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Leaf toughness is an important functional trait that confers resistance to herbivory and mechanical damage. We sought to determine how species composition, climate, seasonality, and nutrient availability influence leaf toughness in two types of tundra in northern Alaska. We measured leaf toughness as force to punch for 11 species of Arctic plants in tussock tundra and dry heath tundra at 17 sites distributed along a latitudinal gradient. Rubus chamaemorus L. and the graminoids occupied opposite ends of the leaf toughness spectrum, with Rubus chamaemorus requiring the least force to punch, whereas one of the graminoids, Eriophorum vaginatum L., required the most. Leaf toughness increased with mean summer temperature for Eriophorum vaginatum and Betula nana L., whereas it declined with warmer temperatures for the other species. Toughness of mature leaves of Eriophorum vaginatum did not vary through the growing season but declined significantly after senescence. Application of N and P fertilizer in an experimental site decreased leaf toughness in three species but had no effect on four others. Leaf toughness of four out of five species in dry heath was greater than for the same species in tussock tundra, but there was no difference in community-weighted mean toughness between tussock tundra and dry heath.

Background & Aims Chronic pancreatitis (CP) is associated with osteopathy (osteoporosis or osteopenia). However, existing literature is mostly limited to retrospective or administrative studies that have not clearly defined the prevalence and risk factors. Our aim was to identify patient- and disease-related associations with osteopathy in a prospective cohort study of CP. Methods We studied 282 subjects with definitive CP enrolled in the PROCEED study who had a baseline dual-energy X-ray absorptiometry (DXA) scan. Osteopenia and osteoporosis were defined using the lowest T-scores. Clinical data were collected using standardized case report forms. Comparisons were performed with a multivariate logistic regression model with forward selection to identify risk factors for osteopathy. Results The majority of subjects had osteopathy on DXA scan (56.0%; 17.0% osteoporosis; 39.0% osteopenia). Subjects with osteopathy had a higher prevalence of traumatic (40.0% vs 26.4%; P = .02) and spontaneous fractures (3.9% vs 0; P = .04). On multivariate analysis, older age (odds ratio [OR], 1.29 per 5 years; 95% confidence interval [CI], 1.15–1.45), female sex (OR, 3.08; 95% CI, 1.75–5.43), white race (OR, 2.68; 95% CI, 1.20–6.01), and underweight body mass index category (OR, 7.40; 95% CI, 1.56–34.99) were associated with higher probability of osteopathy. There were no significant associations between osteopathy and other patient and disease-related features of CP. Conclusion In the largest study of patients with CP who underwent DXA screening, the majority had osteopathy. There are overlapping risk factors with osteopathy in the general population, but the high prevalence in men and younger women supports the need for future investigations into the mechanisms of bone loss in CP. ClinicalTrials.gov number, NCT03099850.

Partial or complete spontaneous regression (SR) of cancer is unusual, particularly in patients with oesophageal cancer. This case report describes a patient with biopsy-proven squamous cell carcinoma of the oesophagus which spontaneously regressed without any treatment. Regression of the primary tumour was confirmed on histological examination of the resected specimen. The process of SR remains an enigma, but potential mechanisms are considered.

Background Association between irritability and depression has been frequently reported, but the nature of this association in the adult population is poorly understood. Objectives We examined associations among irritability (e.g., a feeling of agitation), inflammatory biomarkers, and depression during chemotherapy. Methods Forty-four patients with nonmetastatic breast cancer were assessed at baseline and after 3 months of chemotherapy on The Irritability Scale-Initial Version, severity and new onset of depressive symptoms using the Hamilton Depression Rating Scale, and serum levels of high-sensitivity C-reactive protein and interleukin 6. Results At baseline, high-sensitivity C-reactive protein significantly correlated with physical and mood subscales of The Irritability Scale-Initial Version, but not with depression. Irritability and high-sensitivity C-reactive protein significantly predicted the severity and new onset of moderate to severe depressive symptoms over time, while irritability and interleukin 6 significantly predicted new onset of moderate to severe depressive symptoms. Conclusion The findings suggest that irritability is an independent risk factor of depression and associated with increasing high-sensitivity C-reactive protein. Irritability needs to be effectively managed in patients with cancer undergoing chemotherapy to prevent them from developing depressive symptoms. These preliminary findings should be investigated in future large-sample studies.

To explore association between misdiagnosis of IC/BPS and demographics. Interstitial cystitis/bladder pain syndrome (IC/BPS) is associated with significant diagnostic uncertainty, resulting in frequent misdiagnosis as there is little known about the potential impact of key demographic factors.All patients in the VA system between 1999-2016 were identified by ICD-9/10 codes for IC/BPS (595.1/N30.10) (n = 9,503). ICD code accuracy for true IC/BPS (by strict criteria) was assessed by in-depth chart abstraction (n = 2,400). Associations were explored between rates of misdiagnosis and demographics.IC/BPS criteria were met in only 651 (48.8%) of the 1,334 charts with an ICD code for IC/BPS reviewed in depth. There were no differences in the misdiagnosis rate by race (P=.27) or by ethnicity (P=.97), after adjusting for differences in age and gender. In IC/BPS-confirmed cases, female patients were diagnosed at a younger age than males (41.9 vs. 58.2 years, P.001). Black and Hispanic patients were diagnosed at a younger age compared to White (41.9 vs. 50.2 years, P.001) and non-Hispanic patients, respectively (41.1 vs. 49.1 years, P=.002).There was a high rate of misdiagnosis of IC/BPS overall, with only 48.8% of patients with an ICD code for IC/BPS meeting diagnostic criteria. There were no significant associations between diagnostic accuracy and race/ethnicity. Black and Hispanic patients were more likely to receive a diagnosis of IC/BPS at a younger age, suggesting there may be differing natural histories or presentation patterns of IC/BPS between racial/ethnic groups.

PURPOSE: Aging associated with progressive declines in physical function is well-known; however, little is known about the trajectories of physical function before and after breast cancer diagnosis. The current study examined the trajectories in objective measures of physical function over 20 years for women with breast cancer and matched controls. METHODS: 2712 community-dwelling women (452 breast cancer cases and 1:5 matched cancer-free controls) aged 65 years or older at baseline (1986-1988) within the Study of Osteoporotic Fractures were followed for 20 years. Objective physical function was assessed up to 9 times, including hand-grip strength, timed chair stand, gait speed and quadriceps strength. Linear mixed models were used to model physical function changes in terms of secular time trend, group (cases or controls), period (pre-and post-diagnosis status), and their interaction terms. RESULTS: We observed all measures of physical function declined over time. While no differences in trends between cases and controls during the pre-diagnosis period were observed, after cancer diagnosis, grip strength and gait speed declined significantly faster in cases than controls. Quadriceps strength significantly decreased ~7 pounds shortly after breast cancer diagnosis, and then improved over time. CONCLUSION: Our prospective study revealed that older breast cancer survivors had significantly worse declines in grip strength and gait speed and a sharp, short-term drop followed by gradual improvement over time in quadriceps strength, compared to women without cancer. These findings suggest exercise training targeting muscle strength and mobility would be beneficial among older breast cancer survivors.

Introduction: The favorable outcomes with immunotherapy for mesothelioma were somewhat unexpected because this tumor has a low tumor mutation burden which has been associated with benefit in other cancers. Because chromosomal rearrangements are common in mesothelioma and have neoantigenic potential, we sought to determine whether they are associated with survival in patients treated with immunotherapy.Methods: Pleural biopsies of mesothelioma after at least one line of therapy were obtained from patients (n = 44) before treatment with nivolumab alone (NCT29908324) or in combination with ipilimumab (NCT30660511). RNA and whole-genome sequencing were performed to identify the junctions resulting from chromosomal rearrangements and antigen processing and presentation gene set expression. Associations with overall survival (OS) were estimated using Cox models. An OS cutoff of 1.5 years was used to distinguish patients with and without durable benefit for use in receiving operating characteristic curves.Results: Although tumor junction burdens were not predictive of OS, we identified significant interactions between the junction burdens and multiple antigen processing and presentation gene sets. The "regulation of antigen processing and presentation of peptide antigen" gene set revealed an interaction with tumor junction burden and was predictive of OS. This interaction also predicted 1.5-year or greater survival with an area under the receiving operating characteristic curve of 0.83. This interaction was not predictive of survival in a separate cohort of patients with mesothelioma who did not receive immune checkpoint inhibitors.Conclusions: Analysis of structural variants and antigen presentation gene set expression may facilitate patient selection for immune checkpoint inhibitors. (C) 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc.

There are limited data regarding the effect of treatment delays on important long-term outcomes among men with intermediate/high-risk prostate cancer (PC).We identified 3,962 men with intermediate/high-risk disease from the SEARCH cohort treated with radical prostatectomy (RP) from 1988 to 2018. Cox proportional hazard models assessed the association between time from biopsy to RP (up to 1 year) and time to castration-resistant PC (CRPC), metastasis and all-cause mortality. Interaction terms were used to test for effect modification by risk group.Of the 3,962 men, 167 developed CRPC, 248 developed metastases and 884 died after a median followup of 85 months. Longer delays between biopsy and RP were associated with a decreased risk of CRPC (adjusted HR=0.88, 95% CI: 0.80-0.98, p=0.02), independent of D'Amico risk group (interaction p0.05). In men with intermediate and high-risk disease, we found no statistically significant association between length of time to RP and risk of developing metastases (p=0.5 and 0.9, respectively) or all-cause mortality (p=0.1 and 0.1, respectively).Among men with intermediate and high-risk PC, we found no statistically significant increased risk of adverse long-term outcomes, including CRPC, metastasis and death, for men who had treatment delays up to 1 year following PC diagnosis.

