The legacy of Hillsborough:Liberating truth, challenging power

In April 1989, ninety-six men, women and children, supporters of Liverpool Football Club, died in a severe crush at an FA Cup semi-final at Hillsborough Stadium, Sheffield. Hundreds were injured and thousands traumatised. Within hours, the causes and circumstances of the disaster were contested. While a judicial inquiry found serious institutional failures in the policing and management of the capacity crowd, no criminal prosecutions resulted, and the inquests returned ‘accidental death’ verdicts. Immediately, the authorities claimed that drunken, violent fans had caused the fatal crush. Denied legitimacy, survivors’ accounts revealed a different story criticising the parlous state of the stadium, inadequate stewarding, negligent policing, failures in the emergency response and flawed processes of inquiry and investigation. Reflecting on two decades of research and contemporaneous interviews with bereaved families and survivors, this article contrasts the official discourse with those alternative accounts – the ‘view from below’. It demonstrates the influence of powerful institutional interests on the inquiries and investigations. It maps the breakthrough to full documentary disclosure following the appointment of the Hillsborough Independent Panel, its research and key findings published in September 2012. The campaigns by families and survivors were vindicated and the fans, including those who died, were exonerated. The process is discussed as an alternative method for liberating truth, securing acknowledgement and pursuing justice.

The effects of global climate change on the cycling and processes of persistent organic pollutants (POPs) in the North Sea

The fate and cycling of two selected legacy persistent organic pollutants (POPs), PCB 153 and gamma-HCH, in the North Sea in the 21st century have been modelled with combined hydrodynamic and fate and transport ocean models
(HAMSOM and FANTOM, respectively). To investigate the impact of climate variability on POPs in the North Sea in the 21st century, future scenario model runs for three 10-year periods to the year 2100 using plausible levels of both in
situ concentrations and atmospheric, river and open boundary inputs are performed. This slice mode under a moderate scenario (A1B) is sufficient to provide a basis for further analysis. For the HAMSOM and atmospheric forcing, results of the IPCC A1B (SRES) 21st century scenario are utilized, where surface forcing is provided by the REMO downscaling of the ECHAM5 global atmospheric model, and open boundary conditions are provided by the MPIOM global ocean model.
Dry gas deposition and volatilization of gamma-HCH increase in the future relative to the present by up to 20% (in the spring and summer months for deposition and in summer for volatilization). In the water column, total mass of
gamma-HCH and PCB 153 remain fairly steady in all three runs. In sediment,
gamma-HCH increases in the future runs, relative to the present, while PCB 153 in sediment decreases exponentially in all three runs, but even faster in the future, due to the increased number of storms, increased duration of gale wind conditions and increased water and air temperatures, all of which are the result of climate change. Annual net sinks exceed sources at the ends of all periods.
Overall, the model results indicate that the climate change scenarios considered here generally have a negligible influence on the simulated fate and transport of the two POPs in the North Sea, although the increased number and magnitude of storms in the 21st century will result in POP resuspension and ensuing revolatilization events. Trends in emissions from primary and secondary sources will remain the key driver of levels of these contaminants over time.

‘Who Ate All the Pride?’:Patriotic Sentiment and English National Football Support.

The growing popularity of English national insignia in international football tournaments has been widely interpreted as evidence of the emergence of a renewed English national consciousness. However, little empirical research has considered how people in England actually understand football support in relation to national identity. Interview data collected around the time of the Euro 2000 and the 2002 World Cup tournaments fail to substantiate the presumption that support for the England football team maps onto claims to patriotic sentiment in any straightforward way. People with far-right political affiliations did generally use national football support to symbolise a general pride in English national identity. However, other people either claimed not to support the England national team precisely because of its associations with nationalism, or else bracketed the domain of football support from more general connotations of English patriotism.

Automatic Analysis of Digital Retinal Images for Glaucoma Detection

In this paper we propose a novel automated glaucoma detection framework for mass-screening that operates on inexpensive retinal cameras. The proposed methodology is based on the assumption that discriminative features for glaucoma diagnosis can be extracted from the optical nerve head structures,
such as the cup-to-disc ratio or the neuro-retinal rim variation. After automatically segmenting the cup and optical disc, these features are feed into a machine learning classifier. Experiments were performed using two different datasets and from the obtained results the proposed technique provides
better performance than approaches based on appearance. A main advantage of our approach is that it only requires a few training samples to provide high accuracy over several different glaucoma stages.

Presentation of lacrimo-auriculodento- digital (LADD) syndrome in a young female patient

BACKGROUND: Lacrimo-auriculo-dento-digital (LADD) syndrome (OMIM #149730) is an autosomal-dominant congenital disorder that can be caused by heterozygous mutations in the tyrosine kinase domains of the genes encoding fibroblast growth factor receptors 2 (FGFR2) and 3 (FGFR3), and has been found in association with a mutation in the FGF10 gene, which encodes an Fgfr ligand. Clinical signs vary, but the condition is characterised by involvement of the lacrimal and salivary systems, cup-shaped ears, hearing loss and dental abnormalities. Additional features may include involvement of the hands and feet with other body systems particularly the kidneys.

CASE REPORT: Previous literature on the subject has been reviewed and this case is the first presentation of LADD syndrome in the Republic of Ireland, as a sporadic case in a 12-year-old girl who exhibited a range of dental and digital anomalies.

TREATMENT: Her general medical practitioner managed her medical care whilst her oral care necessitated a multidisciplinary approach involving restorative and orthodontic elements.

FOLLOW-UP: The initial restorative phase of treatment has successfully improved the appearance of the patient's anterior teeth using direct resin composite build-ups.

Downregulation of the Wnt inhibitor CXXC5 predicts a better prognosis in acute myeloid leukemia

The gene CXXC5 on 5q31 is frequently deleted in acute myeloid leukemia (AML) with del(5q), suggesting that inactivation of CXXC5 might play a role in leukemogenesis. Here, we investigated the functional and prognostic implications of CXXC5 expression in AML. CXXC5 mRNA was downregulated in AML with MLL rearrangements, t(8;21) and GATA2 mutations. As a mechanism of CXXC5 inactivation, we found evidence for epigenetic silencing by promoter methylation. Patients with CXXC5 expression below the median level had a lower relapse rate (45% vs 59%; P = .007) and a better overall survival (OS, 46% vs 28%; P < .001) and event-free survival (EFS, 36% vs 21%; P < .001) at 5 years, independent of cytogenetic risk groups and known molecular risk factors. In gene-expression profiling, lower CXXC5 expression was associated with upregulation of cell-cycling genes and codownregulation of genes implicated in leukemogenesis (WT1, GATA2, MLL, DNMT3B, RUNX1). Functional analyses demonstrated CXXC5 to inhibit leukemic cell proliferation and Wnt signaling and to affect the p53-dependent DNA damage response. In conclusion, our data suggest a tumor suppressor function of CXXC5 in AML. Inactivation of CXXC5 is associated with different leukemic pathways and defines an AML subgroup with better outcome.

The molecular basis of galactosemia - Past, present and future

Galactosemia, an inborn error of galactose metabolism, was first described in the 1900s by von Ruess. The subsequent 100years has seen considerable progress in understanding the underlying genetics and biochemistry of this condition. Initial studies concentrated on increasing the understanding of the clinical manifestations of the disease. However, Leloir's discovery of the pathway of galactose catabolism in the 1940s and 1950s enabled other scientists, notably Kalckar, to link the disease to a specific enzymatic step in the pathway. Kalckar's work established that defects in galactose 1-phosphate uridylyltransferase (GALT) were responsible for the majority of cases of galactosemia. However, over the next three decades it became clear that there were two other forms of galactosemia: type II resulting from deficiencies in galactokinase (GALK1) and type III where the affected enzyme is UDP-galactose 4'-epimerase (GALE). From the 1970s, molecular biology approaches were applied to galactosemia. The chromosomal locations and DNA sequences of the three genes were determined. These studies enabled modern biochemical studies. Structures of the proteins have been determined and biochemical studies have shown that enzymatic impairment often results from misfolding and consequent protein instability. Cellular and model organism studies have demonstrated that reduced GALT or GALE activity results in increased oxidative stress. Thus, after a century of progress, it is possible to conceive of improved therapies including drugs to manipulate the pathway to reduce potentially toxic intermediates, antioxidants to reduce the oxidative stress of cells or use of "pharmacological chaperones" to stabilise the affected proteins.

Why 2014 was the year of the whistle-blower in sport

The FIFA World Cup was one of the sports highlights of 2014. Off the field, however, it has been an annus horribilis for football’s world governing body.1 FIFA has been dogged throughout by controversy relating to the award of the 2018 and 2022 World Cups to Russia and Qatar.

Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial

BACKGROUND: Long-term hormone therapy has been the standard of care for advanced prostate cancer since the 1940s. STAMPEDE is a randomised controlled trial using a multiarm, multistage platform design. It recruits men with high-risk, locally advanced, metastatic or recurrent prostate cancer who are starting first-line long-term hormone therapy. We report primary survival results for three research comparisons testing the addition of zoledronic acid, docetaxel, or their combination to standard of care versus standard of care alone.

METHODS: Standard of care was hormone therapy for at least 2 years; radiotherapy was encouraged for men with N0M0 disease to November, 2011, then mandated; radiotherapy was optional for men with node-positive non-metastatic (N+M0) disease. Stratified randomisation (via minimisation) allocated men 2:1:1:1 to standard of care only (SOC-only; control), standard of care plus zoledronic acid (SOC + ZA), standard of care plus docetaxel (SOC + Doc), or standard of care with both zoledronic acid and docetaxel (SOC + ZA + Doc). Zoledronic acid (4 mg) was given for six 3-weekly cycles, then 4-weekly until 2 years, and docetaxel (75 mg/m(2)) for six 3-weekly cycles with prednisolone 10 mg daily. There was no blinding to treatment allocation. The primary outcome measure was overall survival. Pairwise comparisons of research versus control had 90% power at 2·5% one-sided α for hazard ratio (HR) 0·75, requiring roughly 400 control arm deaths. Statistical analyses were undertaken with standard log-rank-type methods for time-to-event data, with hazard ratios (HRs) and 95% CIs derived from adjusted Cox models. This trial is registered at ClinicalTrials.gov (NCT00268476) and ControlledTrials.com (ISRCTN78818544).

FINDINGS: 2962 men were randomly assigned to four groups between Oct 5, 2005, and March 31, 2013. Median age was 65 years (IQR 60-71). 1817 (61%) men had M+ disease, 448 (15%) had N+/X M0, and 697 (24%) had N0M0. 165 (6%) men were previously treated with local therapy, and median prostate-specific antigen was 65 ng/mL (IQR 23-184). Median follow-up was 43 months (IQR 30-60). There were 415 deaths in the control group (347 [84%] prostate cancer). Median overall survival was 71 months (IQR 32 to not reached) for SOC-only, not reached (32 to not reached) for SOC + ZA (HR 0·94, 95% CI 0·79-1·11; p=0·450), 81 months (41 to not reached) for SOC + Doc (0·78, 0·66-0·93; p=0·006), and 76 months (39 to not reached) for SOC + ZA + Doc (0·82, 0·69-0·97; p=0·022). There was no evidence of heterogeneity in treatment effect (for any of the treatments) across prespecified subsets. Grade 3-5 adverse events were reported for 399 (32%) patients receiving SOC, 197 (32%) receiving SOC + ZA, 288 (52%) receiving SOC + Doc, and 269 (52%) receiving SOC + ZA + Doc.

INTERPRETATION: Zoledronic acid showed no evidence of survival improvement and should not be part of standard of care for this population. Docetaxel chemotherapy, given at the time of long-term hormone therapy initiation, showed evidence of improved survival accompanied by an increase in adverse events. Docetaxel treatment should become part of standard of care for adequately fit men commencing long-term hormone therapy.

FUNDING: Cancer Research UK, Medical Research Council, Novartis, Sanofi-Aventis, Pfizer, Janssen, Astellas, NIHR Clinical Research Network, Swiss Group for Clinical Cancer Research.

Protocol-driven adjustment of ocular hypotensive medication in patients at low risk of conversion to glaucoma

AIM: To investigate the safety and potential savings of decreasing medication use in low-risk patients with ocular hypertension (OH).
METHODS: Patients with OH receiving pressure-lowering medication identified by medical record review at a university hospital underwent examination by a glaucoma specialist with assessment of visual field (VF), vertical cup-to-disc ratio (vCDR), central corneal thickness and intraocular pressure (IOP). Subjects with estimated 5-year risk of glaucoma conversion <15% were asked to discontinue ≥1 medication, IOP was remeasured 1 month later and risk was re-evaluated at 1 year.
RESULTS: Among 212 eyes of 126 patients, 44 (20.8%) had 5-year risk >15% and 14 (6.6%) had unreliable baseline VF. At 1 month, 15 patients (29 eyes, 13.7%) defaulted follow-up or refused to discontinue medication and 11 eyes (5.2%) had risk >15%. The remaining 69 patients (107 eyes, 50.7%) successfully discontinued 141 medications and completed 1-year follow-up. Mean IOP (20.5±2.65 mm Hg vs 20.3±3.40, p=0.397) did not change, though mean VF pattern SD (1.58±0.41 dB vs 1.75±0.56 dB, p=0.001) and glaucoma conversion risk (7.31±3.74% vs 8.76±6.28%, p=0.001) increased at 1 year. Mean defect decreased (-1.42±1.60 vs -1.07±1.52, p=0.022). One eye (0.47%) developed a repeatable VF defect and 13 eyes (6.1%) had 5-year risk >15% at 1 year. The total 1-year cost of medications saved was US$4596.
CONCLUSIONS: Nearly half (43.9%) of low-risk OH eyes in this setting could safely reduce medications over 1 year, realising substantial savings.Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.