Individual Trials Research Articles

Vaccination Schedule and Age Influence Impaired Responsiveness to Hepatitis B Vaccination: A Randomized Trial in Central Asia

Vaccination against hepatitis B virus (HBV) is the most cost-efficient measure to prevent infection. Still, vaccination coverage among adults in Central Asia, including Kyrgyzstan, remains suboptimal, and data about immune responses to HBV vaccination are lacking. HBV vaccination is given as three injections, whereby the second and third doses are given 1 and 6 months after the first (0-1-6 scheme). However, compliance with the third dose is low in Kyrgyzstan, presumably due to the long time interval between the second and third doses, suggesting that a shortened vaccination schedule could result in better adherence and increased seroconversion. Thus, we conducted a randomized trial of individuals aged 17–66 years comparing the 0-1-6 scheme against a shorter 0-1-3 scheme. Primary outcome measures were post-vaccination titers and the percentage of participants with protective post-vaccination titers (≥10 mIU/mL). Compliance with the completeness of blood draws and administered third vaccine dose was better with the 0-1-3 scheme than with the 0-1-6 scheme. In both study arms combined, younger age (<40 years) was associated with better vaccine protection. The 0-1-6 scheme resulted in higher post-vaccination titers (52 versus 15 mIU/mL, p = 0.002) and a higher seroprotection rate (85% versus 64%, p = 0.01) than the 0-1-3 scheme, whereby post-vaccination titers correlated negatively with age in the 0-1-3 scheme. Thus, the 0-1-6 scheme should continue to be the preferred HBV vaccination schedule, but interventions to improve compliance with the third vaccine dose are needed.

A Guidebook for Assessing Mathematical Logic Intelligence in Kindergarten

Many children still need help understanding numbers; children also cannot differentiate between round, triangular, and square shapes. Apart from that, teachers only carry out assessments at the end of the learning semester and do not use assessment guides, especially on aspects of children's mathematical logic intelligence in their daily activities at school. Based on this, this research aims to develop a guidebook for assessing mathematical logic intelligence in kindergarten. This type of research is development research. This research uses the ADDIE model. The research subjects are learning media experts and learning material experts. The test subjects were fifteen teachers. The methods used to collect data are interviews, documentation, and questionnaires. The data collection instrument uses a questionnaire sheet. The data analysis technique used is quantitative descriptive statistical analysis. The research results are the results of material media validation tests with a test percentage value of 96.3% and the eligibility criteria being "very valid." The assessment from media experts was 98.7%, with the eligibility criteria being "very valid." The assessment score from the effectiveness instrument expert has a test percentage value of 97%, with the eligibility criteria being "very valid." The effectiveness test of individual trials were 95.69% "very effective" and small group 91.67% "very effective". It was concluded that the mathematical logic intelligence assessment guidebook is very suitable and adequate for teachers in kindergarten. The research implication is that the developed mathematical logic intelligence assessment guidebook can be used in learning activities.

Study protocol for a randomized controlled trial to adapt a posttraumatic stress disorder intervention of patients with opioid-stimulant polysubstance use receiving methadone maintenance treatment

BackgroundThe purpose of the Treatment for Harnessing Resiliency, Improving emotional regulation, and empowering indiViduals for a brighter future (THRIVE) study is to adapt an evidence-based posttraumatic stress disorder (PTSD) treatment for use among a polysubstance population receiving methadone maintenance treatment (MMT) at an opioid treatment program. Polysubstance use of high-risk combinations, such as illicit opioids and stimulants, is a critical public health issue. Individuals who engage in these high-risk combinations are more likely to have histories of childhood trauma, multiple traumas, PTSD, and greater PTSD severity as compared to mono-substance using individuals. Trauma, co-morbid mental health disorders such as PTSD, and polysubstance use complicate treatment outcomes. This study will use eight study phases to adapt an existing evidence-based PTSD intervention, Skills Training in Affective and Interpersonal Regulation with Narrative Therapy (STAIR-NT), via a massed treatment model (i.e., condensed treatment schedule) for patients in MMT who are engaged in sustained opioid-stimulant polysubstance use.Methods and analysisThe intervention is an adapted version of the STAIR-NT protocol. The massed version created includes four 60-min sessions of skill building and two weeks of four 60-min sessions of narrative therapy. A preliminary randomized controlled trial (RCT) with 80 participants, randomized 1:1, will be conducted to assess the intervention's implementation and impact on primary short-term outcomes of polysubstance use and PTSD symptoms.Ethics and disseminationThe results of this study will inform a fully-powered effectiveness trial for individuals with PTSD and polysubstance use receiving MMT. The findings are expected to provide valuable insights into improving both PTSD and substance use outcomes, and real-world implementation insights to integrating trauma-informed care in treatment settings for vulnerable populations.RegistrationThis study is registered at ClinicalTrials.Gov as NCT06307340. Registration date 03/2024.

