Citations

Background: The Green-Anderson (GA) leg-length data remain the gold standard for the age-based assessment of leg lengths in children despite their methodologic weaknesses. We aimed to summarize current growth trends among a cross-sectional cohort of modern U.S. children using quantile regression methods and to compare the median femoral and tibial lengths of the modern U.S. children with those of the GA cohort. Methods: A retrospective review of scanograms and upright slot-scanning radiographs obtained in otherwise healthy children between 2008 and 2020 was completed. A search of a radiology registry revealed 3,508 unique patients between the ages of 2 and 18 years for whom a standard-of-care scanogram or slot-scanning radiograph had been made. All patients with systemic illness, genetic conditions, or generalized diseases that may affect height were excluded. Measurements from a single leg at a single time point per subject were included, and the latest available time point was used for children who had multiple scanograms made. Quantile regression analysis was used to fit the lengths of the tibia and femur and overall leg length separately for male patients and female patients. Results: Seven hundred patients (328 female and 372 male) met the inclusion criteria. On average, the reported 50th percentile tibial lengths from the GA study at each time point were shorter than the lengths in this study by 2.2 cm (range, 1.4 to 3.3 cm) for boys and 2 cm (range, 1.1 to 3.1 cm) for girls. The reported 50th percentile femoral lengths from the GA study at each time point were shorter than the lengths in this study by 1.8 cm (range, 1.1 to 2.5 cm) for boys and 1.7 cm (range, 0.8 to 2.3 cm) shorter for girls. Conclusions: This study developed new growth charts for femoral and tibial lengths in a modern U.S. population of children. The new femoral and tibial lengths at nearly all time points are 1 to 3 cm longer than traditional GA data. The use of GA data for epiphysiodesis could result in underestimation of expected childhood growth. Level of Evidence: Prognostic Level IV . See Instructions for Authors for a complete description of levels of evidence.

Abstract Background Vedolizumab (VDZ) is a gut-selective humanised monoclonal anti-α4β7 integrin antibody for treatment of UC and CD. This post-authorization safety study (PASS) compared long-term safety in patients (pts) treated with VDZ or other biologics for UC or CD. Methods This was a prospective, observational, multicentre, cohort study in pts with UC or CD starting treatment with VDZ or other biologics (NCT02674308, EUPAS6469). Pts were biologic naïve (VDZ=35%, Other biologic=65%) or had prior exposure to biologics other than VDZ and were followed for up to 7 yrs. Pts were treated under usual standard of care as directed by their physician with no discontinuation from the study due to physician-directed treatment changes. The primary safety outcome was serious infections and was compared between cohorts using a Cox proportional hazards model adjusted by propensity score (with other biologics as reference). Secondary safety outcomes were adverse events (AE) of special interest (AESI) as listed in Tables 2 and 3. Results In total, 5208 patients were enrolled across 21 countries between Mar 2015 and Jul 2019. The full analysis set comprised 5008 pts (VDZ=2502; other biologic=2506) and mean (SD) study duration was 37.4 (14.1) months. Consistent with the observational nature of the study and the current standard of care, the baseline characteristics in the two cohorts were imbalanced (Table 1). The overall treatment-emergent Adverse Event (AE) rate was 61.3% (VDZ) and 59.5% (other biologic), with serious AEs in 27.5% (VDZ) and 25.7% (other biologic), respectively. In UC pts, the incidence rate (IR) of serious infections were: 0.014 (95% CI: 0.010, 0.019) [VDZ] and 0.015 (0.010, 0.023) [other biologic], with a hazard ratio (HR) of 1.018 (0.931, 1.114), p=0.70 (Table 2). In CD pts, corresponding findings were 0.012 (95% CI: 0.008, 0.017) [VDZ] and 0.006 (95% CI: 0.004, 0.009) [other biologic] with HR of 1.035 (0.959, 1.117), p=0.38 (Table 3). The incidence of primary and secondary safety outcomes is reported in Table 2 for UC and Table 3 for CD. There were no safety issues relating to pregnancy and no cases of PML observed. There were 19 deaths in the VDZ cohort (1 case of pneumonia deemed as treatment-related); and 13 deaths in the other biologic cohort, 2 cases deemed treatment-related (one case septic shock and pneumonia; one case non-small cell lung cancer). Clinical outcomes and quality of life (QoL) measures were comparable between cohorts. Conclusion In this long-term, prospective, real-world observational study of a large multinational population under routine standard of care there was no new safety signal identified in relation to VDZ. Results are consistent with the known safety profile of VDZ.

