The early impact of the UK's new alcohol taxation system on product strength and price: an exploratory comparative descriptive study.

OBJECTIVES: We explored the early impact of changes to the UK alcohol tax system, implemented in August 2023, on the strength and price of alcoholic products available for sale on the website of the largest supermarket in England. STUDY DESIGN: Our comparative descriptive study using longitudinal brand-level data was not preregistered and should be considered exploratory. METHODS: Data were collected weekly (May to October 2023) using automated web scraping tools. Outcomes were product strength (% alcohol by volume [ABV]) and price (per 10 mL of pure alcohol and per litre of product). We undertook paired t-tests, two-sample Kolmogorov-Smirnov tests, and quantile regression to compare outcomes before and after the tax changes. Beer, cider, spirits, and ready-to-drinks (RTDs) were analysed separately. RESULTS: There was a reduction in the mean strength of beer, driven by manufacturers reformulating a small number of weaker beers, moving them into a lower tax band (<3.5%ABV). The mean price per 10 mL of alcohol and per litre of product was significantly higher after the new tax system for beer, cider, and spirits and significantly lower for RTDs. Increases in the price of beer tended to occur across the entire distribution, whereas increases in the price of cider occurred among more expensive products. CONCLUSIONS: Changes to product strength tended to occur among weaker products near the new lowest tax band, suggesting tax bands may be a potential stimulus for change. Reformulation of stronger products would have better public health potential. Longer term monitoring, including data on purchasing/consumption, is required.

The independent and joint risks of alcohol consumption, smoking, and excess weight on morbidity and mortality: a systematic review and meta-analysis exploring synergistic associations.

OBJECTIVE: Alcohol consumption, smoking, and excess weight independently increase the risk of morbidity/mortality. Less is known about how they interact. This research aims to quantify the independent and joint associations of these exposures across health outcomes and identify whether these associations are synergistic. STUDY DESIGN: The protocol for this systematic review and meta-analysis was pre-registered (PROSPERO CRD42021231443). METHODS: Medline and Embase were searched between 1 January 2010 and 9 February 2022. Eligible peer-reviewed observational studies had to include adult participants from Organisation for Co-Operation and Development countries and report independent and joint associations between at least two eligible exposures (alcohol, smoking, and excess weight) and an ICD-10 outcome (or equivalent). For all estimates, we calculated the synergy index (SI) to identify whether joint associations were synergistic. Meta-analyses were conducted for outcomes with sufficiently homogenous data. RESULTS: The search returned 26,290 studies, of which 98 were included. Based on 138,130 participants, the combined effect (SI) of alcohol and smoking on head and neck cancer death/disease was 3.78 times greater than the additive effect of each exposure (95% confidence interval [CI] = 2.61, 5.48). Based on 2,603,939 participants, the combined effect of alcohol and excess weight on liver disease/death was 1.55 times greater than the additive effect of each exposure (95% CI = 1.33, 1.82). CONCLUSION: Synergistic associations suggest the true population-level risk may be underestimated. In the absence of bias, individuals with multiple risks would experience a greater absolute risk reduction from an intervention that targets a single exposure than individuals with a single risk.

Sexual assault and coincident alcohol use in attendees at a genitourinary medicine clinic in the south of England.

To investigate the relationship between alcohol consumption and the experience of sexual assault, either as victim or perpetrator, among genitourinary (GU) medicine department attendees in Portsmouth, UK, we carried out a cross-sectional survey of consecutive patients attending the walk-in service when a researcher was available. Self-completed questionnaires were used and anonymized data were collected from 1186 participants (response rate 34%). Responses showed that 15.6% of female and 3.7% of male participants had ever being sexually assaulted. Women who reported sexual assault drank more on a heavy night out than those who did not report sexual assault (mean 21.3 versus 17.0 units, P = 0.041). Over half of the victims had been drinking prior to the relevant assault. Twenty-seven participants (2.3%) admitted to having sex with a person who was not fully willing. Of these, 59% had been drinking prior to the assault, and the majority believed alcohol had contributed to the assault. Any strategies aiming to reduce the incidence of sexual assault must address hazardous drinking as a high priority.

