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Background and aims\ud \ud UK alcohol consumption per capita has fallen by 18% since 2004 while the alcohol‐specific death rate has risen by 6%. Inconsistent consumption trends across the population may explain this. Drawing on the theory of the collectivity of drinking cultures and age‐period‐cohort analyses, we tested whether consumption trends are consistent across lighter and heavier drinkers for three temporal processes: (i) the life course, (ii) calendar time, (iii) successive birth cohorts.\ud \ud Design\ud \ud Sex‐specific quantile age‐period‐cohort regressions using repeat cross‐sectional survey data.\ud \ud Setting\ud \ud Great Britain, 1984‐2011.\ud \ud Participants\ud \ud Adult (18+) drinkers responding to 17 waves of the General Lifestyle Survey (total N=175,986).\ud \ud Measurements\ud \ud Dependent variable: The 10th, 25th, 50th, 75th, 90th, 95th and 99th quantiles of the logged weekly alcohol consumption distribution (excluding abstainers). Independent variables: seven age groups (18‐24, 25‐34 … 65‐74, 75+), five time periods (1984‐1988 … 2002‐2006, 2008‐2011) and 16 five‐year birth cohorts (1915‐1919 … 1990‐1994). Additional control variables: ethnicity and UK country.\ud \ud Findings\ud \ud Within age, period and cohort trends, changes in consumption were not consistently in the same direction at different quantiles of the consumption distribution. When they were, the scale of change sometimes differed between quantiles. For example, consumption among women decreased by 18% (CI95: ‐32% ‐ ‐2%) but increased by 11% (CI95: 2% ‐ 21%) at the median and by 28% (CI95: 19%‐38%) at the 99th quantile, implying consumption fell among lighter drinkers and rose among heavier drinkers. This type of polarised trend also occurred between 1984‐1988 and 1996‐2000 for men and women. Age trends showed collectivity but cohort trends showed a mixture of collectivity and polarisation.\ud \ud Conclusions\ud \ud Countervailing alcohol consumption and alcohol‐related harm trends in the UK may be explained by lighter and heavier drinkers having different period and cohort trends as well as by the presence of cohort trends that mean consumption may rise in some age groups while falling in others.

The spillover of viral pathogens from wild animal reservoirs into human populations is the predominant cause of emerging disease events worldwide and represents an acute and persistent threat to global health, economy, and biodefence. The ability of a virus to specifically attach to cell-surface receptors during host-cell entry is a critical determinant of cross-species transmission. Through crystallographic and biochemical analysis, this thesis presents a structural rationale for the determinants of differential host-cell receptor recognition, for paramyxo- and arenaviruses, two groups of important emerging viral pathogens. Comparative study of the protein architectures of cellular attachment-mediating glycoproteins from two non-pathogenic viral species—Whitewater Arroyo arenavirus (WWAV) and Cedar henipavirus (CedPV)—with those of highly pathogenic members within the same genera, provides a template for understanding the molecular basis of distinct receptor tropism characteristics. We demonstrate that the attachment glycoprotein of WWAV, whilst possessing a conserved overall fold, is highly diversified relative to pathogenic arenaviruses, despite the ability to recognise an overlapping repertoire of host-cell entry receptors. Whilst as yet poorly defined auxiliary receptors permit arenaviral entry into human cells in vitro, therefore not unequivocally precluding zoonosis of WWAV at the point of cellular attachment, primary receptor utilisation is a correlate of pathogenicity and therefore can account for the non-pathogenic nature of WWAV. In contrast, analysis of the attachment glycoprotein of CedPV reveals no such structural incompatibilities with established henipaviral entry receptors. Thus, these data support the hypothesis that zoonosis of CedPV is not restricted by cellular-attachment and, by extension, host cell attachment alone is insufficient to account for the severe pathogenesis of henipaviruses. The data and analyses presented herein provide a blueprint for the prediction of receptor tropism characteristics and therein assessment of the zoonotic potential of emerging viruses. Furthermore, in presenting a structure-based classification of the discrete structural states adopted by the conformationally labile arenaviral attachment glycoproteins, we provide a template for improved vaccine design.

