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Classical Brownian motion (BM) has been commonly used in monitoring clinical trials including those with covariate adaptive randomization (CAR). Independent increment property is commonly assumed in the sequential monitoring process of the clinical trials with CAR designs. However, in reality, correlation may exist in the error terms of the underlying model, resulting in dependent increment in the sequential monitoring process. We conducted simulations for estimating the Hurst exponent to evaluate the stochastic property in the covariate adaptive randomized clinical trials under two scenarios: 1. CAR designs with independent and identically distributed error terms. 2. CAR designs with correlated error terms. The theoretical properties of covariate adaptive randomized clinical trials with correlated error structure were investigated. A test statistic including the covariance pattern of the error terms was proposed. In our study, the sequential test statistics under CAR procedure is shown to be asymptotically Brownian motion when the error structure is correctly specified. Further, Brownian motion is a special case of fractional Brownian motion when Hurst exponent equals to 0.5. Our simulations are consistent with the theoretical asymptotic results. [ABSTRACT FROM AUTHOR]

Mortality in infants with hypoplastic left heart syndrome (HLHS) is strongly correlated with right ventricle (RV) dysfunction. Cell therapy has demonstrated potential improvements of RV dysfunction in animal models related to HLHS, and neonatal human derived c-kit+ cardiac-derived progenitor cells (CPCs) show superior efficacy when compared to adult human cardiac-derived CPCs (aCPCs). Neonatal CPCs (nCPCs) have yet to be investigated in humans. The CHILD trial (Autologous Cardiac Stem Cell Injection in Patients with Hypoplastic Left Heart Syndrome) is a Phase I/II trial aimed at investigating intramyocardial administration of autologous nCPCs in HLHS infants by assessing the feasibility, safety, and potential efficacy of CPC therapy. Using an open-label, multicenter design, CHILD investigates nCPC safety and feasibility in the first enrollment group (Group A/Phase I). In the second enrollment group, CHILD uses a randomized, double-blinded, multicenter design (Group B/Phase II), to assess nCPC efficacy based on RV functional and structural characteristics. The study plans to enroll 32 patients across 4 institutions: Group A will enroll 10 patients, and Group B will enroll 22 patients. CHILD will provide important insights into the therapeutic potential of nCPCs in patients with HLHS. Clinical Trial Registrationhttps://clinicaltrials.gov/ct2/home NCT03406884, First posted January 23, 2018. [ABSTRACT FROM AUTHOR]

Objectives. We demonstrated the effectiveness of an accelerated hepatitis B vaccination schedule in drug users. Methods. We compared the long-term effectiveness of accelerated (0–1–2 months) and standard (0–1–6 months) hepatitis B vaccination schedules in preventing hepatitis B virus (HBV) infections and anti-hepatitis B (anti-HBs) antibody loss during 2-year follow-up in 707 drug users (HIV and HBV negative at enrollment and completed 3 vaccine doses) from February 2004 to October 2009. Results. Drug users in the accelerated schedule group had significantly lower HBV infection rates, but had a similar rate of anti-HBs antibody loss compared with the standard schedule group over 2 years of follow-up. No chronic HBV infections were observed. Hepatitis C positivity at enrollment and age younger than 40 years were independent risk factors for HBV infection and antibody loss, respectively. Conclusions. An accelerated vaccination schedule was more preferable than a standard vaccination schedule in preventing HBV infections in drug users. To overcome the disadvantages of a standard vaccination schedule, an accelerated vaccination schedule should be considered in drug users with low adherence. Our study should be repeated in different cohorts to validate our findings and establish the role of an accelerated schedule in hepatitis B vaccination guidelines for drug users. [ABSTRACT FROM AUTHOR]

It remains unclear when the fetus is most susceptible to the effects of particulate air pollution. We conducted a population-based study in a large urban area to evaluate associations between preterm birth (PTB) and fetal growth and exposures to fine particles (PM) during narrow periods of gestation. We identified 177,816 births during 2005-2007 among mothers who resided in Harris County, Texas at the time of delivery. We created three mutually exclusive categories of mildly (33-36 completed weeks of gestation), moderately (29-32 weeks of gestation), and severely (20-28 weeks of gestation) PTB, and among full term infants, we identified those who were born small for their gestational age. Using routine air monitoring data, we generated county-level daily time series of estimated ambient air levels of PM and then computed exposure metrics during every 4 weeks of a mother's pregnancy. We evaluated associations in each 4-week period using multiple logistic regression. A 10 μg/m increase in PM exposure in the first 4 weeks of pregnancy significantly increased the odds of mildly, moderately and severely PTB by 16, 71 and 73 %, respectively. Associations were stronger when infants with birth defects were excluded. Our findings indicate an association between PM and PTB, with stronger associations for moderately and severely PTB infants. Efforts should continue to implement stricter air quality standards and improve ambient air quality. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: To assess the distribution of proportion of deaths from causes other than colorectal cancer (CRC) over time and temporal trends of cause-specific cumulative incidence of death due to six leading causes in patients with CRC. Methods: Overall, 375,462 patients with CRC in nine Surveillance, Epidemiology, and End Results registries from 1975 to 2009 were included. Competing risks proportional hazards regression was used to examine the effect of diagnostic periods on the risk of cause-specific death. Results: From 1975 to 2009 by 5-year interval, the proportion of deaths from causes other than CRC increased significantly with diagnostic periods according to the lengths of follow-up (P < .0001). The 5-year risk of death significantly decreased with diagnostic periods for all-cause, CRC, and circulation diseases among all age groups (<65, 65–74, and ≥75 years) but increased for chronic obstructive pulmonary disease, diabetes, and Alzheimer disease among patients aged 65 years or older. Conclusions: Deaths due to causes other than CRC increased significantly over time regardless of tumor stage and site but more sharply in those with early-stage and distal colon cancer. The increasing leading causes of death are chronic obstructive pulmonary disease, diabetes, and Alzheimer disease, which may be prevented or delayed substantially by modification or intervention in lifestyle or other factors. [Copyright &y& Elsevier]

