Parallel Cohort Research Articles

Socioeconomic disadvantage and polygenic risk of overweight in early and mid-life: a longitudinal population cohort study spanning 12 years

We describe BMI by socioeconomic disadvantage and by polygenic risk in parallel cohorts of children and adults (their parents). We examine whether hypothetically intervening to reduce childhood disadvantage could reduce adolescent obesity. From a population-based cohort (N=5107) with a mixed design (survey and direct assessment), 24-31% had genotype data: 1607 children (50% male) followed biennially from age 2-3 to 14-15; 2406 adults (36% male) followed from mean age 35-47 years. Exposures were polygenic risk score for BMI, and neighbourhood- and family-level socioeconomic disadvantage categorised as 'most' (top two cohort-specific quintiles), 'average', or 'least' disadvantage (bottom two quintiles). We explored trends in estimated BMI and risk of overweight/obesity by disadvantage, stratified by polygenic risk. We used generalised linear regression to estimate the reduction in overweight/obesity at 14-15 years in children living in 'least/average disadvantage' in early childhood relative to those in 'most disadvantage', adjusted for confounders. Causal effect estimates were obtained separately for children with higher and lower polygenic risk. A positive trend between disadvantage and overweight/obesity was most apparent among participants with high polygenic risk. Among children with higher polygenic risk (n=805), hypothetical target trial results imply that intervening to lessen population-wide neighbourhood disadvantage from most to least disadvantage could reduce adolescent overweight/obesity by 32% (risk ratio (RR) 0.68, 95% CI 0.50-0.92), or by 42% if intervening to lessen family disadvantage (RR 0.58, 95% CI 0.42-0.79). Positive effects were smaller when isolating the population to those with lower polygenic risk (7-17%), and for the whole population, regardless of polygenic risk (25-39%). Children at higher polygenic risk of obesity suffer disproportionate BMI impacts of disadvantage. At the population-level, and especially for those with higher polygenic risk, tackling disadvantage could potentially reduce obesity and associated morbidity, mortality, and costs. Australian National Health and Medical Research Council. Funding information is detailed in the funding statement.

Enhancing puncture skills training with generative AI and digital technologies: a parallel cohort study.

Traditional puncture skills training for refresher doctors faces limitations in effectiveness and efficiency. This study explored the application of generative AI (ChatGPT), templates, and digital imaging to enhance puncture skills training. 90 refresher doctors were enrolled sequentially into 3 groups: traditional training; template and digital imaging training; and ChatGPT, template and digital imaging training. Outcomes included theoretical knowledge, technical skills, and trainee satisfaction measured at baseline, post-training, and 3-month follow-up. The ChatGPT group increased theoretical knowledge scores by 17-21% over traditional training at post-training (81.6 ± 4.56 vs. 69.6 ± 4.58, p < 0.001) and follow-up (86.5 ± 4.08 vs. 71.3 ± 4.83, p < 0.001). It also outperformed template training by 4-5% at post-training (81.6 ± 4.56 vs. 78.5 ± 4.65, p = 0.032) and follow-up (86.5 ± 4.08 vs. 82.7 ± 4.68, p = 0.004). For technical skills, the ChatGPT (4.0 ± 0.32) and template (4.0 ± 0.18) groups showed similar scores at post-training, outperforming traditional training (3.6 ± 0.50) by 11% (p < 0.001). At follow-up, ChatGPT (4.0 ± 0.18) and template (4.0 ± 0.32) still exceeded traditional training (3.8 ± 0.43) by 5% (p = 0.071, p = 0.026). Learning curve analysis revealed fastest knowledge (slope 13.02) and skill (slope 0.62) acquisition for ChatGPT group over template (slope 11.28, 0.38) and traditional (slope 5.17, 0.53). ChatGPT responses showed 100% relevance, 50% completeness, 60% accuracy, with 15.9s response time. For training satisfaction, ChatGPT group had highest scores (4.2 ± 0.73), over template (3.8 ± 0.68) and traditional groups (2.6 ± 0.94) (p < 0.01). Integrating AI, templates and digital imaging significantly improved puncture knowledge and skills over traditional training. Combining technological innovations and AI shows promise for streamlining complex medical competency mastery.