CD19-directed chimeric antigen receptor–modified (CAR T) T cells achieve durable remissions in about 30% to 40% of relapsed/refractory large B-cell lymphomas. T-cell exhaustion and/or an immunosuppressive tumor microenvironment may contribute to CAR T-cell failure. Pembrolizumab, an anti-PD1 immune checkpoint inhibitor, may reverse T-cell exhaustion after CAR T-cell therapy. We treated 12 patients with B-cell lymphomas who were either refractory to (n = 9) or relapsed after (n = 3) CD19-directed CAR T-cell (4-1BB–costimulated) therapy with pembrolizumab 200 mg IV every 3 weeks. Median time from CAR T-cell infusion to first pembrolizumab dose was 3.3 months (range, 0.4-42.8 months). Pembrolizumab was well tolerated, and the only grade ≥3 adverse events related to pembrolizumab were neutropenia (n = 3; 25%). Best overall response rate after pembrolizumab was 25% (3 of 12 patients; 1 complete response; 2 partial responses). One (8%) patient had stable disease; thus, 4 of 12 (33%) patients had clinical benefit. After pembrolizumab, 4 patients with clinical benefit had an increase in percentage of CAR T cells by mass cytometry by time of flight (CyTOF); 3 of 4 of these patients also had increases in CAR19 transgene levels by quantitative polymerase chain reaction. Deep immune profiling using CyTOF revealed increased CAR T-cell activation and proliferation and less T-cell exhaustion in clinical responders. Together, PD1 blockade with pembrolizumab after CD19-directed CAR T-cell therapy appears safe and may achieve clinical responses in some patients with B-cell lymphomas refractory to or relapsed after CAR T-cell therapy. This trial was registered at www.clinicaltrials.gove as #NCT02650999.

Background: The need to better understand the molecular underpinnings of the heterogeneous outcomes of patients with prostate cancer is a pressing global problem and a key research priority for Movember. To address this, the Movember Global Action Plan 1 Unique tissue microarray (GAP1-UTMA) project constructed a set of unique and richly annotated tissue microarrays (TMA) from prostate cancer samples obtained from multiple institutions across several global locations. Methods: Three separate TMA sets were built that differ by purpose and disease state. Results: The intended use of TMA1 (Primary Matched LN) is to validate biomarkers that help determine which clinically localized prostate cancers with associated lymph node metastasis have a high risk of progression to lethal castration-resistant metastatic disease, and to compare molecular properties of high-risk index lesions within the prostate to regional lymph node metastases resected at the time of prostatectomy. TMA2 (Pre vs. Post ADT) was designed to address questions regarding risk of castration-resistant prostate cancer (CRPC) and response to suppression of the androgen receptor/androgen axis, and characterization of the castration-resistant phenotype. TMA3 (CRPC Met Heterogeneity)'s intended use is to assess the heterogeneity of molecular markers across different anatomic sites in lethal prostate cancer metastases. Conclusions: The GAP1-UTMA project has succeeded in combining a large set of tissue specimens from 501 patients with prostate cancer with rich clinical annotation. Impact: This resource is now available to the prostate cancer community as a tool for biomarker validation to address important unanswered clinical questions around disease progression and response to treatment.

Evidence-based lifestyle interventions tailored to young adults with serious mental illness are needed to reduce their cardiometabolic risk. This study evaluated the effectiveness of a group lifestyle intervention ("PeerFIT") enhanced with mobile health (mHealth) compared with one-on-one mHealth coaching (basic education supported by activity tracking [BEAT]) for young adults with serious mental illness who were overweight or obese.Participants were young adults ages 18-35 years with serious mental illness and a body mass index ≥25 kg/mParticipants were 150 young adults with a mean ± SD body mass index of 37.1±7.4. Intent-to-treat analyses revealed no significant between-group difference for weight-loss, CRF, or CVD outcomes at 6 and 12 months. Participants in both conditions achieved clinically significant CVD risk reduction, weight loss, and CRF from baseline to 6 and 12 months, and all these improvements were statistically significant (p0.01).The PeerFIT group lifestyle intervention was not superior to one-on-one mHealth coaching in achieving clinically significant changes in weight, CRF, and CVD risk reduction. Although both interventions improved outcomes, low-intensity mHealth coaching may be a more scalable approach for addressing modifiable cardiometabolic risk factors among young adults with serious mental illness.

Patients with stable ischemic heart disease (SIHD) may present with a variety of symptoms including typical angina, angina equivalents such as dyspnea or no symptoms. We sought to determine whether symptom status affects periprocedural safety and long-term mortality in patients undergoing PCI.Prospectively enrolled consecutive patients undergoing PCI for SIHD at six hospitals in Australia between 2005 to 2018 as part of the Melbourne Interventional Group registry. Symptom status was recorded at the time of PCI and patients undergoing staged PCI were excluded.Overall, 11,730 patients with SIHD were followed up for a median period of 5 years (maximum 14.0 years, interquartile range 2.2-9.0 years) with 1,317 (11.2%) being asymptomatic. Asymptomatic patients were older, and more likely to be male, have triple-vessel disease, with multiple comorbidities including renal failure, diabetes and heart failure (all P.01). These patients had significantly higher rates of periprocedural complications and major adverse cardiovascular events at 30-days. Long-term mortality was significantly higher in asymptomatic patients (27.2% vs 18.0%, P.001). On cox regression for long-term mortality, after adjustment for more important clinical variables, asymptomatic status was an independent predictor (Hazard ratio (HR) 1.39 95% CI 1.16-1.66, P.001).In a real-world cohort of patients undergoing revascularization for SIHD, absence of symptoms was associated with higher rates of periprocedural complications and, after adjustment for more important clinical variables, was an independent predictor of long-term mortality. As the primary goal of revascularization in SIHD remains angina relief, the appropriateness of PCI in the absence of symptoms warrants justification.

Clinical practice guidelines support sustained use of renin-angiotensin-aldosterone-system (RAAS) inhibitors over time in heart failure with reduced ejection fraction, yet few data are available regarding the frequency, timing or predictors of early treatment discontinuation in clinical practice.Among prevalent or new users of angiotensin-converting enzyme inhibitors (ACEis)/angiotensin receptor blockers (ARBs), angiotensin receptor-neprilysin inhibitors (ARNIs), and mineralocorticoid receptor antagonists (MRAs) in the CHAMP-HF (Change the Management of Patients with Heart Failure) registry, we estimated the frequency and independent predictors of treatment discontinuation during follow-up. Among sites with5 users of a given RAAS inhibitor, we evaluated practice variation in the proportion of patients with treatment discontinuation.Over median follow-up of 18 months, frequency of drug discontinuation of ACEis/ARBs, ARNIs and MRAs was 12.7% (444 of 3509 users), 10.4% (140 of 1352 users), and 20.4% (435 of 2129 users), respectively. An additional, 149 (11.0%) of ARNI users were switched to ACEis/ARBs, and 447 (12.7%) of ACEi/ARB users were switched to ARNIs during follow-up. Across sites, the median proportion of discontinuation of ACEis/ARBs, ARNIs and MRAs was 12.5% (25th-75th percentiles 6.9%-18.9%), 18.8% (25th-75th percentiles 12.5%-28.6%), and 19.6% (25th-75th percentiles 10.7%-27.0%), respectively. Chronic kidney disease was the only independent predictor of increased risk of discontinuation of each of the RAAS inhibitor classes (P0.02 for all). Higher Kansas City Cardiomyopathy Questionnaire overall summary scores independently predicted lower risk of discontinuation of ACEis/ARBs and ARNIs (both P0.001) but not of MRAs. Investigator clinical experience was predictive of lower risks of discontinuation of ACEis/ARBs and MRAs (P0.02) but not of ARNIs. All other independent predictors of discontinuation were unique to individual therapeutic classes.One in 10 patients discontinue ACEis/ARBs or ARNIs, and 1 in 5 discontinue MRAs in routine clinical practice of heart failure with reduced ejection fraction. Unique patient-level and clinician/practice-level factors are associated with premature discontinuation of individual RAAS inhibitors, which may help to guide structured efforts to promote treatment persistence in clinical care.

A 61-year-old male patient had four hospital admissions with Escherichia coli sepsis fever and abnormal liver function tests over an 8-year period of time (maximum aspartate aminotransferase 82 IU/L, maximum alkaline phosphatase 231 IU/L and bilirubin normal). On each occasion he was

Background Maternal nutrition is associated with epigenetic and cardiometabolic risk factors in offspring. Research in humans has primarily focused on assessing the impact of individual nutrients. Objective We sought to assess the collective impact of maternal dietary monounsaturated (MUFA), polyunsaturated (PUFA), and saturated fat (SFA) on epigenetic aging and cardiometabolic risk markers in healthy newborn infants using a geometric framework approach. Design Body fatness (n = 162), aortic intima-media thickness (n = 131), heart rate variability (n = 118), and epigenetic age acceleration (n = 124) were assessed in newborn infants. Maternal dietary intake was cross-sectionally assessed in the immediate postpartum period via a validated 80-item self-administered food-frequency questionnaire. Generalized additive models were used to explore interactive associations of nutrient intake, with results visualized as response surfaces. Results After adjustment for total energy intake, maternal age, gestational age, and sex there was a 3-way interactive association of MUFA, PUFA, and SFA (P = 0.001) with newborn epigenetic aging. This suggests that the nature of each fat class association depends upon one another. Response surfaces revealed MUFA was positively associated with newborn epigenetic age acceleration only at proportionately lower intakes of SFA or PUFA. We also demonstrate a potential beneficial association of omega-3 PUFA with newborn epigenetic age acceleration (P = 0.008). There was no significant association of fat class with newborn aortic intima-media thickness, heart rate variability, or body fatness. Conclusions In this study, we demonstrate an association between maternal dietary fat class composition and epigenetic aging in newborns. Future research should consider other characteristics such as the source of maternal dietary fatty acids.

Background In individuals at clinical high-risk for psychosis, elevated cortisol levels predict subsequent onset of psychotic disorder. However, it is unclear whether cortisol alterations are evident at an earlier clinical stage and promote progression of psychosis expression. This study aimed to address this issue by investigating whether cortisol levels in childhood were associated with the emergence of attenuated psychotic symptoms in early adulthood. In exploratory analyses, we examined whether cortisol and psychosocial stress measures interacted in predicting attenuated psychotic symptoms. Methods A sample of children (N = 109) enriched for psychosis risk factors were recruited at age 9–12 years and assessed at age 11–14 years (T1) and 17–21 years (T2). Measures of psychopathology, psychosocial stressors, and salivary cortisol were obtained at T1. Attenuated psychotic symptoms were assessed at T2 using the Prodromal Questionnaire. Results Diurnal cortisol (β = 0.915, 95% confidence interval: 0.062–1.769) and daily stressors (β = 0.379, 95% confidence interval: 0.034–0.723) at T1 were independently associated with total Prodromal Questionnaire scores at T2 after accounting for demographic factors and T1 psychopathology. Exploratory analyses indicated a significant interaction between T1 diurnal cortisol and daily stressors (β = 0.743, 95% confidence interval: 0.081–1.405), with the highest predicted T2 total Prodromal Questionnaire scores occurring when both diurnal cortisol and daily stressors were increased. Conclusions Our findings suggest that daily stressors and elevations in diurnal cortisol in late childhood/early adolescence increases risk for developing attenuated psychotic symptoms. These findings emphasize the importance of assessing environmental and biological risk factors for psychosis during neurodevelopmentally vulnerable time periods.

Objective : To investigate the clinical efficacy and safety of the controlled distraction-compression technique using an expandable titanium cage (ETC) in posttraumatic kyphosis (PTK).Methods : We retrospectively studied and collected data on 20 patients with PTK. From January 2014 to December 2017, the controlled distraction-compression technique using ETC was consecutively performed in 20 patients with PTK of the thoracolumbar zone (range, 36–82 years). Among them, nine were males and 11 were females and the mean age was 61.5 years. The patients were followed regularly at 1, 3, 6, and 12 months, and the last follow-up was more than 2 years after surgery.Results : The mean follow-up period was 27.3±7.3 months (range, 14–48). The average operation time was 286.8±33.1 minutes (range, 225–365). The preoperative regional kyphotic angle (RKA) ranged from 35.6° to 70.6° with an average of 47.5°±8.1°. The immediate postoperative mean RKA was 5.9°±3.8° (86.2% correction rate, p=0.000), and at the last follow-up more than 2 years later, the mean RKA was 9.2°±4.9° (80.2% correction rate, p=0.000). The preoperative mean thoracolumbar kyphosis was 49.1°±9.2° and was corrected to an average of 8.8°±5.3° immediately after surgery (p=0.000). At the last follow-up, a correction of 11.9°±6.3° was obtained (p=0.000). The preoperative mean back visual analog scale (VAS) score was 7.9±0.8 and at the last follow-up, the VAS score was improved to a mean of 2.3±1.0 with a 70.9% correction rate (p=0.000). The preoperative mean Oswestry disability index (ODI) score was 32.3±6.9 (64.6%) and the last follow-up ODI score was improved to a mean of 6.85±2.9 (3.7%) with a 78.8% correction rate (p=0.000). The overall complication was 15%, with two of distal junctional fractures and one of proximal junctional kyphosis and screw loosening. However, there were no complications directly related to the operation.Conclusion : Posterior vertebral column resection through the controlled distraction-compression technique using ETC showed safe and good results in terms of complications, and clinical and radiologic outcomes in PTK. However, to further evaluate the efficacy of this surgical procedure, more patients need long-term follow-up and there is a need to apply it to other diseases.

Objectives: to quantify radiographic outcomes and identify predictors of late displacement in the nonoperative treatment of LC-2 pelvic ring injuries. Design Retrospective review. Setting Two level 1 trauma centers. Patients/participants Thirty eight patients ≥18 years old with LC-2 pelvic ring injuries. Intervention Nonoperative treatment. Main outcome measurements Crescent fracture displacement measured on initial axial Computed Tomography. Change in pelvic ring alignment measured by the Deformity Index, Simple Ratio, Inlet and Outlet Ratios on successive plain radiographs. Results Patients in this study had minimally displaced LC-2 pelvic ring injuries, with median initial crescent fracture displacement of 2mm and median initial Deformity Index of 2%. No patient had a ≥10 percentage point change in Deformity Index over the treatment period, but small amounts of displacement were seen on the other ratios. No patients initially selected for nonoperative treatment converted to operative treatment. No radiographic predictors of late displacement were identified. Bilateral pubic rami fractures and the presence of a complete sacral fracture ipsilateral to the crescent fracture were not associated with late displacement. Conclusions A spectrum of injury severity and stability exists in the LC-2 pattern. Nonoperative treatment of LC-2 injuries with low initial deformity and crescent fracture displacement results in minimal subsequent displacement. Level of evidence Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

The majority of coronary atherothrombotic events presenting as myocardial infarction (MI) occur as a result of plaque rupture or erosion. Understanding the evolution from a stable plaque into a life-threatening, high-risk plaque is required for advancing clinical approaches to predict atherothrombotic events, and better treat coronary atherosclerosis. Unfortunately, none of the coronary imaging approaches used in clinical practice can reliably predict which plaques will cause an MI. Currently used imaging techniques mostly identify morphological features of plaques, but are not capable of detecting essential molecular characteristics known to be important drivers of future risk. To address this challenge, engineers, scientists, and clinicians have been working hand-in-hand to advance a variety of multimodality intravascular imaging techniques, whereby 2 or more complementary modalities are integrated into the same imaging catheter. Some of these have already been tested in early clinical studies, with other next-generation techniques also in development. This review examines these emerging hybrid intracoronary imaging techniques and discusses their strengths, limitations, and potential for clinical translation from both an engineering and clinical perspective.

Bone marrow failure syndromes encompass a range of inherited and acquired hematological diseases that result in insufficient blood cell production, which leads to severe complications including anemia, weakening of the immune system, impaired coagulation, and increased risk of cancer. Within inherited bone marrow failure syndromes, a number of genetically distinct diseases have been described including Shwachman-Diamond syndrome and Fanconi anemia. Given the genetic complexity and poor prognosis of these inherited bone marrow failure syndromes, there is increasing interest in both characterizing the genetic landscapes of these diseases and developing novel gene therapies in order to effectively monitor and cure patients. These topics were the focus of the winter 2021 International Society for Experimental Hematology New Investigator Webinar, which featured presentations by Drs. Akiko Shimamura and Paula Rio. Here, we review the topics covered within this webinar.

To determine the trends in hospitalizations for heart failure (HF), acute myocardial infarction (AMI), and stroke in the United States (US).A retrospective analysis of the National Inpatient Sample weighted data between January 1, 2004 and December 31, 2018 which included hospitalized adults ≥18 years with a primary discharge diagnosis of HF, AMI, or stroke using International Classification of Diseases-9/10 administrative codes. Main outcomes were hospitalization for HF, AMI, and stroke per 1000 United States adults, length of stay, and in-hospital mortality. There were 33.4 million hospitalizations for HF, AMI, and stroke, with most being for HF (48%). After the initial decline in HF hospitalizations (5.3 hospitalizations/1000 US adults in 2004 to 4 hospitalizations/1000 US adults in 2013, P.001), there was a progressive increase in HF hospitalizations between 2013 and 2018 (4.0 hospitalizations/1000 US adults in 2013 to 4.9 hospitalizations/1000 US adults in 2018; P .001). Hospitalization for AMI decreased (3.1 hospitalizations/1000 US adults in 2004 to 2.5 hospitalizations/1000 US adults in 2010, P.001) and remained stable between 2010 and 2018. There was no significant change for hospitalization for stroke between 2004 and 2011 (2.3 hospitalizations/1000 US adults in 2004 vs 2.3 hospitalizations per 1000 US adults in 2011, P = .614); however, there was a small but significant increase in hospitalization for stroke after 2011 that reached 2.5 hospitalizations/1000 US adults in 2018. Adjusted length of stay and in-hospital mortality decreased for HF, AMI, and stroke hospitalizations.In contrast to the trend of AMI and stroke hospitalizations, a progressive increase in hospitalizations for HF has occurred since 2013. From 2004 to 2018, in-hospital mortality has decreased for HF, AMI, and stroke hospitalizations.

