Specification testing for ordinary differential equation models with fixed design and applications to COVID-19 epidemic models.

Checking the models about the ongoing Coronavirus Disease 2019 (COVID-19) pandemic is an important issue. Some famous ordinary differential equation (ODE) models, such as the SIR and SEIR models have been used to describe and predict the epidemic trend. Still, in many cases, only part of the equations can be observed. A test is suggested to check possibly partially observed ODE models with a fixed design sampling scheme. The asymptotic properties of the test under the null, global and local alternative hypotheses are presented. Two new propositions about U-statistics with varying kernels based on independent but non-identical data are derived as essential tools. Some simulation studies are conducted to examine the performances of the test. Based on the available public data, it is found that the SEIR model, for modeling the data of COVID-19 infective cases in certain periods in Japan and Algeria, respectively, maybe not be appropriate by applying the proposed test.

Longitudinal study of BK Polyomavirus outcomes, risk factors, and kinetics in renal transplantation patients.

BACKGROUND: In the immunocompromised conditions following renal transplantation, BK virus can reactivate and cause BK virus associated nephropathy (BKVN). Increased BK viral loads and extended duration of infection have been linked to development of BKVN. The aim of this study was to observe the incidence of BKV infection and BKVN, and kinetics of infection and disease in renal transplantation recipients. METHODS: From 2014 to 2018, we conducted a longitudinal cohort observational study of 139 renal transplantation patients treated at a single clinic. Quantitative PCR assay was conducted to assess longitudinal BK viral loads. Analysis of patient clinical characteristics was performed to determine risk factors for BKV infection and associated disease. RESULTS: Of our cohort, 29 (20.9%) patients developed high BK viremia, and 7 (5.0%) developed biopsy-confirmed BKVN. Clinical parameters associated with diabetes (FBS, HbA1c) and hyperlipidemia (TG, TC, LDL-C) were found to be correlated with development of high BK viremia or BKVN. In 3 of 4 patients receiving intravenous immunoglobulin (IVIG) treatment, BK viral loads were reduced by at least 1 log within 2-3 months of administration. Significant differences were measured in BK viral loads and kidney function between BK viremic patients and BKVN patients by 3-9 months post-transplantation. CONCLUSIONS: We identified diabetes and hyperlipidemia as potential risk factors for development of high BK viremia and/or BKVN. IVIG was seen to be effective in reducing viral titers. The period 3-9 months post-transplantation was identified as important for development of BKVN from high BK viremia.

Single-index varying coefficient model for functional responses.

Recently, massive functional data have been widely collected over space across a set of grid points in various imaging studies. It is interesting to correlate functional data with various clinical variables, such as age and gender, in order to address scientific questions of interest. The aim of this article is to develop a single-index varying coefficient (SIVC) model for establishing a varying association between functional responses (e.g., image) and a set of covariates. It enjoys several unique features of both varying-coefficient and single-index models. An estimation procedure is developed to estimate varying coefficient functions, the index function, and the covariance function of individual functions. The optimal integration of information across different grid points is systematically delineated and the asymptotic properties (e.g., consistency and convergence rate) of all estimators are examined. Simulation studies are conducted to assess the finite-sample performance of the proposed estimation procedure. Furthermore, our real data analysis of a white matter tract dataset obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study confirms the advantage and accuracy of SIVC model over the popular varying coefficient model.

Ultrahigh dimensional time course feature selection.

Statistical challenges arise from modern biomedical studies that produce time course genomic data with ultrahigh dimensions. In a renal cancer study that motivated this paper, the pharmacokinetic measures of a tumor suppressor (CCI-779) and expression levels of 12,625 genes were measured for each of 33 patients at 8 and 16 weeks after the start of treatments, with the goal of identifying predictive gene transcripts and the interactions with time in peripheral blood mononuclear cells for pharmacokinetics over the time course. The resulting data set defies analysis even with regularized regression. Although some remedies have been proposed for both linear and generalized linear models, there are virtually no solutions in the time course setting. As such, a novel GEE-based screening procedure is proposed, which only pertains to the specifications of the first two marginal moments and a working correlation structure. Different from existing methods that either fit separate marginal models or compute pairwise correlation measures, the new procedure merely involves making a single evaluation of estimating functions and thus is extremely computationally efficient. The new method is robust against the mis-specification of correlation structures and enjoys theoretical readiness, which is further verified via Monte Carlo simulations. The procedure is applied to analyze the aforementioned renal cancer study and identify gene transcripts and possible time-interactions that are relevant to CCI-779 metabolism in peripheral blood.

Experimental study of the dispersion of cough-generated droplets from a person going up- or downstairs.

The dispersion of cough-generated droplets from a person going up- or downstairs was investigated through a laboratory experiment in a water tunnel. This experiment was carried out with a manikin mounted at inclination angles facing the incoming flow to mimic a person going up or down. Detailed velocity measurements and flow visualization were conducted in the water tunnel experiments. To investigate the influence of the initial position on the motion of particles, a virtual particle approach was adopted to simulate the dispersion of particles using the measured velocity field. Particle clustering, which is caused by the unsteadiness of the flow, was observed in both flow visualization and virtual particle simulation. For the case of going upstairs, particles are concentrated below the person's shoulder and move downward with a short travel distance. For the case of going downstairs, particles dispersing over the person's head advect over for a long distance. We also found that the motion of the particles is closely related to the initial position. According to the results in this study, suggestions for the prevention of respiratory infectious disease are made.

Efficacy of a Chinese herbal proprietary medicine (Hemp Seed Pill) for functional constipation.

OBJECTIVES: Functional constipation (FC) is a common clinical complaint. Despite a lack of consolidated evidence, Chinese herbal medicine (CHM) has become a popular alternative treatment for this condition. The aim of this study was to assess, with a rigidly designed study, the efficacy and safety of a CHM proprietary medicine, Hemp Seed Pill (HSP), in optimal dosage for treating FC. METHODS: This study comprised two parts: trial I, a dose determination study, and trial II, a placebo-controlled clinical study. In trial I, the optimal dosage of HSP was first determined from among three doses (2.5, 5.0, and 7.5 g b.i.d.). In trial II, a randomized double-blind study, the efficacy and safety of HSP for FC patients (Rome III criteria) in excessive syndrome as defined by traditional Chinese medicine (TCM) theory were compared with placebo. All participants in trials underwent a 2-week run-in, an 8-week treatment, and an 8-week follow-up. The primary end point was the responder rate for complete spontaneous bowel movement (CSBM) during treatment. Participants with a mean increase of CSBM ≧ 1/week compared with their baselines were defined as responders. Secondary outcome measures included responder rate during follow-up, individual and global symptom assessments, and reported adverse effects (AEs). RESULTS: The dose of 7.5 g b.i.d. showed better therapeutic effect than that of 2.5 and 5.0 g b.i.d. among 96 subjects (32 per arm) in trial I and was therefore selected for comparison with placebo in trial II. In trial II, 120 subjects were randomized into two arms (60 per arm). Responder rates for the HSP and placebo groups were 43.3 and 8.3% during treatment and 30.0 and 15.0% in the follow-up period, respectively (P<0.05). Those in the HSP group showed benefit in terms of increased CSBM, relief in the severity of constipation and straining of evacuation, and effective reduction in the use of rescue therapy when compared with placebo. No serious AE was reported. CONCLUSIONS: HSP (7.5 g b.i.d.) is safe and effective for alleviating FC for subjects in excessive syndrome. Optimal dose determination may be crucial for all CHM studies.

A Two-Stage Estimation Method for Random Coefficient Differential Equation Models with Application to Longitudinal HIV Dynamic Data.

We propose a two-stage estimation method for random coefficient ordinary differential equation (ODE) models. A maximum pseudo-likelihood estimator (MPLE) is derived based on a mixed-effects modeling approach and its asymptotic properties for population parameters are established. The proposed method does not require repeatedly solving ODEs, and is computationally efficient although it does pay a price with the loss of some estimation efficiency. However, the method does offer an alternative approach when the exact likelihood approach fails due to model complexity and high-dimensional parameter space, and it can also serve as a method to obtain the starting estimates for more accurate estimation methods. In addition, the proposed method does not need to specify the initial values of state variables and preserves all the advantages of the mixed-effects modeling approach. The finite sample properties of the proposed estimator are studied via Monte Carlo simulations and the methodology is also illustrated with application to an AIDS clinical data set.

Effects of slope and speed of escalator on the dispersion of cough-generated droplets from a passenger.

During the pandemic of COVID-19, the public is encouraged to take stairs or escalators instead of elevators. However, the dispersion of respiratory droplets in these places, featured by slopes and human motion, is not well understood yet. It is consequently unclear whether the commonly recommended social-distancing guidelines are still appropriate in these scenarios. In this work, we analyze the dispersion of cough-generated droplets from a passenger riding an escalator with numerical simulations, focusing on the effects of the slope and speed of the escalator on the droplet dispersion. In the simulations, a one-way coupled Eulerian-Lagrangian approach is adopted, with the air-flow solved using the Reynolds-averaged Navier-Stokes method and the droplets modeled as passive Lagrangian particles. It is found that the slope alters the vertical concentration of the droplets in the passenger's wake significantly. The deflection of cough-generated jet and the wake flow behind the passenger drive the cough-generated droplets upwards when descending an escalator and downwards when ascending, resulting in both higher suspension height and larger spreading range of the viral droplets on a descending escalator than on an ascending one. These findings suggest that the present social-distancing guidelines may be inadequate on descending escalators and need further investigation.

Dose-Dependent Variation of Synchronous Metabolites and Modules in a Yin/Yang Transformation Model of Appointed Ischemia Metabolic Networks.

AIM: Chinese medicine Danhong injection (DHI) is an effective pharmaceutical preparation for treating cerebral infarction. Our previous study shows that DHI can remarkably reduce the ischemic stroke-induced infarct volume in a dose-dependent manner, but the pharmacological mechanism of the DHI dose-dependent relationship is not clear. Therefore, the dose-dependent efficacy of DHI on cerebral ischemia and the underlying mechanisms were further investigated in this study. METHODS: A middle cerebral artery occlusion (MCAO) model was established and the rats were randomly divided into six groups: sham, vehicle, DHI dose-1, DHI dose-2, DHI dose-3, and DHI dose-4. Forty-one metabolites in serum were selected as candidate biomarkers of efficacy phenotypes by the Agilent 1290 rapid-resolution liquid chromatography system coupled with the Agilent 6550 Q-TOF MS system. Then, the metabolic networks in each group were constructed using the Weighted Correlation Network analysis (WGCNA). Moreover, the Yang and Yin transformation of six patterns (which are defined by up- and downregulation of metabolites) and synchronous modules divided from a synchronous network were used to dynamically analyze the mechanism of the drug's effectiveness. RESULTS: The neuroprotective effect of DHI has shown a dose-dependent manner, and the high-dose group (DH3 and DH4) effect is better. The entropy of the metabolic network and the Yin/Yang index both showed a consistent dose-response relationship. Seven dose-sensitive metabolites maintained constant inverse upregulation or downregulation in the four dose groups. Three synchronous modules for the DH1-DH4 full-course network were identified. Glycine, N-acetyl-L-glutamate, and tetrahydrofolate as a new emerging module appeared in DH2/DH3 and enriched in glutamine and glutamate metabolism-related pathways. CONCLUSION: This study takes the DHI metabolic network as an example to provide a new method for the discovery of multiple targets related to pharmacological effects. Our results show that the three conservative allosteric module nodes, taurine, L-tyrosine, and L-leucine, may be one of the basic mechanisms of DHI in the treatment of cerebral infarction, and the other three new emerging module nodes glyoxylate, L-glutamate, and L-valine may participate in the glutamine and glutamate metabolism pathway to improve the efficacy of DHI.

The motion of respiratory droplets produced by coughing.

