Efficacy Outcomes Research Articles

A large UK single-centre experience in the long-term safety and efficacy of Woven Endobridge in the treatment of wide-neck intracranial aneurysms and risk factors associated with re-bleeding and re-treatment.

Endovascular treatment of wide neck aneurysms remains complicated with a determined and continuous technological effort towards treatment options that can offer safer and efficacious outcomes. The Woven Endobridge device was introduced in 2010 and has become a mainstay endovascular treatment for wide neck and large intracranial aneurysms. A recent review of the Woven Endobridge Clinical Assessment of Intrasaccular Aneurysm Therapy (WEBCAST) and WEBCAST2 trials and the five-year follow-up of patients was published. Our aim is to demonstrate real-life experience of aneurysms and patients treated with Woven Endobridge from a large high-volume specialist centre. A retrospective review was performed of patients treated with Woven Endobridge from March 2013 to March 2018. Primary efficacy outcomes were defined as per Raymond-Roy Occlusion Criteria (RROC) resulting in long-term complete occlusion (RROC1) and adequate occlusion (RROC1 and RROC2). Primary Safety outcomes were defined as procedure-related morbidity, rate of re-bleeding and rate of re-treatment. Seventy-nine aneurysms were treated during the five-year period. Adequate aneurysm occlusion (RROC1 and RROC2) achieved was 81%. Retreatment was required in 18% of patients (14/79). Greater retreatment rate was demonstrated in partially thrombosed aneurysms, aneurysms with larger neck and dome diameter and dome heights. Woven Endobridge treatment of wide-neck intracranial aneurysms offers a safe and efficacious outcome. This large UK single-centre experience demonstrates congruity with recent five-year outcomes of WEBCAST and WEBCAST2 trials.

Multicenter evaluation of the safety and efficacy of selective internal radiation therapy with yttrium-90 resin microspheres in Taiwan: data from the RESIN registry.

The REgistry of Selective Internal radiation therapy in AsiaNs (RESIN) was a multicenter, single-arm, prospective, observational study of 90Y resin microspheres in patients with hepatocellular carcinoma (HCC) or metastatic colorectal cancer (mCRC) from Taiwan. RESIN is the first real-life clinical study of this therapy in an Asian cohort. Study objectives were to evaluate the safety and efficacy of 90Y resin microspheres. Adults with HCC or mCRC scheduled to receive SIRT with 90Y resin microspheres were included. Primary endpoints were best overall response rate (ORR), adverse events, and changes from baseline in liver function. Secondary efficacy endpoints included overall survival (OS). Of 107 enrolled patients, 83 had HCC, and 24 had mCRC. ORR was 55.41% (HCC) and 33.33% (mCRC). Of 58 HCC patients with 6-month post-SIRT data, 13.79% (n=8) had resection, transplantation, transarterial chemoembolization, or radiofrequency ablation as the result of down-staging or down-sizing of their lesions. One hundred and ten treatment emergent adverse events (TEAEs) were reported in 51 patients, and five serious adverse events (SAEs) were reported in five patients. The most frequent TEAEs were abdominal pain, nausea and decreased appetite (HCC), and abdominal pain, decreased appetite, fatigue, and vomiting (mCRC). Two deaths due to SAEs (probably related to SIRT) were reported, both in patients with extensive HCC, active hepatitis infection, and other comorbidities. Median OS was 24.07 (HCC) and 12.66 (mCRC) months. Safety and efficacy outcomes with the routine use of SIRT with 90Y resin microspheres in Taiwan are consistent with published data.

Current Perspectives and Progress in Preoperative Portal Vein Embolization with Stem Cell Augmentation (PVESA).

Portal vein embolization with stem cell augmentation (PVESA) is an emerging approach for enhancing the growth of the liver segment that will remain after surgery (i.e., future liver remnant, FLR) in patients with liver cancer. Conventional portal vein embolization (PVE) aims to induce preoperative FLR growth, but it has a risk of failure in patients with underlying liver dysfunction and comorbid illnesses. PVESA combines PVE with stem cell therapy to potentially improve FLR size and function more effectively and efficiently. Various types of stem cells can help improve liver growth by secreting paracrine signals for hepatocyte growth or by transforming into hepatocytes. Mesenchymal stem cells (MSCs), unrestricted somatic stem cells, and small hepatocyte-like progenitor cells have been used to augment liver growth in preclinical animal models, while clinical studies have demonstrated the benefit of CD133 + bone marrow-derived MSCs and hematopoietic stem cells. These investigations have shown that PVESA is generally safe and enhances liver growth after PVE. However, optimizing the selection, collection, and application of stem cells remains crucial to maximize benefits and minimize risks. Additionally, advanced stem cell technologies, such as priming, genetic modification, and extracellular vesicle-based therapy, that could further enhance efficacy outcomes should be evaluated. Despite its potential, PVESA requires more investigations, particularly mechanistic studies that involve orthotopic animal models of liver cancer with concomitant liver injury as well as larger human trials.

Anticoagulation for Patients With Concomitant Atrial Fibrillation and End-Stage Renal Disease: A Systematic Review and Network Meta-Analysis.