A drunk and disorderly country: a nationwide cross-sectional survey of alcohol use and misuse in Great Britain.

OBJECTIVES: To explore current alcohol drinking patterns, behaviours and attitudes in Great Britain. DESIGN AND SETTING: Independent online cross-sectional survey. PATIENTS AND INTERVENTIONS: Survey of 2221 individuals from a representative panel. MAIN OUTCOME MEASURES AND RESULTS: Excessive alcohol consumption is a widespread problem across Great Britain. Binge-drinking is common among 18-24 year olds, with 19% reporting drinking 10+ drinks on the same drinking day. 'Pre-loading' with alcohol at home before going out was reported by 30% of 18-24-year-old drinkers, of whom 36% get drunk twice or more a month, with 27% having injured themselves while drunk. Among older drinkers, 25% regularly drink to excess, 8% drink seven or more drinks on a typical drinking day and 9% self-reported drink-driving. Male gender was an independent risk factor for heavy (>40 units/week) alcohol abuse (odds ratio 3.05 (95% CI 1.82 to 5.10)). Men (19%) were more likely than women (8%, p<0.001) to report binge-drinking, drink-driving (11% vs 3%, p<0.001), or to have missed work owing to alcohol consumption (12% vs 7%, p<0.001). Young drinkers said they were heavily influenced by overall alcohol price and drink promotions. Increasing average weekly alcohol consumption, age <55 years, male gender, never having been married and being in full-time employment were all independently associated with a history of alcohol-related self-harm. Alcohol abuse was not related to socioeconomic status. CONCLUSIONS: Alcohol abuse remains common across all socioeconomic strata and geographical areas of Great Britain. Minimum pricing strategies and interventions that target cheap on-trade alcohol products seem likely to bring major public health benefits.

Hepatic fibrosis and cirrhosis in the Fontan circulation: a detailed morphological study.

AIMS: To describe the histological features of the liver in patients with a Fontan circulation. METHODS: Specimens from liver biopsies carried out as part of preoperative assessment prior to extracardiac cavopulmonary conversion of an older style Fontan were examined and scored semi-quantitatively for pertinent histological features. To support the use of the scoring, biopsy specimens were also ranked by eye for severity to allow correlation with assigned scores. RESULTS: Liver biopsy specimens from 18 patients with a Fontan circulation were assessed. All specimens showed sinusoidal fibrosis. In 17 cases there was at least fibrous spur formation, with 14 showing bridging fibrosis and 2 showing frank cirrhosis. In 17 cases at least some of the dense or sinusoidal fibrosis was orcein positive, although a larger proportion of the dense fibrous bands were orcein positive compared with the sinusoidal component. All specimens showed marked sinusoidal dilatation, and 14 showed bile ductular proliferation; 1 showed minimal iron deposition, and 1 showed mild lobular lymphocytic inflammation. There was no cholestasis or evidence of hepatocellular damage. Similar appearances were observed in 2 patients with severe tricuspid regurgitation. DISCUSSION: The histological features of the liver in patients with a Fontan circulation are similar to those described in cardiac sclerosis. Sinusoidal dilatation and sinusoidal fibrosis are marked in the Fontan series. The presence of a significant amount of orcein negative sinusoidal fibrosis suggests there may be a remediable component, although the dense fibrous bands are predominantly orcein positive, suggesting chronicity and permanence. No inflammation or hepatocellular damage is evident, suggesting that fibrosis may be mediated by a non-inflammatory mechanism.

Case report of an arterioportal fistula, presenting with accelerated decompensation and sepsis, twenty-six years after initial liver biopsy.

We describe the case of a 55-year-old lady who presented with accelerated hepatic decompensation from an arterioportal fistula (APF). There is histological evidence the APF proceeded a percutaneous liver biopsy performed 26 years ago. She had shown no symptoms or signs of liver disease in the intervening period. The clinical presentation initially was that of portal hypertension but evolved into a systemic inflammatory response syndrome associated with renal and liver failure. We describe how the APF was embolised by interventional radiology and how the timing of this decision was a balance between reversing abnormal haemodynamics and trying to avoid instrumentation of a potentially septic environment. This unusual case reflects the relationship between portal hypertension, sepsis and renal failure.