Abstract: Object: To perform an exploratory study evaluating memantine for several common non-motor problems in Parkinson’s disease. Methods: We conducted a single center, double-blind, placebo controlled pilot trial of memantine, titrated to 20 mg/day, in PD subjects. Inclusion criteria were intentionally broad and included both fluctuating and non-fluctuating patients. After baseline assessments, subjects (N = 40) were randomized to drug and placebo groups. They received a battery of traditional and non-motor assessments. After a safety call (2 weeks after baseline) they returned for identical assessments at week 8. An 8-week open label extension was started if desired. Results: Subject demographics (age 69.1 ± 7.8; 24 males), were similar in the drug and placebo groups. Four dropped from the study while on drug vs. none on placebo. Two of 36 remaining dropped out over the 8-week open label section. Of the 34 who completed the final open label visit, 24 elected to be prescribed memantine after the study. During the controlled trial, there was no significant change in UPDRS section I or II, Epworth sleepiness scale, fatigue severity scale, Hamilton depression scale, Conner adult inventory, PD Quality of Life-39, or clinical global impressions. UPDRS “on” motor scores tended to improved, p = 0.19. Conclusion: Memantine was well tolerated in PD; however, specific measures of sleepiness, fatigue, depression, and attention did not significantly improve. The majority of subjects elected to stay on the drug after the open label extension suggesting some unassessed benefit. [Copyright &y& Elsevier]

Abstract: This study tested the hypothesis that genetic variants of phase II detoxification enzymes and DNA repair proteins affect individual response to DNA damage from alkylating agents. In 171 healthy individuals, an immunoslot blot assay was used to measure O 6-ethylguanosine (O 6-EtGua) adduct levels in peripheral blood lymphocytes treated with N-ethyl-N-nitrosourea (ENU) in vitro. The genotypes of GSTM1, GSTT1, GSTP1 I105V and A114V, MGMT L84F and I143V, XPD D312N and K751Q, and XRCC3 T241M were determined. Demographic and exposure information was collected by in-person interview. Student''s t-test, analysis of (co)variance, and multiple linear regression models were used in statistical analyses. The mean and median (range) O 6-EtGua levels were 94.6 and 84.8 (3.2–508.1)fmol/g DNA, respectively. The adduct level was significantly lower in people who smoked ≥25 years than that in never-smokers (square-root transformed mean values 8.20 versus 9.37, P =0.03). Multiple linear regression models revealed that GSTT1 (β =−2.36, P =0.009) polymorphism was a significant predictor of the level of adducts in 82 never-smokers, whereas the number of years smoked (β =−0.08, P =0.005) and XRCC3 T241M (β =2.22, P =0.007) in 89 ever-smokers. The association between GSTP1 I105V, MGMT I143V, and XPD D312N with the level of adducts was not conclusive. Each polymorphism could explain 2–10% of the variation of the adduct level. These observations suggest that GSTT1 null and XRCC3 T241M polymorphism may have some functional significance in modulating the level of ENU-induced DNA damage and these effects are smoking-dependent. Results from this exploratory study need to be confirmed in other experimental systems. [Copyright &y& Elsevier]

Background: Hemorrhage associated with placenta accreta spectrum (PAS) is a leading cause of maternal morbidity and mortality. Estimating blood loss in these individuals is a critical component of comprehensive preoperative planning., Objective: A semiquantitative score based on transvaginal ultrasound was developed and tested to predict PAS, estimate its severity, and blood loss in individuals with clinical and ultrasound evidence suggesting PAS., Study Design: A secondary analysis was conducted of prospectively collected data from a quaternary center of patients with suspected accreta on 2D ultrasound and clinical suspicion. A predetermined scoring system was applied based on three components: (1) uterine wall (score 0: no loss of hypo-translucent uterine wall with overlying placenta in the lower uterine segment; 1: loss of hypo-translucent <3-cm defect; 2: 3-6-cm defect; and 3: >6-cm defect); (2) arterial vascularity at the uterine wall defect (score 0: no vessels observed; 1: 1-2 vessels over the defect; 2: 3-5 vessels; and 3: >5 vessels); and (3) cervical involvement (score 0: normal cervical length without previa; 1: previa with normal cervical length; 2: short cervix with previa, minimal vascularity and small lacunae; 3: short cervix with previa, increased vascularity and large lacunae). Each patient's three domain scores determined a cumulative, final score of 0-9. Patients were managed at the discretion of a multi-disciplinary team and patient's preference among the following options: cesarean delivery with placenta removal, cesarean delivery with placenta in-situ (conservative) with or without delayed hysterectomy, or cesarean hysterectomy. The frequency of different degrees of placental invasion per pathology examination per score unit was registered. Multiple linear regression analysis was performed for association of blood loss according to score adjusted by risk factors for PAS., Results: A total of 73 patients were evaluated. All 11 patients who had a score of 0 had cesarean delivery with placenta removal without evidence of intraoperative PAS, thus resulting in a 100% negative predictive value. The remaining 62 had scores between 1 and 9. Among patients with scores 0-3 (n=20), only one had intraoperative PAS, yielding a negative predictive value of 97%. Higher scores were associated with severe PAS forms (r=0.301, P=.02). Based on the associations between PAS scores, clinical correlation, and blood loss, we divided patients into four categories: Category 0: PAS score 0; Category 1: scores 1-3; Category 2: scores 4-6; and Category 3: scores 7-9. The median blood loss in Category 0=635±352 mL, Category 1=634±599 mL, Category 2=1549±1284 mL, and Category 3=1895±2106 mL (P<.001). On multivariable analysis, Category 2 (β=0.97, P<.01) and Category 3 (β=1.26, P<.003) were associated with significantly greater blood loss than Category 0, irrespective of type of surgery., Conclusion: The transvaginal ultrasound score separates groups at low risk (Category 0) and at higher risk of PAS (Categories 1-3). Categories 1-3 may provide important clinical information to estimate the risk of severe forms of PAS and of blood loss during surgery. VIDEO ABSTRACT., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Liver transplantation often faces fairness challenges across subgroups defined by sensitive attributes such as age group, gender, and race/ethnicity. Machine learning models for outcome prediction can introduce additional biases. Therefore, we introduce F airness through the E quitable R ate of I mprovement in Multitask Learning (FERI) algorithm for fair predictions of graft failure risk in liver transplant patients. FERI constrains subgroup loss by balancing learning rates and preventing subgroup dominance in the training process. Our results show that FERI maintained high predictive accuracy with AUROC and AUPRC comparable to baseline models. More importantly, FERI demonstrated an ability to improve fairness without sacrificing accuracy. Specifically, for the gender, FERI reduced the demographic parity disparity by 71.74%, and for the age group, it decreased the equalized odds disparity by 40.46%. Therefore, the FERI algorithm advanced fairness-aware predictive modeling in healthcare and provides an invaluable tool for equitable healthcare systems., (©2024 AMIA - All rights reserved.)

