Hodges-Lehmann Research Articles

Efficacy and Safety of Sotatercept Across Ranges of Cardiac Index in Patients with Pulmonary Arterial Hypertension: A Pooled Analysis of PULSAR and STELLAR

BackgroundThis analysis compared effects of the activin signaling inhibitor, sotatercept, across pulmonary arterial hypertension (PAH) subgroups stratified by baseline cardiac index (CI). MethodsPooled data from PULSAR (N=106; NCT03496207) and STELLAR (N=323; NCT04576988) were analyzed using two different CI thresholds, < and ≥ 2.0 L/min/m2 or 2.5 L/min/m2. Median differences in change from baseline at week 24 were evaluated using Hodges-Lehmann (HL) estimator and mean differences by least squares (LS), with 95% confidence intervals and p-values; p=0.05 was significant. Categorial endpoints and time-to-clinical worsening were analyzed by Cochran-Mantel-Haenszel and Cox model (hazard ratio (HR), respectively, without multiplicity adjustment. ResultsOf 429 participants, 51 and 378 had CI <2.0 L/min/m2 and ≥ 2.0 L/min/m2, respectively, whereas 179 and 250 had CI <2.5 L/min/m2 and ≥ 2.5 L/min/m2, respectively. Across all CI subgroups, sotatercept vs placebo significantly improved median 6-minute walk distance (range: 33.9 to 63.7 m: p<0.001), pulmonary vascular resistance (range: -202.8 to -395.4 dyn•s•cm-5; p≤0.002), and N-terminal pro-B-type natriuretic peptide (range: -317.3 to -1041.2 pg/mL; p<0.001). LS means showed reductions in pulmonary and right atrial pressures, decreased right ventricular size and enhanced tricuspid annular plane systolic excursion/ systolic pulmonary artery pressure in all subgroups. Sotatercept significantly delayed time to first occurrence of death or a worsening event in the subset of participants with CI ≥2.5 (HR 0.12; p<0.001), ≥2.0 (HR 0.13; p<0.001), and <2.5 (HR 0.21; p<0.001) L/min/m2. Improvements in World Health Organization functional class (all p<0.050) and European Society of Cardiology/European Respiratory Society risk score (all p<0.001) were seen within each subgroup. ConclusionsEfficacy and safety were consistent across baseline CI subgroups, supporting use of sotatercept in PAH patients irrespective of baseline cardiac hemodynamics.

Outcomes in eyes with retained lens fragments undergoing pars plana lensectomy and scleral-fixated intraocular lens insertion.

To report the visual outcomes and complications in eyes with retained lens fragments (RLF) following cataract surgery undergoing pars plana lensectomy (PPL) and scleral-fixated intraocular lens insertion (SFIOL). Patients with RLF who underwent pars plana vitrectomy (PPV), PPL, and SFIOL insertion from January 2015 to December 2022 were included. The visual acuity (VA) outcomes and complication rates were compared between those receiving sutured versus sutureless SFIOL insertion as well as those undergoing SFIOL insertion at the time of PPV and PPL versus those undergoing SFIOL insertion during a subsequent surgery. 65 eyes of 65 patients were included. Median (interquartile range) pre-operative logarithm of the minimum angle of resolution (logMAR) VA was 2.3 (2-2.3; Snellen: HM). The median logMAR VA improved to 0.14 (Snellen: 20/100), at the most-recent follow-up (p<0.001, Hodges-Lehmann estimator:1.56, 95% confidence interval -1.30 to -1.71). There was no statistically significant difference in VA outcomes and the complication rates, including cystoid macular edema, corneal edema, and retinal detachment, regardless of technique or timing of SFIOL insertion. In this retrospective study with small sample size, similar visual acuity outcomes and complication rates were observed regardless of the timing or technique of SFIOL insertion.

A randomized, multicenter phase III Study of once-per-cycle administration of efbemalenograstim alfa (F-627), a novel long-acting rhG-CSF, for prophylaxis of chemotherapy-induced neutropenia in patients with breast cancer