High-risk relapsed or refractory (R/R) classical Hodgkin lymphoma (HL) is associated with poor outcomes after conventional salvage therapy and autologous hematopoietic cell transplantation (AHCT). Post-AHCT consolidation with brentuximab vedotin (BV) improves progression-free survival (PFS), but with increasing use of BV early in the treatment course, the utility of consolidation is unclear. CD25 is often expressed on Reed-Sternberg cells and in the tumor microenvironment in HL, and we hypothesized that the addition of 90Y-antiCD25 (aTac) to carmustine, etoposide, cytarabine, melphalan (BEAM) AHCT would be safe and result in a transplantation platform that is agnostic to prior HL-directed therapy. Twenty-five patients with high-risk R/R HL were enrolled in this phase 1 dose-escalation trial of aTac-BEAM. Following an imaging dose of 111In-antiCD25, 2 patients had altered biodistribution, and a third developed an unrelated catheter-associated bacteremia; therefore, 22 patients ultimately received therapeutic 90Y-aTac-BEAM AHCT. No dose-limiting toxicities were observed, and 0.6 mCi/kg was deemed the recommended phase 2 dose, the dose at which the heart wall would not receive >2500 cGy. Toxicities and time to engraftment were similar to those observed with standard AHCT, though 95% of patients developed stomatitis (all grade 1-2 per Bearman toxicity scale). Seven relapses (32%) were observed, most commonly in patients with ≥3 risk factors. The estimated 5-year PFS and overall survival probabilities among 22 evaluable patients were 68% and 95%, respectively, and non-relapse mortality was 0%. aTac-BEAM AHCT was tolerable in patients with high-risk R/R HL, and we are further evaluating the efficacy of this approach in a phase 2 trial. This trial was registered at www.clinicaltrials.gov as #NCT01476839.

Tisagenlecleucel is indicated for pediatric and young adult patients with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL) and adult patients with r/r diffuse large B-cell lymphoma (DLBCL). The tisagenlecleucel chimeric antigen receptor (CAR) contains a murine single-chain variable fragment domain; we examined the effects of humoral and cellular immune responses to tisagenlecleucel on clinical outcomes using 2 validated assays. Data were pooled from the ELIANA (registered at www.clinicaltrials.gov as #NCT02435849) and ENSIGN (#NCT02228096) trials in r/r B-ALL (N = 143) and the JULIET trial (#NCT02445248) in r/r DLBCL (N = 115). Humoral responses were determined by flow cytometric measurement of anti-murine CAR19 (mCAR19) antibodies in serum. Cellular responses were determined using T-cell production of interferon-γ in response to 2 different pools of mCAR19 peptides. Pretreatment anti-mCAR19 antibodies were detected in 81% of patients with r/r B-ALL and 94% of patients with r/r DLBCL. Posttreatment anti-mCAR19 antibodies were higher than patient-specific baseline in 42% of r/r B-ALL and 9% of r/r DLBCL patients. Pretreatment and posttreatment anti-mCAR19 antibodies did not affect tisagenlecleucel cellular kinetics, including maximum concentration and persistence (r2 < 0.05), clinical response (day-28 response, duration of response, and event-free survival), and safety. T-cell responses were consistent over time, with net responses

Epstein-Barr virus (EBV) causes endemic Burkitt lymphoma, the leading childhood cancer in sub-Saharan Africa. Burkitt cells retain aspects of germinal center B-cell physiology with MYC-driven B-cell hyperproliferation; however, little is presently known about their iron metabolism. CRISPR/Cas9 analysis highlighted the little-studied ferrireductase CYB561A3 as critical for Burkitt proliferation but not for that of the closely related EBV-transformed lymphoblastoid cells or nearly all other Cancer Dependency Map cell lines. Burkitt CYB561A3 knockout induced profound iron starvation, despite ferritinophagy ad plasma membrane transferrin upregulation. Elevated concentrations of ascorbic acid, a key CYB561 family electron donor, or the labile iron source ferrous citrate rescued Burkitt CYB561A3 deficiency. CYB561A3 knockout caused catastrophic lysosomal and mitochondrial damage and impaired mitochondrial respiration. Conversely, lymphoblastoid B cells with the transforming EBV latency III program were instead dependent on the STEAP3 ferrireductase. These results highlight CYB561A3 as an attractive therapeutic Burkitt lymphoma target.

BACKGROUND AND METHODS: Treatment strategies for pancreatic cancer patients are made by a multidisciplinary team (MDT) board. We aimed to assess intra-observer variance at MDT boards. Participating units staged, assessed resectability, and made treatment allocations for the same patients as they did two years earlier. We disseminated clinical information and CT images of pancreatic cancer patients judged by one MDT board to have nonmetastatic pancreatic cancer to the participating units. All units were asked to re-assess the TNM stage, resectability, and treatment allocation for each patient. To assess intra-observer variance, we computed %-agreements for each participating unit, defined as low (75%) agreement.RESULTS: Eighteen patients were re-assessed by six MDT boards. The overall agreement was moderate for TNM-stage (ranging from 50%-70%) and resectability assessment (53%) but low for treatment allocation (46%). Agreement on resectability assessments was low to moderate. Findings were similar but more pronounced for treatment allocation. We observed a shift in treatment strategy towards increasing use of neoadjuvant chemotherapy, particularly in patients with borderline resectable and locally advanced tumors.CONCLUSIONS: We found substantial intra-observer agreement variations across six different MDT boards of 18 pancreatic cancer patients with two years between the first and second assessment.

The authors sought to investigate associations between sacubitril/valsartan adherence and clinical outcomes after hospitalization for heart failure with reduced ejection fraction (HFrEF).Sacubitril/valsartan improves outcomes in HFrEF, though the extent to which medication adherence is associated with outcomes in routine care is less well characterized.The authors analyzed patients aged ≥65 years hospitalized for HFrEF within the Get With the Guidelines-Heart Failure registry linked with Medicare claims between October 2015 and September 2018 who were discharged with sacubitril/valsartan. Sacubitril/valsartan adherence was assessed using medication fills to calculate proportion of days covered (PDC) through 90 days postdischarge. Associations between postdischarge adherence (PDC or ≥80%) and risk of readmission and death within 1 year were examined by comparing cumulative incidences and adjusted event rates.Among 897 patients prescribed sacubitril/valsartan at discharge, 295 (32.9%) had PDC ≥80% and 602 (67.1%) had PDC 80%. Baseline characteristics were balanced between groups. Compared with patients with PDC 80%, patients with PDC ≥80% had a significantly lower adjusted hazard of all-cause rehospitalization (HR: 0.66 [95% CI: 0.48-0.89]) and death (HR: 0.42 [95% CI: 0.22-0.79]) at 90 days and at 1 year (HR: 0.69 [95% CI: 0.56-0.86] and HR: 0.53 [95% CI: 0.38-0.74], respectively). For every 5 percentage point increase in PDC, patients experienced a significant reduction in rehospitalization (HR: 0.98 [95% CI: 0.97-0.99]) and death (HR: 0.96 [95% CI: 0.94-0.97]) at 1 year.In patients hospitalized for HFrEF and discharged on sacubitril/valsartan, high adherence to sacubitril/valsartan within 90 days after discharge was associated with substantially lower rates of readmission and death. Additional efforts to improve adherence with sacubitril/valsartan and other guideline-directed medical therapies in HFrEF are warranted.

Purpose: This study provides a contemporary assessment of the treatment patterns, health care resource utilization (HRU) and costs among metastatic castration-sensitive prostate cancer (mCSPC) patients in the U.S. Materials and Methods: Adults with mCSPC were selected from Optum's de-identified Clinformatics® Data Mart Database (Commercial insurance/Medicare Advantage [COM/MA]; January 1, 2014–July 31, 2019) or Medicare Fee-for-Service (FFS; January 1, 2014–December 31, 2017). The index date was the first metastatic disease diagnosis date on/after the first prostate cancer diagnosis (without prior evidence of castration resistance). Patients were observed for 12 months pre-index (baseline) through their mCSPC period (from index until castration resistance or followup end). First-line (1L) mCSPC therapy was assessed during the mCSPC period; all-cause HRU and health plan-paid costs per-patient-per-year (PPPY) were measured during baseline and mCSPC periods. Results: Among 6,517 COM/MA and 13,324 Medicare-FFS mCSPC patients over ∼10 months (median mCSPC period), 38% and 48% remained untreated/deferred treatment, and 45% and 46% received 1L androgen deprivation therapy (ADT) monotherapy, respectively. 1L abiraterone acetate and docetaxel were used among 7% and 6% of COM/MA and 1% and 2% of Medicare-FFS patients, respectively. HRU increased from baseline to mCSPC period, resulting in increased health plan-paid costs from $21,201 to $108,767 in COM/MA and from $16,819 to $69,639 PPPY in Medicare-FFS. Conclusions: This study highlights the limited use of newer therapies that improve survival in men with mCSPC in the U.S. HRU and costs increased substantially after onset of metastasis. Given the emergence of newer effective mCSPC therapies, further evaluation of future real-world mCSPC treatment patterns and outcomes is warranted.

