Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry Analysis of Urinary Oligosaccharides and Glycoamino Acids for the Diagnosis of Mucopolysaccharidosis and Glycoproteinosis.

BACKGROUND: Mucopolysaccharidosis (MPS) and glycoproteinosis are 2 groups of heterogenous lysosomal storage disorders (LSDs) caused by defective degradation of glycosaminoglycans (GAGs) and glycoproteins, respectively. Oligosaccharides and glycoamino acids have been recognized as biomarkers for MPS and glycoproteinosis. Given that both groups of LSDs have overlapping clinical features, a multiplexed assay capable of unambiguous subtyping is desired for accurate diagnosis, and potentially for severity stratification and treatment monitoring. METHODS: Urinary oligosaccharides were derivatized with 3-methyl-1-phenyl-2-pyrazoline-5-one (PMP) and analyzed by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) together with the underivatized glycoamino acids. Novel biomarkers were identified with a semi-targeted approach with precursor mass scanning, the fragmentation pattern (if applicable), and the biochemical basis of the condition. RESULTS: A UPLC-MS/MS analysis with improved chromatographic separation was developed. Novel biomarkers for MPS-IIIA, IIIB, IIIC, and VII were identified and validated. A total of 28 oligosaccharides, 2 glycoamino acids, and 2 ratios were selected as key diagnostic biomarkers. Validation studies including linearity, lower limit of quantitation (LLOQ), and precision were carried out with the assay performance meeting the required criteria. Age-specific reference ranges were collected. In the 76 untreated patients, unambiguous diagnosis was achieved with 100% sensitivity and specificity. Additionally, the levels of disease-specific biomarkers were substantially reduced in the treated patients. CONCLUSIONS: A multiplexed UPLC-MS/MS assay for urinary oligosaccharides and glycoamino acids measurement was developed and validated. The assay is suitable for the accurate diagnosis and subtyping of MPS and glycoproteinosis, and potentially for severity stratification and monitoring response to treatment.

Simultaneous Activity and Attenuation Estimation in TOF-PET With TV-Constrained Nonconvex Optimization.

An alternating direction method of multipliers (ADMM) framework is developed for nonsmooth biconvex optimization for inverse problems in imaging. In particular, the simultaneous estimation of activity and attenuation (SAA) problem in time-of-flight positron emission tomography (TOF-PET) has such a structure when maximum likelihood estimation (MLE) is employed. The ADMM framework is applied to MLE for SAA in TOF-PET, resulting in the ADMM-SAA algorithm. This algorithm is extended by imposing total variation (TV) constraints on both the activity and attenuation map, resulting in the ADMM-TVSAA algorithm. The performance of this algorithm is illustrated using the penalized maximum likelihood activity and attenuation estimation (P-MLAA) algorithm as a reference.

Simultaneous activity and attenuation estimation in TOF-PET with TV-constrained nonconvex optimization.

An alternating direction method of multipliers (ADMM) framework is developed for nonsmooth biconvex optimization for inverse problems in imaging. In particular, the simultaneous estimation of activity and attenuation (SAA) problem in time-of-flight positron emission tomography (TOF-PET) has such a structure when maximum likelihood estimation (MLE) is employed. The ADMM framework is applied to MLE for SAA in TOF-PET, resulting in the ADMM-SAA algorithm. This algorithm is extended by imposing total variation (TV) constraints on both the activity and attenuation map, resulting in the ADMM-TVSAA algorithm. The performance of this algorithm is illustrated using the penalized maximum likelihood activity and attenuation estimation (P-MLAA) algorithm as a reference. Additional results on step-size tuning and on the use of unconstrained ADMM-SAA are presented in the previous arXiv submission: arXiv:2303.17042v1.

Sensitivity analysis of individual treatment effects: A robust conformal inference approach.

We propose a model-free framework for sensitivity analysis of individual treatment effects (ITEs), building upon ideas from conformal inference. For any unit, our procedure reports the Γ-value, a number which quantifies the minimum strength of confounding needed to explain away the evidence for ITE. Our approach rests on the reliable predictive inference of counterfactuals and ITEs in situations where the training data are confounded. Under the marginal sensitivity model of [Z. Tan, J. Am. Stat. Assoc. 101, 1619-1637 (2006)], we characterize the shift between the distribution of the observations and that of the counterfactuals. We first develop a general method for predictive inference of test samples from a shifted distribution; we then leverage this to construct covariate-dependent prediction sets for counterfactuals. No matter the value of the shift, these prediction sets (resp. approximately) achieve marginal coverage if the propensity score is known exactly (resp. estimated). We describe a distinct procedure also attaining coverage, however, conditional on the training data. In the latter case, we prove a sharpness result showing that for certain classes of prediction problems, the prediction intervals cannot possibly be tightened. We verify the validity and performance of the methods via simulation studies and apply them to analyze real datasets.

Conformalized Survival Analysis.

