Transition to anomalous dynamics in a simple random map.

The famous doubling map (or dyadic transformation) is perhaps the simplest deterministic dynamical system exhibiting chaotic dynamics. It is a piecewise linear time-discrete map on the unit interval with a uniform slope larger than one, hence expanding, with a positive Lyapunov exponent and a uniform invariant density. If the slope is less than one, the map becomes contracting, the Lyapunov exponent is negative, and the density trivially collapses onto a fixed point. Sampling from these two different types of maps at each time step by randomly selecting the expanding one with probability p, and the contracting one with probability 1-p, gives a prototype of a random dynamical system. Here, we calculate the invariant density of this simple random map, as well as its position autocorrelation function, analytically and numerically under variation of p. We find that the map exhibits a non-trivial transition from fully chaotic to completely regular dynamics by generating a long-time anomalous dynamics at a critical sampling probability pc, defined by a zero Lyapunov exponent. This anomalous dynamics is characterized by an infinite invariant density, weak ergodicity breaking, and power-law correlation decay.

Existence of multiple noise-induced transitions in Lasota-Mackey maps.

We prove the existence of multiple noise-induced transitions in the Lasota-Mackey map, which is a class of one-dimensional random dynamical system with additive noise. The result is achieved with the help of rigorous computer assisted estimates. We first approximate the stationary distribution of the random dynamical system and then compute certified error intervals for the Lyapunov exponent. We find that the sign of the Lyapunov exponent changes at least three times when increasing the noise amplitude. We also show numerical evidence that the standard non-rigorous numerical approximation by finite-time Lyapunov exponent is valid with our model for a sufficiently large number of iterations. Our method is expected to work for a broad class of nonlinear stochastic phenomena.

Volume-Outcome Relationship in Cancer Survival Rates: Analysis of a Regional Population-Based Cancer Registry in Japan.

BACKGROUND: There is limited data on the relationship between hospital volumes and outcomes with respect to cancer survival in Japan. The primary objective of this study was to evaluate the effect of hospital volume on cancer survival rate using a population-based cohort database. METHODS: Using the Kanagawa cancer registry, propensity score matching was employed to create a dataset for each cancer type by selecting 1:1 matches for cases from high- and other-volume hospitals. The 5-year survival rate was estimated and the hazard ratio (HR) for hospital volume was calculated using a Cox proportional hazard model. Additional analyses were performed limited to cancer patients who underwent surgical operation, chemotherapy, and other treatments in each tumor stage and at the time of diagnosis. RESULTS: The number of cases with complete data, defined as common cancers (prostate, kidney, bladder, esophagus, stomach, liver, pancreas, colon, breast, and lung), was 181,039. Adjusted HR differed significantly among hospital volume categories for the most common cancers except bladder, and the trends varied according to cancer type. The HR ranged from 0.76 (95%CI, 0.74-0.79) for stomach cancer to 0.85 (0.81-0.90) for colon cancer. CONCLUSIONS: This study revealed that a relationship may exist between hospital volume and cancer survival in Japan.

PET imaging of 11C-labeled thiamine tetrahydrofurfuryl disulfide, vitamin B1 derivative: First-in-human study.

Vitamine B1 thiamine is an essential component for glucose metabolism and energy production. The disulfide derivative, thiamine tetrahydrofurfuryl disulfide (TTFD), is more absorbent compared to readily-available water-soluble thiamine salts since it does not require the rate-limiting transport system required for thiamine absorption. However, the detailed pharmacokinetics of thiamine and TTFD under normal and pathological conditions were not clarified yet. Recently, 11C-labeled thiamine and TTFD were synthesized by our group, and their pharmacokinetics were investigated by PET imaging in normal rats. In this study, to clarify the whole body pharmacokinetics of [11C]TTFD in human healthy volunteers, we performed first-in-human PET imaging study with [11C]TTFD, along with radiation dosimetry of [11C]TTFD in humans. METHODS: Synthesis of [11C]TTFD was improved for clinical study. Dynamic whole-body PET images were acquired on three young male normal subjects after intravenous injection of [11C]TTFD. VOIs were defined for source organs on the PET images to measure time-course of [11C]TTFD uptake as percentage injected dose and the number of disintegrations for each organ. Radiation dosimetry was calculated with OLINDA/EXM. RESULTS: We succeeded in developing the improved synthetic method of [11C]TTFD for the first-in-human PET study. In the whole body imaging, uptake of [11C]TTFD by various tissues was almost plateaued at 10 min after intravenous injection, afterward gradually increased for the brain and urinary bladder (urine). %Injected dose was high in the liver, kidney, urinary bladder, heart, spine, brain, spleen, pancreas, stomach, and salivary glands, in this order. %Injected dose per gram of tissue was high also in the pituitary. By dosimetry, the effective radiation dose of [11C]TTFD calculated was 5.5 µSv/MBq (range 5.2-5.7). CONCLUSION: Novel synthetic method enabled clinical PET study with [11C]TTFD, which is a safe PET tracer with a dosimetry profile comparable to other common 11C-PET tracers. Pharmacokinetics of TTFD in the pharmacological dose and at different nutritional states could be further investigated by future quantitative PET studies. Noninvasive in vivo PET imaging for pathophysiology of thiamine-related function may provide diagnostic evidence of novel information about vitamin B1 deficiency in human tissues.

Contribution of chemotherapy to improved prognosis in stage 4 gastric cancer: trend analysis of a regional population-based cancer registry in Japan.

OBJECTIVES: Little is known about time trends in the prognosis of gastric cancer (GC), since the introduction of new chemotherapeutic agents. This study aimed to analyze how the increased number of available chemotherapeutic options affected the prognosis of GC and which patient types benefited within in a large population. METHODS: From a population-based cancer registry in Japan, 35,751 cases of GC were identified. Of these, 8214 cases were stage 4. The time trend for 3-year survival in stage 4 GC according to patient characteristics (age and tumor location) was estimated in relation to the introduction of new anticancer drugs. Multiple imputation was performed for sensitivity analysis to strengthen the missing data. In addition, we estimated the 5-year survival rate for distal-GC (DGC) and proximal-GC (PGC), and the hazard ratio (HR) was estimated by Cox proportional hazard model. RESULTS: Improvement of overall survival was accelerated in stage 4 cases over time. The prognosis was improved from 11.4% to 13.2%, subsequent to the approval of several oncologic drugs since 2009. Younger patients were more likely to have improved survival rates in response to the increase in chemotherapy options (< 60-year-old, 5.4%: 60-70, 2.2%; 70-80, 0.3%) from 2007 to 2015. The HR for DGC vs. PGC was 1.11 (95% CI 1.08-1.15), and PGC showed a higher rate of improved outcomes (2.4% vs. 0.6%). CONCLUSIONS: This analysis showed that improvement in the GC survival rate was accelerated by the introduction of new chemotherapeutic strategies and it was most evident among younger patients and in patients with PGC.

Arabidopsis GEX1 Is a Nuclear Membrane Protein of Gametes Required for Nuclear Fusion During Reproduction.

During the life cycle of flowering plants, nuclear fusion, or karyogamy, occurs three times: once during female gametogenesis, when the two polar nuclei fuse in the central cell, and twice during double fertilization. In Arabidopsis thaliana, nuclear fusion events during sexual reproduction proceed without the breakdown of the nuclear envelope, indicating that nuclear membrane fusion is essential for the completion of this process. Arabidopsis gamete expressed 1 (GEX1) is a membrane protein that is conserved among plant species. GEX1 shares homology with the yeast karyogamy protein Kar5, which is primarily expressed in the nuclear membrane. The GEX1 family represents a putative karyogamy factor. Herein, we show that GEX1 is required for the nuclear fusion events in Arabidopsis reproduction. GEX1-deficient mature female gametophytes were found to contain two unfused polar nuclei in close proximity within the central cell. Electron microscopy showed that the outer membrane of the polar nuclei was connected via the endoplasmic reticulum, whereas the inner membrane remained unfused. These results indicate that GEX1 is involved in polar nuclear membrane fusion following the fusion of the outer nuclear membrane. Furthermore, sperm nuclear fusion events were defective in the fertilized egg and central cell following plasmogamy in the fertilization of gex1-1 female gametophytes by gex1-1 pollen. An analysis of GEX1 localization in the female gametophyte using a transgenic line expressing GFP-tagged GEX1 driven by the GEX1 promoter showed that GEX1 is a nuclear membrane protein in the egg and central cell. Time-lapse live-cell imaging showed that in developing female gametophytes, the nuclear GFP-GEX1 signal was first detectable in the central cell shortly before the polar nuclei came in close contact, and then in the egg cell. Thus, we suggest that the GEX1-family proteins are nuclear membrane proteins involved in karyogamy in the reproduction of eukaryotes including flowering plants.

Permutations uniquely identify states and unknown external forces in non-autonomous dynamical systems.

It has been shown that a permutation can uniquely identify the joint set of an initial condition and a non-autonomous external force realization added to the deterministic system in given time series data. We demonstrate that our results can be applied to time series forecasting as well as the estimation of common external forces. Thus, permutations provide a convenient description for a time series data set generated by non-autonomous dynamical systems.

Manufacturing Industry Cancer Risk in Japan: A Multicenter Hospital-Based Case Control Study.

BACKGROUND: It is well known that specific occupations can cause harm in developing malignant neoplasms. Chemical exposure is particularly high in the manufacturing industry and workers in this sector may face a higher occupational risk for cancer. We aimed to estimate inequalities in the risk of cancers related to occupational chemical exposure in various manufacturing categories. METHODS: Using nationwide clinical inpatient data (1984-2017) in Japan, we undertook a multicenter, case-control study with regard to risks of developing cancers among various manufacturing industry categories. Using the food manufacturing industry as the reference group, odds ratios and 95% confidence intervals for each industry were estimated by conditional logistic regression, adjusted for sex, age, admission period, and the admitting hospital. Medical record summaries accounting for 89% of industrial categories with high odds ratios were collected to confirm diagnoses made on the basis of histology. We estimated industrial hazards based on the Pollutant Release and Transfer Register. RESULTS: A reduced risk for some of common cancers was observed among lumber and wood products industries. Leather tanning, leather products and fur tended to show a higher risk: 2.36 (95% CI 1.15-4.83) for pancreatic cancer, 2.85 (95% CI 1.26-6.47) for liver cancer and 2.00 (95% CI 1.01-3.99) for lung cancer. For the electronics category, observations of high risk ranged from 2.09 (95%CI 1.18-3.70) for ureter cancer, to 2.49 (95% CI 1.79-3.55) for kidney cancer. CONCLUSIONS: This study revealed industry risk inequalities in manufacturing categories were present with regard to the risk of common cancers in Japan.

Asymptotic estimates of SARS-CoV-2 infection counts and their sensitivity to stochastic perturbation.

Despite the importance of having robust estimates of the time-asymptotic total number of infections, early estimates of COVID-19 show enormous fluctuations. Using COVID-19 data from different countries, we show that predictions are extremely sensitive to the reporting protocol and crucially depend on the last available data point before the maximum number of daily infections is reached. We propose a physical explanation for this sensitivity, using a susceptible-exposed-infected-recovered model, where the parameters are stochastically perturbed to simulate the difficulty in detecting patients, different confinement measures taken by different countries, as well as changes in the virus characteristics. Our results suggest that there are physical and statistical reasons to assign low confidence to statistical and dynamical fits, despite their apparently good statistical scores. These considerations are general and can be applied to other epidemics.

The Prognosis of Hepatocellular Carcinoma Treated with Sorafenib in Combination with TACE.

OBJECTIVE: Sorafenib have been shown to be effective in the treatment of advanced HCC and has been standard therapy since its release in Japan in 2009 (Llovet et al., 2008; Cheng et al., 2009). However, due to a low response rate, more aggressive combination treatment has been utilized as a multimodal strategy. The present study aimed to determine the efficacy of sorafenib alone and in combination with transarterial chemoembolization (TACE) for the treatment of advanced HCC. METHODS: All patients with unresectable advanced HCC who were prescribed sorafenib at Kanto Rosai Hospital were included in the study. Five-year overall survival (OS) rates were estimated for patients treated with sorafenib alone or in combination with TACE. Multivariate and univariate regression analyses were performed to identify factors affecting OS. Analysis using propensity score matching and inverse-probability weights were also performed. RESULTS: A total of 46 patients were treated with sorafenib up to June 2018. The total sorafenib dose administered was higher in the TACE combination group (70900 mg vs. 24000 mg vs. with sorafenib alone), although the relative dose intensity was lower (11.7% vs. 17.6%, respectively). The 5-year survival prognosis estimated using the Kaplan-Meier method was longer in patients treated with sorafenib in combination with TACE versus sorafenib alone (36.3% vs. 7.7%). Combination with TACE was the only factor associated with improved OS in both univariate and multivariate analysis. Among cases matched by propensity scores the hazard rate for combination with TACE was 0.067 (95% CI 0.091-1.128). CONCLUSION: With an array of therapeutic options currently available, it is important to determine the efficacy of different multimodal strategies, such as sorafenib combined TACE, for patients with unresectable HCC.

Risk of cancer and longest-held occupations in Japanese workers: A multicenter hospital-based case-control study.

OBJECTIVES: Little is known about the risk of developing various cancers according to occupation and occupational physical activity. METHODS: Using nationwide clinical inpatient data (1984-2017) in Japan, we undertook a multicentered, matched case-control study with regard to the risk of developing various cancers according to occupation and using patients admitted with fractures as controls. Using standardized national occupation and industrial classifications, we first identified the longest-held job for each patient. Using sales workers as the reference group, odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by conditional logistic regression, adjusted for age, admission period, and the admitting hospital, with smoking, alcohol consumption, and lifestyle diseases as covariates. The risk of high and low occupational physical activity was also estimated. RESULTS: Across all occupations, a reduced risk for all common cancers among males was observed among those occupations associated with high physical activities, such as agriculture. People in these occupations tended to show a lower risk for most cancers, including, for example, prostate cancer (OR 0.58, 95% CI 0.45-0.75) and lung cancer (OR 0.63, 95% CI 0.51-0.76). For females, the breast cancer risk was low in women engaged in agriculture (OR 0.58, 95% CI 0.45-0.75) and in those occupations with high levels of occupational physical activity (OR 0.58, 95% CI 0.52-0.66). CONCLUSIONS: This study revealed differences in cancer risk among diverse occupations in Japan. Specifically, those occupations associated with high levels of physical activity may be associated with a decreased risk of cancer.

Anomalous Diffusion in Random Dynamical Systems.

Consider a chaotic dynamical system generating diffusionlike Brownian motion. Consider a second, nonchaotic system in which all particles localize. Let a particle experience a random combination of both systems by sampling between them in time. What type of diffusion is exhibited by this random dynamical system? We show that the resulting dynamics can generate anomalous diffusion, where in contrast to Brownian normal diffusion the mean square displacement of an ensemble of particles increases nonlinearly in time. Randomly mixing simple deterministic walks on the line, we find anomalous dynamics characterized by aging, weak ergodicity breaking, breaking of self-averaging, and infinite invariant densities. This result holds for general types of noise and for perturbing nonlinear dynamics in bifurcation scenarios.

Occupational Class and Risk of Cardiovascular Disease Incidence in Japan: Nationwide, Multicenter, Hospital-Based Case-Control Study.

Background In contemporary Western settings, higher occupational class is associated with lower risk for cardiovascular disease ( CVD ) incidence, including coronary heart disease ( CHD ) and stroke. However, in non-Western settings (including Japan), the occupational class gradient for cardiovascular disease risk has not been characterized. Methods and Results Using a nationwide, multicenter hospital inpatient data set (1984-2016) in Japan, we conducted a matched hospital case-control study with ≈1.1 million study subjects. Based on a standard national classification, we coded patients according to their longest-held occupational class (blue-collar, service, professional, manager) within each industrial sector (blue-collar, service, white-collar). Using blue-collar workers in blue-collar industries as the referent group, odds ratios and 95% CI s were estimated by conditional logistic regression with multiple imputation, matched for sex, age, admission date, and admitting hospital. Smoking and drinking were additionally controlled. Higher occupational class (professionals and managers) was associated with excess risk for CHD . Even after controlling for smoking and drinking, the excess odds across all industries remained significantly associated with CHD , being most pronounced among managers employed in service industries (odds ratio, 1.19; 95% CI , 1.08-1.31). On the other hand, the excess CHD risk in higher occupational class was offset by their lower risk for stroke (eg, odds ratio for professionals in blue-collar industries, 0.77; 95% CI , 0.70-0.85). Conclusions The occupational "gradient" in cardiovascular disease (with lower risk observed in higher status occupations) may not be a universal phenomenon. In contemporary Japanese society, managers and professionals may experience higher risk for CHD .

An overview of the extremal index.

For a wide class of stationary time series, extreme value theory provides limiting distributions for rare events. The theory describes not only the size of extremes but also how often they occur. In practice, it is often observed that extremes cluster in time. Such short-range clustering is also accommodated by extreme value theory via the so-called extremal index. This review provides an introduction to the extremal index by working through a number of its intuitive interpretations. Thus, depending on the context, the extremal index may represent (i) the loss of independently and identically distributed degrees of freedom, (ii) the multiplicity of a compound Poisson point process, and (iii) the inverse mean duration of extreme clusters. More recently, the extremal index has also been used to quantify (iv) recurrences around unstable fixed points in dynamical systems.

Occupational class and male cancer incidence: Nationwide, multicenter, hospital-based case-control study in Japan.

Little is known about socioeconomic inequalities in male cancer incidence in nonwestern settings. Using the nationwide clinical and occupational inpatient data (1984-2016) in Japan, we performed a multicentered, matched case-control study with 214 123 male cancer cases and 1 026 247 inpatient controls. Based on the standardized national classifications, we grouped patients' longest-held occupational class (blue-collar, service, professional, manager), cross-classified by industrial cluster (blue-collar, service, white-collar). Using blue-collar workers in blue-collar industries as the referent group, odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by conditional logistic regression with multiple imputation, matched for age, admission date, and admitting hospital. Smoking and alcohol consumption were additionally adjusted. Across all industries, a reduced risk with higher occupational class (professionals and managers) was observed for stomach and lung cancer. Even after controlling for smoking and alcohol consumption, the reduced odds persisted: OR of managers in white-collar industries was 0.80 (95% CI 0.72-0.90) for stomach cancer, and OR of managers in white-collar industries was 0.66 (95% CI 0.55-0.79) for lung cancer. In white-collar industries, higher occupational class men tended to have lower a reduced risk for most common types of cancer, with the exception of professionals who showed an excess risk for prostate cancer. We documented socioeconomic inequalities in male cancer incidence in Japan, which could not be explained by smoking and alcohol consumption.

Occupational inequalities in female cancer incidence in Japan: Hospital-based matched case-control study with occupational class.

BACKGROUND: Socioeconomic inequalities in female cancer incidence have previously been undocumented in Japan. METHODS: Using a nationwide inpatient dataset (1984-2016) in Japan, we identified 143,806 female cancer cases and 703,157 controls matched for sex, age, admission date, and admitting hospital, and performed a hospital-based matched case-control study. Based on standardized national classification, we categorized patients' socioeconomic status (SES) by occupational class (blue-collar, service, professional, manager), cross-classified by industry sector (blue-collar, service, white-collar). Using blue-collar workers in blue-collar industries as the reference group, we estimated the odds ratio (OR) for each cancer incidence using conditional logistic regression with multiple imputation, adjusted for major modifiable risk factors (smoking, alcohol consumption). RESULTS: We identified lower risks among higher-SES women for common and overall cancers: e.g., ORs for managers in blue-collar industries were 0.67 (95% confidence interval [CI], 0.46-0.98) for stomach cancer and 0.40 (95% CI, 0.19-0.86) for lung cancer. Higher risks with higher SES were evident for breast cancer: the OR for professionals in service industries was 1.60 (95% CI, 1.29-1.98). With some cancers, homemakers showed a similar trend to subjects with higher SES; however, the magnitude of the OR was weaker than those with higher SES. CONCLUSIONS: Even after controlling for major modifiable risk factors, socioeconomic inequalities were evident for female cancer incidence in Japan.

Cholangiocarcinoma Prognosis Varies over Time Depending on Tumor Site and Pathology.