Effect of yoga on balance, falls, and bone metabolism: a systematic review of randomized controlled trials in healthy individuals.

Yoga's effects on interconnected bone health parameters viz balance, falls, fear of falling (FOF), bone mineral density (BMD), and bone turnover markers (BTMs) in healthy individuals are unclear. We critically evaluated randomized controlled trials (RCTs) that compared yoga to no intervention control (NIC) or comparators such as Tai Chi, on these parameters in healthy individuals. We systematically searched multiple scientific data bases using a predefined protocol. We summarized data qualitatively when there was heterogeneity in reporting. A meta-analysis of those studies comparing yoga to NIC was done. Since the included studies used different scales for the same outcomes, we used standardised mean differences (SMDs) to allow pooling. We assessed the risk of bias with the Cochrane RoB2 tool for randomized trials and graded certainty of evidence using the GRADE approach. Eighteen RCTs with 1408 participants were evaluated. Fifteen explored yoga's effects on balance and/or falls or FOF, and three RCTs, its effect on BMD and BTMs. Yoga types included Hatha, Vinyasa, Ashtanga, Iyengar, Bikram, and specially designed yoga protocols. Twenty-four kinds of balance assessment tools were used in the studies. Study durations varied from 6weeks to 14months. Almost all the studies reported positive effects of yoga on balance compared to NIC, and non-inferiority when compared to active interventions such as Tai Chi. Meta-analysis of four RCTs comparing yoga to NIC demonstrated significant improvements in static balance with yoga (SMD = 2.36; 95% CI 1.13-3.58; P = 0.0002, I2 = 93% ⊕ ⊕ ⊝ ⊝). Yoga's effects on falls and FOF were mixed. Two studies showed a positive effect of yoga on bone formation. Yoga was found to have a positive effect on BMD in only one study. Meta-analysis of two RCTs showed no significant effect on BMD for yoga compared to NIC. The studies exhibited substantial heterogeneity in terms of yoga styles, intervention durations, and assessment methods. In healthy adults, low certainty evidence shows that yoga has a beneficial effect on balance. Its effect on BMD remains unclear. Standardised protocols and longer-term research are necessary to facilitate more definitive conclusions on yoga's role in enhancing skeletal health and preventing falls.

Dorsolateral prefrontal cortex drives strategic aborting by optimizing long-run policy extraction.

Real world choices often involve balancing decisions that are optimized for the short-vs. long-term. Here, we reason that apparently sub-optimal single trial decisions in macaques may in fact reflect long-term, strategic planning. We demonstrate that macaques freely navigating in VR for sequentially presented targets will strategically abort offers, forgoing more immediate rewards on individual trials to maximize session-long returns. This behavior is highly specific to the individual, demonstrating that macaques reason about their own long-run performance. Reinforcement-learning (RL) models suggest this behavior is algorithmically supported by modular actor-critic networks with a policy module not only optimizing long-term value functions, but also informed of specific state-action values allowing for rapid policy optimization. The behavior of artificial networks suggests that changes in policy for a matched offer ought to be evident as soon as offers are made, even if the aborting behavior occurs much later. We confirm this prediction by demonstrating that single units and population dynamics in macaque dorsolateral prefrontal cortex (dlPFC), but not parietal area 7a or dorsomedial superior temporal area (MSTd), reflect the upcoming reward-maximizing aborting behavior upon offer presentation. These results cast dlPFC as a specialized policy module, and stand in contrast to recent work demonstrating the distributed and recurrent nature of belief-networks.

