Trend change of the transmission route of COVID-19-related symptoms in Japan.

OBJECTIVES: The Japanese prime minister declared a state of emergency on April 7 2020 to combat the outbreak of coronavirus disease 2019 (COVID-19). This declaration was unique in the sense that it was essentially driven by the voluntary restraint of the residents. We examined the change of the infection route by investigating contact experiences with COVID-19-positive cases. STUDY DESIGN: This study is a population-level questionnaire-based study using a social networking service (SNS). METHODS: To assess the impact of the declaration, this study used population-level questionnaire data collected from an SNS with 121,375 respondents (between March 27 and May 5) to assess the change in transmission routes over the study period, which was measured by investigating the association between COVID-19-related symptoms and (self-reported) contact with COVID-19-infected individuals. RESULTS: The results of this study show that the declaration prevented infections in the workplace, but increased domestic infections as people stayed at home. However, after April 24, workplace infections started to increase again, driven by the increase in community-acquired infections. CONCLUSIONS: While careful interpretation is necessary because our data are self-reported from voluntary SNS users, these findings indicate the impact of the declaration on the change in transmission routes of COVID-19 over time in Japan.

[Estimating the basic reproduction number of COVID-19 in Wuhan, China].

Objective: The number of confirmed and suspected cases of the COVID-19 in Hubei province is still increasing. However, the estimations of the basic reproduction number of COVID-19 varied greatly across studies. The objectives of this study are 1) to estimate the basic reproduction number (R(0)) of COVID-19 reflecting the infectiousness of the virus and 2) to assess the effectiveness of a range of controlling intervention. Methods: The reported number of daily confirmed cases from January 17 to February 8, 2020 in Hubei province were collected and used for model fit. Four methods, the exponential growth (EG), maximum likelihood estimation (ML), sequential Bayesian method (SB) and time dependent reproduction numbers (TD), were applied to estimate the R(0). Results: Among the four methods, the EG method fitted the data best. The estimated R(0) was 3.49 (95%CI: 3.42-3.58) by using EG method. The R(0) was estimated to be 2.95 (95%CI: 2.86-3.03) after taking control measures. Conclusions: In the early stage of the epidemic, it is appropriate to estimate R(0) using the EG method. Meanwhile, timely and effective control measures were warranted to further reduce the spread of COVID-19.

Effects of branched chain amino acid supplementation on patient care outcomes in adults and children with liver cirrhosis: A systematic review.

BACKGROUND & AIMS: Malnutrition is highly prevalent in chronic liver disease (CLD) due to alterations in nutrient utilization, malabsorption and poor intake. Low serum concentrations of branched chain amino acids (BCAA) in the presence of elevated aromatic acid concentrations is commonly observed in adult and children with liver cirrhosis and is associated with malnutrition and other adverse patient outcomes. The efficacy of BCAA supplementation has not been well established in adults and children with CLD. The purpose of this review was to critically evaluate the literature regarding the impact of BCAA supplementation related to changes in body composition, muscle strength, liver biomarkers, medical and hepatic complications (hepatic encephalopathy (HE), ascites, edema) and patient care outcomes (event free survival, health related quality of life, length of hospitalization). METHODS: A total of 40 articles retrieved from PubMed or Web of Science databases (1989-2017) were included. RESULTS: BCAA supplementation may be beneficial in improving muscle strength, ascites and edema with potential clinically significant improvements in HE in adult liver patients. In children, limited data have shown that BCAA supplementation may exert favourable effects on weight, fat mass, fat free mass and serum albumin level. CONCLUSIONS: Heterogeneity of study findings attributed to variability in BCAA dose (total, relative proportions), duration, disease severity and lack of uniformity in tools used for assessing patient outcomes limit overall conclusions. Longitudinal studies examining the efficacy of BCAA supplementation as a therapeutic treatment of malnutrition in chronic liver disease is warranted.

Maternal body mass index and risk of birth and maternal health outcomes in low- and middle-income countries: a systematic review and meta-analysis.