Existing survival analysis techniques heavily rely on strong modelling assumptions and are, therefore, prone to model misspecification errors. In this paper, we develop an inferential method based on ideas from conformal prediction, which can wrap around any survival prediction algorithm to produce calibrated, covariate-dependent lower predictive bounds on survival times. In the Type I right-censoring setting, when the censoring times are completely exogenous, the lower predictive bounds have guaranteed coverage in finite samples without any assumptions other than that of operating on independent and identically distributed data points. Under a more general conditionally independent censoring assumption, the bounds satisfy a doubly robust property which states the following: marginal coverage is approximately guaranteed if either the censoring mechanism or the conditional survival function is estimated well. Further, we demonstrate that the lower predictive bounds remain valid and informative for other types of censoring. The validity and efficiency of our procedure are demonstrated on synthetic data and real COVID-19 data from the UK Biobank.

Examining the impact of sex differences and the COVID-19 pandemic on health and health care: findings from a national cross-sectional study.

Objective: To examine the association of the coronavirus disease 2019 (COVID-19) pandemic, the association of sex, and the joint association of sex and the COVID-19 pandemic with health communication, physical activity, mental health, and behavioral health. Materials and Methods: We drew data from the National Cancer Institute's 2020 Health Information National Trends Survey. We described and compared the characteristics of social determinants of health, physical activity, mental health, alcohol use, patterns of social networking service use, and health information data sharing. Analyses were weighted to provide nationally representative estimates. Multivariate models (multiple linear regression, multiple logistic regression, and multinomial logistic model) were used to assess the sole and joint association with sex and pandemic. In addition, we applied the Bonferroni correction to adjust P values to decrease the risks of type I errors when making multiple statistical tests. Results: Females were more likely to use mobile health and health communication technologies than males, and the difference increased after the pandemic. The association between sex and mental health was significant after the COVID-19 pandemic. Females were more likely to experience depression or anxiety disorders. Both males and females had a slight decrease in terms of the quantity and intensity of physical activity and females were less likely to perform moderate exercise and strength training regularly. Males were likely to drink more alcohol than females. Conclusion: The COVID-19 pandemic amplifies the differences between males and females in health communication, physical activity, mental health, and behavioral health. Intersectional analyses of sex are integral to addressing issues that arise and mitigating the exacerbation of inequities. Responses to the pandemic should consider diverse perspectives, including sex and gender.

Replication and generalization in applied neuroimaging.

There is much interest in translating neuroimaging findings into meaningful clinical diagnostics. The goal of scientific discoveries differs from clinical diagnostics. Scientific discoveries must replicate under a specific set of conditions; to translate to the clinic we must show that findings using purpose-built scientific instruments will be observable in clinical populations and instruments. Here we describe and evaluate data and computational methods designed to translate a scientific observation to a clinical setting. Using diffusion weighted imaging (DWI), Wahl et al. (2010) observed that across subjects the mean fractional anisotropy (FA) of homologous pairs of tracts is highly correlated. We hypothesize that this is a fundamental biological trait that should be present in most healthy participants, and deviations from this assessment may be a useful diagnostic metric. Using this metric as an illustration of our methods, we analyzed six pairs of homologous white matter tracts in nine different DWI datasets with 44 subjects each. Considering the original FA measurement as a baseline, we show that the new metric is between 2 and 4 times more precise when used in a clinical context. Our framework to translate research findings into clinical practice can be applied, in principle, to other neuroimaging results.

[Clinical study of 28 patients with adult-to-infant living donor liver transplantation].

OBJECTIVE: To summarize our experience in adult-to-infant living donor liver transplantation (A-ILDLT) and to analyze the efficacy and complications of A-ILDLT. METHODS: The clinical data, surgical strategies and complications of 28 adult donors and infantile recipients who underwent A-ILDLT from April 2006 to December 2009 were retrospectively analyzed. These 28 patients (14 boys and 14 girls) aged from 80 days to 11.5 months with body weights of 3.08 to 10.3 kg at the time of operation . They suffered from biliary atresia with decompensated cirrhosis. The living donors were 15 mothers, 9 fathers, 3 grandma and 1 elder brother with ABO compatible with the infantile recipients. 27 Donor organs were the left lateral lobe grafts (segment II, III) and 1 graft was segment II. All patients were followed up for 5 to 24 months. RESULTS: These grafts were orthotopically transplanted into the infantile recipients. The average length of stay was 9.3 days for the donor group without any complications. Postoperative immunosuppression included prednisone, Cyclosporin and mycophenolate mofetil (MMF). A total of 24 postoperative complications occurred in 20 recipients, including 5 vascular complications, 4 bleeding, 7 pneumonia, 2 bowel obstruction, 4 intestinal perforation and 3 rejection. Three recipients died of hepatic arterial thrombosis (HAT). The perioperative mortality rate of recipients was 10.7% (3/28) and the survival rate was 89.3% in peroperative period. One died of stricture of hepatic vein and 1 of accidental asphyxia during follow-up term. At present, 23 cases are still alive. CONCLUSION: A-ILDLT has become an effective method to infants with end-stage liver disease. The postoperative vascular complication is the predominant cause of death.

