HEALTH VALUE IN FOOD SAFETY SURVEILLANCE INITIATIVES

Recognizing the increasing concern about the potential health effects of genetically modified foods, this research provides a framework for economic value of monitoring genetically modified food for their potential long-term human health effects. This is with the view of helping policy makers improve resource allocation decisions in the face of competing public health initiatives. Using a hypothetical population exposed to a hypothetical product, we estimate the health value associated with a post-market surveillance initiative. The analysis indicate that the principal challenge confronting decision makers in the implementation of post-market surveillance initiatives is prioritising products for monitoring given the uncertainty associated with outcomes and effects.Food Consumption/Nutrition/Food Safety,

Dystrophin Gene Mutation Location and the Risk of Cognitive Impairment in Duchenne Muscular Dystrophy

Contains fulltext : 88828.pdf (publisher's version ) (Open Access)BACKGROUND: A significant component of the variation in cognitive disability that is observed in Duchenne muscular dystrophy (DMD) is known to be under genetic regulation. In this study we report correlations between standardised measures of intelligence and mutational class, mutation size, mutation location and the involvement of dystrophin isoforms. METHODS AND RESULTS: Sixty two male subjects were recruited as part of a study of the cognitive spectrum in boys with DMD conducted at the Sydney Children's Hospital (SCH). All 62 children received neuropsychological testing from a single clinical psychologist and had a defined dystrophin gene (DMD) mutation; including DMD gene deletions, duplications and DNA point mutations. Full Scale Intelligence Quotients (FSIQ) in unrelated subjects with the same mutation were found to be highly correlated (r = 0.83, p = 0.0008), in contrast to results in previous publications. In 58 cases (94%) it was possible to definitively assign a mutation as affecting one or more dystrophin isoforms. A strong association between the risk of cognitive disability and the involvement of groups of DMD isoforms was found. In particular, improvements in the correlation of FSIQ with mutation location were identified when a new classification system for mutations affecting the Dp140 isoform was implemented. SIGNIFICANCE: These data represent one of the largest studies of FSIQ and mutational data in DMD patients and is among the first to report on a DMD cohort which has had both comprehensive mutational analysis and FSIQ testing through a single referral centre. The correlation between FSIQ results with the location of the dystrophin gene mutation suggests that the risk of cognitive deficit is a result of the cumulative loss of central nervous system (CNS) expressed dystrophin isoforms, and that correct classification of isoform involvement results in improved estimates of risk

A longitudinal study of change in substance use from before to during the COVID-19 pandemic in young adults

Introduction We assessed change in substance use from before to during the COVID-19 pandemic in young adults and identified factors associated with initiation/increase in use. Methods The sample comprised young adults from a longitudinal investigation of 1294 youth recruited at ages 12-13 (1999-2000) in 10 Montr eal-area high schools. Pre-pandemic data on use of cannabis, alcohol, combustible ciga- rette, e-cigarette and binge drinking were collected at ages 20.4, 24.0 and 30.6. During COVID-19, data were col- lected from December 2020 to June 2021 (age 33.6). We studied the prevalence of any and weekly/daily use from age 20.4 to 33.6. Individual-level change in substance use during the pandemic was estimated as differences in the fre- quency of use from age 30.6 to 33.6 versus from age 24.0 to 30.6. Heterogeneity in the risk of initiated/increased sub- stance use during COVID-19 across sociodemographic subgroups was assessed using modified Poisson regression. Results The prevalence of cannabis use increased from 17.5% to 23.1% from before to during the pandemic; e-ciga- rette use increased from 3.8% to 5.4%. In individual change analyses, the proportion of participants whose substance use did not change ranged from 48.9% (alcohol) to 84.0% (e-cigarettes). The incidence of initiated/increased canna- bis use (22.4%), and quit/decreased alcohol (35.2%) and binge drinking (53.5%) were higher during the pandemic than between ages 24.0 to 30.6. Low education and living alone were associated with higher risks of initiated/ increased use of most substances. Discussion Most participants reported stable patterns in substance use from before to during the COVID-19 pandemic