Accelerating adverse pregnancy outcomes research amidst rising medication use: parallel retrospective cohort analyses for signal prioritization

BackgroundPregnant women are significantly underrepresented in clinical trials, yet most of them take medication during pregnancy despite the limited safety data. The objective of this study was to characterize medication use during pregnancy and apply propensity score matching method at scale on patient records to accelerate and prioritize the drug effect signal detection associated with the risk of preterm birth and other adverse pregnancy outcomes.MethodsThis was a retrospective study on continuously enrolled women who delivered live births between 2013/01/01 and 2022/12/31 (n = 365,075) at Providence St. Joseph Health. Our exposures of interest were all outpatient medications prescribed during pregnancy. We limited our analyses to medication that met the minimal sample size (n = 600). The primary outcome of interest was preterm birth. Secondary outcomes of interest were small for gestational age and low birth weight. We used propensity score matching at scale to evaluate the risk of these adverse pregnancy outcomes associated with drug exposure after adjusting for demographics, pregnancy characteristics, and comorbidities.ResultsThe total medication prescription rate increased from 58.5 to 75.3% (P < 0.0001) from 2013 to 2022. The prevalence rate of preterm birth was 7.7%. One hundred seventy-five out of 1329 prenatally prescribed outpatient medications met the minimum sample size. We identified 58 medications statistically significantly associated with the risk of preterm birth (P ≤ 0.1; decreased: 12, increased: 46).ConclusionsMost pregnant women are prescribed medication during pregnancy. This highlights the need to utilize existing real-world data to enhance our knowledge of the safety of medications in pregnancy. We narrowed down from 1329 to 58 medications that showed statistically significant association with the risk of preterm birth even after addressing numerous covariates through propensity score matching. This data-driven approach demonstrated that multiple testable hypotheses in pregnancy pharmacology can be prioritized at scale and lays the foundation for application in other pregnancy outcomes.

Anti–Programmed Death Ligand 1 Plus Targeted Therapy in Anaplastic Thyroid Carcinoma

Anaplastic thyroid carcinoma (ATC) is a rare and lethal cancer. Although progress has been made in recent years in patients with mutated BRAF tumors, those who respond initially eventually die of their disease; furthermore, there are no approved therapies for non-BRAF mutated tumors. To determine whether treatment with matched-targeted therapy plus immune checkpoint inhibitors were associated with improved overall survival (OS). A phase 2 trial at a single center, tertiary institution with parallel cohorts, assigning treatment with targeted therapy according to the tumor mutation status. Patients with mutated BRAF V600E tumors received vemurafenib/cobimetinib plus atezolizumab (cohort 1); those with mutated RAS (NRAS, KRAS, or HRAS) or NF1/2 tumors received cobimetinib plus atezolizumab (cohort 2). Patients without any of these variants were assigned to receive bevacizumab plus atezolizumab (cohort 3). Patients were enrolled from August 3, 2017, to July 7, 2021. All consecutive, systemic therapy-naive patients with ATC with active disease and who met eligibility criteria were considered for participation. The analysis was conducted in September 2023. Patients were assigned to targeted therapy based on the driver mutation as follow: BRAF V600E (cohort 1, vemurafenib plus cobimetinib), RAS/NF (cohort 2, cobimetinib), or non-BRAF/RAS/NF (cohort 3, bevacizumab). All received atezolizumab. The primary outcome of the study was median OS of the entire targeted therapy cohort, compared with historical median OS of 5 months. Forty-three patients with ATC were enrolled in the targeted therapy cohorts, of which 42 were included in the primary analysis. The median OS in patients across these 3 cohorts was 19 months (95% CI, 7.79-43.24). Median OS and progression-free survival per cohort were as follows: cohort 1: 43 months (95% CI, 16-not estimable [NE]), 13.9 months (6.6-64.1); cohort 2: 8.7 months (95% CI, 5.1-37.0) and 4.8 months (1.8-14.7); cohort 3 (vascular endothelial growth factor inhibitor group): 6.21 months (4.1-NE) and 1.3 months (1.3-NE), respectively. In this nonrandomized clinical trial, atezolizumab combined with targeted therapy resulted in a longer median OS than historical landmark, achieving the study's primary end point, with cohort 1 achieving the longest OS. ClinicalTrials.gov Identifier: NCT03181100.

Indocyanine green in left side colorectal surgery segmental resection to decrease anastomotic leak: A parallel retrospective cohort study of 115 patients

BackgroundWe investigated the impact of Indocyanine Green (ICG) angiography on reducing anastomotic leakage (AL) after elective left segmental colon resection, including transverse resection. While ICG is widely used in colorectal surgery to assess vascularization, its true effect on AL, particularly in left segmental resections, remains unclear. Study designThis retrospective, monocentric cohort study included patients undergoing left and transverse colon resection from January 2017 to July 2023. Patients were divided into ICG and no-ICG groups. The primary outcome was AL, with secondary outcomes including postoperative morbidity and length of stay. ResultsOf the 115 patients enrolled, 53 received ICG and 63 did not. AL occurred in 6 patients in the no-ICG group, but none in the ICG group. No significant correlation was found between ICG use and other confounding factors. Postoperative length of stay was also shorter in the ICG group. ConclusionsThe use of ICG was associated with a reduction in AL, with no cases in the ICG group. These findings suggest a potential benefit of ICG, warranting confirmation in future large-scale studies. Clinical trial registrationclinicaltrial.gov (NCT05981937).