Importance: The binary classification of spina bifida lesions as myelomeningocele (with sac) or myeloschisis (without sac) belies a spectrum of morphologies, which have not been correlated to clinical characteristics and outcomes., Objective: To characterize spina bifida lesion types and correlate them with preoperative presentation and postoperative outcomes., Design: Secondary analysis of images and videos obtained during fetoscopic spina bifida repair surgery from 2020-2023., Setting: Fetal surgery was performed at a quaternary care center., Participants: A prospective cohort of patients referred for fetal spina bifida underwent fetoscopic repair under an FDA-approved protocol. Of 60 lesions repaired, 57 had available images and were included in the analysis., Interventions or Exposures: We evaluated lesion morphology on high-resolution intraoperative images and videos to categorize lesions based on placode exposure and nerve root stretching., Main Outcomes and Measures: The reproducibility of the lesion classification was assessed via Kappa interrater agreement. Preoperative characteristics analyzed include ventricle size, tonsillar herniation level, lower extremities movement, and lesion dimensions. Outcomes included surgical time, need for patch for skin closure, gestational age at delivery, preterm premature rupture of membranes (PPROM), and neonatal cerebrospinal fluid (CSF) diversion., Results: We distinguished five lesion types that differ across a range of sac sizes, nerve root stretching, and placode exposure, with 93% agreement between examiners (p<0.001). Fetal characteristics at preoperative evaluation differed significantly by lesion type, including lesion volume (p<0.001), largest ventricle size (p=0.008), tonsillar herniation (p=0.005), and head circumference (p=0.03). Lesion level, talipes, and lower extremities movement did not differ by type. Surgical and perinatal outcomes differed by lesion type, including need for patch skin closure (p<0.001), gestational age at delivery (p=0.01), and NICU length of stay (p<0.001). PPROM, CSF leakage at birth, and CSF diversion in the NICU did not differ between lesion groups. Linear regression associated severity of ventriculomegaly with lesion type, but not with tonsillar herniation level., Conclusions and Relevance: There is a distinct phenotypic spectrum in open spina bifida with differential baseline presentation and outcomes. Severity of ventriculomegaly is associated with lesion type, rather than tonsillar herniation level. Our findings expand the classification of spina bifida to reveal a spectrum that warrants further study., Competing Interests: Disclosure: The authors declare no competing financial interest.

Background and Aims: Coronary flow capacity (CFC) is associated with an observed 10-year survival probability for individual patients before and after actual revascularization for comparison to virtual hypothetical ideal complete revascularization., Methods: Stress myocardial perfusion (mL/min/g) and coronary flow reserve (CFR) per pixel were quantified in 6979 coronary artery disease (CAD) subjects using Rb-82 positron emission tomography (PET) for CFC maps of artery-specific size-severity abnormalities expressed as percent left ventricle with prospective follow-up to define survival probability per-decade as fraction of 1.0., Results: Severely reduced CFC in 6979 subjects predicted low survival probability that improved by 42% after revascularization compared with no revascularization for comparable severity (P = .0015). For 283 pre-and-post-procedure PET pairs, severely reduced regional CFC-associated survival probability improved heterogeneously after revascularization (P < .001), more so after bypass surgery than percutaneous coronary interventions (P < .001) but normalized in only 5.7%; non-severe baseline CFC or survival probability did not improve compared with severe CFC (P = .00001). Observed CFC-associated survival probability after actual revascularization was lower than virtual ideal hypothetical complete post-revascularization survival probability due to residual CAD or failed revascularization (P < .001) unrelated to gender or microvascular dysfunction. Severely reduced CFC in 2552 post-revascularization subjects associated with low survival probability also improved after repeat revascularization compared with no repeat procedures (P = .025)., Conclusions: Severely reduced CFC and associated observed survival probability improved after first and repeat revascularization compared with no revascularization for comparable CFC severity. Non-severe CFC showed no benefit. Discordance between observed actual and virtual hypothetical post-revascularization survival probability revealed residual CAD or failed revascularization., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Cardiac-derived c-kit+ progenitor cells (CPCs) are under investigation in the CHILD phase I clinical trial (NCT03406884) for the treatment of hypoplastic left heart syndrome (HLHS). The therapeutic efficacy of CPCs can be attributed to the release of extracellular vesicles (EVs). To understand sources of cell therapy variability we took a machine learning approach: combining bulk CPC-derived EV (CPC-EV) RNA sequencing and cardiac-relevant in vitro experiments to build a predictive model. We isolated CPCs from cardiac biopsies of patients with congenital heart disease (n = 29) and the lead-in patients with HLHS in the CHILD trial (n = 5). We sequenced CPC-EVs, and measured EV inflammatory, fibrotic, angiogeneic, and migratory responses. Overall, CPC-EV RNAs involved in pro-reparative outcomes had a significant fit to cardiac development and signaling pathways. Using a model trained on previously collected CPC-EVs, we predicted in vitro outcomes for the CHILD clinical samples. Finally, CPC-EV angiogenic performance correlated to clinical improvements in right ventricle performance., Competing Interests: Joshua M. Hare reports having a patent for cardiac cell-based therapy and holds equity in Vestion Inc. and maintains a professional relationship with Vestion Inc. as a consultant and member of the Board of Directors and Scientific Advisory Board. Vestion Inc. did not play a role in the design, conduct, or funding of the study. Dr. Joshua Hare is the Chief Scientific Officer, a compensated consultant and board member for Longeveron Inc. and holds equity in Longeveron. Dr. Hare is also the co-inventor of intellectual property licensed to Longeveron. The University of Miami is an equity owner in Longeveron Inc., which has licensed intellectual property from the University of Miami., (© 2023 The Author(s).)

Objectives: To compare cancer centre (CC) executives' attitudes towards palliative care between National Cancer Institute-designated CCs (NCI-CCs) and non-NCI-designated CCs (non-NCI-CCs) in 2018 and to examine the changes in attitudes and beliefs between 2009 and 2018., Methods: CC chief executives at all NCI-CCs and a random sample of non-NCI-CCs were surveyed from April to August 2018. Twelve questions examined the executives' attitudes towards palliative care integration, perceived barriers and self-assessments. The primary outcome was agreement on the statement 'a stronger integration of palliative care services into oncology practice will benefit patients at my institution.' Survey findings from 2018 were compared with data from 2009 to examine changes in attitudes., Results: 52 of 77 (68%) NCI-CCs and 88 of 126 (70%) non-NCI-CCs responded to the survey. A vast majority of executives at NCI-CCs and non-NCI-CCs endorsed palliative care integration (89.7% vs 90.0%; p>0.999). NCI-CCs were more likely to endorse increasing funding for palliative care (52.5% vs 23.1%; p=0.01) and hiring physician specialists (70.0% vs 37.5%; p=0.004) than non-NCI-CCs. The top three perceived barriers among NCI-CCs and non-NCI-CCs were limited institutional budgets (57.9% vs 59.0%; p=0.92), poor reimbursements (55.3% vs 43.6%; p=0.31), and lack of adequately trained palliative care physicians and nurses (52.6% vs 43.6%; p=0.43). Both NCI-CCs and non-NCI-CCs favourably rated their palliative care services (89.7% vs 71.8%; p=0.04) with no major changes since 2009., Conclusion: CC executives endorse integration of palliative care, with greater willingness to invest in palliative care among NCI-CCs. Resource limitation continues to be a major barrier., Competing Interests: Competing interests: DH received grants from Helsinn outside the submitted work., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Subendocardial ischemia is commonly diagnosed but not quantified by imaging., Objectives: This study sought to define size and severity of subendocardial and transmural stress perfusion deficits, clinical associations, and outcomes., Methods: Regional rest-stress perfusion in mL/min/g, coronary flow reserve, coronary flow capacity (CFC), relative stress flow, subendocardial stress-to-rest ratio and stress subendocardial-to-subepicardial ratio as percentage of left ventricle were measured by positron emission tomography (PET) with rubidium Rb 82 and dipyridamole stress in serial 6,331 diagnostic PETs with prospective 10-year follow-up for major adverse cardiac events with and without revascularization., Results: Of 6,331 diagnostic PETs, 1,316 (20.7%) had severely reduced CFC with 41.4% having angina or ST-segment depression (STΔ) >1 mm during hyperemic stress, increasing with size. For 5,015 PETs with no severe CFC abnormality, 402 (8%) had angina or STΔ during stress, and 82% had abnormal subendocardial perfusion with 8.7% having angina or STΔ >1 mm during dipyridamole stress. Of 947 cases with stress-induced angina or STΔ >1 mm, 945 (99.8%) had reduced transmural or subendocardial perfusion reflecting sufficient microvascular function to increase coronary blood flow and reduce intracoronary pressure, causing reduced subendocardial perfusion; only 2 (0.2%) had normal subendocardial perfusion, suggesting microvascular disease as the cause of the angina. Over 10-year follow-up (mean 5 years), severely reduced CFC associated with major adverse cardiac events of 44.4% compared to 8.8% for no severe CFC (unadjusted P < 0.00001) and mortality of 15.2% without and 6.9% with revascularization (P < 0.00002) confirmed by multivariable Cox regression modeling. For no severe CFC, mortality was 3% with and without revascularization (P = 0.90)., Conclusions: Reduced subendocardial perfusion on dipyridamole PET without regional stress perfusion defects is common without angina, has low risk of major adverse cardiac events, reflecting asymptomatic nonobstructive diffuse coronary artery disease, or angina without stenosis. Severely reduced CFC causes angina in fewer than one-half of cases but incurs high mortality risk that is significantly reduced after revascularization., Competing Interests: Funding Support and Author Disclosures Research supported by internal funds of the Weatherhead PET Center. Dr Gould has received internal funding from the Weatherhead PET Center and is the applicant for 510(k) U.S. Food and Drug Administration–cleared HeartSee K202679 PET software. Dr Johnson has received internal funding from Weatherhead PET Center for Preventing and Reversing Atherosclerosis and research support from St. Jude Medical (for CONTRAST [Can Contrast Injection Better Approximate FFR Compared to Pure Resting Physiology] trial; NCT02184117) and Volcano/Philips Corporation (for the DEFINE-FLOW [Combined Pressure and Flow Measurements to Guide Treatment of Coronary Stenoses] trial; NCT02328820). To avoid any conflict of interest, Drs Gould, Nguyen, Johnson, and Kirkeeide waived their rights to the royalties that they were personally eligible to receive from sales of the intellectual property developed by them and licensed by the University of Texas Health Science Center (UTHealth) to third parties. UTHealth approved their request that all derived royalties be redirected to student scholarships or UTHealth’s Weatherhead PET Center research. UTHealth has a financial interest related to intellectual property via its affiliation with the UTHealth’s Weatherhead PET Imaging Center. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: It is unclear how well palliative care teams are staffed at US cancer centers. Our primary objective was to compare the composition of palliative care teams between National Cancer Institute (NCI)-designated cancer centers and non-NCI-designated cancer centers in 2018. We also assessed changes in team composition between 2009 and 2018. Methods: This national survey examined the team composition in palliative care programs at all 61 NCI-designated cancer centers and in a random sample of 60 of 1252 non-NCI-designated cancer centers in 2018. Responses were compared to those from our 2009 survey. The primary outcome was the presence of an interprofessional team defined as a palliative care physician, nurse, and psychosocial member. Secondary outcomes were the size and number of individual disciplines. Results: In 2018, 52/61 (85%) of NCI-designated and 27/38 (71%) non-NCI-designated cancer centers in the primary outcome comparison responded to the survey. NCI-designated cancer centers were more likely to have interprofessional teams than non-NCI-designated cancer centers (92% vs 67%; P  = .009). Non-NCI-designated cancer centers were more likely to have nurse-led teams (14.8% vs 0.0%; P  = .01). The median number of disciplines did not differ between groups (NCI, 6.0; non-NCI, 5.0; P  = .08). Between 2009 and 2018, NCI-designated and non-NCI-designated cancer centers saw increased proportions of centers with interprofessional teams (NCI, 64.9% vs 92.0%, P  < .001; non-NCI, 40.0% vs 66.7%; P  = .047). Conclusion: NCI-designated cancer centers were more likely to report having an interprofessional palliative care team than non-NCI-designated cancer centers. Growth has been limited over the past decade, particularly at non-NCI-designated cancer centers.