Faecal haemoglobin concentration in adenoma, before and after polypectomy, approaches the ideal tumour marker

BACKGROUND: Polypectomy may be performed at colonoscopy and then subsequent surveillance undertaken. It is thought that faecal haemoglobin concentration (f-Hb), estimated by quantitative faecal immunochemical tests (FIT), might be a useful tumour marker. METHODS: Consecutive patients enrolled in colonoscopy surveillance were approached at two hospitals. A specimen for FIT was provided before colonoscopy and, ideally after 3 weeks, a second FIT sample from those who had polypectomy. A single FIT system (OC-Sensor io, Eiken Chemical Co., Ltd) was used to generate f-Hb. RESULTS: 1103 Patients were invited; 643 returned a FIT device (uptake: 58.3%). Four patients had known inflammatory bowel disease (IBD) and were excluded, leaving 639 (57.9%) with an age range of 25–90 years (median 64 years), 54.6% male. Of 593 patients who had a f-Hb result and completed colonoscopy, advanced neoplasia was found in 41 (6.9%); four colorectal cancer (CRC): 0.7% and 37 advanced adenoma (AA): 6.3%, and a further 127 (21.4%) had non-advanced adenoma (NAA). The median f-Hb was significantly greater in AA as compared to NAA; 6.0 versus 1.0 μg Hb/g faeces, p < 0.0001.134/164 (81.7%) of invited patients returned a second FIT device: 28 were patients with AA in whom median pre-polypectomy f-Hb was 19.2, falling to 3.5 μg Hb/g faeces post-polypectomy, p = 0.01, and 106 with NAA had median pre-polypectomy f-Hb 0.8 compared to 1.0 μg Hb/g faeces post-polypectomy, p = 0.96. CONCLUSIONS: Quantitative FIT could provide a good tumour marker in post-polypectomy surveillance, reduce colonoscopy requirements and minimise potential risk to patients

The effectiveness and cost-effectiveness of minimal access surgery amongst people with gastro-oesophageal reflux disease – a UK collaborative study

*Corresponding author randomised arm of the trial (178 allocated to surgical management,179 allocated to continued, but optimised,medical management) and 453 recruited to the parallel non-randomised preference arm (261 chose surgical management, 192 chose to continue with best medical management). The type of fundoplication was left to the discretion of the surgeon. Main outcome measures: Participants completed a baseline reflux questionnaire, developed specifically for this study, containing a disease-specific outcome measure, the Short Form with 36 Items (SF-36), the EuroQol-5 Dimensions (EQ-5D) and the Beliefs about Medicines and Surgery questionnaires (BMQ/BSQ).Postal questionnaires were completed at participant specific time intervals after joining the trial (equivalent to approximately 3 and 12 months after surgery).Intraoperative data were recorded by the surgeons and all other in-hospital data were collected by the research nurse. At the end of the study period, participants completed a discrete choice experiment questionnaire. Results: The randomised groups were well balanced at entry. Participants had been taking GORD medication for a median of 32 months; the mean age of participants was 46 years and 66% were men. Of 178 randomised to surgery, 111 (62%) actually had fundoplication.There was a mixture of clinical and personal reasons why some patients did not have surgery, sometimes Objectives: To evaluate the clinical effectiveness, costeffectiveness and safety of a policy of relatively early laparoscopic surgery compared with continued medical management amongst people with gastro-oesophageal reflux disease (GORD) judged suitable for both policies. Design: Relative clinical effectiveness was assessed by a randomised trial (with parallel non-randomised preference groups) comparing a laparoscopic surgerybased policy with a continued medical management policy. The economic evaluation compared the costeffectiveness of the two management policies in order to identify the most efficient provision of future care and describe the resource impact that various policies for fundoplication would have on the NHS.Setting: A total of 21 hospitals throughout the UK with a local partnership between surgeon(s) and gastroenterologist(s) who shared the secondary care of patients with GORD.Participants: The 810 participants, who were identified retrospectively or prospectively via their participating clinicians, had both documented evidence of GORD (endoscopy and/or manometry/24-hour pH monitoring) and symptoms for longer than 12 months. In addition,the recruiting clinician(s) was clinically uncertain about which management policy was best.Intervention: Of the 810 eligible patients who consented to participate, 357 were recruited to the related to long waiting times. A total or partial wrap procedure was performed depending on surgeon preference. Complications were uncommon and there were no deaths associated with surgery. By the equivalent of 12 months after surgery, 38% in the randomised surgical group (14% amongst those who had surgery) were taking reflux medication compared with 90% in the randomised medical group. There were substantial differences (one-third to one-half standard deviation) favouring the randomised surgical group across the health status measures, the size depending on assumptions about the proportion that actually had fundoplication. These differences were the same or somewhat smaller than differences observed at 3 months. The lower the reflux score, the worse the symptoms at trial entry and the larger the benefit observed after surgery. The preference surgical group had the lowest reflux scores at baseline. These scores improved substantially after surgery, and by 12 months they were better than those in the preference medical group. The BMQ/BSQ and discrete choice experiment did distinguish the preference groups from each other and from the randomised groups. The latter indicated that the risk of serious complications was the most important single attribute of a treatment option. A within trial cost-effectiveness analysis suggested that the surgery policy was more costly (mean £2049) but also more effective [+0.088 quality-adjusted life-years (QALYs)]. The estimated incremental cost per QALY was £19,000–£23,000, with a probability between 46% (when 62% received surgery) and 19% (when all received surgery) of cost-effectiveness at a threshold of £20,000 per QALY. Modelling plausible longer-term scenarios (such as lifetime benefit after surgery) indicated a greater likelihood (74%) of costeffectiveness at a threshold of £20,000, but applying a range of alternative scenarios indicated wide uncertainty.The expected value of perfect information was greatest for longer-term quality of life and proportions of surgical patients requiring medication.Conclusions: Amongst patients requiring long-term medication to control symptoms of GORD, surgical management significantly increases general and refluxspecific health-related quality of life measures, at least up to 12 months after surgery. Complications of surgery were rare. A surgical policy is, however, more costly than continued medical management. At a threshold of £20,000 per QALY it may well be cost-effective, especially when putative longer-term benefits are taken into account, but this is uncertain.The more troublesome the symptoms, the greater the potential benefit from surgery. Uncertainty about cost-effectiveness would be greatly reduced by more reliable information about relative longer-term costs and benefits of surgical and medical policies. This could be through extended follow-up of the reflux trial cohorts or of other cohorts of fundoplication patients.Peer reviewedPublisher PD

Molecular simulations studies of gas adsorption in metal–organic frameworks

Using computational tools ranging from molecular simulations – including both Monte Carlo and molecular dynamics methods – to quantum mechanical (QM) calculations (primarily at density functional theory (DFT) level), this work focuses on addressing some of the challenges faced in molecular simulations of gas adsorption in metal–organic frameworks (MOFs). This work consists of two themes: one concerns gas adsorption in MOFs with coordinatively unsaturated metal sites (cus’s), and the other one deals with predicting and understanding the breathing behaviour of the flexible MOF MIL-53(Sc). It has been shown experimentally that incorporation of cus’s – also known as “open” metal sites or unsaturated metal centres – into MOFs significantly enhances the uptake of certain gases such as CO2 and CH4. As a result of the considerably enhanced, localized guest-molecule interactions with the cus’s, it, however, remains a challenge to predict correctly adsorption isotherms and/or mechanisms in MOFs with cus’s using grand-canonical Monte Carlo (GCMC) simulations based on generic classical force fields. To address this problem, two multi-scale modelling approaches – which combine GCMC simulations with QM calculations – have been proposed in this work. The first approach is based on the direct implementation of a fluid–framework potential energy surface, calculated by a hybrid DFT/ab initio method, in the GCMC simulations. The second approach involves parameterization of ab initio force fields for GCMC simulations of gas adsorption in MOFs with cus’s. This approach focuses on the generation of accurate ab initio reference data, selection of semiempirical model potentials, and force-field fitting through a multi-objective genetic algorithm approach. The multi-scale simulation strategy not only yields adsorption isotherms in very good agreement with experimental data but also correctly captures adsorption mechanisms, including the adsorption on the cus’s, observed experimentally but absent from GCMC simulations based on generic force fields. The second challenge that this work aims to address concerns the “breathing” phenomenon of MOFs, in which the framework structure adapts its pore opening to accommodate guest molecules, for example. The breathing effect gives rise to some exceptional properties of these MOFs and hence promising applications. However, framework flexibility often poses a challenge for computational studies of such MOFs, because suitable flexible force fields for frameworks are lacking and the effort involved in developing a new one is no less a challenge. Here, an alternative to the force-field-based approach is adopted. Ab initio molecular dynamics (AIMD) simulations – which combine classical molecular dynamics simulations with electronic-structure calculations “on the fly” – have been deployed to study structural changes of the breathing MOF MIL-53(Sc) in response to changes in temperature over the range 100–623 K and adsorption of CO2 at 0–0.9 bar at 196 K. AIMD simulations employing dispersion-corrected DFT accurately simulated the experimentally observed closure of MIL-53(Sc) upon solvent removal and the transition of the empty MOF from the closed-pore phase to the very-narrow-pore phase with increasing temperature. AIMD simulations were also used to mimic the CO2 adsorption of MIL-53(Sc) in silico by allowing the MIL-53(Sc) framework to evolve freely in response to CO2 loadings corresponding to the two steps in the experimental adsorption isotherm. The resulting structures enabled the structure determination of the two CO2-containing intermediate and large-pore phases observed by experimental synchrotron X-ray diffraction studies with increasing CO2 pressure; this would not have been possible for the intermediate structure via conventional methods because of diffraction peak broadening. Furthermore, the strong and anisotropic peak broadening observed for the intermediate structure could be explained in terms of fluctuations of the framework predicted by the AIMD simulations. Fundamental insights from the molecular-level interactions further revealed the origin of the breathing of MIL-53(Sc) upon temperature variation and CO2 adsorption. Both the multi-scale simulation strategy for gas adsorption in MOFs with cus’s and the AIMD study of the stimuli-responsive breathing behaviour of MIL-53(Sc) illustrate the power and promise of combining molecular simulations with quantum mechanical calculations for the prediction and understanding of MOFs

Hsp90 governs dispersion and drug resistance of fungal biofilms

Fungal biofilms are a major cause of human mortality and are recalcitrant to most treatments due to intrinsic drug resistance. These complex communities of multiple cell types form on indwelling medical devices and their eradication often requires surgical removal of infected devices. Here we implicate the molecular chaperone Hsp90 as a key regulator of biofilm dispersion and drug resistance. We previously established that in the leading human fungal pathogen, Candida albicans, Hsp90 enables the emergence and maintenance of drug resistance in planktonic conditions by stabilizing the protein phosphatase calcineurin and MAPK Mkc1. Hsp90 also regulates temperature-dependent C. albicans morphogenesis through repression of cAMP-PKA signalling. Here we demonstrate that genetic depletion of Hsp90 reduced C. albicans biofilm growth and maturation in vitro and impaired dispersal of biofilm cells. Further, compromising Hsp90 function in vitro abrogated resistance of C. albicans biofilms to the most widely deployed class of antifungal drugs, the azoles. Depletion of Hsp90 led to reduction of calcineurin and Mkc1 in planktonic but not biofilm conditions, suggesting that Hsp90 regulates drug resistance through different mechanisms in these distinct cellular states. Reduction of Hsp90 levels led to a marked decrease in matrix glucan levels, providing a compelling mechanism through which Hsp90 might regulate biofilm azole resistance. Impairment of Hsp90 function genetically or pharmacologically transformed fluconazole from ineffectual to highly effective in eradicating biofilms in a rat venous catheter infection model. Finally, inhibition of Hsp90 reduced resistance of biofilms of the most lethal mould, Aspergillus fumigatus, to the newest class of antifungals to reach the clinic, the echinocandins. Thus, we establish a novel mechanism regulating biofilm drug resistance and dispersion and that targeting Hsp90 provides a much-needed strategy for improving clinical outcome in the treatment of biofilm infections