. A recent development in the Met Office forecasting system is the inclusion of large‐scale blending (LSB) in the convective‐scale data assimilation scheme. This method aims to reduce the synoptic‐scale forecast error in the analysis by reducing the influence of the convective‐scale data assimilation at scales that are too large to be constrained by the limited domain. These scales are instead initialised using output from the global data assimilation scheme, which we expect to reduce the forecast error and thus improve the spread–skill relationship. In this study, we quantify the impact of LSB on the spread–skill relationship of hourly precipitation accumulations by comparing forecast ensembles with and without LSB over a 17‐day summer trial period. This trial found modest but significant improvements to the spread–skill relationship as calculated using metrics based on the Fractions Skill Score. Skill is improved for a lower precipitation centile by an average of 0.56% at the largest scales, but a corresponding degradation of spread limits the overall correction. The spread–skill disparity is reduced the most in the higher centiles due to a more muted spread response, with significant reductions of up to 0.40% obtained at larger scales. Case‐study analysis using a novel extension of the Localised Fractions Skill Score demonstrates how spread–skill improvements transfer to smaller‐scale features, not just the scales that have been blended. There are promising signs that further spread–skill improvements can be made by implementing LSB more fully within the ensemble, and we encourage the Met Office to continue developing this technique.

#2063 Safety and efficacy of vadadustat vs darbepoetin alfa in patients on maintenance dialysis by prespecified subgroups of baseline ESA dose

Abstract Background and Aims Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor approved in Europe, Australia, Japan for the treatment of anemia in patients with dialysis-dependent (DD)-CKD. In the INNO2VATE global phase 3 trials in patients with DD-CKD, including 2 separate trials in patients new to dialysis [NCT02865850] and on maintenance dialysis [NCT02892149], vadadustat was noninferior to the erythropoiesis -stimulating agent (ESA) darbepoetin alfa for cardiovascular safety and hemoglobin efficacy. Among patients with DD-CKD, high ESA dose requirements have been associated with an increased risk of cardiovascular complications. In this secondary analysis, we compared cardiovascular safety and hematological efficacy of vadadustat and darbepoetin alfa across baseline ESA dose categories. Method In the INNO2VATE trials, 3554 patients on maintenance dialysis were randomized 1:1 to vadadustat or darbepoetin alfa, stratified according to geographic region, New York Heart Association heart failure classification, and hemoglobin concentration at trial entry. Data were analyzed for prespecified subgroups of patients categorized by their baseline ESA (epoetin alfa/equivalents) dose: low (&amp;lt;90 U/kg/week), intermediate (90-299 U/kg/week), or high (≥300 U/kg/week). Within these dose subgroups, the key safety endpoint was the first occurrence of an adjudicated major adverse cardiovascular event (MACE: first occurrence of all-cause mortality, nonfatal myocardial infarction [MI], or nonfatal stroke) using a time-to-event analysis. Primary and secondary efficacy endpoints were mean change in hemoglobin concentration from baseline during the primary (weeks 24-36) and secondary (weeks 40-52) evaluation periods, respectively. Results More participants were in the low (vadadustat: n = 916 [53%], darbepoetin alfa: n = 968 [55%]) and intermediate (vadadustat: n = 724 [42%], darbepoetin alfa: n = 693 [39%]) than in the high (vadadustat: n = 102 [6%], darbepoetin alfa: n = 98 [6%]) baseline ESA dose subgroups. Hazard ratios for the occurrence of first MACE between vadadustat and darbepoetin alfa in the 3 baseline ESA dose subgroups were as follows: low dose, 0.99 (95% CI, 0.81 to 1.23); intermediate dose, 0.93 (95% CI, 0.74 to 1.18); and high dose, 0.62 (95% CI, 0.34 to 1.14) (Fig.). Similar results were observed for other key MACE-related endpoints, including all-cause mortality, MACE plus hospitalizations for heart failure or thromboembolic events, cardiovascular MACE (first occurrence of cardiovascular mortality, nonfatal MI, or nonfatal stroke), and cardiovascular death. Mean hemoglobin concentrations increased in both treatment groups throughout the trial period. The least squares mean treatment difference (vadadustat compared to darbepoetin alfa) for change in hemoglobin concentration from baseline to the primary efficacy period was –0.10 g/dL (95% CI, –0.19 to –0.02), –0.20 g/dL (95% CI, –0.30 to –0.09), and –0.39 g/dL (95% CI, –0.67 to –0.11) for the low, intermediate, and high baseline ESA dose subgroups, respectively. Similar results were observed for the secondary efficacy period. Across baseline ESA dose subgroups, the proportion of patients whose average hemoglobin concentration was within target range was similar between the vadadustat and darbepoetin alfa arms during the primary efficacy period (low: odds ratio [OR], 0.89; 95% CI, 0.74, 1.08; intermediate: OR, 0.87; 95% CI, 0.70, 1.09; high: OR, 0.90; 95% CI 0.49, 1.64). Similar results were observed during the secondary efficacy period. Conclusion The cardiovascular safety and efficacy of vadadustat was similar to darbepoetin alfa in patients with DD-CKD irrespective of baseline ESA dose. In patients requiring higher ESA doses at baseline, the risk of MACE was numerically (but not significantly) lower in vadadustat-treated patients. Further investigation is required to confirm or refute this trend.