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The challenge that delegated legislation poses to parliamentary sovereignty and associated supremacy in the UK is purportedly addressed through what we term the 'constitutional bargain of delegated law-making'. This has three elements: the proper limitation of delegation by Parliament through well-designed parent legislation; the exercise of self-restraint by the Executive in the use of delegated authority; and the enablement of meaningful scrutiny by Parliament. As a paradigm situation in which delegated law-making might be said to be necessary, the first year of the Covid-19 pandemic is an apposite context in which to assess the robustness of that bargain. Our analysis uses a sample of Westminster-generated pandemic-related secondary instruments as a peephole into the broader dynamics of this constitutional bargain and further reveals its significant frailties; frailties that are exposed, but not created, by the pandemic. [ABSTRACT FROM AUTHOR]

There has been much speculation about the effects of the COVID-19 pandemic on the tourism sector. Common narratives have variously depicted an unprecedented crisis, a time of opportunity for innovation and transformation and a chance to build a 'new normal'. The aim of this paper is to investigate how owners and operators of micro- and small enterprises in tourism and hospitality in the United Kingdom made sense of the pandemic and its effects on their businesses. Situated in long-term research engagements with the businesses, three interlocking interpretative repertoires emerged from the analysis of 16 semi-structured interviews conducted between March and May 2021. Participants did not share a progress-driven approach to business change, there was no evidence of a radical 'new normal' emerging and COVID was not perceived as a crisis. While these findings appear counter-intuitive, their principal contribution is as a valid counterpoint to policy and academic discourse about COVID as crisis and opportunity. Furthermore, they highlight the importance of developing more nuanced accounts of the tourism business during and relating to the pandemic. Terms like 'crisis' and 'opportunity' used by policy-makers, practitioners and academics only partially reflect the deliberative efforts and practical perspectives of owners and operators of tourism enterprises. [ABSTRACT FROM AUTHOR]

Identification of genomic variability in population plays an important role in the clinical diagnostics of human genetic diseases. Thanks to rapid technological development in the field of massive parallel sequencing technologies, also known as next-generation sequencing (NGS), complex genomic analyses are now easier and cheaper than ever before, which consequently leads to more effective utilization of these techniques in clinical practice. However, interpretation of data from NGS is still challenging due to several issues caused by natural variability of DNA sequences in human populations. Therefore, development and realization of projects focused on description of genetic variability of local population (often called "national or digital genome") with a NGS technique is one of the best approaches to address this problem. The next step of the process is to share such data via publicly available databases. Such databases are important for the interpretation of variants with unknown significance or (likely) pathogenic variants in rare diseases or cancer or generally for identification of pathological variants in a patient's genome. In this paper, we have compiled an overview of published results of local genome sequencing projects from United Kingdom and Europe together with future plans and perspectives for newly announced ones. [ABSTRACT FROM AUTHOR]

Introduction: Recent years have seen a dramatic escalation of off-label prescribing for gabapentin and pregabalin (gabapentinoids) owing in part to generic versions of each being released over the past two decades, but also in part as a response to increasing calls for multimodal and non-opioid pain management strategies. In this context, several recent articles have been published alleging widespread misuse, with speculations on the unappreciated addictive potential of the gabapentinoid class of drugs. Reports of a 1% population-level abuse prevalence stem from a single internet survey in the UK, and the vanishingly small adverse event outcomes data do not support such frequency. In this targeted narrative review, we aim to disabuse pain physicians and other clinicians, pharmacists, and policymakers of both the positive and negative myths concerning gabapentinoid medications. Results: Gabapentinoids inhibit the joint action of voltage-gated calcium channel (VGCC) α2δ subunits in conjunction with the n-methyl-d-aspartate (NMDA) receptor, with subsequent downregulation of VGCC expression and excitatory neurotransmitter release, and possibly synaptogenesis as well, through actions on thrombospondins. These activities reduce the likelihood of central sensitization, which explains in part the efficacy of the gabapentinoids in the management of neuropathic pain. Gabapentinoids also facilitate slow-wave sleep, a relatively rare phenomenon among central nerve system-acting agents, which is also thought to explain some of the therapeutic benefit of the class in conditions such as fibromyalgia. The number needed to treat to see benefit overlaps that of the nonsteroidal anti-inflammatory drugs, but with a considerably improved safety profile. Along these lines, in the context of over 50 million prescriptions per year in the USA alone, the gabapentinoids display remarkably low risk, including risks of misuse, abuse, and dependence. Furthermore, the neurobiology of these agents does not lend plausibility to the allegations, as they have never been shown to elicit dopaminergic activity within the nucleus accumbens, and in addition likely confer a "negative-feedback loop" for habituation and dependence by serving as functional NMDA antagonists, possibly through their actions on thrombospondins. Clinical and epidemiological addictionology studies corroborate the lack of any significant addictive potential of the gabapentinoids, and these drugs are increasingly being used in the treatment of addiction to other substances, with excellent results and no evidence of cross-addiction. However, among individuals with other substance use disorders and, in particular opioid use disorder, there are consistent data showing misuse of gabapentinoids in up to 20% of this population. Although there are allegations of using gabapentinoids to amplify the hedonic effects of opioids, the vast majority of misuse events appear to occur in an attempt to ameliorate opioid withdrawal symptoms. Furthermore, rare but potentially serious respiratory depression may occur, again amplified in the context of opioid or other sedative use. Careful risk:benefit assessment and stratification are warranted when prescription of a gabapentinoid is under consideration, in particular among individuals using opioids. Conclusions: Gabapentinoids remain a vital tool in the pain physician's multimodal armamentarium, but these drugs may not be effective in every clinical situation. Individuals with central sensitization and pain associated with slow-wave sleep deficits and potentially persons with comorbid addictions may benefit the most. The gabapentinoids appear to possess no addictive potential on their own, based on laboratory and clinical data, but they may be abused by persons with opioid use disorders; consequently, cautious risk stratification must take place. [ABSTRACT FROM AUTHOR]

The Thames Estuary (UK) is an industrialized, macrotidal ecosystem characterized by a long history of metal pollution. Nevertheless, a holistic understanding of the metal fate is still missing. This study aims at identifying the main environmental mechanisms affecting metal behaviour in the Thames Estuary using copper and zinc as representative examples. A suite of multivariate statistical analyses performed on data from long-term monitoring of metal distribution in the estuary indicated that total metal concentrations are primarily correlated with suspended solids, being thus indirectly influenced by the interaction between freshwater discharge and the tide. These data were used to set up a three-dimensional hydrodynamic and water quality model to simulate the transport of sediments and metals within the estuary. Model results ratify that high metal concentrations might occur in the central part of the estuary as consequence of fine sediment resuspension. Such an effect of the hydrodynamics is highlighted by the differences between months characterized by low or high river discharge as well as neap or spring tide. We discuss the physical mechanisms of such transport processes and their direct implication for the management of sediment and metal contamination in estuarine areas especially in terms of long-term analysis. Developing a model able to assess future trends helps in planning the correct strategies for recovery and maintenance. Further research is needed to improve the accuracy of models of this kind as well as to investigate the potential effects of climate change for this and other similar systems. [ABSTRACT FROM AUTHOR]

Background: This study aimed to describe the management of cases of suspected and confirmed canine multicentric lymphoma (ML) in first opinion practice (FOP) and investigate whether socioeconomic factors are associated with initial management., Methods: Clinical narratives from electronic health records collected by the Small Animal Veterinary Surveillance Network (SAVSNET) were searched to identify dogs with peripheral lymphadenomegaly in which ML was the major differential. Cases were grouped as either ML confirmed (ML-C) or ML suspected but not confirmed (ML-S). Associations between initial management and socioeconomic factors were assessed via multivariable logistic regression., Results: Two hundred and sixty-four cases with ML-C and 410 with ML-S were identified. There was an increased probability that owners of ML-C cases resided in less deprived areas. Moreover, a diagnosis was made more commonly in insured dogs. Only insured pets were more likely to be treated with chemotherapy following diagnosis. The majority of dogs in both groups were treated with corticosteroids alone (ML-S, n = 256/410; ML-C, n = 123/264). A small minority were referred (n = 30/674)., Conclusion: Socioeconomic inequalities appear to be associated with the diagnosis and management of dogs with suspected or confirmed ML in FOP. Most dogs with suspected multicentric lymphoma (in the UK) are managed in FOP (n = 644/674). Consequently, expanding the knowledge base relevant to this setting offers an opportunity to improve the management of canine lymphoma., (© 2022 British Veterinary Association.)

The United Kingdom's (UK's) imminent departure from the European Union (EU) has a further but usually overlooked consequence: The UK will also be leaving the various global fora where it has been represented with other Member States of the EU. In many cases, the UK will still have to comply with the global regulatory tools, including norms and standards, made by these fora. The UK's departure from the EU thus raises the more general question of how those formally outside the fora that set global norms and standards can navigate membership procedures in order to become involved in setting them. This article focuses on the example of the International Council on Harmonisation (ICH) and its work in harmonizing good clinical practice (GCP) in relation to clinical trials for pharmaceuticals. By reference to this example, the article underlines the importance of the ICH to global standard-setting for GCP and the importance of engagement in this forum by those that do not have a formal role in setting the standards, but that must abide by them nonetheless if they are to trade globally. Subsequently, the article explains the formal procedures for membership and involvement in standard-setting. In doing so, the article aims to provide a roadmap towards membership and a say in global standard-setting. [ABSTRACT FROM AUTHOR]

The combined impact of common and rare exonic variants in COVID-19 host genetics is currently insufficiently understood. Here, common and rare variants from whole-exome sequencing data of about 4000 SARS-CoV-2-positive individuals were used to define an interpretable machine-learning model for predicting COVID-19 severity. First, variants were converted into separate sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. The Boolean features selected by these logistic models were combined into an Integrated PolyGenic Score that offers a synthetic and interpretable index for describing the contribution of host genetics in COVID-19 severity, as demonstrated through testing in several independent cohorts. Selected features belong to ultra-rare, rare, low-frequency, and common variants, including those in linkage disequilibrium with known GWAS loci. Noteworthily, around one quarter of the selected genes are sex-specific. Pathway analysis of the selected genes associated with COVID-19 severity reflected the multi-organ nature of the disease. The proposed model might provide useful information for developing diagnostics and therapeutics, while also being able to guide bedside disease management., (© 2021. The Author(s).)

Objectives:To evaluate the frequency of personality disorders in Parkinson's disease (PD) patients and in a group of healthy controls. Methods: Patients affected by PD diagnosed according to the United Kingdom Parkinson's disease Society Brain Bank diagnostic criteria and a group of healthy controls were enrolled in the study. PD patients with cognitive impairment were excluded from the study. Structured Clinical Interview for Personality Disorders-II (SCID-II) has been performed to evaluate the presence of personality disorders. Presence of personality disorders, diagnosed according to the DSM-IV, was confirmed by a psychiatric interview. Clinical and pharmacological data were also recorded using a standardized questionnaire. Results:100 PD patients (57 men; mean age 59.0610.2 years) and 100 healthy subjects (52 men; mean age 58.1611.4 years) were enrolled in the study. The most common personality disorder was the obsessive-compulsive personality disorder diagnosed in 40 PD patients and in 10 controls subjects (p-value,0.0001) followed by the depressive personality disorder recorded in 14 PD patients and 4 control subjects (p-value 0.02). Obsessive-compulsive personality disorder was also found in 8 out of 16 de novo PD patients with a short disease duration. Conclusion:PD patients presented a high frequency of obsessive-compulsive personality disorder that does not seem to be related with both disease duration and dopaminergic therapy. [ABSTRACT FROM AUTHOR]

There has been increasing recognition that diet plays an important role in the pathogenesis of prostate cancer. Despite this, the largely heterogenous nature of prostate cancer and nutritional research often means that no definitive conclusions can be drawn for those seeking answers in this important topic. In this review article, we summarize the key evidence available in this topic to date. Although we found mounting evidence on certain nutritional components being important in prostate cancer prevention and progression, further high quality studies are needed to fully understand the complex nature of diet and prostate cancer. • There is now increasing evidence that diet plays a major role in prostate cancer biology and tumorigenesis. • In a health conscious society, it is becoming increasingly common for Urologists to be asked about the impact of diet on prostate cancer. • In the present review, we explore the current evidence for the role of different dietary components and its' effect on prostate cancer prevention and progression. • A literature search was conducted using PubMed® to identify key studies. • There was some evidence to suggest that green tea, isoflavones, lycopenes, cruciferous vegetables and omega 3 polyunsaturated fatty acid intake to be beneficial in the prevention and/or progression of prostate cancer. • There was also evidence to suggest that a high total fat, meat (especially well cooked) and multivitamin intake may be associated with an increased risk of developing prostate cancer. • To date publications have been highly heterogeneous and variable in quality and design. More robust, high quality research trials are needed to help us understand the complex relationship between diet and prostate cancer. [ABSTRACT FROM AUTHOR]

Hepatitis G virus (HGV) is a flavivirus that can cause acute hepatitis and persistent infection but its role in chronic liver disease or primary liver cancer is unproven. In this study we have examined the prevalence of HGV RNA in the serum of patients with hepatitis C virus (HCV) infection and in patients with cryptogenic chronic liver disease, including non-alcoholic steatohepatitis (NASH), and in patients with HCV-related hepatocellular carcinoma (HCC) and HCC arising in patients with cryptogenic liver disease. One-hundred and thirty patients who were positive for antibody to HCV (anti-HCV), 54 patients with cryptogenic chronic liver disease (including 17 patients with NASH) and 46 patients with hepatitis C-related (n=27) or cryptogenic liver disease-related HCC (n=19) were studied. HGV RNA was detected using nested reverse transcriptase–polymerase chain reaction (RT–PCR) and was found in 16.1% of patients with HCV infection. HGV RNA was not detected in any patient with cryptogenic liver disease. In patients with HCC, 7/34 samples were positive for HGV RNA and six out of seven HGV-positive subjects also had HCV infection. Only one patient with HCC in cryptogenic liver disease was positive for HGV RNA. Hence, cryptogenic liver disease in the UK is not caused by HGV/GBVc infection. It seems unlikely that HGV plays a significant role in hepatocarcinogenesis. [ABSTRACT FROM AUTHOR]