Trial Registration Information Research Articles

Results reporting for clinical trials led by medical universities and university hospitals in the Nordic countries was often missing or delayed.

To systematically evaluate timely reporting of clinical trial results at medical universities and university hospitals in the Nordic countries. In this cross-sectional study, we included trials (regardless of intervention) registered in the EU Clinical Trials Registry and/or ClinicalTrials.gov, completed 2016-2019, and led by a university with medical faculty or university hospital in Denmark, Finland, Iceland, Norway, or Sweden. We identified summary results posted at the trial registries, and conducted systematic manual searches for results publications (e.g., journal articles, preprints). We present proportions with 95% confidence intervals (CI), and medians with interquartile range (IQR). https://osf.io/wua3r RESULTS: Among 2,112 included clinical trials, 1,650 (78.1%, 95%CI 76.3-79.8%) reported any results during our follow-up; 1,097 (51.9%, 95%CI 49.8-54.1%) reported any results within 2 years of the global completion date; and 48 (2.3%, 95%CI 1.7-3.0%) posted summary results in the registry within 1 year. Median time from global completion date to results reporting was 690 days (IQR 1,103). 856/1,681 (50.9%) of ClinicalTrials.gov-registrations were prospective. Denmark contributed approximately half of all trials. Reporting performance varied widely between institutions. Missing and delayed results reporting of academically led clinical trials is a pervasive problem in the Nordic countries. We relied on trial registry information, which can be incomplete. Institutions, funders, and policy makers need to support trial teams, ensure regulation adherence, and secure trial reporting before results are permanently lost.

Systematic analysis of the design, methodology, and patient population characteristics of the pediatric direct oral anticoagulant trials of venous thromboembolism treatment.

The pediatric direct oral anticoagulation (DOAC) trials provide an opportunity to evaluate and characterize challenges in their design and execution to inform future antithrombotic trials. To perform a systematic review of pediatric DOAC trials for the treatment of venous thromboembolism to critically appraise their methodology and understand the feasibility and challenges. We performed a systematic search of MEDLINE, EMBASE, the Cochrane Library, and ClinicalTrials.gov (January 2002 to December 2022). Studies reporting the results of interventional trials of a DOAC for the treatment of acute venous thromboembolism in children and their respective design papers were included. Trial registration information was reviewed in ClinicalTrials.gov. Discrepancies in study design, targeted populations, sample size, and analyses between planned and actual trial conduct were examined qualitatively. Five published studies and unpublished data for 2 additional trials were included. All trials had modifications to their design or methodology and discrepancies between the trial's registration and the final published study, suggesting feasibility challenges. Modifications to the eligibility criteria, changes in sample size, challenges with the recruitment of younger patients, and an enrolled population not matching the clinical target population were identified for all trials. Discrepancies in outcome reporting, particularly for secondary endpoints, were also common. DOAC trials experienced feasibility challenges that led to design or methodology modifications. Future pediatric antithrombotic trials will need to be adaptive in their design, prioritize enrollment of younger children and input from clinicians providing care to target populations, ensure that enrolled populations match the clinical population, and select clinically meaningful endpoints.

The relationship between continuation of exercise habit for three years and endothelial function in patients with hypertension.

The aim of this study was to evaluate the relationship between continuation of exercise habit for a long period and endothelial function assessed by flow-mediated vasodilation (FMD) in patients with hypertension. This study was a multicenter retrospective observational study. A total of 639 patients with hypertension were enrolled in this study. The subjects were divided into two groups based on information on exercise habit: a regular exercise group and a non-regular exercise group (control group). The regular exercise group was defined as patients who had an exercise habit during a 3-year follow-up period. There was no significant difference in FMD at baseline between the regular exercise group and control group. The change in FMD examined by the Wilcoxon signed rank test was significantly larger in the regular exercise group than in the control group (0.4 (-1.4, 2.0) % vs. -0.1 (-2.2, 1.4) %, p = 0.008). After adjustment for confounding factors for FMD, the odds ratio for increase in FMD was significantly larger in the regular exercise group than in the control groups. (OR: 1.59, 95% CI: 1.14-2.21, p = 0.006) A cubic spline curve revealed that even subjects with regular exercise who had a mean exercise intensity of less than 20 Mets・hour/week a had higher odds ratio for increase in endothelial function compared to the control group. These findings suggest that patients with hypertension who engage in regular exercise exhibited better endothelial function compared to those who do not exercise. Clinical Trial Registry Information: http://www.umin.ac.jp (UMIN000012951).

