Imaging Drug Uptake by Bioorthogonal Stimulated Raman Scattering Microscopy

Stimulated Raman scattering (SRS) microscopy in tandem with bioorthogonal Raman labelling strategies is set to revolutionise the direct visualisation of intracellular drug uptake. Rational evaluation of a series of Raman-active labels has allowed the identification of highly active labels which have minimal perturbation on the biological efficacy of the parent drug. Drug uptake has been correlated with markers of cellular composition and cell cycle status, and mapped across intracellular structures using dual-colour and multi-modal imaging. The minimal phototoxicity and low photobleaching associated with SRS microscopy has enabled real-time imaging in live cells. These studies demonstrate the potential for SRS microscopy in the drug development process

A Microfluidic Device for Whole-Animal Drug Screening Using Electrophysiological Measures in the Nematode C. Elegans

This paper describes the fabrication and use of a microfluidic device for performing whole-animal chemical screens using non-invasive electrophysiological readouts of neuromuscular function in the nematode worm, C. elegans. The device consists of an array of microchannels to which electrodes are attached to form recording modules capable of detecting the electrical activity of the pharynx, a heart-like neuromuscular organ involved in feeding. The array is coupled to a tree-like arrangement of distribution channels that automatically delivers one nematode to each recording module. The same channels are then used to perfuse the recording modules with test solutions while recording the electropharyngeogram (EPG) from each worm with sufficient sensitivity to detect each pharyngeal contraction. The device accurately reported the acute effects of known anthelmintics (anti-nematode drugs) and also correctly distinguished a specific drug-resistant mutant strain of C. elegans from wild type. The approach described here is readily adaptable to parasitic species for the identification of novel anthelmintics. It is also applicable in toxicology and drug discovery programs for human metabolic and degenerative diseases for which C. elegans is used as a model.Chemistry and Chemical Biolog

Raman imaging of nanocarriers for drug delivery

The efficacy of pharmaceutical agents can be greatly improved through nanocarrier delivery. Encapsulation of pharmaceutical agents into a nanocarrier can enhance their bioavailability and biocompatibility, whilst also facilitating targeted drug delivery to specific locations within the body. However, detailed understanding of the in vivo activity of the nanocarrier-drug conjugate is required prior to regulatory approval as a safe and effective treatment strategy. A comprehensive understanding of how nanocarriers travel to, and interact with, the intended target is required in order to optimize the dosing strategy, reduce potential off-target effects, and unwanted toxic effects. Raman spectroscopy has received much interest as a mechanism for label-free, non-invasive imaging of nanocarrier modes of action in vivo. Advanced Raman imaging techniques, including coherent anti-Stokes Raman scattering (CARS) and stimulated Raman scattering (SRS), are paving the way for rigorous evaluation of nanocarrier activity at the single-cell level. This review focuses on the development of Raman imaging techniques to study organic nanocarrier delivery in cells and tissues

The co-evolutionary relationship between energy service companies and the UK energy system: Implications for a low-carbon transition

The Energy Service Company (ESCo) business model is designed to reward businesses by satisfying consumers' energy needs at less cost and with fewer carbon emissions via energy demand management and/or sustainable supply measures. In contrast, the revenue of the incumbent Energy Utility Company (EUCo) model is coupled with the sale of units of energy, which are predominantly sourced from fossil fuels. The latter is currently dominant in the UK. This paper addresses two questions. First, why has the ESCo model traditionally been confined to niche applications? Second, what role is the ESCo model likely to play in the transition to a low-carbon UK energy system? To answer these, the paper examines the core characteristics of the ESCo model, relative to the EUCo model. The paper then examines how ESCos have co-evolved with the various dimensions of the energy system (i.e. ecosystems, institutions, user practices, technologies and business models) to provide insight into how ESCos might help to shape the future UK energy system. We suggest that institutional and technological changes within the UK energy system could result in a more favourable selection environment for ESCos, consequently enabling the ESCo model to proliferate at the expense of the EUCo model. © 2013 Elsevier Ltd

Transplantation of organs from deceased donors with meningitis and encephalitis: a UK registry analysis.

BACKGROUND: Deceased organ donors, where the cause of death is meningitis or encephalitis, are a potential concern because of the risks of transmission of a potentially fatal infection to recipients. METHODS: Using the UK Transplant Registry, a retrospective cohort analysis of deceased organ donors in the UK was undertaken to better understand the extent to which organs from deceased donors with meningitis and/or encephalitis (M/E) (of both known and unknown cause) have been used for transplantation, and to determine the associated recipient outcomes. RESULTS: Between 2003 and 2015, 258 deceased donors with M/E were identified and the causative agent was known in 188 (72.9%). These donors provided 899 solid organs for transplantation (455 kidneys and 444 other organs). The only recorded case of disease transmission was from a donor with encephalitis of unknown cause at time of transplantation who transmitted a fatal nematode infection to 2 kidney transplant recipients. A further 3 patients (2 liver and 1 heart recipient) died within 30 days of transplantation from a neurological cause (cerebrovascular accident) with no suggestion of disease transmission. Overall, patient and graft survival in recipients of organs from donors with M/E were similar to those for all other types of deceased organ donor. CONCLUSION: Donors dying with M/E represent a valuable source of organs for transplantation. The risk of disease transmission is low but, where the causative agent is unknown, caution is required.National Institute of Health Research, Blood and Transplant Research Unit (NIHR BTRU) on Organ Donation and Transplantation at the University of Cambridge in collaboration with Newcastle University and in partnership with NHS Blood and Transplant (NHSBT), and the NIHR Cambridge Biomedical Research CentreThis is the author accepted manuscript. The final version is available from Wiley via http://dx.doi.org/10.1111/tid.1262

Comparative effectiveness of BNT162b2 versus mRNA-1273 covid-19 vaccine boosting in England: matched cohort study in OpenSAFELY-TPP

Objective To compare the effectiveness of the BNT162b2 mRNA (Pfizer-BioNTech) and mRNA-1273 (Moderna) covid-19 vaccines during the booster programme in England. Design Matched cohort study, emulating a comparative effectiveness trial. Setting Linked primary care, hospital, and covid-19 surveillance records available within the OpenSAFELY-TPP research platform, covering a period when the SARS-CoV-2 delta and omicron variants were dominant. Participants 3 237 918 adults who received a booster dose of either vaccine between 29 October 2021 and 25 February 2022 as part of the national booster programme in England and who received a primary course of BNT162b2 or ChAdOx1. Intervention Vaccination with either BNT162b2 or mRNA-1273 as a booster vaccine dose. Main outcome measures Recorded SARS-CoV-2 positive test, covid-19 related hospital admission, covid-19 related death, and non-covid-19 related death at 20 weeks after receipt of the booster dose. Results 1 618 959 people were matched in each vaccine group, contributing a total 64 546 391 person weeks of follow-up. The 20 week risks per 1000 for a positive SARS-CoV-2 test were 164.2 (95% confidence interval 163.3 to 165.1) for BNT162b2 and 159.9 (159.0 to 160.8) for mRNA-1273; the hazard ratio comparing mRNA-1273 with BNT162b2 was 0.95 (95% confidence interval 0.95 to 0.96). The 20 week risks per 1000 for hospital admission with covid-19 were 0.75 (0.71 to 0.79) for BNT162b2 and 0.65 (0.61 to 0.69) for mRNA-1273; the hazard ratio was 0.89 (0.82 to 0.95). Covid-19 related deaths were rare: the 20 week risks per 1000 were 0.028 (0.021 to 0.037) for BNT162b2 and 0.024 (0.018 to 0.033) for mRNA-1273; hazard ratio 0.83 (0.58 to 1.19). Comparative effectiveness was generally similar within subgroups defined by the primary course vaccine brand, age, previous SARS-CoV-2 infection, and clinical vulnerability. Relative benefit was similar when vaccines were compared separately in the delta and omicron variant eras. Conclusions This matched observational study of adults estimated a modest benefit of booster vaccination with mRNA-1273 compared with BNT162b2 in preventing positive SARS-CoV-2 tests and hospital admission with covid-19 20 weeks after vaccination, during a period of delta followed by omicron variant dominance

Deceased Organ Donors With a History of Increased Risk Behavior for the Transmission of Blood-Borne Viral Infection: The UK Experience.

BACKGROUND: Deceased organ donors are routinely screened for behaviors that increase the risk of transmissible blood-borne viral (BBV) infection, but the impact of this information on organ donation and transplant outcome is not well documented. Our aim was to establish the impact of such behavior on organ donation and utilization, as well transplant recipient outcomes. METHODS: We identified all UK deceased organ donors from 2003 to 2015 with a disclosed history of increased risk behavior (IRB) including intravenous drug use (IVDU), imprisonment and increased risk sexual behavior. RESULTS: Of 17 262 potential donors, 659 (3.8%) had IRB for BBV and 285 (1.7%) were seropositive for BBV, of whom half had a history of IRB (mostly IVDU [78.5%]). Of actual donors with IRB, 393 were seronegative for viral markers at time of donation. A history of recent IVDU was associated with fewer potential donors proceeding to become actual organ donors (64% vs 75%, P = 0.007). Donors with IRB provided 1091 organs for transplantation (624 kidneys and 467 other organs). Transplant outcome was similar in recipients of organs from donors with and without IRB. There were 3 cases of unexpected hepatitis C virus transmission, all from an active IVDU donor who was hepatitis C virus seronegative at time of donation, but was found to be viremic on retrospective testing. CONCLUSIONS: Donors with a history of IRB provide a valuable source of organs for transplantation with good transplant outcomes and there is scope for increasing the use of organs from such donors.The National Institute of Health Research, Blood and Transplant Research Unit (NIHR BTRU) on Organ Donation and Transplantation at the University of Cambridge in collaboration with Newcastle University and in partnership funded this research with NHS Blood and Transplant (NHSBT)

Trends in weight gain recorded in English primary care before and during the Coronavirus-19 pandemic: An observational cohort study using the OpenSAFELY platform

Background: Obesity and rapid weight gain are established risk factors for noncommunicable diseases and have emerged as independent risk factors for severe disease following Coronavirus Disease 2019 (COVID-19) infection. Restrictions imposed to reduce COVID-19 transmission resulted in profound societal changes that impacted many health behaviours, including physical activity and nutrition, associated with rate of weight gain. We investigated which clinical and sociodemographic characteristics were associated with rapid weight gain and the greatest acceleration in rate of weight gain during the pandemic among adults registered with an English National Health Service (NHS) general practitioner (GP) during the COVID-19 pandemic. Methods and findings: With the approval of NHS England, we used the OpenSAFELY platform inside TPP to conduct an observational cohort study of routinely collected electronic healthcare records. We investigated changes in body mass index (BMI) values recorded in English primary care between March 2015 and March 2022. We extracted data on 17,742,365 adults aged 18 to 90 years old (50.1% female, 76.1% white British) registered with an English primary care practice. We estimated individual rates of weight gain before (δ-prepandemic) and during (δ-pandemic) the pandemic and identified individuals with rapid weight gain (>0.5 kg/m2/year) in each period. We also estimated the change in rate of weight gain between the prepandemic and pandemic period (δ-change = δ-pandemic—δ-prepandemic) and defined extreme accelerators as the 10% of individuals with the greatest increase in their rate of weight gain (δ-change ≥1.84 kg/m2/year) between these periods. We estimated associations with these outcomes using multivariable logistic regression adjusted for age, sex, index of multiple deprivation (IMD), and ethnicity. P-values were generated in regression models. The median BMI of our study population was 27.8 kg/m2, interquartile range (IQR) [24.3, 32.1] in 2019 (March 2019 to February 2020) and 28.0 kg/m2, IQR [24.4, 32.6] in 2021. Rapid pandemic weight gain was associated with sex, age, and IMD. Male sex (male versus female: adjusted odds ratio (aOR) 0.76, 95% confidence interval (95% CI) [0.76, 0.76], p < 0.001), older age (e.g., 50 to 59 years versus 18 to 29 years: aOR 0.60, 95% CI [0.60, 0.61], p < 0.001]); and living in less deprived areas (least-deprived-IMD-quintile versus most-deprived: aOR 0.77, 95% CI [0.77, 0.78] p < 0.001) reduced the odds of rapid weight gain. Compared to white British individuals, all other ethnicities had lower odds of rapid pandemic weight gain (e.g., Indian versus white British: aOR 0.69, 95% CI [0.68, 0.70], p < 0.001). Long-term conditions (LTCs) increased the odds, with mental health conditions having the greatest effect (e.g., depression (aOR 1.18, 95% CI [1.17, 1.18], p < 0.001)). Similar characteristics increased odds of extreme acceleration in the rate of weight gain between the prepandemic and pandemic periods. However, changes in healthcare activity during the pandemic may have introduced new bias to the data. Conclusions: We found female sex, younger age, deprivation, white British ethnicity, and mental health conditions were associated with rapid pandemic weight gain and extreme acceleration in rate of weight gain between the prepandemic and pandemic periods. Our findings highlight the need to incorporate sociodemographic, physical, and mental health characteristics when formulating research, policies, and interventions targeting BMI in the period of post pandemic service restoration and in future pandemic planning

Effect of pre-exposure use of hydroxychloroquine on COVID-19 mortality: a population-based cohort study in patients with rheumatoid arthritis or systemic lupus erythematosus using the OpenSAFELY platform.

BACKGROUND: Hydroxychloroquine has been shown to inhibit entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into epithelial cells in vitro, but clinical studies found no evidence of reduced mortality when treating patients with COVID-19. We aimed to evaluate the effectiveness of hydroxychloroquine for prevention of COVID-19 mortality, as opposed to treatment for the disease. METHODS: We did a prespecified observational, population-based cohort study using national primary care data and linked death registrations in the OpenSAFELY platform, which covers approximately 40% of the general population in England, UK. We included all adults aged 18 years and older registered with a general practice for 1 year or more on March 1, 2020. We used Cox regression to estimate the association between ongoing routine hydroxychloroquine use before the COVID-19 outbreak in England (considered as March 1, 2020) compared with non-users of hydroxychloroquine and risk of COVID-19 mortality among people with rheumatoid arthritis or systemic lupus erythematosus. Model adjustment was informed by a directed acyclic graph. FINDINGS: Between Sept 1, 2019, and March 1, 2020, of 194 637 people with rheumatoid arthritis or systemic lupus erythematosus, 30 569 (15·7%) received two or more prescriptions of hydroxychloroquine. Between March 1 and July 13, 2020, there were 547 COVID-19 deaths, 70 among hydroxychloroquine users. Estimated standardised cumulative COVID-19 mortality was 0·23% (95% CI 0·18 to 0·29) among users and 0·22% (0·20 to 0·25) among non-users; an absolute difference of 0·008% (-0·051 to 0·066). After accounting for age, sex, ethnicity, use of other immunosuppressive drugs, and geographical region, no association with COVID-19 mortality was observed (HR 1·03, 95% CI 0·80 to 1·33). We found no evidence of interactions with age or other immunosuppressive drugs. Quantitative bias analyses indicated that our observed associations were robust to missing information for additional biologic treatments for rheumatological disease. We observed similar associations with the negative control outcome of non-COVID-19 mortality. INTERPRETATION: We found no evidence of a difference in COVID-19 mortality among people who received hydroxychloroquine for treatment of rheumatological disease before the COVID-19 outbreak in England. Therefore, completion of randomised trials investigating pre-exposure prophylactic use of hydroxychloroquine for prevention of severe outcomes from COVID-19 are warranted. FUNDING: Medical Research Council