Disease progression modeling with temporal realignment: An emerging approach to deepen knowledge on chronic diseases.

The recent development of the first disease-modifying drug for Alzheimer's disease represents a major advancement in dementia treatment. Behind this breakthrough is a quarter century of research efforts to understand the disease not by a particular symptom at a given moment, but by long-term sequential changes in multiple biomarkers. Disease progression modeling with temporal realignment (DPM-TR) is an emerging computational approach proposed with this biomarker-based disease concept. By integrating short-term clinical observations of multiple disease biomarkers in a data-driven manner, DPM-TR provides a way to understand the progression of chronic diseases over decades and predict individual disease stages more accurately. DPM-TR has been developed primarily in the area of neurodegenerative diseases but has recently been extended to non-neurodegenerative diseases, including chronic obstructive pulmonary, autoimmune, and ophthalmologic diseases. This review focuses on opportunities for DPM-TR in clinical practice and drug development and discusses its current status and challenges.

Exercise training outcomes in patients with chronic heart failure with reduced ejection fraction depend on patient background.

Background: The aim of this study was to identify significant factors affecting the effectiveness of exercise training using information of the HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) study. Methods: Background factors influencing the effect of exercise training were comprehensively surveyed for 2,130 patients by multivariable Cox regression analysis with the stepwise variable selection, and only significant factors were selected that were statistically distinguished from dummy noise factors using the Boruta method. Results: The analysis suggested that the use of beta-blockers, pulse pressure, hemoglobin level, electrocardiography findings, body mass index, and history of stroke at baseline potentially influenced the exercise effect on all-cause death (AD). Therefore, a hypothetical score to estimate the effect of exercise training was constructed based on the analysis. The analysis suggested that the score is useful in identifying patients for whom exercise training may be significantly effective in reducing all-caused death and hospitalization (ADH) as well as AD. Such a subpopulation accounted for approximately 40% of the overall study population. On the other hand, in approximately 45% of patients, the effect of exercise was unclear on either AD or ADH. In the remaining 15% of patients, it was estimated that the effect of exercise might be unclear for ADH and potentially rather increase AD. Conclusions: This study is the first analysis to comprehensively evaluate the effects of various factors on the outcome of exercise training in chronic heart failure, underscoring the need to carefully consider the patient's background before recommending exercise training. However, it should be noted that exercise training can improve many outcomes in a wide variety of diseases. Therefore, given the limitations involved in post-hoc analyses of a single clinical trial, the characteristics of patients to whom the results of this analysis can be applied need attention, and also further research is necessary on the relationship between the degree of exercise and the outcomes. A new clinical trial would be needed to confirm the factors detected and the appropriateness of the score.

Data-driven disease progression model of Parkinson's disease and effect of sex and genetic variants.

As Parkinson's disease (PD) progresses, there are multiple biomarker changes, and sex and genetic variants may influence the rate of progression. Data-driven, long-term disease progression model analysis may provide precise knowledge of the relationships between these risk factors and progression and would allow for the selection of appropriate diagnosis and treatment according to disease progression. To construct a long-term disease progression model of PD based on multiple biomarkers and evaluate the effects of sex and leucine-rich repeat kinase 2 (LRRK2) mutations, a technique derived from the nonlinear mixed-effects model (Statistical Restoration of Fragmented Time course [SReFT]) was applied to datasets of patients provided by the Parkinson's Progression Markers Initiative. Four biomarkers, including the Unified PD Rating Scale, were used, and a covariate analysis was performed to investigate the effects of sex and LRRK2-related mutations. A model of disease progression over ~30 years was successfully developed using patient data with a median of 6 years. Covariate analysis suggested that female sex and LRRK2 G2019S mutations were associated with 21.6% and 25.4% significantly slower progression, respectively. LRRK2 rs76904798 mutation also tended to delay disease progression by 10.4% but the difference was not significant. In conclusion, a long-term PD progression model was successfully constructed using SReFT from relatively short-term individual patient observations and depicted nonlinear changes in relevant biomarkers and their covariates, including sex and genetic variants.

Model-based meta-analysis of ethnic differences and their variabilities in clearance of oral drugs classified by clearance mechanism.