Coronavirus disease 2019 has become a global pandemic infectious respiratory disease with high mortality and infectiousness. This paper investigates respiratory droplet transmission, which is critical to understanding, modeling, and controlling epidemics. In the present work, we implemented flow visualization, particle image velocimetry, and particle shadow tracking velocimetry to measure the velocity of the airflow and droplets involved in coughing and then constructed a physical model considering the evaporation effect to predict the motion of droplets under different weather conditions. The experimental results indicate that the convection velocity of cough airflow presents the relationship t -0.7 with time; hence, the distance from the cougher increases by t 0.3 in the range of our measurement domain. Substituting these experimental results into the physical model reveals that small droplets (initial diameter D ≤ 100 µm) evaporate to droplet nuclei and that large droplets with D ≥ 500 µm and an initial velocity u 0 ≥ 5 m/s travel more than 2 m. Winter conditions of low temperature and high relative humidity can cause more droplets to settle to the ground, which may be a possible driver of a second pandemic wave in the autumn and winter seasons.

Defect-Rich Copper-doped Ruthenium Hollow Nanoparticles for Efficient Hydrogen Evolution Electrocatalysis in Alkaline Electrolyte.

It is of great importance to develop highly efficient and stable Pt-free catalysts for electrochemical hydrogen generation from water electrolysis. Here, monodisperse 7.5 nm copper-doped ruthenium hollow nanoparticles (NPs) with abundant defects and amorphous/crystalline hetero-phases were prepared and employed as efficient hydrogen evolution electrocatalysts in alkaline electrolyte. Specifically, these NPs only require a low overpotential of 25 mV to achieve a current density of 10 mA cm-2 in 1.0 M KOH and show acceptable stability after 2000 potential cycles, which represents one of the best Ru-based electrocatalysts for hydrogen evolution. Mechanism analysis indicates that Cu incorporation can modify the electronic structure of Ru shell, thereby optimizing the energy barrier for water adsorption and dissociation processes or H adsorption/desorption. Cu doping paired with the defect-rich and highly open hollow structure of the NPs greatly enhances hydrogen evolution activity.

[Risk factors for capillary leak syndrome in children with tetralogy after operation].

OBJECTIVE: To determine risk factors of capillary leak syndrome(CLS) in children with tetralogy after operation. METHODS: Clinical data were retrospectively collected and analyzed from 32 tetralogy cases with CLS and 50 cases without CLS(control group), who received operation under cardiopulmonary bypass (CBP) in our hospital from October 2002 to December 2006. Risk factors with statistical significance were screened with univariate logistic regression analysis, independent risk factors of CLS were determined with multivariate logistic regression analysis. Postoperative outcome was compared between CLS group and control group. RESULT: Logistic analysis showed that the risk factors for CLS were age(OR=6.783), duration of CBP(OR=4.756)and MGoon index (OR=3.826). There were statistical differences in injection of colloid, time of inotropic drugs and ventilation between CLS and control groups(P<0.01). Eight CLS cases underwent peritoneal dialysis and 2 CLS cases died. CONCLUSION: The risk factors of CLS in children with tetralogy after CBP are age, duration of CBP and MGoon index.

A Randomized Controlled Trial of Chinese Medicine on Nonmotor Symptoms in Parkinson's Disease.

Nonmotor symptoms (NMS) of Parkinson's disease (PD) have devastating impacts on both patients and their caregivers. Jiawei-Liujunzi Tang (JLT) has been used to treat some NMS of PD based on the Chinese medicine theory since Qing dynasty. Here we report a double-blind, randomized, placebo-controlled, add-on clinical trial aiming at evaluating the efficacy and safety of the JLT in treating NMS in PD patients. We randomly assigned 111 patients with idiopathic PD to receive either JLT or placebo for 32 weeks. Outcome measures were baseline to week 32 changes in Movement Disorder Society-Sponsored Revision of Unified PD Rating Scale (MDS-UPDRS) Parts I-IV and in NMS assessment scale for PD (NMSS). We observed improvements in the NMSS total score (p = 0.019), mood/cognition (p = 0.005), and reduction in hallucinations (p = 0.024). In addition, post hoc analysis showed a significant reduction in constipation (p < 0.001). However, there was no evidence of improvement in MDS-UPDRS Part I total score (p = 0.216) at week 32. Adverse events (AEs) were mild and comparable between the two groups. In conclusion, long-term administration of JLT is well tolerated and shows significant benefits in improving NMS including mood, cognition, and constipation.

