Analysis Of Pooled Data Research Articles

Impact of body mass index and its change on survival outcomes in patients with early breast cancer: A pooled analysis of individual-level data from BCIRG-001 and BCIRG-005 trials.

The relationships between body mass index (BMI) and survival rates are complex, and have not been thoroughly investigated in breast cancer patients who received adjuvant chemotherapy. We collected data on 2394 patients from two randomized, phase III clinical trials that investigated adjuvant chemotherapy in breast cancer identified in Project Data Sphere. The objective was to examine the effect of baseline BMI, BMI after adjuvant chemotherapy, and BMI change from baseline to post-adjuvant chemotherapy on disease-free survival (DFS) and overall survival (OS). Restricted cubic splines were used to examine potential non-linear associations between continuous BMI value and survival. Stratified analyses involved chemotherapy regimens. Severe obesity (BMI≥40.0kg/m2) at baseline was independently associated with worse DFS (hazard ration [HR]=1.48, 95% confidence interval [CI] 1.02-2.16, P=0.04) and OS (HR=1.79, 95%CI 1.17-2.74, P=0.007) compared with underweight/normal weight (BMI≤24.9kg/m2). A BMI loss >10% was also an independent prognostic factor for adverse OS (HR=2.14, 95%CI 1.17-3.93, P=0.014). Stratified analyses revealed that severe obesity adversely affected DFS (HR=2.38, 95%CI 1.26-4.34, P=0.007) and OS (HR=2.90, 95%CI 1.46-5.76, P=0.002) in the docetaxel-based group, but not in the non-docetaxel-based group. Restricted cubic splines revealed a "J-shaped" association of baseline BMI with risk of recurrence or all-cause death, and this relationship was more pronounced in the docetaxel-based group. In early breast cancer patients treated with adjuvant chemotherapy, baseline severe obesity was significantly linked to worse DFS and OS, and a BMI loss over 10% from baseline to post-adjuvant chemotherapy also negatively affected OS. Moreover, the prognostic role of BMI might differ between docetaxel-based and non-docetaxel-based groups.

239MO Impact of body mass index and its change on survival outcomes in patients with early breast cancer: A pooled analysis of individual-level data from BCIRG-001 and BCIRG-005 trials

239MO Impact of body mass index and its change on survival outcomes in patients with early breast cancer: A pooled analysis of individual-level data from BCIRG-001 and BCIRG-005 trials

Effectiveness and Safety of Prenatal Valacyclovir for Congenital Cytomegalovirus Infection: Systematic Review and Meta-analysis

ABSTRACT One of the most common causes of infection-related fetal malformations is congenital cytomegalovirus (CMV), which affects approximately 0.5% to 2% of newborns. Several approaches have been investigated for screening, prevention, and treatment; one drug that shows activity against CMV is valacyclovir, and prenatal administration of this drug has been investigated in the context of preventing fetal disorders due to CMV. Although studies and clinical trials have been done regarding the safety and effectiveness of valacyclovir, clinical attitudes regarding universal CMV screening and prenatal valacyclovir treatment have yet to change. This article is a systematic review and meta-analysis of the safety and effectiveness of prenatal valacyclovir in CMV-infected pregnancies. Inclusion criteria included pregnancies with CMV infection diagnosed through serology, with a primary outcome of incidence of congenital CMV confirmed by polymerase chain reaction from amniocentesis. Secondary outcomes included symptomatic infection (rash, jaundice, microcephaly, seizures, hepatosplenomegaly, hearing loss, visual loss, retinitis, and central nervous system anomalies), asymptomatic infection, perinatal death, pregnancy termination, fetal anomaly, or severe symptoms. Adverse events related to the administration of valacyclovir were also recorded. Because relatively few studies were available for inclusion, the authors were unable to assess publication bias, but other risk of bias was assessed using standard tools. Final analysis included 8 studies and 620 pregnant women with CMV in 2 randomized controlled trials and 6 observational studies. One randomized controlled trial focused on valacyclovir treatment for CMV infection acquired in early pregnancy, and the other assessed valacyclovir treatment between 34 and 38 weeks' gestation to reduce risk of CMV within 1 year of delivery. The latter of the 2 studies was not included in pooled data synthesis because of inclusion criteria differences. Three studies focused on valacyclovir treatment for confirmed maternal CMV infection; pooled data analysis showed that valacyclovir-treated pregnancies had lower risk of congenital CMV (odds ratio [OR], 0.37; 95% confidence interval [CI], 0.21–0.64; P < 0.001). When contracted in the first trimester, risk of vertical transmission was lower in those who were treated with valacyclovir (OR, 0.34; 95% CI, 0.15–0.74; P = 0.001); however, there was no effect observed in those with CMV in the periconceptual period. Analysis additionally showed that prenatal valacyclovir treatment was more likely to result in asymptomatic children (OR, 2.98; 95% CI, 1.18–7.55; P = 0.021), but no other significant perinatal differences were observed. These results show that treatment of CMV with prenatal valacyclovir reduces the risk of congenital CMV and its associated complications. Limitations of this analysis include the heterogeneity of inclusion and measurement criteria, as well as small samples to assess perinatal outcomes. Risks associated with the drug were small, and adverse events resolved after patients discontinued valacyclovir. The findings are consistent with previous research showing the benefit of valacyclovir. Further research should assess perinatal outcomes associated with valacyclovir treatment, as well as the role of valacyclovir in secondary versus primary infection. In particular, larger randomized controlled trials should be implemented to determine the association of valacyclovir treatment with the risk of fetal structural anomalies, symptomatic infection, and neurocognitive impairment.