Pengembangan Game Edukasi Berbasis Android PADA Materi Jenis Konektivitas Internet Kelas X TKJ SMKN 1 Sepulu

The development of technology in the world of education can produce learning innovations, one of which is educational games. This study aims to develop an Android-based educational game application as a learning medium on the material of internet connectivity types for class X TKJ students at SMKN 1 Sepulu. This study uses the Research and Development (RD) method with the ADDIE development model consisting of five stages: analysis, design, development, implementation, and evaluation. The results of the study indicate that this educational game application has succeeded in increasing the effectiveness of learning through validation testing and user trials. Validation by media experts obtained a percentage of 96.3% and material experts 98.4%, both in the "very good" category. User trials involving students were carried out in three stages, namely individual trials 95.7%, small groups 96.0%, and large groups 90.7%, all in the "very good" category. With these results, this Android-based educational game application is considered suitable for use as a learning medium to increase student motivation and learning outcomes. This study shows that the development of educational game-based learning media can be an innovative solution to support more interesting and effective learning.

Development of a novel tool for individual treatment trials in mucopolysaccharidosis.

Mucopolysaccharidosis (MPS) encompasses a group of genetic lysosomal storage disorders, linked to reduced life expectancy and a significant lack of effective treatment options. Immunomodulatory drugs could have the potential to be a relevant medical approach, as the accumulation of undegraded substances initiates an innate immune response, which leads to inflammation and clinical deterioration. However, immunomodulators are not licensed for this indication. Consequently, we aim to provide evidence advocating fast access to innovative individual treatment trials (ITTs) with immunomodulatory drugs and high-quality evaluation of drug effects by implementing a risk-benefit model tailored for MPS. The iterative methodology of our novel decision analysis framework (DAF) involves three key steps: (i) literature review on promising treatment targets and immunomodulators in MPS; (ii) quantitative risk-benefit assessment (RBA) of selected molecules; (iii) assigning phenotypic profiles and quantitative evaluations. The results facilitate a personalized application of the model and are based on published evidence as well as interdisciplinary experts' consensus and patient perspectives. Four promising immunomodulators have been identified: adalimumab, abatacept, anakinra, and cladribine. An improvement in mobility is most likely with adalimumab, while anakinra is anticipated as a treatment of choice for neuronopathic MPS patients. Nevertheless, a comprehensive RBA should always be completed on an individual basis. Our evidence-based DAF tool for ITTs directly addresses the substantial unmet medical need in MPS and characterizes an initial stride toward precision medicine with immunomodulators.

Searching for consistent postemergence weed control in progressively inconsistent weather

Abstract Foliar applied postemergence herbicides are a critical component of corn and soybean weed management programs in North America. Rainfall and air temperature around the time of application may affect the efficacy of herbicides applied postemergence in corn or soybean production fields. However, previous research utilized a limited number of site-years and may not capture the range of rainfall and air temperatures that these herbicides are exposed to throughout North America. The objective of this research was to model the probability of achieving successful weed control (≥85%) with commonly applied postemergence herbicides across a broad range of environments. A large database of over 10,000 individual herbicide evaluation field trials conducted throughout North America was used in this study. The database was filtered to include only trials with a single postemergence application of fomesafen, glyphosate, mesotrione, or fomesafen + glyphosate. Waterhemp (Amaranthus tuburculatus (Moq.) J. D. Sauer), morningglory species (Ipomoea spp.), and giant foxtail (Setaria faberi Herrm.) were the weeds of focus. Separate random forest models were created for each weed species by herbicide combination. The probability of successful weed control deteriorated when the average air temperature within the first ten d after application was <19 or >25 C for most of the herbicide by weed species models. Additionally, dryer conditions prior to postemergence herbicide application reduced the probability of successful control for several of the herbicide by weed species models. As air temperatures increase and rainfall becomes more variable, weed control with many of the commonly used postemergence herbicides is likely to become less reliable.

Examining interrelations among trajectories of mindful awareness, acceptance, and values-consistent actions in acceptance-based behavioral therapy for generalized anxiety disorder

ABSTRACT The goal of this study was to understand how mindful awareness, acceptance, and values-consistent action change across acceptance-based behavioral therapy (ABBT) for generalized anxiety disorder (GAD) and determine their effect on symptoms. We examined weekly data from 31 individuals who received ABBT as part of a randomized control trial for individuals with GAD (Hayes-Skelton, Roemer, & Orsillo, 2013). Participants answered questions weekly about three components of ABBT, including the percentages of time they spent over their past week: 1) aware of the present moment, 2) accepting of their internal experiences, and 3) engaging in values. GAD symptoms were examined using two self-report measures (DASS-21 Stress subscale and PSWQ) and two clinician-rated interview measures (CSR and SIGH-A) at pre- and post-treatment. 1 Mindful awareness, acceptance, and values-consistent action increased linearly across ABBT. All three change trajectories were positively correlated (Z’s 2.99 to 8.74, p’s < .001). Mindful awareness, acceptance, and values-consistent action across treatment predicted decreases in GAD symptoms above and beyond baseline for most outcome measures (Z’s −1.95 to −3.03, p’s < .05), with the exception that mindfulness did not predict DASS-stress (Z = −1.39, p = .17). These findings are consistent with the structure and model of ABBT.