Early remission of deliberate self-harm predicts emotion regulation capacity in adulthood: 12.4 years follow-up of a randomized controlled trial of adolescents with repeated self-harm and borderline features

AbstractEmotion regulation capacity, critical for adult functioning and mental health, develops strongly during adolescence in healthy individuals. Deficits in emotion regulation is often referred to as emotion dysregulation [ED] and is associated with various mental health problems, including repeated deliberate self-harm [DSH] which peaks in adolescence. Dialectical Behaviour Therapy for adolescents [DBT-A] systematically targets ED through strategies such as changing coping behaviours and has previously been shown to effectively induce DSH remission in adolescents. However, whether such remission is associated with improved emotion regulation capacity in adulthood, and whether this effect is mediated by changes in use of coping strategies has not been previously studied. Prospective long-term follow-up study of an RCT comparing DBT-A with enhanced usual care [EUC] for adolescents presenting to community child and adolescent psychiatric outpatient clinics with borderline personality features and repeated self-harm. Assessments included both structured interviews and self-report at baseline and 1.6, 3.1 and 12.4 years follow-up. In the final follow-up, adult ED was measured and data were collected for 61 (80%) of the original 77 participants. DSH remission was assessed at 1.6 years follow-up, and use of coping strategies at 3.1 and 12.4 years follow-ups. A mediation analysis was conducted within a causal inference framework. Both treatment groups increased their use of functional coping skills from adolescence to adulthood, while only DBT-A was associated with decreases in dysfunctional coping. There was a direct effect of DSH remission 1 year after treatment on adult ED, particularly for participants who did not receive DBT-A. There was a negative association between reductions in dysfunctional coping and adult ED, however this did not mediate the effect of DSH remission. This is the first study to report that early DSH remission in adolescence predicted lower ED in adulthood. These results highlight the importance of early DSH remission and provides new insight into the long-term relationship between DSH and ED. Clinical trial registration information: “Treatment for Adolescents with Deliberate Self-harm”; http://ClinicalTrials.gov/;NCT00675129

Long-term safety and efficacy of MBA-P01 for the treatment of glabellar lines: results from a multicenter, repeated-dose, open-label extension study

Purpose Following the introduction of new type of botulinum toxin (MBA-P01), a recent phase 3 study demonstrated that MBA-P01 showed comparable efficacy and safety to onabotulinumtoxin A for reducing glabellar lines. The primary objective of this study was to evaluate the long-term safety of repeated MBA-P01 administration for the treatment of glabellar lines. Materials and methods This multicenter, single-group, repeated-dose, long-term open-label extension study evaluated repeated treatment with MBA-P01 (20 U, five treatments over 16 months), with posttreatment evaluation performed up to 52 weeks. Results Based on the safety assessment results, no specific irreversible adverse reactions were associated with the safety profile of MBA-P01. Repeated treatment with MBA-P01 was effective for a treatment duration of 3–5 months. Conclusion In conclusion, multiple cycles of treatment of glabellar lines with MBA-P01 at a dose of 20 U were well tolerated. Clinical trial registration information: This study is registered in ClincalTrials.gov (NCT05321979).

Evaluating Compliance of Randomized Controlled Trial Abstracts in Plastic Surgery Journals with CONSORT Guidelines Using GPT-4 AI

Background: The quality of reporting in randomized controlled trials (RCTs) is crucial for accurate interpretation and synthesis of evidence. The Consolidated Standards of Reporting Trials (CONSORT) guidelines provide a standardized framework for reporting RCT abstracts. This study aimed to evaluate the adherence of RCT abstracts published in three major plastic surgery journals to the CONSORT tool guideline for reporting abstracts, utilizing Generative Pre-trained Transformer 4 artificial intelligence (GPT-4 AI) technology. Methods: Abstracts of RCTs published between 2010 and 2023 were collected. The GPT-4 AI model was utilized to assess the abstracts based on the CONSORT criteria. Descriptive statistics were used to report the compliance scores and identify areas where abstracts lacked compliance. Results: Of the initially identified 500 abstracts, a total of 371 RCT abstracts met the inclusion criteria and were analyzed. The mean CONSORT score was 10.05 (±2.22), with a median score of 10.72. Specific areas where abstracts lacked compliance included trial design (39.6%), participant details (28.8%), intervention descriptions (15.6%), randomization process (25.3%), and the number of participants analyzed (33.4%). Trial registration (18.3%) and funding information (15.1%) were also frequently missing. Conclusions: Our study’s innovative use of the GPT-4 AI model for analysis demonstrated the potential of AI technology in streamlining and enhancing the evaluation of research compliance. We advocate for heightened awareness and more rigorous application of CONSORT guidelines among authors, reviewers, and journal editors. Emphasizing the role of AI technology in the evaluative process can further improve the reporting quality of future RCTs in plastic surgery, contributing to more reliable and transparent research in the field.

