This report contains new and follow-up metric data relating to the eight main recommendations of the Lancet Standing Commission on Liver Disease in the UK, which aim to reduce the unacceptable ...harmful consequences of excess alcohol consumption, obesity, and viral hepatitis. For alcohol, we provide data on alcohol dependence, damage to families, and the documented increase in alcohol consumption since removal of the above-inflation alcohol duty escalator. Alcoholic liver disease will shortly overtake ischaemic heart disease with regard to years of working life lost. The rising prevalence of overweight and obesity, affecting more than 60% of adults in the UK, is leading to an increasing liver disease burden. Favourable responses by industry to the UK Government's soft drinks industry levy have been seen, but the government cannot continue to ignore the number of adults being affected by diabetes, hypertension, and liver disease. New direct-acting antiviral drugs for the treatment of chronic hepatitis C virus infection have reduced mortality and the number of patients requiring liver transplantation, but more screening campaigns are needed for identification of infected people in high-risk migrant communities, prisons, and addiction centres. Provision of care continues to be worst in regions with the greatest socioeconomic deprivation, and deficiencies exist in training programmes in hepatology for specialist registrars. Firm guidance is needed for primary care on the use of liver blood tests in detection of early disease and the need for specialist referral. This report also brings together all the evidence on costs to the National Health Service and wider society, in addition to the loss of tax revenue, with alcohol misuse in England and Wales costing £21 billion a year (possibly up to £52 billion) and obesity costing £27 billion a year (treasury estimates are as high as £46 billion). Voluntary restraints by the food and drinks industry have had little effect on disease burden, and concerted regulatory and fiscal action by the UK Government is essential if the scale of the medical problem, with an estimated 63 000 preventable deaths over the next 5 years, is to be addressed.
Abstract Conducting polymers have been developed as substrates for in vitro studies with a range of cell types including electrically-excitable cells such as nerve and smooth muscle. The goal of this ...study was to optimise and characterise a range of polypyrrole materials to act as substrates for electrical stimulation of differentiating skeletal myoblasts. Although all of the polymer materials provided suitable substrates for myoblast adhesion and proliferation, significant differences became apparent under the low-serum conditions used for differentiation of primary myoblasts. The significance of the work lies in the design and control of polymer materials to facilitate different stages of skeletal muscle cell proliferation and/or differentiation, opening up opportunities for engineering of this tissue. This paper therefore constitutes not just a biocompatibility assessment but a comprehensive study of how synthesis conditions affect the final outcome in terms of cell response.
Chimeric antigen receptor (CAR) T cells have demonstrated promising efficacy, particularly in hematologic malignancies. One challenge regarding CAR T cells in solid tumors is the immunosuppressive ...tumor microenvironment (TME), characterized by high levels of multiple inhibitory factors, including transforming growth factor (TGF)-β. We report results from an in-human phase 1 trial of castration-resistant, prostate cancer-directed CAR T cells armored with a dominant-negative TGF-β receptor (NCT03089203). Primary endpoints were safety and feasibility, while secondary objectives included assessment of CAR T cell distribution, bioactivity and disease response. All prespecified endpoints were met. Eighteen patients enrolled, and 13 subjects received therapy across four dose levels. Five of the 13 patients developed grade ≥2 cytokine release syndrome (CRS), including one patient who experienced a marked clonal CAR T cell expansion, >98% reduction in prostate-specific antigen (PSA) and death following grade 4 CRS with concurrent sepsis. Acute increases in inflammatory cytokines correlated with manageable high-grade CRS events. Three additional patients achieved a PSA reduction of ≥30%, with CAR T cell failure accompanied by upregulation of multiple TME-localized inhibitory molecules following adoptive cell transfer. CAR T cell kinetics revealed expansion in blood and tumor trafficking. Thus, clinical application of TGF-β-resistant CAR T cells is feasible and generally safe. Future studies should use superior multipronged approaches against the TME to improve outcomes.