Distribution of the interleukin-8 receptors, CXCR1 and CXCR2, in inflamed gut tissue.

There is increasing evidence to suggest that the potent neutrophil chemoattractant interleukin-8 (IL-8) has an important role in the pathogenesis of inflammatory bowel disease. IL-8 mediates its actions via two cell surface receptors, CXCR1 and CXCR2. This paper describes the distribution of these IL-8 receptors in the normal gastrointestinal tract and how this is modified in ulcerative colitis (UC). Paraffin-embedded colonic resection specimens were stained with monoclonal antibodies directed against CXCR1 and CXCR2 in ten cases of total UC, 16 cases of appendicitis, and 11 histologically normal sections. A semiquantitative scale of 0-4 was used to assess the proportion and intensity of positively stained cells within certain defined areas of tissue. A comparative assessment was made of the distribution of various cell populations. Dual immunostaining was used to confirm the phenotype of positively staining cells. In the histologically normal colon, the antibody against CXCR1 stained a subpopulation of macrophages deep to the epithelium and germinal centre lymphocytes. A similar pattern of staining was seen in acute appendicitis, with in addition some positively stained neutrophil polymorphs. In UC, there was up-regulation of CXCR1, with a striking increase in positively stained macrophages throughout the mucosa and of B and T lymphocytes outside the germinal centre areas. There was also intense up-regulation of CXCR1 expression by the luminal epithelium, reflected in the epithelial staining score (mean+/-SE=1.8+/-0.44 for UC cases, vs. 0.23+/-0.16 for controls and 0.25+/-0.14 for acute appendicitis). CXCR2 was only expressed on a small population of lamina propria mononuclear cells and crypt epithelial cells, with no significant differences observed between the groups. These results suggest that IL-8 may, through CXCR1, have a role beyond neutrophil recruitment in mediating the immune response in UC and that this is not merely a consequence of the acute inflammation seen in UC.

Primary rat and mouse hepatic stellate cells express the macrophage inhibitor cytokine interleukin-10 during the course of activation In vitro.

Activation of local tissue macrophages (Kupffer cells) and of quiescent hepatic stellate cells (HSCs) to a myofibroblast phenotype are two key events in liver inflammation and fibrosis. It is known that products of activated macrophages may activate stellate cells. We have hypothesized that the products of activated HSCs may also modulate the activity of Kupffer cells. The cytokine interleukin-10 (IL-10), produced by lymphocytes and macrophages, has profound inhibitory actions on macrophages. Normal rat and mouse HSCs that differentiate in vivo and in vitro to activated myofibroblasts were isolated by enzyme perfusion and density centrifugation with or without centrifugal elutriation, confirmed by vitamin A autofluorescence and positive immunostaining for the myofibroblast markers desmin and smooth muscle actin (SMA). Conditioned media and lysates from these cells were found to down-regulate lipopolysaccharide (LPS)-induced tumor necrosis factor- (TNF-) secretion by the mouse macrophage line RAW 267.4. In highly purified preparations of rat HSCs, messenger RNA (mRNA) for IL-10 was detected by reverse-transcription polymerase chain reaction (RT-PCR), from the time of isolation to up to 120 days of culture on plastic. Long-term cultures of unstimulated mouse HSCs secreted IL-10 protein as detected by immunoblotting and specific enzyme-linked immunosorbent assay (ELISA). IL-10 protein was undetectable by immunohistochemistry in mouse HSCs for the first 3 days in culture. After this, the percentage of IL-10-positive cells increased to 45% at day 7 and 100% by day 14, and expression of IL-10 continued in long-term cultures of up to 120 days. The expression of IL-10 by the stromal cells that govern the fibrotic process in the liver may have important implications for the regulation of inflammation and fibrosis in the liver.

Interleukin-10 expression and function in experimental murine liver inflammation and fibrosis.

Kupffer cells (KC) play a central role in the initiation and perpetuation of hepatic inflammation, which, if uncontrolled, can result in tissue damage, fibrosis, and cirrhosis. Interleukin-10 (IL-10) can inhibit a range of macrophage functions. We hypothesized that the transcription, synthesis, and release of IL-10 may influence the development of liver injury. Rat KC were activated in vitro with lipopolysaccharide (LPS), and expression of IL-10 mRNA compared with IL-13 and IL-1beta by reverse-transcription polymerase chain reaction (RT-PCR). The effects of pretreatment with recombinant IL-10 (rIL-10) on KC phagocytosis, production of superoxide (SO), and tumor necrosis factor (TNF-) were examined by fluorescent activated cell sorter (FACS), reduction of ferricytochrome C, and bioassay, respectively. Rats were administered intraperitoneal carbon tetrachloride (CCl4), and expression of IL-10 mRNA and protein in vivo compared with IL-13 and IL-1beta by RT-PCR and immunoblotting. Results were correlated with histological inflammatory changes. Finally, IL-10 gene-deleted (IL-10-/-) mice and wild-type (WT) controls were administered intraperitoneal CCl4 biweekly for up to 70 days, and the development of inflammation and fibrosis compared by scoring histological changes. IL-10 mRNA was up-regulated early, both in KC in vitro and in whole liver in vivo, concurrent with that of IL-1beta. IL-10 was able to inhibit KC production of both SO and TNF- in vitro, and this was achieved more effectively than IL-4 or IL-13; no such effects were seen on KC phagocytosis. After 70 days of treatment with CCl4, IL-10-/- mice showed significantly more severe fibrosis and exhibited higher hepatic TNF- levels than WT controls. These results suggest that IL-10 synthesized during the course of liver inflammation and fibrosis may modulate KC actions, and influence subsequent progression of fibrosis.

Regulation of interleukin-8 binding and function by heparin and alpha2-macroglobulin.

BACKGROUND: Increased expression of interleukin-8 (IL-8), a potent neutrophil chemoattractant, is associated with a number of inflammatory diseases. Interleukin-8 binds to the glycosaminoglycan (GAG) heparin and the protease inhibitor alpha2-macroglobulin, molecules which regulate the function of a number of cytokines. Heparan sulphate was previously shown to enhance neutrophil chemotactic responses to IL-8. OBJECTIVE: The purpose of this study was to investigate the effect of heparin, heparan sulphate and alpha2-macroglobulin on IL-8 binding to neutrophils and subsequent functional effects in vitro. METHODS: The binding of 125I-IL-8 to normal neutrophils at 4 degrees C was studied and the IL-8 induced neutrophil chemotactic response was investigated using micro-Boyden chambers. Complexation of IL-8 with alpha2-macroglobulin was confirmed using gel filtration chromatography. RESULTS: Heparin, but not heparan sulphate, inhibited the binding of 125I-IL-8 to neutrophils (IC50=26 microg/mL) and IL-8 induced neutrophil chemotactic responses (IC50=4 microg/mL). The specific inhibitory effect of heparin was apparently due to an interaction with IL-8 which was charge-dependent, since dextran sulphate had a greater inhibitory effect on chemotactic responses (IC50=2 microg/mL) and FITC-heparin did not bind to neutrophils. The heparin-induced inhibition of IL-8 binding and chemotactic responses was reversed in a dose-dependent manner in the presence of alpha2-macroglobulin. The binding of 125I-IL-8 to neutrophils in the presence of alpha2-macroglobulin appears to be, in part, through the specific IL-8 receptor. CONCLUSION: These results point to an anti-inflammatory role for heparin and a novel, potentially, pro-inflammatory role for alpha2-macroglobulin which together indicate the importance of cytokine-binding macromolecules in determining net cytokine function.

Chemokine levels in human liver homogenates: associations between GRO alpha and histopathological evidence of alcoholic hepatitis.

Alcoholic hepatitis is characterized by parenchymal neutrophil infiltration. Hepatic synthesis of the neutrophil chemokine interleukin-8 (IL-8) is highly elevated in alcoholic hepatitis and levels correlate with the degree of neutrophil infiltration. The aim of this study was to further determine the spectrum of synthesis of chemokines in liver tissue from patients with alcoholic liver disease and a range of disease control subjects. Subjects were composed of 24 patients with alcoholic liver disease of whom 15 had histopathological evidence of alcoholic hepatitis (10 cirrhotic) and 9 no evidence of alcoholic hepatitis (5 cirrhotic); other controls included; normal liver (n = 6), viral hepatitis (n = 16), primary biliary cirrhosis (n = 5), acute liver failure (n = 4), and miscellaneous liver disease (n = 13). Levels of the C-X-C neutrophil chemokine GRO alpha and the mononuclear cell C-C chemokines: macrophage inflammatory protein 1 alpha, macrophage chemotactic protein 1 and RANTES, were determined by ELISA in liver homogenates. Levels of the neutrophil chemokine GRO alpha were specifically elevated (mean 46 pg/mg, compared with normal liver 11 pg/mg) in patients with alcoholic hepatitis. GRO alpha levels correlated with IL-8 levels and were higher in patients with alcoholic liver disease and parenchymal neutrophil infiltration. Hepatic RANTES was elevated in diseased liver, with the highest levels found in viral hepatitis (mean 117 pg/mg, compared with 24 pg/mg in normal liver). No significant changes in hepatic levels of macrophage inflammatory protein 1 alpha (MIP-1 alpha) or macrophage chemotactic protein 1 (MCP-1) were found. These data provide further supportive evidence that parenchymal neutrophil infiltration in alcoholic hepatitis may be determined by selective upregulation of C-X-C chemokine synthesis.

Plasma inhibitory activity against tumour necrosis factor in fulminant hepatic failure.

1. Soluble tumour necrosis factor receptors released into the circulation inhibit the effects of excess tumour necrosis factor-alpha and represent an important protective response. 2. In this study we have measured the levels of tumour necrosis factor and soluble tumour necrosis factor receptors p55 and p75 in the plasma of 10 patients with fulminant hepatic failure and 10 healthy control subjects. The capacity of the plasmas at varying dilutions to inhibit the biological activity of 1000 pg/ml of recombinant tumour necrosis factor in a tumour necrosis factor cytotoxicity assay in vitro was also determined. 3. The mean plasma levels of tumour necrosis factor in patients with fulminant hepatic failure (48.4 +/- 10.9 pg/ml) were significantly increased compared with normal control subjects (6.1 +/- 1.04 pg/ml, P < 0.01). Plasma soluble tumour necrosis factor receptors p55 and p75 were also significantly elevated in patients with fulminant hepatic failure (18.16 +/- 9.94 ng/ml and 16.06 +/- 9.93 ng/ml respectively) when compared with normal control subjects (1.28 +/- 0.24 ng/ml and 1.62 +/- 0.91 ng/ml, P < 0.001). 4. Fulminant hepatic failure plasma had a much lower capacity to inhibit tumour necrosis factor bioactivity in vitro, with a statistically significant difference between the inhibitory capacity of the fulminant hepatic failure and normal plasma seen at plasma dilutions of 1:5 and 1:20 (P < 0.05). 5. The reduced tumour necrosis factor neutralization capacity observed in fulminant hepatic failure, despite the increased levels of soluble tumour necrosis factor receptors, suggests enhanced susceptibility to the potential deleterious effects of tumour necrosis factor in fulminant hepatic failure.

Circulating and tissue levels of the neutrophil chemotaxin interleukin-8 are elevated in severe acute alcoholic hepatitis, and tissue levels correlate with neutrophil infiltration.

Acute alcoholic hepatitis is characterized by a unique degree of liver neutrophil infiltration, often accompanied by marked peripheral neutrophilia in the absence of demonstrable bacterial or fungal infection. In this study we assayed plasma and tissue levels of a potent neutrophil activator and chemotaxin, interleukin-8, in patients with a spectrum of alcoholic liver diseases and in normal and diseased control subjects. Levels of circulating interleukin-8 were undetectable in normal subjects but highly elevated in patients with alcoholic hepatitis, particularly in those who died (geometric mean = 600 ng/L; confidence interval = 323 to 1,120 vs. geometric mean = 184 ng/L; confidence interval = 114 to 309 in survivors). Levels correlated with biochemical indicators of severe disease (bilirubin: R = 0.38; international prothrombin ratio: R = 0.28; white blood cell count: R = 0.35; creatinine: R = 0.34) and with tumor necrosis factor-alpha (R = 0.43) and soluble tumor necrosis factor receptors (p55; R = 0.59). In contrast, moderate elevations in the levels of circulating interleukin-8 were seen in alcoholic cirrhosis (geometric mean = 93 ng/L; confidence interval = 40 to 213) and in alcoholic patients undergoing alcohol withdrawal (geometric mean = 137 ng/L; confidence interval = 72 to 259). Levels in nonalcoholic inflammatory liver disease were comparatively low (geometric mean = 17 ng/L; confidence interval = 10 to 29).(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of supernatants from Kupffer cells stimulated with galactosamine and endotoxin on the function of isolated rat hepatocytes.

Activated Kupffer cells may release substances that are involved in liver injury induced by galactosamine and endotoxin. In the present study Kupffer cells were isolated from rat livers, cultured for 24 hours and incubated with galactosamine, endotoxin (LPS) or tumor necrosis factor-alpha for 4 or 24 hours. The Kupffer cell-conditioned media were than added in separate experiments to freshly prepared isolated rat hepatocytes to determine their cytotoxic effect. No significant effects on the rate of protein synthesis, as assessed by the incorporation of 14C-leucine on lactate dehydrogenase enzyme release from hepatocytes during 1 h incubation was found as compared with conditioned media from control Kupffer cells. In further experiments, Kupffer cells incubated for 4 hours with LPS and galactosamine were shown to produce thromboxane B2 and also the potentially cytoprotective prostaglandins PGE2 and small amounts of prostacyclin measured as 6-keto-PGF1 alpha. It is concluded that under the conditions of the present experiments, factors secreted by cultured Kupffer cells have no cytotoxic effects on isolated rat hepatocytes during short-term incubation.

Concentrations of interleukin 6 and tumour necrosis factor in serum and stools of children with Shigella dysenteriae 1 infection.

Serum interleukin 6 (IL-6) and tumour necrosis factor (TNF) were measured in children with dysentery during an epidemic caused by Shigella dysenteriae 1. IL-6 and TNF were also measured in fresh stool filtrates from children with acute gastroenteritis. The median serum IL-6 concentration was raised significantly in the children with complications (haemolytic uraemic syndrome, leukemoid reaction, thrombocytopenia, thrombocytosis, and severe colitis lasting more than one week) during the first week (n = 18, 9-7728 pg/ml; median 107) and in the second week (n = 13, 5-312 pg/ml; median 77), compared with convalescent sera (n = 10, < 3-85 pg/ml; median 39; p < 0.02 and < 0.05 respectively). The median IL-6 concentration during the first week was significantly higher in the group with complicated disease than in those with no complications (n = 8, < 3-37 pg/ml; median 5; p < 0.001). Although serum TNF concentrations were significantly raised in the complicated group during the first and second weeks of the illness and in the uncomplicated group compared with convalescence, there was no significant difference in the TNF concentrations between the complicated and uncomplicated groups. IL-6 was detectable in stool filtrates from eight of 13 children with S dysenteriae 1 infection and four of eight children with S flexneri infection. It was not detectable in Cryptosporidia, rotavirus, or adenovirus infections, those with pathogen-negative acute diarrhoea or controls. Seven of 13 children with S dysenteriae 1 and three of nine children with S flexneri infections had TNF detectable in stools. None of the children with Salmonella, Cryptosporidia, rotavirus of children with pathogen-negative diarrhoea and controls had detectable TNF in stool filtrates. It is postulated that the local and generalised vasculitis observed in shigellosis may be related to a direct effect of Shiga toxin on endothelial cells or caused by cytokine production stimulated by endotoxin, or both.