PURPOSE The purpose of this study was to examine racial differences in patient portal activation and research participation among patients with prostate cancer. MATERIALS AND METHODS Participants were African American and White patients with prostate cancer who were treated with radical prostatectomy (n = 218). Patient portal activation was determined using electronic health records, and research participation was measured based on completion of a social determinants survey. RESULTS Thirty-one percent of patients completed the social determinants survey and enrolled in the study and 66% activated a patient portal. The likelihood of enrolling in the study was reduced with greater levels of social deprivation (odds ratio [OR], 0.70; 95% CI, 0.50 to 0.98; P = .04). Social deprivation also had a signification independent association with patient portal activation along with racial background. African American patients (OR, 0.48; 95% CI, 0.23 to 0.91; P = .02) and those with greater social deprivation (OR, 0.58; 95% CI, 0.42 to 0.82; P = .002) had a lower likelihood of activating a patient portal compared with White patients and those with lower social deprivation. CONCLUSION Although the majority of patients with prostate cancer activated their patient portal, rates of patient portal activation were lower among African American patients and those who lived in areas with greater social deprivation. Greater efforts are needed to promote patient portal activation among African American patients with prostate cancer and address access to health information technology among those who live in socially disadvantaged geographic areas.

ObjectiveIndividuals with ankylosing spondylitis (AS) have a greater cardiovascular (CV) risk than those in the general population. The effect of tumor necrosis factor inhibitors (TNFis) on CV risk, including on the development of hypertension (HTN), remains unclear, with some data suggesting higher risk. We assessed the association of TNFi use with incident HTN in a longitudinal AS cohort.MethodsAdults with AS enrolled in a prospective cohort in 2002–2018 were examined every 4–6 months. TNFi use during the preceding 6 months was ascertained at each study visit. We defined HTN by patient-reported HTN, antihypertensive medication use, or, on 2 consecutive visits, systolic blood pressure (BP) ≥ 140 mmHg or diastolic BP ≥ 90 mmHg. We evaluated the association between TNFi use and the development of HTN with marginal structural models, estimated by inverse probability-of-treatment weighting, to account for time-dependent confounders and informative censoring. Potential confounders included age, sex, race, site, nonsteroidal antiinflammatory drug use, and disease activity.ResultsWe included 630 patients without baseline HTN and with at least 1 year of follow-up. Of these, 72% were male, mean age was 39 ± 13 years, and 43% used TNFi at baseline. On follow-up (median 5 yrs), 129 developed incident HTN and 163 started on TNFi during follow-up. TNFi use was not associated with incident HTN (adjusted HR 1.10, 95% CI 0.83–1.37).ConclusionIn our prospective AS cohort, TNFi use was not significantly associated with incident HTN.

Purpose To elucidate strategies for and controversies surrounding the use of anti-inflammatory medications after uneventful cataract surgery, with a focus on the prevention of irreversible vision loss due to cystoid macular edema (CME). Design Perspective. Methods Expert commentary on the management of inflammation after cataract surgery. Discussion includes combination therapy with corticosteroids and nonsteroidal anti-inflammatory drugs (NSAIDs), dosing strategies, and emerging therapies. Results While prescribing both NSAIDs and corticosteroids for cataract surgery is common, these classes have overlapping mechanisms. Combination therapy may speed visual recovery, but there remains little evidence for improved long-term visual outcomes from NSAIDs. The last 2 decades have seen increasing data on potential benefits of pretreatment with NSAIDs 1-3 days prior to cataract surgery. Simultaneously, newly approved “dropless” delivery systems hold promise, and clinical trials are ongoing to assess outcomes of such formulations. Conclusions Optimal pharmacologic treatment for inflammation after cataract surgery remains controversial. A consensus definition for clinically significant CME may facilitate the comparison of anti-inflammatory drugs. And there remains a need for well-designed trials examining both topical and extended-release drug-delivery systems to refine the treatment paradigm.

To compare short- and long-term outcomes after transcatheter aortic valve implantation (TAVI) in the public and private hospital setting.Propensity-matched, retrospective analysis of a prospective registry.Patients with severe aortic stenosis who underwent TAVI at a tertiary public hospital (n=507) and an experienced private hospital (n=436).The primary endpoint was all-cause mortality.Patients that underwent TAVI in the public hospital were younger than patients in the private hospital (82±8 years vs 84±6 years, p0.001), with lower estimated short-term mortality risk (Society of Thoracic Surgeons Predicted Risk of Mortality [STS-PROM] score4.0%: 43% vs 56%, p0.001). There was no difference between public and private hospitals in 30-day mortality (1.5% vs 1.2%, p=1.0), and the rate of complications was similar. Long-term survival was similar in propensity-matched public (n=344) and private (n=344) patient cohorts. The 1-year, 2-year, 5-year and 7-year survival rates were 95%, 90%, 67% and 47% in public patients, and 92%, 86%, 67% and 51% in private patients (p=0.94). In multivariable analysis, the hospital setting was not a predictor of mortality.Despite increased age and predicted mortality in private hospital patients, short- and long-term outcomes after TAVI were comparable between public and private hospital settings. This study demonstrates the feasibility of performing TAVI in a private hospital with a dedicated and experienced team and questions the current restricted access to TAVI in the private sector.

BackgroundAdvanced pancreatic ductal adenocarcinoma (PDAC) is characterized by progressive weight loss and nutritional deterioration. This wasting has been linked to poor survival outcomes, alterations in host defenses, decreased functional ability, and diminished health-related quality of life (HRQOL) in pancreatic cancer patients. There are currently no standardized approaches to the management of pancreatic cancer cachexia. This study explores the feasibility and efficacy of enteral tube feeding of a peptide-based formula to improve weight stability and patient-reported outcomes (PROs) in advanced PDAC patients with cachexia.MethodsThis was a single-institution, single-arm prospective trial conducted between April 2015 and March 2019. Eligible patients were adults (>18years) diagnosed with advanced or locally advanced PDAC and cachexia, defined as greater than 5% unexplained weight loss within 6months from screening. The study intervention included three 28day cycles of a semi-elemental peptide-based formula, administered through a jejunal or gastrojejunal feeding tube. The primary outcome was weight stability at 3months (Cycle 3), defined as weight change less than 0.1kg/baseline BMI unit from baseline. Secondary outcomes included changes in lean body mass, appendicular lean mass, bone mineral density, fat mass, and percent body fat, as measured with a DEXA scan, HRQOL (EORTC QLQC30) and NIH PROMIS PROs assessed at each cycle. Daily activity (steps, distance, active minutes, heart rate, and sleep) were remotely monitored using a wearable activity monitor (Fitbit) over the 3month study period.ResultsThirty-six patients were screened for eligibility, 31 patients consented onto study and underwent jejunal tube placement, and 16 patients completed treatment: mean age 67years (SD 9.3), 43.8% male. Among evaluable patients (n=16), weight stability was achieved in 10 patients (62.5%), thus completing the trial early. Increases in lean body mass (1273.1, SD: 4078, P=0.01) and appendicular lean mass (0.45, SD: 0.6, P=0.02) were observed. Statistically significant improvements at Cycle 3 from baseline were also observed for QLQC30 role function [mean difference (MD): 20.1, P=0.03], appetite (MD: 27.4, P=0.02), and global health scores (MD: 13.3, P=0.05) as well as for NIH PROMIS t-scores for depression (MD: -10.4, P=0.006) and pain interference (MD: -7.5, P=0.05). Objectively monitored (Fitbit) activity levels increased, although statistical significance was not reached.ConclusionsOur findings suggest that enteral nutrition support may improve weight stability, lean body mass, appendicular lean mass and PROs in PDAC patients with cachexia who completed treatment, representing a subsample of the study population. The feasibility and role of enteral feeding in routine care remain unclear, and larger and randomized controlled trials are warranted.

Patients with sickle cell disease (SCD) have a lower risk for HIV-1 infection. We reported restriction of ex vivo HIV-1 infection in SCD peripheral blood mononuclear cells (PBMCs) that was due, in part, to the upregulation of antiviral, inflammatory, and hemolytic factors, including heme oxygenase-1 (HO-1). Here, we investigated whether individuals with sickle cell trait (SCT), who develop mild hemolysis, also restrict HIV-1 infection. Ex vivo infection of SCT PBMCs exhibited an approximately twofold reduction of HIV-1 replication and lower levels of HIV-1 reverse transcription products, 2-long terminal repeat circle, HIV-1 integration, and gag RNA expression. SCT PBMCs had higher HO-1 messenger RNA (mRNA) and protein levels and reduced ribonucleotide reductase 2 (RNR2) protein levels. HO-1 inhibition by tin porphyrin eliminated ex vivo HIV-1 restriction. Among Howard University clinic recruits, higher levels of HO-1 and RNR2 mRNA and lower HIV-1 env mRNA levels were found in SCT individuals living with HIV-1. To determine the population-level effect of SCT on HIV-1 prevalence, we assessed SCT among women living with HIV (WLH) in the WIHS (Women Interagency HIV-1 Study). Among WIHS African-American participants, the prevalence of SCT was lower among women with HIV compared with uninfected women (8.7% vs 14.2%; odds ratio, 0.57; 95% confidence interval, 0.36-0.92; P = .020). WIHS WLH with SCT had higher levels of CD4+/CD8+ ratios over 20 years of follow-up (P = .003) than matched WLH without SCT. Together, our findings suggest that HIV-1 restriction factors, including HO-1 and RNR2, might restrict HIV-1 infection among individuals with SCT and limit the pathogenicity of HIV.