In this study, the ethnic ratios (ERs) of oral clearance between Japanese and Western populations were subjected to model-based meta-analysis (MBMA) for 81 drugs evaluated in 673 clinical studies. The drugs were classified into eight groups according to the clearance mechanism, and the ER for each group was inferred together with interindividual variability (IIV), interstudy variability (ISV), and inter-drug variability within a group (IDV) using the Markov chain Monte Carlo (MCMC) method. The ER, IIV, ISV, and IDV were dependent on the clearance mechanism, and, except for particular groups such as drugs metabolized by polymorphic enzymes or their clearance mechanism is not confirmative, the ethnic difference was found to be generally small. The IIV was well-matched across ethnicities, and the ISV was approximately half of the IIV as the coefficient of variation. To adequately assess ethnic differences in oral clearance without false detections, phase I studies should be designed with full consideration of the mechanism of clearance. This study suggests that the methodology of classifying drugs based on the mechanism that causes ethnic differences and performing MBMA with statistical techniques such as MCMC analysis is helpful for a rational understanding of ethnic differences and for strategic drug development.

Integrated Use of In Vitro and In Vivo Information for Comprehensive Prediction of Drug Interactions Due to Inhibition of Multiple CYP Isoenzymes.

BACKGROUND: Mechanistic static pharmacokinetic (MSPK) models are simple, have fewer data requirements, and have broader applicability; however, they cannot use in vitro information and cannot distinguish the contributions of multiple cytochrome P450 (CYP) isoenzymes and the hepatic and intestinal first-pass effects appropriately. We aimed to establish a new MSPK analysis framework for the comprehensive prediction of drug interactions (DIs) to overcome these disadvantages. METHODS: Drug interactions that occurred by inhibiting CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A in the liver and CYP3A in the intestine were simultaneously analyzed for 59 substrates and 35 inhibitors. As in vivo information, the observed changes in the area under the concentration-time curve (AUC) and elimination half-life (t1/2), hepatic availability, and urinary excretion ratio were used. As in vitro information, the fraction metabolized (fm) and the inhibition constant (Ki) were used. The contribution ratio (CR) and inhibition ratio (IR) for multiple clearance pathways and hypothetical volume (VHyp) were inferred using the Markov Chain Monte Carlo (MCMC) method. RESULT: Using in vivo information from 239 combinations and in vitro 172 fm and 344 Ki values, changes in AUC, and t1/2 were estimated for all 2065 combinations, wherein the AUC was estimated to be more than doubled for 602 combinations. Intake-dependent selective intestinal CYP3A inhibition by grapefruit juice has been suggested. By separating the intestinal contributions, DIs after intravenous dosing were also appropriately inferred. CONCLUSION: This framework would be a powerful tool for the reasonable management of various DIs based on all available in vitro and in vivo information.

A synthetic porphyrin as an effective dual antidote against carbon monoxide and cyanide poisoning.

Simultaneous poisoning by carbon monoxide (CO) and hydrogen cyanide is the major cause of mortality in fire gas accidents. Here, we report on the invention of an injectable antidote against CO and cyanide (CN-) mixed poisoning. The solution contains four compounds: iron(III)porphyrin (FeIIITPPS, F), two methyl-ß-cyclodextrin (CD) dimers linked by pyridine (Py3CD, P) and imidazole (Im3CD, I), and a reducing agent (Na2S2O4, S). When these compounds are dissolved in saline, the solution contains two synthetic heme models including a complex of F with P (hemoCD-P) and another one of F with I (hemoCD-I), both in their iron(II) state. hemoCD-P is stable in its iron(II) state and captures CO more strongly than native hemoproteins, while hemoCD-I is readily autoxidized to its iron(III) state to scavenge CN- once injected into blood circulation. The mixed solution (hemoCD-Twins) exhibited remarkable protective effects against acute CO and CN- mixed poisoning in mice (~85% survival vs. 0% controls). In a model using rats, exposure to CO and CN- resulted in a significant decrease in heart rate and blood pressure, which were restored by hemoCD-Twins in association with decreased CO and CN- levels in blood. Pharmacokinetic data revealed a fast urinary excretion of hemoCD-Twins with an elimination half-life of 47 min. Finally, to simulate a fire accident and translate our findings to a real-life scenario, we confirmed that combustion gas from acrylic cloth caused severe toxicity to mice and that injection of hemoCD-Twins significantly improved the survival rate, leading to a rapid recovery from the physical incapacitation.

Comparison of Predictions by BCS, rDCS and Machine Learning for the Effect of Food on Oral Drug Absorption Based on Features Calculated In silico.

In this study, observed food effects of 473 drugs were categorized into positive, negative, or no effects and compared with the predictions made by machine learning (ML), the Biopharmaceutics Classification System (BCS) and refined Developability Classification System (rDCS). All methods used primarily in silico estimates for prediction, and for ML, four algorithms were evaluated using nested cross-validation to select important information from 371 features calculated based on the chemical structure. Approximately 18 features, including estimated solubility in biorelevant media, were selected as important, and the random forest classifier was the best among four algorithms with 36.6% error rate (ER) and 10.8% opposite prediction rate (OPR). The prediction by rDCS utilizing solubility in a biorelevant medium was somewhat inferior, but not by much; 41.0% ER and 11.4% OPR. Compared with these two methods, the prediction by BCS was inferior; 54.5% ER and 21.4% OPR. ER was improved modestly by using measured features instead of in silico estimates when BCS was applied to a subset of 151 drugs (46.4% from 55.0%). ML and rDCS predicted the food effects of the same subset using in silico estimates with ERs of 37.7% and 42.4%, respectively, suggesting that the predictions by ML and rDCS using in silico features are similar or more accurate than those by BCS using measured features. These results suggest that ML was useful in revealing essential features from complex information and, together with rDCS, is effective in predicting food effects during drug development, including early drug discovery.

Model-based meta-analysis of changes in circulatory system physiology in patients with chronic heart failure.

To characterize and compare various medicines for chronic heart failure (CHF), changes in circulatory physiological parameter during pharmacotherapy were investigated by a model-based meta-analysis (MBMA) of circulatory physiology. The clinical data from 61 studies mostly in patients with heart failure with reduced ejection fraction (HFrEF), reporting changes in heart rate, blood pressure, or ventricular volumes after treatment with carvedilol, metoprolol, bisoprolol, bucindolol, enalapril, aliskiren, or felodipine, were analyzed. Seven cardiac and vasculature function indices were estimated without invasive measurements using models based on appropriate assumptions, and their correlations with the mortality were assessed. Estimated myocardial oxygen consumption, a cardiac load index, correlated excellently with the mortality at 3, 6, and 12 months after treatment initiation, and it explained differences in mortality across the different medications. The analysis based on the present models were reasonably consistent with the hypothesis that the treatment of HFrEF with various medications is due to effectively reducing the cardiac load. Assessment of circulatory physiological parameters by using MBMA would be insightful for quantitative understanding of CHF treatment.

Scores of Health-Related Quality of Life Questionnaire Worsen Consistently in Patients of COPD: Estimating Disease Progression over 30 Years by SReFT with Individual Data Collected in SUMMIT Trial.

The aim of this study was to elucidate the lifelong disease progression of chronic obstructive pulmonary disease (COPD) with biomarker changes and identify their influencing factors, by utilizing a new analysis method, Statistical Restoration of Fragmented Time-course (SReFT). Individual patient data (n = 1025) participating in the Study to Understand Mortality and MorbidITy (SUMMIT, NCT01313676), which was collected within the observational period of 4 years, were analyzed. The SReFT analysis suggested that scores of St. George's Respiratory Questionnaire and COPD assessment test, representative scores of the health-related quality of life (HRQOL) questionnaire, increased consistently for 30 years of disease progression, which was not detected by conventional analysis with a linear mixed effect model. It was estimated by the SReFT analysis that normalized forced expiratory volume in one second for age, sex, and body size (%FEV1) reduced for the initial 10 years from the onset of the disease but thereafter remained constant. The analysis of HRQOL scores and lung functions suggested that smoking cessation slowed COPD progression by approximately half and that exacerbation accelerated it considerably. In conclusion, this retrospective study utilizing SReFT elucidated the progression of COPD over 30 years and associated quantitative changes in the HRQOL scores and lung functions.

Global Comparison of Changes in the Number of Test-Positive Cases and Deaths by Coronavirus Infection (COVID-19) in the World.

