Quantifying Placenta Accreta Spectrum Severity and its associated Blood Loss: A Novel Transvaginal Ultrasound Scoring System.

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 semi-quantitative 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 pre-determined 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 1-9. 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=0.02). 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 <0.001). On multivariable analysis, Category 2 (ß = 0.97, p <0.01) and Category 3 (ß = 1.26, p <0.003) 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.

FERI: A Multitask-based Fairness Achieving Algorithm with Applications to Fair Organ Transplantation.

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 Fairness through the Equitable Rate of Improvement 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.

Morphometric Analysis of Spina Bifida after Fetal Repair Shows New Subtypes with Associated Outcomes.

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.

Coronary flow capacity and survival prediction after revascularization: physiological basis and clinical implications.

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.

Statistical modeling of extracellular vesicle cargo to predict clinical trial outcomes for hypoplastic left heart syndrome.

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.

Subendocardial and Transmural Myocardial Ischemia: Clinical Characteristics, Prevalence, and Outcomes With and Without Revascularization.

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.

Palliative medicine integration in the USA: cancer centre executives' attitudes.

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.

Estimation of hurst exponent for sequential monitoring of clinical trials with covariate adaptive randomization.

BACKGROUND: 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. METHODS: 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. CONCLUSION: 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.

Autologous Cardiac Stem Cell Injection in Patients with Hypoplastic Left Heart Syndrome (CHILD Study).

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 Registration https://clinicaltrials.gov/ct2/home NCT03406884, First posted January 23, 2018.

A National Survey of Palliative Care Team Compositions.

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.

Applications of Covariate Adjusted Nonparametric Methods to CCTRN Clinical Trials.

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.

Allografts for Skin Closure during In Utero Spina Bifida Repair in a Sheep Model.

OBJECTIVES: Use of off-label tissue graft materials, such as acellular dermal matrix (ADM), for in utero repair of severe spina bifida (SB), where primary skin layer closure is not possible, is associated with poor neurological outcomes. The cryopreserved human umbilical cord (HUC) patch has regenerative, anti-inflammatory, and anti-scarring properties, and provides watertight SB repair. We tested the hypothesis that the HUC is a superior skin patch to ADM for reducing inflammation at the repair site and preserving spinal cord function. METHODS: In timed-pregnant ewes with twins, on gestational day (GD) 75, spina bifida was created without a myelotomy (functional model). On GD 95, repair was performed using HUC vs. ADM patches (randomly assigned) by suturing them to the skin edges. Additionally, full thickness skin closure as a primary skin closure (PSC) served as a positive control. Delivery was performed on GD 140, followed by blinded to treatment neurological assessments of the lambs using the Texas Spinal Cord Injury Scale (TSCIS) for gait, proprioception, and nociception. Lambs without spina bifida were used as controls (CTL). Ex vivo magnetic resonance imaging of spines at the repair site were performed, followed by quantitative pathological assessments. Histological assessments (blinded) included Masson's trichrome, and immunofluorescence for myeloperoxidase (MPO; neutrophils) and for reactive astrocytes (inflammation) by co-staining vimentin and GFAP. RESULTS: The combined hind limbs' TSCIS was significantly higher in the HUC group than in ADM and PSC groups, p = 0.007. Both ADM and PSC groups exhibited loss of proprioception and mild to moderate ataxia compared to controls. MRI showed increased pathological findings in the PSC group when compared to the HUC group, p = 0.045. Histologically, the meningeal layer was thickened (inflammation) by 2-3 fold in ADM and PSC groups when compared to HUC and CTL groups, p = 0.01. There was lower MPO positive cells in the HUC group than in the ADM group, p = 0.018. Posterior column astrocyte activation was increased in ADM and PSC lambs compared to HUC lambs, p = 0.03. CONCLUSION: The HUC as a skin patch for in utero spina bifida repair preserves spinal cord function by reducing underlying inflammation when compared to ADM.

Peripheral Blood Biomarkers Associated With Improved Functional Outcome in Patients With Chronic Left Ventricular Dysfunction: A Biorepository Evaluation of the FOCUS-CCTRN Trial.

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 (VO2 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.

A Phase II study of autologous mesenchymal stromal cells and c-kit positive cardiac cells, alone or in combination, in patients with ischaemic heart failure: the CCTRN CONCERT-HF trial.

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.

Design and rationale of the randomized trial of comprehensive lifestyle modification, optimal pharmacological treatment and utilizing PET imaging for quantifying and managing stable coronary artery disease (the CENTURY study).

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.

Mortality Prediction by Quantitative PET Perfusion Expressed as Coronary Flow Capacity With and Without Revascularization.

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.

Analysis of Annual Costs of Mobile Clinics in the Southern United States.

INTRODUCTION: Mobile clinics provide an efficient manner for delivering healthcare services to at-risk populations, and there is a need to understand their economics. This study analyzes the costs of operating selected mobile clinic programs representing service categories in dental, dental/preventive, preventive care, primary care/preventive, and mammography/primary care/preventive. METHODS: The methodology included a self-reported survey of 96 mobile clinic programs operating in Texas, North Carolina, Georgia, and Florida; these states did not expand Medicaid and have a large proportion of uninsured individuals. Data were collected over an 8-month period from November 2016 to July 2017. The cost analyses were conducted in 2018, and were analyzed from the provider perspective. The average annual estimated costs; as well the costs per patient in each mobile clinic program within different service delivery types were assessed. Costs reported in the study survey were classified into recurrent direct costs and capital costs. RESULTS: Results indicate that mean operating costs range from about $300 000 to $2.5 million with costs increasing from mammography/primary care/preventive delivery to dental/preventive. The majority of mobile clinics provided dental care followed by dental/preventive. The cost per patient visit for all mobile clinic service types ranged from $65 to $529, and appears to be considerably less than those reported in the literature for fixed clinic services. CONCLUSION: The overall costs of all delivery types in mobile clinics were lower than the costs of providing care to Medicare beneficiaries in federally funded health centers, making mobile clinics a sound economic complement to stationary healthcare facilities.

Variability analysis of epileptic EEG using the maximal overlap discrete wavelet transform.

PURPOSE: To determine if there is a difference in the wavelet variances of seizure and non-seizure channels in the EEG of an epileptic subject. METHODS: A six-level decomposition was applied using the Maximal Overlap Discrete Wavelet Transform (MODWT). The wavelet variance and 95% CIs were calculated for each level of the decomposition. The number of changes in variance for each level were found using a change-point detection method of Whitcher. The Kruskal-Wallis test was used to determine if there were differences in the median number of change points within channels and across frequency bands (levels). RESULTS: No distinctive pattern was found for the wavelet variances to differentiate the seizure and non-seizure channels. The seizure channels tended to have lower variances for each level and overall, but this pattern only held for one of the three seizure channels (RAST4). The median number of change points did not differ between the seizure and non-seizure channels either within each channel or across the frequency bands. CONCLUSION: The use of the MODWT in examining the variances and changes in variance did not show specific patterns which differentiate between seizure and non-seizure channels.

Middle Cerebral Artery Doppler Velocimetry for the Diagnosis of Twin Anemia Polycythemia Sequence: A Systematic Review.

Twin anemia polycythemia sequence (TAPS) is a rare complication of monochorionic diamniotic (MCDA) twins. Middle cerebral artery peak systolic velocity (MCA-PSV) measurements are used to screen for TAPS while fetal or neonatal hemoglobin levels are required for definitive diagnosis. We sought to perform a systematic review of the efficacy of MCA-PSV in diagnosing TAPS. Search criteria were developed using relevant terms to query the Pubmed, Embase, and SCOPUS electronic databases. Publications reporting diagnostic characteristics of MCA-PSV measurements (i.e., sensitivity, specificity or receiver operator curves) were included. Each article was assessed for bias using the Quality Assessment of Diagnostic Accuracy Studies II (QUADAS II) tool. Results were assessed for uniformity to determine whether meta-analysis was feasible. Data were presented in tabular form. Among publications, five met the inclusion criteria. QUADAS II analysis revealed that four of the publications were highly likely to have bias in multiple areas. Meta-analysis was precluded by non-uniformity between definitions of TAPS by MCA-PSV and neonatal or fetal hemoglobin levels. High-quality prospective studies with consistent definitions and ultrasound surveillance protocols are still required to determine the efficacy of MCA-PSV in diagnosing TAPS. Other ultrasound findings (e.g., placenta echogenicity discordance) may augment Doppler studies.

Allogeneic Mesenchymal Cell Therapy in Anthracycline-Induced Cardiomyopathy Heart Failure Patients: The CCTRN SENECA Trial.

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 × 108 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.