Abstract The discovery of immunoglobulin E (IgE) (1) has contributed significantly to the understanding of hypersensitivity reactions mediated by reaginic antibody (2) and has led to the development of new diagnostic procedures in the field of allergology (3, 4). Recent studies have demonstrated the production of IgE protein by peripheral blood lymphocytes in vitro and have examined the kinetics and pharmacologic control of IgE biosynthesis (5, 6). The purpose of this communication is to describe our observation of in vitro production of IgE protein and antigen-specific IgE antibodies by peripheral blood mononuclear cells obtained from atopic and nonatopic individuals. A modification of the lymphocyte culture method of Waldmann et al. (7) was used in our studies. Blood, 60 ml, was obtained from 11 patients, eight of whom are atopic (geometric mean serum IgE, 247 ng/ml; range 61 to 1079) and three of whom are nonatopic (geometric mean serum IgE, 96 ng/ml; range 73 to 143).

AbstractAimThe Turnbull–Cutait pull‐through procedure (TCO) restores intestinal continuity in the setting of chronic pelvic sepsis, colorectal anastomotic leak, complex pelvic fistulas and technical challenges related to complicated rectal cancer. The aim of this study was to evaluate the outcomes of the TCO for salvaging complex pelvic conditions and to compare it to hand‐sewn immediate coloanal anastomosis (CAA).MethodsThis is a retrospective single‐institution study where we searched a prospectively maintained database to identify patients who underwent the TCO. Patient demographics, operative indications and outcomes were analysed. TCO success was defined as maintenance of intestinal continuity and being stoma‐free. Kaplan–Meier analysis was employed for stoma‐free survival analysis.ResultsA total of 81 patients with TCO and 129 patients with CAA were included. The TCO success rate was 69% at a median of 1.4 years’ follow‐up with 25 (31%) patients ending up with a permanent stoma compared to 22 (17%) in the CAA group with a median follow‐up of 4 years (P = 0.03). The Kaplan–Meier cumulative incidence of TCO success at 1, 3 and 5 years was 79%, 60% and 51%, respectively, compared to 91%, 81% and 73% after CAA.ConclusionThe TCO has a high success rate for patients with complex pelvic conditions who may be facing a permanent stoma as their only option.

Abstract Background: Guidelines suggest the use of the Khorana score to select patients with solid cancer receiving chemotherapy for thromboprophylaxis to prevent venous thromboembolism (VTE), but its performance in different types of cancers remains uncertain. Methods: The present analysis includes individual patient data from seven randomized controlled trials that had compared prophylactic (ultra)-low-molecular-weight heparin (LMWH) with placebo or observation in patients with solid cancer. The analysis addresses the performance of the continuous and dichotomized Khorana score in predicting the 6-month risk of VTE in the trial control groups, overall and in types of cancer studies, as well as the efficacy and safety of LMWH among patients with a high-risk Khorana score. Random effects meta-analysis provided the basis for summary estimates. Findings: In the 3,403 patients from the control groups included in the analyses, the mean age was 61 years, 59% were male, and 58% had lung cancer. During 6-months of follow-up, 188 patients (5.5%) developed VTE. Overall, the 6-month VTE incidence was 9.8% among high-risk Khorana score patients and 6.4% among low-to-intermediate risk patients (OR 1.6; 95%-CI 1.1-2.2). The dichotomous Khorana score performed differently in lung cancer patients (OR 1.1; 95%-CI, 0.72-1.7) than in those with other types of cancer (OR 4.4; 95%-CI, 2.7-7.3; P interaction=0.002). Among high-risk patients, LMWH decreased the risk of VTE by 64% compared to placebo or observation (OR 0.36; 95%-CI, 0.22-0.58). In the group of patients with types of cancer other than lung cancer and a high-risk Khorana score (N=619), the 6-month VTE incidence was 3.3% (95% CI, 1.4 to 7.7) among LMWH recipients and 13% (95% CI, 6.8 to 24) among those not receiving LMWH (OR 0.23, 95% CI, 0.11 to 0.46; P <0.001). There was no difference in major bleeding (OR 1.2, 95% CI, 0.56 to 2.5). Interpretation: The Khorana score performs poorly in differentiating between those at high and low risk of VTE in patients with lung cancer, but is associated with a 4-fold increased risk of VTE in those with other types of cancer. Thromboprophylaxis is effective and safe in patients with a high-risk Khorana score. Funding: Canadian Institutes of Health Research knowledge synthesis grant, KRS 126594 Registration: International Prospective Register for Systematic Reviews (PROSPERO), CRD42013003526. Disclosures Van Es: Pfizer: Employment, Other: Comment: Dr. van Es reports personal fees from Pfizer as a member of their advisory board. These fees are unrelated to this project.. Crowther: Alexion: Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Boehringer Ingelheim: Speakers Bureau; Leo Pharma: Research Funding; Pfizer: Honoraria; Portola: Consultancy; Shinogi: Consultancy. Macbeth: Cancer Research UK: Research Funding; Pfizer: Other: Provision of Dalteparin for FRAGMATIC trial. Griffiths: Pfizer: Consultancy, Other: Comment: I run an academic clinical trials unit, have received educational/investigator intiated research grants from companies that make these heparin agents. As consultant > 3 years ago, advised Pfizer on clinical trial designs unrelated to this study., Research Funding. Streiff: Roche: Research Funding; Portola: Research Funding; Janssen Scientific Affairs, LLC: Consultancy, Research Funding; CSL Behring: Consultancy, Research Funding. Ageno: Daiichi Sankyo: Consultancy, Honoraria; Bayer AG: Consultancy, Honoraria, Research Funding; BMS-Pfizer: Consultancy, Honoraria; Boehringer Ingelheim: Consultancy, Honoraria. Bozas: PharmaMar: Honoraria. Maraveyas: Bayer: Other: Personal fees and conference attendance; Bristol-Myers Squibb: Other: Grants and personal fees; Leo Pharma: Other: Grants, personal fees and conference attendance; Pfizer: Other: Personal fees. Loprinzi: Bristol Myers: Other: Grant - unrelated to this project; Janssen: Other: Grant - unrelated to this project. McBane: Bristol Myers Squibb: Other: Research grant for cancer associated VTE. Schünemann: Canadian Institutes of Health Research: Research Funding.

Abstract Background: Parenteral anticoagulants may improve outcomes in patients with cancer by reducing the risk of venous thromboembolism (VTE) and through a direct anti-tumour effect. Study-level meta-analysis indicates a reduction in VTE and provide moderate certainty that a small survival benefit exists; it is unclear if patients with specific cancers benefit more or less. Utilizing data from randomized controlled trials (RCT), this individual participant data meta-analysis examines the impact of heparin on survival, VTE and major bleeding in oncological patients randomized to low-molecular weight heparin (LMWH) or no LMWH. Methods: We performed a comprehensive systematic search for all RCTS (last search date March 2017) and contacted authors and sponsors to obtain individual participant data of patients with solid cancers and no other indication for prophylactic or therapeutic anticoagulation. We utilized the GRADE approach to evaluate the certainty of evidence and produce an evidence profile. All analyses followed the intention-to-treat principle. We calculated the impact on mortality through multivariable hierarchical models with patient-level variables as fixed effects and a categorical trial variable as a random effect. We adjusted the analysis for age, cancer type and metastasis status. To investigate whether intervention effects vary by predefined subgroups, including type of cancer, we tested interaction terms in the statistical model. Results: A total of 18 RCTs (n=10,041 participants) were eligible for inclusion and we obtained data from 82.4% of the participants (13 RCTs, n=8,278; n=4,139 for LMWH and n=4,139 for no LMWH). The meta-analysis revealed an adjusted relative risk of mortality within one year of 0.99 (95% CI: 0.95, 1.03) and a hazard ratio of 0.97 (95% CI: 0.82, 1.14) after one year. The relative risk for VTE was 0.58 (95% CI: 0.48, 0.71), 0.57 (95% CI: 0.44, 0.74) for symptomatic deep vein thrombosis and 0.58 (95%CI: 0.44, 0.77) for symptomatic pulmonary embolism, separately. For every 1,000 patients treated, approximately 16 fewer would experience symptomatic DVT and 16 fewer would experience any PE. The adjusted relative risk for major bleeding throughout trial duration was 1.24 (95% CI: 0.91, 1.69; P=0.17). Subgroup analysis, by cancer type, of VTE occurrence throughout trial duration identified lung cancer OR=0.52 (95% CI: 0.39, 0.68; P<0.001) and pancreatic cancer OR=0.55 (95% CI: 0.35, 0.88; P=0.01) patients as experiencing the greatest benefit from LMWH treatment. The certainty of the evidence for the outcomes was moderate to high. Conclusion: LMWH reduces risk of VTE without increasing risk of bleeding but does not improve survival across all patients. Funding: Canadian Institutes of Health Research knowledge synthesis grant, KRS 126594 Registration: International Prospective Register for Systematic Reviews (PROSPERO), CRD42013003526. Disclosures Schünemann: Canadian Institutes of Health Research: Research Funding. Crowther: Alexion: Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Boehringer Ingelheim: Speakers Bureau; Leo Pharma: Research Funding; Pfizer: Honoraria; Portola: Consultancy; Shinogi: Consultancy. Macbeth: Pfizer: Other: Provision of Dalteparin for FRAGMATIC trial; Cancer Research UK: Research Funding. Griffiths: Pfizer: Consultancy, Other: Comment: I run an academic clinical trials unit, have received educational/investigator intiated research grants from companies that make these heparin agents. As consultant > 3 years ago, advised Pfizer on clinical trial designs unrelated to this study., Research Funding. Van Es: Pfizer: Employment, Other: Comment: Dr. van Es reports personal fees from Pfizer as a member of their advisory board. These fees are unrelated to this project.. Streiff: Roche: Research Funding; Portola: Research Funding; Janssen Scientific Affairs, LLC: Consultancy, Research Funding; CSL Behring: Consultancy, Research Funding. Ageno: BMS-Pfizer: Consultancy, Honoraria; Bayer AG: Consultancy, Honoraria, Research Funding; Boehringer Ingelheim: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria. Bozas: PharmaMar: Honoraria. McBane: Bristol Myers Squibb: Other: Research grant for cancer associated VTE. Maraveyas: Bayer: Other: Personal fees and conference attendance; Bristol-Myers Squibb: Other: Grants and personal fees; Leo Pharma: Other: Grants, personal fees and conference attendance; Pfizer: Other: Personal fees. Loprinzi: Bristol Myers: Other: Grant - unrelated to this project; Janssen: Other: Grant - unrelated to this project.