BACKGROUND: Cholangiocarcinoma is a relatively rare cancer that is difficult to diagnose and has a poor prognosis. Currently, knowledge concerning its etiology, tumor localization, and pathological features remains limited. The present study aimed to clarify the clinico-epidemiologic nature of cholangiocarcinoma with its clinical subtypes using the largest regional cancer registry in Japan. METHODS: Using a regional cancer registry in Kanagawa prefecture, Japan, we estimated three-year and five-year survival rates of cholangiocarcinoma patients, who were classified into two groups: intrahepatic (i-CCA) and extrahepatic cholangiocarcinoma (e-CCA) cases. The hazard ratio for each subtype, including pathological tissue type and tumor site, was calculated. RESULTS: During the period from 1976 to 2013, 14,287 cases of cholangiocarcinoma were identified. The prognosis markedly improved after 2006, when a new type of chemotherapy for cholangiocarcinoma was introduced in Japan. Patients with i-CCA were more likely to be younger, and less likely to undergo surgery than those with e-CCA. The prognosis of cases with i-CCA was poor compared to that of patients with e-CCA. CONCLUSION: In Japan, i-CCA was more likely to develop in younger people and to have a poor prognosis. The prognosis of both i-CCA and e-CCA cases markedly improved after 2006. The present study describes clinico-epidemiological features of cholangiocarcinoma that may be useful for determining therapeutic strategies for this disease.

Efficacy of direct-acting antiviral treatment for chronic hepatitis C: A single hospital experience.

AIM: To evaluate the efficacy of direct-acting antivirals (DAAs) in Kanto Rosai Hospital. METHODS: All patients with hepatitis C virus (HCV) who underwent DAA prescription were enrolled in this study. The present study was a single center retrospective analysis using patients infected with HCV genotype 1 or 2. Resistance analysis was performed by using direct sequencing and cycleave PCR in genotype 1 patients treated with interferon (IFN)-free DAA. The primary endpoint was sustained virologic response at 12 wk after therapy (SVR12). RESULTS: A total of 117 patients participated in the study, including 135 with genotype 1 and 42 with genotype 2. Of the 135 patients with genotype 1, 16 received protease inhibitor + IFN + ribavirin and all achieved SVR. Of the 119 patients who received IFN-free DAA (in different combinations), 102 achieved SVR and 9 failed (7/9 were on daclatasvir/asunaprevir and 2/9 on ledipasvir/sofosbuvir). Efficacy analysis was done only for 43 patients who received daclatasvir/asunaprevir. From this analysis, Y93 resistance-associated substitutions were significantly correlated with SVR. CONCLUSION: The SVR rate was 98% for genotype 1 and 100% for genotype 2. However, caution is needed for HCV NS5A resistance-associated substitutions that are selected by HCV NS5A inhibitors because cerebrovascular adverse events are induced by some DAA drugs.

Primary Hepatic Lymphoma Complicated by a Hepatic Inflammatory Pseudotumor and Tumor-Forming Pancreatitis.

BACKGROUND: Hepatic inflammatory pseudotumor (IPT) is considered to be benign in biological behavior, and its malignant transformation is extremely rare. There has only been one published case of primary hepatic lymphoma complicated by hepatic IPT. CASE PRESENTATION: A 73-year-old man presented with obstructive jaundice and a pancreatic head mass. Histology of the mass revealed chronic pancreatitis with lymphoid follicle formation, leading to a diagnosis of a suspicion of follicular pancreatitis. After a choledochojejunostomy, a hepatic tumor was detected, and a biopsy revealed lymphoplasmacytic infiltration. Immunohistochemistry confirmed the polyclonal nature of lymphoplasma cells, indicative of an IPT. The hepatic tumor disappeared during follow-up, but the patient exhibited a high fever related to tumor recurrence. A biopsy revealed the co-existence of a diffuse large B-cell lymphoma and an IPT. IgG4-related disease was excluded because storiform fibrosis, obliterative phlebitis, and a significant increase in IgG4-immunoreactive cells were absent in all investigated tissues. The tumor completely disappeared after chemotherapy. CONCLUSION: Careful observation is necessary in this kind of situation because the presence of a hepatic IPT may represent an increased risk of malignant transformation.