Effectiveness of Eupatorium Perfoliatum 30C in Preventing Dengue Fever-A Prospective, Community-Based, Open Label, Parallel Cohort Study in Delhi, India.

The study was undertaken to evaluate the protective effect of Eupatorium perfoliatum (EP) 30C on the incidence of dengue fever. This study was designed as a prospective, open label, parallel cohort study. Participants were enrolled in two medicine cohort (MC) communities and one control cohort (CC) community. Participants in MC who were more than 5 years of age received four medicated globules and those aged between 1 and 5 years received two medicated globules of EP 30C once a week for 10 weeks. Participants in CC received no medical intervention. Both cohorts received information and educational material regarding dengue. The primary outcome was incidence of dengue cases based on laboratory confirmation or the clinical definition of dengue as per the case definition notified by the National Vector-Borne Disease Control Program, Government of India, during the 14 weeks of intervention and observation. The analysis included 20,607 participants residing in three slums of Delhi, of which MC and CC included 15,298 and 5,309 participants respectively. The overall protective effect of EP 30C in MC against probable/laboratory-confirmed dengue was 59.59% (95% confidence interval [CI], 50.74 to 66.85, p = 0.0001). The overall protective effect of EP 30C against laboratory-confirmed dengue was 72.78% (95% CI, 54.45 to 83.74, p = 0.0001): 26 cases per 15,298 (0.13 per 1,000 person-weeks) in MC versus 33 cases per 5,309 (0.46 per 1,000 person-weeks) in CC. The use of EP 30C was associated with some protection against probable and laboratory-confirmed dengue.

Efficacy and Safety of Admilparant, an LPA1 Antagonist in Pulmonary Fibrosis: A Phase 2 Randomized Clinical Trial.

Idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF) have high morbidity and mortality; thus, novel treatments are needed. Assess efficacy and safety of admilparant (BMS-986278), an oral lysophosphatidic acid receptor 1 antagonist, in patients with IPF and PPF. This phase 2, randomized, double-blind, placebo-controlled trial included parallel cohorts of patients with IPF (n = 278 randomized, n = 276 treated) or PPF (n = 125 randomized, n = 123 treated) who received 30-mg admilparant, 60-mg admilparant, or placebo (1:1:1) twice daily for 26 weeks. Background antifibrotics (both cohorts) and immunosuppressants (PPF only) were permitted. Rates of change in percentage of predicted forced vital capacity (ppFVC) over 26 weeks for IPF were -2.7% (placebo), -2.8% (30-mg), and -1.2% (60-mg) and for PPF were -4.3% (placebo), -2.9% (30-mg), and -1.1% (60-mg). Treatment differences between 60-mg admilparant and placebo were 1.4% (95% CI, -0.1 to 3.0) for IPF and 3.2% (95% CI, 0.7 to 5.7) for PPF. Treatment effect was observed with or without background antifibrotics in both cohorts. Diarrhea occurred at similar frequencies in admilparant arms versus placebo. Transient day 1 post-dose blood pressure reductions were observed in all arms in both cohorts but greater with admilparant. Treatment discontinuations due to adverse events were similar across IPF arms and lower with admilparant (2.5% [30-mg]; 0% [60-mg]) versus placebo (17.1%) for PPF. In this first phase 2 study to evaluate antifibrotic treatment in parallel IPF and PPF cohorts, 60-mg admilparant slowed lung function decline and was safe and well tolerated, supporting further evaluation in phase 3 trials. Clinical trial registration available at www. gov, ID: NCT04308681.

Ziftomenib in relapsed or refractory acute myeloid leukaemia (KOMET-001): a multicentre, open-label, multi-cohort, phase 1 trial