Citrus supplementation in subjective cognitive decline: results of a 36-week, randomized, placebo-controlled trial

BackgroundDeveloping interventions for older adults with subjective cognitive decline (SCD) has the potential to prevent dementia in this at-risk group. Preclinical models indicate that Citrus-derived phytochemicals could benefit cognition and inflammatory processes, but results from clinical trials are still preliminary. The aim of this study is to determine the effects of long-term supplementation with Citrus peel extract on cognitive performance and inflammation in individuals with SCD.MethodsEighty participants were randomly assigned to active treatment (400 mg of Citrus peel extract containing 3.0 mg of naringenin and 0.1 mg of auraptene) or placebo at 1:1 ratio for 36 weeks. The primary endpoint was the change in the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) total score across the 36-week trial period. Other cognitive outcomes included tests and scales evaluating verbal memory, attention, executive and visuospatial functions, and memory concerns. The secondary endpoint was the change of interleukin-8 (IL-8) levels over the 36-week trial period in a subsample of 60 consecutive participants. An Intention-to-treat approach with generalized linear mixed models was used for data analysis.ResultsThe RBANS total score showed significant improvement in both Citrus peel extract and placebo groups at 36 weeks (p for time < .001, d = 0.36, p time x treatment = .910). Significant time effects were also found in cognitive domains of short- and long-term verbal memory (p < .001) and scales of subjective memory (p < .01), with no significant time x treatment interaction. The largest effect sizes were observed in verbal memory in the placebo group (d = 0.69 in short-term, and d = 0.78 in long-term verbal memory). Increased IL-8 levels were found at 36-week follow-up in both Citrus peel extract and placebo groups (p for time = .010, d = 0.21, p time x treatment = .772). Adverse events were balanced between groups.ConclusionsIn this randomized clinical trial, long-term Citrus peel extract supplementation did not show cognitive benefits over placebo in participants with SCD, possibly due to high placebo response. These findings might have specific implications for designing future nutraceutical trials in individuals experiencing SCD.Trial registrationThe trial has been registered at the United States National Library of Medicine at the National Institutes of Health Registry of Clinical Trials under the code NCT04744922 on February 9th, 2021 (https://www.clinicaltrials.gov/ct2/show/NCT04744922).

N‐acetylcysteine as a treatment for substance use cravings: A meta‐analysis

AbstractN‐acetylcysteine (NAC) may serve as a novel pharmacotherapy for substance use and substance craving in individuals with substance use disorders (SUDs), possibly through its potential to regulate glutamate. Though prior meta‐analyses generally support NAC's efficacy in reducing symptoms of craving, individual trials have found mixed results. The aims of this updated meta‐analysis were to (1) examine the efficacy of NAC in treating symptoms of craving in individuals with SUD and (2) explore subgroup differences, risk of bias and publication bias across trials. Database searches of PubMed, Cochrane Library and ClinicalTrials.gov were conducted in June and July of 2023 to identify relevant randomized control trials (RCTs). The meta‐analysis consisted of 9 trials which analysed data from a total of 623 participants. The most targeted substance in the clinical trials was alcohol (3/9; 33.3%), followed by tobacco (2/9; 22.2%) and multiple substances (2/9; 22.2%). Meta‐analysis, subgroup analyses and leave‐one‐out analyses were conducted to examine the treatment effect on craving symptoms and adverse events (AEs). Risk of bias assessments, Egger's tests and funnel plot tests were conducted to examine the risk of bias and publication bias. NAC did not significantly outperform placebo in reducing symptoms of craving in the meta‐analysis (SMD = 0.189, 95% CI = −0.015–0.393). Heterogeneity was very high in the meta‐analysis (99.26%), indicating that findings may have been influenced by clinical or methodological differences in the study protocols. Additionally, results indicate that there may be publication bias present. Overall, our findings are contrary to those of prior meta‐analyses, suggesting a limited impact of NAC on substance craving. However, the high heterogeneity and presence of publication bias identified warrants cautious interpretation of the meta‐analytic outcomes.

Survodutide, a glucagon receptor/GLP-1 receptor (GCGR/GLP-1R) dual agonist, improves cardiometabolic parameters in adults with obesity: analysis of a placebo-controlled, randomised phase 2 trial

Abstract Background Obesity increases the risk of cardiovascular (CV) disease and contributes to CV risk factors, such as hypertension (HTN) and dyslipidaemia. Survodutide is a GCGR/GLP-1R dual agonist in clinical development for obesity. In a phase 2 clinical trial in individuals with obesity without diabetes, survodutide elicited up to 18.7% mean reduction in body weight after 46 weeks (primary endpoint) according to actual treatment.1 Purpose We explored the effect of survodutide on cardiometabolic parameters in this trial cohort. Methods 387 people aged ≥18 to &amp;lt;75 years with body mass index (BMI) ≥27 kg/m2 without diabetes were randomised 1:1:1:1:1 to once-weekly subcutaneous survodutide (0.6, 2.4, 3.6, 4.8 mg) or placebo (PBO) for 46 weeks (wk), comprising an initial 20-wk escalation period when the dose could be adjusted for gastrointestinal (GI) tolerability, followed by a 26-wk maintenance period. We evaluated changes from baseline (BL) to wk 46 in waist circumference; lipid parameters (triglyceride [TG], high-density lipoprotein [HDL], very low-density lipoprotein [VLDL], low-density lipoprotein [LDL], total cholesterol [TC], and non-HDL cholesterol [non-HDL-C]); and blood pressure (BP) by presence/absence of HTN before and at screening. Data were analysed descriptively for all participants receiving ≥1 dose of study drug with data for ≥1 efficacy endpoint, i.e. full analysis set (FAS), according to doses received during the maintenance period (actual treatment) and according to doses assigned at randomization (planned treatment) using on-treatment data. Results In the FAS (n=384), BL demographic and clinical characteristics were similar across treatment groups: overall mean age 49.1 years, BMI 37.1 kg/m2, 262 (68.2%) female, 301 (78.4%) White, 40 (10.4%) Asian, and 37 (9.6%) Black. Before and at screening, 133 (34.6%) participants had hypertension and 108 (28.1%) had dyslipidaemia. Waist circumference was reduced in all survodutide doses vs PBO; the largest mean reduction was 16.6 cm (4.8 mg group; actual treatment). Survodutide was associated with reductions of up to 10.2 mmHg in SBP and 4.8 mmHg in DBP from BL to wk 46 by actual treatment; similar reductions were observed for planned treatment, and reductions were comparable with/without HTN before and at screening (Figure 1). A marked decrease in mean TG was observed in all survodutide groups by planned treatment (Figure 2). Mean HDL was relatively unchanged over the period. Small decreases occurred in mean VLDL (all survodutide doses) and mean LDL (2.4 and 3.6 mg doses). Mean TC and non-HDL-C decreased in 0.6, 2.4, and 3.6 mg groups. Conclusion In people living with obesity, the GCGR/GLP-1R dual agonist survodutide was associated with clinically meaningful reductions in waist circumference, BP (with/out HTN before and at screening), and TG.

Transcatheter versus surgical aortic valve replacement in lower-risk patients: an updated meta-analysis of randomised controlled trials

