Average Lifetime Hemoglobin Concentration Improves Prediction of Cognitive Outcomes in Pediatric Patients with Sickle Cell Anemia

Background: Sickle cell anemia (SCA) is associated with cognitive challenges that often worsen as children age. Previous work has established relationships between hematological markers of disease severity (i.e., hemoglobin concentration) and various neurological outcomes, including cognitive impairment. However, most studies have related static, often isolated hemoglobin concentration (Hb) values obtained from a single time-point closest to data collection. Studies of pediatric patients with phenylketonuria and Type I diabetes have demonstrated that longitudinal change and variability in phenylalanine and glucose, respectively, are better indicators of neurological and cognitive outcomes than a single value alone. Our study aimed to be the first study of pediatric patients with SCA to examine the extent to which indices of Hb control (e.g., lifetime average and variability), collected routinely in this patient group, may provide additional prognostic information. Methods: Data were collected from pediatric patients (aged 4-18 years at enrolment) with and without SCA enrolled on the Sleep Asthma Cohort-III (SAC-III) follow-up study. SAC is a mixed retrospective-prospective study assessing the impact of nocturnal oxygen desaturation on SCA complications. The present investigation assessed participants (see Figure 1 for complete participant demographics) who underwent cognitive evaluation using Wechsler scales measuring domains of IQ, processing speed (i.e., processing speed index [PSI] and Cancellation subtest), and executive function (working memory index [WMI]). Participant demographics and appropriate medical data and history (i.e., hydroxyurea therapy, silent infarction) were obtained via questionnaires and analysis of medical records. Hb (d/L) measures assessed included average lifetime values (i.e., mean and median), variability over the lifetime (i.e., standard deviation), and the single value obtained closest to data collection. Results: Correlation analyses indicated a strong positive relationship between the mean and median Hb values along with large positive associations between the average and contemporaneous values. Small non-significant correlations were demonstrated between variability and average Hb values (see Figure 1). Initial hierarchical linear regression analyses demonstrated that neither hydroxyurea use nor silent infarct (SCI) status were predictors of any cognitive outcomes or Hb values, so they were not included in any further analyses. Separate regression analyses for each cognitive outcome found that mean lifetime Hb values was the only significant predictor of IQ (p = .04, η 2 = .13) and the Cancellation subtest (p = .005, η 2 = .22). Mean lifetime Hb values approached significance for PSI (p = .09, η 2 = .08), but was not a predictor for WMI (p = .33, η 2 = .03). Conclusion: Our study demonstrated that despite strong correlations between Hb obtained closest to testing and average lifetime values (i.e., rs = .64 and .69), only lifetime Hb predicted cognitive outcomes, particularly processing speed scores from the Cancellation subtest. Variability was not strongly related to other indices of Hb control and did not predict any cognitive outcomes. These results mirror those obtained from other pediatric populations indicating that static, one time values may not best represent clinical manifestations of chronic illness, and the choice of Hb value can differentially influence research study results and clinical prognosis. Future longitudinal work in larger samples is needed, but Hb obtained over the lifetime appears to provide a more precise picture of patients' cognitive developmental trajectory than a single contemporaneous Hb value alone. Figure 1 Figure 1. Disclosures Kirkham: Bluebird Bio: Honoraria; Novartis: Honoraria; Global Blood Therapeutics: Consultancy. Howard: Imara: Consultancy, Honoraria; Global Blood Therapeutics: Consultancy; Novartis: Consultancy, Honoraria; Resonance Health: Honoraria; Novo Nordisk: Consultancy; Agios Pharmaceuticals: Consultancy; Forma Therapeutics: Consultancy; Bluebird Bio: Research Funding.

On history-dependent mixed shock models

In this paper, we consider a history-dependent mixed shock model which is a combination of the history-dependent extreme shock model and the history-dependent $\delta$ -shock model. We assume that shocks occur according to the generalized Pólya process that contains the homogeneous Poisson process, the non-homogeneous Poisson process and the Pólya process as the particular cases. For the defined survival model, we derive the corresponding survival function, the mean lifetime and the failure rate. Further, we study the asymptotic and monotonicity properties of the failure rate. Finally, some applications of the proposed model have also been included with relevant numerical examples.

Reliability Test Plan for an Extended Birnbaum-Saunders Distribution

Birnbaum-Saunders distribution has been widely studied in statistical literature because this distribution accommodates several interesting properties. The purpose of this paper is to introduce a new parametric distribution based on the Birnbaum-Saunders model and develop a new acceptance sampling plans for derived extended Birnbaum-Saunders distribution when the mean lifetime test is truncated at a predetermined time. For various acceptance numbers, confidence levels and values of the ratio of the fixed experimental time to the specified mean life, the minimum sample size necessary to assure a specified mean lifetime worked out. The results are illustrated by a numerical example. The operating characteristic functions of the sampling plans and producer’s risk and the ratio of true mean life to a specified mean life that ensures acceptance with a pre-assigned probability are tabulated. This paper presents relevant characteristics of the new distribution and a new acceptance sampling plans when the lifetime of a product adopts an extended Birnbaum-Saunders distribution. Based on this study, the optimal number of testers demanded is decreases as test termination time increases. Moreover, the operating characteristic values increases as the mean life ratio increases, which indicate that items with increased mean life will be accepted with higher probability compared with items with lower mean life ratio.

Healthcare utilization and costs in hepatocellular carcinoma (HCC) patients treated at a large referral center in Washington (WA) State.

e16149 Background: Though the treatment landscape for HCC has changed significantly in the last several years with the refinement of liver-directed therapy techniques and the introduction of multiple new drugs, few studies have investigated the impact of the changing treatment landscape on lifetime treatment costs, particularly in Barcelona Clinic Liver Cancer (BCLC) stage C disease. We therefore sought to investigate real-world clinical characteristics, treatment patterns, healthcare use, and costs in patients with HCC treated at a single high-volume institution in WA. Methods: We conducted a retrospective cohort study of patients diagnosed with HCC between 2007 and 2018 at a single clinical cancer center using a database containing abstracted data from the electronic medical record (EMR) linked to cancer registry data and health claims from commercial insurance plans, Medicare, and Medicaid. We described clinical characteristics, including BCLC stage and Child Pugh score, and treatment patterns. We investigated the mean per patient lifetime treatment costs by BCLC stage using Kaplan-Meier cost estimator methods. Results: The final cohort included 215 patients, majority white (71%), male (68%), and with underlying hepatitis C (61%). Most patients had either Child Pugh A (76%) or B (20%) liver disease and BCLC A (45%), B (20%), or C (19%) stage HCC. Only 40% of BCLC C patients received systemic chemotherapy. Mean per patient lifetime costs were highest in BCLC A ($289,318) and BCLC C ($255,430) patients and lowest in BCLC D ($123,701) patients (Table). Surgical costs, hospital costs, imaging, and outpatient visits were the major contributors to total lifetime costs in BCLC A patients. Chemotherapy costs were highest in BCLC C patients, but still were not the predominant area of spending. Conclusions: In a WA state cohort of HCC patients, mean lifetime costs were highest in patients with BCLC A disease, largely driven by surgery and hospital costs. As utilization of newer and less toxic therapies in BCLC C patients increases, mean lifetime costs in this group may surpass other stages.[Table: see text]

Intravital Metabolic Autofluorescence Imaging Captures Macrophage Heterogeneity Across Normal and Cancerous Tissue