Ziftomenib (KO-539) is an oral selective menin inhibitor with known preclinical activity in menin-dependent acute myeloid leukaemia models. The primary objective of this study was to determine the recommended phase 2 dose in patients with relapsed or refractory acute myeloid leukaemia based on safety, pharmacokinetics, pharmacodynamics, and preliminary activity. KOMET-001 is a multicentre, open-label, multi-cohort, phase 1/2 clinical trial of ziftomenib in adults with relapsed or refractory acute myeloid leukaemia. Results of the phase 1 study, conducted at 22 hospitals in France, Italy, Spain, and the USA, are presented here and comprise the dose-escalation (phase 1a) and dose-validation and expansion (phase 1b) phases. Eligible patients were aged 18 years or older, had relapsed or refractory acute myeloid leukaemia, and had an Eastern Cooperative Oncology Group performance status of 2 or less. For phase 1a, patients (all molecular subtypes) received ziftomenib (50-1000 mg) orally once daily in 28-day cycles. For phase 1b, patients with NPM1 mutations or with KMT2A rearrangements were randomly assigned (1:1) using third-party interactive response technology to two parallel dose cohorts (200 mg and 600 mg ziftomenib). Primary endpoints were maximum tolerated dose or recommended phase 2 dose in phase 1a, and safety, remission rates, and pharmacokinetics supporting recommended phase 2 dose determination in phase 1b. Analyses were performed in all patients who received at least one dose of ziftomenib (modified intention-to-treat population). Phase 1a/1b is complete. This trial is registered with ClinicalTrials.gov, NCT04067336, and the EU Clinical Trials register, EudraCT 2019-001545-41. From Sept 12, 2019, to Aug 19, 2022, 83 patients received 50-1000 mg ziftomenib (39 [47%] were male and 44 [53%] were female). Median follow-up was 22·3 months (IQR 15·4-30·2). Of 83 patients, the most common grade 3 or worse treatment-emergent adverse events were anaemia (20 [24%]), febrile neutropenia (18 [22%]), pneumonia (16 [19%]), differentiation syndrome (12 [15%]), thrombocytopenia (11 [13%]), and sepsis (ten [12%]). Overall, 68 of 83 patients had serious adverse events, with two reported treatment-related deaths (one differentiation syndrome and one cardiac arrest). Differentiation syndrome rate and severity influenced the decision to halt enrolment of patients with KMT2A rearrangements. In Phase 1b, no responses were reported in patients treated at the 200 mg dose level. At the recommended phase 2 dose of 600 mg, nine (25%) of 36 patients with KMT2A rearrangement or NPM1 mutation had complete remission or complete remission with partial haematologic recovery. Seven (35%) of 20 patients with NPM1 mutation treated at the recommended phase 2 dose had a complete remission. Ziftomenib showed promising clinical activity with manageable toxicity in heavily pretreated patients with relapsed or refractory acute myeloid leukaemia. Phase 2 assessment of ziftomenib combination therapy in the upfront and relapsed or refractory setting is ongoing. Kura Oncology.

Cognitive and Social-Emotional Development in Girls With Fragile X Syndrome.

To evaluate the developmental trajectory of key cognitive, social, and emotional features in girls with fragile X syndrome (FXS). This longitudinal, parallel cohort study collected data between January 2018 and December 2022. Participants were evaluated 3 times with ∼12-18 months between visits. Participants included 65 girls with FXS, 6 to 16 years, and 52 age- and developmentally-matched girls without FXS. Participants' scores from direct assessment and caregiver report evaluated 3 cognitive domains (verbal abilities, nonverbal abilities, executive function) and 4 social-emotional domains (depression, general anxiety, social behavior, and social anxiety). Participants included 117 girls (mean [M] [SD] age at study entry: FXS M = 10.59 [3.00]; comparison M = 10.45 [2.40])). Omnibus tests showed 4 domains with significant group differences: Verbal (P < .0001, eg, Differential Abilities Scale-II(DAS-II), Picture Vocabulary (-6.25 [1.87])), nonverbal (P < .0001, eg, Kaufman Test of Educational Achievement, Third Edition, Brief Form, Math (-8.56 [2.90])), executive function (P < .0001, eg, NIH Toolbox List Sorting (-6.26 [1.48])), and social anxiety (P < .03, eg, Anxiety, Depression, and Mood Scale (ADAMS) Social Avoidance (1.50 [0.65])). Three domains had significant group by age interaction: Verbal (P < .04, eg, DAS-II, Word Definitions (-1.33 [0.55])), social behavior (P < .01, eg, Social Responsiveness Scale-2 Social Communication (1.57 [0.51])), and social anxiety (P < .01, eg, ADAMS Social Avoidance (0.46 [0.19])). These findings support the development of early, disorder specific interventions for girls with FXS targeting verbal and nonverbal skills, executive function, social behavior, and social anxiety.