Suicidal Ideation, Clinical Worsening and Outcomes among Child Participants in Trauma-Focused Treatment.

Research on clinical trajectories of children with suicidal ideation (SI) and clinical worsening (CW) during cognitive behavioral therapy (CBT) for childhood trauma is limited. The current study utilized secondary data from a randomized clinical trial comparing Trauma-Focused CBT versus Stepped care CBT to examine (1) clinical profile and outcomes of children with SI, recurrent thoughts of death/dying, and past attempts; and (2) clinical worsening during treatment and difference in outcomes. Children (ages 4-12) and their parents (N = 183) participated and 132 completed treatment. Interviews assessing SI, thoughts of death/dying, past attempts, and number/type of trauma were conducted with children (ages 7-12) and parents. Outcome measures (baseline and post-treatment) completed by parents included child posttraumatic stress symptoms, impairment, and internalizing and externalizing problems and an independent evaluator rated overall severity. Children (ages 7-12), parents and therapists completed ratings during treatment that indicated CW. Results did not differ by treatment group; thus, the pooled sample was used. Children with SI at baseline had higher severity than children without. For completers, no children (n = 14) with SI at baseline had SI at post-treatment. Child (n = 3) and therapist (n = 5) ratings of CW were low. Eighteen children (13.64%) were rated as CW by parents. Most ratings occurred at the beginning of treatment. Children with therapist ratings of CW had higher internalizing problems. Findings suggest that children with SI and CW can improve from trauma-focused CBT. More research is needed on the clinical trajectory of children with SI and trauma, and on clinical tools to monitor CW. Clinical trial registration information: https://clinicaltrials.gov : NCT02537678.

Safety and effectiveness of vortioxetine in patients with major depressive disorder in a real-life clinical setting in India: results from an interventional, flexible-dose study

Objective Vortioxetine has demonstrated safety and efficacy in improving symptoms of major depressive disorder (MDD), including overall functioning in real-world settings. This is the first study in a real-life clinical setting in India to evaluate effectiveness and safety of vortioxetine in patients with MDD. Methods This interventional, open-label study consisted of a 12-week treatment period with flexible doses of vortioxetine (5–20 mg/day) in adult patients (aged 18–65 years) with a confirmed MDD diagnosis. Effectiveness outcomes included change from baseline to week 12 in Patient Health Questionnaire-9 (PHQ-9) and Clinical Global Impression–Severity (CGI-S) scores, along with CGI-Improvement (CGI-I) scores at week 12, using a mixed model for repeated measures. Adverse events (AEs) were recorded for safety outcome assessments. Results Of 395 patients who received vortioxetine, 42.3% were women mean age 38.9 years; 322 patients completed the study. Significant improvement in depressive symptoms was observed in change from baseline to week 12 least squares (LS) mean (SE) PHQ-9 total score (−9.36 [0.276]; p<.0001) and CGI-S score (−2.14 [0.065]; p<.0001). LS mean (SE) CGI-I score showed significant improvement at week 12 (1.93 [0.067]; p<.0001). Subgroup analysis across age, sex, disease severity, and body mass index showed significant improvements in depression symptoms and severity. A total of 35.4% (n = 140) of patients experienced treatment-emergent AEs (mostly mild-moderate); nausea and pruritus were the most frequent (6.6%, n = 26 each). Conclusion Safety and effectiveness of vortioxetine in improving symptoms of MDD over a 12-week period was demonstrated in a real-life clinical setting in India. Clinical trial registration information Open-label, flexible-dose study of vortioxetine in patients with major depressive disorder in India; Clinical Trials.gov ID: NCT04288895; https://www.clinicaltrials.gov/study/NCT04288895

Are Clinical Practice Guidelines Representative of Patients With Distal Radius Fractures? A Review of Patient Demographics and Patient-Reported Outcome Measures Used to Inform Guidelines

Clinical practice guidelines (CPGs) are recommendations developed for broad application to optimize high-quality care and decision-making. The composition of patients and outcome measures used in studies informing CPGs; however, has not been rigorously evaluated. With growing evidence that outcomes in musculoskeletal surgery vary by sociocultural factors, we aimed to: (1) review the linguistic, racial, and ethnic representation of the patients in the studies informing CPGs for distal radius fractures and (2) assess their use of linguistically and culturally adapted patient-reported outcome measures (PROMs). The American Academy of Orthopaedic Surgeons website was used to identify relevant studies. Key variables were extracted, including inclusion and exclusion criteria, language of study, patient language and proficiency, patient race and ethnicity, and use of translated or culturally adapted PROMs. If provided, the clinical trial registration page for the study was evaluated. Descriptive statistics were used to describe the frequency of each variable. Fifty-four published texts were evaluated. Participant language was reported in four (7%) of the published texts and six (11%) when including the clinical trial registration information. Of the published texts, one (2%) reported ethnic group/race data and 40 (74%) used PROMs. Of those using PROMs, eight (20%) of 40 reported the use of translated PROMs, and three (8%) of 40 reported the use of culturally adapted PROMs. There is a lack of reporting of linguistic, racial, and ethnic data and inconsistent use of PROMs, particularly those that are translated and culturally adapted, in studies included in the American Academy of Orthopaedic Surgeons CPG for distal radius fractures. As sociocultural characteristics and PROMs are associated with outcomes, ensuring they are broadly represented in studies, may improve equity and shared decision-making. Greater inclusion and reporting of demographic data and PROMs arerequired in musculoskeletal studies to ensure broad applicability and advance health equity.

Tenecteplase Versus Alteplase in Acute Ischemic Stroke in Chinese Patients: Protocol for the ORIGINAL Study

Background Tenecteplase, a bioengineered variant of alteplase, is a new alternative thrombolytic agent. The ORIGINAL study aims to evaluate the efficacy and safety of tenecteplase versus standard care in Chinese patients with acute ischemic stroke within 4.5 hours of symptom onset. Methods This is a multicenter phase III study that employs a randomized (1:1), active‐controlled, parallel‐group, prospective, open‐label, blinded–end point design. Adult participants (aged ≥18 years) with acute ischemic stroke who are eligible for intravenous thrombolysis within 4.5 hours of symptom onset according to current guideline recommendations are recruited from ≈55 neurology clinics/stroke centers throughout China. Results The primary objective of the ORIGINAL study is to demonstrate the noninferiority of tenecteplase (0.25 mg/kg) to alteplase (0.9 mg/kg) on the basis of the proportion of patients who achieve a modified Rankin Scale score of 0 or 1 on day 90, that is, a favorable functional outcome. The prespecified noninferiority risk ratio margin is 0.937. Secondary end points include other functional outcomes and the following safety end points: adjudicated symptomatic intracerebral hemorrhage (up to 36 hours after the end of study drug administration) based on the European Cooperative Acute Stroke Study III definition; all‐cause death within 90 days; and the proportion of patients with a modified Rankin Scale score of 5 or 6 on day 90. Conclusions It is anticipated that the results of this study will contribute to the growing body of evidence for the noninferiority of tenecteplase to alteplase given within 4.5 hours of acute ischemic stroke symptom onset and support a new indication for tenecteplase in China. Clinical Trial Registration Information NCT04915729 ( https://clinicaltrials.gov/study/NCT04915729 )

Are Orthopaedic Clinical Trials Linguistically and Culturally Diverse? A Systematic Review.

Underrepresentation and misrepresentation of historically underrepresented populations in randomized controlled trials (RCTs) may have implications for the validity of research results and their application for diverse populations. To evaluate the representation of historically linguistically, racially, and ethnically underrepresented participants in orthopaedic randomized controlled trials (RCTs) and to assess the use of translated and culturally adapted patient reported outcome measures (PROMs). Separate and comprehensive literature searches of PubMed, Web of Science, and Embase databases were performed to identify RCTs utilizing PROMs between the years 2012 - 2022 among the top five highest 5-year impact factor orthopaedic journals according to the 2021 Journal Citation Reports database. The primary outcomes of interest included reporting of linguistic, racial and ethnic demographic characteristics of trial participants and the utilization of translated PROMs. The methodological quality of each clinical trial was assessed using the Jadad Criteria. 230 RCTs met inclusion criteria. The language of participants was reported in 14% of trials and in 17% of trials when searching both the published text and clinical trial registration information. In addition, race and/or ethnicity was reported in 11% of trials, and the use of translated PROMs was reported in 7% of trials. Among the six multinational studies, none reported the language of the study population nor the use of translated PROMs. Notably, four studies (2%) reported utilizing culturally adapted PROMs. The average Jadad score was 3.07. Participant language, race, and ethnicity are infrequently reported in orthopaedic clinical trials, potentially limiting the application and interpretation of study results. Similarly, the linguistic and cultural adaptation of PROMs utilized are often not reported, which also limits interpretations of the validity and generalizability of orthopedic study results. Researchers and journals should promote standard reporting of demographic data and methods of PROM adaptation to ensure results are generalizable to diverse patient populations. III.

Ticagrelor with or without aspirin following percutaneous coronary intervention in high-risk patients with concomitant peripheral artery disease: A subgroup analysis of the TWILIGHT randomized clinical trial

The optimal antiplatelet regimen after percutaneous coronary intervention (PCI) in patients with peripheral artery disease (PAD) is still debated. This analysis aimed to compare the effect of ticagrelor monotherapy versus ticagrelor plus aspirin in patients with PAD undergoing PCI. In the TWILIGHT trial, patients at high ischemic or bleeding risk that underwent PCI were randomized after 3 months of dual antiplatelet therapy (DAPT) to aspirin or matching placebo in addition to open-label ticagrelor for 12 additional months. In this post-hoc analysis, patient cohorts were examined according to the presence or absence of PAD. The primary endpoint was Bleeding Academic Research Consortium (BARC) 2, 3, or 5 bleeding. The key secondary endpoint was a composite of all-cause death, myocardial infarction (MI), or stroke. Endpoints were assessed at 12 months after randomization. Among 7,119 patients, 489 (7%) had PAD and were older, more likely to have comorbidities, and multivessel disease. PAD patients had more bleeding or ischemic complications than no-PAD patients. Ticagrelor monotherapy compared to ticagrelor plus aspirin was associated with less BARC 2, 3, or 5 bleeding in PAD (4.6% vs 8.7%; HR 0.52; 95%CI 0.25-1.07) and no-PAD patients (4.0% vs 7.0%; HR 0.56; 95%CI 0.45-0.69; interaction P-value .830) and a similar risk of death, MI, or stroke in these 2 groups (interaction P-value .446). Despite their higher ischemic and bleeding risk, patients with PAD undergoing PCI derived a consistent benefit from ticagrelor monotherapy after 3 months of DAPT in terms of bleeding reduction without any relevant increase in ischemic events. CLINICAL TRIAL REGISTRY INFORMATION:: https://www. gov/study/NCT02270242.

Burden of disease in Lambert-Eaton myasthenic syndrome: taking the patient's perspective.

Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune-mediated neuromuscular disorder leading to muscle weakness, autonomic dysregulation and hyporeflexia. Psychosocial well-being is affected. Previously, we assessed burden of disease for Myasthenia gravis (MG). Here, we aim to elucidate burden of disease by comparing health-related quality of life (HRQoL) of patients with LEMS to the general population (genP) as well as MG patients. A questionnaire-based survey included sociodemographic and clinical data along with standardized questionnaires, e.g. the Short Form Health (SF-36). HRQoL was evaluated through matched-pairs analyses. Participants from a general health survey served as control group. 46 LEMS patients matched by age and gender were compared to 92 controls from the genP and a matched cohort of 92 MG patients. LEMS participants showed lower levels of physical functioning (SF-36 mean 34.2 SD 28.6) compared to genP (mean 78.6 SD 21.1) and MG patients (mean 61.3 SD 31.8). LEMS patients showed lower mental health sub-scores compared to genP (SF-36 mean 62.7 SD 20.2, vs. 75.7 SD 15.1) and MG patients (SF-36 mean 62.7 SD 20.2, vs. 66.0 SD 18.). Depression, anxiety and fatigue were prevalent. Female gender, low income, lower activities of daily living, symptoms of depression, anxiety and fatigue were associated with a lower HRQoL in LEMS. HRQoL is lower in patients with LEMS compared to genP and MG in a matched pair-analysis. The burden of LEMS includes economic and social aspects as well as emotional well-being. TRIAL REGISTRATION INFORMATION: drks.de: DRKS00024527, submitted: February 02, 2021, https://drks.de/search/en/trial/DRKS00024527 .

Evidence of mirror therapy for recruitment of ipsilateral motor pathways in stroke recovery: A resting fMRI study

Mirror therapy (MT) has been proposed to promote motor recovery post-stroke through activation of mirror neuron system, recruitment of ipsilateral motor pathways, or/and increasing attention toward the affected limb. However, neuroimaging evidence for these mechanisms is still lacking. To uncover the underlying mechanisms, we designed a randomized controlled study and used a voxel-based whole-brain analysis of resting-state fMRI to explore the brain reorganizations induced by MT. Thirty-five stroke patients were randomized to an MT group (n ​= ​16) and a conventional therapy (CT) group (n ​= ​19) for a 4-week intervention. Before and after the intervention, the Fugl-Meyer Assessment Upper Limb subscale (FMA-UL) and resting-state fMRI were collected. A healthy cohort (n ​= ​16) was established for fMRI comparison. The changes in fractional amplitude of low-frequency fluctuation (fALFF) and seed-based functional connectivity were analyzed to investigate the impact of intervention. Results showed that greater FMA-UL improvement in the MT group was associated with the compensatory increase of fALFF in the contralesional precentral gyrus (M1) region and the re-establishment of functional connectivity between the bilateral M1 regions, which facilitate motor signals transmission via the ipsilateral motor pathways from the ipsilesional M1, contralesional M1, to the affected limb. A step-wise linear regression model revealed these two brain reorganization patterns collaboratively contributed to FMA-UL improvement. In conclusion, MT achieved motor rehabilitation primarily by recruitment of the ipsilateral motor pathways. Trial Registration Information: http://www.chictr.org.cn. Unique Identifier. ChiCTR-INR-17013644, submitted on December 2, 2017.

Program for the Education and Enrichment of Relational Skills (PEERS®) for Italy: A Randomized Controlled Trial of a Social Skills Intervention for Autistic Adolescents.

The Program for the Education and Enrichment of Relational Skills (PEERS®) is an intervention targeting social skills for autistic adolescents and those with other social challenges. The efficacy of the PEERS® on adolescents has been extensively explored but the program has not been validated in Italy. In the present study, we adapted PEERS® to Italian culture and evaluated its efficacy in an Italian sample. A Randomized Controlled Trial was conducted, analyzing the results of 37 autistic adolescents who were randomly assigned to two groups: experimental group (TG) and waitlist group (WL). The primary outcomes (social abilities) and secondary outcomes (co-occurring conditions, executive functions) were assessed at four time points. No differences were found at pre-treatment between groups on baseline measures and primary outcomes. At post-treatment, significant group differences emerged in primary outcomes (social knowledge and social performance) and secondary outcomes (emotion regulation). The groups' results pooled together (TG + WL) confirmed the findings at post-treatment and showed further changes in primary outcomes (global social competence and social cognition) and secondary outcomes (externalizing problems, emotive and behavioral total problems, functional problems related to depressive symptoms). The improvements were maintained at a 3-month follow-up, except for global social competence and social cognition. Additionally, new results emerged regarding internalizing problems and global executive functioning. The efficacy of the Italian version of PEERS® was ascertained on primary and secondary outcomes. Innovative findings on emotion regulation, behavioral problems, and depression symptoms also emerged.Clinical trial registration information Program for the Education and Enrichment of Relational Skills (PEERS®) for Italy. An RCT's Study on Social Skills Intervention for Adolescents with Autism Spectrum Disorder (ASD). URL: http://clinicaltrials.gov . TRN: NCT05473104. Release Date: July 21, 2022.

Rapid Rescue Treatment with Diazepam Nasal Spray Leads to Faster Seizure Cluster Termination in Epilepsy: An Exploratory Post Hoc Cohort Analysis.

Although prompt treatment of status epilepticus is standard of care, the effect of timing of rescue therapy administration for seizure clusters in epilepsy remains unknown. Seizure clusters are a rare but clinically important condition, and benzodiazepines are the cornerstone rescue therapy for seizure clusters in epilepsy. We characterized temporal patterns from a large dataset of treated seizure clusters in the safety study of diazepam nasal spray. This post hoc analysis used timing data of treated seizure clusters recorded by care partners and patients in seizure diaries during a 1-year safety study. Data analysis used time from seizure start to administration of diazepam. From 4466 observations, 3225 had data meeting criteria for analysis. Overall, median times from seizure start to dose administration, dose administration to seizure termination, and total seizure duration were 2, 3, and 7min, respectively. In seizure clusters treated in < 5min (median 1.0min), median time from dose to seizure termination was 2.0min, and median total seizure duration was 4.0min. Among seizure clusters treated in ≥ 5min (median 10.0min), median time to seizure termination was 10.0min, and median total seizure duration was 23.0min. Previously published safety results reported that over a mean participation of 1.5years, 82.2% of patients had ≥ 1 treatment-emergent adverse events (TEAEs) irrespective of relationship to treatment, including 30.7% with serious TEAEs; 18.4% had TEAEs deemed at least possibly related to the study drug, none of which were serious. There were no events of cardiorespiratory depression. Echoing the importance of early use of benzodiazepines in status epilepticus, the findings from this exploratory analysis of patients with refractory epilepsy and frequent seizure clusters identify a potential benefit of early diazepam nasal spray treatment leading to faster seizure resolution within the seizure cluster. Trial Registration Information: ClinicalTrials.gov identifier NCT02721069 ( https://clinicaltrials.gov/ct2/show/NCT02721069 ).

End-of-life experiences in individuals with dementia with Lewy bodies and their caregivers: A mixed-methods analysis.

Dementia with Lewy bodies (DLB) is one of the most common degenerative dementias, but research on end-of-life experiences for people with DLB and their caregivers is limited. Dyads of individuals with moderate-advanced DLB and their primary informal caregivers were recruited from specialty clinics, advocacy organizations, and research registries and followed prospectively every 6 months. The current study examines results of caregiver study visits 3 months after the death of the person with DLB. These visits included the Last Month of Life survey, study-specific questions, and a semi-structured interview querying end-of-life experiences. Individuals with DLB (n = 50) died 3.24 ± 1.81 years after diagnosis, typically of disease-related complications. Only 44% of caregivers reported a helpful conversation with clinicians regarding what to expect at the end of life in DLB. Symptoms commonly worsening prior to death included: cognition and motor function, ADL dependence, behavioral features, daytime sleepiness, communication, appetite, and weight loss. Almost 90% of participants received hospice care, but 20% used hospice for <1 week. Most caregivers reported overall positive experiences in the last month of life, but this was not universal. Having information about DLB and what to expect, access to support, and hospice care were healthcare factors associated with positive and negative end of life experiences. Hospice experiences were driven by communication, care coordination, quality care, and caregiver education. Most caregivers of individuals who died with DLB reported positive end-of-life experiences. However, the study identified multiple opportunities for improvement relating to clinician counseling of patients/families, support/hospice referrals, and monitoring individuals with DLB to identify approaching end of life. Future research should quantitatively identify changes that herald end of life in DLB and develop tools that can assist clinicians in evaluating disease stage to better inform counseling and timely hospice referrals. Trial registration information: NCT04829656.

Rapid Improvements in Itch with Tapinarof Cream 1% Once Daily in Two Phase3 Trials in Adults with Mild to Severe Plaque Psoriasis.