CCTRN is a Cardiovascular Cell Therapy Research Network. There were three randomized double blinded controlled stem cell clinical trials conducted in its first phase. The main results of these three clinical trials were published with conventional parametric models such as T test and nonparametric test such as Wilcoxon rank sum test without adjusting covariates. In this article, we conducted further analysis of the primary outcomes of these studies using a class of covariate adjusted nonparametric methods.

Cell therapy trials for heart failure (HF) have shown modest improvement; however, the mechanisms underlying improvement in some patients but not others are not well understood. Although immune cells are important in the course of HF, our understanding of the immune processes in HF is limited. The objective of this study was to evaluate associations between temporal changes in peripheral blood (PB) cell subpopulations and improved outcome in patients with chronic ischemic cardiomyopathy after bone marrow-derived mononuclear cell therapy or placebo in the FOCUS-CCTRN trial. Peripheral blood was collected at days 0, 1, 30, 90, and 180 from consented participants. We used flow cytometry to compare PB populations in patients with the best (cohort 1) or worst functional outcome (cohort 2) in three primary endpoints: left ventricular (LV) ejection fraction, LV end-systolic volume, and maximal oxygen consumption (VO 2 max). A linear mixed model was used to assess changes over time in 32 cell populations. The difference between each time point and baseline was calculated as linear contrast. Compared with cohort 2, patients who improved (cohort 1) had a higher frequency of CD45 + CD19 + B cells at days 0, 1, 90, and 180. CD11B + cells increased over baseline at day 1 in both cohorts and remained higher in cohort 2 until day 30. CD45 + CD133 + progenitor cells decreased over baseline at day 30 in cohort 1. We identified specific cell subpopulations associated with improved cardiac function in patients with chronic LV dysfunction. These findings may improve patient selection and prediction of outcomes in cell therapy trials., Competing Interests: DT has a financial interest in Miromatrix Medical, Inc. DT have financial interests in Stem Cell Security, LLC. This relationship was monitored in accordance with the conflict of interest policies by the Texas Heart Institute. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Chacon Alberty, Perin, Willerson, Gahremanpour, Bolli, Yang, Traverse, Lai, Pepine and Taylor.)

Background: The literature reports no randomized trial in chronic coronary artery disease (CAD) of a comprehensive management strategy integrating intense lifestyle management, maximal medical treatment to specific goals and high precision quantitative cardiac positron emission tomography (PET) for identifying high mortality risk patients needing essential invasive procedures. We hypothesize that this comprehensive strategy achieves greater risk factor reduction, lower major adverse cardiovascular events and fewer invasive procedures than standard practice., Methods: The CENTURY Study (NCT00756379) is a randomized-controlled-trial study in patients with stable or at high risk for CAD. Patients are randomized to standard of care (Standard group) or intense comprehensive lifestyle-medical treatment to targets and PET guided interventions (Comprehensive group). Comprehensive Group patients are regularly consulted by the CENTURY team implementing diet/lifestyle/exercise program and medical treatment to target risk modification. Cardiac PET at baseline, 24-, and 60-months quantify the physiologic severity of CAD and guide interventions in the Comprehensive group while patients and referring physicians of the Standard group are blinded to PET results. The primary end-point is the CENTURY risk score reduction during 5 years follow-up. The secondary endpoint is a composite of death, non-fatal myocardial infarction, stroke, and coronary revascularization., Conclusions: The CENTURY Study is the first study in stable CAD to test the incremental benefit of a comprehensive strategy integrating intense lifestyle modification, medical treatment to specific goals, and high-precision quantitative myocardial perfusion imaging to guide revascularization. A total of 1028 patients have been randomized, and the 5 years follow-up will conclude in 2022., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objectives: This study sought to determine the relationship between the severity of reduced quantitative perfusion parameters and mortality with and without revascularization., Background: The physiological mechanisms for differential mortality risk of coronary flow reserve (CFR) and coronary flow capacity (CFC) before and after revascularization are unknown., Methods: Global and regional rest-stress (ml/min/g), CFR, their regional per-pixel combination as CFC, and relative stress in ml/min/g were measured as percent of LV in all serial routine 5,274 diagnostic PET scans with systematic follow-up over 10 years (mean 4.2 ± 2.5 years) for all-cause mortality with and without revascularization., Results: Severely reduced CFR of 1.0 to 1.5 and stress perfusion ≤1.0 cc/min/g incurred increasing size-dependent risks that were additive because regional severely reduced CFC (CFCsevere) was associated with the highest major adverse cardiac event rate of 80% (p < 0.0001 vs. either alone) and a mortality risk of 14% (vs. 2.3% for no CFCsevere; p = 0.001). Small regions of CFCsevere ≤0.5% predicted high risk (p < 0.0001 vs. no CFCsevere) related to a wave front of border zones at risk around the small most severe center. By receiver-operating characteristic analysis, relative stress topogram maps of stress (ml/min/g) as a fraction of LV defined these border zones at risk or for mildly reduced CFC (area under the curve [AUC]: 0.69) with a reduced relative tomographic subendocardial-to-subepicardial ratio. CFCsevere incurred the highest mortality risk that was reduced by revascularization (p = 0.005 vs. no revascularization) for artery-specific stenosis not defined by global CFR or stress perfusion alone., Conclusions: CFC is associated with the size-dependent highest mortality risk resulting from the additive risk of CFR and stress (ml/min/g) that is significantly reduced after revascularization, a finding not seen for global CFR. Small regions of CFCsevere ≤0.5% of LV also carry a high risk because of the surrounding border zones at risk defined by relative stress perfusion and a reduced relative subendocardial-to-subepicardial ratio., Competing Interests: Funding Support and Author Disclosures This work was supported by internal funds of the Weatherhead PET Center. Dr. Gould has received internal funding from the Weatherhead PET Center; and is the 510(k) applicant for Food and Drug Administration–cleared HeartSee K171303 PET software (to avoid any conflict of interest. Dr. Gould assigned any royalties arising from PET software to the University of Texas for research or student scholarships). Dr. Johnson has received internal funding from the Weatherhead PET Center for Preventing and Reversing Atherosclerosis; and has received research support from St. Jude Medical (for NCT02184117) and Volcano/Philips Corporation (for NCT02328820). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: CONCERT-HF is an NHLBI-sponsored, double-blind, placebo-controlled, Phase II trial designed to determine whether treatment with autologous bone marrow-derived mesenchymal stromal cells (MSCs) and c-kit positive cardiac cells (CPCs), given alone or in combination, is feasible, safe, and beneficial in patients with heart failure (HF) caused by ischaemic cardiomyopathy., Methods and Results: Patients were randomized (1:1:1:1) to transendocardial injection of MSCs combined with CPCs, MSCs alone, CPCs alone, or placebo, and followed for 12 months. Seven centres enrolled 125 participants with left ventricular ejection fraction of 28.6 ± 6.1% and scar size 19.4 ± 5.8%, in New York Heart Association class II or III. The proportion of major adverse cardiac events (MACE) was significantly decreased by CPCs alone (-22% vs. placebo, P = 0.043). Quality of life (Minnesota Living with Heart Failure Questionnaire score) was significantly improved by MSCs alone (P = 0.050) and MSCs + CPCs (P = 0.023) vs. placebo. Left ventricular ejection fraction, left ventricular volumes, scar size, 6-min walking distance, and peak oxygen consumption did not differ significantly among groups., Conclusions: This is the first multicentre trial assessing CPCs and a combination of two cell types from different tissues in HF patients. The results show that treatment is safe and feasible. Even with maximal guideline-directed therapy, both CPCs and MSCs were associated with improved clinical outcomes (MACE and quality of life, respectively) in ischaemic HF without affecting left ventricular function or structure, suggesting possible systemic or paracrine cellular mechanisms. Combining MSCs with CPCs was associated with improvement in both these outcomes. These results suggest potential important beneficial effects of CPCs and MSCs and support further investigation in HF patients., (© 2021 European Society of Cardiology.)

