Respiratory syncytial virus and other vaccine-preventable infections in Multiple Myeloma. A population-based study on 8672 myeloma patients diagnosed 2008-2021 from the Swedish Myeloma Registry.

Not available.

The rainbow connection: Disrupting background affect, overcoming barriers and emergent emotional collectives at "Pride in London".

This article focuses on a large-scale parade in the UK that is often overlooked in research concerned with the sociology of political emotions and group dynamics; "Pride in London". This is an annual parade celebrating, and raising awareness about, the LGBTQ+ community and commemorating the Stonewall riots. Following a brief description of the study context, participants and methods, the article illustrates the use of reflexive thematic analysis of 23 interviewee accounts of the parade. Analysis of emotional habitus and affective practices preceding, and on the day of, the parade offer an insight into the manifestation of collective emotion. Three themes are developed exploring the use of recognizable and emotive symbols, physicality of embodied emotion and spatial arrangement and the encompassing nature of group emotion. Finally, the interplay between background and foreground emotion is explored as a way of understanding and demonstrating the fluidity and temporality of affective experience and expression when people are engaged in collective action at a social justice event.

Thyroid dysfunction in preterm neonates exposed to iodine.

BACKGROUND: Infants <32 weeks' gestation should not be exposed to topical iodine and its avoidance is recommended during pregnancy and breast feeding. Exposure to contrast media and topical iodine is frequently used in many preterm neonates. AIM: To determine whether thyrotropin levels in preterm infants are affected by exposure to intrapartum/neonatal topical iodine and/or the use of iodinated contrast media. DESIGN: Infants <32 weeks' gestation were recruited. Maternal and neonatal exposures to iodinated contrast media and topical iodine were recorded; levels of thyrotropin and thyroxine were measured from blood-spot cards on postnatal days 7, 14, 28 and the equivalent of 36 weeks' gestation. RESULTS: One hundred and twenty-five infants were exposed to topical iodine/contrast media and 48 infants were unexposed. No infants were treated for hypothyroidism; three infants (exposed group) had transient hyperthyrotropinaemia. Mean thyrotropin levels were significantly higher on postnatal days 7, 14 and 28 in infants exposed to topical iodine prior to caesarean section compared to unexposed infants, a relationship which persisted after adjustment. CONCLUSIONS: In the context of this study, neonatal thyroid dysfunction was seen following exposure to iodine via caesarean section but not via exposure to contrast media.

Establishment and molecular characterisation of seven novel soft-tissue sarcoma cell lines.

BACKGROUND: Soft-tissue sarcomas (STS) are a diverse group of malignancies that remain a diagnostic and therapeutic challenge. Relatively few reliable cell lines currently exist. Rapidly developing technology for genomic profiling with emerging insights into candidate functional (driver) aberrations raises the need for more models for in vitro functional validation of molecular targets. METHODS: Primary cell culture was performed on STS tumours utilising a differential attachment approach. Cell lines were characterised by morphology, immunocytochemistry, proliferation assays, short tandem repeat (STR) and microarray-based genomic copy number profiling. RESULTS: Of 47 STS cases of various subtypes, half formed adherent monolayers. Seven formed self-immortalised cell lines, including three undifferentiated pleomorphic sarcomas, two dedifferentiated liposarcomas (one of which had received radiotherapy), a leiomyosarcoma and a myxofibrosarcoma. Two morphologically distinct yet genetically identical variants were established in separate cultures for the latter two tumours. All cell lines demonstrated genomic and phenotypic features that not only confirm their malignant characteristics but also confirm retention of DNA copy number aberrations present in their parent tumours that likely include drivers. CONCLUSIONS: These primary cell lines are much-needed additions to the number of reliable cell lines of STS with complex genomics available for initial functional validation of candidate molecular targets.

Physical Activity Is Prospectively Associated With Adolescent Nonalcoholic Fatty Liver Disease.