Impact of human leukocyte antigen mismatching on outcomes of liver transplantation: a meta-analysis.

AIM: To assess the effect of human leukocyte antigen (HLA) mismatching on liver graft outcome and acute rejection from a meta-analysis of available cohort studies. METHODS: Articles in PubMed/MEDLINE, EMBASE and the Cochrane database from January 1970 to June 2009, including non-English literature identified in these databases, were searched. Only studies comparing HLA or sub-phenotype matching with mismatching were extracted. The percentage of graft survival was extracted by "Engauge Digitizer" from survival curves if the raw data were not displayed. A meta-analysis was performed when at least 3 studies provided data. RESULTS: Sixteen studies met the inclusion criteria. A lower number of HLA mismatches (0-2 vs 3-6) did reduce the incidence of acute rejection (relative risk: 0.77, P = 0.03). The degree of HLA mismatching (0-2 vs 3-6) had no significant effect on 1-year [hazard ratio (HR): 1.04, P = 0.68] and 5-year (HR: 1.09, P = 0.38) graft survival. In sub-phenotype analysis, the degree of HLA-A, B and DR mismatching (0 vs 1-2) had no significant effect on 1-year and 5-year graft survival, either. The HRs and P-values were 0.95, 0.71 (HLA-A, 1-year); 1.06, 0.60 (HLA-A, 5-year); 0.77, 0.16 (HLA-B, 1-year); 1.07, 0.56 (HLA-DR, 1-year); 1.18, 0.23 (HLA-DR, 5-year), respectively. CONCLUSION: The results of this systematic review imply that good HLA compatibility can reduce the incidence of acute rejection in spite of having no influence on graft outcomes. To obtain a short recovery time and minimize rejection post transplantation, HLA matching studies should be considered before the operation.

Adult to pediatric living donor liver transplantation for portal cavernoma.

AIM: Portal cavernoma (PC) is an important cause of non-cirrhotic portal hypertension with severe complications, such as variceal hemorrhage in pediatric patients. With the development of new surgical techniques, living donor liver transplantation (LDLT) has recently been recognized as a viable but challenging treatment option for PC. The purpose of the present study was to summarize the efficacy of LDLT in PC patients and to carry out a follow-up study of pediatric recipients. METHODS: The primary indication for LDLT in our research was PC with severe variceal bleeding and liver function decompensation. Three patients were diagnosed with PC following evaluation with computed tomography angiography and abdominal color Doppler ultrasonography (CDU). RESULTS: Various surgical techniques, including jump bypass grafting for portal vein anastomosis, were carried out according to the range and degree of cavernous transformation within the splenic vein and superior mesenteric vein. Postoperative CDU confirmed the early integrity of the portal vein (PV) in each patient. PV rethrombosis occurred in one patient 7 days after LDLT, despite anticoagulation therapy with coumadin. Two of the three patients had no further episodes of variceal hemorrhage during the 2-year follow-up period. CONCLUSIONS: The present study is the first report of the successful use of LDLT to treat pediatric PC patients. We conclude that LDLT is effective for the majority of pediatric patients with PC.

Successful treatment of Epstein-Barr Virus-associated haemophagocytic syndrome arising after living donor liver transplantation.

A 6-year-old girl received an orthotopic liver transplant secondary to liver failure of unknown etiology. Several days after liver transplantation, she developed pancytopenia and Epstein -Barr Virus (EBV)-positive seroconvert after transplant. Taking of medical history to provide evidence of pancytopenia correlated with EBV infection after transplant. Bone-marrow biopsy was carry out to confirm haemophagocytic syndrome (HPS). Laboratory investigations, including blood routine count, microscopic blood film examination, serum ferritin concentration, and liver function tests were carried out starting from the first day of suspected HPS infection, continuing until 15 weeks post-infection. Liver transplantation followed with a combination of cyclosporin A, corticosteroids, VP-16, and supportive strategies.

[Survey of psychological health of parents of children with malignant tumor].

OBJECTIVE: To understand the psychological problems of parents of children with malignant tumor so as to provide them with adequate psychological healthcare service. METHODS: A questionnaire-based survey was conducted in 68 parents of children with malignant tumor using an internationally standard anxiety scale. RESULTS: The 68 parents had a mean score of 44.68+/-11.26 for the scale with 6.42+/-2.25 anxiety symptoms on average. The average anxiety score of the mothers was 58.38+/-8.85, and 53.30+/-9.17 for the fathers, showing obviously difference (P<0.05). The average anxiety score of the parents with positive attitudes for treatment was 55.07+/-8.91, and that for the parents who gave up treatment for economic reasons was 66.71+/-4.50, with also significant difference (P<0.001). CONCLUSION: The parents of children with malignancies almost invariably show anxiety symptom of different degrees, which can be attributed to their gender and economic status.