BackgroundExcess alcohol consumption has serious adverse effects on health and results in violence-related harm.ObjectiveThis study investigated the impact of change in community alcohol availability on alcohol consumption and alcohol-related harms to health, assessing the effect of population migration and small-area deprivation.DesignA natural experiment of change in alcohol outlet density between 2006 and 2011 measured at census Lower Layer Super Output Area level using observational record-linked data.SettingWales, UK; population of 2.5 million aged ≥ 16 years.Outcome measuresAlcohol consumption, alcohol-related hospital admissions, accident and emergency (A&E) department attendances from midnight to 06.00 and violent crime against the person.Data sourcesLicensing Act 2003 [Great Britain.Licensing Act 2003. London: The Stationery Office; 2003. URL:www.legislation.gov.uk/ukpga/2003/17/contents(accessed 8 June 2015)] data on alcohol outlets held by the 22 local authorities in Wales, alcohol consumption data from annual Welsh Health Surveys 2008–12, hospital admission data 2006–11 from the Patient Episode Database for Wales (PEDW) and A&E attendance data 2009–11 were anonymously record linked to the Welsh Demographic Service age–sex register within the Secure Anonymised Information Linkage Databank. A final data source was recorded crime 2008–11 from the four police forces in Wales.MethodsOutlet density was estimated (1) as the number of outlets per capita for the 2006 static population and the per quarterly updated population to assess the impact of population migration and (2) using new methods of network analysis of distances between each household and alcohol outlets within 10 minutes of walking and driving. Alcohol availability was measured by three variables: (1) the previous quarterly value; (2) positive and negative change over the preceding five quarters; and (3) volatility, a measure of absolute quarterly changes during the preceding five quarters. Longitudinal statistical analysis used multilevel Poisson models of consumption and Geographically Weighted Regression (GWR) spatial models of binge drinking, Cox regression models of hospital admissions and A&E attendance and GWR models of violent crime against the person, each as a function of alcohol availability adjusting for confounding variables. The impact on health inequalities was investigated by stratifying models within quintiles of the Welsh Index of Multiple Deprivation.ResultsThe main finding was that change in walking outlet density was associated with alcohol-related harms: consumption, hospital admissions and violent crime against the person each tracked the quarterly changes in outlet density. Alcohol-related A&E attendances were not clinically coded and the association was less conclusive. In general, social deprivation was strongly associated with the outcome measures but did not substantially modify the associations between the outcomes and alcohol availability. We found no evidence for an important effect of population migration.LimitationsLimitations included the absence of any standardised methods of alcohol outlet data collation, processing and validation, and incomplete data on on-sales and off-sales. We were dependent on the quality of clinical coding and administrative records and could not identify alcohol-related attendances in the A&E data set.ConclusionThis complex interdisciplinary study found that important alcohol-related harms were associated with change in alcohol outlet density. Future work recommendations include defining a research standard for recording outlet data and classification of outlet type, the methodological development of residence-based density measures and a health economic analysis of model-predicted harms.FundingThe National Institute for Health Research Public Health Research programme. Additional technical and computing support was provided by the Farr Institute at Swansea University, made possible by the following grant:Centre for the Improvement of Population Health through E-records Research (CIPHER) and Farr Institute capital enhancement. CIPHER and the Farr Institute are funded by Arthritis Research UK, the British Heart Foundation, Cancer Research UK, the Chief Scientist Office (Scottish Government Health Directorates), the Economic and Social Research Council, the Engineering and Physical Sciences Research Council, the Medical Research Council, the National Institute for Health Research, the National Institute for Social Care and Health Research (Welsh Government) and the Wellcome Trust (grant reference MR/K006525/1).

Catalyst-mediated protein modification is a powerful approach for the imaging and engineering of natural proteins. We have previously developed affinity-guided 4-dimethylaminopyridine (AGD) chemistry as an efficient protein modification method using a catalytic acyl transfer reaction. However, because of the high electrophilicity of the thioester acyl donor molecule, AGD chemistry suffers from nonspecific reactions to proteins other than the target protein in crude biological environments, such as cell lysates, live cells, and tissue samples. To overcome this shortcoming, we here report a new acyl donor/organocatalyst system that allows more specific and efficient protein modification. In this method, a highly nucleophilic pyridinium oxime (PyOx) catalyst is conjugated to a ligand specific to the target protein. The ligand-tethered PyOx selectively binds to the target protein and facilitates the acyl transfer reaction of a mild electrophilic N-acyl-N-alkylsulfonamide acyl donor on the protein surface. We demonstrated that the new catalytic system, called AGOX (affinity-guided oxime) chemistry, can modify target proteins, both in test tubes and cell lysates, more selectively and efficiently than AGD chemistry. Low-background fluorescence labeling of the endogenous cell-membrane proteins, carbonic anhydrase XII and the folate receptor, in live cells allowed for the precise quantification of diffusion coefficients in the protein's native environment. Furthermore, the excellent biocompatibility and bioorthogonality of AGOX chemistry were demonstrated by the selective labeling of an endogenous neurotransmitter receptor in mouse brain slices, which are highly complicated tissue samples.

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Reflecting the increasing risk in elderly patients with diffuse large B cell lymphoma (DLBCL), prognostic predictors other than the International Prognostic Index have attracted more attention. This study presents the first analysis of the prognostic utility of the Geriatric Nutritional Risk Index (GNRI) in combination with the Charlson Comorbidity Index (CCI) for overall survival (OS) in elderly DLBCL patients. A multicentre retrospective was conducted on a cohort of 451 patients (≥65 years). The GNRI and CCI were independent predictors in a multivariate Cox proportional hazard model. There was a nonlinear correlation between the GNRI and OS in a Cox model with restricted cubic spline. Multivariate receiver operating characteristic curves showed a significant improvement in prediction accuracy when the GNRI was added to CCI. Adding the GNRI to CCI yielded a significant category-free net reclassification improvement (0Á556; 95% CI: 0Á378-0Á736, P < 0Á001) and integrated discrimination improvement (0Á094; 95% CI: 0Á067-0Á122, P < 0Á001). The decision curve analysis demonstrated the clinical net benefit associated with the adoption of the GNRI. The GNRI was not only a predictor of OS but also remarkably improved the prognosis prediction accuracy when incorporated with the CCI, having the ability to stratify the prognosis of elderly DLBCL patients.

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A dipalmitoylphosphatic acid (DPPA) monolayer at the air/liquid interface is used as a binding layer to incorporate glucose oxidase (GOx) from the subphase. The effects of the adsorption time of GOx on the behavior of the mixed DPPA/GOx monolayer and the relevant structure of the mixed LB film were studied using the characteristics of the pressure-area (pi-A) isotherm, Brewster angle microscopy (BAM), and atomic force microscopy (AFM). The experimental results show that two equilibrium states of GOx adsorption exist in the presence of a DPPA monolayer. The first equilibrium stage occurs at tens of minutes after spreading of DPPA, and a surface pressure of ca. 7.5 mN/m is obtained. The second equilibrium stage approaches slowly, and a higher equilibrium surface pressure (ca. 16 mN/m) was obtained at ca. 8 h after the first stage. The BAM and AFM images show that, after the second equilibrium stage is reached, a more condensed phase and rough morphology are obtained on the mixed DPPA/GOx monolayer, indicating a higher amount of GOx incorporated into the mixed film. For the first equilibrium stage of GOx adsorption, DPPA molecules can still pack regularly and closely under compression, suggesting that GOx molecules are mainly located beneath the DPPA monolayer at the compressed state. A more uniform phase was detected on a film prepared after the first equilibrium stage was reached. The present result indicates that distinct structures and properties of mixed DPPA/GOx films can be prepared from the various stages of GOx adsorption.

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Tumor lysis syndrome (TLS) is a life-threatening oncological emergency, in which control of serum uric acid (S-UA) levels is important. S-UA-lowering efficacy of a new xanthine oxidase inhibitor, febuxostat, was retrospectively evaluated in seven patients with hematological malignancies who were at an intermediate risk of developing TLS. A 10-mg dose of febuxostat was initiated and chemotherapy was started within 24 h of administering the first dose of febuxostat. Febuxostat was continued until at least day 7 of chemotherapy treatment. The UA-lowering treatment was considered effective if febuxostat reduced S-UA levels to ≤7.5 mg/dl by day 5. The mean S-UA level at base line was 6.4±2.6 mg/dl and, on day 5, the mean S-UA level was 4.7±1.8 mg/dl. All the patients achieved S-UA levels ≤7.5 mg/dl. Serum creatinine levels decreased from 0.93±0.25 to 0.85±0.25 mg/dl. The estimated glomerular filtration rate values increased from 69.7±24.5 to 76.9±26.2 ml/min. No adverse reactions were noted during the study period and no patients experienced progressive TLS. Successful control of S-UA and improved renal function were obtained in response to febuxostat treatment in cancer patients at a risk of TLS.