Some neuropsychiatric disease, including schizophrenia, may originate during prenatal development, following periods of gestational hypoxia and placental oxidative stress. Here we investigated if ...gestational hypoxia promotes damaging secretions from the placenta that affect fetal development and whether a mitochondria-targeted antioxidant MitoQ might prevent this. Gestational hypoxia caused low birth-weight and changes in young adult offspring brain, mimicking those in human neuropsychiatric disease. Exposure of cultured neurons to fetal plasma or to secretions from the placenta or from model trophoblast barriers that had been exposed to altered oxygenation caused similar morphological changes. The secretions and plasma contained altered microRNAs whose targets were linked with changes in gene expression in the fetal brain and with human schizophrenia loci. Molecular and morphological changes in vivo and in vitro were prevented by a single dose of MitoQ bound to nanoparticles, which were shown to localise and prevent oxidative stress in the placenta but not in the fetus. We suggest the possibility of developing preventative treatments that target the placenta and not the fetus to reduce risk of psychiatric disease in later life.
Summary Background Daclizumab, a humanised monoclonal antibody, reduced multiple sclerosis disease activity in previous non-randomised studies. We aimed to assess whether daclizumab reduces disease ...activity in patients with active relapsing multiple sclerosis who are receiving interferon beta treatment. Methods We did a phase 2, randomised, double-blind, placebo-controlled study at 51 centres in the USA, Canada, Germany, Italy, and Spain. Patients with active relapsing multiple sclerosis who were taking interferon beta were randomly assigned to receive add-on subcutaneous daclizumab 2 mg/kg every 2 weeks (interferon beta and high-dose daclizumab group), daclizumab 1 mg/kg every 4 weeks (interferon beta and low-dose daclizumab group), or interferon beta and placebo for 24 weeks. The randomisation scheme was generated by Facet Biotech. All patients and assessors were masked to treatment with the exception of Facet Biotech bioanalysts who prepared data for the data safety monitoring board or generated pharmacokinetic or pharmacodynamic data, a drug accountability auditor, and the site pharmacist. The primary endpoint was total number of new or enlarged gadolinium contrast-enhancing lesions measured on brain MRI scans every 4 weeks between weeks 8 and 24. Effects of daclizumab on prespecified subsets of lymphocytes and quantitative T-cell proliferative response were assessed in an exploratory pharmacodynamic substudy. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov , number NCT00109161. Findings From May, 2005, to March, 2006, 288 patients were assessed for eligibility, and 230 were randomly assigned to receive interferon beta and high-dose daclizumab (n=75), interferon beta and low-dose daclizumab (n=78), or interferon beta and placebo (n=77). The adjusted mean number of new or enlarged gadolinium contrast-enhancing lesions was 4·75 in the interferon beta and placebo group compared with 1·32 in the interferon beta and high-dose daclizumab group (difference 72%, 95% CI 34% to 88%; p=0·004) and 3·58 in the interferon beta and low-dose daclizumab group (25%, −76% to 68%; p=0·51). In the pharmacodynamic substudy, daclizumab was not associated with significant changes in absolute numbers of T cells, B cells, or natural killer cells, or T-cell proliferative response compared with interferon beta alone. The number of CD56bright natural killer cells was seven to eight times higher in both daclizumab groups than in the interferon beta and placebo group (interferon beta and low-dose daclizumab group p=0·002; interferon beta and high-dose daclizumab group p<0·0001). Common adverse events were equally distributed across groups. Interpretation Add-on daclizumab treatment reduced the number of new or enlarged gadolinium contrast-enhancing lesions compared with interferon beta alone and might reduce multiple sclerosis disease activity to a greater extent than interferon beta alone. Funding Facet Biotech and Biogen Idec.
Based on records dating from 1859 to 2021, we provide an overview of the marine animal diversity reported for Galiano Island, British Columbia, Canada. More than 650 taxa are represented by 20,000 ...species occurrence records in this curated dataset, which includes dive records documented through the Pacific Marine Life Surveys, museum voucher specimens, ecological data and crowd-sourced observations from the BC Cetacean Sightings Network and iNaturalist.
We describe Galiano Island's marine animal diversity in relation to the Salish Sea's overall biodiversity and quantify the proportional contributions of different types of sampling effort to our current local knowledge. Overviews are provided for each taxonomic group in a format intended to be accessible to amateur naturalists interested in furthering research into the region's marine biodiversity. In summary, we find that the Pacific Marine Life Surveys, a regional community science diving initiative, account for 60% of novel records reported for Galiano Island. Voucher specimens account for 19% and crowd-sourced biodiversity data 18% of novel records, respectively, with the remaining 3% of reports coming from other sources. These findings shed light on the complementarity of different types of sampling effort and demonstrate the potential for community science to contribute to the global biodiversity research community. We present a biodiversity informatics framework that is designed to enable these practices by supporting collaboration among researchers and communities in the collection, curation and dissemination of biodiversity data.
Outer surface protein C (OspC) plays a pivotal role in mediating tick-to-host transmission and infectivity of the Lyme disease spirochete, Borreliella burgdorferi. OspC is a helical-rich homodimer ...that interacts with tick salivary proteins, as well as components of the mammalian immune system. Several decades ago, it was shown that the OspC-specific monoclonal antibody, B5, was able to passively protect mice from experimental tick-transmitted infection by B. burgdorferi strain B31. However, B5's epitope has never been elucidated, despite widespread interest in OspC as a possible Lyme disease vaccine antigen. Here, we report the crystal structure of B5 antigen-binding fragments (Fabs) in complex with recombinant OspC type A (OspC
). Each OspC monomer within the homodimer was bound by a single B5 Fab in a side-on orientation, with contact points along OspC's α-helix 1 and α-helix 6, as well as interactions with the loop between α-helices 5 and 6. In addition, B5's complementarity-determining region (CDR) H3 bridged the OspC-OspC' homodimer interface, revealing the quaternary nature of the protective epitope. To provide insight into the molecular basis of B5 serotype specificity, we solved the crystal structures of recombinant OspC types B and K and compared them to OspC
. This study represents the first structure of a protective B cell epitope on OspC and will aid in the rational design of OspC-based vaccines and therapeutics for Lyme disease.
The spirochete Borreliella burgdorferi is a causative agent of Lyme disease, the most common tickborne disease in the United States. The spirochete is transmitted to humans during the course of a tick taking a bloodmeal. After B. burgdorferi is deposited into the skin of a human host, it replicates locally and spreads systemically, often resulting in clinical manifestations involving the central nervous system, joints, and/or heart. Antibodies directed against B. burgdorferi's outer surface protein C (OspC) are known to block tick-to-host transmission, as well as dissemination of the spirochete within a mammalian host. In this report, we reveal the first atomic structure of one such antibody in complex with OspC. Our results have implications for the design of a Lyme disease vaccine capable of interfering with multiple stages in B. burgdorferi infection.
Researchers should accept research grants from the food industry, write Paul Aveyard and Derek Yach, but Anna B Gilmore and Simon Capewell say that it biases science
OBJECTIVESExploration of experience of harms due to another person's drinking within a demographic particularly vulnerable to these consequences. Importance of study: Largest sampling of young ...Australian risky drinkers, who are underrepresented in general population surveys. The range of harms due to others' drinking reported here is more comprehensive than documented elsewhere. STUDY TYPECross-sectional self-report survey. METHODSParticipants were 14-19 years old and screened as being within the riskiest-drinking 25% for their age cohort. The convenience sample of 3465 was recruited primarily by social media advertising. Face-to-face interviews were conducted in all eight Australian capital cities (n = 596), supplemented by online surveys (n = 2869). Past 12-month experience of 13 harms due to others' drinking was assessed by age, gender and perpetrator. RESULTSFemales were more likely to experience seven harms, mainly characterised by fear and harassment, including being harassed or bothered at a party or some other private setting (41% vs 34% of males, p < 0.001), being given unwanted sexual attention (71% vs 47%, p < 0.001) and being put in fear (33% vs 20%, p < 0.001). Males were more likely to experience three harms, characterised by aggression: being yelled at, criticised or verbally abused (38% vs 33% of females, p = 0.002), being pushed or shoved (42% vs 28%, p < 0.001) and being physically hurt (17% vs 11%, p < 0.001). Teenagers of a legal alcohol-purchase age were more likely to experience harassment in public settings (49% vs 32-34%, p < 0.001) and unwanted sexual attention (66% vs 51-59%, p < 0.001) compared with younger teenagers. Seven of the harms studied were more likely (p < 0.01) to be perpetrated by people the respondents knew, and five (those associated with fear and aggression) were more likely to be perpetrated by strangers. CONCLUSIONYoung people who are risky drinkers commonly experience multiple harms from others' drinking. Many of these alcohol harms to others are reported here for the first time, as previous studies of adolescent drinking have focused almost exclusively on the harms young people have experienced from their own drinking. This refocusing on the harms caused by the drinking of others may prompt greater community concern and concomitant calls for better alcohol regulation.
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