Background: Anthracycline-induced cardiomyopathy (AIC) may be irreversible with a poor prognosis, disproportionately affecting women and young adults. Administration of allogeneic bone marrow-derived mesenchymal stromal cells (allo-MSCs) is a promising approach to heart failure (HF) treatment., Objectives: SENECA (Stem Cell Injection in Cancer Survivors) was a phase 1 study of allo-MSCs in AIC., Methods: Cancer survivors with chronic AIC (mean age 56.6 years; 68% women; NT-proBNP 1,426 pg/ml; 6 enrolled in an open-label, lead-in phase and 31 subjects randomized 1:1) received 1 × 10 8 allo-MSCs or vehicle transendocardially. Primary objectives were safety and feasibility. Secondary efficacy measures included cardiac function and structure measured by cardiac magnetic resonance imaging (CMR), functional capacity, quality of life (Minnesota Living with Heart Failure Questionnaire), and biomarkers., Results: A total of 97% of subjects underwent successful study product injections; all allo-MSC-assigned subjects received the target dose of cells. Follow-up visits were well-attended (92%) with successful collection of endpoints in 94% at the 1-year visit. Although 58% of subjects had non-CMR compatible devices, CMR endpoints were successfully collected in 84% of subjects imaged at 1 year. No new tumors were reported. There were no significant differences between allo-MSC and vehicle groups with regard to clinical outcomes. Secondary measures included 6-min walk test (p = 0.056) and Minnesota Living with Heart Failure Questionnaire score (p = 0.048), which tended to favor the allo-MSC group., Conclusions: In this first-in-human study of cell therapy in patients with AIC, transendocardial administration of allo-MSCs appears safe and feasible, and CMR was successfully performed in the majority of the HF patients with devices. This study lays the groundwork for phase 2 trials aimed at assessing efficacy of cell therapy in patients with AIC.

Clostridioides difficile spores can survive in the environment in either mono- or mixed-species biofilms. However, no previous studies have investigated chemical disinfection of C. difficile spores embedded in biofilms. Thus, the purpose of this study was to assess the in vitro effectiveness of hospital disinfectants against C. difficile spores embedded within biofilms. Five unique C. difficile strains embedded in three different biofilm types grown for 72 or 120 h were exposed to seven different hospital disinfectants. C. difficile abundance [as log(number of CFU/milliliter)] was calculated after manufacturer-determined contact times along with biofilm biomass and microscopy. The primary analysis compared differences between C. difficile vegetative cell and spore counts as well as amounts of biomass after exposure to disinfectants. C. difficile vegetative cells and spores were recovered from biofilms regardless of the type of biofilm growth or biofilm growth time. No disinfectant was able to completely eliminate C. difficile from the biofilms. Overall, Clorox, ortho -phthalaldehyde (OPA), and Virex were most effective at killing C. difficile spores regardless of biofilm age, ribotype, or wash conditions (whether biofilms are washed or unwashed) ( P = 0.001, each). Clorox and OPA were also effective at killing total vegetative cell growth ( P  = 0.001, each), but Virex was found to be ineffective against vegetative cell growth in biofilms ( P  = 0.77). Clorox and Virex were most effective in reducing biomass, followed by Nixall, OPA, and Vital Oxide. No disinfectant was able to completely eliminate C. difficile embedded within biofilms although differences among disinfectants were noted. Future research will be required to determine methods to eradicate this persister reservoir., (Copyright © 2019 American Society for Microbiology.)

