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Multi-arm trials are increasingly of interest because for many diseases; there are multiple experimental treatments available for testing efficacy. Several novel multi-arm multi-stage (MAMS) clinical trial designs have been proposed. However, a major hurdle to adopting the group sequential MAMS routinely is the computational effort of obtaining stopping boundaries. For example, the method of Jaki and Magirr for time-to-event endpoint, implemented in R package MAMS, requires complicated computational efforts to obtain stopping boundaries. In this study, we develop a group sequential MAMS survival trial design based on the sequential conditional probability ratio test. The proposed method is an improvement of the Jaki and Magirr's method in the following three directions. First, the proposed method provides explicit solutions for both futility and efficacy boundaries to an arbitrary number of stages and arms. Thus, it avoids complicated computational efforts for the trial design. Second, the proposed method provides an accurate number of events for the fixed sample and group sequential designs. Third, the proposed method uses a new procedure for interim analysis which preserves the study power. [ABSTRACT FROM AUTHOR]

Objective: Examine the influence of household income on health‐related quality of life (HRQOL) among children with newly diagnosed acute myeloid leukemia (AML). Design: Secondary analysis of data prospectively collected from pediatric patients receiving treatment for AML at 14 hospitals across the United States. Exposure: Household income was self‐reported on a demographic survey. The examined mediators included the acuity of presentation and treatment toxicity. Outcome: Caregiver proxy reported assessment of patient HRQOL from the Peds QL 4.0 survey. Result: Children with AML (n = 131) and caregivers were prospectively enrolled to complete PedsQL assessments. HRQOL scores were better for patients in the lowest versus highest income category (mean ± SD: 76.0 ± 14 household income <$25,000 vs. 59.9 ± 17 income ≥$75,000; adjusted mean difference: 11.2, 95% CI: 2.2–20.2). Seven percent of enrolled patients presented with high acuity (ICU‐level care in the first 72 h), and 16% had high toxicity (any ICU‐level care); there were no identifiable differences by income, refuting mediating roles in the association between income and HRQOL. Enrolled patients were less likely to be Black/African American (9.9% vs. 22.2%), more likely to be privately insured (50.4% vs. 40.7%), and more likely to have been treated on a clinical trial (26.7% vs. 18.5%) compared to eligible unenrolled patients not enrolled. Evaluations of potential selection bias on the association between income and HRQOL suggested differences in HRQOL may be smaller than observed or even in the opposing direction. Conclusions: While primary analyses suggested lower household income was associated with superior HRQOL, differential participation may have biased these results. Future studies should partner with patients/families to identify strategies for equitable participation in clinical research. [ABSTRACT FROM AUTHOR]

Background: Pediatric acute myeloid leukemia (AML) chemotherapy increases the risk of life‐threatening complications, including septic shock (SS). An area‐based measure of social determinants of health, the social disorganization index (SDI), was hypothesized to be associated with SS and SS‐associated death (SS‐death). Methods: Children treated for de novo AML on two Children's Oncology Group trials at institutions contributing to the Pediatric Health Information System (PHIS) database were included. The SDI was calculated via residential zip code data from the US Census Bureau. SS was identified via PHIS resource utilization codes. SS‐death was defined as death within 2 weeks of an antecedent SS event. Patients were followed from 7 days after the start of chemotherapy until the first of end of front‐line therapy, death, relapse, or removal from study. Multivariable‐adjusted Cox regressions estimated hazard ratios (HRs) comparing time to first SS by SDI group. Results: The assembled cohort included 700 patients, with 207 (29.6%) sustaining at least one SS event. There were 233 (33%) in the SDI‐5 group (highest disorganization). Adjusted time to incident SS did not statistically significantly differ by SDI (reference, SDI‐1; SDI‐2: HR, 0.84 [95% confidence interval (CI), 0.51–1.41]; SDI‐3: HR, 0.70 [95% CI, 0.42–1.16]; SDI‐4: HR, 0.97 [95% CI, 0.61–1.53]; SDI‐5: HR, 0.72 [95% CI, 0.45–1.14]). Nine patients (4.4%) with SS experienced SS‐death; seven of these patients (78%) were in SDI‐4 or SDI‐5. Conclusions: In a large, nationally representative cohort of trial‐enrolled pediatric patients with AML, there was no significant association between the SDI and time to SS. Time to first septic shock event was not associated with the social disorganization index (SDI), an area‐based measure of social determination of health, in children with acute myeloid leukemia treated on two Children's Oncology Group trials. Septic shock–associated mortality is rare in children with acute myeloid leukemia, and differences by SDI were not able to be detected. [ABSTRACT FROM AUTHOR]

Background: Despite the widespread implementation of telemedicine, there are limited data regarding its impact on key components of care for patients with incurable or high‐risk cancer. For these patients, high‐quality care requires detailed conversations regarding treatment priorities (advance care planning) and clinical care to minimize unnecessary acute care (unplanned hospitalizations). Whether telemedicine affects these outcomes relative to in‐person clinic visits was examined among patients with cancer at high risk for 6‐month mortality. Methods: This retrospective cohort study included adult patients with cancer with any tumor type treated at the University of Pennsylvania who were newly identified between April 1 and December 31, 2020, to be at high risk for 6‐month mortality via a validated machine learning algorithm. Separate modified Poisson regressions were used to assess the occurrence of advance care planning and unplanned hospitalizations for telemedicine as compared to in‐person visits. Additional analyses were done comparing telemedicine type (video or phone) as compared to in‐person clinic visits. Results: The occurrence of advance care planning was similar between telemedicine and in‐person visits (6.8% vs. 6.0%; adjusted risk ratio [aRR], 1.25; 95% CI, 0.92–1.69). In regard to telemedicine subtype, patients exposed to video encounters were modestly more likely to have documented advance care planning in comparison to those seen in person (7.5% vs. 6.0%; aRR, 1.48; 95% CI, 1.03–2.11). The 3‐month risk for unplanned hospitalization was comparable for telemedicine compared to in‐person clinic encounters (21% vs. 18%; aRR, 1.06; 95% CI, 0.81–1.38). Conclusions: In this study, care delivered by telemedicine, compared to in‐person clinic visits, produced comparable rates of advance care planning conversations without increasing hospitalizations, which suggests that vulnerable patients can be managed safely by telemedicine. In this study, care delivered by telemedicine, compared to in‐person clinic visits, produced comparable rates of advance care planning conversations without increasing hospitalizations, which suggests that vulnerable patients can be managed safely by telemedicine. [ABSTRACT FROM AUTHOR]

Cancer immunotherapy trials are frequently characterized by delayed treatment effects such that the proportional hazards assumption is violated and the log-rank test suffers a substantial loss of statistical power. To increase the efficacy of the trial design, a variety of weighted log-rank tests have been proposed for fixed sample and group sequential trial designs. However, in such a group sequential design, it is often not recommended for futility interim monitoring due to possible delayed treatment effect which could result a high false-negative rate. To resolve this problem, we propose a group sequential design using a piecewise weighted log-rank test which provides an event-driven approach based on number of events after the delayed time. That is, the interim looks will not be conducted until the planned number of events observed after the delay time. Thus, it avoids the possibility of false-negative rate due to the delayed treatment effect. Furthermore, with an event-driven approach, the proposed group sequential design is robust against the underlying survival, accrual and censoring distributions. The group sequential designs using Fleming-Harrington-($$\rho ,\gamma $$ ρ , γ) weighted log-rank test and a new weighted log-rank test are also discussed. [ABSTRACT FROM AUTHOR]