OBJECTIVES: The aim of the present study was to assess whether objectively measured physical activity at mean ages 12 and 14 years are prospectively associated with ultrasound scan liver fat and stiffness (alanine aminotransferase, aspartate aminotransferase [AST], and γ-glutamyl transferase [GGT]) assessed at mean age 17.8 years. METHODS: Participants were from the Avon Longitudinal Study of Parents and Children. Total physical activity (counts per minute) and minutes of moderate to vigorous physical activity (MVPA) were measured using ActiGraph accelerometers at mean ages 12 and 14 years. RESULTS: Greater total physical activity and MVPA at ages 12 and 14 years were associated with lower odds of liver fat and lower GGT levels at mean age 17.8 years, such as per 15-minute increase in daily MVPA at age 12 years, the confounder adjusted odds ratio of liver fat was 0.47 (95% confidence interval [CI] 0.27-0.84). Associations attenuated after additional adjustment for fat mass as a potential confounder (eg, per 15-minute increase in daily MVPA at age 12 years, the odds ratio of liver fat attenuated to 0.65 [95% CI 0.35-1.21]) or a potential mediator (eg, per 15-minute increase in daily MVPA at age 12 years the odds ratio of liver fat attenuated to 0.59 [95% CI 0.32-1.09]). Results did not further attenuate after additional adjustment for insulin resistance. There was some evidence that greater total physical activity and MVPA at age 12 years were associated with the higher AST levels. CONCLUSIONS: Adolescents who were more active in childhood have lower odds of fatty liver and lower GGT levels. These findings are likely to be, at least in part, explained by adiposity.

Childhood energy intake is associated with nonalcoholic fatty liver disease in adolescents.

BACKGROUND: Greater adiposity is an important risk factor for nonalcoholic fatty liver disease (NAFLD). Thus, it is likely that dietary intake is involved in the development of the disease. Prospective studies assessing the relation between childhood dietary intake and risk of NAFLD are lacking. OBJECTIVE: This study was designed to explore associations between energy, carbohydrate, sugar, starch, protein, monounsaturated fat, polyunsaturated fat, saturated fat, and total fat intake by youth at ages 3, 7, and 13 y and subsequent (mean age: 17.8 y) ultrasound scan (USS)-measured liver fat and stiffness and serum alanine aminotransferase, aspartate aminotransferase, and γ-glutamyltransferase. We assessed whether observed associations were mediated through fat mass at the time of outcome assessment. METHODS: Participants were from the Avon Longitudinal Study of Parents and Children. Trajectories of energy and macronutrient intake from ages 3-13 y were obtained with linear-spline multilevel models. Linear and logistic regression models examined whether energy intake and absolute and energy-adjusted macronutrient intake at ages 3, 7, and 13 y were associated with liver outcomes. RESULTS: Energy intake at all ages was positively associated with liver outcomes; for example, the odds of having a USS-measured liver fat per 100 kcal increase in energy intake at age 3 y were 1.79 (95% CI: 1.14, 2.79). Associations between absolute macronutrient intake and liver outcomes were inconsistent and attenuated to the null after adjustment for total energy intake. The majority of associations attenuated to the null after adjustment for fat mass at the time liver outcomes were assessed. CONCLUSION: Higher childhood and early adolescent energy intake is associated with greater NAFLD risk, and the macronutrients from which energy intake is derived are less important. These associations appear to be mediated, at least in part, by fat mass at the time of outcome assessment.

Weight trajectories through infancy and childhood and risk of non-alcoholic fatty liver disease in adolescence: the ALSPAC study.

BACKGROUND & AIMS: Adiposity is a key risk factor for NAFLD. Few studies have examined prospective associations of infant and childhood adiposity with subsequent NAFLD risk. We examined associations of weight-for-height trajectories from birth to age 10 with liver outcomes in adolescence, and assessed the extent to which associations are mediated through fat mass at the time of outcome assessment. METHODS: Individual trajectories of weight and height were estimated for participants in the Avon Longitudinal Study of Parents and Children using random-effects linear-spline models. Associations of birthweight (adjusted for birth length) and weight change (adjusted for length/height change) from 0-3 months, 3 months-1 y, 1-3 y, 3-7 y, and 7-10 y with ultrasound scan (USS) determined liver fat and stiffness, and serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT) at mean age 17.8 y were assessed with linear and logistic regressions. Mediation by concurrent fat mass was assessed with adjustment for fat mass at mean age 17.8 y. RESULTS: Birth weight was positively associated with liver stiffness and negatively with ALT and AST. Weight change from birth to 1 y was not associated with outcomes. Weight change from 1-3 y, 3-7 y, and 7-10 y was consistently positively associated with USS and blood-based liver outcomes. Adjusting for fat mass at mean age 17.8 y attenuated associations toward the null, suggesting associations are largely mediated by concurrent body fatness. CONCLUSIONS: Greater rates of weight-for-height change between 1 y and 10 y are consistently associated with adverse liver outcomes in adolescence. These associations are largely mediated through concurrent fatness.

Treatment of non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is now the commonest cause of chronic liver disease in developed countries. Treatment depends on the stage of disease, and non-invasive methods for risk stratification are urgently needed. Lifestyle modification (aimed at weight loss and increasing physical activity) and management of the features of metabolic syndrome are vital for all patients with NAFLD. Metformin is the first-line therapy for diabetic patients with NAFLD and also reduces the risk of hepatocellular carcinoma. Clinicians should have a low threshold for introducing a statin for the management of dyslipidaemia. Antihypertensive agents that target the renin-angiotensin system should be first-line in NAFLD for the management of hypertension. For patients with progressive disease, liver-directed pharmacotherapy with vitamin E should be considered. Non-alcoholic steatohepatitis cirrhosis is an increasingly common indication for liver transplantation.

Level of Evidence for the Treatment of Chronic Noninsertional Achilles Tendinopathy.

BACKGROUND: Noninsertional Achilles tendinopathy affects both athletes and sedentary individuals, and its incidence is rising. Conservative management is the mainstay of treatment, but a variety of operative techniques have been described to treat recalcitrant cases. We seek to outline the current available evidence for surgical management of noninsertional Achilles tendinopathy. STUDY DESIGN AND METHODS: A systematic review was performed using the MEDLINE and EMBASE databases, and all articles were reviewed by at least 2 authors. Each article was assigned a level of evidence in accordance with the standards of Journal of Bone and Joint Surgery. The available data were reviewed and a level of evidence was assigned to each intervention of interest, based on the revised classifications of Wright. RESULTS AND CONCLUSION: A total of 46 articles met inclusion and exclusion criteria. There is fair evidence (grade B) in support of open debridement with 1 level II study, 1 level III study, and 8 level IV studies. There is fair evidence (grade B) in support of arthroscopic or minimally invasive surgical techniques. There is poor evidence (grade C) in support of flexor hallucis longus transfer, longitudinal tenotomy, peritenolysis, gastrocnemius recession, and plantaris excision. There is insufficient evidence (grade I) to provide a recommendation about other surgical treatment methods for noninsertional Achilles tendinopathy.Levels of Evidence: Level III: Systematic review.

Levels and distribution profiles of Per- and Polyfluoroalkyl Substances (PFAS) in a high Arctic Svalbard ice core.

Per- and polyfluoroalkyl substances (PFAS) are a group of persistent organic contaminants of which some are toxic and bioaccumulative. Several PFAS can be formed from the atmospheric degradation of precursors such as fluorotelomer alcohols (FTOHs) as well as hydrochlorofluorocarbons (HFCs) and other ozone-depleting chlorofluorocarbon (CFC) replacement compounds. Svalbard ice cores have been shown to provide a valuable record of long-range atmospheric transport of contaminants to the Arctic. This study uses a 12.3 m ice core from the remote Lomonosovfonna ice cap on Svalbard to understand the atmospheric deposition of PFAS in the Arctic. A total of 45 PFAS were targeted, of which 26 were detected, using supercritical fluid chromatography (SFC) tandem mass spectrometry (MS/MS) and ultra-performance liquid chromatography (UPLC) MS/MS. C2 to C11 perfluoroalkyl carboxylic acids (PFCAs) were detected continuously in the ice core and their fluxes ranged from 2.5 to 8200 ng m-2 yr-1 (9.51-16,500 pg L-1). Trifluoroacetic acid (TFA) represented 71 % of the total mass of C2 - C11 PFCAs in the ice core and had increasing temporal trends in deposition. The distribution profile of PFCAs suggested that FTOHs were likely the atmospheric precursor to C8 - C11 PFCAs, whereas C2 - C6 PFCAs had alternative sources, such as HFCs and other CFC replacement compounds. Perfluorooctanesulfonic acid (PFOS) was also widely detected in 82 % of ice core subsections, and its isomer profile (81 % linear) indicated an electrochemical fluorination manufacturing source. Comparisons of PFAS concentrations with a marine aerosol proxy showed that marine aerosols were insignificant for the deposition of PFAS on Lomonosovfonna. Comparisons with a melt proxy showed that TFA and PFOS were mobile during meltwater percolation. This indicates that seasonal snowmelt and runoff from post-industrial accumulation on glaciers could be a significant seasonal source of PFAS to ecosystems in Arctic fjords.