The association between preconception cannabis use and gestational diabetes mellitus: The Preconception Period Analysis of Risks and Exposures Influencing health and Development (PrePARED) consortium.

The metabolic changes that ultimately lead to gestational diabetes mellitus (GDM) likely begin before pregnancy. Cannabis use might increase the risk of GDM by increasing appetite or promoting fat deposition and adipogenesis. We aimed to assess the association between preconception cannabis use and GDM incidence. We analysed individual-level data from eight prospective cohort studies. We identified the first, or index, pregnancy (lasting ≥20 weeks of gestation with GDM status) after cannabis use. In analyses of pooled individual-level data, we used logistic regression to estimate study-type-specific odds ratios (OR) and 95% confidence intervals (CI), adjusting for potential confounders using random effect meta-analysis to combine study-type-specific ORs and 95% CIs. Stratified analyses assessed potential effect modification by preconception tobacco use and pre-pregnancy body mass index (BMI). Of 17,880 participants with an index pregnancy, 1198 (6.7%) were diagnosed with GDM. Before the index pregnancy, 12.5% of participants used cannabis in the past year. Overall, there was no association between preconception cannabis use in the past year and GDM (OR 0.97, 95% CI 0.79, 1.18). Among participants who never used tobacco, however, those who used cannabis more than weekly had a higher risk of developing GDM than those who did not use cannabis in the past year (OR 2.65, 95% CI 1.15, 6.09). This association was not present among former or current tobacco users. Results were similar across all preconception BMI groups. In this pooled analysis of preconception cohort studies, preconception cannabis use was associated with a higher risk of developing GDM among individuals who never used tobacco but not among individuals who formerly or currently used tobacco. Future studies with more detailed measurements are needed to investigate the influence of preconception cannabis use on pregnancy complications.

Multi environmental evaluation for selection of stable and high yielding sugarcane (Saccharum officinarum L.) clones based on AMMI and GGE biplot models

The present study was aimed to evaluate the G x E (genotype x environment) interaction using AMMI and GGE biplot analysis to identify sugarcane (Saccharum officinarum L.) genotypes that combine high yield and stability in multi-location trials. Twelve advanced clones generated in the sugarcane breeding programs along with three standards (Co 86032, CoC 671 and Co 09004) were evaluated for cane and sugar yield using randomized complete block design with three replicates over two plant crops and one ratoon during 2019 to 2021 across two years and locations. Data was collected on yield traits and sugar quality characters. Stability parameters were determined. The data was also investigated using GGE biplot and the AMMI models. The results of combined analyses of variance exhibited significant differences among genotypes at the three test environments and when locations were combined. The GE interaction was also significant for all the traits, indicating inconsistency of performance of the genotypes over the locations and seasons. Pooled data analysis of 15 genotypes indicated the superiority of Co 15017 and CoN 15071 for CCS yield across six environments. Two clones, Co 15017 and CoSnk 15102 recorded higher mean cane yield as compared with three standards across the six experimental conditions. Multivariate (AMMI and GGE biplot) statistical analysis indicated that CoSnk 15102 exhibited higher and more stable commercial cane sugar yield and cane yield per hectare, indicating this genotype’s suitability across the test locations. The results of such multi-environmental trials with the elucidation of GE interaction using AMMI and GGE are of great significance in guiding the selection and recommendation of stable and superior varieties in sugarcane production zones.