BackgroundF-627 (efbemalenograstim alfa) is a novel long acting granulocyte colony-stimulating factor (G-CSF) that contains two human G-CSF fused to a human immunoglobulin G2 (hIgG2) -Fc fragment with a peptide linker. This studyevaluated the efficacy and safety of F-627, also known as efbemalenograstim alfa (Ryzneuta®) in reducing neutropenia compared with filgrastim (GRAN®).MethodsThis was a multicenter, randomized, open-label, active-controlled non-inferiority study. Two hundred thirty nine (239) patients were enrolled in thirteen centers and received the chemotherapy with epirubicin (100 mg/m2) and cyclophosphamide (600 mg/m2) on day 1 of each cycle for a maximum of four cycles. Patients were randomized to receive either a single 20 mg subcutaneous (s.c.) injection of F-627 on day 3 of each cycle or daily s.c. injection of filgrastim 5 µg/kg/d starting from day 3 of each cycle. The primary endpoint was the duration of grade 3 or 4 neutropenia in cycle 1. The safety profile was also evaluated.ResultsThe mean (SD) duration of grade 3 or 4 neutropenia in cycle 1 was 0.68 (1.10) and 0.71 (0.95) days for the F-627 and the filgrastim groups, respectively. The Hodges-Lehmann estimate of the between-group median difference (F-627 vs filgrastim) in the duration of grade 3 or 4 neutropenia in cycle 1 was 0 day and the upper limit of the one-sided 97.5% CI was 0 day, which was within the prespecified non-inferiority margin of 1-day. Results for all efficacy endpoints in cycles 2 − 4 were consistent with the results in cycle 1, however a trend towards a lower incidence and a shorter duration of grade 3 or 4 neutropenia and grade 4 neutropenia was observed in the F-627 group compared with the filgrastim group. The ANC nadir in the F-627 group was significantly higher than that in the filgrastim group in each cycle. A single fixed dose of F-627 was well tolerated and as safe as standard daily filgrastim.ConclusionsA single fixed dose of 20 mg of F-627 in each cycle was as safe and effective as a daily dose of filgrastim 5 µg/kg/d in reducing neutropenia and its complications in patients who received four cycles of EC.Trial registrationClinicalTrials.gov: NCT04174599, on 22/11/2019.

The influence of adverse events on inpatient outcomes in a tertiary hospital using a diagnosis-related group database

Adverse events (AEs) are a significant concern for healthcare systems. However, it is difficult to evaluate their influence because of the complexity of various medical services. This study aimed to assess the influence of AEs on the outcomes of hospitalized patients using a diagnosis-related group (DRG) database. We conducted a case–control study of hospitalized patients at a multi-district tertiary hospital with 2200 beds in China, using data from a DRG database. An AE refers to an unintended physical injury caused or contributed to by medical care that requires additional hospitalization, monitoring, treatment, or even death. Relative weight (RW), a specific indicator of DRG, was used to measure the difficulty of diagnosis and treatment, disease severity, and medical resources utilized. The primary outcomes were hospital length of stay (LOS) and hospitalization costs. The secondary outcome was discharge to home. This study applied DRG-based matching, Hodges–Lehmann estimate, regression analysis, and subgroup analysis to evaluate the influence of AEs on outcomes. Two sensitivity analyses by excluding short LOS and changing adjustment factors were performed to assess the robustness of the results. We identified 2690 hospitalized patients who had been divided into 329 DRGs, including 1345 patients who experienced AEs (case group) and 1345 DRG-matched normal controls. The Hodges–Lehmann estimate and generalized linear regression analysis showed AEs led to prolonged LOS (unadjusted difference, 7 days, 95% confidence interval [CI] 6–8 days; adjusted difference, 8.31 days, 95% CI 7.16–9.52 days) and excess hospitalization costs (unadjusted difference, $2186.40, 95% CI: $1836.87-$2559.16; adjusted difference, $2822.67, 95% CI: $2351.25-$3334.88). Logistic regression analysis showed AEs were associated with lower odds of discharge to home (unadjusted odds ratio [OR] 0.66, 95% CI 0.54–0.82; adjusted OR 0.75, 95% CI 0.61–0.93). The subgroup analyses showed that the results for each subgroup were largely consistent. LOS and hospitalization costs increased significantly after AEs in complex diseases (RW ≥ 2) and in relation to high degrees of harm subgroups (moderate harm and above groups). Similar results were obtained in sensitivity analyses. The burden of AEs, especially those related to complex diseases and severe harm, is significant in China. The DRG database serves as a valuable source of information that can be utilized for the evaluation and management of AEs.

Virtual reality treatment could reduce anxiety for women undergoing cesarean section with spinal anesthesia: a randomized controlled trial.

Cesarean section may result in adverse psychosocial and behavioral outcomes because women put considerable emphasis on the process of birth. Virtual reality treatment has been shown by many studies to reduce anxiety and improve patient satisfaction. Therefore, we designed a randomized controlled trial to investigate whether the application of virtual reality technology during cesarean section can reduce maternal anxiety and improve satisfaction. We recruited 128 women undergoing elective cesarean delivery with proposed spinal anesthesia and randomly assigned them to either virtual reality or routine care. The virtual reality intervention was a virtual reality program tailored specifically for women undergoing cesarean section. Primary outcome was the change in anxiety score (change = preoperative-intraoperative score). Secondary outcomes included patient satisfaction score, requirement of intraoperative sedative and analgesic drugs, and respiratory rate. The change in anxiety score in the virtual reality group was significantly higher than that in the routine care group (30 [20, 47.5] vs 10 [- 10, 23.8], respectively; P < 0.001, with Hodges-Lehmann median difference estimate of 20 (95% confidence interval CI, 15-30)). There were no significant differences between the two groups in patient satisfaction scores, the requirement of intraoperative sedative and analgesic drugs, and respiratory rate and side effects. Virtual reality treatment could reduce the anxiety of women undergoing elective cesarean section, which is beneficial to the mother and baby. Trial registration This study was registered at the Chinese Clinical Trial Registry (ChiCTR2200061936) on July 11, 2022, and can be reached at https://www.chictr.org.cn/showprojEN.html?proj=173329.