Pediatric cancer treatment, especially for brain tumors, can have profound and complicated late effects. With the survival rates increasing because of improved detection and treatment, a more comprehensive understanding of the impact of current treatments on neurocognitive function and brain structure is critically needed. A frontline medulloblastoma clinical trial (SJMB03) has collected data, including treatment, clinical, neuroimaging, and cognitive variables. Advanced methods for modeling and integrating these data are critically needed to understand the mediation pathway from the treatment through brain structure to neurocognitive outcomes. We propose an integrative Bayesian mediation analysis approach to model jointly a treatment exposure, a high‐dimensional structural neuroimaging mediator, and a neurocognitive outcome and to uncover the mediation pathway. The high‐dimensional imaging‐related coefficients are modeled via a binary Ising–Gaussian Markov random field prior (BI‐GMRF), addressing the sparsity, spatial dependency, and smoothness and increasing the power to detect brain regions with mediation effects. Numerical simulations demonstrate the estimation accuracy, power, and robustness. For the SJMB03 study, the BI‐GMRF method has identified white matter microstructure that is damaged by cancer‐directed treatment and impacts late neurocognitive outcomes. The results provide guidance on improving treatment planning to minimize long‐term cognitive sequela for pediatric brain tumor patients. [ABSTRACT FROM AUTHOR]

A multi‐arm trial allows simultaneous comparison of multiple experimental treatments with a common control and provides a substantial efficiency advantage compared to the traditional randomized controlled trial. Many novel multi‐arm multi‐stage (MAMS) clinical trial designs have been proposed. However, a major hurdle to adopting the group sequential MAMS routinely is the computational effort of obtaining total sample size and sequential stopping boundaries. In this paper, we develop a group sequential MAMS trial design based on the sequential conditional probability ratio test. The proposed method provides analytical solutions for futility and efficacy boundaries to an arbitrary number of stages and arms. Thus, it avoids complicated computational effort for the methods proposed by Magirr et al. Simulation results showed that the proposed method has several advantages compared to the methods implemented in R package MAMS by Magirr et al. [ABSTRACT FROM AUTHOR]

The employment of ultra‐thin lithium metal anode with high loading cathode is the key to realizing high‐energy‐density rechargeable lithium batteries. Ultra‐thin lithium foils are routinely loaded on a copper substrate in batteries, however, the close contact of these two metals causes galvanic corrosion in the presence of electrolyte, which results in irreversible consumption of lithium and decomposition of electrolyte. Herein, a lightweight and highly conductive flexible graphite paper (GP) is applied to replace Cu foil as the current collector for lithium metal anode. It is demonstrated that the application of GP prevents galvanic corrosion and maintains intimate and steady contact between Li foil and GP current collector during cycling, thereby improving the electrochemical performance of the battery. A 1.08 Ah pouch cell assembled with Li@GP anode and LiNi0.8Co0.1Mn0.1O2 cathode exhibits a long lifetime of 240 cycles with a capacity retention of 91.6% under limited Li, high cathode loading and lean electrolyte conditions. [ABSTRACT FROM AUTHOR]

Background: Timely targeted treatment initiation can be challenging because additional biomarker testing is needed for eligibility. The authors hypothesized that timely targeted treatment improves survival relative to nontimely initiation in metastatic HER2+ gastroesophageal adenocarcinoma (GEA). Methods: The authors performed a retrospective cohort study of metastatic HER2+ GEA treated with first‐line (1L) systemic therapy from January 2011 to December 2017 using a nationwide electronic health record–derived deidentified database. Timely targeted treatment—trastuzumab initiation within 14 days after starting 1L chemotherapy—was assessed as a time‐varying exposure. Nontimely targeted treatment included patients who initiated trastuzumab after 14 days or who lacked documentation of receiving trastuzumab. Extended Cox regressions compared overall survival (OS) and progression‐free survival (PFS) between timely and nontimely groups. Results: A total of 320 patients were included; 59.1% received timely trastuzumab. Relative to nontimely initiation, timely trastuzumab was associated with significantly higher OS (2‐year OS, 32.1% vs 15.3%; adjusted hazard ratio [HR], 0.67; 95% CI, 0.51‐0.88) and PFS (2‐year PFS, 9.2% vs 3.7%; adjusted HR, 0.71; 95% CI, 0.55‐0.93). Results remained similar in sensitivity analyses 1) using alternative "timeliness" definitions up to 70 days after starting 1L chemotherapy, 2) comparing any trastuzumab, regardless of timing of initiation, to no trastuzumab, and 3) excluding patients lacking documentation of receiving trastuzumab. Conclusions: Improved survival was observed among metastatic HER2+ GEA patients treated with trastuzumab versus those who were not, regardless of timing of initiation. Although these results reassure clinicians that modest targeted treatment delays may not be detrimental to outcomes, efforts should still ensure that all metastatic HER2+ GEA patients receive trastuzumab. Time‐to‐treatment initiation is an important quality metric in oncology, but there is a paucity of data on the impact of timely targeted treatment for which additional biomarker testing is needed to identify eligible patients. In this study of patients with metastatic HER2‐overexpressing gastroesophageal adenocarcinoma, overall and progression‐free survival rates were higher for patients treated with trastuzumab compared to those who were not, regardless of the timing of initiation. [ABSTRACT FROM AUTHOR]

In this paper, we consider weak solutions of the Euler–Lagrange equation to a variational energy functional modeling the geometrically nonlinear Cosserat micropolar elasticity of continua in dimension three, which is a system coupling between the Poisson equation and the equation of |$p$| -harmonic maps (⁠|$2\le p\le 3$|⁠). We show that if a weak solution is stationary, then its singular set is discrete for |$2

This paper discusses the design of clinical trials where the primary endpoint is a recurrent event with the focus on the sample size calculation. For the problem, a few methods have been proposed but most of them assume a multiplicative treatment effect on the rate or mean number of recurrent events. In practice, sometimes the additive treatment effect may be preferred or more appealing because of its intuitive clinical meaning and straightforward interpretation compared to a multiplicative relationship. In this paper, new methods are presented and investigated for the sample size calculation based on the additive rates model for superiority, non‐inferiority, and equivalence trials. They allow for flexible baseline rate function, staggered entry, random dropout, and overdispersion in event numbers, and simulation studies show that the proposed methods perform well in a variety of settings. We also illustrate how to use the proposed methods to design a clinical trial based on real data. [ABSTRACT FROM AUTHOR]

We use blow up analysis for local integral equations to provide a blow up rates of solutions of higher order Hardy–Hénon equation in a bounded domain with an isolated singularity, and show the asymptotic radial symmetry of the solutions near the singularity. This work generalizes the correspondence results of Jin–Xiong (in, Asymptotic symmetry and local behavior of solutions of higher order conformally invariant equations with isolated singularities. arXiv:1901.01678) on higher order conformally invariant equations with an isolated singularity. [ABSTRACT FROM AUTHOR]

• Immune checkpoint inhibitor (ICI) therapy is commonly used in the second line setting in patients with mesothelioma. • Among real-world patients with mesothelioma, second-line ICI therapy improved overall survival compared to chemotherapy. • Our findings are in contrast with a recent clinical trial, highlighting the importance of real-world evidence. Second-line immune checkpoint inhibition (ICI) was recently shown to have a survival advantage over placebo in malignant pleural mesothelioma (MPM), but the survival comparison to chemotherapy in patients with MPM receiving routine clinical care is unknown. Our objective was to examine the effectiveness of second-line ICI versus chemotherapy on overall survival (OS) outcomes in real-world patients with advanced MPM. We performed a multicenter retrospective cohort study of real-world adult patients with advanced MPM who received first-line platinum-based chemotherapy and at least two total lines of systemic therapy. Patients received either second-line chemotherapy (gemcitabine and/or vinorelbine) or ICI therapy (pembrolizumab or nivolumab ± ipilimumab). The primary outcome was OS, defined as the time from second-line therapy initiation to death or end of the observation period. We used Kaplan-Meier methods and Cox proportional hazards modeling with adjustment for relevant patient demographic and clinical variables to compare OS between the two second-line treatment groups. Of the 176 patients with MPM, the median age was 75 years (IQR: 69–79.5 years), and most were white (77%), male (74%), and had epithelioid histology (67%). Thirty-five percent (61) received second-line chemotherapy and 65% (1 1 5) ICI therapy (80 pembrolizumab, 31 nivolumab, and 4 nivolumab + ipilimumab). Treatment with ICI was associated with significantly longer median OS compared to chemotherapy (8.7 vs 5.0 months, p=0.001; adjusted hazard ratio: 0.52, 95% CI: 0.34–0.81). The estimated 12-month OS probability was 36.7% (95% CI: 27.6%-45.8%) and 15.6% (95% CI: 7.7%-26.1%) in the ICI and chemotherapy groups, respectively. In this "real-world" population of patients with MPM, treatment with ICI was associated with improved OS outcomes compared to chemotherapy in the second-line setting, in contrast with a recent clinical trial. Our findings suggest that ICI may benefit patients with advanced MPM and progression after initial platinum-based chemotherapy. [ABSTRACT FROM AUTHOR]

BACKGROUND: Anti human epidermal growth factor receptor 2 (anti‐HER2) therapy with trastuzumab improves overall survival in patients with advanced, HER2‐positive gastroesophageal adenocarcinoma (GEA) and is now incorporated into national guidelines. However, little is known about adherence to and determinants of timely HER2 testing and trastuzumab initiation in routine practice. METHODS: The authors performed a cross‐sectional study of patients who had advanced GEA diagnosed between January 2011 and June 2019 in a nationwide electronic health record‐derived database. The annual prevalences of both timely HER2 testing (defined within 21 days after advanced diagnosis) and timely trastuzumab initiation (defined within 14 days after a positive HER2 result) were calculated. Log‐binomial regressions estimated adjusted prevalence ratios comparing timely HER2 testing and trastuzumab initiation by patient and tumor characteristics. RESULTS: In total, the cohort included 6032 patients with advanced GEA of whom 1007 were HER2‐positive. Between 2011 and 2019, timely HER2 testing increased from 22.4% to 44.5%, whereas timely trastuzumab initiation remained stable at 16.3%. No appreciable differences in timely testing or trastuzumab initiation were noted by age, sex, race, or insurance status. Compared with patients who had metastatic disease at diagnosis, patients who had early stage GEA who did not undergo surgery were less likely to receive timely HER2 testing and trastuzumab initiation (testing prevalence ratio, 0.69; 95% CI, 0.64‐0.75; treatment prevalence ratio, 0.32; 95% CI, 0.18‐0.56), as were patients with early stage disease who subsequently developed a distant recurrence (testing prevalence ratio, 0.56; 95% CI, 0.47‐0.65; treatment prevalence ratio, 0.61; 95% CI, 0.24‐1.55). CONCLUSIONS: In patients with advanced GEA, guideline‐recommended HER2 testing and anti‐HER2 therapy remain underused. Uptake may improve with universal HER2 testing regardless of stage. Timely HER2 biomarker testing and targeted therapy administration remain in use for patients with advanced gastroesophageal adenocarcinoma. Compared with patients initially diagnosed with de novo metastatic disease, those diagnosed with early stage disease who develop a recurrence or who do not undergo curative surgery are less likely to receive timely precision oncology care. [ABSTRACT FROM AUTHOR]

The development of normal tissue radiation dose-response models for children with cancer has been challenged by many factors, including small sample sizes; the long length of follow-up needed to observe some toxicities; the continuing occurrence of events beyond the time of assessment; the often complex relationship between age at treatment, normal tissue developmental dynamics, and age at assessment; and the need to use retrospective dosimetry. Meta-analyses of published pediatric outcome studies face additional obstacles of incomplete reporting of critical dosimetric, clinical, and statistical information. This report describes general methods used to address some of the pediatric modeling issues. It highlights previous single- and multi-institutional pediatric dose-response studies and summarizes how each PENTEC taskforce addressed the challenges and limitations of the reviewed publications in constructing, when possible, organ-specific dose-effect models. [ABSTRACT FROM AUTHOR]

Objectives. Recent studies have shown that the slightly elevated circulating levels of ketone bodies (KBs) played a significant role in the treatment of various diseases. This study is aimed at investigating the association between different levels of KBs and kidney function in patients with type 2 diabetes mellitus (T2DM). Methods. A retrospective study of 955 patients with T2DM (426 women and 529 men) admitted to our hospital from December 2017 to September 2019 was conducted. Patients were divided into different groups in line with the levels of KBs (low-normal group: 0.02-0.04 mmol/L, middle-normal group: 0.05-0.08 mmol/L, high-normal group: 0.09-0.27 mmol/L, and slightly elevated group: >0.27 and <3.0 mmol/L). Results. In the present study, individuals with high-normal levels of KBs had the lowest risk of diabetic kidney disease (DKD) and increased peak systolic velocity (PSV); those with middle-normal levels of KBs had the lowest risk of increased renal arterial resistive index (RI), with a positive correlation between increased α1-microglobulin and KB concentration. In addition, the indicators of glomerulus, renal tubules, and renal arteries were all poor with slightly elevated circulating levels of KBs, and KB concentration lower than 0.09 mmol/L can be applied as the threshold for low risk of renal function damage. Conclusions. In summary, slightly elevated circulating levels of ketone bodies are not of benefit for renal function in patients with type 2 diabetes mellitus. [ABSTRACT FROM AUTHOR]

Background: Whether social determinants of health are associated with survival in the context of pediatric oncology-targeted immunotherapy trials is not known. We examined the association between poverty and event-free survival (EFS) and overall survival (OS) for children with high-risk neuroblastoma treated in targeted immunotherapy trials.Methods: We conducted a retrospective cohort study of 371 children with high-risk neuroblastoma treated with GD2-targeted immunotherapy in the Children's Oncology Group trial ANBL0032 or ANBL0931 at a Pediatric Health Information System center from 2005 to 2014. Neighborhood poverty exposure was characterized a priori as living in a zip code with a median household income within the lowest quartile for the cohort. Household poverty exposure was characterized a priori as sole coverage by public insurance. Post hoc analyses examined the joint effect of neighborhood and household poverty using a common reference. All statistical tests were 2-sided.Results: In multivariable Cox regressions adjusted for disease and treatment factors, household poverty-exposed children experienced statistically significantly inferior EFS (hazard ratio [HR] = 1.90, 95% confidence interval [CI] = 1.28 to 2.82, P = .001) and OS (HR = 2.79, 95% CI = 1.63 to 4.79, P < .001) compared with unexposed children. Neighborhood poverty was not independently associated with EFS or OS. In post hoc analyses exploring the joint effect of neighborhood and household poverty, children with dual-poverty exposure (neighborhood poverty and household poverty) experienced statistically significantly inferior EFS (HR = 2.21, 95% CI = 1.48 to 3.30, P < .001) and OS (HR = 3.70, 95% CI = 2.08 to 6.59, P < .001) compared with the unexposed group.Conclusions: Poverty is independently associated with increased risk of relapse and death among neuroblastoma patients treated with targeted immunotherapy. Incorporation of social and environmental factors in future trials as health-care delivery intervention targets may increase the benefit of targeted therapies. [ABSTRACT FROM AUTHOR]

Pediatric phase I trials are usually carried out after the adult trial testing the same agent has started, but not completed yet. As the pediatric trial progresses, in light of the accrued interim data from the concurrent adult trial, the pediatric protocol often is amended to modify the original pediatric dose escalation design. In practice, this is done frequently in an ad hoc way, interrupting patient accrual and slowing down the trial. We developed a pediatric‐continuous reassessment method (PA‐CRM) to streamline this process, providing a more efficient and rigorous method to find the maximum tolerated dose for pediatric phase I oncology trials. We use a discounted joint likelihood of the adult and pediatric data, with a discount parameter controlling information borrowing between pediatric and adult trials. According to the interim adult and pediatric data, the discount parameter is adaptively updated using the Bayesian model averaging method. Numerical study shows that the PA‐CRM improves the efficiency and accuracy of the pediatric trial and is robust to various model assumptions. [ABSTRACT FROM AUTHOR]

• Protaetia brevitarsis larvae effectively converted spent mushroom substrate from Auricularia auricula (SMS-AA) and Lentinula edodes (SMS-LE). • The larvae produced nutrient-enriched organic fertilizer with a phytotoxicity-free. • The larvae were able to efficiently digest and thus utilize lignocellulose. • We present a new strategy for the use of woodchip-derived spent mushroom substrates. The edible mushroom industry produces massive amounts of spent mushroom substrate (SMS). Thus, there is an urgent need for high-value utilization technology to process the SMS, especially SMSs originating from woodchips. Protaetia brevitarsis larvae (PBL) can feed on various types of organic matter and can produce organic fertilizer and insect protein. In this study, we investigated the potential of PBL to utilize and convert SMSs from Auricularia auricula (SMS-AA) and Lentinula edodes (SMS-LE) cultivation. The results showed that the PBL were able to feed on SMS-AA and SMS-LE and form nutrient-enriched organic fertilizer with a low phytotoxicity and high humic acid content. Further analysis of the organic carbon dynamics suggested that PBL can efficiently digest and utilize lignin. This study demonstrates a new strategy for the utilization of SMSs originating from woodchips, and provides a new model for further investigations on the mechanism of lignin decomposition. [ABSTRACT FROM AUTHOR]

Group sequential designs using Lan-DeMets error spending functions are proposed for historical control trials with time-to-event endpoints. Both O'Brien–Fleming and Gamma family types of sequential decision boundaries are derived based on sequential log-rank tests, which follow a Brownian motion in a transformed information time. Simulation results show that the proposed group sequential designs using historical controls preserve the overall type I error and power. [ABSTRACT FROM AUTHOR]

• The study cohort comprised children with leukemia who underwent partially CD3+-depleted peripheral stem cell transplantation (PSCT). • Three-year overall survival was 61.8% (95% confidence interval [CI], 50.2% to 71.4%) and event-free survival was 52.0% (95% CI, 40.3% to 62.4%). • Age ≥15 years and second complete remission were associated with worse outcomes. • The incidence of severe chronic graft-versus-host disease was lower in CD3+-depleted PSCTthan in T cell-replete PSCT. Most children who may benefit from stem cell transplantation lack a matched related donor. Alternative donor transplantations with an unrelated donor (URD) or a partially matched related donor (PMRD) carry an increased risk of graft-versus-host-disease (GVHD) and mortality compared with matched related donor transplantations. We hypothesized that a strategy of partial CD3+/CD19+ depletion for URD or PMRD peripheral stem cell transplantation (PSCT) would attenuate the risks of GVHD and mortality. We enrolled 84 pediatric patients with hematologic malignancies at the Children's Hospital of Philadelphia and the Children's Hospital of Wisconsin between April 2005 and February 2015. Two patients (2.4%) experienced primary graft failure. Relapse occurred in 23 patients (27.4%; cumulative incidence 26.3%), and 17 patients (20.2%) experienced nonrelapse mortality (NRM). Grade III-IV acute GVHD was observed in 18 patients (21.4%), and chronic GVHD was observed and graded as limited in 24 patients (35.3%) and extensive in 8 (11.7%). Three-year overall survival (OS) was 61.8% (95% confidence interval [CI], 50.2% to 71.4%) and event-free survival (EFS) was 52.0% (95% CI, 40.3% to 62.4%). Age ≥15 years was associated with decreased OS (P =.05) and EFS (P =.05). Relapse was more common in children in second complete remission (P =.03). Partially CD3+-depleted alternative donor PSCT NRM, OS, and EFS compare favorably with previously published studies of T cell-replete PSCT. Historically, T cell-replete PSCT has been associated with a higher incidence of extensive chronic GVHD compared with limited chronic GVHD, which may explain the comparatively low relapse and NRM rates in our study cohort despite similar overall rates of chronic GVHD. Partial T cell depletion may expand donor options for children with malignant transplantation indications lacking a matched related donor by mitigating, but not eliminating, chronic GVHD. [ABSTRACT FROM AUTHOR]

Abstract In this paper, we consider the fractional Hardy–Hénon equations with an isolated singularity. If the isolated singularity is located at the origin, we give a classification of solutions to this equation. If the isolated singularity is located at infinity, in the case of exterior domains, we provide decay estimates of solutions and their gradients at infinity. Our results are an extension of the classical work by Caffarelli, Gidas et al. [ABSTRACT FROM AUTHOR]

Highlights • P. brevitarsis larvae can convert agricultural residues to organic manure. • Maize and sawdust were converted to manure by larvae. • Larval digestion produced non-phytotoxic manure with high quality humic acids. • Manure humic acids shared structural similarities with soil humic acids. • P. brevitarsis offers a solution to the buildup of agricultural residues in China. Abstract Utilization of the organic residues produced after crop harvesting is currently an important issue across the world. The edible insect Protaetia brevitarsis larvae can feed various organic matters. In this paper, we investigated the potential to utilize the insect to convert herbaceous and ligneous plant residues. We feed the insect larvae with maize straw and sawdust and analyzed the produced insect manure. P. brevitarsis larval was found to be able to digest both herbaceous and ligneous straw and insect manure extract shown no phytotoxicity. The mass fractions of humic acids (HAs) in the insect manure derived from maize straw and sawdust digestion were 24.37% and 14.46%, respectively. The 13C cross-polarization magic-angle spinning nuclear magnetic resonance (CP–MAS NMR) spectra data indicated that the HAs in the insect manure were similar to those found in the soil. These data suggested that P. brevitarsis larvae can be used to convert agricultural residues and produce organic fertilizers. [ABSTRACT FROM AUTHOR]

Cancer immunotherapy trials are frequently characterized by a delayed treatment effect that violates the proportional hazards assumption. The log-rank test (LRT) suffers a substantial loss of statistical power under the nonproportional hazards model. Various group sequential designs using weighted LRTs (WLRTs) have been proposed under the fixed delayed treatment effect model. However, patients enrolled in immunotherapy trials are often heterogeneous, and the duration of the delayed treatment effect is a random variable. Therefore, we propose group sequential designs under the random delayed effect model using the random delayed distribution WLRT. The proposed group sequential designs are developed for monitoring the efficacy of the trial using the method of Lan-DeMets alpha-spending function with O’Brien-Fleming stopping boundaries or a gamma family alpha-spending function. The maximum sample size for the group sequential design is obtained by multiplying an inflation factor with the sample size for the fixed sample design. Simulations are conducted to study the operating characteristics of the proposed group sequential designs. The robustness of the proposed group sequential designs for misspecifying random delay time distribution and domain is studied via simulations. [ABSTRACT FROM AUTHOR]

Despite the importance of adverse event (AE) reporting, AEs are under-reported on clinical trials. We hypothesized that electronic medical record (EMR) data can ascertain laboratory-based AEs more accurately than those ascertained manually. EMR data on 12 AEs for patients enrolled on two Children's Oncology Group (COG) trials at one institution were extracted, processed and graded. When compared to gold standard chart data, COG AE report sensitivity and positive predictive values (PPV) were 0-21·1% and 20-100%, respectively. EMR sensitivity and PPV were >98·2% for all AEs. These results demonstrate that EMR-based AE ascertainment and grading substantially improves laboratory AE reporting accuracy. [ABSTRACT FROM AUTHOR]

Background: Adolescents with cancer engage in sexual behaviors and are exposed to teratogenic chemotherapy. There are no data regarding pregnancy screening patterns for adolescents before chemotherapy exposure.Methods: A cross-sectional study of leukemia and emergency room (ER) admissions in the Pediatric Health Information System from 1999 to 2011 was conducted. Females who were 10 to 18 years old and 1) had newly diagnosed acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML) or 2) had ER visits with computed tomography (CT) of the abdomen/pelvis were included. The exposure was a hospital visit with either chemotherapy or an abdominal/pelvic CT scan. The main outcome was a pregnancy test billed on the same day or before the teratogenic exposure within the same index admission. Log-binomial regressions were used to compute prevalence ratios and 95% confidence intervals comparing pregnancy screening in the leukemia and ER cohorts.Results: A total of 35,650 admissions were identified. The proportion of visits with an appropriately timed pregnancy test was 35%, 64%, and 58% in the ALL (n = 889), AML (n = 127), and ER cohorts (n = 34,634), respectively. Patients with ALL were significantly less likely to have a pregnancy test than the ER cohort (adjusted prevalence ratio, 0.71; 95% confidence interval, 0.65-0.78), but there was no significant difference between the AML and ER cohorts (adjusted prevalence ratio, 1.12; 95% confidence interval, 0.99-1.27). There was substantial hospital-level variation in pregnancy screening patterns.Conclusions: Adolescents with acute leukemia and ER visits have low rates of pregnancy screening before teratogenic exposures. Standardized practice guidelines for pregnancy screening among adolescents may improve screening rates. Cancer 2016;122:3394-3400. © 2016 American Cancer Society. [ABSTRACT FROM AUTHOR]

Purpose: Corticosteroids can affect sleep patterns, mood, and behavior. Two of the most commonly prescribed corticosteroids in acute lymphoblastic leukemia (ALL), dexamethasone and prednisone, may impact sleep differently, but no research has compared these medications in children. The current study tested the hypothesis that dexamethasone and prednisone differentially affect sleep in children with ALL to understand how these medications contribute to health-related quality of life (HRQL).Methods: Parents of 81 children 3-12 years old in maintenance therapy for ALL completed a baseline measure of child sleep (dexamethasone n = 55, prednisone n = 26), and 61 parents returned 28 days of child sleep diaries starting the first day of a 5-day steroid course (dexamethasone n = 43, prednisone n = 18). Parents also completed measures of HRQL and fatigue on the last day of steroids and the last day of the month.Results: At baseline, parents reported more sleep disturbances in children taking dexamethasone than prednisone. Across the month, children taking dexamethasone experienced poorer sleep quality compared to children taking prednisone. During corticosteroid treatment, children taking dexamethasone also experienced more night awakenings than children taking prednisone. Sleep variables accounted for almost half of the variance in HRQL during time off steroids and also significantly contributed to fatigue during the corticosteroids course and time off corticosteroids.Conclusions: Sleep is an essential component of HRQL in children taking corticosteroids, and the impact on sleep is more pronounced in children taking dexamethasone compared to prednisone. Screening for sleep disturbances and offering brief interventions to manage steroid-related sleep disruptions may improve HRQL. [ABSTRACT FROM AUTHOR]

Although inferior outcomes of children with Down syndrome ( DS) and acute lymphoid leukaemia ( ALL) are established, national supportive care patterns for these patients are unknown. A validated retrospective cohort of paediatric patients diagnosed with ALL from 1999 to 2011 was assembled from the US Pediatric Health Information System ( PHIS) database to examine organ toxicity, sepsis, and resource utilization in children with and without DS. Among 10699 ALL patients, 298 had DS- ALL (2·8%). In a multivariate model, DS was associated with increased risk of cardiovascular (odds ratio [ OR] 2·0, 95% confidence interval [ CI] 1·6-2·7), respiratory ( OR 2·1, 95% CI: 1·6-2·9), neurologic ( OR 3·4, 95% CI 1·9-6·2), and hepatic ( OR 1·4, 95% CI 1·0-1·9) dysfunction and sepsis ( OR 1·8, 95% CI: 1·4-2·4). Children with DS- ALL used significantly more respiratory support, insulin, and anti-infectives, including broad-spectrum Gram-positive agents, quinolones, and azoles. They used significantly fewer analgesics and antiemetics compared to non- DS- ALL children. Ultimately, this study confirms the increased risk of infectious and end-organ toxicity in children with DS- ALL and quantifies important differences in resource utilization between children with DS and non- DS ALL. These findings highlight the importance of investigating the impact of these care variations and developing specific supportive care guidelines for this population. [ABSTRACT FROM AUTHOR]

Longitudinal neuroimaging data plays an important role in mapping the neural developmental profile of major neuropsychiatric and neurodegenerative disorders and normal brain. The development of such developmental maps is critical for the prevention, diagnosis, and treatment of many brain-related diseases. The aim of this paper is to develop a spatio-temporal Gaussian process (STGP) framework to accurately delineate the developmental trajectories of brain structure and function, while achieving better prediction by explicitly incorporating the spatial and temporal features of longitudinal neuroimaging data. Our STGP integrates a functional principal component model (FPCA) and a partition parametric space–time covariance model to capture the medium-to-large and small-to-medium spatio-temporal dependence structures, respectively. We develop a three-stage efficient estimation procedure as well as a predictive method based on a kriging technique. Two key novelties of STGP are that it can efficiently use a small number of parameters to capture complex non-stationary and non-separable spatio-temporal dependence structures and that it can accurately predict spatio-temporal changes. We illustrate STGP using simulated data sets and two real data analyses including longitudinal positron emission tomography data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and longitudinal lateral ventricle surface data from a longitudinal study of early brain development. [ABSTRACT FROM AUTHOR]

Purpose: Clinical trials data from National Cancer Institute (NCI)-funded cooperative oncology group trials could be enhanced by merging with external data sources. Merging without direct patient identifiers would provide additional patient privacy protections. We sought to develop and validate a matching algorithm that uses only indirect patient identifiers. Methods: We merged the data from two Phase III Children’s Oncology Group (COG) trials for de novo acute myeloid leukemia (AML) with the Pediatric Health Information Systems (PHIS). We developed a stepwise matching algorithm that used indirect identifiers including treatment site, gender, birth year, birth month, enrollment year and enrollment month. Results from the stepwise algorithm were compared against the direct merge method that used date of birth, treatment site, and gender. The indirect merge algorithm was developed on AAML0531 and validated on AAML1031. Results: Of 415 patients enrolled on the AAML0531 trial at PHIS centers, we successfully matched 378 (91.1%) patients using the indirect stepwise algorithm. Comparison to the direct merge result suggested that 362 (95.7%) matches identified by the indirect merge algorithm were concordant with the direct merge result. When validating the indirect stepwise algorithm using the AAML1031 trial, we successfully matched 157 out of 165 patients (95.2%) and 150 (95.5%) of the indirectly merged matches were concordant with the directly merged matches. Conclusions: These data demonstrate that patients enrolled on COG clinical trials can be successfully merged with PHIS administrative data using a stepwise algorithm based on indirect patient identifiers. The merged data sets can be used as a platform for comparative effectiveness and cost effectiveness studies. [ABSTRACT FROM AUTHOR]

The rapid acceleration of genetic data collection in biomedical settings has recently resulted in the rise of genetic compendiums filled with rich longitudinal disease data. One common feature of these data sets is their plethora of interval‐censored outcomes. However, very few tools are available for the analysis of genetic data sets with interval‐censored outcomes, and in particular, there is a lack of methodology available for set‐based inference. Set‐based inference is used to associate a gene, biological pathway, or other genetic construct with outcomes and is one of the most popular strategies in genetics research. This work develops three such tests for interval‐censored settings beginning with a variance components test for interval‐censored outcomes, the interval‐censored sequence kernel association test (ICSKAT). We also provide the interval‐censored version of the Burden test, and then we integrate ICSKAT and Burden to construct the interval censored sequence kernel association test—optimal (ICSKATO) combination. These tests unlock set‐based analysis of interval‐censored data sets with analogs of three highly popular set‐based tools commonly applied to continuous and binary outcomes. Simulation studies illustrate the advantages of the developed methods over ad hoc alternatives, including protection of the type I error rate at very low levels and increased power. The proposed approaches are applied to the investigation that motivated this study, an examination of the genes associated with bone mineral density deficiency and fracture risk. [ABSTRACT FROM AUTHOR]

In oncology clinical trials, overall survival, time to progression, and progression-free survival are three commonly used endpoints. Empirical correlations among them have been published for different cancers, but statistical models describing the dependence structures are limited. Recently, Fleischer et al. proposed a statistical model that is mathematically tractable and shows some flexibility to describe the dependencies in a realistic way, based on the assumption of exponential distributions. This paper aims to extend their model to the more flexible Weibull distribution. We derived theoretical correlations among different survival outcomes, as well as the distribution of overall survival induced by the model. Model parameters were estimated by the maximum likelihood method and the goodness of fit was assessed by plotting estimated versus observed survival curves for overall survival. We applied the method to three cancer clinical trials. In the non-small-cell lung cancer trial, both the exponential and the Weibull models provided an adequate fit to the data, and the estimated correlations were very similar under both models. In the prostate cancer trial and the laryngeal cancer trial, the Weibull model exhibited advantages over the exponential model and yielded larger estimated correlations. Simulations suggested that the proposed Weibull model is robust for data generated from a range of distributions. [ABSTRACT FROM AUTHOR]

Objective: Our aim was to expand research on predictors of health-related quality of life (HRQOL) for adolescent and young adult survivors of childhood brain tumors who are not living independently by evaluating the mediating role of family functioning in the association of disease severity/treatment late effects with survivor self-report and caregiver-proxy report of physical and emotional HRQOL. Methods: Mothers (N= 186) and their survivors living at home (N= 126) completed self-report and caregiver-proxy report of physical and emotional HRQOL. Mothers completed family functioning measures of general family functioning, caregiving demands, and caregiver distress. Medical file review and caregiver report were used to evaluate disease severity/treatment late effects. Results: Using structural equation models, family functioning was adjusted for sociodemographic factors. Disease severity/treatment late effects had significant direct effects on self-report and caregiver-proxy report of physical and emotional HRQOL. Family functioning had a significant direct effect on caregiver-proxy report of physical and emotional HRQOL, but these findings were not confirmed for self-report HRQOL. Model-fit indices suggested good fit of the models, but the mediation effect of family functioning was not supported. Conclusions: Disease severity/treatment late effects explained self-report and caregiver-proxy report of physical and emotional HRQOL for these adolescent and young adult survivors of childhood brain tumors. Family functioning was implicated as an important factor for caregiver-proxy report only. To enhance physical and emotional HRQOL, findings underscore the importance of coordinated, multidisciplinary follow-up care for the survivors who are not living independently and their families to address treatment late effects and support family management. [ABSTRACT FROM AUTHOR]

Identifying drivers of viral diversity is key to understanding the evolutionary as well as epidemiological dynamics of the COVID-19 pandemic. Using rich viral genomic data sets, we show that periods of steadily rising diversity have been punctuated by sudden, enormous increases followed by similarly abrupt collapses of diversity. We introduce a mechanistic model of saltational evolution with epistasis and demonstrate that these features parsimoniously account for the observed temporal dynamics of inter-genomic diversity. Our results provide support for recent proposals that saltational evolution may be a signature feature of SARS-CoV-2, allowing the pathogen to more readily evolve highly transmissible variants. These findings lend theoretical support to a heightened awareness of biological contexts where increased diversification may occur. They also underline the power of pathogen genomics and other surveillance streams in clarifying the phylodynamics of emerging and endemic infections. In public health terms, our results further underline the importance of equitable distribution of up-to-date vaccines. Author summary: The coronavirus responsible for the COVID-19 pandemic, SARS-CoV-2, has shown a remarkable ability to evolve novel, increasingly transmissible variants. Using large amounts of viral sequences sampled during the pandemic, we map the genomic diversity over time. We find that the pathogen has followed a clear pattern of punctuated evolution, where periods of genetic drift are interrupted by sudden large increases in diversity followed by similarly abrupt collapses. This is in contrast to the pattern previously identified for influenza, which does not show similarly sudden increases in diversity. Using a mathematical model, we show that the observed pattern can result from rare evolutionary jumps (saltations) occurring within some hosts, in combination with epistasis. One possible explanation for such jumps is accelerated evolution within immunocompromised hosts, underscoring the importance of equitable vaccine distribution. Furthermore, a simple modification of the model to include incomplete cross immunity offers an explanation for recently observed patterns of variant co-circulation. [ABSTRACT FROM AUTHOR]

Abstract: The aim of this paper is to develop a spatial Gaussian predictive process (SGPP) framework for accurately predicting neuroimaging data by using a set of covariates of interest, such as age and diagnostic status, and an existing neuroimaging data set. To achieve a better prediction, we not only delineate spatial association between neuroimaging data and covariates, but also explicitly model spatial dependence in neuroimaging data. The SGPP model uses a functional principal component model to capture medium-to-long-range (or global) spatial dependence, while SGPP uses a multivariate simultaneous autoregressive model to capture short-range (or local) spatial dependence as well as cross-correlations of different imaging modalities. We propose a three-stage estimation procedure to simultaneously estimate varying regression coefficients across voxels and the global and local spatial dependence structures. Furthermore, we develop a predictive method to use the spatial correlations as well as the cross-correlations by employing a cokriging technique, which can be useful for the imputation of missing imaging data. Simulation studies and real data analysis are used to evaluate the prediction accuracy of SGPP and show that SGPP significantly outperforms several competing methods, such as voxel-wise linear model, in prediction. Although we focus on the morphometric variation of lateral ventricle surfaces in a clinical study of neurodevelopment, it is expected that SGPP is applicable to other imaging modalities and features. [Copyright &y& Elsevier]

Abstract: Impaired immunologic recovery (IR) after hematopoietic stem cell transplantation (HSCT) is associated with increased risk for infections and relapse. Stem cell source and graft manipulation influence the kinetics of IR. Partial T cell depletion of peripheral blood stem cell (PBSC) grafts is a novel alternative method of graft manipulation for children. We compared IR in children undergoing HSCT for hematologic malignancies receiving either T cell–depleted (TCD)-PBSCs (n = 55) or umbilical cord blood (UCB) (n = 21) over a 7-year period at a single institution. PBSC grafts underwent ex vivo negative selection for CD3+ cells using the CliniMACS system with partial T cell add-back. Recovery of CD4+ T cells was significantly delayed in TCD-PBSC recipients compared with UCB recipients, owing to impaired CD4+/CD45RA+ (naïve) T cell lymphopoiesis. Recovery of total CD3+ cells and CD3+/CD8+ cells was similar in the 2 groups. The TCD-PBSC recipients had a marked deficit in CD19+ and, to a lesser extent, IgA/IgM, owing to the need for B cell depletion of these grafts to attenuate the risk of lymphoproliferative disease after TCD HSCT. There were no significant between-group differences in response to mitogen stimulation, time to independence from intravenous immunoglobulin supplementation, or incidence of viral reactivation. Transplantation outcomes of relapse, transplantation-related mortality, event-free survival, and overall survival were similar in the 2 groups. Efforts to enhance IR after partial TCD-PBSC transplantation, such as selective αβ T cell depletion, hold promise for further improvement of this transplantation approach. [Copyright &y& Elsevier]