Before and after - Nutritional transformation of dysmorphism in a case of Costello syndrome.

Costello syndrome is a type of RASopathy mapped to HRAS gene in chromosome 11, characterized by prenatal overgrowth, postnatal failure to thrive, classic facial gestalt and multisystem involvement including cardiomyopathy and intellectual disability. We present a 7 months old child with severe failure to thrive whose "subtle" facial dysmorphism at the time eluded clinical recognition of the syndrome. It was only with optimization of his nutritional status that dysmorphic features became more apparent, which affirmed the molecular diagnosis of Costello syndrome from exome sequencing. The case illustrated how drastic failure to thrive can be in Costello syndrome, and how nutritional status can transform dysmorphic features in a child. It also highlights the importance of serial dysmorphic evaluation in difficult cases.

Functional Nonlinear Mixed Effects Models for Longitudinal Image Data.

Motivated by studying large-scale longitudinal image data, we propose a novel functional nonlinear mixed effects modeling (FNMEM) framework to model the nonlinear spatial-temporal growth patterns of brain structure and function and their association with covariates of interest (e.g., time or diagnostic status). Our FNMEM explicitly quantifies a random nonlinear association map of individual trajectories. We develop an efficient estimation method to estimate the nonlinear growth function and the covariance operator of the spatial-temporal process. We propose a global test and a simultaneous confidence band for some specific growth patterns. We conduct Monte Carlo simulation to examine the finite-sample performance of the proposed procedures. We apply FNMEM to investigate the spatial-temporal dynamics of white-matter fiber skeletons in a national database for autism research. Our FNMEM may provide a valuable tool for charting the developmental trajectories of various neuropsychiatric and neurodegenerative disorders.

Covariance-enhanced discriminant analysis.

Linear discriminant analysis has been widely used to characterize or separate multiple classes via linear combinations of features. However, the high dimensionality of features from modern biological experiments defies traditional discriminant analysis techniques. Possible interfeature correlations present additional challenges and are often underused in modelling. In this paper, by incorporating possible interfeature correlations, we propose a covariance-enhanced discriminant analysis method that simultaneously and consistently selects informative features and identifies the corresponding discriminable classes. Under mild regularity conditions, we show that the method can achieve consistent parameter estimation and model selection, and can attain an asymptotically optimal misclassification rate. Extensive simulations have verified the utility of the method, which we apply to a renal transplantation trial.

[Clinical analysis of gastroesophageal reflux induced cough].

OBJECTIVE: To investigate the clinical features, diagnosis and management of gastroesophageal reflux induced cough (GERC). METHODS: The continuous ambulatory esophageal pH measurement was performed for 24 hour in 41 cases with chronic cough who had normal chest roentgenographic presentation, negative histamine provocation test and no abnormality of nasal cavity. The symptom association probability (SAP) was adopted to analyze the correlation of cough with gastroesophageal reflux. The anti-reflux treatment was given for 12 weeks to those patients with Demeester score >or= 14.72 and/or SAP >or= 75%. RESULTS: Twenty six out of 41 cases were diagnosed as patients with gastroesophageal reflux. The cough was completely cured in 12 cases after antireflux treatment. The SAP of cough in this cured group (proximal probe 0.75 +/- 0.21, distal probe 0.91 +/- 0.12, respectively) was significantly higher than that of patients who failed in response to antireflux treatment (proximal probe 0.36 +/- 0.31, distal probe 0.47 +/- 0.30, respectively, P < 0.05). CONCLUSION: The gastroesophageal reflux may be an independent factor which could induce chronic cough. Not only the frequency and severity of gastroesophageal reflux but also the SAP were helpful in making the diagnosis of GERC. Satisfied effect was achieved after sufficient anti-reflux treatment in patients with GERC.