Simulation comparison of modified confidence intervals based on robust estimators for coefficient of variation: skewed distributions case with real applications

In this article, we propose confidence intervals for the population coefficient of variation based on some robust estimators such as trimmed mean, winsorized mean, Hodges-Lehmann estimator and trimean. The proposed confidence intervals and their bootstrap versions were compared with the existing confidence intervals for the population coefficient of variation. The performances of the proposed confidence intervals were evaluated via a Monte-Carlo simulation study by considering the coverage probability, average width, standard deviation of widths, and coefficient of variation of widths as comparison criteria. The proposed confidence intervals performed well in terms of coverage probability on symmetrical distributions. In the case of skewed distributions, they were closer to the nominal confidence level and had narrower widths than the others. As a result, we proposed to use confidence intervals based on the Hodges-Lehmann estimator and winsorized mean for small sample sizes ( n = 10 and 15 ) and larger sample sizes for skewed distributions, respectively. The real-life datasets were analyzed to support the simulation results and confirm the practical applications of the proposed confidence intervals.

Primary Analysis of Spartan: A Phase 2 Trial to Assess the Efficacy and Safety of Crizanlizumab in Patients with Sickle Cell Disease Related Priapism

Introduction: Priapism is a painful, sustained penile erection that occurs in 35% of adult men with sickle cell disease (SCD) and may result from the underlying mechanism of vaso-occlusion. To date, there is no effective disease-modifying drug proven to treat priapism. Crizanlizumab is a monoclonal antibody that binds and blocks P-selectin, a key mechanistic component of vascular endothelial adhesion. Based on the results of the SUSTAIN trial, crizanlizumab was approved by the FDA to reduce the frequency of vaso-occlusive crises in patients with SCD aged ≥16 years. In this primary analysis of the Phase 2 SPARTAN trial (NCT03938454), we evaluated the efficacy and safety of crizanlizumab after 26 weeks of treatment in patients with SCD-related priapism. Methods: The SPARTAN trial included male patients aged ≥12 years with all SCD genotypes who experienced ≥4 priapic episodes lasting ≥60 min over the 14-week period preceding screening. Eligible patients also experienced ≥3 priapic episodes during the subsequent 12-week screening period with ≥1 event occurring within 4 weeks prior to the first treatment. After enrollment priapic events were documented through electronic self-reporting tools and validated patient-reported outcomes surveys for 26 weeks and included start/end date, sleep status, duration, non-pharmacological treatment, triggers, emergency department visit, and pain intensity during the screening period. Baseline priapic events were collected for each patient during the 12-week screening period. Patients received crizanlizumab 5.0 mg/kg IV infusion on week 1, week 3, and every 4 weeks thereafter. The primary endpoint was percent reduction from adjusted baseline period in priapic events by 26 weeks. Percent reduction from baseline in priapic events was tested using a one-sided Wilcoxon's Sign Rank test. Hodges-Lehmann estimate of median percent reduction in priapic events (with 95% CIs) was also reported. Results: Data cutoff was March 28, 2023. Of the 36 patients enrolled, 26 (72.2%) were between 18 and 40 years, and the median (range) age was 29 (14-58) years. Most patients were HbSS genotype (n=29, [80.6%]) and more than half were on hydroxyurea (n=21, [58.3%]). Patient-reported history prior to crizanlizumab treatment revealed that more than half of patients experienced priapism daily or every other day (n=21, [58.3%]) and most reported a duration of 1 to 5 h (n=33, [91.7%]). The most common patient-reported emotions at the start of the study were frustration and exhaustion, reported by ≈50% of patients. The median (IQR) baseline number of priapic events adjusted for 26 weeks per patient was 42 (13-73) events ( Table). All patients experienced events lasting 1 to ≤4 h, although some also experienced severe events lasting &amp;gt;4 to 6 h (n=19, [52.8%]) and &amp;gt;6 to ≤12 h (n=11, [30.6%]). In one case, 38 days of screening period baseline data was not reported, resulting in a strong outlier that affected the results ( Patient 1, Figure). Thirty-six patients received ≥1 dose of crizanlizumab, with a median cumulative dose of 35.0 mg/kg over 26 weeks; 5 patients each missed 1 infusion and 1 patient missed 2 infusions. The Hodges-Lehmann estimate of median percent reduction from baseline in priapic events per patient was 46.0% (95% CI: 23.5%-65.4%; P=.068). Twenty-eight patients (77.8%) reported a reduction from baseline in priapic events ( Figure). A subgroup analysis revealed a trend towards a larger percent reduction in events for patients with ≥22 baseline events, possibly indicating that patients with severe disease benefitted more from treatment. The most frequent treatment-emergent adverse event (TEAE) was headache (16.7%). No patients discontinued crizanlizumab prematurely and only one patient withdrew consent by week 26. Conclusions: Primary analyses from the SPARTAN trial showed that patients with SCD-related priapism treated with crizanlizumab over 26 weeks experienced approximately half as many priapic events compared with baseline. There was a trend towards a more significant reduction in frequency of episodes in patients with severe disease. Crizanlizumab was safe and well tolerated, with observed TEAEs consistent with the safety profile seen in other clinical trials. Final analyses of the SPARTAN trial will provide data over 52 weeks and may provide further support for the role of crizanlizumab in reducing frequency of priapic events.