Abstract Background Long-term clinical outcomes after transcatheter [TAVI] and surgical [SAVR] aortic valve replacement are of utmost importance in lower-risk patients. Event rates are diminished in lower-risk patients, therefore individual trials may be separately underpowered to assess low-frequency outcomes. New randomised data has emerged, including 4, 5 and 10-year follow-up from the Evolut Low Risk, PARTNER-3 and NOTION trials, respectively. Purpose To perform a systematic review and meta-analysis of randomised trials studying long-term outcomes in patients with severe aortic stenosis at low-surgical risk undergoing TAVI versus SAVR. Methods Trials randomising patients at lower surgical risk in trials comparing TAVI with SAVR were systematically identified. The prespecified primary endpoint was all-cause death. Key secondary endpoints included stroke, death or disabling stroke, cardiac death, new permanent pacemaker, aortic valve reintervention, and new-onset atrial fibrillation. Reconstructed individual patient data [IPD] was obtained via digitisation of Kaplan-Meier survival curves. Using these data, Cox proportional hazards regression was performed using frailty models on the primary outcome of all-cause death. To assess total lifetime lost, the restricted mean survival time [RMST] was calculated. Conventional pairwise random effects meta-analyses were also performed. This analysis was prospectively registered [CRD42023484976]. Results 4 eligible trials contributed data from 3557 patients with a weighted mean follow-up duration of approximately 4 years (47.6 months). In the reconstructed IPD pooled analyses, there was no significant difference in the hazard of death [hazard ratio 1.15, 95% CI 0.93 to 1.41, p=0.20] or RMST [Δ-0.8 months, p=0.09] (Figure 1). In pairwise meta-analyses, there was no difference between TAVI and SAVR in all-cause death [relative risk (RR) 0.94, 95% confidence interval (CI) 0.78 to 1.13, p=0.51] (Figure 2). There was also no significant difference for stroke [RR 0.94, 95% CI 0.59 to 1.50, p=0.80], or a composite of death or disabling stroke [RR 0.92, 95% CI 0.70 to 1.22, p=0.57]. There was an increase in new pacemaker implantation with TAVI [RR 2.15, 95% CI 1.50 to 3.07, p&amp;lt;0.001], and a reduction in new AF with TAVI [RR 0.43, 95% CI 0.26 to 0.70, p&amp;lt;0.001]; there was no significant difference in any other endpoint (Figure 2). Conclusions The present analysis demonstrates no difference in major clinical outcomes with TAVI or SAVR in lower-risk patients at 4-years follow-up. These results were consistent when analysed using pooled reconstructed IPD or conventional meta-analyses and there were no differences in RMST. These data are informative for lower-risk patients and clinicians, but longer-term follow-up is required to confirm whether equivalence is maintained.Kaplan-Meier plot comparing TAVI vs SAVRForest plot for key clinical endpoints

Rosuvastatin effect on atherosclerotic plaque microcalcification

Abstract Background and Aims Atherosclerotic plaque fluorine-18 sodium fluoride (18F-NaF) uptake on positron emission tomography with computed tomography (PET-CT) identifies active microcalcification and has been shown to correlate with clinical instability in patients with cardiovascular (CV) disease. Statin therapy promotes coronary macrocalcification over time. Our aim was to investigate rosuvastatin effect on atheroma 18F-NaF uptake. Methods Subjects with high CV risk but without CV events underwent 18F-NaF-PET-CT in a single-centre. Those with subclinical atherosclerosis and significant 18F-NaF plaque uptake were included in a single-arm clinical trial, treated with rosuvastatin 20mg/daily for six months, and re-evaluated by 18F-NaF-PET-CT. Primary endpoint was reduction in maximum atheroma 18F-NaF uptake in the coronary, aortic or carotid arteries, assessed by the tissue-to-background ratio (TBR). The secondary endpoint was corrected uptake per lesion (CUL) variation. Results Forty individuals were enrolled and 38 included in the pharmacological trial; mean age was 64 years-old, two-thirds were male and most were diabetic. The 10-year expected CV risk was 9.5% (6.0-15.3) for SCORE2 and 31.7±18.7% for ASCVD systems. After six months of rosuvastatin treatment (n=34), low-density lipoprotein cholesterol lowered from 133.6±33.8 to 58.8±20.7 mg.dL-1 (60% relative reduction, p&amp;lt;0.01). There was a significant 19% reduction in maximum plaque 18F-NaF uptake after treatment, from 1.96 (1.78-2.22) to 1.53 (1.40-2.10), p&amp;lt;0.001 (primary endpoint analysis). The secondary endpoint CUL was reduced by 23% (p=0.003). Conclusion In a single-centre non-randomized clinical trial of high CV risk individuals with subclinical atherosclerosis, the maximum atherosclerotic plaque 18F-NaF uptake was significantly reduced after six months of high-intensity statin.Graphical abstractTrial design

RNA mis-splicing in children with congenital myotonic dystrophy is associated with physical function.