Macrophages are dynamic immune cells that govern both normal tissue function and disease progression. However, standard methods to measure heterogeneity in macrophage function within tissues require tissue excision and fixation, which limits our understanding of diverse macrophage function in vivo. Two-photon microscopy of the endogenous metabolic co-enzymes NAD(P)H and flavin adenine dinucleotide (FAD) (metabolic autofluorescence imaging) enables dynamic imaging of mouse models in vivo. Here, we demonstrate metabolic autofluorescence imaging to assess cell-level macrophage heterogeneity in response to normal and cancerous tissue microenvironments in vivo. NAD(P)H and FAD fluorescence intensities and lifetimes were measured for both tissue-resident macrophages in mouse ear dermis and tumor-associated macrophages in pancreatic flank tumors. Metabolic and spatial organization of macrophages were determined by performing metabolic autofluorescence imaging and single macrophage segmentation in mice engineered for macrophage-specific fluorescent protein expression. Tumor-associated macrophages exhibited decreased optical redox ratio [NAD(P)H divided by FAD intensity] compared to dermal macrophages, indicating that tumor-associated macrophages are more oxidized than dermal macrophages. The mean fluorescence lifetimes of NAD(P)H and FAD were longer in dermal macrophages than in tumor-associated macrophages, which reflects changes in NAD(P)H and FAD protein-binding activities. Dermal macrophages had greater heterogeneity in optical redox ratio, NAD(P)H mean lifetime, and FAD mean lifetime compared to tumor-associated macrophages. Similarly, standard markers of macrophage phenotype (CD206 and CD86) assessed by immunofluorescence revealed greater heterogeneity in dermal macrophages compared to tumor-associated macrophages. Ultimately, metabolic autofluorescence imaging provides a novel tool to assess tissue-specific macrophage behavior and cell-level heterogeneity in vivo in animal models.

Reliability analysis for systems subject to mutually dependent degradation and shock processes

This paper studies the reliability problem for systems subject to two types of dependent competing failure processes, that is, soft failure and hard failure processes. A soft failure happens when the total degradation of the system exceeds a given critical level, while a hard failure occurs when the accumulative shock load caused by shocks surpasses the hard failure threshold. These two failure processes are mutually dependent due to the fact that external shocks will bring sudden increments in the degradation of the system, and the total amount of degradation will decrease the hard failure threshold of the system. The system fails whenever either of these two failure modes happens. Assuming that the arrival of shocks follows a Poisson process, the reliability function of the system under cumulative shock model is derived by using some analytical techniques. Some important reliability indices, including the mean lifetime of the system, the expected number of shocks until system failure, the probabilities of soft and hard failures, are calculated explicitly. Moreover, a special case that the hard failure process and soft failure process are mutually independent is also discussed. Monte Carlo method is employed to calculate the multiple integrals existing in the expressions of reliability function and reliability indices. A numerical example of the Reinforced Concrete pier columns on sea bridge is presented to illustrate the proposed model.

Inactivation of Aβ42 Protomer-dimer Dissociation Reaction via Increasing Protomer Size

Amyloid fibril growth is supposed to be common pathogenic causes for neurodegenerative diseases, triggered by sufficient amounts of growth nuclei species. Since the molecular entity of growth nuclei is regarded as fibril-like aggregates, clarifying the minimum size of thermodynamically stable fibril-like aggregates has been a long standing problem to understand molecular mechanisms of amyloid fibril growth. We studied this problem by examining relationship between the size of fibril-like amyloid-β(1-42) (Aβ42) aggregates and their thermodynamic stability. Seven different protomer dimers were examined as Aβ42 fibril-like aggregate models with employing atomistic molecular dynamics simulations. This study has found that increase of protomer size suppresses conformational fluctuation of these aggregates and inactivates protomer-protomer dissociation reactions by making timescales much longer than mean lifetime of human beings at the point of pentamer dimer formation. This observation shows apparent contribution of protomer size to stabilization of fibril-like aggregates, thus implying that dimer formation of relatively small protomers is a turning point toward growth nuclei formation. Meanwhile, Aβ42 monomer dissociation from the edges of protomers can occur within timescales ranging from microsecond to second and could work for Aβ42 protomer decomposition. This observation implies that suppressing the decomposition route leads to stable Aβ42 growth nuclei formation.

Economic Determination of Modified Multiple Dependent State Sampling Plan under Some Lifetime Distributions

In this paper, the modification of multiple dependent state sampling plan is proposed and designed for assuring a mean lifetime of the products under Birnbaum–Saunders distribution and Weibull distribution. The optimal parameters of the proposed plan are determined based on two points on the operating characteristic curve approach. Different combinations of producer’s risk and consumer’s risk are considered for plan parameters determination. The efficacy of the proposed plan is compared with those of other existing sampling plans using an average sample number and operating characteristic function. The economic designing of the proposed plan is also considered and the comparative study is done based on the total cost of the inspection.