Patisiran Treatment in Patients with Transthyretin Cardiac Amyloidosis

BackgroundTransthyretin amyloidosis, also called ATTR amyloidosis, is associated with accumulation of ATTR amyloid deposits in the heart and commonly manifests as progressive cardiomyopathy. Patisiran, an RNA interference therapeutic agent, inhibits the production of hepatic transthyretin.MethodsIn this phase 3, double-blind, randomized trial, we assigned patients with hereditary, also known as variant, or wild-type ATTR cardiac amyloidosis, in a 1:1 ratio, to receive patisiran (0.3 mg per kilogram of body weight) or placebo once every 3 weeks for 12 months. A hierarchical procedure was used to test the primary and three secondary end points. The primary end point was the change from baseline in the distance covered on the 6-minute walk test at 12 months. The first secondary end point was the change from baseline to month 12 in the Kansas City Cardiomyopathy Questionnaire–Overall Summary (KCCQ-OS) score (with higher scores indicating better health status). The second secondary end point was a composite of death from any cause, cardiovascular events, and change from baseline in the 6-minute walk test distance over 12 months. The third secondary end point was a composite of death from any cause, hospitalizations for any cause, and urgent heart failure visits over 12 months.ResultsA total of 360 patients were randomly assigned to receive patisiran (181 patients) or placebo (179 patients). At month 12, the decline in the 6-minute walk distance was lower in the patisiran group than in the placebo group (Hodges–Lehmann estimate of median difference, 14.69 m; 95% confidence interval [CI], 0.69 to 28.69; P=0.02); the KCCQ-OS score increased in the patisiran group and declined in the placebo group (least-squares mean difference, 3.7 points; 95% CI, 0.2 to 7.2; P=0.04). Significant benefits were not observed for the second secondary end point. Infusion-related reactions, arthralgia, and muscle spasms occurred more often among patients in the patisiran group than among those in the placebo group.ConclusionsIn this trial, administration of patisiran over a period of 12 months resulted in preserved functional capacity in patients with ATTR cardiac amyloidosis. (Funded by Alnylam Pharmaceuticals; APOLLO-B ClinicalTrials.gov number, NCT03997383.)

The association of Sirtuin1 (SIRT1) polymorphism and downregulation of STAT4 gene expression with increased susceptibility to COVID-19 infection

ABSTRACT Sirtuin1 (SIRT1) is an epigenetic modulator that belongs to sirtuins family and participates in many physiologic reactions, as genomic stabilization, apoptosis, proliferation, and inflammation. STAT4 (signal transducer and activator of transcription 4) gene is a component of JAK-STAT signaling pathway, which plays key role in activating cellular-mediated immune responses. The present study aimed to investigate the association between SIRT1 rs12778366 SNP, expression level of STAT4 gene and susceptibility to COVID-19 infections as well as their correlation to clinicopathological data. The present study included 100 ICU patients with severe COVID-19 infection and 100 age- and sex-matched healthy controls. DNA was extracted. Genotyping of SNP in SIRT1 (rs12778366) was performed, Total RNA was extracted from PBMCs. Reverse transcription was done. STAT4 gene expression levels were evaluated with GAPDH as internal control using real-time PCR. We found a significantly higher frequency of ‘C’ allele and C/T genotype in case vs. control. The association was of low strength (φ = 0.105 for alleles, and 0.154 for genotypes). This was associated with higher expression of STAT4 gene (P < 0.001) and increased tendency for lower respiratory complications. Median STAT4 (FC) (Median = 0.18, 95% CI = 0.15–0.27) was lower than normal control value of 1.0. This difference was statistically significant (Hodges-Lehmann location estimator = 0.217, P < 0.001). SIRT1 polymorphism and decreased expression of STAT4 gene are associated with increased susceptibility to COVID-19 infection and correlate to its phenotypic manifestations.

The effect of date fruit consumption on early postpartum hemorrhage: a randomized clinical trial

BackgroundPostpartum hemorrhage, anemia, and iron deficiency are important health problems. Using safe, cheap, and available methods to reduce the amount of hemorrhage after childbirth can be effective for the mother's health during this period. Therefore, this study was conducted to determine the effect of date fruit consumption on the amount of hemorrhage after natural childbirth.MethodsThis randomized clinical trial was conducted on 98 women referred to the maternity ward of Al-Zahra Hospital in Rasht using the available sampling method. The primary outcome was postpartum hemorrhage, measured using the Pictorial Blood Loss Assessment Chart (PBLAC). Two hours after delivery, 100 g of date fruits were given to the intervention group, and the amount of hemorrhage was recorded during the first 24 h. Comparison between the two groups was done with the Mann–Whitney test with the Hodges–Lehmann estimator and corresponding exact conditional nonparametric confidence interval (CI) as effect estimate. A P < 0.05 was considered significant.ResultsThe median of postpartum hemorrhage after normal delivery in the date and control groups was 35.0 [interquartile range (IQR): 22.0 to 39.8] and 39.0 [IQR: 27.5 to 64.5], respectively. Using the Hodges–Lehmann estimator, on average, the median postpartum hemorrhage in the date group was 9.0 (95% CI: 2.00–18.0) units lower than the control group (P = 0.009).ConclusionConsumption of dates effectively reduces the amount of hemorrhage after natural childbirth; thus, consuming this fruit during postpartum period is recommended. Also to confirm the findings, it is recommended to conduct similar studies in this field.Trial registrationThis trial was registered with the Iranian Registry of Clinical Trials; https://www.irct.ir/trial/59197 (IRCT20210607051505N2) on 31/10/2021.

Study on the influencing factors of piecewise multi-strain crossover epidemic spread under data contamination

The ongoing impact of the novel coronavirus disease 2019 (COVID-19) on work and daily life persists as we transition from emergency to normal circumstances. The continuous mutation of viral strains has resulted in a shift from a single strain to multiple cross-strains, contributing to the spread of the epidemic. Variations in infection rates of the same strain occur because of the implementation of diverse preventive measures at different times. This study investigated the dynamics of the pandemic in the presence of concurrent strains. Building on the classical Susceptible, Exposed, Infected, and Recovered (SEIR) model, a robust piecewise multi-strain cross-epidemic trend prediction model was proposed that employs the Hodges–Lehmann estimator to handle uncertain and contamination-prone epidemic information. A comparative analysis of epidemic spread trend curves across diverse populations using different robust methods revealed the superiority of the Hodges–Lehmann estimator-based model over the traditional method. The accurate prediction results of the model demonstrate its high reliability in tracking the changing trend of the COVID-19 outbreak, thereby supporting its implementation in subsequent epidemic prevention and control measures.

Oral Corticosteroid Reduction Between Biologics Initiated and Non-Initiated Patients with Severe Asthma.

The oral corticosteroid (OCS)-sparing effect of several biologics (BIOs) has been shown in clinical trials. To date, no study has evaluated differences in OCS dose reduction between BIO-initiated and BIO-non-initiated patients in real-world clinical practice. We compared dose reductions in maintenance OCS between BIO-initiated and BIO-non-initiated severe asthma patients in a real-world setting. This retrospective cohort study used the data from the Diagnosis Procedure Combination database of Medical Data Vision in Japan. Severe asthma patients with continuous use of OCS were selected from December 2015 to February 2020. The primary endpoint was the proportion reduction in daily maintenance OCS dose from Week 0 to Week 24. Analyses were performed using inverse probability treatment weighting. In total, 2927 patients were included (BIO-initiated: 239 patients, BIO-non-initiated: 2688 patients). Adjusted median (quartile [Q] 1-Q3) proportion reduction in daily maintenance OCS dose at Week 24 from the index date was 25.0% (0.0-100.0%) and 0.0% (0.0-83.3%) in the BIO-initiated and BIO-non-initiated groups, respectively (Hodges-Lehmann estimate [95% confidence interval], 0.0000% [0.0000-0.3365%]). Respective proportions of patients in the BIO-initiated and BIO-non-initiated groups achieving dose reductions from the index date in the daily maintenance OCS dose at Week 24 were >0% reduction, 56.6% and 44.1% (odds ratio [OR] 1.6554); ≥25% reduction, 50.5% and 40.6% (OR 1.4888); ≥50% reduction, 42.8% and 33.7% (OR 1.4714); and 100% reduction, 26.2% and 24.4% (OR 1.1005). Among severe asthma patients, the daily dose of maintenance OCS was reduced with BIO treatment. Although a higher percentage of patients in the BIO-initiated group had an OCS reduction of ≤75% than the BIO-non-initiated group, we found no clear difference in OCS reduction. Our findings will be justified by further research that incorporates a longer observation period and variables excluded from this study. ClinicalTrials.gov (NCT05136547).