Children’s Health in London and Luton (CHILL) cohort: a 12-month natural experimental study of the effects of the Ultra Low Emission Zone on children’s travel to school

BackgroundThe Ultra-Low Emission Zone (ULEZ), introduced in Central London in April 2019, aims to enhance air quality and improve public health. The Children's Health in London and Luton (CHILL) study evaluates the impact of the ULEZ on children's health. This analysis focuses on the one-year impacts on the shift towards active travel to school.MethodsCHILL is a prospective parallel cohort study of ethnically diverse children, aged 6–9 years attending 84 primary schools within or with catchment areas encompassing London’s ULEZ (intervention) and Luton (non-intervention area). Baseline (2018/19) and one-year follow-up (2019/20) data were collected at school visits from 1992 (58%) children who reported their mode of travel to school ‘today’ (day of assessment). Multilevel logistic regressions were performed to analyse associations between the introduction of the ULEZ and the likelihood of switching from inactive to active travel modes, and vice-versa. Interactions between intervention group status and pre-specified effect modifiers were also explored.ResultsAmong children who took inactive modes at baseline, 42% of children in London and 20% of children in Luton switched to active modes. For children taking active modes at baseline, 5% of children in London and 21% of children in Luton switched to inactive modes. Relative to the children in Luton, children in London were more likely to have switched from inactive to active modes (OR 3.64, 95% CI 1.21–10.92). Children in the intervention group were also less likely to switch from active to inactive modes (OR 0.11, 0.05–0.24). Moderator analyses showed that children living further from school were more likely to switch from inactive to active modes (OR 6.06,1.87–19.68) compared to those living closer (OR 1.43, 0.27–7.54).ConclusionsImplementation of clean air zones can increase uptake of active travel to school and was particularly associated with more sustainable and active travel in children living further from school.

Circulating monocytes decrease significantly following disease-directed therapy and may reflect disease expansion in Langerhans Cell Histiocytosis.

We aimed to examine the association between relative monocytosis and the recurrence of pulmonary Langerhans Cell Histiocytosis. Clinical, laboratory, radiographic and treatment data for 86 patients with a histopathological diagnosis of Langerhans Cell Histiocytosis over a 20-year duration. Parameters such as biological sex, age at diagnosis, time to diagnosis, molecular diagnostic data and imaging were collected. Treatment responses were assessed predominantly through radiography, with RECIST 1.1 criteria applied to MRI or CT scans and PERCIST utilized for serial PET imaging. Investigators also assessed peripheral blood absolute monocyte count at various time points, including initial diagnosis and the most recently available value. While peripheral blood absolute monocyte count between the earliest assessed timepoint and latest value did not differ, the mean value on progression (0.94K/µL), however, was significantly higher than that following re-institution of therapy (0.31, p = 0.000794. Our observation of relative monocytosis on LCH disease progression may be related to an increase in circulating LCH on disease progression or from increased monocyte production for later differentiation into mature dendritic cells that participate in MHC Class 1 upregulation. This trend is especially evident in pulmonary LCH which is incited by tissue trauma and irritation by environmental factors. The phenomena observed in our study parallel other non-LCH cohorts, specifically in published findings from our own group in patients with Rosai Dorfman and Erdheim Chester Disease. To further elucidate the molecular underpinnings of LCH and explore the etiology of this monocyte trend, expanded integrated genomic-transcriptomic sequencing analyses to evaluate the molecular character of LCH and ultimately clarify the origin of this monocyte trend are in progress. These studies are poised to offer invaluable insight to the molecular mechanisms underlying LCH, specifically as they pertain to monocyte signaling and differentiation.

Fat Grafting and Prepectoral Prosthetic Reconstruction with Polyurethane-Covered Implants: Protective Role against Adjuvant Radiotherapy.

Background/Objectives: Breast cancer treatment increasingly incorporates immediate prepectoral prosthetic reconstruction after conservative mastectomy, including nipple-sparing (NSMs) and skin-sparing mastectomies (SSMs). Although recent data from the literature show that postmastectomy radiotherapy (PMRT) after prepectoral reconstruction presents good clinical results, with reduction in capsular contracture and implant migration, compared to the traditional submuscular technique, these patients have higher rates of long-term complications when compared with nonradiated patients. This study evaluates the protective effects of autologous fat grafting to reduce long-term radiotherapy-induced complications in breast cancer patients submitted for prepectoral reconstruction with polyurethane-covered (PU) implants. Methods: A pilot study with two parallel cohorts of patients undergoing an NSM or SSM followed by PMRT was conducted. Patients were randomly assigned to either of the two groups to ensure homogeneity. One cohort underwent autologous fat grafting sessions, individually tailored based on periodic evaluations by the principal investigator (PI), M. Salgarello, at least six months after PMRT. The control group received standard clinical follow-ups without fat grafting. Inclusion criteria ensured participants were disease-free, non-smokers, and had a LENT-SOMA score within 2. Results: Preliminary findings indicate significant differences between the groups, with improved outcomes observed in patients undergoing tailored lipofilling. Specifically, these patients experienced a notable reduction in capsular contracture severity and reported higher satisfaction with the aesthetic results compared to the control group. Conclusions: Autologous fat grafting, customized per patient by the PI based on ongoing evaluations, appears to mitigate some adverse effects of radiotherapy in prepectoral breast reconstruction, suggesting a viable option for enhancing surgical outcomes in irradiated patients. Further research is needed to substantiate these findings and evaluate long-term benefits.