Given the dearth of established safe and effective interventions to respond to COVID-19, there is an urgent ethical imperative to conduct meaningful clinical research. The good news is that interventions to be tested are not in short supply. Unfortunately, the human and material resources needed to conduct these trials are finite. It is essential that trials be robust and meet enrollment targets and that lower-quality studies not be permitted to displace higher-quality studies, delaying answers to critical questions. Yet, with few exceptions, existing research review bodies and processes are not designed to ensure these conditions are satisfied. To meet this challenge, we offer guidance for research institutions about how to ethically consolidate and prioritize COVID-19 clinical trials, while recognizing that consolidation and prioritization should also take place upstream (among manufacturers and funders) and at a higher level (e.g. nationally). In our proposed three-stage process, trials must first meet threshold criteria. Those that do are evaluated in a second stage to determine whether the institution has sufficient capacity to support all proposed trials. If it does not, the third stage entails evaluating studies against two additional sets of comparative prioritization criteria: those specific to the study and those that aim to advance diversification of an institution’s research portfolio. To implement these criteria fairly, we propose that research institutions form COVID-19 research prioritization committees. We briefly discuss some important attributes of these committees, drawing on the authors’ experiences at our respective institutions. Although we focus on clinical trials of COVID-19 therapeutics, our guidance should prove useful for other kinds of COVID-19 research, as well as non-pandemic research, which can raise similar challenges due to the scarcity of research resources.

AbstractIt is important to employ radiation dose reduction techniques in pediatric computed tomography (CT) to reduce potential risks of radiation‐induced malignancy. Automatic tube potential (kV) selection tools have been developed and become available on many CT scanners, which select the optimum kV based on the patient size and clinical task to improve the radiation dose efficiency. However, its use in pediatric CT has been mostly empirical, following manufacturer’s default recommendation without solid demonstration for quality improvement. This study aimed to implement an automatic tube potential tool (CAREkV, Siemens Healthcare) into routine pediatric CT practice, using the “Plan‐Do‐Study‐Act” quality improvement process, in place of an existing kV/mAs technique chart. The design of this quality improvement project involved Plan‐Do‐Study‐Act stages. Plan and Do stages identified the criteria for optimal automatic kV selection; a range of phantoms representing typical pediatric groups were scanned on a dual‐source 128‐slice scanner using a fast‐pitch scanning mode. The identified CAREkV settings were implemented into the CT protocol and evaluated after a 6‐month period. In the Study stage, an objective evaluation of the image metrics and radiation dose for two similar patient cohorts using CAREkV and the technique‐chart, respectively, were compared. The kV selected, image quality and radiation dose determined by CAREkV were comparable to those obtained while using the technique‐chart. The CAREkV was successfully implemented into our pediatric abdominopelvic CT practice. By utilizing the “PDSA” process optimal image quality and radiation dose reduction were achieved with an automatic kV selection tool to improve CT workflow.