Abstract: Many large-scale longitudinal imaging studies have been or are being widely conducted to better understand the progress of neuropsychiatric and neurodegenerative disorders and normal brain development. The goal of this article is to develop a multiscale adaptive generalized estimation equation (MAGEE) method for spatial and adaptive analysis of neuroimaging data from longitudinal studies. MAGEE is applicable to making statistical inference on regression coefficients in both balanced and unbalanced longitudinal designs and even in twin and familial studies, whereas standard software platforms have several major limitations in handling these complex studies. Specifically, conventional voxel-based analyses in these software platforms involve Gaussian smoothing imaging data and then independently fitting a statistical model at each voxel. However, the conventional smoothing methods suffer from the lack of spatial adaptivity to the shape and spatial extent of region of interest and the arbitrary choice of smoothing extent, while independently fitting statistical models across voxels does not account for the spatial properties of imaging observations and noise distribution. To address such drawbacks, we adapt a powerful propagation–separation (PS) procedure to sequentially incorporate the neighboring information of each voxel and develop a new novel strategy to solely update a set of parameters of interest, while fixing other nuisance parameters at their initial estimators. Simulation studies and real data analysis show that MAGEE significantly outperforms voxel-based analysis. [Copyright &y& Elsevier]

Survival data can contain an unknown fraction of subjects who are “cured” in the sense of not being at risk of failure. We describe such data with cure-mixture models, which separately model cure status and the hazard of failure among non-cured subjects. No diagnostic currently exists for evaluating the fit of such models; the popular Schoenfeld residual (Schoenfeld, 1982. Partial residuals for the proportional hazards regression-model. Biometrika 69, 239–241) is not applicable to data with cures. In this article, we propose a pseudo-residual, modeled on Schoenfeld's, to assess the fit of the survival regression in the non-cured fraction. Unlike Schoenfeld's approach, which tests the validity of the proportional hazards (PH) assumption, our method uses the full hazard and is thus also applicable to non-PH models. We derive the asymptotic distribution of the residuals and evaluate their performance by simulation in a range of parametric models. We apply our approach to data from a smoking cessation drug trial. [ABSTRACT FROM PUBLISHER]

We introduce a new survival distribution, of Pareto type, that arises from a cure-mixture frailty model. We describe its properties and demonstrate connections with familiar distributions including the Pareto and exponential. We derive its characteristic function and moments. [ABSTRACT FROM AUTHOR]

Increased understanding of the underlying mechanisms of cognitive remediation is needed to facilitate development of intervention strategies for childhood cancer survivors experiencing cognitive late effects. Accordingly, a pilot functional magnetic resonance imaging (fMRI) study was conducted with 14 cancer survivors (12.02 ± 0.09 years old), who participated in a cognitive remediation clinical trial, and 28 healthy children (12.7 ± 0.6 years old). The ventral visual areas, cerebellum, supplementary motor area, and left inferior frontal cortex were significantly activated in the healthy participants during a continuous performance task. In survivors, brain activation in these regions was diminished at baseline, and increased upon completion of remediation and at a 6-month follow-up. The fMRI activation index for each region of interest was inversely associated with the Conners' Clinical Competence Index (p<.01). The pilot study suggests that fMRI is useful in evaluating neural responses to cognitive remediation. [ABSTRACT FROM PUBLISHER]

Twin imaging studies have been valuable for understanding the relative contribution of the environment and genes on brain structures and their functions. Conventional analyses of twin imaging data include three sequential steps: spatially smoothing imaging data, independently fitting a structural equation model at each voxel, and finally correcting for multiple comparisons. However, conventional analyses are limited due to the same amount of smoothing throughout the whole image, the arbitrary choice of smoothing extent, and the decreased power in detecting environmental and genetic effects introduced by smoothing raw images. The goal of this paper is to develop a two-stage multiscale adaptive regression method (TwinMARM) for spatial and adaptive analysis of twin neuroimaging and behavioral data. The first stage is to establish the relationship between twin imaging data and a set of covariates of interest, such as age and gender. The second stage is to disentangle the environmental and genetic influences on brain structures and their functions. In each stage, TwinMARM employs hierarchically nested spheres with increasing radii at each location and then captures spatial dependence among imaging observations via consecutively connected spheres across all voxels. Simulation studies show that our TwinMARM significantly outperforms conventional analyses of twin imaging data. Finally, we use our method to detect statistically significant effects of genetic and environmental variations on white matter structures in a neonatal twin study. [ABSTRACT FROM PUBLISHER]

Summary In smoking cessation clinical trials, subjects commonly receive treatment and report daily cigarette consumption over a period of several weeks. Although the outcome at the end of this period is an important indicator of treatment success, substantial uncertainty remains on how an individual's smoking behavior will evolve over time. Therefore it is of interest to predict long-term smoking cessation success based on short-term clinical observations. We develop a Bayesian method for prediction, based on a cure-mixture frailty model we proposed earlier, that describes the process of transition between abstinence and smoking. Specifically we propose a two-stage prediction algorithm that first uses importance sampling to generate subject-specific frailties from their posterior distributions conditional on the observed data, then samples predicted future smoking behavior trajectories from the estimated model parameters and sampled frailties. We apply the method to data from two randomized smoking cessation trials comparing bupropion to placebo. Comparisons of actual smoking status at one year with predictions from our model and from a variety of empirical methods suggest that our method gives excellent predictions. [ABSTRACT FROM AUTHOR]

ABSTRACT Aims Smoking cessation trials generally record information on daily smoking behavior, but base analyses on measures of smoking status at the end of treatment (EOT). We present an alternative approach that analyzes the entire sequence of daily smoking status observations. Methods We analyzed daily abstinence data from a smoking cessation trial, using two longitudinal logistic regression methods: a mixed-effects (ME) model and a generalized estimating equations (GEE) model. We compared results to a standard analysis that takes abstinence status at EOT as outcome. We evaluated time-varying covariates (smoking history and time-varying drug effect) in the longitudinal analysis and compared ME and GEE approaches. Results We observed some differences in the estimated treatment effect odds ratios across models, with narrower confidence intervals under the longitudinal models. GEE yields similar results to ME when only baseline factors appear in the model, but gives biased results when one includes time-varying covariates. The longitudinal models indicate that the quit probability declines and the drug effect varies over time. Both the previous day's smoking status and recent smoking history predict quit probability, independently of the drug effect. Conclusion When analysing outcomes of studies from smoking cessation interventions, longitudinal models with multiple outcome data points, rather than just end of treatment, can makes efficient use of the data and incorporate time-varying covariates. The generalized estimating equations approach should be avoided when using time-varying predictors. [ABSTRACT FROM AUTHOR]

We propose a flexible parametric model to describe alternating states recurrent-event data where there is a possibility of cure with each type of event. We begin by introducing a novel cure model in which a common frailty influences both the cure probability and the hazard function given not cured. We then extend our model to data with recurring events of two alternating types. We assume that each type of event has a gamma frailty, and we link the frailties by a Clayton copula. We illustrate the model with an analysis of data from two smoking cessation trials comparing bupropion and placebo, in which each subject potentially experienced a series of lapse and recovery events. Our analysis suggests that bupropion increases the probability of permanent cure and decreases the hazard of lapse, but does not affect the distribution of time to recovery during a lapse. The data suggest a positive but non-significant association between the lapse and recovery frailties. A simulation study suggests that the estimates have little bias and that their 95 per cent confidence intervals have nearly nominal coverage in samples of practical size. Copyright © 2010 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Drosophila dendritic arborization (da) neurons contain subclasses of neurons with distinct dendritic morphologies. We investigated calcium/calmodulin-dependent protein kinase II (CaMKII) regulation of dendritic structure and dynamics in vivo using optically transparent Drosophila larvae. CaMKII increases the dynamic nature and formation of dendritic filopodia throughout larval development but only affects neurons that normally contain dendritic filopodia. In parallel, we examined the effects of Rac1 activity on dendritic structure to explore signaling specificity. In contrast to CaMKII activity, Rac1 does not alter filopodia stability but instead causes de novo filopodia formation on all da neurons. Although both mediators increase cytoskeletal turnover, measured by fluorescence recovery after photo-bleaching experiments, only CaMKII increases the dynamic nature of dendritic filopodia. CaMKII signaling thus appears to use mechanisms and machinery distinct from Rac1 signaling. This study illustrates a molecular means of uncoupling cytoskeletal regulation from morphological regulation. Our results suggest that Drosophila dendritic filopodia may share some cytoskeletal regulatory mechanisms with mammalian dendritic filopodia. Furthermore, general dendrite cytoskeletal compartmentalization is conserved in multipolar neurons. [ABSTRACT FROM AUTHOR]