Ineffective antibody-mediated responses are a key characteristic of chronic viral infection. However, our understanding of the intrinsic mechanisms that drive this dysregulation are unclear. Here, we identify that targeting the epigenetic modifier BMI-1 in mice improves humoral responses to chronic lymphocytic choriomeningitis virus. BMI-1 was upregulated by germinal center B cells in chronic viral infection, correlating with changes to the accessible chromatin landscape, compared to acute infection. B cell-intrinsic deletion of Bmi1 accelerated viral clearance, reduced splenomegaly and restored splenic architecture. Deletion of Bmi1 restored c-Myc expression in B cells, concomitant with improved quality of antibody and coupled with reduced antibody-secreting cell numbers. Specifically, BMI-1-deficiency induced antibody with increased neutralizing capacity and enhanced antibody-dependent effector function. Using a small molecule inhibitor to murine BMI-1, we could deplete antibody-secreting cells and prohibit detrimental immune complex formation in vivo. This study defines BMI-1 as a crucial immune modifier that controls antibody-mediated responses in chronic infection.

Background The association between dietary protein intake and the risk of mortality is still controversial. The present study aimed to examine the associations between dietary total, animal and plant protein intake and all-cause and cause-specific mortality. Methods Community-dwelling men aged ≥ 70 years were recruited from local government areas surrounding Concord Hospital in Sydney, New South Wales for the Concord Health and Ageing in Men Project (CHAMP). The research dietitian administered a standardised validated diet history questionnaire to capture baseline dietary intake. In total, 794 men participated in a detailed diet history interview at the third wave. Adequacy of protein intake was assessed by comparing participant intake with the Nutrient Reference Values. Total protein intake was categorised into quintiles. Sources of protein were also captured. Mortality was ascertained through the New South Wales death registry. Cox proportional hazard models were used to assess the association between dietary total, animal and plant protein intake and risk of mortality. Results The mean age of the CHAMP men was 81 years. In total, 162 men died during a median follow-up of 3.7 years. Of these, 54 (33.3%) and 49 (30.2%) men died due to cancer and cardiovascular disease, respectively. There were U-shaped associations between protein intake and all-cause and cancer mortality. In multiple adjusted analysis, the second (hazard ratio [HR] = 0.38; 95% confidence interval [CI] = 0.18-0.82) and third (HR = 0.36; 95% CI = 0.16-0.82) quintiles of protein intakes were significantly associated with reduced risk of all-cause and only second quintile (HR = 0.47; 95% CI = 0.10-0.93) of protein intake was significantly associated with cancer mortality. Each serve increase in animal protein was significantly associated with 12% (HR = 1.12; 95% CI = 1.00-1.26) and 23% (HR = 1.23; 95% CI = 1.02-1.49) increased risk of all-cause mortality and cancer mortality respectively. Conversely, each serve increase in plant protein intake was significantly associated with 25% (HR = 0.75; 95% CI 0.61-0.92) and 28% (HR = 0.72; 95% CI = 0.53-0.97) reduced risk of all-cause and cancer mortality, respectively. No such associations were observed for cardiovascular disease mortality. Conclusions Both second and third quintiles of total protein intake were associated with reduced all-cause and cancer mortality. Plant protein was inversely associated with all-cause and cancer mortality, whereas animal protein intake was positively associated with mortality.

Purpose Accurate diagnosis of amyloidosis remains a significant clinical challenge and unmet need for patients. The amyloid-reactive peptide p5+14 radiolabeled with iodine-124 has been developed for the detection of amyloid by PET/CT imaging. In a first-in-human evaluation, the dosimetry and tissue distribution of 124I-p5+14 peptide in patients with systemic amyloidosis. Herein, we report the dosimetry and dynamic distribution in the first three enrolled patients with light chain-associated (AL) amyloidosis. Procedures The radiotracer was assessed in a single-site, open-label phase 1 study (NCT03678259). The first three patients received a single intravenous infusion of 124I-p5+14 peptide (≤37 MBq). Serial PET/CT imaging was performed during the 48 h post-infusion. Dosimetry was determined as a primary endpoint for each patient and gender-averaged mean values were calculated. Pharmacokinetic parameters were estimated from whole blood radioactivity measurements and organ-based time activity data. Lastly, the biodistribution of radiotracer in major organs was assessed visually and compared to clinically appreciated organ involvement. Results Infusion of the 124I-p5+14 was well tolerated with rapid uptake in the heart, kidneys, liver, spleen, pancreas, and lung. The gender-averaged whole-body effective radiation dose was estimated to be 0.23 (± 0.02) mSv/MBq with elimination of the radioactivity via renal and gastrointestinal routes. The whole blood elimination t1/2 of 21.9 ± 7.6 h. Organ-based activity concentration measurements indicated that AUClast tissue:blood ratios generally correlated with the anticipated presence of amyloid. Peptide uptake was observed in 4/5 clinically suspected organs, as noted in the medical record, as well as six anatomic sites generally associated with amyloidosis in this population. Conclusion Peptide 124I-p5+14 rapidly distributes to anatomic sites consistent with the presence of amyloid in patients with systemic AL. The dosimetry estimates established in this cohort are acceptable for whole-body PET/CT imaging. Pharmacokinetic parameters are heterogeneous and consistent with uptake of the tracer in an amyloid compartment. PET/CT imaging of 124I-p5+14 may facilitate non-invasive detection of amyloid in multiple organ systems.

OBJECTIVE To evaluate the impact of obesity on etanercept (ETN) drug exposure in children with juvenile idiopathic arthritis (JIA). METHODS We conducted a pilot, cross-sectional, observational study in a real-world cohort of children with JIA receiving ETN as standard of care from a single center. We analyzed the relationship between body size and ETN plasma concentrations, adjusting for dosage. Body size was analyzed as a continuous measure using weight and body mass index (BMI) percentiles and categorically using BMI percentile classifications according to the CDC guidelines. RESULTS We enrolled a total of 29 children. Each child provided one plasma sample for ETN concentration measurement, and all participants were receiving subcutaneous ETN dosed weekly. We observed that the ETN concentration normalized for dose decreased significantly as a function of weight (p = 0.004) and BMI percentile (p = 0.04). Similarly, we observed a progressive decline in mean and median dose-normalized concentrations across higher body size categories. Because of reaching maximum ETN dosage (50 mg), 7 of 8 children (87.5%) with obesity received a weight-based dosage < 0.8 mg/kg/dose. CONCLUSIONS We found that higher body weight and BMI percentile are significantly and negatively associated with ETN drug serum concentration, accounting for differences in dosing. Our data suggest that children who are obese may be routinely under-dosed using current dosing strategies. Inadequate dosing may increase the risk for therapeutic failure and long-term morbidity in a developing child. As a result, characterizing adequate drug exposure in children of all sizes is an important step toward precision dosing.

Purpose To examine the efficacy and safety of corneal cross-linking (CXL) for stabilization of progressive keratoconus. Design Observer-masked, randomized, controlled, parallel-group superiority trial. Participants Sixty participants 10 to 16 years of age with progressive keratoconus, one eye of each deemed the study eye. Methods The study eye was randomized to either CXL plus standard care or standard care alone, with spectacle or contact lens correction as necessary for vision. Main Outcome Measures The primary outcome was steep keratometry (K2) in the study eye as a measure of the steepness of the cornea at 18 months. Secondary outcomes included keratoconus progression defined as a 1.5-diopter (D) increase in K2, visual acuity, keratoconus apex corneal thickness, and quality of life. Results Of 60 participants, 30 were randomized to CXL and standard care groups. Of these, 30 patients in the CXL group and 28 patients in the standard care group were analyzed. Mean K2 in the study eye 18 months after randomization was 49.7 D (standard deviation [SD], 3.8 D) in the CXL group and 53.4 D (SD, 5.8 D) in the standard care group. The adjusted mean difference in K2 in the study eye was –3.0 D (95% confidence interval [CI], –4.9 to –1.1 D; P = 0.002), favoring CXL. Adjusted differences between groups in uncorrected and corrected vision favored eyes receiving CXL: –0.31 logarithm of the minimum angle of resolution (logMAR; 95% CI, –0.50 to –0.11 logMAR; P = 0.002) and –0.51 logMAR (95% CI, –1.37 to 0.35 logMAR; P = 0.002). Keratoconus progression in the study eye occurred in 2 patients (7%) randomized to CXL compared with 12 patients (43%) randomized to standard care. The unadjusted odds ratio suggests that on average, patients in the CXL arm had 90% (odds ratio, 0.1; 95% CI, 0.02–0.48; P = 0.004) lower odds of experiencing progression compared with those receiving standard care. Conclusions CXL arrests progression of keratoconus in the majority of young patients. CXL should be considered as a first-line treatment in progressive disease. If the arrest of keratoconus progression induced by CXL is sustained in longer follow-up, particular benefit may be derived from avoiding a later requirement for contact lens wear or corneal transplantation.