Theophylline improves steroid sensitivity in acute alcoholic hepatitis.

UNLABELLED: Corticosteroid therapy has shown some benefit in severe acute alcoholic hepatitis (AAH); however, this is limited by uncertainty in patient selection and variable clinical response. Theophylline has been shown to ameliorate impaired steroid sensitivity in chronic obstructive pulmonary disease by facilitating corticosteroid-induced silencing of proinflammatory genes. We aimed to explore the mechanistic basis of the variable response to corticosteroid therapy seen in patients with AAH and to address the extent to which theophylline can improve this response. The ability of dexamethasone to inhibit phytohemagglutinin-induced lymphocyte proliferation was assessed by (3)H-thymidine incorporation in 12 severe AAH patients and age-matched and sex-matched controls. Steroid sensitivity was measured in terms of I(max), the maximum inhibition of proliferation. The effect of 10(-5) M theophylline and, in survivors, change in I(max) during recovery were observed. Lymphocyte steroid sensitivity was found to be significantly reduced in AAH compared with controls (I(max) 67[+/-4.5]% versus 95[+/-2.3]%, P = 0.0002) and correlated with clinical markers of steroid responsiveness. In survivors, I(max) increased in recovery. Theophylline 10(-5) M significantly increased lymphocyte steroid sensitivity (I(max) 86[+/-6.6]% versus 67[+/-5.0]%, P = 0.027). CONCLUSION: Acute alcoholic hepatitis is associated with significant lymphocyte steroid insensitivity, which improves in recovery and can be ameliorated ex vivo by theophylline. This offers potential to rationalize corticosteroid prescribing in AAH and, furthermore, justifies investigation of this novel role for an existing pharmacological agent in this common and frequently fatal condition.

Acetate, the key modulator of inflammatory responses in acute alcoholic hepatitis.

UNLABELLED: Acute alcoholic hepatitis is characterized by disproportionate macrophage inflammatory cytokine responses to bacterial lipopolysaccharide. Lack of knowledge of the underlying mechanism has limited progress toward effective therapy. We postulated a novel mechanism by which ethanol increases histone acetylation, increasing proinflammatory gene transcription and cytokine synthesis. Cytokine responses to lipopolysaccharide in a human macrophage cell line cultured in 86 mM ethanol, 1 mM acetate, and normal media were measured by multiplex immunoassay. Changes in histone acetylation were determined by immunofluorescence microscopy and chromatin immunoprecipitation on presentation. The effect of ethanol and acetate on acetyl-coenzyme A (acetyl-coA) synthetases, which convert acetate to acetyl-coA, the substrate for histone acetylation, was determined by quantitative reverse-transcription polymerase chain reaction and immunoblotting. Knockdown of acetyl-coA synthetases by short hairpin RNA (shRNA) was used to determine their role in ethanol's enhancement of the inflammatory cytokine response. Ethanol-exposed macrophages developed enhanced interleukin 6 (IL6), IL8, and tumor necrosis factor alpha responses to lipopolysaccharide with time-dependent increases in histone acetylation that could be prevented by inhibition of ethanol metabolism. Chromatin immunoprecipitation confirmed increased histone acetylation at promoter regions of specific cytokine genes. The effect of ethanol was reproduced by incubation with acetate, the principal hepatic metabolite of ethanol, and both ethanol and acetate reduced histone deacetylase activity and up-regulated acetyl-coA synthetases. Knockdown of the acetyl-coA synthetases abrogated the effect of ethanol on cytokine production. CONCLUSION: Synthesis of metabolically available acetyl-coA from acetate is critical to the increased acetylation of proinflammatory gene histones and consequent enhancement of the inflammatory response in ethanol-exposed macrophages. This mechanism is a potential therapeutic target in acute alcoholic hepatitis.

