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.

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.

The use of interferon-alpha in virus infections.

The interferons (IFN) act too slowly to arrest acute viral infections, but interferon-alpha (IFN alpha) preparations have proved useful in some chronic infections and will clearly be used increasingly in these in the future. In the preparations derived from human leucocytes or cultured B lymphoblastoid cells, which are in routine clinical use, mixtures of a number of distinct subtypes of human IFN alpha have been identified. There are also 3 slightly different versions of the same single subtype, IFN alpha-2, made by recombinant DNA procedures in bacteria. IFN alpha preparations are injected intramuscularly or subcutaneously. Dose-related side effects are common but usually tolerable, but prolonged treatment may cause increasing fatigue and depression. Some patients form neutralising antibodies which block the effects of the IFN; these appear to be relatively more common after recombinant IFN alpha-2 than after IFN derived from human cells. Given intranasally, IFN alpha can prevent a subsequent experimental rhinovirus infection, or the spread of natural colds within a family. Repeated administration progressively damages the nasal mucosa, so that long term prophylaxis is not possible. IFN alpha has proved useful in patients with papillomavirus warts of the larynx, ano-genital region (condyloma acuminata) and skin (common warts). Treatment regimens remain to be optimised and are likely to include surgery or other treatments. IFN alpha and zidovudine (azidothymidine) synergistically inhibit the growth of HIV in vitro, and combination are on trial in patients with early AIDS. Very large doses of IFN alpha are effective against Kaposi's sarcoma in some AIDS patients. In chronic hepatitis B, continuing virus replication may lead to cirrhosis or primary liver cancer. Earlier clinical trials with IFN alpha gave inconclusive results, but recent large studies have confirmed that 25 to 40% of patients obtain benefit; this probably results from both the antiviral and the immunomodulatory effects of IFN alpha. In patients with chronic hepatitis C, the biochemical markers usually improve rapidly during IFN alpha administration, but relapse if treatment is stopped after only a few months; to increase the chances of sustained cure, the treatment period is now being prolonged.

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.

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.

Temporary sequential atrioventricular pacing in myocardial infarction.

The loss of atrial contraction can seriously impair cardiac output when complete heart block follows myocardial infarction. We describe two cases in which temporary sequential atrioventricular pacing was lifesaving. The pacemaker used was a previously explanted internal pacemaker. By avoiding the need for an expensive dedicated temporary pacemaker this technique may be more widely applied.

IL-8 as a circulating cytokine: induction by recombinant tumour necrosis factor-alpha.

Tumour necrosis factor-alpha (TNF-alpha) is a pivotal cytokine at the centre of a cascade of cytokines and inflammatory mediators which modulate the host response to infection and trauma, and in particular the metabolic changes resulting in shock and subsequent multi-organ failure. The cytokine IL-8--predominantly an activator and chemotactic factor for circulating polymorphonuclear neutrophil leucocytes--is produced in response to TNF-alpha in vitro, and high circulating levels of IL-8 are found in septic primates. We have studied the release of IL-8 into the circulation of subjects with chronic hepatitis B undergoing a 10 week pilot trial of recombinant TNF-alpha (rTNF-alpha) therapy in doses of 15-100 micrograms/m2. A marked dose-dependent increase in plasma IL-8 levels was seen commencing at 30-60 min after the start of rTNF-alpha infusion and peaking between 2 and 3 h (mean peak level 4300 ng/l). The temporal pattern of IL-8 production exactly echoed that of IL-6, another component of the cytokine cascade, but peak plasma levels of IL-8 were up to 17 times higher than those of IL-6. This study confirms in vitro data suggesting that IL-8 is a component of the acute circulating cytokine cascade with a potential role in the modulation of the acute immune and metabolic response to infection and trauma.

Sarcoidosis presenting with an acute Guillain-Barré syndrome.

A 28 year old Caucasian male presented with an acute Guillain-Barré syndrome and bilateral facial weakness. He had an abnormal chest radiograph. Lumbar puncture revealed acellular fluid with a raised protein count and lung function tests showed a restrictive ventilatory defect. The patient deteriorated and required mechanical ventilation for 14 days. Steroids and plasmapheresis were not used and the patient spontaneously recovered. Two months after presentation limb power was almost normal but there was residual partial bilateral facial weakness. The chest radiograph remained abnormal and repeat lung function tests showed a persistent restrictive ventilatory defect and a reduced gas transfer coefficient. A transbronchial biopsy revealed non-caseating granulomata. The association between neurosarcoidosis and Guillain-Barré polyneuropathy is discussed and the literature reviewed.

Sarcoidosis and lymphoma.

Hodgkin's Disease may mimic sarcoidosis, as seen in this case report.

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.

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.

Metastatic uterine leiomyosarcoma in association with recurrent lung abscess.

A case of metastatic uterine leiomyosarcoma complicated by recurrent lung abscesses is described.

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.

Elevated plasma interleukin-6 and increased severity and mortality in alcoholic hepatitis.

Recent studies in alcoholic hepatitis have proposed a role for the cytokine tumour necrosis factor-alpha (TNF-alpha) a mediator of endotoxic shock in sepsis. In this study plasma levels of the closely related cytokine interleukin-6 (IL-6) were assayed in 96 samples from 58 patients with severe alcoholic hepatitis, and 69 patients in control groups (21 normal, 10 alcoholic without liver disease, 10 inactive alcoholic cirrhosis, 18 chronic liver disease, 10 chronic renal failure). Plasma IL-6 levels were markedly elevated in patients with alcoholic hepatitis when compared with all control groups (P less than 0.001). IL-6 levels were higher in patients who died (P = 0.04) and correlated with the features of severe disease including: increased grade of encephalopathy, increased neutrophil count, increased prothrombin ratio, hypotension, increased serum creatinine and increased serum bilirubin. Surprisingly, no correlation was found between levels of plasma IL-6 and plasma TNF-alpha or endotoxin, or the presence of infection; an inverse correlation was found between plasma IL-6 and serum globulins. These findings provide further evidence that the IL-6/TNF cytokine system is activated in severe alcoholic hepatitis and may mediate hepatic or extra-hepatic tissue damage.

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)