PhD

dissertationThe mechanisms of the anticonvulsant activity of cannabidiol (CBD) and the central excitation of delta9- -tetrahydrocannabinol (Delta9 -THC) were investigated electrophysiologically with conscious, unrestrained cobalt epileptic rats. The well-known antiepileptics, trimethadione, ethosuximide and phenytoln, were included as reference drugs. Direct measurements were made of spontaneously firing, epileptic potentials from a primary focus on the parietal cortex and convulsions were monitored visually. Ethosuximide and trimethadione decreased the frequency of focal potentials, but phenytoin and CBD exerted no such effect. Although CBD did not suppress the focal abnormality, it abolished jaw and limb clonus. Consequently, CBD may produce its anticonvulsant effect by depressing seizure spread in the CNS. In contrast, delta9-THC markedly increased the frequency of focal potentials, evoked generalized bursts of polyspikes and produced frank convulsions, 11-OH-delta9 -THC, the major metabolite of delta -THC displayed only one of the excitatory properties of the parent compound: production of bursts of poiyspikes. In contrast to delta-THC and its 11-OH-metabolite, CBD, even in very high doses, did not induce any excitatory effects or convulsions. The present study provides the first evidence that CBD exerts anticonvulsant activity against the motor manifestations of a focal epilepsy, and that the mechanism of the effect may involve a depression of seizure spread in the CNS

HPV Vaccination in Japan: The Continuing Debate and Global Impacts

In June 2013, the Japanese Ministry of Health, Labour, and Welfare (MHLW) suspended its active recommendation of the human papillomavirus (HPV) vaccination after a small number of highly publicized alleged adverse events stoked public fears about the vaccine’s safety.2 While the MHLW continues to provide the HPV vaccination for those who request it through the National Immunization Programme (NIP), as of mid-April, the suspension of the HPV vaccination recommendation continues. Since the release of our CSIS report The HPV Vaccination in Japan: Issues and Options3 in May 2014, anti-vaccine groups have strengthened their control of the narrative surrounding the HPV vaccine, intensified their activities, and continued to capture media and public attention. The medical community has split as prominent personalities have come forward to support claims of adverse effects linked to the HPV vaccine even in the absence of any evidence of association. Countermeasures by the MHLW, medical professional groups, and others have been comparatively weak and, it appears, ineffectual. It remains unclear how and when this increasingly complicated and difficult situation will be resolved. In this paper, we outline major events with regards to the HPV vaccine controversy in Japan since May 2014, highlighting long-term implications of the rapid drop in vaccination coverage and recommending how to best move forward. There are also two addendums that explore global perspectives on the current situation in Japan and examine examples of how other countries have dealt with concerns and opposition to the HPV vaccine

Determination of aflatoxin B1 level in rice (Oryza sativa L.) through near-infrared spectroscopy and an improved simulated annealing variable selection method

Direct quantification analysis of near-infrared (NIR) spectra is challenging because the number of spectral variables is usually considerably higher than the number of samples. To mitigate the so-called curse of dimensionality, var�iable selection is often performed before multivariate calibration. There has been much work in this regard, where the developed variable selection method can be categorized as individual variable selection, such as uninformative variable elimination or variable importance in projection, and continuous interval variable selection method such as interval partial least squares or moving window partial least squares. In this study, a new individual variable se�lection method, modified simulated annealing (MSA), was proposed and used in conjunction with the partial least squares regression (PLSR) model. The interpretability of the selected variables in the determination of aflatoxin B1 levels in white rice was assessed. The results revealed that the PLSR model combined with MSA not only yielded higher accuracy than the full-spectrum PLSR but also successfully shrank the variable space. The developed simplified PLSR model using MSA produced satisfactory performances, with root mean square error of calibration (RMSEC) of 0.11 μg/kg and 0.56 μg/kg, and root mean square error of prediction (RMSEP) of 7.16 μg/kg and 14.42 μg/kg, were obtained for the low-aflatoxin B1-level- and high-aflatoxin-B1-level samples, respectively. Specifically, the MSA-based models yielded improvements of 97.80% (calibration set) and 44.62% (prediction set) as well as 95.85% (calibration set) and 62.57% (prediction set) for both datasets when compared with the full-spectrum PLSR (low aflatoxin: RMSEC = 5.02 μg/kg, RMSEP = 12.93 μg/kg; high aflatoxin: RMSEC = 13.50 μg/kg, RMSEP = 38.53 μg/kg). Compared with the baseline method of simulated annealing (SA) (low aflatoxin: RMSEC = 0.21 μg/kg, RMSEP = 9.78 μg/kg; high aflatoxin: RMSEC = 12.27 μg/kg, RMSEP = 38.53 μg/kg), the MSA significantly improved the predictive performance of the regression models, with the number of selected variables being almost half of that in the SA. A comparison with other commonly used variable selection methods of selectivity ratio (low aflatoxin: RMSEC = 6.09 μg/kg, RMSEP = 13.75 μg/kg; high aflatoxin: RMSEC = 13.74 μg/kg, RMSEP = 41.13 μg/kg), unin�formative variable elimination (low aflatoxin: RMSEC = 0.32 μg/kg, RMSEP = 5.11 μg/kg; high aflatoxin: RMSEC = 3.80 μg/kg, RMSEP = 17.76 μg/kg), and variable importance in projection (low aflatoxin: RMSEC = 2.67 μg/kg, RMSEP = 10.71 μg/kg; high aflatoxin: RMSEC = 13.51 μg/kg, RMSEP = 32.53 μg/kg) also indicated the promising efficacy of the proposed MSA

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Host Gene Expression Profiling of Dengue Virus Infection in Cell Lines and Patients

Dengue is the most prevalent mosquito-born viral disease affecting humans, yet there is, at present, no drug treatment for the disease nor are there any validated host targets for therapeutic intervention. Using microarray technology to monitor the response of virtually every human gene, we aimed to identify the ways in which humans interact with dengue virus during infection in order to discover new therapeutic targets that could be exploited to control viral replication. From the activated genes, we identified three pathways common to in vitro and in vivo infection; the NF-κB initiated immune pathway, the type I interferon pathway, and the ubiquitin proteasome pathway. We next found that inhibiting the ubiquitin proteasome pathway, or activating the type I interferon pathway, resulted in significant inhibition of viral replication. However, inhibiting the NF-κB initiated immune pathway had no effect on viral replication. We suggest that drugs that target the ubiquitin proteasome pathway may prove effective at killing the dengue virus, and, if used therapeutically, improve clinical outcome in dengue disease

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication