Intravenous iron for heart failure, iron deficiency definitions, and clinical response: the IRONMAN trial.

BACKGROUND AND AIMS: What is the relationship between blood tests for iron deficiency, including anaemia, and the response to intravenous iron in patients with heart failure? METHODS: In the IRONMAN trial, 1137 patients with heart failure, ejection fraction ≤ 45%, and either serum ferritin < 100 µg/L or transferrin saturation (TSAT) < 20% were randomized to intravenous ferric derisomaltose (FDI) or usual care. Relationships were investigated between baseline anaemia severity, ferritin and TSAT, to changes in haemoglobin from baseline to 4 months, Minnesota Living with Heart Failure (MLwHF) score and 6-minute walk distance achieved at 4 months, and clinical events, including heart failure hospitalization (recurrent) or cardiovascular death. RESULTS: The rise in haemoglobin after administering FDI, adjusted for usual care, was greater for lower baseline TSAT (Pinteraction < .0001) and ferritin (Pinteraction = .028) and more severe anaemia (Pinteraction = .014). MLwHF scores at 4 months were somewhat lower (better) with FDI for more anaemic patients (overall Pinteraction = .14; physical Pinteraction = .085; emotional Pinteraction = .043) but were not related to baseline TSAT or ferritin. Blood tests did not predict difference in achieved walking distance for those randomized to FDI compared to control. The absence of anaemia or a TSAT ≥ 20% was associated with lower event rates and little evidence of benefit from FDI. More severe anaemia or TSAT < 20%, especially when ferritin was ≥100 µg/L, was associated with higher event rates and greater absolute reductions in events with FDI, albeit not statistically significant. CONCLUSIONS: This hypothesis-generating analysis suggests that anaemia or TSAT < 20% with ferritin > 100 µg/L might identify patients with heart failure who obtain greater benefit from intravenous iron. This interpretation requires confirmation.

Safety and Immunogenicity of mRNA-1010, an Investigational Seasonal Influenza Vaccine, in Healthy Adults: Final Results From a Phase 1/2 Randomized Trial.

BACKGROUND: Seasonal influenza remains a global public health concern. A messenger RNA (mRNA)-based quadrivalent seasonal influenza vaccine, mRNA-1010, was investigated in a 3-part, first-in-human, phase 1/2 clinical trial. METHODS: In Parts 1-3 of this stratified, observer-blind study, adults aged ≥18 years old were randomly assigned to receive a single dose (6.25 µg to 200 µg) of mRNA-1010 or placebo (Part 1) or an active comparator (Afluria; Parts 2-3). Primary study objectives were assessment of safety, reactogenicity, and humoral immunogenicity of mRNA-1010, placebo (Part 1), or active comparator (Parts 2-3). Exploratory endpoints included assessment of cellular immunogenicity (Part 1) and antigenic breadth against vaccine heterologous (A/H3N2) strains (Parts 1-2). RESULTS: In all study parts, solicited adverse reactions were reported more frequently for mRNA-1010 than placebo or Afluria and most were grade 1 or 2 in severity. No vaccine-related serious adverse events or deaths were reported. In Parts 1-2, a single dose of mRNA-1010 (25 µg to 200 µg) elicited robust Day 29 hemagglutination inhibition (HAI) titers that persisted through 6 months. In Part 3, lower doses of mRNA-1010 (6.25 µg to 25 µg) elicited Day 29 HAI titers that were higher or comparable to Afluria for influenza A strains. Compared with Afluria, mRNA-1010 (50 µg) elicited broader A/H3N2 antibody responses (Part 2). mRNA-1010 induced greater T-cell responses than placebo at Day 8 that were sustained or stronger at Day 29 (Part 1). CONCLUSIONS: Data support the continued development of mRNA-1010 as a seasonal influenza vaccine. CLINICALTRIALS.GOV IDENTIFIER: NCT04956575 (https://clinicaltrials.gov/study/NCT04956575).

Early prediction of endocrine responsiveness in ER+/HER2-negative metastatic breast cancer (MBC): pilot study with 18F-fluoroestradiol (18F-FES) CT/PET.