Patients with psoriasis report pruritus as their most bothersome symptom. Tapinarof cream 1% once daily demonstrated significant efficacy versus vehicle and was well tolerated in adults with mild to severe plaque psoriasis in two 12-week trials: PSOARING1 (NCT03956355) and PSOARING2 (NCT03983980). Here, we present patient-reported pruritus outcomes from these trials. Outcomes included a Peak Pruritus Numerical Rating Scale (PP-NRS) score of 0 or 1 (itch-free state); Dermatology Life Quality Index (DLQI) itch item scores; and Psoriasis Symptom Diary (PSD) itch item scores. Analyses included 683 tapinarof- and 342 vehicle-treated patients. At baseline, mean pruritus scores were similar across trials with only 7-11% of patients reporting an itch-free state. At week12, the proportion of tapinarof-treated patients achieving an itch-free state was 50% in both trials compared with 32% (P = 0.0007) and 27% (P < 0.0001) in the vehicle groups. Improvements were apparent at the earliest assessments with continued improvement over the course of the trials. There were rapid and statistically significant improvements in the proportion of patients with a ≥ 4-point improvement in PP-NRS for tapinarof-treated patients versus vehicle from week2 with 68% vs 46% (P = 0.0004) and 60% vs 31% (P = 0.0001) at week12 achieving a response in each trial. Significantly greater reductions in itch with tapinarof versus vehicle were also demonstrated at week12 for DLQI itch item1 (P = 0.0026 and P < 0.0001), PSD item1 (both P < 0.0001), and PSD item2 (both P < 0.0001). Tapinarof was highly efficacious in reducing pruritus across multiple patient-reported outcome measures, with rapid, statistically significant, and clinically meaningful improvements. The high proportion of patients achieving the treatment target of an itch-free state at week12 (50%) is a noteworthy clinical outcome for a non-steroidal topical cream in the treatment of mild to severe plaque psoriasis. Clinical trial registration information: NCT03956355, NCT03983980.

Association of cumulative low-density lipoprotein cholesterol exposure with vascular function

The relationship between cumulative low-density lipoprotein cholesterol (LDL-C) exposure and progression of atherosclerosis remains uncertain. The aim of this study was to determine the relationship between cumulative LDL-C level and flow-mediated vasodilation (FMD), nitroglycerine-induced vasodilation (NID) and the presence of plaque in the common carotid artery (CCA). This was a cross-sectional study. We measured FMD in 8208 subjects, NID in 1822 subjects, and CCA plaque in 591 subjects who were not taking lipid-lowering drugs. The subjects were divided into four groups based on cumulative LDL-C exposure: <4000 mg·year/dL, 4000-4999 mg·year/dL, 5000-5999 mg·year/dL, and ≥6000 mg·year/dL. The odds ratio of the lower quartile of FMD in the cholesterol-year-score <4000 mg·year/dL group was significantly higher than the odds ratios in the other groups. The odds ratio of the lower quartile of NID in the <4000 mg·year/dL group was significantly higher than the odds ratios in the 5000-5999 mg·year/dL and ≥6000 mg·year/dL groups. The odds ratio of the prevalence of CCA plaque in the <4000 mg·year/dL group was significantly higher than that in the ≥6000 mg·year/dL group. Endothelial dysfunction occurred from cumulative LDL-C exposure of 4000 mg·year/dL, vascular smooth muscle dysfunction occurred from cumulative LDL-C exposure of 5000 mg·year/dL, and prevalence of CCA plaque occurred from cumulative LDL-C exposure of 6000 mg·year/dL. CLINICAL TRIAL REGISTRY INFORMATION: http://www.umin.ac.jp (UMIN000012950, UMIN000012951, and UMIN000012952, UMIN000003409).

Triglyceride-glucose index, low-density lipoprotein levels, and cardiovascular outcomes in chronic stable cardiovascular disease: results from the ONTARGET and TRANSCEND trials.

The triglyceride-glucose index (TyG) has been proposed as an alternative to insulin resistance and as a predictor of cardiovascular outcomes. Little is known on its role in chronic stable cardiovascular disease and its predictive power at controlled low density lipoprotein (LDL) levels. Our study population consisted of 29 960 participants in the ONTARGET and TRANSCEND trials that enrolled patients with known atherosclerotic disease. Triglycerides and glucose were measured at baseline. TyG was calculated as the logarithmized product of fasting triglycerides and glucose divided by 2. The primary endpoint of both trials was a composite of cardiovascular death, myocardial infarction, stroke, or hospitalization for heart failure. The secondary endpoint was all-cause death and the components of the primary endpoint. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CI) with extensive covariate adjustment for demographic, medical history, and lifestyle factors. During a mean follow-up of 4.3 years, 4895 primary endpoints and 3571 all-cause deaths occurred. In fully adjusted models, individuals in the highest compared to the lowest quartile of the TyG index were at higher risk for the primary endpoint (HR 1.14; 95% CI 1.05-1.25) and for myocardial infarction (HR 1.30; 95% CI 1.11-1.53). A higher TyG index did not associate with the primary endpoint in individuals with LDL levels < 100 mg/dL. A higher TyG index is associated with a modestly increased cardiovascular risk in chronic stable cardiovascular disease. This association is largely attenuated when LDL levels are controlled. www.clinicaltrials.gov: NCT00153101.