Because randomized coronary revascularization trials in stable coronary artery disease (CAD) have shown no reduced myocardial infarction (MI) or mortality, the threshold of quantitative myocardial perfusion severity was analyzed for association with reduced death, MI, or stroke after revascularization within 90 d after PET. Methods: In a prospective long-term cohort of stable CAD, regional, artery-specific, quantitative myocardial perfusion by PET, coronary revascularization within 90 d after PET, and all-cause death, MI, and stroke (DMS) at 9-y follow-up (mean ± SD, 3.0 ± 2.3 y) were analyzed by multivariate Cox regression models and propensity analysis. Results: For 3,774 sequential rest-stress PET scans, regional, artery-specific, severely reduced coronary flow capacity (CFC) (coronary flow reserve ≤ 1.27 and stress perfusion ≤ 0.83 cc/min/g) associated with 60% increased hazard ratio for major adverse cardiovascular events and 30% increased hazard of DMS that was significantly reduced by 54% associated with revascularization within 90 d after PET ( P = 0.0369), compared with moderate or mild CFC, coronary flow reserve, other PET metrics or medical treatment alone. Depending on severity threshold for statistical certainty, up to 19% of this clinical cohort had CFC severity associated with reduced DMS after revascularization. Conclusion: CFC by PET provides objective, regional, artery-specific, size-severity physiologic quantification of CAD severity associated with high risk of DMS that is significantly reduced after revascularization within 90 d after PET, an association not seen for moderate to mild perfusion abnormalities or medical treatment alone., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.)

Effective recruitment is a prerequisite for successful execution of a clinical trial. ALLHAT, a large hypertension treatment trial (N = 42, 418), provided an opportunity to evaluate adaptive modeling of recruitment processes using conditional moving linear regression. Our statistical modeling of recruitment, comparing Brownian and fractional Brownian motion, indicates that fractional Brownian motion combined with moving linear regression is better than classic Brownian motion in terms of higher conditional probability of achieving a global recruitment goal in four week ahead projections. Further research is needed to evaluate how recruitment modeling can assist clinical trialists in planning and executing clinical trials. Clinical Trial Registration: www.clinicaltrials.gov NCT00000542., Competing Interests: Declaration of conflicting interests The authors report no financial conflicts of interest.

Autologous bone marrow mononuclear cell (BM-MNC) therapy for patients with ST-segment elevation myocardial infarction (STEMI) has produced inconsistent results, possibly due to BM-MNC product heterogeneity. Patient-specific cardiovascular risk factors (CRFs) may contribute to variations in BM-MNC composition. We sought to identify associations between BM-MNC subset frequencies and specific CRFs in STEMI patients. Bone marrow was collected from 191 STEMI patients enrolled in the CCTRN TIME and LateTIME trials. Relationships between BM-MNC subsets and CRFs were determined with multivariate analyses. An assessment of CRFs showed that hyperlipidemia and hypertension were associated with a higher frequency of CD11b + cells (P = 0.045 and P = 0.016, respectively). In addition, we found that females had lower frequencies of CD11b + (P = 0.018) and CD45 + CD14 + (P = 0.028) cells than males, age was inversely associated with the frequency of CD45 + CD31 + cells (P = 0.001), smoking was associated with a decreased frequency of CD45 + CD31 + cells (P = 0.013), glucose level was positively associated with the frequency of CD45 + CD3 + cells, and creatinine level (an indicator of renal function) was inversely associated with the frequency of CD45 + CD3 + cells (P = 0.015). In conclusion, the frequencies of monocytic, lymphocytic, and angiogenic BM-MNCs varied in relation to patients' CRFs. These phenotypic variations may affect cell therapy outcomes and might be an important consideration when selecting patients for and reviewing results from autologous cell therapy trials.

The association between O3 exposure and preterm birth (PTB) remains unclear. We evaluated associations for three categories of PTB and O3 in Harris County, Texas, during narrow periods of gestation. We computed two sets of exposure metrics during every 4 weeks of pregnancy for 152,214 mothers who delivered singleton, live-born infants in 2005-2007, accounting first for temporal variability and then for temporal and spatial sources of variability in ambient O3 levels. Associations were assessed using multiple logistic regression. We also examined the potential for a fixed cohort bias. In the bias-corrected cohort where associations were somewhat stronger, elevated odds ratios (ORs) per 10 parts per billion increase in O3 exposure (county-level metric) were detected for the fifth (OR=1.08, 95% confidence interval (CI): 1.04-1.12), sixth (OR=1.05, 95% CI=1.01-1.09), and seventh (OR=1.07, 95% CI=1.03-1.10) 4-week periods of pregnancy for late PTB (33-36 completed weeks gestation), the fifth (OR=1.13, 95% CI=1.02-1.25) and seventh (OR=1.15, 95% CI=1.04-1.27) 4-week periods of pregnancy for moderate PTB (29-32 completed weeks gestation), and the fifth (OR=1.21, 95% CI=1.08-1.36) 4-week period of pregnancy for severe PTB (20-28 completed weeks gestation). Conversely, decreased odds were found in the first 4-week period of pregnancy for severe PTB (OR=0.83, 95% CI=0.74-0.94). Associations were slightly attenuated using the spatially interpolated (kriged) metrics, and for women who did not work outside of the home. Our analyses confirm reports in other parts of the United States and elsewhere with findings that suggest that maternal exposure to ambient levels of O3 is associated with PTB.

Following latent class analysis (LCA) approach we examined patterns of HIV risk using two related domains of behavior: drug use, and sexual activity among 523 injection drug users (IDUs) recruited into the 2009 National HIV behavioral surveillance system. Using posterior probability of endorsing six drug and sexual items, we identified three distinct classes representing underlying HIV risk. Forty percent of our participants were at highest risk, 25 % at medium risk, and 35 % at lowest risk for HIV infection. Compared to the Lowest-risk class members, the Highest-risk class members had riskier drug and sexual behaviors and had higher prevalence of HIV cases (6 vs. 4 %). This analysis underscores the merit of LCA to empirically identify risk patterns using multiple indicators and our results show HIV risk varies among IDUs as their drug and sexual behaviors. Tailored and targeted prevention and treatment interventions for the dual risk pattern are required rather than for drug or sexual risk in silos.

