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AbstractBackgroundMagnetic Resonance Spectroscopy (MRS) is a non‐invasive technique assessing the concentration of various metabolites within the brain, both cross‐sectionally to characterize disease type and severity, and longitudinally to assess disease progression and potential treatment efficacy in the context of disease‐modifying interventions. In such context, the involvement of multiple imaging facilities inevitably introduces variability, whose amount must be known to inform on comparability between sites and sensitivity to change. Our objective is to study variability in the concentration of various brain metabolites using a dedicated MRS phantom and assess impact of field strength.Methods30 sites are being considered to participate in an on‐going clinical trial in metachromatic leukodystrophy. Site qualification mandates the scanning of a dedicated MRS phantom. 30 of these HD‐polyethylene spheres were simultaneously manufactured and filled with the same mixture of chemicals mimicking main metabolite concentrations. To date, 14 sites provided data (5 1.5T scanners and 9 3T). All sites implemented a standardized single‐voxel MRS sequence. MRS voxel was placed within the phantom and acquisition repeated 3 times. Spectra were centrally analyzed using LCModel v6.3 and quality controlled by Bioclinica. Repeat acquisitions were requested for parameter deviations, voxel positioning and/or shimming issues. Results only include passing datasets. Coefficient of Variation (CV) was calculated for NAA/Cr, Cho/Cr, mI/Cr, Glx/Cr and Lac/Cr ratios for each site and overall. LCModel quality metrics (FHWM and S/N) were also extracted to assess spectra quality. Comparison between field strengths was carried out using t‐tests.ResultsAverage CV by site was 2.0% for NAA/Cr (2.5% at 1.5T and 1.8% at 3T), 2.4% for Cho/Cr, 3.0% for mI/Cr, 4.5% for Glx/Cr and 6.1% for Lac/Cr. CVs were generally lower at 3T (except for Lac/Cr) although difference was not significant. As expected, Signal‐to‐Noise was higher at 3T (p=0.05). Overall CV by metabolite across scanners was much higher (ranging from 4.6% for Cho/Cr up to 12.1% for Lac/Cr).ConclusionMRS measures of metabolite concentrations have low variability at scanner‐level, insensitive to field strength. Nevertheless, variability across sites is much higher and would require, if possible, cross‐calibration. These phantom data make such calibration possible and will improve sensitivity of subject data analyses.

Background: The majority of small papillary thyroid cancers (sPTCs) are treated surgically, rather than by active surveillance. Patient and clinician preference for surgery may be partially driven by the use of cancer terminology. Some experts propose that changing terminology would better communicate the indolent nature of sPTCs and improve uptake of active surveillance. Others argue that terminology that includes “cancer” correctly reflects the biological nature of these tumors. The views of informed lay publics can provide value-based perspectives on complex issues and guide policy discussions. Methods: We recruited 40 people for three community juries, held in Sydney, Wodonga, and Cairns, Australia. Participants were of diverse backgrounds and ages, recruited through random digit dialing and a topic-blinded social media strategy. Juries were informed about thyroid cancer, overdiagnosis, and overtreatment, and heard arguments for and against terminology change before deliberation. The deliberative process in Jury 1 led to a refinement of jury charge, the updated version that was then used in Juries 2 and 3. Results: Jury 1 favored no terminology change, and Juries 2 and 3 were divided on the topic. Key reasons for opposing terminology change included a strong desire to retain terminology that aligns with the pathological definition of cancer, and to avoid even a minimal risk of harm that could arise if patients became complacent in follow-up. Key reasons to support terminology change included a desire to reduce psychological distress, stigma, and discrimination associated with a cancer diagnosis, and an argument that terminology change may be a more effective trigger for health system reform compared with other options. The juries unanimously recommended community education and health system reforms to reduce harms of overtreatment, and expressed an expectation that clinicians and researchers reach agreement on clinical guidelines to promote better uptake of active surveillance. Conclusions: The conceptual tension between a pathological and an outcome-based understanding of cancer was apparent in deliberation. This highlights an ongoing challenge for those advocating changing disease terminology. Regardless of action on terminology, jurors shared a strong expectation that practical changes would be made to respond to the harms of overtreatment.

Abstract The treatment of cancer with proton radiation therapy was first suggested in 1946 followed by the first treatments in the 1950s. As of 2020, almost 200 000 patients have been treated with proton beams worldwide and the number of operating proton therapy (PT) facilities will soon reach one hundred. PT has long moved from research institutions into hospital-based facilities that are increasingly being utilized with workflows similar to conventional radiation therapy. While PT has become mainstream and has established itself as a treatment option for many cancers, it is still an area of active research for various reasons: the advanced dose shaping capabilities of PT cause susceptibility to uncertainties, the high degrees of freedom in dose delivery offer room for further improvements, the limited experience and understanding of optimizing pencil beam scanning, and the biological effect difference compared to photon radiation. In addition to these challenges and opportunities currently being investigated, there is an economic aspect because PT treatments are, on average, still more expensive compared to conventional photon based treatment options. This roadmap highlights the current state and future direction in PT categorized into four different themes, ‘improving efficiency’, ‘improving planning and delivery’, ‘improving imaging’, and ‘improving patient selection’.

BACKGROUND AND OBJECTIVES: The effects of in utero methamphetamine exposure on behavioral problems in school-aged children are unclear. Our objective for this study was to evaluate behavior problems in children at aged 3, 5, and 7.5 years who were prenatally exposed to methamphetamine. METHODS: Subjects were enrolled in the Infant Development, Environment, and Lifestyle study, a longitudinal prospective study of prenatal methamphetamine exposure and child outcomes. Exposed and comparison groups were matched on birth weight, race, education, and health insurance. At ages 3, 5, and 7.5 years, 339 children (171 exposed) were assessed for behavior problems by using the Child Behavior Checklist. Generalized estimating equations were used to determine the effects of prenatal methamphetamine exposure, age, and the interaction of exposure and age on behavior problems. Caregiver psychological symptoms were assessed by using the Brief Symptom Inventory. RESULTS: Analyses adjusted for covariates revealed that relative to age 3, children at 5 years had less externalizing and aggressive behavior and more internalizing behavior, somatic complaints, and withdrawn behavior. By age 7.5, aggressive behavior continued to decrease, attention problems increased and withdrawn behavior decreased. There were no main effects for methamphetamine exposure and no interactions of exposure and age. Caregiver psychological symptoms predicted all behavior problems and the quality of the home predicted externalizing problems and externalizing syndrome scores. CONCLUSIONS: Behavioral effects longitudinally from ages 3 to 7.5 years were not associated with prenatal methamphetamine exposure, whereas caregiver psychological symptoms and the quality of the home were predictors of behavior problems.

In this study, we tested the hypothesis that the RyR1 Ca2+ channel closure is sensitive to outward trans-SR membrane Ca2+ gradients established by SERCA1 pumping. To perform these studies, we employed stopped-flow rapid-kinetic fluorescence methods to measure and assess how variation in trans-SR membrane Ca2+ distribution affects evolution of RyR1 Ca2+ leaks in RyR1/ CASQ1/SERCA1-rich membrane vesicles. Our studies showed that rapid filling of a Mag-Fura-2-sensitive free Ca2+ pool during SERCA1-mediated Ca2+ sequestration appears to be a crucial condition allowing RyR1 Ca2+ channels to close once reloading of luminal Ca2+ stores is complete. Disruption in the filling of this pool caused activation of Ruthenium Red inhibitable RyR1 Ca2+ leaks, suggesting that SERCA1 pump formation of outward Ca2+ gradients is an important aspect of Ca2+ flux control channel opening and closing. In addition, our observed ryanodine-induced shift in luminal Ca2+ from free to a CTC–Ca+-sensitive, CASQ1-associated bound compartment underscores the complex organization and regulation of SR luminal Ca2+. Our study provides strong evidence that RyR1 functional states directly and indirectly influence the compartmentation of luminal Ca2+. This, in turn, is influenced by the activity of SERCA1 pumps to fill luminal pools while synchronously reducing Ca2+ levels on the cytosolic face of RyR1 channels.