BACKGROUND: 18F-fluoroestradiol (FES) positron emission tomography (PET)/computed tomography (CT) is considered an accurate diagnostic tool to determine whole-body endocrine responsiveness. In the endocrine therapy (ET)-FES trial, we evaluated 18F-FES PET/CT as a predictive tool in estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC). PATIENTS AND METHODS: Eligible patients underwent an 18F-FES PET/CT at baseline. Patients with standardized uptake value (SUV) ≥ 2 received single-agent ET until progressive disease; patients with SUV < 2 were randomized to single-agent ET (arm A) or chemotherapy (ChT) (arm B). The primary objective was to compare the activity of first-line ET versus ChT in patients with 18F-FES SUV < 2. RESULTS: Overall, 147 patients were enrolled; 117 presented with 18F-FES SUV ≥ 2 and received ET; 30 patients with SUV < 2 were randomized to ET or ChT. After a median follow-up of 62.4 months, 104 patients (73.2%) had disease progression and 53 died (37.3%). Median progression-free survival (PFS) was 12.4 months [95% confidence interval (CI) 3.1-59.6 months] in patients with SUV < 2 randomized to arm A versus 23.0 months (95% CI 7.7-30.0 months) in arm B, [hazard (HR) = 0.71, 95% CI 0.3-1.7 months]; median PFS was 18.0 months (95% CI 11.2-23.1 months) in patients with SUV ≥ 2 treated with ET. Median overall survival (OS) was 28.2 months (95% CI 14.2 months-not estimable) in patients with SUV < 2 randomized to ET (arm A) versus 52.8 months (95% CI 16.2 months-not estimable) in arm B (ChT). Median OS was not reached in patients with SUV ≥ 2. 60-month OS rate was 41.6% (95% CI 10.4% to 71.1%) in arm A, 42.0% (95% CI 14.0% to 68.2%) in arm B, and 59.6% (95% CI 48.6% to 69.0%) in patients with SUV ≥ 2. In patients with SUV ≥ 2, 60-month OS rate was 72.6% if treated with aromatase inhibitors (AIs) versus 40.6% in case of fulvestrant or tamoxifen (P < 0.005). CONCLUSIONS: The ET-FES trial demonstrated that ER+/HER2- MBC patients are a heterogeneous population, with different levels of endocrine responsiveness based on 18F-FES CT/PET SUV.

The effects of telehealth-delivered mindfulness meditation, cognitive therapy, and behavioral activation for chronic low back pain: a randomized clinical trial.

BACKGROUND: Chronic low back pain (CLBP) is a significant problem affecting millions of people worldwide. Three widely implemented psychological techniques used for CLBP management are cognitive therapy (CT), mindfulness meditation (MM), and behavioral activation (BA). This study aimed to evaluate the relative immediate (pre- to post-treatment) and longer term (pre-treatment to 3- and 6-month follow-ups) effects of group, videoconference-delivered CT, BA, and MM for CLBP. METHODS: This is a secondary analysis of a three-arm, randomized clinical trial comparing the effects of three active treatments-CT, BA, and MM-with no inert control condition. Participants were N = 302 adults with CLBP, who were randomized to condition. The primary outcome was pain interference, and other secondary outcomes were also examined. The primary study end-point was post-treatment. Intent-to-treat analyses were undertaken for each time point, with the means of the changes in outcomes compared among the three groups using an analysis of variance (ANOVA). Effect sizes and confidence intervals are also reported. RESULTS: Medium-to-large effect size reductions in pain interference were found within BA, CT, and MM (ds from - .71 to - 1.00), with gains maintained at both follow-up time points. Effect sizes were generally small to medium for secondary outcomes for all three conditions (ds from - .20 to - .71). No significant between-group differences in means or changes in outcomes were found at any time point, except for change in sleep disturbance from pre- to post-treatment, improving more in BA than MM (d = - .49). CONCLUSIONS: The findings from this trial, one of the largest telehealth trials of psychological treatments to date, critically determined that group, videoconference-delivered CT, BA, and MM are effective for CLBP and can be implemented in clinical practice to improve treatment access. The pattern of results demonstrated similar improvements across treatments and outcome domains, with effect sizes consistent with those observed in prior research testing in-person delivered and multi-modal psychological pain treatments. Thus, internet treatment delivery represents a tool to scale up access to evidence-based chronic pain treatments and to overcome widespread disparities in healthcare. TRIAL REGISTRATION: Clinicaltrials.gov, NCT03687762.

Bifidobacterium longum subsp. longum BG-L47 boosts growth and activity of Limosilactobacillus reuteri DSM 17938 and its extracellular membrane vesicles.