Background: Hepatitis B vaccine provides a model for improving uptake and completion of multidose vaccinations in the drug-using community., Methods: The Drugs, AIDS, STDs, and Hepatitis (DASH) project conducted a randomized controlled trial among not-in-treatment current drug users in 2 urban neighborhoods. Neighborhoods were cluster-randomized to receive a standard behavioral intervention (which provided information on human immunodeficiency virus [HIV]) or an enhanced behavioral intervention (designed to increase acceptance of or adherence to the hepatitis B vaccination protocol). Participants within clusters were randomized to a standard vaccination schedule (vaccines at 0, 1, and 6 months) or an accelerated vaccination schedule (vaccines at 0, 1, and 2 months). The outcomes were completion of the 3-dose vaccine and seroprotection against hepatitis B virus (HBV)., Results: Of participants with negative screening results for HIV and HBV, 77% accepted hepatitis B vaccination, and 75% of vaccinees received all 3 doses. Injection drug users (IDUs) on the accelerated schedule were significantly more likely to receive 3 doses (76%) than those on the standard schedule (66%; P = .04), although for drug users as a whole the corresponding adherence rates were 77% and 73%, respectively. No difference in adherence was observed between the behavioral intervention groups. Predictors of adherence were older age, African American race, stable housing, and alcohol use. Cumulative HBV seroprotection (≥10 mIU/mL) was gained within 12 months by 65% of those completing the schedule. Seroprotection at 6 months was greater for those on the accelerated schedule., Conclusion: The accelerated vaccination schedule improves hepatitis B vaccination adherence among IDUs.

Noise in neonatal intensive care units (NICUs) may impede growth and development for extremely low-birth-weight (ELBW, < 1000 g) newborns. We calculated correlations between NICU sound levels and ELBW neonates' heart rate and arterial blood pressure to evaluate whether this population experiences noise-induced stress. Sound levels inside the incubator, heart rate (HR), and arterial blood pressure recordings were simultaneously collected for eight ELBW neonates for 15 minutes during the first week of life. Cross-correlation functions were calculated for NICU noise, HR, and mean arterial blood pressure (MABP) recordings for each subject. ELBW neonates' HR and MABP were significantly correlated ( R = 0.16 at 2-second lag time), with stronger correlation apparent for higher-birth-weight ELBW newborns (0.22 versus 0.10). Lower-birth-weight newborns responded to increased noise with HR acceleration from 45 to 130 seconds after noise events, and higher-birth-weight infants initially responded with an HR deceleration at 25 to 60 seconds, then HR acceleration ~175 seconds after noise increased. MABP was not as strongly correlated with NICU sound levels, although some correlation coefficients were slightly outside the 95% confidence interval. Higher-birth-weight newborns' more mature neurological systems may be responsible for stronger correlations between HR and MABP. NICU noise influenced newborns' HR, indicating that these infants hear and respond to NICU sounds. ELBW newborns in the first week of life seem to maintain a relatively stable blood pressure in response to moderate NICU sound levels (50 to 60 dBA).

This study tested the hypothesis that genetic variants of phase II detoxification enzymes and DNA repair proteins affect individual response to DNA damage from alkylating agents. In 171 healthy individuals, an immunoslot blot assay was used to measure O6-ethylguanosine (O6-EtGua) adduct levels in peripheral blood lymphocytes treated with N-ethyl-N-nitrosourea (ENU) in vitro. The genotypes of GSTM1, GSTT1, GSTP1 I(105)V and A(114)V, MGMT L(84)F and I(143)V, XPD D(312)N and K(751)Q, and XRCC3 T(241)M were determined. Demographic and exposure information was collected by in-person interview. Student's t-test, analysis of (co)variance, and multiple linear regression models were used in statistical analyses. The mean and median (range) O6-EtGua levels were 94.6 and 84.8 (3.2-508.1)fmol/g DNA, respectively. The adduct level was significantly lower in people who smoked >or=25 years than that in never-smokers (square-root transformed mean values 8.20 versus 9.37, P=0.03). Multiple linear regression models revealed that GSTT1 (beta=-2.36, P=0.009) polymorphism was a significant predictor of the level of adducts in 82 never-smokers, whereas the number of years smoked (beta=-0.08, P=0.005) and XRCC3 T(241)M (beta=2.22, P=0.007) in 89 ever-smokers. The association between GSTP1 I(105)V, MGMT I(143)V, and XPD D(312)N with the level of adducts was not conclusive. Each polymorphism could explain 2-10% of the variation of the adduct level. These observations suggest that GSTT1 null and XRCC3 T(241)M polymorphism may have some functional significance in modulating the level of ENU-induced DNA damage and these effects are smoking-dependent. Results from this exploratory study need to be confirmed in other experimental systems.

Purpose: To examine the associations between physical activity and body mass index (BMI) among females aged 14 to 17 yr., Methods: A convenience sample of 65 Mexican American, 58 African American, and 49 non-Hispanic white girls in an urban high school in Texas participated in this study. Physical activity was assessed by ankle actigraphy. Average activity per period (before, during and after school) of the day and total activity were derived by a software program as movements per minute. The Center for Disease Control and Prevention 2000 BMI charts were used to calculate overweight status. Pearson correlation coefficient and analysis of variance were used to determine the strength of association and to compare activity levels by BMI status., Results: There was a statistically significant inverse association between total diurnal physical activity level and BMI (r=-0.37; P<0.05); and a statistically significant association between after-school activity and BMI (r= -0.28; P<0.05). After adjusting for the effects of age, race, and sexual maturity, total diurnal activity level was 10% less (P=0.03) for overweight females; for females at risk of overweight, diurnal activity level was 6% less (P=0.04) than for normal-weight females. Ethnic differences showed an 8% lower activity level among African American than for non-Hispanic white and 6% lower than for Mexican American females., Conclusion: The study indicated that adolescent females in schools are at risk for inactivity at certain times of the day. Schools in partnership with their communities should assume a major role to promote participation in physical activity among adolescents through innovative activity programs in schools.