We conducted a systematic review and meta-analysis of population-based cohort studies of maternal body mass index (BMI) and risk of adverse birth and health outcomes in low- and middle-income countries. PubMed, Embase, CINAHL and the British Nursing Index were searched from inception to February 2014. Forty-two studies were included. Our study found that maternal underweight was significantly associated with higher risk of preterm birth (odds ratio [OR], 1.13; 95% confidence interval [CI], 1.01-1.27), low birthweight (OR, 1.66; 95% CI, 1.50-1.84) and small for gestational age (OR, 1.85; 95% CI, 1.69-2.02). Compared with mothers with normal BMI, overweight or obese mothers were at increased odds of gestational diabetes, pregnancy-induced hypertension, pre-eclampsia, caesarean delivery and post-partum haemorrhage. The population-attributable risk (PAR) indicated that if women were entirely unexposed to overweight or obesity during the pre-pregnancy or early pregnancy period, 14% to 35% fewer women would develop gestational diabetes, pre-eclampsia or pregnancy-induced hypertension in Brazil, China, India, Iran or Thailand. The highest PAR of low birthweight attributable to maternal underweight was found in Iran (20%), followed by India (18%), Thailand (10%) and China (8%). Treatment and prevention of maternal underweight, overweight or obesity may help reduce the burden on maternal and child health in developing countries.

Maternal and perinatal outcomes among nulliparous adolescents in low- and middle-income countries: a multi-country study.

OBJECTIVE: To investigate the risk of adverse pregnancy outcomes and caesarean section among adolescents in low- and middle-income countries. DESIGN: Secondary analysis using facility-based cross-sectional data from the World Health Organization (WHO) Global Survey on Maternal and Perinatal Health. SETTING: Twenty-three countries in Africa, Latin America, and Asia. POPULATION: Women admitted for delivery in 363 health facilities during 2-3 months between 2004 and 2008. METHODS: We constructed multilevel logistic regression models to estimate the effect of young maternal age on risks of adverse pregnancy outcomes. MAIN OUTCOME MEASURES: Risk of adverse pregnancy outcomes among young mothers. RESULTS: A total of 78 646 nulliparous mothers aged ≤24 years and their singleton infants were included in the analysis. Compared with mothers aged 20-24 years, adolescents aged 16-19 years had a significantly lower risk of caesarean section (adjusted OR 0.75, 95% CI 0.71-0.79). When the analysis was restricted to caesarean section indicated for presumed cephalopelvic disproportion, the risk of caesarean section was significantly higher among mothers aged ≤15 years (aOR 1.27, 95% CI 1.07-1.49) than among those aged 20-24 years. Higher risks of low birthweight and preterm birth were found among adolescents aged 16-19 years (aOR 1.10, 95% CI 1.03-1.17; aOR 1.16, 95% CI 1.09-1.23, respectively) and ≤15 years (aOR 1.33, 95% CI 1.14-1.54; aOR 1.56, 95% CI 1.35-1.80, respectively). CONCLUSIONS: Adolescent girls experiencing pregnancy at a very young age (i.e. <16 years) have an increased risk of adverse pregnancy outcomes.

20-kDa placental hGH-V has diminished diabetogenic and lactogenic activities compared with 22-kDa hGH-N while retaining antilipogenic activity.

Placental human growth hormone-variant (hGH-V) and pituitary human growth hormone-N (hGH-N) are of identical size (22 kDa) but differ in 13 residues scattered throughout the protein. Several isoforms of GH are produced by the hGH-N and hGH-V genes including a 20-kDa hGH-V resulting from a 45-bp deletion caused by the use of an alternative acceptor site within exon 3. To date, the biological properties of the 20-kDa GH-V have not been characterized in vivo. Using young male Wistar rats fed either chow or a high-fat (HF) diet for 4 wk postweaning, we investigated the effect of 7 days treatment with either 22-kDa hGH-N, 20-kDa hGH-V (5 ug x g(-1) x day(-1) sc), or vehicle on body composition and endocrine and metabolic profiles. Total body growth (absolute weight gain and linear growth trajectory) in the 20-kDa hGH-V-treated animals was intermediary between that of control and hGH-N-treated animals. Both 22-kDa hGH-N and 20-kDa hGH-V significantly reduced total body fat mass compared with control animals, and there were no differences between the GH isoforms in anti-lipogenic activity in animals fed the HF diet. Fasting plasma insulin and C peptide were significantly increased in animals on the HF diet and further increased by hGH-N but were unchanged in 20-kDa hGH-V-treated animals compared with saline-treated controls. Plasma volume as assessed by hematocrit was increased in hGH-N-treated animals but was unchanged in 20-kDa hGH-V-treated animals compared with controls. Furthermore, 20-kDa hGH-V had reduced lactogenic (prolactin receptor mediated) activity characteristic of hGH-N as tested in vitro compared with the 20-kDa hGH-N and 22-kDa hGH-N variants. In summary, placental 20-kDa hGH-V retains some of the growth-promoting and all antilipogenic activities of pituitary 22-kDa hGH-N but has diminished diabetogenic and lactogenic properties compared with the native 22-kDa hGH-N.