Muscimol as a treatment for nerve injury-related neuropathic pain: a systematic review and meta-analysis of preclinical studies.

: Muscimol's quick onset and GABAergic properties make it a promising candidate for the treatment of pain. This systematic review and meta-analysis of preclinical studies aimed at summarizing the evidence regarding the efficacy of muscimol administration in the amelioration of nerve injury-related neuropathic pain. : Two independent researchers performed the screening process in Medline, Embase, Scopus and Web of Science extracting data were extracted into a checklist designed according to the PRISMA guideline. A standardized mean difference (SMD [95% confidence interval]) was calculated for each. To assess the heterogeneity between studies, I2 and chi-square tests were utilized. In the case of heterogeneity, meta-regression and subgroup analyses were performed to identify the potential source. : Twenty-two articles met the inclusion criteria. Pooled data analysis showed that the administration of muscimol during the peak effect causes a significant reduction in mechanical allodynia (SMD = 1.78 [1.45-2.11]; P < 0.0001; I2 = 72.70%), mechanical hyperalgesia (SMD = 1.62 [1.28-1.96]; P < 0.0001; I2 = 40.66%), and thermal hyperalgesia (SMD = 2.59 [1.79-3.39]; P < 0.0001; I2 = 80.33%). This significant amendment of pain was observed at a declining rate from 15 minutes to at least 180 minutes post-treatment in mechanical allodynia and mechanical hyperalgesia, and up to 30 minutes in thermal hyperalgesia (P < 0 .0001). : Muscimol is effective in the amelioration of mechanical allodynia, mechanical hyperalgesia, and thermal hyperalgesia, exerting its analgesic effects 15 minutes after administration for up to at least 3 hours.

Comparative Efficacy of Tirzepatide, Teneligliptin, and Empagliflozin in HbA1c Reduction in Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis

This study’s objective was to evaluate the effectiveness of three different families of drugs (Empagliflozin [an SGLT-2 inhibitor], Tirzepatide [a GLP-1 receptor co-agonist], and Teneligliptin [DPP-4 inhibitor] used in the treatment of type 2 diabetes in lowering HbA1c levels in people with type 2 diabetes mellitus (T2DM). The effectiveness of different families of diabetic drugs was assessed using a meta-analytic approach. Data were gathered from a variety of research publications using ICTRP, CT.gov, and PubMed databases. The data were analyzed, and conclusions were drawn using forest plots. Teneligliptin (a DPP-4 Inhibitor) substantially lowered HbA1c levels in T2DM patients compared to other classes of T2DM drugs with a P-value of 0.0002 and 95% CI -0.63 [-0.97 to -0.30] after reviewing many pertinent articles. The pooled data analysis showed that Tirzepatide and Empagliflozin did not significantly lower HbA1c levels, with the P-value for Tirzepatide being P = 0.55 and for Empagliflozin, it was P = 0.64. According to our research, Teneligliptin may be more effective than Empagliflozin and Tirzepatide as a monotherapy for lowering HbA1c levels in T2DM patients. To corroborate these findings, further research studies are required.

Pooled Phase 2 and 3 Efficacy and Safety Data on Budesonide Oral Suspension in Adolescents with Eosinophilic Esophagitis.