The aim of this study was to identify a Bifidobacterium strain that improves the performance of Limosilactobacillus reuteri DSM 17938. Initial tests showed that Bifidobacterium longum subsp. longum strains boosted the growth of DSM 17938 during in vivo-like conditions. Further characterization revealed that one of the strains, BG-L47, had better bile and acid tolerance compared to BG-L48, as well as mucus adhesion compared to both BG-L48 and the control strain BB536. BG-L47 also had the capacity to metabolize a broad range of carbohydrates and sugar alcohols. Mapping of glycoside hydrolase (GH) genes of BG-L47 and BB536 revealed many GHs associated with plant-fiber utilization. However, BG-L47 had a broader phenotypic fiber utilization capacity. In addition, B. longum subsp. longum cells boosted the bioactivity of extracellular membrane vesicles (MV) produced by L. reuteri DSM 17938 during co-cultivation. Secreted 5'-nucleotidase (5'NT), an enzyme that converts AMP into the signal molecule adenosine, was increased in MV boosted by BG-L47. The MV exerted an improved antagonistic effect on the pain receptor transient receptor potential vanilloid 1 (TRPV1) and increased the expression of the immune development markers IL-6 and IL-1ß in a peripheral blood mononuclear cell (PBMC) model. Finally, the safety of BG-L47 was evaluated both by genome safety assessment and in a human safety study. Microbiota analysis showed that the treatment did not induce significant changes in the composition. In conclusion, B. longum subsp. longum BG-L47 has favorable physiological properties, can boost the in vitro activity of L. reuteri DSM 17938, and is safe for consumption, making it a candidate for further evaluation in probiotic studies. IMPORTANCE: By using probiotics that contain a combination of strains with synergistic properties, the likelihood of achieving beneficial interactions with the host can increase. In this study, we first performed a broad screening of Bifidobacterium longum subsp. longum strains in terms of synergistic potential and physiological properties. We identified a superior strain, BG-L47, with favorable characteristics and potential to boost the activity of the known probiotic strain Limosilactobacillus reuteri DSM 17938. Furthermore, we demonstrated that BG-L47 is safe for consumption in a human randomized clinical study and by performing a genome safety assessment. This work illustrates that bacteria-bacteria interactions differ at the strain level and further provides a strategy for finding and selecting companion strains of probiotics.

Endovascular Ablation of the Right Greater Splanchnic Nerve in Heart Failure With Preserved Ejection Fraction: Rationale, Design and Lead-in Phase Results of the REBALANCE-HF Trial.

OBJECTIVE: Splanchnic vasoconstriction augments transfer of blood volume from the abdomen into the thorax, which may increase filling pressures and hemodynamic congestion in patients with noncompliant hearts. Therapeutic interruption of splanchnic nerve activity holds promise to reduce hemodynamic congestion in patients with heart failure with preserved ejection fraction (HFpEF). Here we describe (1) the rationale and design of the first sham-controlled, randomized clinical trial of splanchnic nerve ablation for HFpEF and (2) the 12-month results of the lead-in (open-label) trial's participants. METHODS: REBALANCE-HF is a prospective, multicenter, randomized, double-blinded, sham-controlled clinical trial of endovascular, transcatheter, right-sided greater splanchnic nerve ablation for volume management (SAVM) in patients with HFpEF. The primary objectives are to evaluate the safety and efficacy of SAVM and identify responder characteristics to inform future studies. The trial consists of an open-label lead-in phase followed by the randomized, sham-controlled phase. The primary efficacy endpoint is the reduction in pulmonary capillary wedge pressure (PCWP) at 1-month follow-up compared to baseline during passive leg raise and 20W exercise. Secondary and exploratory endpoints include health status (Kansas City Cardiomyopathy Questionnaire), 6-minute walk test distance, New York Heart Association class, and NTproBNP levels at 3, 6 and 12 months. The primary safety endpoint is device- or procedure-related serious adverse events at the 1-month follow-up. RESULTS: The lead-in phase of the study, which enrolled 26 patients with HFpEF who underwent SAVM, demonstrated favorable safety outcomes and reduction in exercise PCWP at 1 month post-procedure and improvements in all secondary endpoints at 6 and 12 months of follow-up. The randomized phase of the trial (n = 44 SAVM; n = 46 sham) has completed enrollment, and follow-up is ongoing. CONCLUSION: REBALANCE-HF is the first sham-controlled randomized clinical trial of greater splanchnic nerve ablation in HFpEF. Initial 12-month open-label results are promising, and the results of the randomized portion of the trial will inform the design of a future pivotal clinical trial. SAVM may offer a promising therapeutic option for patients with HFpEF. TRIAL REGISTRATION: NCT04592445.

Five-year follow-up of randomized clinical trial for pre-emptive inferior mesenteric artery embolization during endovascular aneurysm repair.

OBJECTIVE: Type II endoleak (T2EL) is the most common type of endoleak after endovascular aneurysm repair (EVAR) and a common indication for reintervention due to late sac enlargement. Although pre-emptive embolization of the inferior mesenteric artery (IMA) has been proposed to prevent this, no studies have prospectively demonstrated its efficacy. This study aimed to prove the validity of IMA embolization during EVAR in selective cases by analyzing the mid-term outcomes of a randomized clinical trial (RCT). METHODS: This single-center, parallel-group, non-blinded RCT included participants at high risk of T2EL, characterized by a patent IMA in conjunction with one or more following risk factors: a patent IMA ≥3 mm in diameter, lumbar arteries ≥2 mm in diameter, or an aortoiliac-type aneurysm. The participants were randomly assigned to two groups in a 1:1 ratio: one undergoing EVAR with IMA embolization and the other without. The primary endpoint was T2EL occurrence. The secondary endpoints included aneurysm sac changes and reintervention. In addition to RCT participants, outcomes of patients with low risk of T2EL were also analyzed. RESULTS: The embolization and non-embolization groups each contained 53 patients. Five-year follow-up after the last patient enrollment revealed that T2ELs occurred in 28.3% and 54.7% of patients in the IMA embolization and non-embolization groups, respectively (P = .006). Both freedom from T2EL-related sac enlargement ≥5 mm and cumulative incidence of sac shrinkage ≥5 mm were significantly higher in the IMA embolization group than in the non-embolization group (95.5% vs 73.6% at 5 years; P = .021; 54.2% vs 33.6% at 5 years; P = .039, respectively). The freedom from T2EL-related sac enlargement ≥10 mm, an alternative indicator for T2EL-related reintervention, showed similar results (100% vs 90.4% at 5 years; P = .019). Outcomes in the low-risk group were preferable than those in the non-embolization group and comparable to those in the IMA embolization group. CONCLUSIONS: A lower threshold for pre-emptive IMA embolization when implementing EVAR would be more appropriate if limited to patients at high risk of T2ELs.

A muscarinic receptor antagonist reverses multiple indices of diabetic peripheral neuropathy: preclinical and clinical studies using oxybutynin.

Preclinical studies indicate that diverse muscarinic receptor antagonists, acting via the M1 sub-type, promote neuritogenesis from sensory neurons in vitro and prevent and/or reverse both structural and functional indices of neuropathy in rodent models of diabetes. We sought to translate this as a potential therapeutic approach against structural and functional indices of diabetic neuropathy using oxybutynin, a muscarinic antagonist approved for clinical use against overactive bladder. Studies were performed using sensory neurons maintained in vitro, rodent models of type 1 or type 2 diabetes and human subjects with type 2 diabetes and confirmed neuropathy. Oxybutynin promoted significant neurite outgrowth in sensory neuron cultures derived from adult normal rats and STZ-diabetic mice, with maximal efficacy in the 1-100 nmol/l range. This was accompanied by a significantly enhanced mitochondrial energetic profile as reflected by increased basal and maximal respiration and spare respiratory capacity. Systemic (3-10 mg/kg/day s.c.) and topical (3% gel daily) oxybutynin reversed paw heat hypoalgesia in the STZ and db/db mouse models of diabetes and reversed paw tactile allodynia in STZ-diabetic rats. Loss of nerve profiles in the skin and cornea of db/db mice was also prevented by daily topical delivery of 3% oxybutynin for 8 weeks. A randomized, double-blind, placebo-controlled interventional trial was performed in subjects with type 2 diabetes and established peripheral neuropathy. Subjects received daily topical treatment with 3% oxybutynin gel or placebo for 6 months. The a priori designated primary endpoint, significant change in intra-epidermal nerve fibre density (IENFD) in skin biopsies taken before and after 20 weeks of treatments, was met by oxybutynin but not placebo. Secondary endpoints showing significant improvement with oxybutynin treatment included scores on clinical neuropathy, pain and quality of life scales. This proof-of-concept study indicates that muscarinic antagonists suitable for long-term use may offer a novel therapeutic opportunity for treatment of diabetic neuropathy. Trial registry number: NCT03050827.

The selective serotonin reuptake inhibitor sertraline alters learning from aversive reinforcements in patients with depression: evidence from a randomized controlled trial.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) are first-line pharmacological treatments for depression and anxiety. However, little is known about how pharmacological action is related to cognitive and affective processes. Here, we examine whether specific reinforcement learning processes mediate the treatment effects of SSRIs. METHODS: The PANDA trial was a multicentre, double-blind, randomized clinical trial in UK primary care comparing the SSRI sertraline with placebo for depression and anxiety. Participants (N = 655) performed an affective Go/NoGo task three times during the trial and computational models were used to infer reinforcement learning processes. RESULTS: There was poor task performance: only 54% of the task runs were informative, with more informative task runs in the placebo than in the active group. There was no evidence for the preregistered hypothesis that Pavlovian inhibition was affected by sertraline. Exploratory analyses revealed that in the sertraline group, early increases in Pavlovian inhibition were associated with improvements in depression after 12 weeks. Furthermore, sertraline increased how fast participants learned from losses and faster learning from losses was associated with more severe generalized anxiety symptoms. CONCLUSIONS: The study findings indicate a relationship between aversive reinforcement learning mechanisms and aspects of depression, anxiety, and SSRI treatment, but these relationships did not align with the initial hypotheses. Poor task performance limits the interpretability and likely generalizability of the findings, and highlights the critical importance of developing acceptable and reliable tasks for use in clinical studies. FUNDING: This article presents research supported by NIHR Program Grants for Applied Research (RP-PG-0610-10048), the NIHR BRC, and UCL, with additional support from IMPRS COMP2PSYCH (JM, QH) and a Wellcome Trust grant (QH).

The antidepressant effect of whole-body hyperthermia is associated with the classical interleukin-6 signaling pathway.