Description of a novel method for detection of sleep-disordered breathing in brachycephalic dogs.

Sleep-disordered breathing (SDB), defined as any difficulty in breathing during sleep, occurs in brachycephalic dogs. Diagnostic methods for SDB in dogs require extensive equipment and laboratory assessment. To evaluate the usability of a portable neckband system for detection of SDB in dogs. We hypothesized that the neckband is a feasible method for evaluation of SDB and that brachycephaly predisposes to SDB. Twenty-four prospectively recruited client-owned dogs: 12 brachycephalic dogs and 12 control dogs of mesocephalic or dolicocephalic breeds. Prospective observational cross-sectional study with convenience sampling. Recording was done over 1 night at each dog's home. The primary outcome measure was the obstructive Respiratory Event Index (OREI), which summarized the rate of obstructive SDB events per hour. Additionally, usability, duration of recording, and snore percentage were documented. Brachycephalic dogs had a significantly higher OREI value (Hodges-Lehmann estimator for median difference = 3.5, 95% confidence interval [CI] 2.2-6.8; P < .001) and snore percentage (Hodges-Lehmann estimator = 34.2, 95% CI 13.6-60.8; P < .001) than controls. A strong positive correlation between OREI and snore percentage was detected in all dogs (rs = .79, P < .001). The neckband system was easy to use. Brachycephaly is associated with SDB. The neckband system is a feasible way of characterizing SDB in dogs.

Phase 3 Trial of Sotatercept for Treatment of Pulmonary Arterial Hypertension

BackgroundPulmonary arterial hypertension is a progressive disease involving proliferative remodeling of the pulmonary vessels. Despite therapeutic advances, the disease-associated morbidity and mortality remain high. Sotatercept is a fusion protein that traps activins and growth differentiation factors involved in pulmonary arterial hypertension.MethodsWe conducted a multicenter, double-blind, phase 3 trial in which adults with pulmonary arterial hypertension (World Health Organization [WHO] functional class II or III) who were receiving stable background therapy were randomly assigned in a 1:1 ratio to receive subcutaneous sotatercept (starting dose, 0.3 mg per kilogram of body weight; target dose, 0.7 mg per kilogram) or placebo every 3 weeks. The primary end point was the change from baseline at week 24 in the 6-minute walk distance. Nine secondary end points, tested hierarchically in the following order, were multicomponent improvement, change in pulmonary vascular resistance, change in N-terminal pro–B-type natriuretic peptide level, improvement in WHO functional class, time to death or clinical worsening, French risk score, and changes in the Pulmonary Arterial Hypertension–Symptoms and Impact (PAH-SYMPACT) Physical Impacts, Cardiopulmonary Symptoms, and Cognitive/Emotional Impacts domain scores; all were assessed at week 24 except time to death or clinical worsening, which was assessed when the last patient completed the week 24 visit.ResultsA total of 163 patients were assigned to receive sotatercept and 160 to receive placebo. The median change from baseline at week 24 in the 6-minute walk distance was 34.4 m (95% confidence interval [CI], 33.0 to 35.5) in the sotatercept group and 1.0 m (95% CI, −0.3 to 3.5) in the placebo group. The Hodges–Lehmann estimate of the difference between the sotatercept and placebo groups in the change from baseline at week 24 in the 6-minute walk distance was 40.8 m (95% CI, 27.5 to 54.1; P<0.001). The first eight secondary end points were significantly improved with sotatercept as compared with placebo, whereas the PAH-SYMPACT Cognitive/Emotional Impacts domain score was not. Adverse events that occurred more frequently with sotatercept than with placebo included epistaxis, dizziness, telangiectasia, increased hemoglobin levels, thrombocytopenia, and increased blood pressure.ConclusionsIn patients with pulmonary arterial hypertension who were receiving stable background therapy, sotatercept resulted in a greater improvement in exercise capacity (as assessed by the 6-minute walk test) than placebo. (Funded by Acceleron Pharma, a subsidiary of MSD; STELLAR ClinicalTrials.gov number, NCT04576988.)