The objective of this study was to evaluate the efficacy and safety of budesonide oral suspension (BOS) in adolescents with eosinophilic esophagitis (EoE). This post hoc analysis pooled data from two 12-week, randomized, double-blind, placebo-controlled studies of BOS 2.0 mg twice daily (b.i.d.) (phase 2, NCT01642212; phase 3, NCT02605837) in patients aged 11-17 years with EoE and dysphagia. Efficacy endpoints included histologic (≤6, ≤1, and <15 eosinophils per high-power field [eos/hpf]), dysphagia symptom (≥30% reduction in Dysphagia Symptom Questionnaire [DSQ] scores from baseline), and clinicopathologic (≤6 eos/hpf and ≥30% reduction in DSQ scores from baseline) responses at week 12. Change from baseline to week 12 in peak eosinophil counts, DSQ scores, EoE Histology Scoring System (EoEHSS) grade (severity) and stage (extent) total score ratios (TSRs), and total EoE Endoscopic Reference Scores (EREFS) were assessed. Safety outcomes were also examined. Overall, 76 adolescents were included (BOS, n = 45; placebo, n = 31). Significantly more patients who received BOS than placebo achieved histologic responses (≤6 eos/hpf: 46.7% vs 6.5%; ≤1 eos/hpf: 42.2% vs 0.0%; <15 eos/hpf: 53.3% vs 9.7%; P < 0.001) and a clinicopathologic response (31.1% vs 3.2%; P = 0.003) at week 12. More BOS-treated than placebo-treated patients achieved a dysphagia symptom response at week 12 (68.9% vs 58.1%; not statistically significant P = 0.314). BOS-treated patients had significantly greater reductions in EoEHSS grade and stage TSRs ( P < 0.001) and total EREFS ( P = 0.021) from baseline to week 12 than placebo-treated patients. BOS was well tolerated, with no clinically meaningful differences in adverse events versus placebo. BOS 2.0 mg b.i.d. significantly improved most efficacy outcomes in adolescents with EoE versus placebo.

Associations between stimulant use and return to illicit opioid use following initiation onto medication for opioid use disorder.

The aim of this study was to estimate how ongoing stimulant use affects return to illicit opioid use after initiation onto medication for opioid use disorder (MOUD). This was a secondary analysis of pooled data from two clinical trials comparing buprenorphine (BUP-NX) and extended-release naltrexone (XR-NTX). Thirteen opioid treatment programs and HIV clinics across 10 states in the United States from 2014 to 2019 took part in this study. A total of 528 participants who initiated MOUD as part of trial participation were included. Nearly half (49%) were between 30 and 49 years of age, 69% were male and 66% were non-Hispanic White. The primary outcome was first self-reported day of non-prescribed opioid use following MOUD initiation, and the exposure of interest was daily stimulant use (methamphetamine, amphetamines or cocaine). Both were defined using time-line follow-back. Among participants reporting at least 1day of illicit opioid use, we also examined relapse to ongoing use, defined as (1) 7days of continuous opioid use or (2) 4 consecutive weeks with self-reported opioid use, one or more positive urine drug screens (UDS) for opioids or one or more missing UDS. Forty-seven per cent of participants reported stimulant use following MOUD initiation, 58% returned to illicit opioid use and 66% of those relapsed to ongoing use. Stimulant use was strongly associated with increased risk of misusing opioids after MOUD initiation when measured daily [adjusted hazard ratio (aHR) = 9.23, 95% confidence interval (CI) = 6.80-12.50, P < 0.001] and over a 7-day period (aHR = 1.27 for each additional day, CI = 1.18-1.37, P < 0.001). Using stimulants weekly or more often was associated with increased likelihood of relapse to ongoing opioid use compared with less than weekly or no stimulant use (adjusted odds ratio = 2.30, CI = 1.05-5.39, P = 0.044). People initiated on medication for opioid use disorder who subsequently use stimulants appear to be more likely to return to and continue using non-prescribed opioids compared with those without stimulant use. The association appears to be stronger among patients who initiate buprenorphine compared with those who initiate extended-release naltrexone.

Pre-vaccination monocyte-to-lymphocyte ratio as a biomarker for the efficacy of malaria candidate vaccines: A subgroup analysis of pooled clinical trial data.