Global differences in changes in the numbers of population-adjusted daily test-positive cases (NPDP) and deaths (NPDD) by COVID-19 were analyzed for 49 countries, including developed and developing countries. The changes as a proportion of national population were compared, adjusting by the beginning of test-positive cases increase (BPI) or deaths increase (BDI). Remarkable regional differences of more than 100-fold in NPDP and NPDD were observed. The trajectories of NPDD after BDI increased exponentially within 20 days in most countries. Machine learning analysis suggested that NPDD on 30 days after BDI was the highest in developed Western countries (1180 persons per hundred million), followed by countries in the Middle East (128), Latin America (97), and Asia (7). Furthermore, in Western countries with positive rates of the PCR test of less than 7.0%, the increase in NPDP was slowing-down two weeks after BPI, and subsequent NPDD was only 15% compared with those with higher positive rates, which suggested that the situation of testing might have affected the velocity of COVID-19 spread. The causes behind remarkable differences between regions possibly include genetic factors of inhabitants because distributions of the race and of the observed infection increasing rates were in good agreement globally.

Model-based meta-analysis to evaluate optimal doses of direct oral factor Xa inhibitors in atrial fibrillation patients.

The noninferiority of direct oral factor Xa (FXa) inhibitors (rivaroxaban, apixaban, and edoxaban) in treatment of atrial fibrillation were demonstrated compared with warfarin by several large clinical trials; however, subsequent meta-analyses reported a higher risk of major bleeding with rivaroxaban than with the other FXa inhibitors. In the present study, we first estimated the changes of prothrombin time (PT) in 5 randomized trials based on reported population pharmacokinetic and pharmacodynamic models and then carried out a model-based meta-analysis to obtain models describing the relationship between PT changes and the event rates of ischemic stroke/systemic embolism (SE) and of major bleeding. By using the models, we simulated the optimal therapeutic doses for each FXa inhibitor. It was suggested that dose reduction of rivaroxaban from the current 20 mg/d to 10 mg/d would decrease patient deaths from major bleeding (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.64-0.74) with little increase in those for ischemic stroke/SE (HR, 1.11; 95% CI, 1.07-1.20). The overall decrease in the mortality caused by both events was estimated as 5.81 per 10 000 patient-years (95% CI, 3.92-8.16), with an HR of 0.87 (95% CI, 0.83-0.91). For apixaban and edoxaban, no distinct change in the overall mortality was simulated by dose modification. This study suggested that the current dose of rivaroxaban might be excessive and would need to be reduced to decrease the excess risk of major bleeding.

Optimal production of L-threo-2,3-dihydroxyphenylserine (L-threo-DOPS) on a large scale by diastereoselectivity-enhanced variant of L-threonine aldolase expressed in Escherichia coli.

This study examined the efficient production and optimal separation procedures for pure L-threo-3,4-dihydroxyphenylserine (L-threo-DOPS) from a mixture of diastereomers synthesized by whole-cell aldol condensation reaction, harboring diastereoselectivity-enhanced L-threonine aldolase in Escherichia coli JM109. The addition of the reducing agent sodium sulfite was found to stimulate the production of L-threo-DOPS without affecting the diastereoselectivity ratio, especially at the 50 mM concentration. The optimal pH for diastereoselective synthesis was 6.5. The addition of Triton X-100 also strongly affected the synthesis yield, showing the highest conversion yield at a 0.75% concentration; however, the diastereoselectivity of the L-threonine aldolase was not affected. Lowering the temperature to 10°C did not significantly affect the diastereoselectiviy without affecting the synthesis rate. At the optimized conditions, a mixture of L-threo-DOPS and L-erythro-DOPS was synthesized by diastereoselectivity-enhanced L-threonine aldolase from E. coli in a continuous process for 100 hr, yielding an average of 4.0 mg/mL of L-threo-DOPS and 60% diastereoselectivity (de), and was subjected to two steps of ion exchange chromatography. The optimum separation conditions for the resin and solvent were evaluated in which it was found that a two-step process with the ion-exchange resin Dowex 50 W × 8 and activated carbon by washing with 0.5 N acetic acid was sufficient to separate the L-threo-DOPS. By using two-step ion-exchange chromatography, synthesized high-purity L-threo-DOPS of up to 100% was purified with a yield of 71%. The remaining substrates, glycine and 3,4-dihydroxybenzaldehyde, were recovered successfully with a yield of 71.2%. Our results indicate this potential procedure as an economical purification process for the synthesis and purification of important L-threo-DOPS at the pharmaceutical level.

Determinants of carotid atherosclerosis in the general Mongolian population.

OBJECTIVE: Atherosclerotic risk factors contribute to carotid atherosclerosis. Carotid intima-media thickness (IMT), as assessed using a non-invasive high-resolution ultrasound, can predict cardiovascular disease (CVD). Whereas the control of CVD is crucial for the Mongolian people, the studies on carotid atherosclerosis are lacking. The present population-based survey was a cross-sectional investigation of the determinants of carotid IMT in the general Mongolian population. METHODS: A total of 344 Mongolian volunteers, aged 18 to 69 years, without CVD and on no medication, were recruited from a health screening setting. The current smoking habits, body mass index, mean blood pressure (MBP), blood total cholesterol (TC), glucose, insulin and carotid IMT (maximum level) were measured. RESULTS: Mongolian males had a significantly higher prevalence of current smoking and a higher level of IMT than females (average = .58 mm in males vs .46 in females). Both a single and multiple regression analysis adjusted for all the measures revealed that IMT was significantly and positively correlated with age, male sex, MBP, TC and glucose among all of the participants. IMT was significantly and positively correlated with age, followed by MBP, TC and glucose among males, while among females, IMT was significantly and positively correlated with age, followed by MBP and TC. CONCLUSIONS: Age was the strongest determinant of carotid atherosclerosis, and the increases in blood pressure and cholesterol levels were also important measures in both sexes as well as glucose levels in males in particular, thus suggesting a preventive strategy for CVD in the general Mongolian population.

[Study on the diagnostic role of NT-proBNP assay for assessment of cardiac function, and the effect of renal function--comparable study with BNP].

We, in the present study, studied the stability, operability, and economy as a whole of NT-proBNP assay, and further on the performance of diagnosing cardiac failure as a laboratory test. It was found to be superior to BNP assay not only as a reagent but also as a clinical test to diagnose cardiac functions. On the other hand, it is reported that NT-proBNP is influenced by the renal function more than BNP, and we investigated it precisely. As a result, NT-proBNP was equally influenced as BNP when the estimated glomerular filtration rate (eGFR) was more than 60 ml/min. When eGFR decreased further, BNP was also increased by the decreased renal clearance. Thereby, NT-proBNP was increased relatively more than BNP because BNP was catabolized by other mechanisms than renal clearance. Therefore, NT-proBNP may be superior to BNP in regard to estimate secretion of BNP from the heart particularly when renal function was decreased. In conclusion, NT-proBNP is an excellent biomarker to diagnose heart failure.

Comparative study of atherosclerotic parameters in Mongolian and Japanese patients with hypertension and diabetes mellitus.

AIM: Cardiovascular disease is becoming increasingly more problematic in Mongolia. The cardioankle vascular index (CAVI) and circulating C-reactive protein (CRP) are new atherosclerosis-related parameters, but no comparative studies of atherosclerotic parameters including CAVI and CRP are available between Mongolian and Japanese populations, such as disease populations of hypertension (HT) and diabetes mellitus (DM). Our study objective was to examine atherosclerotic profiles in HT and DM patients in both countries. METHODS: From a hospital-based population, 156 Mongolian outpatients with HT and DM (men: 46%, mean age: 57.1 years) and 156 age- and sex-matched Japanese outpatients with HT and DM (men: 46%, age: 57.7) were recruited. Body mass index (BMI), heart rate (HR), blood pressure (BP), pulse pressure (PP), ankle-brachial index (ABI), ultrasonographic carotid intima-media thickness (IMT), blood total cholesterol (T-Cho), glucose, insulin and homeostasis model assessment of insulin resistance (HOMA-IR) were measured, in addition to CAVI and CRP. RESULTS: The levels of BMI, HR, BP, PP, insulin and IMT were significantly higher and T-Cho and glucose were significantly lower in the Mongolian patients in comparison to the Japanese patients. Particularly, the levels of CAVI (mean+/-SD) (8.1+/-1.1 vs. 8.8+/-1.2) and CRP(median[interquartile range])(0.05[0.03-0.12]vs. 0.19[0.09-0.42]mg/dL)were significantly higher in Mongolian than Japanese patients. These significant differences remained unchanged, even after taking into account multiple variables, including BP and HOMA-IR. In addition, except for CAVI in the subgroup of DM, generally similar trends regarding atherosclerotic parameters were seen in the subgroup by sex and disease (HT, DM and HT plus DM). CONCLUSION: These findings suggest that Mongolian patients with HT and DM may be at higher risk for cardiovascular disease than Japanese patients.

Enhanced synthesis of L-threo-3,4-dihydroxyphenylserine by high-density whole-cell biocatalyst of recombinant L-threonine aldolase from Streptomyces avelmitilis.

L-threo-3,4-Dihydroxyphenylserine (DOPS) is a chiral unnatural beta-hydroxy amino acid used for the treatment of Parkinson disease. We developed a continuous bioconversion system for DOPS production that uses whole-cell biocatalyst of recombinant Escherichia coli expressing L-threonine aldolase (L-TA) genes cloned from Streptomyces avelmitilis MA-4680. Maximum conversion rates were observed at 2 M glycine, 145 mM 3,4-dihydroxybenzaldehyde, 0.75% Triton-X, 5 g E. coli cells/l, pH 6.5 and 10 degrees C. In the optimized condition, overall productivity was 8 g/l, which represents 40 times the synthesis yield possible with no optimization of conditions.

[A case of unresectable advanced gallbladder cancer successfully treated by oral S-1 and hepatic arterial infusion (HAI) of low-dose CDDP therapy].

The patient was a 64-year-old woman. Oral S-1 and hepatic arterial infusion (HAI) of low-dose CDDP therapy were started for unresectable advanced gallbladder cancer associated with liver metastasis and numerous lymph node metastases. Marked regression of the liver metastasis and lymph node metastases was observed by this treatment, and upon completion of the second course they had almost completely resolved. The tumor marker values also converted to negative. We report a case in which oral S-1 and HAI of low-dose CDDP therapy was effective against advanced gallbladder cancer associated with liver metastasis and multiple lymph node metastases.

Synthesis of L-threo-3,4-dihydroxyphenylserine (L-threo-DOPS) with thermostabilized low-specific L-threonine aldolase from Streptomyces coelicolor A3(2).

Stability-enhanced mutants, H44, 11-94, 5A2-84, and F8, of L-threonine aldolase (L-TA) from Streptomyces coelicolor A3(2) (SCO1085) were isolated by an error-prone PCR followed by a high-throughput screening. Each of these mutant, had a single amino acid substitution: H177Y in the H44 mutant, A169T in the 11-94 mutant, D104N in the 5A2-84 mutant and Fl81 in the F8 mutant. The residual L-TA activity of the wild-type L-TA after a heat treatment for 20 min at 60 degrees C was only 10.6%. However, those in the stability-enhanced mutants were 85.7% for the H44 mutant, 58.6% for the F8 mutant, 62.1% for the 5A2-84 mutant, and 67.6% for the 11-94 mutant. Although the half-life of the wild-type L-TA at 63 degrees C was 1.3 min, those of the mutant L-TAs were longer: 14.6 min for the H44 mutant, 3.7 min for the 11-94 mutant, 5.8 min for the 5A2-84 mutant, and 5.0 min for the F8 mutant. The specific activity did not change in most of the mutants, but it was decreased by 45% in the case of mutant F8. When the aldol condensation of glycine and 3,4-dihydroxybenzaldehyde was studied by using whole cells of Escherichia coli containing the wild-type L-TA gene, L-threo-3,4-dihydroxyphenylserine (L.-threo-DOPS) was successfully synthesized with a yield of 2.0 mg/ml after 20 repeated batch reactions for 100 h. However, the L-threo-DOPS synthesizing activity of the enzyme decreased with increased cycles of the batch reactions. Compared with the wild-type L-TA, H44 L-TA kept its L-threo-DOPS synthesizing activity almost constant during the 20 repeated batch reactions for 100 h, yielding 4.0 mg/ml of L-threo-DOPS. This result showed that H44 L-TA is more effective than the wild-type L-TA for the mass production of L-threo-DOPS.