There is urgent need for novel antidepressant treatments that confer therapeutic benefits via engagement with identified mechanistic targets. The objective of the study was to determine whether activation of the classical anti-inflammatory interleukin-6 signaling pathways is associated with the antidepressant effects of whole-body hyperthermia. A 6-week, randomized, double-blind study compared whole-body hyperthermia with a sham condition in a university-based medical center. Medically healthy participants aged 18-65 years who met criteria for major depressive disorder, were free of psychotropic medication use, and had a baseline 17-item Hamilton Depression Rating Scale score ≥ 16 were randomized with 1-to-1 allocation in blocks of 6 to receive whole-body hyperthermia or sham. Of 338 individuals screened, 34 were randomized, 30 received interventions and 26 had ≥ 2 blood draws and depressive symptom assessments. Secondary data analysis examined change in the ratio of IL-6:soluble IL-6 receptor pre-intervention, post-intervention, and at weeks 1 and 4. Hierarchical linear modeling tested whether increased IL-6:soluble IL-6 receptor ratio post-intervention was associated with decreased depressive symptom at weeks 1, 2, 4 and 6 for those randomized to whole-body hyperthermia. Twenty-six individuals were randomized to whole-body hyperthermia [n = 12; 75 % female; age = 37.9 years (SD = 15.3) or sham [n = 14; 57.1 % female; age = 41.1 years (SD = 12.5). When compared to the sham condition, active whole-body hyperthermia only increased the IL-6:soluble IL-6 receptor ratio post-treatment [F(3,72) = 11.73,p < .001], but not pre-intervention or at weeks 1 and 4. Using hierarchical linear modeling, increased IL-6:sIL-6R ratio following whole-body hyperthermia moderated depressive symptoms at weeks 1, 2, 4 and 6, such that increases in the IL-6:soluble IL-6 receptor ratio were associated with decreased depressive symptoms at weeks 1, 2, 4 and 6 for those receiving the active whole-body hyperthermia compared to sham treatment (B = -229.44, t = -3.82,p < .001). Acute activation of classical intereukin-6 signaling might emerge as a heretofore unrecognized novel mechanism that could be harnessed to expand the antidepressant armamentarium.

Pharmacogenetic guided versus standard warfarin dosing for routine clinical care with its pharmacoeconomic impact: a randomized controlled clinical trial.

BACKGROUND: Empirical use of pharmacogenetic test(PGT) is advocated for many drugs, and resource-rich setting hospitals are using the same commonly. The clinical translation of pharmacogenetic tests in terms of cost and clinical utility is yet to be examined in hospitals of low middle income countries (LMICs). AIM: The present study assessed the clinical utility of PGT by comparing the pharmacogenetically(PGT) guided- versus standard of care(SOC)- warfarin therapy, including the health economics of the two warfarin therapies. METHODS: An open-label, randomized, controlled clinical trial recruited warfarin-receiving patients in pharmacogenetically(PGT) guided- versus standard of care(SOC)- study arms. Pharmacogenetic analysis of CYP2C9*2(rs1799853), CYP2C9*3(rs1057910) and VKORC1(rs9923231) was performed for patients recruited to the PGT-guided arm. PT(Prothrombin Time)-INR(international normalized ratio) testing and dose titrations were allowed as per routine clinical practice. The primary endpoint was the percent time spent in the therapeutic INR range(TTR) during the 90-day observation period. Secondary endpoints were time to reach therapeutic INR(TRT), the proportion of adverse events, and economic comparison between two modes of therapy in a Markov model built for the commonest warfarin indication- atrial fibrillation. RESULTS: The study enrolled 168 patients, 84 in each arm. Per-protocol analysis showed a significantly high median time spent in therapeutic INR in the genotype-guided arm(42.85%; CI 21.4-66.75) as compared to the SOC arm(8.8%; CI 0-27.2)(p < 0.00001). The TRT was less in the PG-guided warfarin dosing group than the standard-of-care dosing warfarin group (17.85 vs. 33.92 days) (p = 0.002). Bleeding and thromboembolic events were similar in the two study groups. Lifetime expenditure was ₹1,26,830 in the PGT arm compared to ₹1,17,907 in the SOC arm. The QALY gain did not differ in the two groups(3.9 vs. 3.65). Compared to SOC, the incremental cost-utility ratio was ₹35,962 per QALY gain with PGT test opting. In deterministic and probabilistic sensitivity analysis, the base case results were found to be insensitive to the variation in model parameters. In the cost-effectiveness-acceptability curve analysis, a 90% probability of cost-effectiveness was reached at a willingness-to-pay(WTP) of ₹ 71,630 well below one time GDP threshold of WTP used. CONCLUSION: Clinical efficacy and the cost-effectiveness of the warfarin pharmacogenetic test suggest its routine use as a point of care investigation for patient care in LMICs.