Objective To identify the potential biomarkers of interstitial cystitis/painful bladder syndrome (IC), a chronic syndrome of bladder-centric pain with unknown etiology that has an adverse impact on quality of life, we analyzed the urine and serum metabolomes of a cohort of IC patients and non-disease controls (NC). Methods Home collection of serum and urine samples was obtained from 19 IC and 20 NC females in the Veterans Affairs (VA) Health Care System. IC was diagnosed independently by thorough review of medical records using established criteria. Biostatistics and bioinformatics analyses, including univariate analysis, unsupervised clustering, random forest analysis, and metabolite set enrichment analysis (MSEA), were then utilized to identify potential IC biomarkers. Results Metabolomics profiling revealed distinct expression patterns between NC and IC. Random forest analysis of urine samples suggested discriminators specific to IC; these include phenylalanine, purine, 5-oxoproline, and 5-hydroxyindoleacetic acid. When these urinary metabolomics-based analytes were combined into a single model, the AUC was 0.92, suggesting strong potential clinical value as a diagnostic signature. Serum-based metabolomics did not provide potential IC discriminators. Conclusion Analysis of serum and urine revealed that women with IC have distinct metabolomes, highlighting key metabolic pathways that may provide insight into the pathophysiology of IC. The findings from this pilot study suggest that integrated analyses of urinary metabolites, purine, phenylalanine, 5-oxoproline, and 5-HIAA, can lead to promising IC biomarkers for pathophysiology of IC. Validation of these results using a larger dataset is currently underway.

Background and Aims By different mechanisms, image-enhancement techniques (linked color imaging [LCI]) and mucosal exposure devices (Endocuff-assisted colonoscopy [EAC]) can improve the adenoma detection rate (ADR) during screening colonoscopy. The impact of the combination of the 2 techniques has never been studied. This study aimed to compare the ADR between the combination of LCI and EAC (LCI+EAC), LCI alone, EAC alone, and standard high-definition (HD) colonoscopy. Methods This prospective randomized controlled trial included participants who underwent screening colonoscopy. Participants were randomized to LCI+EAC, LCI, EAC, and standard HD colonoscopy. All colonoscopies were performed by endoscopists with a recorded ADR ≥35%. The primary outcome was the ADR. Secondary outcomes were proximal ADR (pADR) and the mean number of adenomas per colonoscopy (APC). Results One thousand participants were included in the study. The LCI+EAC group provided the highest ADR and pADR. The ADRs in the LCI+EAC, LCI, EAC, and standard HD colonoscopy groups were 57.2%, 52.8%, 51.6%, and 47.6%, respectively, with pADRs of 38.4%, 34.8%, 33.6%, and 28.0%, respectively. The mean numbers of APC were 1.28, 1.20, 1.16, and .89, respectively. After a multiple comparison adjustment, a significant difference in pADR was only observed between the LCI+EAC and standard HD colonoscopy groups (difference, 10.3 percentage points; 95% confidence interval, .02%-17.4%; P = .05). The incidence rate ratios of the adenoma numbers were significantly higher in the LCI+EAC (1.43), LCI (1.34), and EAC (1.30) groups relative to the standard HD colonoscopy group (.89) (P Conclusions The combination of LCI and EAC can significantly improve the detection of pADR and APC but not ADR by high-ADR performers. (Clinical trial registration number: TCTR20190319001.)

Sodium-glucose cotransporter-2 inhibitor therapy is well suited for initiation during the heart failure hospitalization, owing to clinical benefits that accrue rapidly within days to weeks, a strong safety and tolerability profile, minimal to no effects on blood pressure, and no excess risk of adverse kidney events. There is no evidence to suggest that deferring initiation to the outpatient setting accomplishes anything beneficial. Instead, there is compelling evidence that deferring in-hospital initiation exposes patients to excess risk of early postdischarge clinical worsening and death. Lessons from other heart failure with reduced ejection fraction therapies highlight that deferring initiation of guideline-recommended medications to the U.S. outpatient setting carries a >75% chance they will not be initiated within the next year. Recognizing that 1 in 4 patients hospitalized for worsening heart failure die or are readmitted within 30 days, clinicians should embrace the in-hospital period as an optimal time to initiate sodium-glucose cotransporter-2 inhibitor therapy and treat this population with the urgency it deserves.

Background/Purpose We sought to analyze the use of angioembolization (AE) after pediatric splenic injuries at adult and pediatric trauma centers (ATCs/PTCs). Methods The National Trauma Data Bank (2010–2015) was queried for patients ( Results 14,027 encounters met inclusion criteria. 514 (3.7%) patients underwent AE. When compared to PTCs, patients were older, had a higher ISS, and more often presented in shock at ATCs (p Conclusions AE was associated with improved splenic salvage at ATCs in select patients but appeared overutilized when compared to outcomes at PTCs. PTCs accomplished a higher splenic salvage rate with a lower AE utilization. Level of evidence III – Retrospective cohort study.

Background Greater variability in the estimated glomerular filtration rate (eGFR) is associated with higher mortality in patients with chronic kidney disease (CKD). Heart failure (HF) is common in CKD and may increase variability through changes in hemodynamic and volume regulation. We sought to determine if patients with vs without HF have higher kidney function variability in CKD, and to define the association with mortality. Methods and Results Patients undergoing coronary angiography from 2003 to 2013 with an eGFR of less than 60 mL/min/1.73 m2 were evaluated from the Duke Databank for Cardiovascular Disease. Variability in the eGFR, measured as the coefficient of variation (CV) of residuals from the regression of eGFR vs time, was calculated spanning 3 months to 2 years after catheterization. Mortality was assessed 2 to 7 years after catheterization. Patients were grouped into 3 HF phenotypes: HF with reduced ejection fraction, HF with preserved ejection, and no HF. Regression was used to evaluate associations between HF phenotypes and variability in the eGFR and between variability in the eGFR and mortality rate with stratification by HF phenotype. Among 3767 participants, the median eGFR at baseline was 45 mL/min/1.73 m2 (interquartile range 33-53 mL/min/1.73 m2), and longitudinal measures of eGFR over 21 months had within-patient residual variability (CV) of 14% (9%–20%). In adjusted analyses, variability in the eGFR was greater in those with HF with preserved ejection (n = 695, CV difference 0.98%, 95% confidence interval 0.14%–1.81%) or HF with reduced ejection fraction (n = 800, CV difference 2.51%, 95% confidence interval 1.66%–3.37%) relative to no HF (n = 2272). In 3068 participants eligible for mortality analysis, the presence of HF and greater variability in the eGFR were each associated independently with higher mortality, but there was no evidence of interaction between variability in the eGFR and any HF phenotype (all P for interaction ≥.49). Conclusions Variability in the eGFR is greater in patients with HF and associated with mortality. Prediction algorithms and classification schemes should consider not only static, but also dynamic eGFR variability in HF and CKD prognostication.

Substance use is common among those with heart failure (HF) and is associated with worse clinical outcomes. Alcohol, tobacco, cannabis, and cocaine are commonly abused substances that can contribute to the development and worsening of HF. Heavy alcohol consumption can lead to dilated cardiomyopathy, whereas moderate intake may decrease incident HF. Tobacco increases the risk of HF through coronary artery disease and coronary artery disease–independent mechanisms. Continued smoking worsens outcomes for those with HF and cessation is associated with an improved risk of major adverse cardiac events. Cannabis has complex interactions on the cardiovascular system depending on the method of consumption, amount consumed, and content of cannabinoids. Delta-9-tetrahydrocannabinol can increase sympathetic tone, cause vascular dysfunction, and may increase the risk of myocardial infarction. Cannabidiol is cardioprotective in preclinical studies and is a potential therapeutic target. Cocaine increases sympathetic tone and is a potent proarrhythmogenic agent. It increases the risk of myocardial infarction and can also lead to a dilated cardiomyopathy. The use of beta-blockers in those with HF and cocaine use is likely safe and effective. Future studies are needed to further elucidate the impact of these substances both on the development of HF and their effects on those who have HF.