Improving the efficiency and efficacy of robust sequential bifurcation under data contamination

Robust sequential bifurcation (RSB) is an outlier-resistant factor screening method. It combines robust statistics with the sequential bifurcation procedure, which can handle the factor screening problem when response data is contaminated. Due to the low relative efficiency of robust estimator (median & MAD) and apparent discrepancy between the robust statistic and standard normal distribution, RSB is further improved on efficiency and efficacy in this article. Firstly, the properties of four robust estimators and three new robust statistics are introduced, and distributions of robust statistics are explored. Then, stopping rules and importance tests are modified. Finally, the performance of new method is shown and compared through simulation examples. Results indicate that the statistic constructed by Hodges-Lehmann and Shamos estimators clearly outperforms the others in efficiency and efficacy and without loss of robustness. In addition, empirical quantile of robust statistic is provided for performing screening in the case of small sample size.

Methods for analyse performance in distributed systems

The purpose of this article is to analyze various methods for measuring central tendency in statistics, including arithmetic mean, median, winsorized mean, outlier exclusion method, Hodges-Lehmann estimator, and quantile estimation and much more. The advantages and disadvantages of each of these methods are discussed, as well as their practical applications in performance analysis in distributed systems. In particular, we focus on the importance of selecting an appropriate measure of central tendency that is robust to outliers and accurately reflects the distribution of the data. We also provide examples of how these methods can be applied to real-world datasets to gain insights into the underlying patterns and trends. Overall, this article provides a comprehensive overview of the different techniques for measuring central tendency and offers practical guidance for researchers and analysts looking to make informed decisions about perfomance analysis.

Effects of interleukin-6 inhibition with ziltivekimab in patients at high risk of atherosclerotic events in Japan: results from the phase 2 RESCUE-2 trial

Abstract Introduction In the US phase 2 RESCUE trial, ziltivekimab, a fully human monoclonal antibody against the ligand of the pro-inflammatory cytokine interleukin-6, was shown to reduce biomarkers of inflammation in patients with chronic kidney disease (CKD) and elevated levels of high-sensitivity C-reactive protein (hsCRP), a marker of inflammation and cardiac risk.1 Here, we present outcomes from the phase 2 RESCUE-2 trial of ziltivekimab in a patient population from Japan. Purpose To evaluate the efficacy and safety of ziltivekimab 15 mg and 30 mg compared with placebo in Japanese patients with non-dialysis-dependent CKD (NDD-CKD). Methods We conducted a randomized, double-blind, placebo-controlled trial in 36 patients aged ≥20 years with stage 3–5 NDD-CKD and hsCRP ≥2 mg/L. Patients were randomly assigned to receive subcutaneous ziltivekimab 15 mg (n=11) or 30 mg (n=12), or placebo (n=13) at weeks 0, 4 and 8. The primary endpoint was percentage change in hsCRP levels from baseline to end of treatment (EOT) (average of week 10 and week 12 values); secondary endpoints included percentage change from baseline to EOT in levels of fibrinogen, serum amyloid A (SAA), N-terminal pro B-type natriuretic peptide (NT-proBNP) and lipids. Analysis of endpoints was performed using Wilcoxon two-sample test; differences between treatment groups were calculated using the Hodges–Lehmann estimator. Results Baseline characteristics are shown in the Table. At EOT, median hsCRP levels were reduced by 96% and 93% in the ziltivekimab 15 mg and 30 mg groups, respectively, compared with 27% for placebo (both p&amp;lt;0.001 vs placebo). At both doses, ziltivekimab provided rapid and sustained suppression of hsCRP over the 12-week treatment period (Figure). Statistically significant reductions in levels of the inflammatory markers SAA (15 mg: 71%; 30 mg: 58%; placebo: 30%; both p&amp;lt;0.01 vs placebo) and fibrinogen (38%; 34%; 2%; both p&amp;lt;0.0001 vs placebo) were also observed. Ziltivekimab was well tolerated, did not result in persistent neutropenia or thrombocytopenia, and had minimal effect on liver enzyme levels. There was a non-significant increase in low-density lipoprotein levels and a neutral effect on high-density lipoprotein levels. There was a limited, but statistically significant (p&amp;lt;0.05 vs placebo) increase in triglycerides, whereby levels increased in some patients and decreased in others. Conclusion Ziltivekimab effectively reduced inflammatory biomarkers associated with atherosclerosis in patients from Japan with CKD and residual inflammatory risk as measured by hsCRP. A significant reduction of more than 90% in hsCRP levels for both doses of ziltivekimab was demonstrated, with a safety profile similar to placebo. Overall, the results of the RESCUE-2 trial in Japan are consistent with the efficacy and safety results of the US-based RESCUE trial. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): This study was funded by Novo Nordisk A/S. Medical writing support was provided by Johanna Scheinost PhD, PharmaGenesis Oxford Central, Oxford, UK, with funding from Novo Nordisk A/S.

The effect of manually facilitated flexion of the thoracic spine on the interspinous space among horses with impinging dorsal spinous processes of the thoracic vertebrae

Impinging dorsal spinous processes (IDSP) are typically diagnosed and graded using radiography, during which the effect of the horses’ thoracolumbar posture on the interspinous spaces is not commonly considered. Posture can be altered from a spontaneous, relatively extended, or lordotic, position by manual facilitation of thoracic flexion (‘thoracic lift’). This study aimed to ascertain if the thoracic vertebral interspinous space distances were increased by using facilitated thoracic flexion to alter the posture in horses diagnosed with IDSP. Seven horses of mixed breed and sex, median age 9.1 years (interquartile range, 7.2–12.4 years), with a diagnosis of thoracic IDSP with no history of spinal surgery, were included in the study. Two sets of radiographs were obtained. The initial set was taken in the horses’ spontaneous posture and the second in the manually facilitated flexed posture. Each image was anonymised allowing blinded measurement of the interspinous spaces. Analysis was performed using Hodges-Lehmann median differences estimates. An increase in the median interspinous space distance was achieved after manual facilitation of thoracic flexion at every thoracic intervertebral space (5th-18th thoracic [T] vertebra). The greatest median increase was seen between T7-T8 and T12-T13 (3.1 mm and 3.0 mm, respectively) whereas the lowest median increase was seen between T17-T18 (0.7 mm). In this study, thoracic interspinous space distances could be increased by using manual facilitation to alter the thoracic posture in horses with IDSP, which could affect grading and decision making.

Use of low molecular weight heparin and hemoglobin fall in COVID-19 patients: A STROBE-compliant study

In patients with coronavirus disease 2019 (COVID-19), anticoagulation was suggested as a mitigating strategy. However, little research has been conducted on the adverse consequences of anticoagulant medication. This study aimed to investigate the adverse effect of low molecular weight heparin (LMWH) on hemoglobin fall in COVID-19 treatment. The electronic medical records of COVID-19 patients with pneumonia were collected (including clinical characteristics, vaccination status, complete blood count, coagulation profile, inflammatory cytokines, serum biochemical indicators, and computerized tomography imaging score). Whether they received LMWH, patients were divided into the LMWH group and the control group. Count data were represented as frequency distribution, and a 2-tailed test was used to compare the 2 groups. Spearman rank correlation was used to evaluate the interrelation between changes in hemoglobin and LMWH. The confounding factors were excluded by logistic regression analysis. A total of 179 COVID-19 pneumonia patients were enrolled (81 in the LMWH group and 98 in the control group). The change in hemoglobin was −6.0g/L (IQR −10.8 to 1.0) in the LMWH group and −2.0g/L (IQR −7.0 to 4.0) in the control group (P < .001, between-group difference, −5.0 g/L; 95% confidence interval, −7.0 to −3.0, calculated with the use of the Mann–Whitney U test and the Hodges–Lehmann estimate of confidence intervals for pseudo-medians). The results of multivariate regression analysis showed that after adjusting for confounding factors, LMWH use was not associated with a decrease in hemoglobin (P > .05). In nonsevere COVID-19 patients with pneumonia, the preventive use of LMWH did not lower hemoglobin.

Real-world outcomes of the hypotension prediction index in the management of intraoperative hypotension during non-cardiac surgery: a retrospective clinical study.

The Hypotension Prediction Index (HPI) is a validated algorithm developed by applying machine learning for predicting intraoperative arterial hypotension (IOH). We evaluated whether the HPI, combined with a personalized treatment protocol, helps to reduce IOH (depth and duration) and perioperative events in real practice. This was a single-center retrospective study including 104 consecutive adults undergoing urgent or elective non-cardiac surgery with moderate-to-high risk of bleeding, requiring invasive blood pressure and continuous cardiac output monitoring. Depending on the sensor, two comparable groups were identified: patients managed following the institutional protocol of personalized goal-directed fluid therapy (GDFT, n = 52), or this GDFT supported by the HPI (HPI, n = 52). The time-weighted average of hypotension for a mean arterial pressure < 65mmHg (TWAMAP<65), postoperative complications and length of hospital stay (LOS) were automatically downloaded from medical records and revised by clinicians blinded to the management received by patients. Differences in preoperative variables (i.e. physical status -ASA class-, acute kidney Injury-AKI- risk) and outcomes were analyzed using non-parametric tests with Hodges-Lehmann estimator for the median of differences. ASA class and AKI risk were similar (p = 0.749 and p = 0.837, respectively). Blood loss was also comparable (p = 0.279). HPI patients had a lower TWAMAP<65 [0.09mmHg (0-0.48mmHg)] vs [0.23mmHg (0.01 to 0.97mmHg)], p = 0.037. Postoperative complications were less prevalent in the HPI patients (0.46 ± 0.98 vs. 0.88 ± 1.20), p = 0.035. Finally, LOS was significantly shorter among HPI patients with a median difference of 2days (p = 0.019). The HPI combined with a GDFT protocol may help to minimize the severity of IOH during non-cardiac surgery.