Pre-vaccination monocyte-to-lymphocyte ratio was previously suggested as a marker for malaria vaccine effectiveness. We investigated the potential of this cell ratio as a marker for malaria vaccine efficacy and effectiveness. Effectiveness was investigated by using clinical malaria endpoint, and efficacy was investigated by using surrogate endpoints of Plasmodium falciparum prepatent period, parasite density, and multiplication rates in a controlled human malaria infection trial (CHMI). We evaluated the correlation between monocyte-to-lymphocyte ratio and RTS,S vaccine effectiveness using Cox regression modeling with clinical malaria as the primary endpoint. Of the 1704 participants in the RTS,S field trial, data on monocyte-to-lymphocyte ratio was available for 842 participants, of whom our analyses were restricted. We further used Spearman Correlations and Cox regression modeling to evaluate the correlation between monocyte-to-lymphocyte ratio and Whole Sporozoite malaria vaccine efficacy using the surrogate endpoints. Of the 97 participants in the controlled human malaria infection vaccine trials, hematology and parasitology information were available for 82 participants, of whom our analyses were restricted. The unadjusted efficacy of RTS,S malaria vaccine was 54% (95% CI: 37%-66%, p <0.001). No correlation was observed between monocyte-to-lymphocyte ratio and RTS,S vaccine efficacy (Hazard Rate (HR):0.90, 95%CI:0.45-1.80; p = 0.77). The unadjusted efficacy of Whole Sporozoite malaria vaccine in the appended dataset was 17.6% (95%CI:10%-28.5%, p<0.001). No association between monocyte-to-lymphocyte ratio and the Whole Sporozoite malaria vaccine was found against either the prepatent period (HR = 1.16; 95%CI:0.51-2.62, p = 0.72), parasite density (rho = 0.004, p = 0.97) or multiplication rates (rho = 0.031, p = 0.80). Monocyte-to-lymphocyte ratio alone may not be an adequate marker for malaria vaccine efficacy. Further investigations on immune correlates and underlying mechanisms of immune protection against malaria could provide a clearer explanation of the differences between those protected in comparison with those not protected against malaria by vaccination.

Efficacy of Erenumab for Migraine Prevention in Japanese Patients with Episodic and Chronic Migraine: Results of a Post-Hoc Pooled Analysis.

Erenumab, a fully human monoclonal antibody against the calcitonin gene-related peptide receptor, is approved in Japan for the prevention of adult migraine. This post-hoc analysis evaluated the efficacy of erenumab in Japanese patients with low-frequency episodic migraine (LFEM) versus those with high-frequency episodic migraine (HFEM) and chronic migraine (CM). A pooled analysis of data from the 24-week double-blind treatment phases (DBTPs) of phase 2 and 3 studies evaluated the efficacy of once-monthly erenumab 70mg in Japanese patients. Patients were categorized into subgroups by monthly migraine days (MMD): LFEM and HFEM/CM. The main efficacy outcomes were change from baseline in MMD, acute migraine-specific medication treatment days (MSMD), and six-item Headache Impact Test (HIT-6™) scores. Patients with migraine (n=532) were included in the analysis (LFEM, n=215; HFEM, n=215; CM, n=102). Overall, mean age was 44years, 86.5% were female, and 63.3-88.2% had used or were taking migraine preventive treatment at baseline. Throughout the DBTP, the placebo-adjusted mean change from baseline in MMD, MSMD, and HIT-6 scores with erenumab was similar across LFEM and HFEM/CM subgroups. The proportion of patients achieving at least 50% or 75% reduction from baseline in MMD and MSMD was similar across migraine frequency groups. Reduction in MMD moderately correlated with improvement in HIT-6 scores in the LFEM and HFEM/CM groups. Furthermore, the proportion of patients converting from HFEM/CM to LFEM during the DBTP was higher in the erenumab group than in the placebo. In Japanese patients with different migraine frequencies, erenumab treatment resulted in significant improvements in MMD, MSMD, and headache impact. This pooled analysis of data from phase 2 and 3 studies increases confidence that erenumab is efficacious in patients with high MMD, which is associated with increased disability.

Integrated partially linear model for multi-centre studies with heterogeneity and batch effect in covariates

Multi-centre study is increasingly used for borrowing strength from multiple research groups to obtain reproducible study findings. Regression analysis is widely used for analysing multi-group studies, however, some of the regression predictors are nonlinear and/or often measured with batch effects. Also, the group compositions are potentially heterogeneous across different centres. The conventional pooled data analysis can cause biased regression estimates. This paper proposes an integrated partially linear regression model (IPLM) to account for predictor's nonlinearity, general batch effect, group composition heterogeneity, and potential measurement-error in covariates simultaneously. A local linear regression-based approach is employed to estimate the nonlinear component and a regularization procedure is introduced to identify the predictors' effects. The IPLM-based method has estimation consistency and variable-selection consistency. Moreover, it has a fast computing algorithm and its effectiveness is supported by simulation studies. A multi-centre Alzheimer's disease research project is provided to illustrate the proposed IPLM-based analysis.

43758 Bimekizumab safety and tolerability in patients with moderate to severe plaque psoriasis: Analysis of pooled data from up to three years of treatment in five phase 3/3b clinical trials

43758 Bimekizumab safety and tolerability in patients with moderate to severe plaque psoriasis: Analysis of pooled data from up to three years of treatment in five phase 3/3b clinical trials

Effectiveness of Platelet rich Plasma in Treating Spinal Cord Injuries: A Systematic Review and Meta analysis

Background: The present systematic review and meta-analysis was designed to investigate platelet-rich plasma as an effective treatment for spinal cord injury in animal models. Method: An extensive literature search was conducted using electronic databases. The included studies were summarized based on the investigated outcomes, including functional recovery and cavity size. Data were recorded as mean and standard deviation. The relationship between variables and the outcomes was investigated based on the “meta” command in the STATA 17.0 statistical program. Results: In total, 9 articles were included in the present meta-analysis. Pooled data analysis showed that the administration of platelet-rich plasma significantly improved the motor function of animals (SMD= 1.5; 95%CI: 0.9 - 2.1; p&lt; 0.0001). In subgroup analysis based on the severity of the injury, platelet-rich plasma administration significantly improved the motor function of animals in both moderate (SMD= 2.59l 95%CI: 1.59 - 3.59; p&lt; 0.0001; I2= 30.22%) and severe injuries (SMD= 1.22; 95%CI: 0.64 - 1.79; p&lt; 0.0001; I2= 56.35%); However, the recovery of function was significantly more in animals with moderate spinal cord injury (Meta-regression coefficient= -1.36; 95%CI: -2.68 - -0.09; p= 0.035). In the assessment of cavity size, pooled data analysis showed that PRP administration results in a significant reduction in cavity size (SMD= -2.2; 95%CI: -3.44 - -0.95; p&lt; 0.0001). Discussion: This meta-analysis showed that the administration of platelet-rich plasma can significantly improve motor function and reduce the cavity size in animals with moderate to severe spinal cord injuries.

Disparities in Eye Care Utilization by Self-Reported Vision Difficulty and Diabetes Status in the United States

ABSTRACT Purpose To assess differences in eye care utilization by vision difficulty (VD), diabetes status, and sociodemographic characteristics for American adults. Methods The analysis pooled cross-sectional data from the National Health Interview Survey (2010–2018) from US adults ≥ 18 years. The outcome measure was eye care utilization in the past year. The primary independent variable included four groups: no VD or diabetes, only diabetes, only VD, and diabetes and VD. VD was defined as self-reported difficulty seeing even with glasses or contacts. Diabetic status was defined as ever receiving this diagnosis by a health professional. Multivariable logistic regression analyses examined associations between eye care utilization, VD, diabetic status, and sociodemographic characteristics. Results Of the 284,599 adults included in this study, the majority were female (55%), White (73%), and non-Hispanic (84%). In regression analysis, as compared to adults without diabetes or VD, adults with both diabetes and VD had the greatest utilization (OR = 2.49, 99% CI = 2.18–2.85). Females had higher utilization than men (OR = 1.45, 99% CI = 1.41–1.50). Higher levels of education was associated with greater utilization (OR = 1.82, 99% CI = 1.72–1.92). White and American Indian adults without diabetes had higher utilization compared to other races (OR = 1.17, 99% CI = 1.12–1.24, 0.98–1.39). Conclusion While adults with VD and diabetes are better connected to eye care, significant eye care disparities persist for marginalized groups in the U.S. Identifying and understanding these disparities and eliminating barriers to care is critical to better support all patient populations.

Effectiveness, safety and tolerability of perampanel by age group when used to treat people with focal and generalized epilepsy in clinical practice: The PERMIT Extension study

ObjectiveTo assess the effectiveness and safety/tolerability of perampanel (PER) in people with epilepsy (PWE) treated in everyday clinical practice for focal and generalized seizures, both in the total cohort and by age group. MethodsThe PERMIT Extension study was a pooled analysis of data from PWE included in two large previous clinical practice studies (PERMIT and PROVE). Retention was assessed over 12 months. Effectiveness was assessed based on total seizures and by seizure type (focal and generalized) after 3, 6, and 12 months of PER treatment and at final follow-up (last observation carried forward; “last visit”); assessments included responder rate (≥50% seizure frequency reduction from baseline) and seizure freedom rate (no seizures since at least the previous visit). Safety/tolerability was assessed throughout PER treatment by evaluating adverse events (AEs). All assessments were conducted for the total population and by age category (<12, ≥12 to <18, ≥18 to <65, and ≥65 years at baseline). ResultsFull Analysis Set included 6,822 PWE (51.1% female; mean age, 36.9 years; mean duration of epilepsy 21.4 years) with 6,433, 4,648, and 6,233 PWE assessed for retention, effectiveness, and safety/tolerability, respectively. The majority of PWE (81.1%) were aged 18–64 at baseline, with 4.5% aged <12 years, 8.4% aged 12–17 years, and 5.9% aged ≥65 years. In the overall population, retention rates at 3, 6, and 12 months were 88.0%, 77.6%, and 61.4%, respectively; responder rates at 12 months were 58.5% for total seizures, 54.6% for focal seizures, and 77.7% for generalized seizures, and corresponding seizure freedom rates were 23.6%, 19.0%, and 51.3%, respectively. PER was effective regardless of age category, although effectiveness was greatest in PWE aged ≥65 years, for both focal and generalized seizures. In the overall population, the incidence of AEs was 49.2% and the most frequent AEs (≥5% of PWE) were dizziness/vertigo (13.4%), somnolence (8.8%), irritability (7.3%), and behavioral disorders (5.3%); AEs led to treatment discontinuation in 18.3% of PWE over 12 months. The incidence of AEs and the discontinuation rate due to AEs increased with increasing age (55.0% and 23.9%, respectively, in PWE aged ≥65 years). ConclusionIn this study, the largest pooled analysis of PER clinical practice data conducted to date, PER was shown to be effective and generally well tolerated when used to treat people with focal or generalized epilepsy in everyday clinical practice, regardless of age category. No new or unexpected side effects emerged following long-term use in the real-world setting.

Efficacy of tofacitinib on enthesitis in patients with active psoriatic arthritis: analysis of pooled data from two phase 3 studies

BackgroundTofacitinib is an oral Janus kinase inhibitor for the treatment of psoriatic arthritis (PsA). This post hoc analysis assessed tofacitinib efficacy on enthesitis by baseline location and severity, and impact on disease activity and patient-reported outcomes (PROs), in patients with PsA.MethodsData were pooled from two phase 3 studies (NCT01877668/NCT01882439) in patients with PsA receiving tofacitinib 5 or 10 mg twice daily to month (M)6 or placebo to M3. Endpoints were: change from baseline in Leeds Enthesitis Index (LEI) or Spondyloarthritis Research Consortium of Canada Enthesitis Index (SPARCC); proportions of patients with enthesitis, relapsed enthesitis after resolution, de novo enthesitis, low disease activity (LDA) or remission (minimal disease activity/very low disease activity; Psoriatic Arthritis Disease Activity Score; Disease Activity Index for Psoriatic Arthritis, and Composite Psoriatic Disease Activity in Psoriatic Arthritis); and PROs (Functional Assessment of Chronic Illness Therapy-Fatigue [FACIT-F] total and arthritis pain Visual Analog Scale scores). Descriptive statistics were generated by visit and treatment. Change from baseline in PROs was evaluated by multivariate linear regression.ResultsSeven hundred ten patients from two studies were included: 479 had LEI > 0; 545 had SPARCC > 0; and 136 had LEI = 0 and SPARCC = 0 at baseline. At baseline, among patients with LEI > 0 or SPARCC > 0, mean LEI and SPARCC across treatments and enthesitis locations/severities ranged from 1.0–4.4 and 1.3–9.4, respectively. Across several baseline enthesitis locations/severities, changes from baseline in LEI and SPARCC up to M3 were greater with tofacitinib (-2.0–0.4 and -3.5–0.2) vs placebo (-‍0.9–‍0.4 and -1.5–1.1). Enthesitis at M6 was more common in patients with greater baseline enthesitis severity. At M6, ≤ 40% of patients with baseline LEI > 0 or SPARCC > 0 whose enthesitis had resolved by M1/M3 experienced a relapse, and < 14% of patients with baseline LEI = 0 and SPARCC = 0 had de novo enthesitis. LDA/remission rates generally increased with tofacitinib over time. Baseline LEI location was significantly associated with change from baseline in arthritis pain score, while baseline SPARCC severity was significantly associated with change from baseline in FACIT-F total and arthritis pain scores.ConclusionTofacitinib treatment resulted in improvements in enthesitis in patients with PsA, regardless of baseline location or severity.Trial registrationNCT01877668;NCT01882439.