Background Increased apposition of the frontal and parietal bones of the skull during embryogenesis may be a risk factor for the subsequent development of premature skull fusion, or craniosynostosis. Human craniosynostosis is a prevalent, and often serious embryological and neonatal pathology. Other than known mutations in a small number of contributing genes, the aetiology of craniosynostosis is largely unknown. Therefore, the identification of novel genes which contribute to normal skull patterning, morphology and premature suture apposition is imperative, in order to fully understand the genetic regulation of cranial development. Results Using advanced imaging techniques and quantitative measurement, we show that genetic deletion of the highly-conserved transcription factor Grainyhead-like 3 (Grhl3) in mice (Grhl3 −/− ) leads to decreased skull size, aberrant skull morphology and premature apposition of the coronal sutures during embryogenesis. Furthermore, Grhl3 −/− mice also present with premature collagen deposition and osteoblast alignment at the sutures, and the physical interaction between the developing skull, and outermost covering of the brain (the dura mater), as well as the overlying dermis and subcutaneous tissue, appears compromised in embryos lacking Grhl3. Although Grhl3 −/− mice die at birth, we investigated skull morphology and size in adult animals lacking one Grhl3 allele (heterozygous; Grhl3 +/− ), which are viable and fertile. We found that these adult mice also present with a smaller cranial cavity, suggestive of post-natal haploinsufficiency in the context of cranial development. Conclusions Our findings show that our Grhl3 mice present with increased apposition of the frontal and parietal bones, suggesting that Grhl3 may be involved in the developmental pathogenesis of craniosynostosis.

The Trypanosoma brucei Hsp70/J-protein machinery plays an essential role in survival, differentiation, and pathogenesis of the protozoan parasite, and is an emerging target against African Trypanosomiasis. This study evaluated a set of small molecules, inspired by the malonganenones and nuttingins, as modulators of the chaperone activity of the cytosolic heat inducible T. brucei Hsp70 and constitutive TbHsp70.4 proteins. The compounds were assessed for cytotoxicity on both the bloodstream form of T. b. brucei parasites and a mammalian cell line. The compounds were then investigated for their modulatory effect on the aggregation suppression and ATPase activities of the TbHsp70 proteins. A structure−activity relationship for the malonganenone-class of alkaloids is proposed based upon these results.

Methicillin-resistant Staphylococcus aureus (MRSA) is an important cause of ventilator-associated pneumonia (VAP). Patients with VAP have poorly functioning neutrophils, related to increased levels of the complement fragment C5a. The antibiotic linezolid has been useful in controlling MRSA-related VAP infections; however clinical benefit does not always correlate with antimicrobial effect, suggesting the possibility of immunomodulatory properties. Here the effects of linezolid on healthy and dysfunctional neutrophils (modelled by C5a-induced injury) was investigated. Functional assays (killing, phagocytosis, transmigration, and respiratory burst) were used to assess the effects of pre-, co- and post-incubating linezolid (0.4–40 mg/L) with healthy neutrophils relative to those with C5a-induced injury. C5a decreased neutrophil killing, and phagocytosis of MRSA. Furthermore, C5a significantly decreased neutrophil transmigration to IL-8, but did not affect respiratory burst. Co-incubation of linezolid significantly improved killing of MRSA by dysfunctional neutrophils, which was supported by concomitant increases in phagocytosis. Conversely linezolid impaired killing responses in healthy neutrophils. Pre- or post-incubation of linezolid prior or following C5a induced injury had no effect on neutrophil function. This study suggests that linezolid has immunomodulatory properties that protect human neutrophils from injury and provides insight into its mode of action beyond a basic antibiotic.

OBJECTIVES To evaluate changes in radiation exposure from computed tomography (CT) among patients undergoing liver transplantation in our unit over a 10-year period. METHODS We evaluated 134 elective patients, without hepatocellular carcinoma or cholangiocarcinoma who underwent transplantation in 2007-2008 and 2017-2018. CT scans performed in our hospital up to 2 years pre transplant and 1 year post transplant were evaluated. RESULTS There was an increase in mean estimated effective radiation dose per patient in 2017-2018 compared to 2007-2008 (77.8 mSv ± 6.2 vs 56.7 mSv ± 5.9, p 100 mSv of ionising radiation in the 2017-2018 patients (29% vs 11%, p

Background: There has been a steady improvement in the survival of patients with multiple myeloma (MM) due to better understanding of the pathophysiology, use of novel agents, and risk-adapted therapy. These improvements were largely observed in clinical trials and tertiary center populations and questions remain about the generalizability of these findings to patients in community settings. Here, we compared the experience of patients seen at Mayo Clinic, Rochester (MAYO) and those followed in the Surveillance, Epidemiology, and End Results Program (SEER), to gain a better understanding of current trends in survival. Methods: We studied all patients with MM diagnosed between 01/2004 and 12/2018 seen at MAYO and those followed in SEER (18 registry research data 2000-2018, 11/2020 submission). For comparison with SEER, MAYO patients who were alive at the end of SEER follow-up (12/31/2018) were censored. For the estimation of relative survival, patients alive at the end of 2019 were censored to align with the published United States general population rate tables. Overall survival (OS) estimates were calculated using the method described by Kaplan and Meier. Multivariable-adjusted proportional hazards regression models were used to assess the association between the 5-year interval of diagnosis and overall survival. Expected OS estimates were calculated based on United States general population rate tables from the Human Mortality Database using a conditional approach. Standardized mortality ratios (SMR) were calculated by dividing the number of observed deaths by the number of expected deaths in age- and sex-matched general United States population controls. Linear regression models were fit to test for trends in SMRs over time. Results: The median age at diagnosis was 3 years lower in patients seen at MAYO compared to patients followed in SEER. The proportion of patients 75 years and older at the time of diagnosis was higher in SEER (26.3%) compared to MAYO (15.3%). Median OS was 6.7 years (95% CI 6.3-7.1) for MAYO compared to 4.6 years (95% CI 4.5-4.7) in SEER (Figure 1). When stratifying OS by year of diagnosis (in 5-year-intervals: 2004-2008, 2009-2013, 2014-2018), improvements were seen in both patient populations over time, albeit to a greater extent in patients seen at MAYO (Figures 2 and 3). The results were consistent after adjusting for age and sex in both MAYO and SEER. There were improvements in OS across all three 5-year intervals and age groups in both patient populations. In MAYO, these improvements were most pronounced during the second 5-year interval for younger patients (< 65 years) and more pronounced during the last 5-year interval for older patients (> 65 years). In SEER, the improvements were more gradual across the three 5-year intervals, but it was noted that the relative improvements in younger patients were greater than in older patients during the last 5-year interval. Early mortality decreased over time in both patient populations: from 11% to 6% at MAYO and from 23% to 16% in SEER (Figure 4). To examine the observed improvements in the context of the survival trends of the general population, we stratified the SMRs by patient population, age at diagnosis, and year of diagnosis, and a lack of improvement in excess mortality was observed among older patients (>75 years) in both populations over time (Figure 5). Three- and five-year overall survival estimates were higher in patients seen at MAYO compared to patients followed in SEER, but the survival advantage diminished with increasing follow-up time (Figure 6). On further sub-group analysis within MAYO patients, excess mortality was observed for all International staging system (ISS) stages and patients with high-risk (HR) cytogenetics. Stratifying the SMRs by age and risk group, decreases in excess mortality were most pronounced among older patients, particularly those with indolent disease (Figure 7). Conclusions: Survival outcomes in MM continued to improve in both patient populations. These improvements were more pronounced in MAYO compared to SEER, which may be partially explained by differences in access to specialized care. The most pronounced improvements were observed among younger patients and those with favorable disease characteristics. Future efforts need to focus on improving therapies for patients with unfavorable disease characteristics and on increasing access to specialized care in community settings. Figure 1 Figure 1. Disclosures Kapoor: Glaxo SmithKline: Research Funding; Takeda: Research Funding; Sanofi: Research Funding; Amgen: Research Funding; Sanofi: Consultancy; Pharmacyclics: Consultancy; Ichnos Sciences: Research Funding; BeiGene: Consultancy; Regeneron Pharmaceuticals: Research Funding; AbbVie: Research Funding; Karyopharm: Research Funding; Karyopharm: Consultancy; Cellectar: Consultancy. Dingli: Alexion: Consultancy; Apellis: Consultancy; Janssen: Consultancy; Novartis: Research Funding; GSK: Consultancy; Sanofi: Consultancy. Gertz: Ionis Pharmaceuticals: Other: Advisory Board; Aurora Biopharma: Other: Stock option; AbbVie Inc, Celgene Corporation: Other: Data Safetly & Monitoring; Akcea Therapeutics, Ambry Genetics, Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Karyopharm Therapeutics, Pfizer Inc (to Institution), Sanofi Genzyme: Honoraria; Akcea Therapeutics, Alnylam Pharmaceuticals Inc, Prothena: Consultancy. Lin: Novartis: Consultancy; Celgene: Consultancy, Research Funding; Juno: Consultancy; Takeda: Research Funding; Gamida Cell: Consultancy; Vineti: Consultancy; Merck: Research Funding; Bluebird Bio: Consultancy, Research Funding; Legend: Consultancy; Sorrento: Consultancy; Janssen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding. Dispenzieri: Sorrento Therapeutics: Consultancy; Janssen: Consultancy, Research Funding; Takeda: Research Funding; Oncopeptides: Consultancy; Alnylam: Research Funding; Pfizer: Research Funding. Kumar: Tenebio: Research Funding; Amgen: Consultancy, Research Funding; Oncopeptides: Consultancy; Bluebird Bio: Consultancy; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Novartis: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche-Genentech: Consultancy, Research Funding; Beigene: Consultancy; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Carsgen: Research Funding; Antengene: Consultancy, Honoraria; BMS: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding.