The Efficacy of an mHealth App in Facilitating Weight Loss Among Japanese Fitness Center Members: Regression Analysis Study.

BACKGROUND: Self-tracking smartphone apps have emerged as promising tools to encourage healthy behaviors. In this longitudinal study, we used gym use data from members of a major fitness club that operates gyms throughout Japan from January 2014 to December 2019. OBJECTIVE: Our objective was to assess the extent to which a health and fitness self-tracking mobile app introduced to gym members on January 1, 2018, contributed to their weight loss. The app allows users to input information regarding diet, sleep, weight, and gym exercise so that they can receive personalized feedback from an artificial intelligence chatbot to improve their health behaviors. METHODS: We used linear regression to quantify the association between app use and weight loss. The primary outcome of the study was the weight loss achieved by each gym user, which was calculated as the difference between their initial and final weights in kilograms, as recorded in the app. Individuals who did not attend the gym or failed to use the mobile app at least twice during the study period were excluded from the analysis. The model accounted for age, gender, distance between the gym and the member's residence, average weekly number of times a member used the gym, user's gym membership length in weeks, average weekly number of times a member input information into the app, and the number of weeks that the app was used at least once. RESULTS: Data from 26,589 participants were analyzed. Statistically significant associations were detected between weight loss and 2 metrics related to app use: the average weekly frequency of use and the total number of weeks in which the app was used at least once. One input per week was found to be associated with a loss of 62.1 (95% CI 53.8-70.5) g, and 1 week of app use was associated with 21.7 (95% CI 20.5-22.9) g of weight loss from the day of the first input to that of the final input to the app. Furthermore, the average number of times that a member used the gym weekly was also shown to be statistically significantly associated with weight loss: 1 use per week was associated with 255.5 (95% CI 228.5-282.6) g of weight loss. CONCLUSIONS: This empirical study demonstrated a significant association between weight loss among gym members and not only the frequency of weekly gym use but also the use of a health and fitness self-tracking app. However, further work is needed to examine the mechanisms through which mobile apps affect health behaviors and to identify the specific app features that are most effective in promoting weight loss.

Inter-prefectural Travel and Network Connectedness During the COVID-19 Pandemic in Japan.

BACKGROUND: Increases in human mobility have been linked to rises in novel coronavirus disease 2019 (COVID-19) transmission. The pandemic era in Japan has been characterized by changes in inter-prefectural mobility across state of emergency (SOE) declarations and travel campaigns, but they have yet to be characterized. METHODS: Using Yahoo Japan mobility data extracted from the smartphones of more than 10 million Japanese residents, we calculated the monthly number of inter-prefectural travel instances, stratified by residential prefecture and destination prefecture. We then used this adjacency matrix to calculate two network connectedness metrics, closeness centrality and effective distance, that reliably predict disease transmission. RESULTS: Inter-prefectural mobility and network connectedness decreased most considerably during the first SOE, but this decrease dampened with each successive SOE. Mobility and network connectedness increased during the Go To Travel campaign. Travel volume between distant prefectures decreased more than travel between prefectures with geographic proximity. Closeness centrality was found to be negatively correlated with the rate of COVID-19 infection across prefectures, with the strength of this association increasing in tandem with the infection rate. Changes in effective distance were more visible among geographically isolated prefectures (Hokkaido and Okinawa) than among metropolitan, central prefectures (Tokyo, Aichi, Osaka, and Fukuoka). CONCLUSION: The magnitude of reductions in human mobility decreased with each subsequent state of emergency, consistent with pandemic fatigue. The association between network connectedness and rates of COVID-19 infection remained visible throughout the entirety of the pandemic period, suggesting that inter-prefectural mobility may have contributed to disease spread.

Prevalence and appropriateness of indwelling urinary catheters in Japanese hospital wards: a multicenter point prevalence study.

BACKGROUND: Indwelling urinary catheters are commonly used in hospitalized patients, which can lead to the development of urinary catheter complications, including catheter-associated urinary tract infection (CAUTI). Limited reports on the appropriateness of urinary catheter use exist in Japan. This study investigated the prevalence and appropriateness of indwelling urinary catheters, and the incidence of CAUTI in non-intensive care unit (non-ICU) wards in Japanese hospitals. METHODS: This prospective observational study was conducted in 7 non-ICU wards from 6 hospitals in Japan from October 2017 to June 2018. At each hospital the study teams evaluated urinary catheter prevalence through in-person bedside evaluation for at least 5 days of each week for 3 months. Catheter associated urinary tract infection (CAUTI) incidence and appropriateness of catheter use was collected via chart review. RESULTS: We assessed 710 catheter-days over 5528 patient-days. The mean prevalence of indwelling urinary catheter use in participating wards was 13% (range: 5% to 19%), while the mean incidence of CAUTI was 9.86 per 1000 catheter-days (range: 0 to 33.90). Approximately 66% of the urinary catheter days assessed had an appropriate indication for use (range: 17% to 81%). A physician's order for catheter placement was present in only 10% of catheterized patients. CONCLUSION: This multicenter study provides epidemiological information about the appropriate use of urinary catheters in Japanese non-ICU wards. A multimodal intervention may help improve the appropriate use of urinary catheters.

Jerveratrum-Type Steroidal Alkaloids Inhibit ß-1,6-Glucan Biosynthesis in Fungal Cell Walls.

The limited number of available effective agents necessitates the development of new antifungals. We report that jervine, a jerveratrum-type steroidal alkaloid isolated from Veratrum californicum, has antifungal activity. Phenotypic comparisons of cell wall mutants, K1 killer toxin susceptibility testing, and quantification of cell wall components revealed that ß-1,6-glucan biosynthesis was significantly inhibited by jervine. Temperature-sensitive mutants defective in essential genes involved in ß-1,6-glucan biosynthesis, including BIG1, KEG1, KRE5, KRE9, and ROT1, were hypersensitive to jervine. In contrast, point mutations in KRE6 or its paralog SKN1 produced jervine resistance, suggesting that jervine targets Kre6 and Skn1. Jervine exhibited broad-spectrum antifungal activity and was effective against human-pathogenic fungi, including Candida parapsilosis and Candida krusei. It was also effective against phytopathogenic fungi, including Botrytis cinerea and Puccinia recondita. Jervine exerted a synergistic effect with fluconazole. Therefore, jervine, a jerveratrum-type steroidal alkaloid used in pharmaceutical products, represents a new class of antifungals active against mycoses and plant-pathogenic fungi. IMPORTANCE Non-Candida albicans Candida species (NCAC) are on the rise as a cause of mycosis. Many antifungal drugs are less effective against NCAC, limiting the available therapeutic agents. Here, we report that jervine, a jerveratrum-type steroidal alkaloid, is effective against NCAC and phytopathogenic fungi. Jervine acts on Kre6 and Skn1, which are involved in ß-1,6-glucan biosynthesis. The skeleton of jerveratrum-type steroidal alkaloids has been well studied, and more recently, their anticancer properties have been investigated. Therefore, jerveratrum-type alkaloids could potentially be applied as treatments for fungal infections and cancer.

Differential Biosynthesis and Roles of Two Ferrichrome-Type Siderophores, ASP2397/AS2488053 and Ferricrocin, in Acremonium persicinum.

Ferrichromes are a family of fungal siderophores with cyclic hexapeptide structures. Most fungi produce one or two ferrichrome-type siderophores. Acremonium persicinum MF-347833 produces ferrichrome-like potent Trojan horse antifungal antibiotics ASP2397 and AS2488053, the aluminum- and iron-chelating forms of AS2488059, respectively. Here, we show by gene sequencing followed by gene deletion experiments that A. persicinum MF-347833 possesses two nonribosomal peptide synthetase genes responsible for AS2488059 and ferricrocin assembly. AS2488059 was produced under iron starvation conditions and excreted into the media to serve as a defense metabolite and probably an iron courier. In contrast, ferricrocin was produced under iron-replete conditions and retained inside the cells, likely serving as an iron-sequestering molecule. Notably, the phylogenetic analyses suggest the different evolutionary origin of AS2488059 from that of conventional ferrichrome-type siderophores. Harnessing two ferrichrome-type siderophores with distinct biological properties may give A. persicinum a competitive advantage for surviving the natural environment.

Reduced mortality during the COVID-19 outbreak in Japan, 2020: a two-stage interrupted time-series design.

BACKGROUND: Coronavirus disease 2019 (COVID-19) continues to be a major global health burden. This study aims to estimate the all-cause excess mortality occurring in the COVID-19 outbreak in Japan, 2020, by sex and age group. METHODS: Daily time series of mortality for the period January 2015-December 2020 in all 47 prefectures of Japan were obtained from the Ministry of Health, Labour and Welfare, Japan. A two-stage interrupted time-series design was used to calculate excess mortality. In the first stage, we estimated excess mortality by prefecture using quasi-Poisson regression models in combination with distributed lag non-linear models, adjusting for seasonal and long-term variations, weather conditions and influenza activity. In the second stage, we used a random-effects multivariate meta-analysis to synthesize prefecture-specific estimates at the nationwide level. RESULTS: In 2020, we estimated an all-cause excess mortality of -20 982 deaths [95% empirical confidence intervals (eCI): -38 367 to -5472] in Japan, which corresponded to a percentage excess of -1.7% (95% eCI: -3.1 to -0.5) relative to the expected value. Reduced deaths were observed for both sexes and in all age groups except those aged <60 and 70-79 years. CONCLUSIONS: All-cause mortality during the COVID-19 outbreak in Japan in 2020 was decreased compared with a historical baseline. Further evaluation of cause-specific excess mortality is warranted.

Effect of emergency declaration on mental health during the COVID-19 pandemic in Japan: A social network service-based difference-in-differences approach.

Strong lockdowns to control COVID-19 pandemic have been enforced globally and strongly restricted social activities with consequent negative effects on mental health. Japan has effectively implemented a unique voluntary policy to control COVID-19, but the mental health impact of the policy has not been examined on a large scale. In this study, we examined the effect of the first declaration on the mental health of affected residents. We used population-level questionnaire data of 17,400 people living under the state of emergency and 9208 who were not through a social-networking-service app and applied a difference-in-differences regression model to estimate the causal effect of the declaration of the state of emergency on psychological wellbeing, stratified by job category. No statistically significant effect of the declaration was observed among all job categories. This suggests that residents' psychological situation has gradually changed, possibly influenced by other factors such as the surrounding environment, rather than the declaration itself. Given that Japan has a unique policy to control COVID-19 instead of a strict lockdown, our results showed the Japanese-style policy may serve as a form of harm reduction strategy, to control the epidemic with minimal psychological harm, and enable a policy that balances disease control and mental health. Caution is necessary that this study used self-reported data from a limited time period before and after the first declaration in April 2020.

Genome-wide screening of genes associated with momilactone B sensitivity in the fission yeast Schizosaccharomyces pombe.

Momilactone B is a natural product with dual biological activities, including antimicrobial and allelopathic properties, and plays a major role in plant chemical defense against competitive plants and pathogens. The pharmacological effects of momilactone B on mammalian cells have also been reported. However, little is known about the molecular and cellular mechanisms underlying its broad bioactivity. In this study, the genetic determinants of momilactone B sensitivity in yeast were explored to gain insight into its mode of action. We screened fission yeast mutants resistant to momilactone B from a pooled culture containing genome-wide gene-overexpressing strains in a drug-hypersensitive genetic background. Overexpression of pmd1, bfr1, pap1, arp9, or SPAC9E9.06c conferred resistance to momilactone B. In addition, a drug-hypersensitive, barcoded deletion library was newly constructed and the genes that imparted altered sensitivity to momilactone B upon deletion were identified. Gene Ontology and fission yeast phenotype ontology enrichment analyses predicted the biological pathways related to the mode of action of momilactone B. The validation of predictions revealed that momilactone B induced abnormal phenotypes such as multiseptated cells and disrupted organization of the microtubule structure. This is the first investigation of the mechanism underlying the antifungal activity of momilactone B against yeast. The results and datasets obtained in this study narrow the possible targets of momilactone B and facilitate further studies regarding its mode of action.

Trends in Healthcare Access in Japan during the First Wave of the COVID-19 Pandemic, up to June 2020.

We evaluated the impact of the new coronavirus disease (COVID-19) on healthcare access in Japan in terms of the number of outpatients and hospitalized patients as well as the length of hospital stays, during the first wave of the pandemic, up to June 2020. This observational study evaluated the monthly average number of outpatients per day at hospitals, the average number of hospitalized patients per day, and the average length of hospital stays per patient, from December 2010 to June 2020, using the hospital reports data, which are open aggregated data on the utilization of hospitals from the Ministry of Health, Labour and Welfare. These numbers were compared with those from the same period of previous years, using a quasi-Poisson regression model. We found a nationwide decrease in the number of outpatients in general hospitals and hospitalized patients, particularly in long-term care beds in Japan, as well as the excess length of hospital stays among psychiatric care patients during the first wave of the COVID-19. This limited access to healthcare demonstrated the importance of the long-term health monitoring of vulnerable populations and the need for urgent management support to healthcare facilities in preparation for possible prolonged pandemics in the future.

Excess All-Cause Deaths during Coronavirus Disease Pandemic, Japan, January-May 20201.

To provide insight into the mortality burden of coronavirus disease (COVID-19) in Japan, we estimated the excess all-cause deaths for each week during the pandemic, January-May 2020, by prefecture and age group. We applied quasi-Poisson regression models to vital statistics data. Excess deaths were expressed as the range of differences between the observed and expected number of all-cause deaths and the 95% upper bound of the 1-sided prediction interval. A total of 208-4,322 all-cause excess deaths at the national level indicated a 0.03%-0.72% excess in the observed number of deaths. Prefecture and age structure consistency between the reported COVID-19 deaths and our estimates was weak, suggesting the need to use cause-specific analyses to distinguish between direct and indirect consequences of COVID-19.

Trends in emergency transportation due to heat illness under the new normal lifestyle in the COVID-19 era, in Japan and 47 prefectures.

In Japan, in response to the spread of the new coronavirus disease (COVID-19), a 'new normal' in the era of the COVID-19 was proposed by the government, which calls for thorough wearing of masks as an infection control measure in the era of the COVID-19, but related heat illness has been a great concern this summer. We applied quasi-Poisson regression models to the daily number of emergency transportations due to heat illness from 2008 to 2020 from the Fire and Disaster Management Agency, Ministry of Internal Affairs and Communications, Japan, to estimate the expected weekly number of emergency transportations from heat illness, with adjustment for their long-term trend and the weather conditions, including temperatures. We found that, at the national level, the number of heat illness emergency transports did not significantly increase or decrease from the annual trend in 2020. By prefecture, on the other hand, there were some prefectures in which the number of heat illness emergency transports was less than the average year, and most of them were in the week of August 10-16. By age group, the number of heat illness emergency transports in the 0-17 and 18-64 age groups was particularly low in some prefectures, and by severity, those in mild cases was particularly low. A caution is necessary that there is a possibility that a decrease in cases possibly associated with COVID-19 measures, such as, outdoor activity restrictions at schools/universities and cancellation of public events, may offset the possible increase in heat illness cases occurring elsewhere associated with wearing masks. Given that the end of the COVID-19 pandemic is not expected yet, continuous and appropriate awareness-raising activities to prevent heat-related illness remain important.

Trends in suicide in Japan by gender during the COVID-19 pandemic, up to September 2020.

Suicide is an extreme consequence of the psychological burden associated with the coronavirus disease 2019 (COVID-19) counter-measures. A quasi-Poisson regression was applied to monthly suicide mortality data obtained from the National Police Agency to estimate the gender-specific excess/exiguous suicide deaths during the COVID-19 pandemic in Japan up to September 2020. We found excess suicide deaths among women in July, August and September, but not among men. Our results indicate the importance of COVID-19 related suicide prevention, especially for women. Timely access to mental health care and financial and social support is urgently needed, as is optimal treatment for mental illness.

Long non-coding NR2F1-AS1 is associated with tumor recurrence in estrogen receptor-positive breast cancers.

The tenacity of late recurrence of estrogen receptor (ER)-positive breast cancer remains a major clinical issue to overcome. The administration of endocrine therapies within the first 5 years substantially minimizes the risk of relapse; however, some tumors reappear 10-20 years after the initial diagnosis. Accumulating evidence has strengthened the notion that long noncoding RNAs (lncRNAs) are associated with cancer in various respects. Because lncRNAs may display high tissue/cell specificity, we hypothesized this might provide new insights to tumor recurrence. By comparing transcriptome profiles of 24 clinical primary tumors obtained from patients who developed distant metastases and patients with no signs of recurrence, we identified lncRNA NR2F1-AS1 whose expression was associated with tumor recurrence. We revealed the relationship between NR2F1-AS1 and the hormone receptor expressions in ER-positive breast cancer cells. Gain of function of NR2F1-AS1 steered cancer cells into quiescence-like state by the upregulation of dormancy inducers and pluripotency markers, and activates representative events of the metastatic cascade. Our findings implicated NR2F1-AS1 in the dynamics of tumor recurrence in ER-positive breast cancers and introduce a new biomarker that holds a therapeutic potential, providing favorable prospects to be translated into the clinical field.

Removal of nonylphenol and nonylphenol monoethoxylate from water and anaerobically digested sewage sludge by Ferrate(VI).

Nonylphenol (NP) and nonylphenol monoethoxylate (NP1EO) have toxic and persistent characteristics, and are incompletely degraded in conventional wastewater treatment processes. These compounds are present in sewage sludge that can be reused as fertilizers or soil conditioners. Accordingly, NP and NP1EO should be properly removed before being discharged in the environment. In this study, potassium ferrate (K2FeO4) containing hexavalent iron (Fe(VI)) was used as an environment-friendly oxidizing agent to mediate NP and NP1EO degradation. The aim of this study was to investigate the effects of pH and Fe(VI) dosage on the degradation of NP and NP1EO in water and anaerobically digested sewage sludge samples. In water samples, under conditions examined in this study, maximum removal efficiencies for NP and NP1EO were 98% and 92%, respectively. For digested sewage sludge samples, the maximum removal efficiencies of NP and NP1EO were 58% and 96%, respectively. The results demonstrated that Fe(VI) can potentially degrade NP and NP1EO in water and digested sewage sludge samples. However, organic matter as a matrix in the sludge sample would inhibit the degradation of NP and NP1EO by Fe(VI). The pH values before and after adding K2FeO4 to the samples had an obvious influence on the removal of NP and NP1EO.

Extracellular vesicles mediate the horizontal transfer of an active LINE-1 retrotransposon.

Long interspersed element-1 (LINE-1 or L1) retrotransposons replicate through a copy-and-paste mechanism using an RNA intermediate. However, little is known about the physical transmission of retrotransposon RNA between cells. To examine the horizontal transfer of an active human L1 retrotransposon mediated by extracellular vesicles (EVs), human cancer cells were transfected with an expression construct containing a retrotransposition-competent human L1 tagged with a reporter gene. Using this model, active retrotransposition events were detected by screening for the expression of the reporter gene inserted into the host genome by retrotransposition. EVs including exosomes and microvesicles were isolated from cells by differential centrifugation. The enrichment of L1-derived reporter RNA transcripts were detected in EVs isolated from cells expressing active L1 retrotransposition. The delivery of reporter RNA was confirmed in recipient cells, and reporter genes were detected in the genome of recipient cells. Additionally, employing qRT-PCR, we found that host-encoded factors are activated in response to increased exposure to L1-derived RNA transcripts in recipient cells. Our results suggest that the horizontal transfer of retrotransposons can occur through the incorporation of RNA intermediates delivered via EVs and may have important implications for the intercellular regulation of gene expression and gene function.

Statistical inference of the rate of RNA polymerase II elongation by total RNA sequencing.

MOTIVATION: Sequencing total RNA without poly-A selection enables us to obtain a transcriptomic profile of nascent RNAs undergoing transcription with co-transcriptional splicing. In general, the RNA-seq reads exhibit a sawtooth pattern in a gene, which is characterized by a monotonically decreasing gradient across introns in the 5'-3' direction, and by substantially higher levels of RNA-seq reads present in exonic regions. Such patterns result from the process of underlying transcription elongation by RNA polymerase II, which traverses the DNA strand in a 5'-3' direction as it performs a complex series of mRNA synthesis and processing. Therefore, data of sequenced total RNAs could be utilized to infer the rate of transcription elongation by solving the inverse problem. RESULTS: Though solving the inverse problem in total RNA-seq has the great potential, statistical methods have not yet been fully developed. We demonstrate what extent the newly developed method can be useful. The objective is to reconstruct the spatial distribution of transcription elongation rates in a gene from a given noisy, sawtooth-like profile. It is necessary to recover the signal source of the elongation rates separately from several types of nuisance factors, such as unobserved modes of co-transcriptionally occurring mRNA splicing, which exert significant influences on the sawtooth shape. The present method was tested using published total RNA-seq data derived from mouse embryonic stem cells. We investigated the spatial characteristics of the estimated elongation rates, focusing especially on the relation to promoter-proximal pausing of RNA polymerase II, nucleosome occupancy and histone modification patterns. AVAILABILITY AND IMPLEMENTATION: A C implementation of PolSter and sample data are available at https://github.com/yoshida-lab/PolSter. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Emerging roles of long non-coding RNA in cancer.

Since comprehensive analysis of the mammalian genome revealed that the majority of genomic products are transcribed in long non-coding RNA (lncRNA), increasing attention has been paid to these transcripts. The applied next-generation sequencing technologies have provided accumulating evidence of dysregulated lncRNA in cancer. The implication of this finding can be seen in many forms and at multiple levels. With impacts ranging from integrating chromatin remodeling complexes to regulating transcription and post-transcriptional processes, aberrant expression of lncRNA may have repercussions in cell proliferation, tumor progression or metastasis. lncRNA may act as enhancers, scaffolds or decoys by physically interacting with other RNA species or proteins, resulting in a direct impact on cell signaling cascades. Even though their functional classification is well-established in the context of cancer, clearer characterization in terms of their phenotypic outputs is needed to optimize and identify suitable candidates that enable the development of new therapeutic strategies and the design of novel diagnostic approaches. The present article aims to outline different cancer-associated lncRNA according to their contribution to tumor suppression or tumor promotion based on their most current functional annotations.

CD44 exerts a functional role during EMT induction in cisplatin-resistant head and neck cancer cells.

A number of studies report that epithelial to mesenchymal transition (EMT) supports the generation and maintenance of cancer stem cells (CSCs), which show tumor seeding ability and drug resistance; however, the molecular mechanisms underlying induction of EMT-associated tumor malignancy remain unclear. The present study reports that oral cancer cells switch from expressing the CD44 variant form (CD44v) to expressing the standard form (CD44s) during acquisition of cisplatin-resistance, which resulted in EMT induction. CD44s induced an EMT phenotype in cisplatin resistant cells by up-regulating ZEB1, a transcriptional repressor of E-cadherin. More importantly, CD44s up-regulated ZEB1 by suppressing microRNA-200c, which is a non-coding RNA that directly represses the ZEB1 gene. These results demonstrate the importance of the association between platinum resistance and CD44s during EMT induction in oral cancer cells.

Extracellular vesicles as trans-genomic agents: Emerging roles in disease and evolution.

The composition of genetic material in extracellular vesicles (EV) has sparked interest particularly in the potential for horizontal gene transfer by EV. Although the RNA content of EV has been studied extensively, few reports have examined the DNA content of EV. It is still unclear how DNA is packaged inside EV, and whether they are functional in recipient cells. In this review, we describe the biological significance of genetic material in EV and their possible impacts in recipient cells, with focus on DNA from cancer cell-derived EV and the potential roles they may play in the cancer microenvironment. Another important feature of the genetic content of EV is the presence of retrotransposon elements. In this review, we discuss the possibility of an EV-mediated mechanism for the dispersal of retrotransposon elements, and their potential involvement in the development of genetically influenced diseases. In addition to this, we discuss the potential involvement of EV in the transfer of genetic material across species, and their possible impacts in modulating genome evolution.