Background The relative benefits of haploidentical HCT using PTCy compared to traditional matched-sibling donor, traditional unrelated donor and umbilical cord blood (UCB) allogeneic HCT for adult acute lymphoblastic leukemia (ALL) is still being defined. Methods We performed a retrospective analysis using the Center for International Blood and Marrow Transplant Research (CIBMTR) database comparing post-HCT outcomes of haploidentical donors with PTCy to HLA-identical sibling donors, 8/8 HLA-MUDs, 7/8 HLA-MUDs, and UCB. Outcomes were overall survival (OS) leukemia-free survival (LFS), relapse, non-relapse mortality (NRM), grade 2-4 and grade 3-4 acute graft-versus-host disease (aGVHD), and chronic GVHD (cGVHD). Eligible patients were adults with ALL in complete remission (CR1, CR2, or CR3) undergoing first allogeneic HCT from 2013 to 2017. Key exclusion included not receiving PTCy for haploidentical HCT and ex vivo T-cell depleted or CD34-selected grafts. Cox proportional hazards multivariable regression analysis was used to compare the treatment groups. Results 4201 patients were studied: 393 haploidentical donor (92 centers), 1627 HLA-identical sibling donor (206 centers), 1646 8/8 HLA-MUD (181 centers), 230 7/8 HLA-MUD (90 centers), and 305 UCB (79 centers). Groups were well matched, however, notable differences between included race, time from diagnosis to HCT (CR1 only), conditioning regimen intensity, donor age, graft source for non-cord (peripheral blood or bone marrow), GVHD prophylaxis modality, and the use of in vivo T-cell depletion. Compared to other groups, haploidentical HCT had the lowest percentage of non-Hispanic white patients (43% vs. 49-74%), was more likely to use reduced-intensity conditioning (42% vs 17-25%), and was more likely to use bone marrow (41% vs. 14-29%). In multivariate analysis comparing haploidentical to matched-sibling donor HCT, no differences were observed in OS, LFS, NRM, relapse, or aGVHD. Compared to haploidentical HCT, the risk of cGVHD was significantly higher with matched-sibling donor HCT (D/R sex match F/M, HR 2.59, P<0.001, D/R sex match, other, HR 1.37, P=0.003). Comparing haploidentical to 8/8 HLA-MUD HCT, no differences were seen in OS, LFS, relapse, or Grade 2-4 aGVHD but 8/8 HLA-MUD HCT was associated with increased incidences of NRM (HR 1.42, P=0.02), grade 3-4 aGVHD (HR 1.59, P=0.005), and cGVHD (HR D/R sex match F/M, HR 2.91, P<0.001, D/R sex match, other, HR 1.38, P=0.001). Comparing haploidentical to 7/8 HLA-MUD HCT, no differences were seen in LFS or relapse but 7/8 HLA-MUD HCT was associated with worse OS (HR 1.38, P=0.01) and increased incidences of NRM (HR 2.13, P=<0.001), grade 2-4 aGVHD (HR 1.33, P=0.04) , grade 3-4 aGVHD (HR 1.86, P=0.003), and cGVHD (HR 1.72, P=<0.001). Comparing haploidentical to UCB HCT, no differences were seen in late OS (>18 months), late LFS, relapse, or cGVHD. Compared to haploidentical HCT, UCB HCT was associated with worse early OS (≤18 months, HR 1.93, P<0.001), worse early LFS (HR 1.40, P=0.007) and increased incidences of NRM (HR 2.08, P<0.001), grade 2-4 aGVHD (HR 1.83, P<0.001), and grade 3-4 aGVHD (HR 1.97, P<0.001). Similar outcomes were observed in sensitivity analyses restricting cohorts to (1) MA conditioning with peripheral blood stem cells and (2) calcineurin inhibitor-based GVHD prophylaxis for matched-sibling, unrelated donor, and UCB HCT. Conclusions For OS and LFS, haploidentical HCT using PTCy for adult ALL was superior to traditional HCT using 7/8 HLA-MUDs and UCB but equivalent to traditional HCT using matched-sibling donors and 8/8 HLA-MUDs. Results were consistent across all subgroups. Haploidentical HCT had a lower incidence of aGVHD compared to 8/8 HLA-MUD, 7/8 HLA-MUD, and UCB HCT and a lower incidence of cGVHD compared to matched-sibling donor, 8/8 HLA-MUD, and 7/8 HLA-MUD HCT. Based on these data, haploidentical HCT with PTCy results in similar survival with less GVHD compared to traditional matched-sibling and 8/8 HLA-matched donor HCT and is the superior alternative donor option for adult patients with ALL needing allogeneic HCT in CR. Figure Disclosures Wieduwilt: Leadiant: Research Funding; Shire: Research Funding; Merck: Research Funding; Macrogeneics: Research Funding; Amgen: Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees. de Lima:Incyte: Other: Personal Fees, advisory board; BMS: Other: Personal Fees, advisory board; Pfizer: Other: Personal fees, advisory board, Research Funding; Celgene: Research Funding; Kadmon: Other: Personal Fees, Advisory board. Kebriaei:Novartis: Other: Served on advisory board; Pfizer: Other: Served on advisory board; Kite: Other: Served on advisory board; Ziopharm: Other: Research Support; Amgen: Other: Research Support; Jazz: Consultancy. Hourigan:Merck: Other: Research Support (CRADA); Sellas: Other: Research Support (CRADA). Weisdorf:FATE Therapeutics: Consultancy; Incyte: Research Funding.