Assessment of psychoeducational outcomes after pediatric liver transplant.

Outcomes research in pediatric liver transplant (LT) has focused on mortality and morbidity but there is a need to also evaluate functional outcomes. Standardized cognitive testing was administered to a cohort of children with infantile chronic liver disease who were transplanted at the University of Alberta during their preschool years. Thirty children had comprehensive assessments with the Bayley Scales of Infant Development or Wechsler testing. Patient variables potentially associated with cognitive delay were analyzed with multiple regression analysis. The mean DQ/IQ score (developmental quotient/intelligence quotient) was 81 +/- 17. Delay (DQ/IQ score < 70), and borderline delay (DQ/IQ 70-84) were each present in 27% of the cohort, with only 46% demonstrating normal cognition. Regression analysis demonstrated that the decreased IQ was associated with pretransplant growth retardation and elevated calcineurin inhibitor levels. Performance IQ had strong correlation with pretransplant growth retardation and elevated serum ammonia, R(2)= 45%, compared to verbal IQ that was associated was elevated calcineurin inhibitor levels, R(2)= 23%. Children post-LT are at high risk for cognitive delay or borderline delay. This is the first study to demonstrate the association calcineurin inhibitors with impaired IQ and also the unique finding of different variables predictive of impaired verbal intelligence quotient (VIQ) versus performance intelligence quotient (PIQ).

Respiratory failure associated with human metapneumovirus infection in an infant posthepatic transplant.

This is the first reported case of respiratory failure associated with human metapneumovirus (hMPV) infection in a liver transplant recipient or in a pediatric solid transplant recipient. A 9-month-old female developed respiratory distress 8 days following a liver transplant. hMPV was detected and she required intubation followed by extracorporeal membrane oxygenation for 26 days. Immunosuppressive medications were stopped during the acute infection except for methylprednisolone as treatment for acute respiratory distress. Serial Doppler ultrasounds were used to monitor for hepatic vessel thromboses and serum liver function tests to assess for hepatic dysfunction and there was no evidence of allograft rejection. The patient recovered from the nosocomial hMPV infection with satisfactory pulmonary function and possible mild developmental delay.

Sex work practices and condom use in female sex workers in Sydney.

The aim of this study was to determine sex work practices and predictors of condom use among female sex workers (SWs) in Sydney. SWs from two centres completed a self-administered questionnaire covering demographic and sexual characteristics and sex work practices. One hundred and forty-eight international (born in Asia) and 141 local SWs (born in Australia, New Zealand or the UK) were recruited. Local SWs saw more clients per shift than international SWs (P = 0.002), but international SWs worked more shifts per week than local SWs (P = 0.001). International SWs used condoms less consistently at work than local SWs (P = 0.001). About 37% of international SWs never used condoms with non-paying partners, compared with 14% of local SWs (P = 0.01). Speaking Thai (odds ratio [OR] 8.9, 95% confidence interval [CI]; 3.19-24.87) or Chinese (OR 17.4; 95% CI 4.98-60.89) (both P < 0.001) and previous sex work in Thailand (OR 10.0 95% CI 2.31-43.52; P = 0.02) were associated with inconsistent condom use. Strategies to improve condom use need to be evaluated.

A cost-effectiveness analysis of heroin detoxification methods in the Australian National Evaluation of Pharmacotherapies for Opioid Dependence (NEPOD).

This economic evaluation was part of the Australian National Evaluation of Pharmacotherapies for Opioid Dependence (NEPOD) project. Data from four trials of heroin detoxification methods, involving 365 participants, were pooled to enable a comprehensive comparison of the cost-effectiveness of five inpatient and outpatient detoxification methods. This study took the perspective of the treatment provider in assessing resource use and costs. Two short-term outcome measures were used-achievement of an initial 7-day period of abstinence, and entry into ongoing post-detoxification treatment. The mean costs of the various detoxification methods ranged widely, from AUD 491 dollars(buprenorphine-based outpatient); to AUD 605 dollars for conventional outpatient; AUD 1404 dollars for conventional inpatient; AUD 1990 dollars for rapid detoxification under sedation; and to AUD 2689 dollars for anaesthesia per episode. An incremental cost-effectiveness analysis was carried out using conventional outpatient detoxification as the base comparator. The buprenorphine-based outpatient detoxification method was found to be the most cost-effective method overall, and rapid opioid detoxification under sedation was the most cost-effective inpatient method.

Elevated levels of ornithine decarboxylase cooperate with Raf/ERK activation to convert normal keratinocytes into invasive malignant cells.

Ornithine decarboxylase (ODC) overexpression coupled with activated Ras is fully sufficient to oncogenically transform primary keratinocytes. To determine the Ras effector pathways that represent the minimal essential contribution to full oncogenic transformation in this context, we evaluated the cooperativity of different Ras effector mutants with overexpressed ODC in an in vivo tracheal xenotransplantation assay for epithelial cell invasiveness. Primary keratinocytes, isolated from either K6/ODC transgenic mouse skin (expressing increased ODC) or from normal littermate skin were infected with retrovirus producing an activated RasV12 or partial loss-of-function effector mutants of RasV12 that selectively induce only the Raf/ERK, RalGDS, or the PI3-kinase signaling pathway. Whereas keratinocytes expressing a fully activated RasV12 are not invasive in tracheal xenotransplants, ODC-overexpressing keratinocytes acquire an invasive phenotype with additional expression of either RasV12 or activation of the Raf/ERK pathway. Independent of a mutated ras, elevated levels of ODC activate the Akt/mTOR signaling pathway as well as the Rho/Rac pathway in primary keratinocytes. Thus, Raf/ERK signaling is sufficient to cooperate with increased ODC activity in the conversion of normal keratinocytes to invasive cells. In order to promote invasiveness in keratinocytes, elevated levels of ODC may cooperate with Raf/ERK via activation of the Akt and Rho/Rac signaling pathway.

Cervical human papillomavirus infections in commercial sex workers-risk factors and behaviours.

We have investigated the prevalence of, and risk factors for, cervical human papillomavirus (HPV) infection in commercial sex workers (CSWs) and controls attending the same sexual health clinics in Sydney. A self-administered 'risk factor' questionnaire was completed and a Pap smear and a specimen for HPV detection and typing were taken. Results from the 288 CSWs and 266 controls were assessed by univariate and multivariate analyses. No significant difference in the rates of cervical HPV infection in CSWs (31.6%) and controls (24.4%) was found but HPV related cytological abnormalities were more common on the CSWs (P <0.05). In both groups, factors independently associated with HPV infection were the use of non-barrier contraception, cytological abnormalities, age under 36 and the number of non-paying sexual partners. A risk factor for CSWs only was sex-work in Japan. A detailed 'work' history from CSWs may be useful to identify unsafe practices or work in countries where safer sex may be less acceptable.

Polyamines regulate gap junction communication in connexin 43-expressing cells.

The control of cell-cell communication through gap junctions is thought to be crucial in normal tissue function and during various stages of tumorigenesis. However, few natural regulators of gap junctions have been found. We show here that increasing the activity of ornithine decarboxylase, or adding polyamines to the outside of cells, increases the level of gap junction communication between various epithelial cells. Conversely, reduction of ornithine decarboxylase activity decreases the level of gap junction communication. This regulation is dependent upon the expression of connexin 43 (Cx43 or Cxalpha1), which is a major connexin expressed in many different cell types, and involves an increase in Cx43 and its cellular re-distribution.

Combined effect of operational variables and enzyme activity on aqueous enzymatic extraction of oil and protein from soybean.

The individual effect of two different enzymes-protease and cellulase-on oil and protein extraction yields combined with other process parameters-enzyme concentration, time of hydrolysis, particle size and solid-to-liquid ratio-was evaluated by Response Surface Methodology. The selection of the enzymes for the study was based on preliminary experiments that showed higher increments in the extraction yield with the use of the two enzymes when compared to hemicellulase and pectinase. The levels of the quantitative parameters studied were: i) enzyme concentration: 0.1, 0.45, 2 w/w %; ii) liquid-to-solid ratio: 0.05, 0.125, 0.2; iii) mean particle size: 212.5, 449.5, 855 µm; iv) time of hydrolysis: 30; 60; 120 min. Experimental data for both oil and protein extraction yields obtained with and without enzymes correlated very well with process parameters (P < 0.0001), resulting in models with high coefficient of determination for oil and protein extraction yields (r(2) = 0.9570 and r(2) = 0.9807, respectively). The use of protease resulted in significantly higher yields over the control (protein yield increased from 27.8 to 66.2%, oil yield increased from 41.8 to 58.7%) only when heat treated flour was used, or when non-heat treated flour with large particle sizes was used in the extraction. The yields of protein and oil from non-heat treated material in general decreased slightly with the use of enzymes.

Regulation of ornithine decarboxylase activity and polyamine transport by agmatine in rat pulmonary artery endothelial cells.

Agmatine, a product of arginine decarboxylation in mammalian cells, is believed to govern cell polyamines by inducing antizyme, which in turn suppresses ornithine decarboxylase (ODC) activity and polyamine uptake. However, since agmatine is structurally similar to the polyamines, it is possible that it exerts antizyme-independent actions on polyamine regulatory pathways. The present study determined whether agmatine inhibited ODC activity and polyamine transport in rat pulmonary artery endothelial cells (PAECs) by an antizyme-dependent mechanism. Agmatine caused time-dependent reductions in ODC activity, which occurred before increases in antizyme. Interventions that suppressed proteasome function caused large increases in ODC activity but failed to attenuate inhibitory effects of agmatine. When agmatine was present in the culture medium, 14C-polyamine uptake was competitively inhibited as evidenced by substantial elevations in K(m) values. If PAECs were incubated with agmatine for periods sufficient to increase antizyme, there were modest decreases in V(max) for putrescine and spermidine but not for spermine. These effects of agmatine on polyamine transport were insensitive to protein synthesis inhibition. Collectively, our findings show that agmatine decreases ODC activity and polyamine transport in PAECs, but a causal role for antizyme in these actions of agmatine is difficult to establish. Nevertheless, these observations are consistent with a model in which PAECs express both antizyme-1 and -2, but only the latter contributes to agmatine-mediated suppression of ODC activity.

Overexpression of the Arabidopsis CBF3 transcriptional activator mimics multiple biochemical changes associated with cold acclimation.

We further investigated the role of the Arabidopsis CBF regulatory genes in cold acclimation, the process whereby certain plants increase in freezing tolerance upon exposure to low temperature. The CBF genes, which are rapidly induced in response to low temperature, encode transcriptional activators that control the expression of genes containing the C-repeat/dehydration responsive element DNA regulatory element in their promoters. Constitutive expression of either CBF1 or CBF3 (also known as DREB1b and DREB1a, respectively) in transgenic Arabidopsis plants has been shown to induce the expression of target COR (cold-regulated) genes and to enhance freezing tolerance in nonacclimated plants. Here we demonstrate that overexpression of CBF3 in Arabidopsis also increases the freezing tolerance of cold-acclimated plants. Moreover, we show that it results in multiple biochemical changes associated with cold acclimation: CBF3-expressing plants had elevated levels of proline (Pro) and total soluble sugars, including sucrose, raffinose, glucose, and fructose. Plants overexpressing CBF3 also had elevated P5CS transcript levels suggesting that the increase in Pro levels resulted, at least in part, from increased expression of the key Pro biosynthetic enzyme Delta(1)-pyrroline-5-carboxylate synthase. These results lead us to propose that CBF3 integrates the activation of multiple components of the cold acclimation response.