Dysregulated RNA alternative splicing is the hallmark of myotonic dystrophy type 1 (DM1). However, the association between RNA mis-splicing and physical function in children with the most severe form of disease, congenital myotonic dystrophy (CDM), is unknown. Eighty-two participants (42 adults with DM1 and 40 children with CDM) with muscle biopsies and measures of myotonia, motor function, and strength were combined from five observational studies. Data were normalized and correlated with an aggregate measure of alternative splicing dysregulation, [MBNL]inferred, in skeletal muscle biopsies. Multiple linear regression analysis was performed to predict [MBNL]inferred using clinical outcome measures alone. Similar analyses were performed to predict 12-month physical function using baseline metrics. Myotonia (measured via vHOT) was significantly correlated with RNA mis-splicing in our cross-sectional population of all DM1 individuals; CDM participants alone displayed no myotonia despite a similar range of RNA mis-splicing. Measures of motor performance and muscle strength were significantly associated with [MBNL]inferred in our cohort of all DM1 individuals and when assessing children with CDMindependently. Multiple linear regression analyses yielded two models capable of predicting [MBNL]inferred from select clinical outcome assessments alone in all subjects(adjusted R2 = 0.6723) or exclusively in children with CDM (adjusted R2 = 0.5875). Our findings establish significant correlations between skeletal muscle performance and a composite measure of alternative splicing dysregulation, [MBNL]inferred, in DM1. The strength of these correlations and the development of predictive models will assist in designing efficacious clinical trials for individuals with DM1, particularly CDM.

Analyses of Wheat Resistance to Fusarium Head Blight Using Different Inoculation Methods

Fusarium head blight is a devastating wheat disease that causes yield reduction and mycotoxins contamination, leading to multiple negative consequences for the economy, health, and food safety. Despite the tremendous efforts that have been undertaken over the last several decades to harness the disease, the problem remains a challenging issue. Due to global warming, its impact has become increasingly severe in Baltic and Nordic countries. The improvement of wheat resistance is hampered by complicated genetic inheritance, the scarcity of adapted resistant breeding materials, and difficulties in obtaining accurate and reproducible data due to the high interaction and dependency of the disease development on the environment. In this study, the resistance of 335 genotypes, 9 of which were of exotic origin and the remainder of which were adapted to the environments of Lithuania, Latvia, Estonia, or Norway, was studied in 8 trials using spray and point inoculation with spore suspensions and grain spawn inoculation under field and/or greenhouse conditions. The best linear unbiased estimates (BLUEs) of each genotype within the individual trials and the adjusted means across the trials were determined to reduce the environmental effects. Genotypes that exhibited excellent Type I or Type II resistance and overall resistance were identified.

Exploiting correlations across trials and behavioral sessions to improve neural decoding.

Traditional neural decoders model the relationship between neural activity and behavior within individual trials of a single experimental session, neglecting correlations across trials and sessions. However, animals exhibit similar neural activities when performing the same behavioral task, and their behaviors are influenced by past experiences from previous trials. To exploit these informative correlations in large datasets, we introduce two complementary models: a multi-session reduced-rank model that shares similar behaviorally-relevant statistical structure in neural activity across sessions to improve decoding, and a multi-session state-space model that shares similar behavioral statistical structure across trials and sessions. Applied across 433 sessions spanning 270 brain regions in the International Brain Laboratory public mouse Neuropixels dataset, our decoders demonstrate improved decoding accuracy for four distinct behaviors compared to traditional approaches. Unlike existing deep learning approaches, our models are interpretable and efficient, uncovering latent behavioral dynamics that govern animal decision-making, quantifying single-neuron contributions to decoding behaviors, and identifying different activation timescales of neural activity across the brain. Code: https://github.com/yzhang511/neural_decoding.

The implementation of sex-and gender-based considerations in exercise-based randomized controlled trials in individuals with stroke: A cross-sectional study.

Emerging evidence suggests that sex-and gender-based factors may influence responses to exercise post-stroke. The Sex and Gender Equity in Research (SAGER) guidelines (2016) published international standards for terminology and considerations for research design and trial reporting. The extent to which sex- and gender-based considerations have been implemented in stroke exercise trials is currently unknown. The objective of this cross-sectional study was to compare the proportion of studies that have implemented sex/gender considerations before and after the publication of the SAGER guidelines. We conducted a comprehensive search of the literature to identify exercise-based trials in individuals with stroke. Study titles, abstracts, introductions (hypothesis statements), methods, results and discussions were assessed for adherence to the SAGER guidelines. The proportion of studies adhering to SAGER guidelines published prior to and including December 31, 2016 and from 2017-March 2023 were compared. Of the 245 studies identified, 150 were published before December 31, 2016, of which 0 (0%) titles/abstracts, 0 (0%) introductions, 21 (14.0%) methods, 8 (5.3%) results, and 7 (4.7%) discussion sections adhered to the SAGER guidelines, and 35 (23.3%) reported proper sex and gender terminology. Of the 95 studies published between 2017-2023, 0 (0%) title/abstracts, 1 (1.0%) introduction, 16 (16.8%) methods, 5 (5.3%) results, and 10 (10.5%) discussion sections adhered to the guidelines, and 37 (38.9%) of studies included proper terminology. The implementation of sex- and gender-based considerations in stroke exercise trials is low, but positively the reporting of proper terminology has increased since the publication of standardized reporting guidelines. This study serves as a call to action for stroke rehabilitation researchers to incorporate sex- and gender-based considerations in all stages of research studies, to improve the rigour and generalizability of findings, and promote health equity.