[Symptom correlation between asthma and gastroesophageal reflux].

OBJECTIVE: To study the symptom correlation between gastroesophageal reflux (GER) and asthma, the significance of 24 hour esophageal pH monitoring in the diagnosis of GER and the efficacy of anti-reflux therapy in asthmatics with GER. METHODS: Twenty-six patients with asthma, who presented with refractory respiratory symptoms despite of regular anti-asthmatic treatment, were enrolled in the study. 24 hour ambulatory esophageal pH monitoring was performed and symptoms, such as cough, chest tightness and pyrosis were recorded. Peak expiratory flow (PEF) was performed hourly. GER was defined by DeMeester score > or = 14.72 or SAP (cough with reflux) > or = 95%. Patients with diagnosed GER were divided into two groups, one of which was given anti-reflux therapy. RESULTS: DeMeester score > or = 14.72 was found in 58% (15/26) of the patients. Symptom association probability (SAP) with cough > or = 95% was found in 2 patients with a DeMeester score < 14.72. Taken together, GER was diagnosed in 17 patients. After anti-reflux therapy, symptoms such as cough, chest tightness and pyrosis improved significantly, and the 24 hour PEF variability decreased significantly as compared to that before therapy [(38 +/- 8)% versus (16 +/- 3%, P < 0.05]. CONCLUSION: The incidence of GER was 58% in this group of moderate to severe asthmatic patients. 24 hour esophageal pH monitoring was of great value in diagnosing GER in asthmatic patients, and anti-reflux therapy was effective in improving symptoms induced by GER in those patients.

[Etiological diagnosis of chronic cough with unknown causes].

OBJECTIVE: To explore the spectrum and frequency of causes for chronic cough in Chinese patients. METHODS: 86 patients with chronic cough were enrolled in the study. The diagnostic procedure was based on the anatomical protocol for diagnosing chronic cough designed by Irwin, and additional cytological assay was performed for sputum induced by hypertonic saline aerosol inhalation. The efficacy of therapy specific to the diagnosis was evaluated. RESULTS: Definite diagnosis was made in 77 (89.5%) out of the 86 patients with chronic cough. The most common causes included cough variant asthma (CVA) (24/86, 27.9%), postnasal drip syndrome (PNDs) (22/86, 25.6%), eosinophilic bronchitis (EB) (13/86, 15.1%), and gastroesophageal reflux (GER) (12/86, 14.0%). After active management based on the diagnosis, cough improved in 72 patients (93.5%). CONCLUSIONS: In addition to CVA, PNDs and GER, eosinophilic bronchitis is also an important cause of chronic cough. A positive response to the specific therapy is essential to a definite diagnosis.

[Clinical feature and airway inflammation in eosinophilic bronchitis].

OBJECTIVE: To study the clinical features and airway inflammation in eosinophilic bronchitis (EB) and the treatment outcomes. METHODS: Irwin's anatomic protocol for diagnosing chronic cough was used in 86 patients with chronic cough, and induced sputum by hypertonic saline aerosol inhalation was performed. Differential cell counts were performed in induced sputum, and eosinophilic cationic protein (ECP) was measured with fluoroimmunoassay, while interleukin-8 (IL-8) was measured with enzyme-linked absorbed immunoassay. EB was diagnosed according to Gibson's criteria and treated with inhaled budesonide 200 - 400 micro g twice daily for four weeks, and in some patients oral prednisone 10 - 15 mg/d or methyl-prednisone 8 - 12 mg/d was given for one week. RESULTS: 13 (15%) out of 86 patients with chronic cough were diagnosed as having EB. Dry cough was the major compliant and all had normal lung function with negative histamine provocation test. The Eos count was 0.1862 +/- 0.1632 and the concentration of ECP (2.53 +/- 2.07) mg/L in induced sputum were significant higher in patients with EB as compared with those normal subjects (P < 0.01). The cough disappeared in all patients at the end of one week of inhaled or orally administered corticosteroids. CONCLUSION: EB, an eosinophilic airway inflammation, is one of important causes of chronic cough and responds well to corticosteroid therapy.