The Efficacy of Various Orthodontic Appliances in the Treatment of Obstructive Sleep Apnea

Objective. The goal of this review was to determine the effectiveness of different types of monobloc and bibloc mandibular advancement device (MAD) devices in the treatment of all forms of obstructive sleep apnea (OSA), by reviewing the available literature. Methods. A systematic literature search was performed in PubMed, ResearchGate, NCBI and Google Scholar databases. The search included articles in English, published in the inclusive time period from 2000 to 2024. Results. A total of 13 studies were analyzed that directly compared the effectiveness of monobloc and bibloc devices. The studies were published in the period from 2000 to 2024, and included crossover and parallel randomized controlled trials, as well as cross and parallel cohort studies. Out of the 13 studies, four were classified as RCT parallel studies, six were RCT crossover studies, two cohort parallel studies, and one cohort crossover study. The duration of the studies was variable, ranging from four weeks to one year, with six studies having a so-called “washout period” between the use of monobloc and bibloc MAD devices. Conclusion. Both monobloc and bibloc devices show significant success rates in the treatment of mild to moderate OSA.

Wearable defibrillator to improve accuracy in selecting candidates to implantable defibrillator: A real-world experience.

The indication for implantable cardioverter defibrillator (ICD) for sudden cardiac death (SCD) prevention relies mostly on left ventricular ejection fraction (LVEF)≤35%. The use of a wearable cardioverter defibrillator (WCD) in the case of dynamic alterations of LVEF may help avoid an improper early ICD implant when a favourable evolution in the post-acute phase is observed and may help reduce costs. This parallel cohort retrospective study included patients with heart failure with reduced ejection fraction (HFrEF) at high risk of arrhythmias recruited in the acute phase and divided into an early ICD cohort and a WCD cohort for primary prevention during the waiting period established by European Society of Cardiology guidelines. A total of 41 consecutive patients were enrolled: 26 in the WCD group and 15 in the early ICD group. Age, LVEF at baseline, causes of HFrEF and drug therapy in the two cohorts were similar. During the waiting period after the inclusion, three patients (11.5%) in the WCD cohort and four (26.7%) in the early ICD cohort developed relevant ventricular arrhythmias (P=0.22); none of them had subsequent LVEF recovery. At the end of the waiting period, 13 patients (50%) in the WCD group and 7 (46.7%) in the early ICD group experienced LVEF recovery (P=0.84). The average cost per patient at the end of the waiting period was €23934 in the early ICD cohort versus €19167 in the WCD cohort (-19.9%). This cost savings from WCD use appears even higher when projected over a 10year period (-41.2%). WCD may represent a cost-effective strategy to more accurately select candidates for the primary prevention ICD implant among high-risk patients with HFrEF. ICD use provides effective protection from SCD and reduces costs compared with an extensive early ICD implant.

Operative versus Nonoperative Treatment of Proximal Hamstring Avulsions

BackgroundOperative treatment is widely used for acute proximal hamstring avulsions, but its effectiveness compared with that of nonoperative treatment has not been shown in randomized trials.MethodsIn this noninferiority trial at 10 centers in Sweden and Norway, we enrolled patients 30 to 70 years of age with a proximal hamstring avulsion in a randomized trial and a parallel observational cohort. Treatments were operative reinsertion of the tendons or nonoperative management. The primary end point was the Perth Hamstring Assessment Tool (PHAT) at 2 years of follow-up. Secondary outcomes included scores on the Lower Extremity Functional Scale (LEFS).ResultsA total of 119 patients were enrolled in the randomized trial and 97 patients in the observational cohort. In the per-protocol analysis of the randomized trial, the mean (±standard deviation) PHAT scores were 79.9±19.5 and 78.5±19.4 in the operative and nonoperative groups, respectively (PHAT scores range from 0 to 100, with higher scores indicating higher function). The prespecified noninferiority limit of 10 points was not crossed (mean difference, −1.2; 95% confidence interval [CI], −8.6 to 6.2; P=0.009 for noninferiority). Analyses of secondary outcomes, including a mean difference in the LEFS score of −1.6 (95% CI, −5.2 to 2.0), aligned with the primary outcome. The observed numbers of adverse events in the randomized trial were nine in the operative group versus three in the nonoperative group (odds ratio, 0.3; 95% CI, 0.1 to 1.2). In the analysis of the observational cohort, the mean PHAT score difference between the nonoperative and operative treatment groups was −2.6 (95% CI, −9.9 to 4.6).ConclusionsIn patients 30 to 70 years of age with proximal hamstring avulsions, nonoperative treatment was noninferior to operative treatment. (Funded by Afa Försäkring and others; ClinicalTrials.gov number, NCT03311997.)

A Phase II Trial of the WEE1 Inhibitor Adavosertib in SETD2-Altered Advanced Solid Tumor Malignancies (NCI 10170).

WEE1 inhibition with adavosertib monotherapy demonstrated limited clinical activity in patients with SETD2-altered solid tumors despite compelling preclinical data indicating a synthetic lethal effect, which did not translate into robust tumor regression. Loss of the H3K36me3 trimethylation mark caused by SETD2-deficiency was confirmed in the majority of evaluable tumors. A subset of patients derived clinical benefit as manifested by minor tumor regressions and prolonged SD.

Editor's Choice – Reduction of Major Amputations after Surgery versus Endovascular Intervention: The BEST-CLI Randomised Trial

BEST-CLI, an international randomised trial, compared an initial strategy of bypass surgery with endovascular treatment in chronic limb threatening ischaemia (CLTI). In this substudy, overall amputation rates and risk of major amputation as an initial or subsequent outcome were evaluated. A total of 1 830 patients were randomised to receive surgical or endovascular treatment in two parallel cohorts: patients with adequate single segment great saphenous vein (SSGSV) (n= 1 434) were assigned to cohort 1; and patients without adequate SSGSV (n= 396) were assigned to cohort 2. Differences in time to first event and number of amputations were evaluated. In cohort 1, there were 410 (45.6%) total amputation events in the surgical group vs. 490 (54.4%) in the endovascular group (p= .001) during a mean follow up of 2.7 years. Approximately one in three patients underwent minor amputation after index revascularisation: 31.5% of the surgical group vs. 34.9% in the endovascular group (p=.17). Subsequent major amputation was required significantly less often in the surgical group compared with the endovascular group (15.0% vs. 25.6%; p= .002). The first amputation was major in 5.6% of patients in the surgical group and 6.0% in the endovascular group (p= .72). Major amputation was required in 10.3% (74/718) of patients in the surgical group and 14.9% (107/716) in the endovascular group (p= .008). In cohort 2, there were 199 amputation events in 132 patients (33.3%) during a mean follow up of 1.6 years: 95 (47.7%) in the surgical group vs. 104 (52.3%) in the endovascular group (p= .49). Major amputation was required in 15.2% (30/197) of patients in the surgical group and 14.1% (28/199) in the endovascular group (p= .74). In patients with CLTI, surgical bypass with SSGSV was more effective than endovascular treatment in preventing major amputations, mainly due to a decrease in major amputations subsequent to minor amputations.

Phase I/II trial of LAVA-1207, a novel bispecific gamma-delta T-cell engager alone, or with low dose IL-2 or pembrolizumab, in metastatic castration resistant prostate cancer (mCRPC).

TPS2672 Background: LAVA-1207 is a humanized bispecific antibody that binds with high affinity to the Vδ2 chain of Vγ9Vδ2-T cells and to prostate-specific membrane antigen (PSMA). It comprises a heterodimer of two fusion proteins, each consisting of a VHH linked to a human IgG1 Fc domain. Preclinical evidence demonstrates that, upon binding both targets, LAVA-1207 leads to potent Vγ9Vδ2-T cell degranulation and cytolytic activity against PSMA-expressing prostate cancer cells. IL-2 is an immune modulator which has been shown to support expansion of activated Vγ9Vδ2-T cells. PD-1 is an inhibitory immune checkpoint receptor that can dampen (Vγ9Vδ2-) T cell reactivity, suggesting that pembrolizumab could potentiate the effect of LAVA-1207. Methods: This trial is a phase 1/2a open label study with a 3+3 design in patients with refractory mCRPC to assess the safety of LAVA-1207 alone or with low dose IL-2 or with pembrolizumab, and to determine the recommended Phase 2a dose (RP2D). Secondary objectives include evaluation of pharmacokinetics, pharmacodynamics, immunogenicity, and preliminary antitumor activity. Exploratory endpoints include evaluation of the effect of study treatment on circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA). LAVA-1207 is administered IV every two weeks. Two parallel cohorts assessing LAVA-1207 with low dose subcutaneous IL-2 have been implemented: (1) single IL-2 administration and (2) three IL-2 administrations on consecutive days per cycle for up to four cycles. An additional dose escalation arm evaluates LAVA-1207 in combination with pembrolizumab, 400mg Q6W, IV. Patients with mCRPC that have failed at least one prior AR therapy and taxane-based chemotherapy (unless deemed medically unsuitable to receive a taxane) will be enrolled on the study. Patients should have progressive disease either by PSA or by RECIST 1.1 or appearance of 2 or more bone metastases. Patients must have ECOG performance status of 0-1. PSMA-PET is performed at baseline. Paired biopsies are requested to further assess LAVA-1207 activity. Dose escalation is ongoing. Expansion arm(s) will be included based on available data from part 1 of the study and may include one or more of LAVA-1207, LAVA-1207 with low dose IL-2, or LAVA-1207 in combination with pembrolizumab. Clinical trial information: NCT05369000 .

