Search

Summary: Background: Vitamin D deficiency has been associated with non‐alcoholic fatty liver disease (NAFLD). However, the role of polymorphisms determining vitamin D status remains unknown. Objectives: The objectives of this study were to determine in UK children with biopsy‐proven NAFLD (i) their vitamin D status throughout a 12‐month period and (ii) interactions between key vitamin D‐related genetic variants (nicotinamide adenine dinucleotide synthase‐1/dehydrocholesterol reductase‐7, vitamin D receptor, group‐specific component, CYP2R1) and disease severity. Methods: In 103 paediatric patients with NAFLD, serum 25‐hydroxyvitamin D (25OHD) levels and genotypes were determined contemporaneously to liver biopsy and examined in relation to NAFLD activity score and fibrosis stage. Results: Only 19.2% of children had adequate vitamin D status; most had mean 25OHD levels considered deficient (<25 nmol·L−1, 25.5%) or insufficient (<50 nmol·L−1, 55.3%). Patients had significantly lower 25OHD levels in winter months (95% CI: 22.7–31.2 nmol·L−1) when compared with spring (30.5–42.1 nmol·L−1; P = 0.0089), summer (36.3–47.2 nmol·L−1; P < 0.0001) and autumn (34.2–47.5 nmol·L−1; P = 0.0003). Polymorphisms in the nicotinamide adenine dinucleotide synthase‐1/dehydrocholesterol reductase‐7 (rs3829251, rs12785878) and vitamin D receptor (rs2228570) genes were independently associated with increased steatosis; while a group‐specific component variant (rs4588) was associated with increased inflammation in liver biopsies. Conclusions: Children with NAFLD in the UK have particularly low winter vitamin D status, with vitamin D insufficiency prevalent throughout the year. Polymorphisms in the vitamin D metabolic pathway are associated with histological severity of paediatric NAFLD. [ABSTRACT FROM AUTHOR]

Since the start of the COVID-19 pandemic, numerous variants of SARS-CoV-2 have been reported worldwide. The advent of variants of concern (VOCs) raises severe concerns amid the serious containment efforts against COVID-19 that include physical measures, pharmacological repurposing, immunization, and genomic/community surveillance. Omicron variant (B.1.1.529) has been identified as a highly modified, contagious, and crucial variant among the five VOCs of SARS-CoV-2. The increased affinity of the spike protein (S-protein), and host receptor, angiotensin converting enzyme-2 (ACE-2), due to a higher number of mutations in the receptor-binding domain (RBD) of the S-protein has been proposed as the primary reason for the decreased efficacy of majorly available vaccines against the Omicron variant and the increased transmissible nature of the Omicron variant. Because of its significant competitive advantage, the Omicron variant and its sublineages swiftly surpassed other variants to become the dominant circulating lineages in a number of nations. The Omicron variant has been identified as a prevalent strain in the United Kingdom and South Africa. Furthermore, the emergence of recombinant variants through the conjunction of the Omicron variant with other variants or by the mixing of the Omicron variant's sublineages/subvariants poses a major threat to humanity. This raises various issues and hazards regarding the Omicron variant and its sublineages, such as an Omicron variant breakout in susceptible populations among fully vaccinated persons. As a result, understanding the features and genetic implications of this variant is crucial. Hence, we explained in depth the evolution and features of the Omicron variant and analyzed the repercussions of spike mutations on infectiousness, dissemination ability, viral entry mechanism, and immune evasion. We also presented a viewpoint on feasible strategies for precluding and counteracting any future catastrophic emergence and spread of the omicron variant and its sublineages that could result in a detrimental wave of COVID-19 cases. [Display omitted] • The emergence of the Omicron variant and its sublineages pose a severe threat. • Significant number of mutations in the Omicron variant has been associated. • The Omicron variant might have evolved separately from all the previous variants. • Omicron and other variants may generate resistant variants to present vaccines. • Genomic surveillance and Omicron-specific vaccines are containment measures. [ABSTRACT FROM AUTHOR]

Objectives: This study was designed to determine the use of dental services and factors associated with their use among the United Kingdoms' older population.Design: A national study involving 1,116 older people (aged 60 or older).Setting: Home Interviews were undertaken exploring the time and reason for last dental visit. In addition, socio-demographic characteristics and proxy oral health measures (self-reported number of teeth and edentulous status) of the respondents were collected.Results: Forty seven percent (528) claimed they visited the dentist within the past year, 10% (116) claimed that the reason for their last visit was because of a dental emergency, 43% (484) were classified as "regular attenders"--having attended the dentist within the past year for a non dental emergency. Bivariate analysis identified that regular dental attendance was associated with age (P < 0.01), social class (P < 0.01), income level (P < 0.01), educational attainment (P < 0.01), self-reported number of teeth possessed (P < 0.01) and edentulous status (P < 0.01). In regression analysis, self reported edentulous status and number of teeth possessed emerged as the most important factors in determining service utilisation. Possessing a full denture was associated with a 6-fold decrease, having accounted for other factors, in the likelihood of attending the dentist within the past year for a non dental-emergency (OR = 0.15, CI 0.10, 0.21).Conclusion: Less than half of the sample population were "regular dental attenders", their attendance was associated with a number of socio-demographic and oral health factors. In particular, edentulous state was a major factor associated with their use of services. [ABSTRACT FROM AUTHOR]

Previous studies have failed to identify mutations in the Wilson’s disease gene ATP7B in a significant number of clinically diagnosed cases. This has led to concerns about genetic heterogeneity for this condition but also suggested the presence of unusual mutational mechanisms. We now present our findings in 181 patients from the United Kingdom with clinically and biochemically confirmed Wilson’s disease. A total of 116 different ATP7B mutations were detected, 32 of which are novel. The overall mutation detection frequency was 98%. The likelihood of mutations in genes other than ATP7B causing a Wilson’s disease phenotype is therefore very low. We report the first cases with Wilson’s disease due to segmental uniparental isodisomy as well as three patients with three ATP7B mutations and three families with Wilson’s disease in two consecutive generations. We determined the genetic prevalence of Wilson’s disease in the United Kingdom by sequencing the entire coding region and adjacent splice sites of ATP7B in 1000 control subjects. The frequency of all single nucleotide variants with in silico evidence of pathogenicity (Class 1 variant) was 0.056 or 0.040 if only those single nucleotide variants that had previously been reported as mutations in patients with Wilson’s disease were included in the analysis (Class 2 variant). The frequency of heterozygote, putative or definite disease-associated ATP7B mutations was therefore considerably higher than the previously reported occurrence of 1:90 (or 0.011) for heterozygote ATP7B mutation carriers in the general population (P < 2.2 × 10-16 for Class 1 variants or P < 5 × 10-11 for Class 2 variants only). Subsequent exclusion of four Class 2 variants without additional in silico evidence of pathogenicity led to a further reduction of the mutation frequency to 0.024. Using this most conservative approach, the calculated frequency of individuals predicted to carry two mutant pathogenic ATP7B alleles is 1:7026 and thus still considerably higher than the typically reported prevalence of Wilson’s disease of 1:30 000 (P = 0.00093). Our study provides strong evidence for monogenic inheritance of Wilson’s disease. It also has major implications for ATP7B analysis in clinical practice, namely the need to consider unusual genetic mechanisms such as uniparental disomy or the possible presence of three ATP7B mutations. The marked discrepancy between the genetic prevalence and the number of clinically diagnosed cases of Wilson’s disease may be due to both reduced penetrance of ATP7B mutations and failure to diagnose patients with this eminently treatable disorder. [ABSTRACT FROM AUTHOR]

The article focuses on the use of hepatocyte transplantation for patients with metabolic liver disease in Great Britain. It also discusses the sources of hepatocytes, the isolation process, preclinical studies and clinical experience, especially in the treatment of liver-based inborn errors of metabolism. The outcome of hepatocyte transplantation would benefit from methods to enhance engraftment and subsequent repopulation of the liver, although the options for this in man will be limited.

Aim: To determine utilisation patterns and calculate treatment Failure and discontinuation rates in patients with open angle glaucoma treated in the United Kingdom with any of six groups of intraocular pressure (IOP) lowering agents. Methods: The UK General Practice Research Database was used to identify newly diagnosed (after 1 January 1997) open angle glaucoma patients who were naive to therapy with any of six index drug groups: carbonic anhydrase inhibitors, latanoprast, miotics, sympathomimetics, timolol, and other (non-timolol) β blockers. Analyses included drug treatment data for 1 year following diagnosis. Outcomes were (1) time to therapy failure, defined as either change in index drug (replacement or addition of therapy) or patient referral for surgery, and (2) time to therapy discontinuation, defined as either therapy failure or no refill of the index drug in a period twice that covered by the first prescription fill. Cox proportional hazard regression and Kaplan-Meier and life table methods were used to compare groups. Results: Among the 2001 eligible patients, a β blocker other than timolol was the most widely prescribed (42%), followed by timolol (32%), carbonic anhydrase inhibitors (10%), and latanoprost (7%). Compared to latanoprost, those treated with any alternative agent were significantly more likely to fail (p ⩽ 0.005 for each comparison) and to discontinue (p ⩽ 0.05 for each comparison) therapy. Failure rates ranged from 13% (latanoprost) 45% (sympathomimetics), and discontinuation rates ranged from 30% (latanoprost) to 63% (miotics). Conclusion: Latanoprost treated - demonstrated lower rates of therapy failure and therapy discontinuation compared with patients treated with other widely used IOP lowering medications, including β blockers. [ABSTRACT FROM AUTHOR]

Compares birth weights of infants of first generation Indian and Pakistani women with those of infants of second generation Asian women. Retrospective case note study of births at the Bolton District General Hospital in England; Lowering of perinatal mortality in children of second generation Asians.

This Review, in addressing the unacceptably high mortality of patients with liver disease admitted to acute hospitals, reinforces the need for integrated clinical services. The masterplan described is based on regional, geographically sited liver centres, each linked to four to six surrounding district general hospitals-a pattern of care similar to that successfully introduced for stroke services. The plan includes the establishment of a lead and deputy lead clinician in each acute hospital, preferably a hepatologist or gastroenterologist with a special interest in liver disease, who will have prime responsibility for organising the care of admitted patients with liver disease on a 24/7 basis. Essential for the plan is greater access to intensive care units and high-dependency units, in line with the reconfiguration of emergency care due to the COVID-19 pandemic. This Review strongly recommends full implementation of alcohol care teams in hospitals and improved working links with acute medical services. We also endorse recommendations from paediatric liver services to improve overall survival figures by diagnosing biliary atresia earlier based on stool colour charts and better caring for patients with impaired cognitive ability and developmental mental health problems. Pilot studies of earlier diagnosis have shown encouraging progress, with 5-6% of previously undiagnosed cases of severe fibrosis or cirrhosis identified through use of a portable FibroScan in primary care. Similar approaches to the detection of early asymptomatic disease are described in accounts from the devolved nations, and the potential of digital technology in improving the value of clinical consultation and screening programmes in primary care is highlighted. The striking contribution of comorbidities, particularly obesity and diabetes (with excess alcohol consumption known to be a major factor in obesity), to mortality in COVID-19 reinforces the need for fiscal and other long delayed regulatory measures to reduce the prevalence of obesity. These measures include the food sugar levy and the introduction of the minimum unit price policy to reduce alcohol consumption. Improving public health, this Review emphasises, will not only mitigate the severity of further waves of COVID-19, but is crucial to reducing the unacceptable burden from liver disease in the UK. [ABSTRACT FROM AUTHOR]

This final report of the Lancet Commission into liver disease in the UK stresses the continuing increase in burden of liver disease from excess alcohol consumption and obesity, with high levels of hospital admissions which are worsening in deprived areas. Only with comprehensive food and alcohol strategies based on fiscal and regulatory measures (including a minimum unit price for alcohol, the alcohol duty escalator, and an extension of the sugar levy on food content) can the disease burden be curtailed. Following introduction of minimum unit pricing in Scotland, alcohol sales fell by 3%, with the greatest effect on heavy drinkers of low-cost alcohol products. We also discuss the major contribution of obesity and alcohol to the ten most common cancers as well as measures outlined by the departing Chief Medical Officer to combat rising levels of obesity-the highest of any country in the west. Mortality of severely ill patients with liver disease in district general hospitals is unacceptably high, indicating the need to develop a masterplan for improving hospital care. We propose a plan based around specialist hospital centres that are linked to district general hospitals by operational delivery networks. This plan has received strong backing from the British Association for Study of the Liver and British Society of Gastroenterology, but is held up at NHS England. The value of so-called day-case care bundles to reduce high hospital readmission rates with greater care in the community is described, along with examples of locally derived schemes for the early detection of disease and, in particular, schemes to allow general practitioners to refer patients directly for elastography assessment. New funding arrangements for general practitioners will be required if these proposals are to be taken up more widely around the country. Understanding of the harm to health from lifestyle causes among the general population is low, with a poor knowledge of alcohol consumption and dietary guidelines. The Lancet Commission has serious doubts about whether the initiatives described in the Prevention Green Paper, with the onus placed on the individual based on the use of information technology and the latest in behavioural science, will be effective. We call for greater coordination between official and non-official bodies that have highlighted the unacceptable disease burden from liver disease in England in order to present a single, strong voice to the higher echelons of government. [ABSTRACT FROM AUTHOR]

This article presents information on the implementation of the recommendations in the "Lancet" Commission report on the diagnosis, prevention and treatment of liver disease in Great Britain. It discusses the slow in progress of implementing improvements in the expertise of general practitioners in liver disease to facilitate earler diagnosis and treatment, and the improvement in hepatology staffing and standards of patient care in the hospital service. INSETS: Panel 1: Summary of the ten key recommendations;Panel 2: Liver activity in the UK, 2014-15.

The article offers a look at the actions launched to address the prevalence of liver disease in Great Britain. It describes the efforts launched to reduce premature mortality and achieve excellence in health care. It also considers the consumption of alcohol, and the prevalence of obesity and viral hepatitis in Great Britain.

Liver involvement in sickle cell disease (SCD) is often referred to as sickle cell hepatopathy (SCH) and is a complication of SCD which may be associated with significant mortality. This review is based on a round-table workshop between paediatric and adult hepatologists and haematologists and review of the literature. The discussion was prompted by the lack of substantial data and guidance in managing these sometimes very challenging cases. This review provides a structured approach for the diagnosis and management of SCH in children and young adults. The term SCH describes any hepatobiliary dysfunction in the context of SCD. Diagnosis and management of biliary complications, acute hepatic crisis, acute hepatic sequestration and other manifestations of SCH are discussed, as well as the role of liver transplantation and haemopoietic stem cell transplantation in the management of SCH., Competing Interests: Competing interests: EK, FL, EF, MDa, NHe, SH, MS, FM, VB, AS, AV, MV, BI, ED, NHa, TG, JH, MDe, MS and AD have nothing to disclose. DR is on advisory boards of Novartis and DSMB of AstraZeneca outside the submitted work. GG reports personal fees from Alexion Pharmaceuticals outside the submitted work. SC reports personal fees from Novartis outside the submitted work. VB reports personal fees from Bluebirdbio and from Addmedica, outside the submitted work., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Previous studies have failed to identify mutations in the Wilson's disease gene ATP7B in a significant number of clinically diagnosed cases. This has led to concerns about genetic heterogeneity for this condition but also suggested the presence of unusual mutational mechanisms. We now present our findings in 181 patients from the United Kingdom with clinically and biochemically confirmed Wilson's disease. A total of 116 different ATP7B mutations were detected, 32 of which are novel. The overall mutation detection frequency was 98%. The likelihood of mutations in genes other than ATP7B causing a Wilson's disease phenotype is therefore very low. We report the first cases with Wilson's disease due to segmental uniparental isodisomy as well as three patients with three ATP7B mutations and three families with Wilson's disease in two consecutive generations. We determined the genetic prevalence of Wilson's disease in the United Kingdom by sequencing the entire coding region and adjacent splice sites of ATP7B in 1000 control subjects. The frequency of all single nucleotide variants with in silico evidence of pathogenicity (Class 1 variant) was 0.056 or 0.040 if only those single nucleotide variants that had previously been reported as mutations in patients with Wilson's disease were included in the analysis (Class 2 variant). The frequency of heterozygote, putative or definite disease-associated ATP7B mutations was therefore considerably higher than the previously reported occurrence of 1:90 (or 0.011) for heterozygote ATP7B mutation carriers in the general population (P < 2.2 × 10(-16) for Class 1 variants or P < 5 × 10(-11) for Class 2 variants only). Subsequent exclusion of four Class 2 variants without additional in silico evidence of pathogenicity led to a further reduction of the mutation frequency to 0.024. Using this most conservative approach, the calculated frequency of individuals predicted to carry two mutant pathogenic ATP7B alleles is 1:7026 and thus still considerably higher than the typically reported prevalence of Wilson's disease of 1:30 000 (P = 0.00093). Our study provides strong evidence for monogenic inheritance of Wilson's disease. It also has major implications for ATP7B analysis in clinical practice, namely the need to consider unusual genetic mechanisms such as uniparental disomy or the possible presence of three ATP7B mutations. The marked discrepancy between the genetic prevalence and the number of clinically diagnosed cases of Wilson's disease may be due to both reduced penetrance of ATP7B mutations and failure to diagnose patients with this eminently treatable disorder.