A common polymorphism in the ABCB11 gene is associated with advanced fibrosis in hepatitis C but not in non-alcoholic fatty liver disease.

Chronic HCV (hepatitis C virus)-associated cirrhosis represents a major indication for liver transplantation. Bile acids contribute to hepatic stellate cell activation as a key event in fibrogenesis. The aim of the present study was to investigate the role of bile acids and polymorphisms in bile acid level-regulating genes on fibrosis progression. A total of 206 subjects with chronic HCV infection were included for ABCB11 (ATP-binding cassette, subfamily B, member II) 1331T>C and NR1H4 (nuclear receptor) -1G>T genotyping, 178 of which were analysed for fibrosis stage. Exclusion criteria were HBV (hepatitis B virus) or HIV coinfection, alcohol >40 g/day and morbid obesity. A total of 358 patients with NAFLD (non-alcoholic fatty liver disease) were genotyped for comparison with a non-viral liver disease. Caucasian individuals (n = 110), undergoing liver resection for focal hepatic metastasis, served as controls. The ABCB11 1331C allele was significantly overrepresented in HCV patients compared with controls {allelic frequency 62.9%; OR (odds ratio), 1.41 [95% CI (confidence interval), 1.012-1.965]}. Median plasma bile acid levels were not significantly increased in the CC compared with TT genotype [7.2 (1-110) µmol/l compared with 3.5 (1-61) µmol/l; values are medians (range). A significant association between the presence of cirrhosis and ABCB11 genotype (CC compared with CT or TT, P=0.047) was observed in the χ2 test and independent of other risk factors of age, gender, body mass index and disease duration in multivariate analysis (P = 0.010). No such association could be observed in fatty liver patients with regard to advanced fibrosis (F ≥ 2). The common ABCB11 1331CC genotype, which is present in 40% of HCV patients and renders the carrier susceptible to increased bile acid levels, is associated with cirrhosis.

"They Don't Think Like Us": Exploring Attitudes of Non-Transgender Students Toward Transgender People Using Discourse Analysis.

Literature concerned with attitudes toward transgender (TG) individuals has been found to be lacking. Predominant research is quantitative and the few qualitative studies either investigated TG experience or attitudes of those with personal experience of TG people.This study investigated this topic using a qualitative approach employing semi-structured interviews exploring beliefs, understanding, and experience of TG people. Foucauldian Discourse Analysis was used to analyze the language used to construct a "transgender" discourse. Participants were cisgender, heterosexual, female participants from Black and ethnic minority backgrounds (n = 6).Prevalent discourses were; "Heteronormativity as a Benchmark," "The Ease of Disclosure'" and "Actualising the Other." Participants consistently drew on discourse that constructed TG as "other." Findings indicate a need to attend to context, as well as content, when exploring attitudes and that covert forms of prejudice need to be addressed and could inform anti-prejudice interventions and the creation of future transphobia measurements.

Disorders of coagulation and hemostasis in abdominal obesity: emerging role of fatty liver.

Abdominal obesity represents a public health concern because its prevalence is reaching epidemic proportions worldwide, and it is associated with an increased risk of cardiovascular morbidity and mortality and other pathological conditions. A large body of evidence suggests that abdominal obesity is associated with a prothrombotic tendency, which may, at least in part, contribute to the increased risk of atherothrombosis in these individuals. This review briefly summarizes the evidence of direct and indirect effects of the accumulation of excess lipid in visceral adipose tissue on coagulation and fibrinolysis. In addition, this article critically appraises the rapidly expanding body of experimental and clinical data that support a potential direct contribution for the accumulation of excess lipid in the liver (i.e., nonalcoholic fatty liver disease, a very frequent pathological condition in subjects with abdominal obesity) in the pathogenesis of the obesity-induced disorders of coagulation and fibrinolysis.

Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease.

UNLABELLED: The role played by the gut in nonalcoholic fatty liver disease (NAFLD) is still a matter of debate, although animal and human studies suggest that gut-derived endotoxin may be important. We investigated intestinal permeability in patients with NAFLD and evaluated the correlations between this phenomenon and the stage of the disease, the integrity of tight junctions within the small intestine, and prevalence of small intestinal bacterial overgrowth (SIBO). We examined 35 consecutive patients with biopsy-proven NAFLD, 27 with untreated celiac disease (as a model of intestinal hyperpermeability) and 24 healthy volunteers. We assessed the presence of SIBO by glucose breath testing (GBT), intestinal permeability by means of urinary excretion of (51)Cr-ethylene diamine tetraacetate ((51)Cr-EDTA) test, and the integrity of tight junctions within the gut by immunohistochemical analysis of zona occludens-1 (ZO-1) expression in duodenal biopsy specimens. Patients with NAFLD had significantly increased gut permeability (compared with healthy subjects; P < 0.001) and a higher prevalence of SIBO, although both were lower than in the untreated celiac patients. In patients with NAFLD, both gut permeability and the prevalence of SIBO correlated with the severity of steatosis but not with presence of NASH. CONCLUSIONS: Our results provide the first evidence that NAFLD in humans is associated with increased gut permeability and that this abnormality is related to the increased prevalence of SIBO in these patients. The increased permeability appears to be caused by disruption of intercellular tight junctions in the intestine, and it may play an important role in the pathogenesis of hepatic fat deposition.

The European NAFLD Registry: A real-world longitudinal cohort study of nonalcoholic fatty liver disease.

Non-Alcoholic Fatty Liver Disease (NAFLD), a progressive liver disease that is closely associated with obesity, type 2 diabetes, hypertension and dyslipidaemia, represents an increasing global public health challenge. There is significant variability in the disease course: the majority exhibit only fat accumulation in the liver but a significant minority develop a necroinflammatory form of the disease (non-alcoholic steatohepatitis, NASH) that may progress to cirrhosis and hepatocellular carcinoma. At present our understanding of pathogenesis, disease natural history and long-term outcomes remain incomplete. There is a need for large, well characterised patient cohorts that may be used to address these knowledge gaps and to support the development of better biomarkers and novel therapies. The European NAFLD Registry is an international, prospectively recruited observational cohort study that aims to establish a large, highly-phenotyped patient cohort and linked bioresource. Here we describe the infrastructure, data management and monitoring plans, and the standard operating procedures implemented to ensure the timely and systematic collection of high-quality data and samples. Already recruiting subjects at secondary/tertiary care centres across Europe, the Registry is supporting the European Union IMI2-funded LITMUS 'Liver Investigation: Testing Marker Utility in Steatohepatitis' consortium, which is a major international effort to robustly validate biomarkers that diagnose, risk stratify and/or monitor NAFLD progression and liver fibrosis stage. The European NAFLD Registry has the demonstrable capacity to support research and biomarker development at scale and pace.

Genetic association studies in drug-induced liver injury.

Genetic studies on drug-induced liver injury (DILI) have proved challenging, both because of their rarity and their difficulty in replicating observed effects. However, significant progress has now been achieved by both candidate-gene and genome-wide association studies. These two approaches are considered in detail, together with examples of DILI due to specific drugs where consistent associations have been reported. Particular consideration is given to associations between antituberculosis drug-related liver injury and the "slow acetylator" genotype for N-acetyltransferase 2, amoxicillin/clavulanate-related liver injury, and the human leukocyte antigen (HLA) class II DRB1*1501 allele and flucloxacillin-related injury and the HLA class I B*5701 allele. Although these associations are drug-specific, the possibility that additional, more general susceptibility genes for DILI exist requires further investigation, ideally by genome-wide association studies involving international collaboration. The possibility of interethnic variation in susceptibility to DILI also requires further study.

Britain's alcohol market: how minimum alcohol prices could stop moderate drinkers subsidising those drinking at hazardous and harmful levels.

Discounting of alcoholic products is universal in U.K. supermarkets with some chains selling own brand spirits for less than the duty payable per item. Eighty per cent of alcohol purchases are made by 30% of the population and this group are the main beneficiaries. In December 2008 the government announced its intention to consult on modifications to the Licensing Act 2003 to enable the introduction of mandatory conditions for the sale of alcoholic products in order to curtail alcohol harm. In this article it is shown that families in Britain have nothing to fear from the introduction of a 50 p/unit minimum price of alcohol as the overall effect should be a reduction in average weekly supermarket bills for the majority while harmful and hazardous drinkers will pay more. By paying less for non-alcoholic products sold by supermarkets, moderate drinkers should no longer be effectively subsidising the alcohol purchased by the harmful and hazardous group.