Policy Responses to the Healthy Aging Challenge: Confronting Hybridity with Social Innovation.

Tackling the issue of healthy aging in society is complex. It requires an interdisciplinary perspective and different forms of innovation. This article provides a commentary on the role of innovation policy in addressing healthy aging, particularly in the UK context. We argue that the wide range of economic activities related to healthy aging is part of a hybrid domain rather than a single sector. This represents a new generation of innovation policy for healthy aging which prioritizes understanding how different actors can be connected to support a spectrum of types of innovation which will contribute to providing better goods, services, and practices for older people. We explore social innovation as it relates to hybrid domains such as healthy aging and discuss the role of place in creating policy which generates both societal and market value. We recommend that policymakers use these concepts to build a better understanding of the economies that are evolving around healthy aging and where opportunities exist to better conceptualize, connect, and support actors, initiatives, and places to optimize economic potential and social outcomes.

Neurovirulent Murine Coronavirus JHM.SD Uses Cellular Zinc Metalloproteases for Virus Entry and Cell-Cell Fusion.

The coronavirus (CoV) S protein requires cleavage by host cell proteases to mediate virus-cell and cell-cell fusion. Many strains of the murine coronavirus mouse hepatitis virus (MHV) have distinct, S-dependent organ and tissue tropisms despite using a common receptor, suggesting that they employ different cellular proteases for fusion. In support of this hypothesis, we found that inhibition of endosomal acidification only modestly decreased entry, and overexpression of the cell surface protease TMPRSS2 greatly enhanced entry, of the highly neurovirulent MHV strain JHM.SD relative to their effects on the reference strain, A59. However, TMPRSS2 overexpression decreased MHV structural protein expression, release of infectious particles, and syncytium formation, and endogenous serine protease activity did not contribute greatly to infection. We therefore investigated the importance of other classes of cellular proteases and found that inhibition of matrix metalloproteinase (MMP)- and a disintegrin and metalloprotease (ADAM)-family zinc metalloproteases markedly decreased both entry and cell-cell fusion. Suppression of virus by metalloprotease inhibition varied among tested cell lines and MHV S proteins, suggesting a role for metalloprotease use in strain-dependent tropism. We conclude that zinc metalloproteases must be considered potential contributors to coronavirus fusion.IMPORTANCE The family Coronaviridae includes viruses that cause two emerging diseases of humans, severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), as well as a number of important animal pathogens. Because coronaviruses depend on host protease-mediated cleavage of their S proteins for entry, a number of protease inhibitors have been proposed as antiviral agents. However, it is unclear which proteases mediate in vivo infection. For example, SARS-CoV infection of cultured cells depends on endosomal acid pH-dependent proteases rather than on the cell surface acid pH-independent serine protease TMPRSS2, but Zhou et al. (Antiviral Res 116:76-84, 2015, doi:10.1016/j.antiviral.2015.01.011) found that a serine protease inhibitor was more protective than a cathepsin inhibitor in SARS-CoV-infected mice. This paper explores the contributions of endosomal acidification and various proteases to coronavirus infection and identifies an unexpected class of proteases, the matrix metalloproteinase and ADAM families, as potential targets for anticoronavirus therapy.

The nsp3 macrodomain promotes virulence in mice with coronavirus-induced encephalitis.

UNLABELLED: All coronaviruses encode a macrodomain containing ADP-ribose-1"-phosphatase (ADRP) activity within the N terminus of nonstructural protein 3 (nsp3). Previous work showed that mouse hepatitis virus strain A59 (MHV-A59) with a mutated catalytic site (N1348A) replicated similarly to wild-type virus but was unable to cause acute hepatitis in mice. To determine whether this attenuated phenotype is applicable to multiple disease models, we mutated the catalytic residue in the JHM strain of MHV (JHMV), which causes acute and chronic encephalomyelitis, using a newly developed bacterial artificial chromosome (BAC)-based MHV reverse genetics system. Infection of mice with the macrodomain catalytic point mutant virus (N1347A) resulted in reductions in lethality, weight loss, viral titers, proinflammatory cytokine and chemokine expression, and immune cell infiltration in the brain compared to mice infected with wild-type virus. Specifically, macrophages were most affected, with approximately 2.5-fold fewer macrophages at day 5 postinfection in N1347A-infected brains. Tumor necrosis factor (TNF) and interferon (IFN) signaling were not required for effective host control of mutant virus as all N1347A virus-infected mice survived the infection. However, the adaptive immune system was required for protection since N1347A virus was able to cause lethal encephalitis in RAG1(-/-) (recombination activation gene 1 knockout) mice although disease onset was modestly delayed. Overall, these results indicate that the BAC-based MHV reverse genetics system will be useful for studies of JHMV and expand upon previous studies, showing that the macrodomain is critical for the ability of coronaviruses to evade the immune system and promote viral pathogenesis. IMPORTANCE: Coronaviruses are an important cause of human and veterinary diseases worldwide. Viral processes that are conserved across a family are likely to be good targets for the development of antiviral therapeutics and vaccines. The macrodomain is a ubiquitous structural domain and is also conserved among all coronaviruses. The coronavirus macrodomain has ADP-ribose-1"-phosphatase activity; however, its function during infection remains unclear as does the reason that coronaviruses have maintained this enzymatic activity throughout evolution. For MHV, this domain has now been shown to promote multiple types of disease, including hepatitis and encephalitis. These data indicate that this domain is vital for the virus to replicate and cause disease. Understanding the mechanism used by this enzyme to promote viral pathogenesis will open up novel avenues for therapies and may give further insight into the role of macrodomain proteins in the host cell since these proteins are found in all living organisms.

The nsp1, nsp13, and M proteins contribute to the hepatotropism of murine coronavirus JHM.WU.

UNLABELLED: Mouse hepatitis virus (MHV) isolates JHM.WU and JHM.SD promote severe central nervous system disease. However, while JHM.WU replicates robustly and induces hepatitis, JHM.SD fails to replicate or induce pathology in the liver. These two JHM variants encode homologous proteins with few polymorphisms, and little is known about which viral proteins(s) is responsible for the liver tropism of JHM.WU. We constructed reverse genetic systems for JHM.SD and JHM.WU and, utilizing these full-length cDNA clones, constructed chimeric viruses and mapped the virulence factors involved in liver tropism. Exchanging the spike proteins of the two viruses neither increased replication of JHM.SD in the liver nor attenuated JHM.WU. By further mapping, we found that polymorphisms in JHM.WU structural protein M and nonstructural replicase proteins nsp1 and nsp13 are essential for liver pathogenesis. M protein and nsp13, the helicase, of JHM.WU are required for efficient replication in vitro and in the liver in vivo. The JHM.SD nsp1 protein contains a K194R substitution of Lys194, a residue conserved among all other MHV strains. The K194R polymorphism has no effect on in vitro replication but influences hepatotropism, and introduction of R194K into JHM.SD promotes replication in the liver. Conversely, a K194R substitution in nsp1 of JHM.WU or A59, another hepatotropic strain, significantly attenuates replication of each strain in the liver and increases IFN-ß expression in macrophages in culture. Our data indicate that both structural and nonstructural proteins contribute to MHV liver pathogenesis and support previous reports that nsp1 is a Betacoronavirus virulence factor. IMPORTANCE: The Betacoronavirus genus includes human pathogens, some of which cause severe respiratory disease. The spread of severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) into human populations demonstrates the zoonotic potential of emerging coronaviruses, and there are currently no vaccines or effective antivirals for human coronaviruses. Thus, it is important to understand the virus-host interaction that regulates coronavirus pathogenesis. Murine coronavirus infection of mice provides a useful model for the study of coronavirus-host interactions, including the determinants of tropism and virulence. We found that very small changes in coronavirus proteins can profoundly affect tropism and virulence. Furthermore, the hepatotropism of MHV-JHM depends not on the spike protein and viral entry but rather on a combination of the structural protein M and nonstructural replicase-associated proteins nsp1 and nsp13, which are conserved among betacoronaviruses. Understanding virulence determinants will aid in the design of vaccines and antiviral strategies.

Higher-order structure of the Rous sarcoma virus SP assembly domain.

UNLABELLED: Purified retroviral Gag proteins can assemble in vitro to form immature virus-like particles (VLPs). By cryoelectron tomography, Rous sarcoma virus VLPs show an organized hexameric lattice consisting chiefly of the capsid (CA) domain, with periodic stalk-like densities below the lattice. We hypothesize that the structure represented by these densities is formed by amino acid residues immediately downstream of the folded CA, namely, the short spacer peptide SP, along with a dozen flanking residues. These 24 residues comprise the SP assembly (SPA) domain, and we propose that neighboring SPA units in a Gag hexamer coalesce to form a six-helix bundle. Using in vitro assembly, alanine scanning mutagenesis, and biophysical analyses, we have further characterized the structure and function of SPA. Most of the amino acid residues in SPA could not be mutated individually without abrogating assembly, with the exception of a few residues near the N and C termini, as well as three hydrophilic residues within SPA. We interpret these results to mean that the amino acids that do not tolerate mutations contribute to higher-order structures in VLPs. Hydrogen-deuterium exchange analyses of unassembled Gag compared that of assembled VLPs showed strong protection at the SPA region, consistent with a higher-order structure. Circular dichroism revealed that a 29mer SPA peptide shifts from a random coil to a helix in a concentration-dependent manner. Analytical ultracentrifugation showed concentration-dependent self-association of the peptide into a hexamer. Taken together, these results provide strong evidence for the formation of a critical six-helix bundle in Gag assembly. IMPORTANCE: The structure of a retrovirus like HIV is created by several thousand molecules of the viral Gag protein, which assemble to form the known hexagonal protein lattice in the virus particle. How the Gag proteins pack together in the lattice is incompletely understood. A short segment of Gag known to be critical for proper assembly has been hypothesized to form a six-helix bundle, which may be the nucleating event that leads to lattice formation. The experiments reported here, using the avian Rous sarcoma virus as a model system, further define the nature of this segment of Gag, show that it is in a higher-order structure in the virus particle, and provide the first direct evidence that it forms a six-helix bundle in retrovirus assembly. Such knowledge may provide underpinnings for the development of antiretroviral drugs that interfere with virus assembly.