Comparative analysis of medical treatments for long-term control of normal tension glaucoma: A systematic review and model-based network meta-analysis.

To evaluate and compare the long-term efficacy of medical treatments for normal tension glaucoma (NTG) in controlling intraocular pressure (IOP), and establish a hierarchical ranking based on their effectiveness. 'Long-term' is defined as a treatment duration of over 12 weeks in randomised controlled trials (RCTs). This systematic review and model-based network meta-analysis (MBNMA) collected data of 795 patients with 997 eyes from RCTs. Patients with NTG were selected based on strict inclusion/exclusion criteria, with randomsation procedures and masking as reported in the individual trials. Eight different medications were compared, including prostaglandin analogues, beta-blockers, brimonidine, unoprostone isopropyl, brovincamine, and palmitoylethanolamide (PEA). Notably, PEA is an oral medication, while other drugs are topical agents. Primary outcome is the long-term efficacy of IOP control across medications with different follow-up durations. Among the eight medications, PEA demonstrates the highest efficacy (Surface under the cumulative ranking, SUCRA = 7.46%), followed by two prostaglandin analogues: travoprost (SUCRA = 6.86%) and latanoprost (SUCRA = 6.76%), then two beta-blockers: nipradilol (SUCRA = 4.90%) and timolol (SUCRA = 4.89%). Both brimonidine and unoprostone isopropyl have SUCRA scores below 4.0%, indicating modest but limited efficacy. Brovincamine has the lowest SUCRA score (1.32%), reflecting minimal effectiveness. This study revealed PEA as a promising agent for long-term IOP control in NTG patients, suggesting potential use as primary or adjunctive therapy. The outcomes call for PEA's consideration in clinical practice and highlight the need for further research into its long-term efficacy and safety for NTG.

The Impact of Neoadjuvant versus Adjuvant Chemotherapy on Survival Outcomes in Locally Advanced Breast Cancer.

The utility of neoadjuvant chemotherapy is expanding in the treatment of breast cancer. Although individual trials have shown comparable survival between patients receiving neoadjuvant and adjuvant chemotherapy, large-scale data analyses for outcomes in patients with locally advanced breast cancer (LABC) are lacking. We conducted an individual-level statistical analysis using patients from six randomized controlled trials (RCTs) investigating survival outcomes with neoadjuvant versus adjuvant chemotherapy in breast cancer by abstracting and analyzing only the patients with LABC. Individual patient data for 779 patients with LABC were collected from six RCTs. Overall and disease-free survival rates were compared between patients receiving neoadjuvant vs. adjuvant chemotherapy with the Cox hazard model and log-rank statistics. Since chemotoxicity causing delays to surgical care is a potential drawback of neoadjuvant chemotherapy, local cohort data were then employed to assess the actual incidence of this, along with the causes behind any delays to surgery in patients receiving neoadjuvant chemotherapy. A time interval from neoadjuvant chemotherapy to surgery of >8 weeks was investigated in a local cohort of 563 patients, representing all locally treated patients receiving neoadjuvant chemotherapy between 2006 and 2019. The statistical analysis demonstrated no overall or disease-free survival differences in LABC patients receiving neoadjuvant vs. adjuvant chemotherapy (p = 0.96 and 0.74, respectively). Within our cohort, 31 (5.5%) patients treated with neoadjuvant chemotherapy experienced a delay of >8 weeks to surgery, with only 13 (2.3%) attributed to chemotherapy-related complications. Our study provides further support for the paradigm shift towards delivering chemotherapy for breast cancer patients in the neoadjuvant setting.