Pediatric Health and System Impacts of Mass Incarceration, 2009–2020: A Matched Cohort Study

ObjectiveThe US has the highest incarceration rate in the world; incarceration’s direct and indirect toll on the health and health care use of youth is rarely investigated. We sought to compare the health of youth with known personal or family justice involvement and a matched cohort of youth without known personal/family justice involvement. MethodsA cross-sectional matched parallel cohort study was conducted. We queried electronic health records on youth (<21 years) with a visit in a large Midwestern pediatric hospital-based institution from January 2009 to December 2020. Youth were located by searching for justice-related (eg, prison, jail) keywords within all clinician notes. Health diagnostic profiles were measured using ICD 9/10 codes. Health care use included total admissions, inpatient days, emergent and urgent visits, and outpatient visits. ResultsAcross all youth at one institution over an 11-year period, 2.2% (N = 38,263) were identified as having probable personal or family justice-involvement. Youth with personal or familial justice involvement had 1.5–16.2 times the prevalence of mental health and physical health diagnoses across all domain groupings compared to a matched sample and the total population sample. From 2009–2020, approximately two-thirds of behavioral health care and nearly a quarter of all hospital inpatient days were attributed to the 2.2% of youth with probable personal or familial justice system involvement. ConclusionThe study illuminates the vast disparities between youth with indirect or direct contact with the criminal legal system and matched youth with no documented contact. Better investment in monitoring and prevention efforts are needed.

#3076 A UK parallel cohort study on renal ANCA associated vasculitis outcomes for avacopan exposed and matched unexposed cohorts

Abstract Background and Aims Avacopan was approved in the UK for severe ANCA associated vasculitis (AAV) in December 2022. The ADVOCATE trial found the differential effect of avacopan on kidney function was greatest in patients with the lowest estimated glomerular filtration rate (eGFR), at highest risk of progression to end stage kidney disease (ESKD). Patients with an eGFR &amp;lt;15 ml/min/1.73 m2, pulmonary haemorrhage requiring invasive ventilation, under 12 months prognosis, use of plasma exchange and dual therapy with cyclophosphamide (CYC) and rituximab (RTX) were excluded from ADVOCATE; all common scenarios in real life practice. We aim to provide further information on these subgroups and evaluate 6 month renal outcome data in the UK. Method Parallel cohort study on renal AAV outcomes for avacopan exposed and matched unexposed cohorts, with severe, active GPA or MPA. 120 patients on avacopan from 7 UK centres have been recruited to date. Controls matched by renal function and age will be presented. Comparisons of ESKD, delta eGFR, eGFR recovery, reduction in proteinuria/haematuria, remission, relapse and mortality will be presented, with subgroup analyses for eGFR&amp;lt;15 ml/min/1.73 m2. Steroid exposure will be presented. Results Baseline characteristics of the avacopan cohort are below. Most received oral prednisolone at avacopan initiation (89%, n = 107) and 54% received intravenous methylprednisolone (n = 65). The majority received RTX alone (44%, n = 53) or RTX and CYC combination therapy (43%, n = 52). Fewer received CYC alone (9%, n = 11) and 3% were initiated on alternative immunosuppression (n = 4). 26% (n = 31) underwent plasma exchange and 13% required haemodialysis (n=16). 3% of patients have died. Excluding dialysis dependent patients at presentation, median eGFR was 22ml/min/1.73 m2 (IQR 10-36). eGFR at the time of avacopan initiation was 21ml/min/1.73 m2 (IQR 11-34). Conclusion Avacopan is commonly being used to treat nephritis in patients with a low eGFR, including haemodialysis dependent and elderly patients. Avacopan is frequently used with RTX and CYC combination therapy. 6 month outcome data will provide new data on important patient subgroups excluded from the ADVOCATE trial.