Comparing clinical trial population representativeness to real-world users of 17 biologics approved for immune-mediated inflammatory diseases: An external validity analysis of 66,639 biologic users from the Italian VALORE project.

To date, no population-based studies have specifically explored the external validity of pivotal randomized clinical trials (RCTs) of biologics simultaneously for a broad spectrum of immuno-mediated inflammatory diseases (IMIDs). The aims of this study were, firstly, to compare the patients' characteristics and median treatment duration of biologics approved for IMIDs between RCTs' and real-world setting (RW); secondly, to assess the extent of biologic users treated for IMIDs in the real-world setting that would not have been eligible for inclusion into pivotal RCT for each indication of use. Using the Italian VALORE distributed database (66,639 incident biologic users), adult patients with IMIDs treated with biologics in the Italian real-world setting were substantially older (mean age ± SD: 50 ± 15 years) compared to those enrolled in pivotal RCTs (45 ± 15 years). In the real-world setting, certolizumab pegol was more commonly used by adult women with psoriasis/ankylosing spondylitis (F/M ratio: 1.8-1.9) compared to RCTs (F/M ratio: 0.5-0.6). The median treatment duration (weeks) of incident biologic users in RW was significantly higher than the duration of pivotal RCTs in almost all indications for use and most biologics (4-100 vs. 6-167). Furthermore, almost half (46.4%) of biologic users from RW settings would have been ineligible for inclusion in the respective indication-specific pivotal RCTs. The main reasons were: advanced age, recent history of cancer and presence of other concomitant IMIDs. These findings suggest that post-marketing surveillance of biologics should be prioritized for those patients.

Type 3 resistant starch from Canna edulis reduce lipid levels in patients with mild hyperlipidemia through altering gut microbiome: A double- blind randomized controlled trial.

Type 3 resistant starch from Canna edulis (Ce-RS3) is an insoluble dietary fiber which could improve blood lipids in animals, but clinically robust evidence is still lacking. We performed a double-blind randomized controlled trial to assess the effects of Ce-RS3 on lipids in mild hyperlipidemia. One hundred and fifteen patients were included followed the recruitment criteria, and were randomly allocated to receive Ce-RS3 or placebo (native starch from Canna edulis) for 12 weeks (20 g/day). In addition to serum lipids, complete blood counts, serum inflammatory factors, antioxidant indexes, and dietary survey, 16 S rRNA sequencing technique was utilized to analyze the gut microbiota alterations. Targeted quantitative metabolomics (TQM) was used to detect metabolite changes. Compared with the placebo, Ce- RS3 significantly decreased levels of total cholesterol, lowdensity lipoprotein cholesterol, and non-high-density lipoprotein cholesterol, and increased the glutathione peroxidase. Based on the 16 S rRNA sequencing, TQM, the correlation analysis, as well as the Kyoto Encyclopedia of Genes (KEGG) and Genomes and Human Metabolome Database (HMDB) analysis, we found that Ce-RS3 could increase the abundances of genera Faecalibacterium and Agathobacter, while reduce the abundances of genera norank_f_Ruminococcaceae and Christensenellaceae_R-7_ group to regulate phenylalanine metabolism, which could reduce the fatty acid biosynthesis and fatty acid elongation in the mitochondria to lower blood lipids. Conclusively, we firstly confirmed the feasibility of Ce-RS3 for clinical application, which presents a novel, effective therapy for the mild hyperlipidemia. (Chictr. org. cn. Clinical study on anti-mild hyperlipidemia of Canna edulis RS3 resistant starch, ID Number: ChiCTR2200062871).

A rank-based approach to evaluate a surrogate marker in a small sample setting.

In clinical studies of chronic diseases, the effectiveness of an intervention is often assessed using "high cost" outcomes that require long-term patient follow-up and/or are invasive to obtain. While much progress has been made in the development of statistical methods to identify surrogate markers, that is, measurements that could replace such costly outcomes, they are generally not applicable to studies with a small sample size. These methods either rely on nonparametric smoothing which requires a relatively large sample size or rely on strict model assumptions that are unlikely to hold in practice and empirically difficult to verify with a small sample size. In this paper, we develop a novel rank-based nonparametric approach to evaluate a surrogate marker in a small sample size setting. The method developed in this paper is motivated by a small study of children with nonalcoholic fatty liver disease (NAFLD), a diagnosis for a range of liver conditions in individuals without significant history of alcohol intake. Specifically, we examine whether change in alanine aminotransferase (ALT; measured in blood) is a surrogate marker for change in NAFLD activity score (obtained by biopsy) in a trial, which compared Vitamin E ($n=50$) versus placebo ($n=46$) among children with NAFLD.

Group sequential two-stage preference designs.

The two-stage preference design (TSPD) enables inference for treatment efficacy while allowing for incorporation of patient preference to treatment. It can provide unbiased estimates for selection and preference effects, where a selection effect occurs when patients who prefer one treatment respond differently than those who prefer another, and a preference effect is the difference in response caused by an interaction between the patient's preference and the actual treatment they receive. One potential barrier to adopting TSPD in practice, however, is the relatively large sample size required to estimate selection and preference effects with sufficient power. To address this concern, we propose a group sequential two-stage preference design (GS-TSPD), which combines TSPD with sequential monitoring for early stopping. In the GS-TSPD, pre-planned sequential monitoring allows investigators to conduct repeated hypothesis tests on accumulated data prior to full enrollment to assess study eligibility for early trial termination without inflating type I error rates. Thus, the procedure allows investigators to terminate the study when there is sufficient evidence of treatment, selection, or preference effects during an interim analysis, thereby reducing the design resource in expectation. To formalize such a procedure, we verify the independent increments assumption for testing the selection and preference effects and apply group sequential stopping boundaries from the approximate sequential density functions. Simulations are then conducted to investigate the operating characteristics of our proposed GS-TSPD compared to the traditional TSPD. We demonstrate the applicability of the design using a study of Hepatitis C treatment modality.

Design and sample size determination for multiple-dose randomized phase II trials for dose optimization.

The U.S. Food and Drug Administration (FDA) has launched Project Optimus to shift dose selection from the maximum tolerated dose (MTD) to the dose that produces the optimal risk-benefit tradeoff. One approach highlighted in the FDA's guidance involves conducting a randomized phase II trial following the completion of a phase I trial, where multiple doses (typically including the MTD and one or two doses lower than the MTD) are compared to identify the optimal dose that maximizes the benefit-risk tradeoff. This article focuses on the design of such a multiple-dose randomized trial, specifically the determination of the sample size. We generalized the standard definitions of type I error and power to accommodate the unique characteristics of dose optimization and derived a decision rule along with an algorithm to determine the optimal sample size. The resulting design is referred to as MERIT (Multiple-dosE RandomIzed Trial design for dose optimization based on toxicity and efficacy). Simulation studies demonstrate that MERIT has desirable operating characteristics, and a sample size between 20 and 40 per dosage arm often offers reasonable power and type I errors to ensure patient safety and benefit. To facilitate the implementation of the MERIT design, we provide software, available at https://www.trialdesign.org.

Effect of esketamine on haemodynamic fluctuations in patients undergoing hysteroscopic surgery: A prospective, double-blind randomized clinical trial.

AIMS: We explored whether esketamine anesthesia during hysteroscopic surgery can reduce intraoperative hemodynamic fluctuations and improve patient benefit. METHODS: A total of 170 patients undergoing hysteroscopic surgery were enrolled, and 151 patients were finally included in the analysis, among which 19 used vasoactive drugs during surgery. Patients were randomly assigned to either the esketamine anesthesia group (E group) or the sufentanil anesthesia group (S group). The primary outcomes were blood pressure and heart rate during the surgery. Secondary outcomes included resistance to laryngeal mask insertion, demand for propofol and remifentanil, nausea and vomiting, Richmond Agitation and Sedation Scale (RASS), dizziness and pain intensity after resuscitation, vasoactive medication treatment, hospitalization time and expenses. RESULTS: E group had a more stable heart rate, systolic blood pressure, diastolic blood pressure and mean blood pressure than the S group (p < 0.001). Patients in E group had a higher demand for propofol (p < 0.001) but better RASS scores (p < 0.001) after resuscitation. The incidence of intraoperative vasoactive medication use was higher in the S group (18.4% vs. 6.7%, p = 0.029). There were no statistically significant differences in terms of resistance to laryngeal mask insertion, remifentanil demand, time required for resuscitation, postoperative pain, dizziness, nausea or vomiting. CONCLUSIONS: Compared with sufentanil, esketamine-induced anesthesia during hysteroscopic surgery can reduce intraoperative hemodynamic fluctuations and the incidence of intraoperative vasoactive medication. Although esketamine-induced anesthesia may increase the demand for propofol during surgery, it does not affect the anesthesia recovery time and the quality of patient recovery is better.

Partial Meal Replacement for Weight Loss after Stroke: Results of a Pilot Clinical Trial.

INTRODUCTION: Over half of patients with acute ischemic stroke are overweight or obese as defined by a body mass index (BMI) ≥25 kg/m2. Professional and government agencies recommend weight management for these persons to improve risk factors for cardiovascular disease, including hypertension, dyslipidemia, vascular inflammation, and diabetes. However, approaches to weight loss have not been adequately tested specifically in patients with stroke. In anticipation of a larger trial with vascular or functional outcomes, we tested the feasibility and safety of a 12-week partial meal replacement (PMR) intervention for weight loss in overweight or obese patients with a recent ischemic stroke. METHODS: This randomized open-label trial enrolled participants from December 2019 to February 2021 (with hiatus from March to August 2020 due to COVID-19 pandemic restrictions on research). Eligible patients had a recent ischemic stroke and BMI 27-49.9 kg/m2. Patients were randomized to a PMR diet (OPTAVIA® Optimal Weight 4 & 2 & 1 Plan®) plus standard care (SC) or SC alone. The PMR diet consisted of four meal replacements supplied to participants, two meals with lean protein and vegetables (self-prepared or supplied), and a healthy snack (also self-prepared or supplied). The PMR diet provided 1,100-1,300 calories per day. SC consisted of one instructional session on a healthy diet. Co-primary outcomes were ≥5% weight loss at 12 weeks and to identify barriers to successful weight loss among participants assigned to PMR. Safety outcomes included hospitalization, falls, pneumonia, or hypoglycemia requiring treatment by self or others. Due to the COVID-19 pandemic, study visits after August 2020 were by remote communication. RESULTS: We enrolled 38 patients from two institutions. Two patients in each arm were lost and could not be included in outcome analyses. At 12 weeks, 9/17 patients in the PMR group and 2/17 patients in the SC group achieved ≥5% weight loss (52.9% vs. 11.9%; Fisher's exact p = 0.03). Mean percent weight change in the PMR group was -3.0% (SD 13.7) and -2.6% (SD 3.4) in the SC group (Wilcoxon rank-sum p = 0.17). No adverse events were attributed to study participation. Some participants had difficulty completing home monitoring of weight. In the PMR group, participants reported that food cravings and dislike for some food products were barriers to weight loss. CONCLUSION: A PMR diet after ischemic stroke is feasible, safe, and effective for weight loss. In future trials, in-person or improved remote outcome monitoring may reduce anthropometric data variation.

Psychosocial Factors Predicting HIV Disclosure Stage Transitions: An Evaluation of A Theory-Based Parental HIV Disclosure Intervention among Parents Living with HIV in China.

Appropriate parental HIV disclosures (i.e., parents living with HIV [PLH] tell their HIV diagnosis to their children) benefit parents, children, and family relations. Psychosocial factors could influence the decision-making process of parental HIV disclosure. Using the Health Action Process Approach to frame stages (pre-intention, intention, and action) in the decision-making process, this study aimed to investigate how psychosocial factors predict HIV disclosure stage transitions among PLH in China. Data were collected from a randomized clinical trial of a theory-based parental HIV disclosure intervention among 791 PLH. The predictive effects of psychosocial factors on disclosure stage transitions were examined using a Markov chain model matrix. Results showed that action self-efficacy and action planning were significant predictors of parental HIV disclosure stage transitions. Considering stage-specific psychosocial predictors may contribute to effective interventions to promote appropriate HIV disclosure among PLH in China.

Efficacy and safety of oral ibrexafungerp in Chinese patients with vulvovaginal candidiasis: a phase III, randomized, double-blind study.

PURPOSE: To evaluate the efficacy and safety of oral ibrexafungerp (HS-10366) versus placebo in Chinese patients with vulvovaginal candidiasis (VVC). METHODS: A double-blind, placebo-controlled, randomized, multicenter phase III study was conducted in symptomatic VVC patients. Patients received (2:1) twice-daily oral ibrexafungerp 300 mg or matching placebo for 1 day. The primary endpoint was clinical cure (vulvovaginal signs and symptoms [VSS] score = 0) at test-of-cure (TOC) on day 11 ± 3. The secondary endpoints included mycological eradication, overall response, and clinical improvement (VSS score ≤ 1) at TOC, and vulvovaginal symptom resolution at follow-up on day 25 ± 4. RESULTS: In total, 360 patients were included in the modified intention-to-treat set (defined as positive Candida cultured and receiving at least one study drug; 239 for ibrexafungerp, 121 for placebo). Compared with placebo, patients receiving ibrexafungerp had a significantly higher proportion of clinical cure (51.0% vs. 25.6%), mycological eradication (55.6% vs. 18.2%), overall response (33.9%, vs. 8.3%) at TOC and complete symptom resolution (74.5% vs. 39.7%, all P < 0.001) at follow-up. Subgroup analysis of clinical cure indicated that patients with C. albicans could benefit from ibrexafungerp over placebo. A similar benefit trend was also observed in those with non-albicans Candida by post-hoc analysis. Further analyses revealed similar efficacy of ibrexafungerp between patients with fluconazole non-susceptible C. albicans and fluconazole susceptible C. albicans regarding clinical cure and mycological eradication. Ibrexafungerp was generally well tolerated. Adverse events were primarily gastrointestinal and were mainly mild in severity. CONCLUSIONS: As a first-in-class antifungal agent, ibrexafungerp demonstrated promising efficacy and favorable safety for VVC treatment in Chinese patients. CHINADRUGTRIALS.ORG. CN REGISTRY NUMBER: CTR20220918.