The genetically and geographically diverse group of viruses within the family Arenaviridae includes a number of zoonotic pathogens capable of causing fatal hemorrhagic fever. The multisubunit GPC glycoprotein spike complex displayed on the arenavirus envelope is a key determinant of species tropism and a primary target of the host humoral immune response. Here, we show that the receptor-binding GP1 subcomponent of the GPC spike from Old World but not New World arenaviruses adopts a distinct, pH-independent conformation in the absence of the cognate GP2. Our analysis provides a structure-based approach to understanding the discrete conformational classes sampled by these therapeutically important targets, informing strategies to develop arenaviral glycoprotein immunogens that resemble GPC as presented on the mature virion surface., The emergence of Old and New World arenaviruses from rodent reservoirs persistently threatens human health. The GP1 subunit of the envelope-displayed arenaviral glycoprotein spike complex (GPC) mediates host cell recognition and is an important determinant of cross-species transmission. Previous structural analyses of Old World arenaviral GP1 glycoproteins, alone and in complex with a cognate GP2 subunit, have revealed that GP1 adopts two distinct conformational states distinguished by differences in the orientations of helical regions of the molecule. Here, through comparative study of the GP1 glycoprotein architectures of Old World Loei River virus and New World Whitewater Arroyo virus, we show that these rearrangements are restricted to Old World arenaviruses and are not induced solely by the pH change that is associated with virus endosomal trafficking. Our structure-based phylogenetic analysis of arenaviral GP1s provides a blueprint for understanding the discrete structural classes adopted by these therapeutically important targets. IMPORTANCE The genetically and geographically diverse group of viruses within the family Arenaviridae includes a number of zoonotic pathogens capable of causing fatal hemorrhagic fever. The multisubunit GPC glycoprotein spike complex displayed on the arenavirus envelope is a key determinant of species tropism and a primary target of the host humoral immune response. Here, we show that the receptor-binding GP1 subcomponent of the GPC spike from Old World but not New World arenaviruses adopts a distinct, pH-independent conformation in the absence of the cognate GP2. Our analysis provides a structure-based approach to understanding the discrete conformational classes sampled by these therapeutically important targets, informing strategies to develop arenaviral glycoprotein immunogens that resemble GPC as presented on the mature virion surface.

Objective To examine the effect of therapeutic hypothermia on MR biomarkers and neurodevelopmental outcomes in babies with mild hypoxic-ischaemic encephalopathy (HIE). Design Non-randomised cohort study. Setting Eight tertiary neonatal units in the UK and the USA. Patients 47 babies with mild HIE on NICHD neurological examination performed within 6 hours after birth. Interventions Whole-body cooling for 72 hours (n=32) or usual care (n=15; of these 5 were cooled for

The substantial increase in prevalence and emergence of antigenically divergent or highly pathogenic influenza A(H7N9) viruses during 2016–17 raises concerns about the epizootic potential of these viruses. We investigated the evolution and adaptation of H7N9 viruses by analyzing available data and newly generated virus sequences isolated in Guangdong Province, China, during 2015–2017. Phylogenetic analyses showed that circulating H7N9 viruses belong to distinct lineages with differing spatial distributions. Hemagglutination inhibition assays performed on serum samples from patients infected with these viruses identified 3 antigenic clusters for 16 strains of different virus lineages. We used ancestral sequence reconstruction to identify parallel amino acid changes on multiple separate lineages. We inferred that mutations in hemagglutinin occur primarily at sites involved in receptor recognition or antigenicity. Our results indicate that highly pathogenic strains likely emerged from viruses circulating in eastern Guangdong Province during March 2016 and are associated with a high rate of adaptive molecular evolution.