Background: The rate of elbow medial ulnar collateral ligament (MUCL) injury and surgery continues to rise steadily. While authors have failed to reach a consensus on the optimal graft or anchor configuration for MUCL reconstruction, the vast majority of the literature is focused on the young, elite athlete population utilizing autograft. These studies may not be as applicable for the “weekend warrior” type of patient or for young kids playing on high school leagues or recreationally without the intent or aspiration to participate at an elite level. Purpose: To investigate the clinical outcomes and complication rates of MUCL reconstruction utilizing only allograft sources in nonelite athletes. Study Design: Case series; Level of evidence, 4. Methods: Patient records were retrospectively analyzed for individuals who underwent allograft MUCL reconstruction at a single institution between 2000 and 2016. A total of 25 patients met inclusion criteria as laborers or nonelite (not collegiate or professional) athletes with a minimum of 2 years of postoperative follow-up. A review of the medical records for the included patients was performed to determine survivorship free of reoperation, complications, and clinical outcomes with use of the Summary Outcome Determination (SOD) and Timmerman-Andrews scores. Statistical analysis included a Wilcoxon rank-sum test to compare continuous variables between groups with an alpha level set at .05 for significance. Subgroup analysis included comparing outcome scores based on the allograft type used. Results: Twenty-five patients met all inclusion and exclusion criteria. The mean time to follow-up was 91 months (range, 25-195 months), and the mean age at the time of surgery was 25 years (range, 12-65 years). There were no revision operations for recurrent instability. The mean SOD score was 9 (range, 5-10) at the most recent follow-up, and the Timmerman-Andrews scores averaged 97 (range, 80-100). Three patients underwent subsequent surgical procedures for ulnar neuropathy (n = 2) and contracture (n = 1), and 1 patient underwent surgical intervention for combined ulnar neuropathy and contracture. Conclusion: Allograft MUCL reconstruction in nonelite athletes demonstrates comparable functional scores with many previously reported autograft outcomes in elite athletes. These results may be informative for elbow surgeons who wish to avoid autograft morbidity in common laborers and nonelite athletes with MUCL incompetency.

Abstract Vascular contributions to cognitive impairment and dementia (VCID) are characterized by the aging neurovascular unit being confronted with and failing to cope with biological insults due to systemic and cerebral vascular disease, proteinopathy including Alzheimer's biology, metabolic disease, or immune response, resulting in cognitive decline. This report summarizes the discussion and recommendations from a working group convened by the National Heart, Lung, and Blood Institute and the National Institute of Neurological Disorders and Stroke to evaluate the state of the field in VCID research, identify research priorities, and foster collaborations. As discussed in this report, advances in understanding the biological mechanisms of VCID across the wide spectrum of pathologies, chronic systemic comorbidities, and other risk factors may lead to potential prevention and new treatment strategies to decrease the burden of dementia. Better understanding of the social determinants of health that affect risks for both vascular disease and VCID could provide insight into strategies to reduce racial and ethnic disparities in VCID.