Concomitant atrial fibrillation and end-stage renal disease is common and associated with an unfavorable prognosis. Although oral anticoagulants have been well established to prevent thromboembolism, the applicability in patients under long-term dialysis remains debatable. The study aimed to determine the efficacy and safety of anticoagulation in the dialysis-dependent population. An updated network meta-analysis based on MEDLINE, EMBASE, and the Cochrane Library was performed. Studies published up to December 2022 were included. Direct oral anticoagulants (DOACs, dabigatran, rivaroxaban, apixaban 2.5/5 mg twice daily), vitamin K antagonists (VKAs), and no anticoagulation were compared on safety and efficacy outcomes. The outcomes of interest were major bleeding, thromboembolism, and all-cause death. A total of 42 studies, including 3 randomized controlled trials, with 185 864 subjects were pooled. VKAs were associated with a significantly higher risk of major bleeding than either no anticoagulation (hazard ratio [HR], 1.47; 95% CI, 1.34-1.61) or DOACs (DOACs versus VKAs; HR, 0.74 [95% CI, 0.64-0.84]). For the prevention of thromboembolism, the efficacies of VKAs, DOACs, and no anticoagulation were equivalent. Nevertheless, dabigatran and rivaroxaban were associated with fewer embolic events. There were no differences in all-cause death with the administration of VKAs, DOACs, or no anticoagulation. For dialysis-dependent populations, dabigatran and rivaroxaban were associated with better efficacy, while dabigatran and apixaban demonstrated better safety. No anticoagulation was a noninferior alterative, and VKAs were associated with the worst outcomes.

Comparison of efficacy between beractant and poractant alfa in respiratory distress syndrome among preterm infants (28-33+6 weeks gestational age) using the less invasive surfactant administration (LISA) technique: A randomized controlled trial.

Exogenous surfactant therapy is vital in managing respiratory distress syndrome (RDS) in preterm infants, with less invasive surfactant administration (LISA) gaining popularity. This study aimed to assess the efficacy and short-term outcomes of LISA using beractant and poractant alfa. In a randomized controlled trial, we enrolled preterm infants (28-33+6 weeks) with RDS requiring surfactant. LISA was employed, with beractant at 100 mg/kg or poractant-alfa at 200 mg/kg. Primary outcome was the need for intubation within 72 hours. Among 120 infants, 3.3% in both groups required intubation within 72 hours (p value 1.00, 95% CI 0.14-6.86). No significant differences in secondary outcomes were noted. However, beractant was significantly more economical than poractant-alfa, with a significantly lower surfactant cost and total care cost for infant hospital stays. Beractant and poractant-alfa exhibit similar efficacy in LISA for preterm infants with RDS. Economic considerations, especially in LMICs, favour beractant. CLINICAL TRIAL REGISTATION: (CTRI/2023/03/050375).

Micro robot as the feature of robotic in healthcare approach from design to application: the State of art and challenges

Micro robots, miniature robotic devices typically ranging from micrometers to a few millimeters in size, hold immense potential in various fields, particularly healthcare. Their diminutive stature enables access to intricate anatomical regions previously unreachable, facilitating targeted drug delivery, localized treatment, and precise monitoring. These robots offer numerous advantages, including enhanced maneuverability, reduced invasiveness, and minimized tissue damage. By navigating through complex biological environments, micro robots can deliver therapies with unprecedented precision, improving treatment efficacy and patient outcomes. Additionally, their small size allows for minimally invasive procedures, reducing recovery times and enhancing patient comfort. Overall, micro robots represent a groundbreaking technological advancement with the potential to revolutionize healthcare delivery and significantly benefit human well-being.Their small size enables access to intricate anatomical regions for targeted drug delivery, localized treatment, and precise monitoring. Despite challenges like size constraints and navigation complexities, innovative solutions and interdisciplinary collaboration are driving their advancement in improving healthcare outcomes.

Treatment of post-treatment Lyme disease symptoms-a systematic review.

Residual symptoms after treatment of Lyme disease, sometimes called post-treatment Lyme disease symptoms (PTLDs), are a matter of ongoing controversy. To guide treatment recommendations, a systematic review was performed of the available literature on specific treatment for PTLDs. A systematic literature search of MEDLINE and CENTRAL was performed. No restrictions on case definitions, study types or specific interventions were applied to enable a comprehensive overview of the available literature. Risk of bias was assessed using the Cochrane risk of bias tools for randomized controlled trials. Certainty of the evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluation approach. Outcomes of interest were quality of life, fatigue, depression and cognition as well as adverse events. After screening 1274 records, eight eligible randomized controlled trials were included. Heterogeneity was observed regarding inclusion criteria, intervention, length of treatment and outcome measures. For efficacy outcomes, results are presented narratively due to heterogeneity. Eligible studies show no statistically significant difference between antibiotics and placebo regarding quality of life, cognition and depression. Results for fatigue were inconsistent whilst studies with low risk of bias showed no statistically significant difference between antibiotics and placebo. Meta-analysis of safety outcomes showed statistically significantly more adverse events for antibiotics compared to placebo. Available literature on treatment of PTLDs is heterogeneous, but overall shows evidence of no effect of antibiotics regarding quality of life, depression, cognition and fatigue whilst showing more adverse events. Patients with suspected PTLDs should not be treated with antibiotics.

Exemplar Hospital initiation trial to Enhance Treatment Engagement (EXHIT ENTRE): protocol for CTN-0098B a randomized implementation study to support hospitals in caring for patients with opioid use disorder

BackgroundHospitalizations involving opioid use disorder (OUD) are increasing. Medications for opioid use disorder (MOUD) reduce mortality and acute care utilization. Hospitalization is a reachable moment for initiating MOUD and arranging for ongoing MOUD engagement following hospital discharge. Despite existing quality metrics for MOUD initiation and engagement, few hospitals provide hospital based opioid treatment (HBOT). This protocol describes a cluster-randomized hybrid type-2 implementation study comparing low-intensity and high-intensity implementation support strategies to help community hospitals implement HBOT.MethodsFour state implementation hubs with expertise in initiating HBOT programs will provide implementation support to 24 community hospitals (6 hospitals/hub) interested in starting HBOT. Community hospitals will be randomized to 24-months of either a low-intensity intervention (distribution of an HBOT best-practice manual, a lecture series based on the manual, referral to publicly available resources, and on-demand technical assistance) or a high-intensity intervention (the low-intensity intervention plus funding for a hospital HBOT champion and regular practice facilitation sessions with an expert hub). The primary efficacy outcome, adapted from the National Committee on Quality Assurance, is the proportion of patients engaged in MOUD 34-days following hospital discharge. Secondary and exploratory outcomes include acute care utilization, non-fatal overdose, death, MOUD engagement at various time points, hospital length of stay, and discharges against medical advice. Primary, secondary, and exploratory outcomes will be derived from state Medicaid data. Implementation outcomes, barriers, and facilitators are assessed via longitudinal surveys, qualitative interviews, practice facilitation contact logs, and HBOT sustainability metrics. We hypothesize that the proportion of patients receiving care at hospitals randomized to the high-intensity arm will have greater MOUD engagement following hospital discharge.DiscussionInitiation of MOUD during hospitalization improves MOUD engagement post hospitalization. Few studies, however, have tested different implementation strategies on HBOT uptake, outcome, and sustainability and only one to date has tested implementation of a specific type of HBOT (addiction consultation services). This cluster-randomized study comparing different intensities of HBOT implementation support will inform hospitals and policymakers in identifying effective strategies for promoting HBOT dissemination and adoption in community hospitals.Trial registrationNCT04921787.

Complications and Efficacies of Surgical Versus Transcatheter Closure for Pediatric Ostium Secundum Atrial Septal Defect: A Meta-Analysis.

The optimal approach for pediatric ostium secundum atrial septal defect (ASD) closure remains uncertain. This study aims to assess complications and efficacies of surgical and transcatheter closures. Systematic search in Medline, Cochrane, and EMBASE databases identified cohort studies until July 2023. Complications, length of hospital stay, and efficacy outcomes were evaluated. Subgroup analyses considered ethnicity, ASD size, age, and rim deficiency involvement. Fourteen cohort studies involving 9695 patients were comprehensively analyzed. Regarding complications, the pediatric patients in the surgery group exhibited higher occurrences of cardiac arrhythmia (odds ratio [OR]: 1.87, 95% confidence interval [CI]: 1.22-2.87, p=0.004), pericardial effusion (OR: 14.80, 95% CI: 6.97-31.43, p<0.00001), and pulmonary complications (OR: 2.58, 95% CI: 1.73-3.85, p<0.00001) compared with those in the transcatheter group. However, no significant difference in fever incidence was observed (OR: 2.57, 95% CI: 0.90-7.34, p=0.08). Furthermore, length of hospital stay was notably shorter in the pediatric transcatheter group (mean difference [MD]: 4.00, 95% CI: 1.71-6.29, p=0.0006). Regarding efficacies, both groups demonstrated similar rates of successful closure (OR: 1.97, 95% CI: 0.56-6.92, p=0.29) and residual shunting (OR: 0.55, 95% CI: 0.17-1.77, p=0.31) in the pediatric cohort. Subgroup analyses revealed that surgical residual shunting was notably lower in the European pediatric population (OR: 0.18, 95% CI: 0.07-0.45, p=0.0002), in cases with ASD size exceeding 15 mm (OR: 0.19, 95% CI: 0.08-0.49, p=0.0006), and in pediatric patients younger than 8 years (OR: 0.33, 95% CI: 0.12-0.92, p=0.03). Interestingly, residual shunting involving complex ASD with rim deficiency was more pronounced in the surgery group (OR: 2.66, 95% CI: 1.33-5.32, p=0.006). Both surgical and transcatheter closures are equally effective, with transcatheter closure showing significantly fewer complications. This meta-analysis offers pivotal insights for clinicians grappling with the optimal approach to pediatric ostium secundum ASD closure. The observed higher incidence of cardiac arrhythmias, pericardial effusions, and pulmonary complications in surgical closures underscores the challenges associated with this modality. In contrast, transcatheter closure, with its comparable efficacy and shorter hospital stays, emerges as an appealing and less invasive alternative. These findings equip clinicians with evidence to make informed decisions, optimizing patient outcomes. Subgroup analyses further refine recommendations, emphasizing tailored considerations for European pediatric patients, larger ASDs, and those under 8 years old, ultimately fostering personalized and improved care strategies.

Fragility of overactive bladder medication clinical trials: A systematic review.

Overactive bladder (OAB) syndrome significantly impairs quality of life, often necessitating pharmacological interventions with associated risks. The fragility of OAB trial outcomes, as measured by the fragility index (FI: smallest number of event changes to reverse statistical significance) and quotient (FQ: FI divided by total sample size expressed as a percentage), is critical yet unstudied. We conducted a systematic search for randomized controlled trials on OAB medications published between January 2000 and August 2023. Inclusion criteria were trials with two parallel arms reporting binary outcomes related to OAB medications. We extracted trial details, outcomes, and statistical tests employed. We calculated FI and FQ, analyzing associations with trial characteristics through linear regression. We included 57 trials with a median sample size of 211 participants and a 12% median lost to follow-up. Most studies investigated anticholinergics (37/57, 65%). The median FI/FQ was 5/3.5%. Larger trials were less fragile (median FI 8; FQ 1.0%) compared to medium (FI: 4; FQ 2.5%) and small trials (FI: 4; FQ 8.3%). Double-blinded studies exhibited higher FQs (median 2.9%) than unblinded trials (6.7%). Primary and secondary outcomes had higher FIs (median 5 and 6, respectively) than adverse events (FI: 4). Each increase in 10 participants was associated with a +0.19 increase in FI (p < 0.001). A change in outcome for a median of five participants, or 3.5% of the total sample size, could reverse the direction of statistical significance in OAB trials. Studies with larger sample sizes and efficacy outcomes from blinded trials were less fragile.

One-year initial efficacy and safety outcomes of the premounted dry-pericardium Vienna self-expandable transcatheter aortic valve system: A first-in-human VIVA feasibility study.

The dry-pericardium Vienna transcatheter aortic valve system is repositionable and retrievable, already premounted on the delivery system, eliminating the need for assembly and crimping of the device before valve implantation. The VIVA first-in-human feasibility study, a prospective, nonrandomized, single-center trial, evaluated the Vienna aortic valve in 10 patients with severe symptomatic aortic stenosis, who were at intermediate or high surgical risk. This study, registered at ClinicalTrials.gov (NCT04861805), focused on the safety, feasibility, clinical and hemodynamic performance of the Vienna system up to 1-year follow-up. The mean patient age was 79 ± 5 years, 60% male. Valve sizes used: 26 mm (10%), 29 mm (30%), 31 mm (60%). Key hemodynamic improvements were significant: mean aortic valve pressure gradient (mmHg) decreased from 48.7 to 8.1, aortic valve area (cm2) increased from 0.75 to 1.91, and maximum jet velocity through the aortic valve (m/s) decreased from 4.41 to 1.95 (p < 0.0001). No moderate/severe paravalvular leakage was observed, and computed tomography scans revealed no evidence of hypo-attenuated leaflet thickening. The study recorded one life-threatening bleeding event, two cases requiring postprocedural pacemaker implantation, and three ischemic events, with only one causing lasting neurological impairment. Importantly, there were no cases of cardiovascular mortality and only one noncardiovascular death, which was confirmed as unrelated to the device. The study indicates the Vienna valve as a potential option for severe symptomatic aortic stenosis, designed to streamline the procedure and potentially lower healthcare costs by reducing resource and equipment needs, also procedural errors. Further research is essential to thoroughly evaluate its safety and efficacy.

Randomized Phase II Trial of Imiquimod with or without 9-Valent HPV Vaccine versus Observation in Patients with High-grade Pre-neoplastic Cervical Lesions (NCT02864147).

We report the results of a randomized phase II trial of imiquimod, a topical immune-response modulator versus imiquimod plus a 9-valent human papillomavirus (HPV) vaccine (9vHPV) versus clinical surveillance in cervical intraepithelial neoplasia (CIN2/3) patients. We randomly allocated 133 patients with untreated CIN2/3 in equal proportions to a 4-month treatment with self-applied vaginal suppositories containing imiquimod (Arm B) or imiquimod plus a 9vHPV (Arm C) versus clinical surveillance (Arm A). The main outcome was efficacy, defined as histologic regression to CIN1 or less. Secondary outcomes were HPV clearance and tolerability. Exploratory objectives included the comparison of cervical CD4/CD8 T-cell infiltration at baseline, mid-study, and posttreatment by flow cytometry among study arms. Of the 114 evaluable patients 77% and 23% harbored CIN2 and CIN3, respectively. Regression to CIN1 or less was observed in 95% of patients in the imiquimod group (Arm B) compared with 79% in the control/surveillance (Arm A); P = 0.043 and 84% in the imiquimod+9vHPV group (Arm C; P = 0.384 vs. Arm A). Neither of the treatment-arm differences from Arm A reached the prespecified α = 0.025 significance level. No significant differences were noted in the secondary outcome of rate of HPV clearance. The number of tissue-resident memory CD4/CD8 T cells in cytobrush samples demonstrated a >5-fold increase in Arm B/imiquimod when compared with Arm A/surveillance (P < 0.01). In contrast, there was no significant difference in T-cell responses among participants in Arm C when compared with Arm A. Imiquimod treatment was well tolerated. Although imiquimod induced a higher regression to CIN1 or less and significant increases in CD4/CD8 T cells infiltrating the cervix, it did not meet its prespecified statistical outcome for efficacy. A higher regression rate than expected was observed in the surveillance arm of this prospective trial. Future clinical trials with imiquimod targeting CIN3 patients are warranted.

Etidronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women.

Osteoporosis is an abnormal reduction in bone mass and bone deterioration, leading to increased fracture risk. Etidronate belongs to the bisphosphonate class of drugs which act to inhibit bone resorption by interfering with the activity of osteoclasts - bone cells that break down bone tissue. This is an update of a Cochrane review first published in 2008. For clinical relevance, we investigated etidronate's effects on postmenopausal women stratified by fracture risk (low versus high). To assess the benefits and harms of intermittent/cyclic etidronate in the primary and secondary prevention of osteoporotic fractures in postmenopausal women at lower and higher risk of fracture, respectively. We searched the Cochrane Central Register of Control Trials (CENTRAL), MEDLINE, Embase, two clinical trial registers, the websites of drug approval agencies, and the bibliographies of relevant systematic reviews. We identified eligible trials published between 1966 and February 2023. We included randomized controlled trials that assessed the benefits and harms of etidronate in the prevention of fractures for postmenopausal women. Women in the experimental arms must have received at least one year of etidronate, with or without other anti-osteoporotic drugs and concurrent calcium/vitamin D. Eligible comparators were placebo (i.e. no treatment; or calcium, vitamin D, or both) or another anti-osteoporotic drug. Major outcomes were clinical vertebral, non-vertebral, hip, and wrist fractures, withdrawals due to adverse events, and serious adverse events. We classified a study as secondary prevention if its population fulfilled one or more of the following hierarchical criteria: a diagnosis of osteoporosis, a history of vertebral fractures, a low bone mineral density T-score (≤ -2.5), or aged 75 years or older. If none of these criteria were met, we considered the study to be primary prevention. We used standard methodological procedures expected by Cochrane. The review has three main comparisons: (1) etidronate 400 mg/day versus placebo; (2) etidronate 200 mg/day versus placebo; (3) etidronate at any dosage versus another anti-osteoporotic agent. We stratified the analyses for each comparison into primary and secondary prevention studies. For major outcomes in the placebo-controlled studies of etidronate 400 mg/day, we followed our original review by defining a greater than 15% relative change as clinically important. For all outcomes of interest, we extracted outcome measurements at the longest time point in the study. Thirty studies met the review's eligibility criteria. Of these, 26 studies, with a total of 2770 women, reported data that we could extract and quantitatively synthesize. There were nine primary and 17 secondary prevention studies. We had concerns about at least one risk of bias domain in each study. None of the studies described appropriate methods for allocation concealment, although 27% described adequate methods of random sequence generation. We judged that only 8% of the studies avoided performance bias, and provided adequate descriptions of appropriate blinding methods. One-quarter of studies that reported efficacy outcomes were at high risk of attrition bias, whilst 23% of studies reporting safety outcomes were at high risk in this domain. The 30 included studies compared (1) etidronate 400 mg/day to placebo (13 studies: nine primary and four secondary prevention); (2) etidronate 200 mg/day to placebo (three studies, all secondary prevention); or (3) etidronate (both dosing regimens) to another anti-osteoporotic agent (14 studies: one primary and 13 secondary prevention). We discuss only the etidronate 400 mg/day versus placebo comparison here. For primary prevention, we collected moderate- to very low-certainty evidence from nine studies (one to four years in length) including 740 postmenopausal women at lower risk of fractures. Compared to placebo, etidronate 400 mg/day probably results in little to no difference in non-vertebral fractures (risk ratio (RR) 0.56, 95% confidence interval (CI) 0.20 to 1.61); absolute risk reduction (ARR) 4.8% fewer, 95% CI 8.9% fewer to 6.1% more) and serious adverse events (RR 0.90, 95% CI 0.52 to 1.54; ARR 1.1% fewer, 95% CI 4.9% fewer to 5.3% more), based on moderate-certainty evidence. Etidronate 400 mg/day may result in little to no difference in clinical vertebral fractures (RR 3.03, 95% CI 0.32 to 28.44; ARR 0.02% more, 95% CI 0% fewer to 0% more) and withdrawals due to adverse events (RR 1.41, 95% CI 0.81 to 2.47; ARR 2.3% more, 95% CI 1.1% fewer to 8.4% more), based on low-certainty evidence. We do not know the effect of etidronate on hip fractures because the evidence is very uncertain (RR not estimable based on very low-certainty evidence). Wrist fractures were not reported in the included studies. For secondary prevention, four studies (two to four years in length) including 667 postmenopausal women at higher risk of fractures provided the evidence. Compared to placebo, etidronate 400 mg/day may make little or no difference to non-vertebral fractures (RR 1.07, 95% CI 0.72 to 1.58; ARR 0.9% more, 95% CI 3.8% fewer to 8.1% more), based on low-certainty evidence. The evidence is very uncertain about etidronate's effects on hip fractures (RR 0.93, 95% CI 0.17 to 5.19; ARR 0.0% fewer, 95% CI 1.2% fewer to 6.3% more), wrist fractures (RR 0.90, 95% CI 0.13 to 6.04; ARR 0.0% fewer, 95% CI 2.5% fewer to 15.9% more), withdrawals due to adverse events (RR 1.09, 95% CI 0.54 to 2.18; ARR 0.4% more, 95% CI 1.9% fewer to 4.9% more), and serious adverse events (RR not estimable), compared to placebo. Clinical vertebral fractures were not reported in the included studies. This update echoes the key findings of our previous review that etidronate probably makes or may make little to no difference to vertebral and non-vertebral fractures for both primary and secondary prevention.

B-Cell Depletion and Efficacy Outcomes of Ofatumumab Are Consistent Across Different Body Mass Index Categories: Insights from ASCLEPIOS I and II Trials (P9-6.002)

B-Cell Depletion and Efficacy Outcomes of Ofatumumab Are Consistent Across Different Body Mass Index Categories: Insights from ASCLEPIOS I and II Trials (P9-6.002)

Early REperfusion Therapy with Intravenous Alteplase for Recovery of VISION in Acute Central Retinal Artery Occlusion (REVISION): Study Protocol of a Phase III Trial.

Meta-analyses of case series of non-arteritic central retinal artery occlusion (CRAO) indicate beneficial effects of intravenous thrombolysis when initiated early after symptom onset. Randomized data is lacking to address this question. REVISION investigates intravenous alteplase within 4.5 hours of monocular vision loss due to acute CRAO. Randomized (1:1), double-blind, placebo-controlled, multicenter adaptive phase III trial. Primary outcome is functional recovery to normal or mildly impaired vision in the affected eye defined as best corrected visual acuity of the Logarithm of the Minimum An-gle of Resolution of 0.5 or less at 30 days (intention-to-treat analysis). Secondary efficacy out-comes include modified Rankin Score at 90 days and quality of life. Safety outcomes include symptomatic intracranial hemorrhage, major bleeding (International Society on Thrombosis and Haemostasis definition) and mortality. Exploratory analyses of optical coherence tomogra-phy/angiography, ultrasound and MRI biomarkers will be conducted. Using an adaptive design with interim analysis at 120 patients, up to 422 participants (211 per arm) would be needed for 80% power (one-sided alpha 0.025) to detect a difference of 15%, assuming functional recovery rates of 10% in the placebo arm and 25% in the alteplase arm. By enrolling patients within 4.5 hours of CRAO onset, REVISION uses insights from meta-analyses of CRAO case series and randomized thrombolysis trials in acute ischemic stroke. Increased rates of early reperfusion and good neurological outcomes in stroke may trans-late to CRAO with its similar pathophysiology. ClinicalTrials.gov: NCT04965038; EU Trial Number: 2023-507388-21-00.

Consistent efficacy outcomes between phase 2 and phase 3 trialsin Crohn's disease or ulcerative colitis in adults: a meta-analysis.

The approval of novel biologic agents and small molecules for the treatment of Crohn's disease (CD) and ulcerative colitis (UC) is dependent on phase 3 randomized controlled trials (RCTs). However, these trials sometimes fail to achieve the expected efficacy outcomes observed in phase 2 trials. We conducted a systematic review of RCTs that evaluated biologic agents and small molecules using paired regimens in both phase 2 and phase 3. We searched Medline, EMBASE, and Cochrane databases up until February 13, 2024. The revised Cochrane tool was utilized to assess the risk of bias. A generalized linear mixed-effects model (GLMM) was employed to estimate the odds ratios (ORs) for efficacy outcomes in phase 2 trials compared to phase 3. We identified a total of 23 trials with 10 paired regimens for CD and 30 trials with 11 paired regimens for UC. The GLMM analysis revealed that phase 2 CD trials had higher outcomes measured by the Crohn's Disease Activity Index (CDAI) by 9-13% without statistical significance: CDAI-150: OR, 1.12 (95% CI 0.83-1.51, p = 0.41); CDAI-100: OR, 1.09 (95% CI 0.88-1.35, p = 0.40); or CDAI-70: OR, 1.13 (95% CI 0.61-2.08, p = 0.66). For UC, two efficacy outcomes were estimated to be equally reported in phase 2/phase 3 pairs: clinical remission: OR, 1.00 (95% CI 0.83-1.20, p = 0.96); endoscopic improvement: OR, 0.98 (95% CI 0.83-1.15, p = 0.79). However, the rate of clinical response was underestimated in phase 2 by 19%: OR, 0.81 (95% CI 0.70-0.95, p = 0.03). The inclusion criterion for the type of Mayo score for UC had a significant interaction with the study phase to influence the difference in clinical response (p = 0.002). Our findings suggest that the main efficacy outcomes for CD and UC remain consistent between phase 2 and phase 3 trials, except for UC response rates. The efficacy data obtained from phase 2 trials can be considered reliable for the design of subsequent phase 3 trials. PROSPERO (CRD42023407947).

Evaluation of the safety and efficacy of peripheral vasopressors to decrease central line placement and associated bloodstream infections

Background In 2020, as a result of evidence of demonstrated safety of an initial pilot program, our institution set out to implement a peripheral vasopressor infusion protocol. Objective To evaluate the use of peripheral lines for vasopressor administration to reduce placement of unnecessary central lines and central line days. Methods This is an Institutional Review Board approved, single center retrospective chart review conducted as pre/post-analysis. Our hospital is a quaternary care, level 1 trauma center in Hartford, Connecticut that serves 100,000-120,000 patients annually. Patients &gt;18 years admitted to an intensive care unit (ICU) were included if meeting protocol specific inclusion criteria pertaining to moderate expected duration and dose of vasopressor. Patients were excluded if vasculature not supportive of placement of two peripheral intravenous (PIV) sites, PIV sites without brisk blood return, had a limb restriction, or metacarpal line. All analyses were conducted with SPSS v. 26 (IBM; Armonk, NY 2019), using an a priori alpha level of 0.05 such that all results yielding p &lt; .05 were deemed statistically significant. Primary efficacy outcomes of this study are number of central lines placed and number of central line days. The primary safety outcome is the number of extravasation events attributed to peripheral administration of vasopressors. Results Overall, 146 patients avoided central line placement constituting a 58.4% ( p &lt; .001) decrease in central line placement with peripheral vasopressor use. Out of 382 administrations there were a total of 14 extravasation events that occurred with peripheral vasopressor use in the post-intervention group. Implementation was associated with a statistically significant reduction in CLABSI occurrence. Conclusions The results of this analysis demonstrate that vasopressors can peripherally administered safely, when proximal to the antecubital fossa, at lower doses, and for short durations of infusion with minimal adverse events.

Abstract CT062: A phase 1 study of tamnorzatinib (ONO-7475), an Axl/Mer dual inhibitor, alone and in combination with nivolumab in patients with advanced or metastatic solid tumors

Abstract Background: Tamnorzatinib (ONO-7475) is an orally active small molecule Axl/Mer dual inhibitor that not only directly acts on cancer cells to suppress their proliferation, but also on immune cells and exerts characteristics of cancer immunotherapy. Methods: We performed a phase 1 study to assess the tolerability, safety, and pharmacokinetics of ONO-7475 alone (Part A) and in combination with nivolumab (NIVO) (Part B) in Japanese patients (pts) with advanced or metastatic solid tumors (NCT03730337). Patients received once-daily ONO-7475 (3-10 mg, orally) as a monotherapy or in combination with NIVO (240 mg, i.v., every 2 weeks). Results: Twelve pts in both Part A and Part B (three each at 3 and 6 mg, and six at 10 mg ONO-7475) received the study treatment. Baseline characteristics, safety, and efficacy outcomes are summarized in the Table. While one of six pts in the Part B 10-mg cohort developed dose-limiting toxicities of grade 4 nephritis, grade 3 colitis, and grade 3 hepatic function abnormal, no others did. In biomarker analyses, activation of T cell function and an increase in T cell number, an increase in inflammatory (M1) macrophages/immunosuppressive (M2) macrophages ratio, and suppression of epithelial-to-mesenchymal transition were observed after treatment. Conclusion: ONO-7475 was tolerated at repeated once-daily oral doses up to 10 mg as a monotherapy and in combination with NIVO in pts with advanced or metastatic solid tumors. TABLE 1. NAND Table. Baseline Characteristics, Safety Outcomes, and Efficacy Outcomes Part A (ONO-7475 alone) N = 12 Part B (ONO-7475 + NIVO) N = 12 Baseline Characteristics Median age, years (range) 63.5 (31–76) 56.0 (39–72) Female, n (%) 8 (66.7) 9 (75.0) ECOG PS, n (%) 0 8 (66.7) 10 (83.3) 1 4 (33.3) 2 (16.7) Safety Outcomes Number of patients with AEs (%) Any grade 11 (91.7) 11 (91.7) Glade ≥3 0 2 (16.7) *2 Number of patients with SAEs (%) 2 (16.7) *1 1 (8.3) *3 *1 Pyrexia and diverticulitis (1 patient each) *2 Grade 4 neutrophil count decreased (1 patient), grade 4 lymphocyte count decreased and nephritis (1 patient each), and grade 3 colitis, enterocolitis infectious, device related infection, anemia, hyperglycemia, and hepatic function abnormal (1 patient) *3 Colitis, hepatic function abnormal, and nephritis Efficacy Outcomes Objective Response Rate, n (%) [95% CI] 0 [0.0, 26.5] 1 (8.3) [0.2, 38.5] Disease Control Rate, n (%) [95% CI] 3 (25.0) [5.5, 57.2] 4 (33.3) [9.9, 65.1] Best Overall Response, n (%) [95% CI] Complete Response 0 [0.0, 26.5] 0 [0.0, 26.5] Partial Response 0 [0.0, 26.5] 1 (8.3) [0.2, 38.5] Stable Disease 3 (25.0) [5.5, 57.2] 3 (25.0) [5.5, 57.2] Progressive Disease 9 (75.0) 5 (41.7) Not Evaluable 0 3 (25.0) Median OS, months [95% CI] 12.21 [4.93, not reached] 16.99 [5.98, not reached] Median PFS, months [95% CI] 1.86 [0.92, 3.84] 2.17 [0.95, 3.78] Citation Format: Yuki Katsuya, Kan Yonemori, Toshio Shimizu, Takafumi Koyama, Sigehisa Kitano, Kazuki Sudo, Shunsuke Kondo, Jun Sato, Hiroaki Hozumi, Noboru Yamamoto. A phase 1 study of tamnorzatinib (ONO-7475), an Axl/Mer dual inhibitor, alone and in combination with nivolumab in patients with advanced or metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT062.

Advancements in Aesthetic Breast Augmentation: Evaluating the Safety, Efficacy, and Naturalistic Outcomes of Ergonomix2 Implants.

This pioneering study evaluates the safety, efficacy, and Aesthetic outcomes of Ergonomix2 Motiva Ergonomic Implants in breast augmentation. It aims to assess their capability to offer more natural touch and dynamics, delineate the learning curve for surgical techniques, and examine their safety profile compared to Ergonomix1 implants. A prospective cohort study was conducted, comparing 31 patients who received Ergonomix2 implants with a control group of 51 patients with Ergonomix1 implants. Eligible patients were those seeking Aesthetic breast augmentation without prior surgeries or chronic illnesses. Detailed documentation of surgical techniques, implant characteristics, and patient demographics was performed. The study assessed surgical learning curve, implant positioning accuracy, and short-term and early complications. Aesthetic outcomes were evaluated using the BreastQ questionnaire and quantitative elastography. Patients with Ergonomix2 implants showed significant improvements in Aesthetic outcomes, including breast contour symmetry and natural feel. The learning curve demonstrated a decrease in surgical time and higher implant positioning accuracy. The safety profile was favorable, with a low complication rate and high patient satisfaction levels. Ergonomix2 implants exhibited enhanced softness and pliability, closely mimicking natural breast tissue, as confirmed by elastographic analyzes. Ergonomix2 implants represent a significant advancement in Aesthetic breast surgery, offering natural-feeling and dynamically adaptable outcomes. Despite the promising results, the need for specialized surgical techniques and further research on long-term safety and efficacy is emphasized. This study contributes foundational knowledge to the field of ergonomic breast implants and their application in modern plastic surgery. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Abstract CT137: Efficacy and immunological outcomes of non-fucosylated anti-CTLA-4 (BMS-986218) + degarelix acetate vs. degarelix acetate alone in men with high-risk localized prostate cancer (Neo-Red-P)

Abstract Background: Men with high-risk localized prostate cancer are at significant risk for disease recurrence and there is currently no role for neoadjuvant therapy. Although androgen deprivation therapy (ADT) is immunomodulatory and can increase CD8 T cell infiltration, these effects are counterbalanced by the expansion of suppressive regulatory T cells (Tregs). We therefore designed a correlative-rich clinical trial for men with high-risk localized prostate cancer to test whether BMS-986218 - a novel afucosylated anti-CTLA-4 antibody optimized for antibody-dependent cell-mediated cytotoxicity (ADCC) - depletes Tregs and augments response to ADT. Methods: Neo-Red-P is a single-center, two-arm, open-label pilot study assessing degarelix (ADT) versus ADT + anti-CTLA-4-NF (BMS-986218) in patients with treatment naïve high-risk localized prostate cancer. Key eligibility criteria included histologically confirmed adenocarcinoma with Gleason sum of ≥4+3 and clinical stage T1c-T3bN0M0. All patients received degarelix (ADT; 240mg SQ) 2 weeks before radical prostatectomy (RP). Patients were randomized to Arm A (ADT only), or Arm B (ADT + BMS-986218 [20mg IV] 2 doses Q2w starting 3 weeks before RP). The primary endpoint was the safety and feasibility of neoadjuvant BMS-986218 in prostate cancer. Secondary endpoints included the pathologic complete response rate, rate of undetectable PSA at 12 months, PSA response rate (&amp;gt;50% decrease pre-RP), and time-to-PSA recurrence. Fresh tumor specimens were collected at RP for single-cell RNA-sequencing, cytometry by time-of-flight, next-generation sequencing, and multiplex immunofluorescence. A treatment naïve cohort of matching demographic and pathological characteristics was collected for comparative analysis (n=14). Results: Between February 26, 2020, and November 15, 2022, 24 patients were enrolled. Severe treatment-related adverse events (TRAE; Grade ≥ 3) were rare in both arms; 0% in the ADT alone arm and 4% in the combination arm, suggesting a tolerable safety profile with the addition of BMS-986218. In the combination arm, 54% of subjects achieved a 50% reduction in PSA versus 33% in the ADT alone arm. In the ADT alone arm, 80% of patients had an undetectable PSA at 12 months, with a median recurrence-free survival of 1.61 years (IQR: 1.50-1.99 years). In the combination group, 75% had an undetectable PSA at 12 months, with a median recurrence-free survival of 1.82 years (IQR: 0.89-2.07 years). The overall recurrence rate in patients treated with combination therapy was 25% (3 of 12 patients) versus 20% (2 of 10 patients) in the ADT alone arm. Correlative studies suggest that aCTLA4-NF mitigates ADT-induced Treg accumulation through enhanced Fc receptor activity and augmented CTL activation, indicating an enhanced anti-tumor response with combination therapy. Conclusions: The neoadjuvant combination of ADT + aCTLA-4-NF (BMS-986218) is feasible, well tolerated, and induces significant remodeling of the immune TME through enhanced Fc receptor and CTL activity. Rates of disease recurrence following surgery were low in this high-risk population, warranting further investigation of combination immuno-hormonal therapy in the neoadjuvant setting for high-risk prostate cancer. Clinical Trial Information: NCT04301414 Citation Format: Patrick J. McCann, Casey R. Ager, Aleksandar Z. Obradovic, Matthew G. Chaimowitz, Samuel Pan, Caroline J. Laplaca, Parin Shah, Renu K. Virk, Christopher B. Anderson, Catherine S. Spina, Karie D. Runcie, Mark N. Stein, Charles G. Drake, Matthew C. Dallos. Efficacy and immunological outcomes of non-fucosylated anti-CTLA-4 (BMS-986218) + degarelix acetate vs. degarelix acetate alone in men with high-risk localized prostate cancer (Neo-Red-P) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT137.