Sickle cell disease (SCD) decreases the oxygen-carrying capacity of red blood cells. Children with SCD have reduced/restricted cerebral blood flow, resulting in neurocognitive deficits. Hydroxyurea is the standard treatment for SCD; however, whether hydroxyurea influences such effects is unclear. A key area of SCD-associated neurocognitive impairment is working memory, which is implicated in other cognitive and academic skills. The neural correlates of working memory can be tested using n-back tasks. We analyzed functional magnetic resonance imaging (fMRI) data of patients with SCD (20 hydroxyurea-treated patients and 11 controls, aged 7–18 years) while they performed n-back tasks. Blood-oxygenation level–dependent (BOLD) signals were assessed during working memory processing at 2 time points: before hydroxyurea treatment and ~1 year after treatment was initiated. Neurocognitive measures were also assessed at both time points. Our results suggested that working memory was stable in the treated group. We observed a treatment-by-time interaction in the right cuneus and angular gyrus for the 2- >0-back contrast. Searchlight-pattern classification of the 2 time points of the 2-back tasks identified greater changes in the pattern and magnitude of BOLD signals, especially in the posterior regions of the brain, in the control group than in the treated group. In the control group at 1-year follow-up, 2-back BOLD signals increased across time points in several clusters (e.g., right inferior temporal lobe, right angular gyrus). We hypothesize that these changes resulted from increased cognitive effort during working memory processing in the absence of hydroxyurea. In the treated group, 0- to 2-back BOLD signals in the right angular gyrus and left cuneus increased continuously with increasing working memory load, potentially related to a broader dynamic range in response to task difficulty and cognitive effort. These findings suggest that hydroxyurea treatment helps maintain working memory function in SCD. [ABSTRACT FROM AUTHOR]

Background Performance validity tests (PVTs) and symptom validity tests (SVTs) are essential to neuropsychological evaluations, helping ensure findings reflect true abilities or concerns. It is unclear how PVTs and SVTs perform in children who received radiotherapy for brain tumors. Accordingly, we investigated the rate of noncredible performance on validity indicators as well as associations with fatigue and lower intellectual functioning. Methods Embedded PVTs and SVTs were investigated in 98 patients with pediatric craniopharyngioma undergoing proton radiotherapy (PRT). The contribution of fatigue, sleepiness, and lower intellectual functioning to embedded PVT performance was examined. Further, we investigated PVTs and SVTs in relation to cognitive performance at pre-PRT baseline and change over time. Results SVTs on parent measures were not an area of concern. PVTs identified 0–31% of the cohort as demonstrating possible noncredible performance at baseline, with stable findings 1 year following PRT. Reliable digit span (RDS) noted the highest PVT failure rate; RDS has been criticized for false positives in pediatric populations, especially children with neurological impairment. Objective sleepiness was strongly associated with PVT failure, stressing need to consider arousal level when interpreting cognitive performance in children with craniopharyngioma. Lower intellectual functioning also needs to be considered when interpreting task engagement indices as it was strongly associated with PVT failure. Conclusions Embedded PVTs should be used with caution in pediatric craniopharyngioma patients who have received PRT. Future research should investigate different cut-off scores and validity indicator combinations to best differentiate noncredible performance due to task engagement versus variable arousal and/or lower intellectual functioning. [ABSTRACT FROM AUTHOR]

Introduction: Childhood cancer survivors (CCS) are at risk for radiotherapy (RT) late effects, including second malignancies. Optimal screening for differentiated thyroid cancer (DTC) in CCS post-RT remains controversial. We assessed the outcome of thyroid ultrasound (US) surveillance in CCS exposed to RT. Methods: 306 CCS were surveilled with thyroid US between 2002–2021. Surveillance was dependent on age at the time of primary diagnosis, interval from receipt of RT, and individual provider. Thyroid US, clinicopathologic features, and outcomes were described. Cutpoints of CCS RT age associated with varying risk of nodule presentation were explored. The selected cutpoints were used to define age categories, which were then used to compare thyroid nodule-related outcomes. Risk factors for thyroid nodule(s) were evaluated using multivariate logistic regression (odds ratio [OR] [95% confidence interval]). Results: The most common CCS diagnoses were leukemia (32%), CNS tumor (26%), and neuroblastoma (18%). Patients received TBI (45%) and/or RT to craniospinal (44%), chest (11%), and neck regions (6%). About 49% (n = 150) of patients had thyroid nodule(s). Forty-four patients underwent surgery, and 28 had DTC: 19 with American Thyroid Association (ATA) low-risk classification, 2 with ATA intermediate-risk, and 7 with ATA high-risk disease. Age cutpoint analyses identified cutpoints 3 and 10; hence, ≤3, >3 to ≤10, and >10 years were used. Of the 9 patients with intermediate- or high-risk disease, 8 were ≤10 years and 1 was >10 years at the time of RT. Female sex (OR = 1.62 [1.13–2.12] p = 0.054) and greater interval between RT and first US (OR = 1.10 [1.04–1.16] p = 0.001) were independent risk factors for nodule presentation. Conclusions: Thyroid US surveillance may be beneficial for CCS exposed to RT at younger ages (≤10 years) for earlier detection of DTC, prior to developing advanced metastatic disease. [ABSTRACT FROM AUTHOR]

Although the study on the regulatory mechanism of endothelial differentiation from the perspective of development provides references for endothelial cell (EC) derivation from pluripotent stem cells, incomplete reprogramming and donor-specific epigenetic memory are still thought to be the obstacles of iPSCs for clinical application. Thus, it is necessary to establish a stable iPSC-EC induction system and investigate the regulatory mechanism of endothelial differentiation. Based on a single-layer culture system, we successfully obtained ECs from porcine iPSCs (piPSCs). In vitro, the derived piPSC-ECs formed microvessel-like structures along 3D gelatin scaffolds. Under pathological conditions, the piPSC-ECs functioned on hindlimb ischemia repair by promoting blood vessel formation. To elucidate the molecular events essential for endothelial differentiation in our model, genome-wide transcriptional profile analysis was conducted, and we found that during piPSC-EC derivation, the synthesis and secretion level of TGF-β as well as the phosphorylation level of Smad2/3 changed dynamically. TGF-β-Smad2/3 signaling activation promoted mesoderm formation and prevented endothelial differentiation. Understanding the regulatory mechanism of iPSC-EC derivation not only paves the way for further optimization, but also provides reference for establishing a cardiovascular drug screening platform and revealing the molecular mechanism of endothelial dysfunction. [ABSTRACT FROM AUTHOR]

This paper is devoted to the fractional Laplacian system with critical exponents. We use the method of moving spheres to derive a Liouville Theorem with at most three radial solutions, and then prove the solutions in R n ∖ { 0 } are radially symmetric and monotonically decreasing. Together with blow up analysis, we get the upper bound of the local solutions in B 1 ∖ { 0 }. Our results is an extension of the classical works by Caffarelli et al. (1989), Caffarelli et al. (2014), Chen and Lin (2015) and Guo and Liu (2008). [ABSTRACT FROM AUTHOR]