Preference to have used a medically supervised injecting centre among injecting drug users in Kings Cross, Sydney.

OBJECTIVE: To assess factors affecting preference to have last injected in a medically supervised injecting centre (MSIC) among injecting drug users (IDUs) attending a needle syringe program (NSP) in Kings Cross, Sydney. METHODS: All NSP attenders over a two-day period in August 1999 were asked where they last injected, whether they injected alone and if they would have preferred to use an MSIC. This was in addition to the routine data collected, which included age, gender and last drug injected. RESULTS: Among the 178 respondents, 52 (29%) last injected in a public place and 77 (44%) last injected alone. Seventy-one per cent of all respondents would have preferred to use an MSIC. Of those who injected in public, 83% would have preferred to use an MSIC compared to 66% of those who injected in private, which was significant (p = 0.03). Age, gender, last drug injected and having injected alone did not affect preference to use an MSIC. CONCLUSIONS: Respondents' high preference to use an MSIC suggests that it may well achieve its public order and public health objectives. IMPLICATIONS: An MSIC may significantly shift current patterns of illicit drug use in Kings Cross, the community impact of which should be monitored and managed.

Inhibition of ornithine decarboxylase (ODC) decreases tumor vascularization and reverses spontaneous tumors in ODC/Ras transgenic mice.

We have shown that ornithine decarboxylase (ODC) overexpression in the skin of TG.AC v-Ha-ras transgenic mice induces the formation of spontaneous skin carcinomas. Treatment of ODC/Ras double transgenic mice with alpha-difluoromethylornithine (DFMO), a specific inhibitor of ODC enzyme activity, causes a rapid regression of these spontaneous tumors. DFMO treatment led to dramatic decreases in ODC activity and putrescine levels, but v-Ha-ras expression was not affected in the regressed tumors. Moreover, cyclin D1 continued to be strongly expressed in the basal epithelial cells of regressed tumors, and there was no decrease in the proliferative index of these same tumor cells. Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling analyses revealed increased DNA fragmentation in DFMO regressed tumors compared with similarly sized spontaneous tumors from ODC/Ras transgenic mice not treated with DFMO. Moreover, the blood vessel count was significantly decreased in regressed tumors within the first four days of DFMO treatment. The decreased vasculature in DFMO regressed tumors was not attributable to altered expression of murine vascular endothelial growth factor (VEGF) isoforms. Elevated levels of ODC activity in the skin of K6/ODC transgenic mice increased the dermal vascularization compared with that in nontransgenic normal littermates. Our results suggest that ODC stimulates an angiogenic factor(s) other than VEGF and/or may play a key role in a cell survival effector pathway of Ras that is independent of a Ras-induced proliferation pathway.

K6/ODC transgenic mice as a sensitive model for carcinogen identification.

Ornithine decarboxylase (ODC), an important enzyme in the polyamine biosynthetic pathway, is aberrantly regulated in many epithelial tumors of rodents and humans. In murine skin, it has been shown that ODC overexpression provides a sufficient condition for tumor promotion. Therefore, we hypothesized that K6/ODC transgenic mice in which ODC overexpression was targeted to hair follicle keratinocytes might provide a sensitive model for identifying genotoxic carcinogens. Ten known carcinogens or noncarcinogens have been tested in the model so far and results are highly concordant with 2-year rodent bioassays (100% concordant). More importantly, each of two chemicals tested that is recognized as a human carcinogen was identified as a carcinogen in K6/ODC transgenic mice. In addition, 7, 12-dimethylbenz(a)anthracene (DMBA) dose response studies indicated that even at a very low dose, 2 nmol, a high percentage of mice (50%) had already developed tumors 8 weeks after treatment. We conclude that the K6/ODC transgenic mouse model is very sensitive to topical application of genotoxic carcinogens and could therefore be a useful mouse model for carcinogen identification and chemical risk assessment.