Pain reduction in adult patients with limb spasticity following single incobotulinumtoxinA injection: analysis of pooled data from phase 2/3 studies

Pain reduction in adult patients with limb spasticity following single incobotulinumtoxinA injection: analysis of pooled data from phase 2/3 studies

Concentrated urine, low urine flow, and postoperative elevation of plasma creatinine: A retrospective analysis of pooled data.

Elevations of plasma creatinine are common after major surgery, but their pathophysiology is poorly understood. To identify possible contributing mechanisms, we pooled data from eight prospective studies performed in four different countries to study circumstances during which elevation of plasma creatinine occurs. We included 642 patients undergoing mixed major surgeries, mostly open gastrointestinal. Plasma and urinary creatinine and a composite index for renal fluid conservation (Fluid Retention Index, FRI) were measured just before surgery and on the first postoperative morning. Urine flow was measured during the surgery. The results show that patients with a postoperative increase in plasma creatinine by >25% had a high urinary creatinine concentration (11.0±5.9 vs. 8.3±5.6 mmol/L; P< 0001) and higher FRI value (3.2±1.0 vs. 2.9±1.1; P< 0.04) already before surgery was initiated. Progressive increase of plasma creatinine was associated with a gradually lower urine flow and larger blood loss during the surgery (Kruskal-Wallis test, P< 0.001). The patients with an elevation > 25% also showed higher creatinine and a higher FRI value on the first postoperative morning (P< 0.001). Elevations to > 50% of baseline were associated with slightly lower mean arterial pressure (73 ± 10 vs. 80 ± 12 mmHg; P< 0.005). We conclude that elevation of plasma creatinine in the perioperative period was associated with low urine flow and greater blood loss during surgery and with concentrated urine both before and after the surgery. Renal water conservation-related mechanisms seem to contribute to the development of increased plasma creatinine after surgery.

Esketamine versus placebo on time to remission in major depressive disorder with acute suicidality

BackgroundEsketamine (ESK) nasal spray, taken with oral antidepressant therapy, is approved for the treatment of depressive symptoms in adults with major depressive disorder (MDD) with acute suicidal ideation or behavior. In pooled analyses of two pivotal phase 3 studies, ASPIRE I and II, remission rates were consistently higher among patients with MDD with active suicidality who were treated with ESK + standard of care (SOC) versus placebo (PBO) + SOC at all time points in the double-blind and most time points in the follow-up phases. The current analysis of the ASPIRE data sets assessed the effect of ESK + SOC versus PBO + SOC on additional remission-related endpoints: time to achieving remission and consistent remission, proportion of patients in remission and consistent remission, and days in remission.MethodsPost hoc analysis of pooled data from ASPIRE I and II (N = 451). Remission and consistent remission were defined as Montgomery-Åsberg Depression Rating Scale (MADRS) total score ≤ 12 at any given visit or two consecutive visits, respectively. Combined endpoints utilizing Clinical Global Impression-Severity of Suicidality-revised version [CGI-SS-r] ≤ 1 (i.e., not suicidal/questionably suicidal) along with the remission and consistent remission definitions (i.e., MADRS total score ≤ 12) were also examined.ResultsThe median times to remission and consistent remission of MDD were significantly shorter in ESK + SOC versus PBO + SOC (15 versus 23 [p = 0.005] and 23 versus 50 days [p = 0.007], respectively) and a greater proportion of patients in ESK + SOC achieved remission and consistent remission by Day 25 (65.2% versus 55.5% and 54.2% versus 39.8%, respectively). Similar results were obtained using the combined endpoint for both remission definitions. The median percent of days in remission during the double-blind treatment phase was significantly greater in ESK + SOC (27.1% or 5 days) versus PBO + SOC (8.3% or 2 days; p = 0.006), and the significant difference was maintained during follow-up.ConclusionTreatment with ESK + SOC versus PBO + SOC resulted in significantly shorter time to remission, greater proportion of patients in remission, and greater percent of days in remission using increasingly rigorous definitions of remission. These findings underscore the clinical benefits of ESK for adults with MDD with suicidality.Trial registrationClinicalTrials.gov registry NCT03039192 (registered February 1, 2017) and NCT03097133 (registered March 31, 2017).