A European perspective on the service delivery systems for assistive technology--differences and similarities between Latvia and Sweden.

National laws and regulations on service delivery systems (SDS) for assistive technology (AT) in Europe aim to support the activity and participation of people with disabilities. The aim of this paper was to study similarities and differences in the SDS for AT of one Eastern and one Western EU member state. The legislation and regulations, and their operationalization were described from the perspective of key actors, with a focus on the ageing population. Semi-structured interviews (N = 14) were conducted in Sweden and Latvia. The informants had various professional backgrounds and organizational roles, and represented different areas of work. Similarities found were connected to legislation and policy, the aim of AT provision, the growth of a private sector and how financial resources affect the SDS. Differences were related to the availability of AT, and to how, and for and by whom the devices were provided, with Latvia prioritizing certain groups over others and excluding older people. In Latvia, despite it not being stated in the legislation, a medical perspective on AT provision was applied, whereas in Sweden, in congruence with the legislation, the perspective was explicitly biopsychosocial. Despite similarities on the legislation and policy level, interpreted based on the perceptions of professionals there are marked differences between Latvia and Sweden in the operationalization of the SDS of AT. To support activity and participation for the ageing population, the services connected to AT need to be carefully thought out and executed, making efficient use of financial resources and professional competencies.

Cell-type-specific activation of the oligoadenylate synthetase-RNase L pathway by a murine coronavirus.

Previous studies have demonstrated that the murine coronavirus mouse hepatitis virus (MHV) nonstructural protein 2 (ns2) is a 2',5'-phosphodiesterase that inhibits activation of the interferon-induced oligoadenylate synthetase (OAS)-RNase L pathway. Enzymatically active ns2 is required for efficient MHV replication in macrophages, as well as for the induction of hepatitis in C57BL/6 mice. In contrast, following intranasal or intracranial inoculation, efficient replication of MHV in the brain is not dependent on an enzymatically active ns2. The replication of wild-type MHV strain A59 (A59) and a mutant with an inactive phosphodiesterase (ns2-H126R) was assessed in primary hepatocytes and primary central nervous system (CNS) cell types-neurons, astrocytes, and oligodendrocytes. A59 and ns2-H126R replicated with similar kinetics in all cell types tested, except macrophages and microglia. RNase L activity, as assessed by rRNA cleavage, was induced by ns2-H126R, but not by A59, and only in macrophages and microglia. Activation of RNase L correlated with the induction of type I interferon and the consequent high levels of OAS mRNA induced in these cell types. Pretreatment of nonmyeloid cells with interferon restricted A59 and ns2-H126R to the same extent and failed to activate RNase L following infection, despite induction of OAS expression. However, rRNA degradation was induced by treatment of astrocytes or oligodendrocytes with poly(I·C). Thus, RNase L activation during MHV infection is cell type specific and correlates with relatively high levels of expression of OAS genes, which are necessary but not sufficient for induction of an effective RNase L antiviral response.

Characteristics of outdoor falls among older people: a qualitative study.

BACKGROUND: Falls are a major threat to older people's health and wellbeing. Approximately half of falls occur in outdoor environments but little is known about the circumstances in which they occur. We conducted a qualitative study to explore older people's experiences of outdoor falls to develop understanding of how they may be prevented. METHODS: We conducted nine focus groups across the UK (England, Wales, and Scotland). Our sample was from urban and rural settings and different environmental landscapes. Participants were aged 65+ and had at least one outdoor fall in the past year. We analysed the data using framework and content analyses. RESULTS: Forty-four adults aged 65 - 92 took part and reported their experience of 88 outdoor falls. Outdoor falls occurred in a variety of contexts, though reports suggested the following scenarios may have been more frequent: when crossing a road, in a familiar area, when bystanders were around, and with an unreported or unknown attribution. Most frequently, falls resulted in either minor or moderate injury, feeling embarrassed at the time of the fall, and anxiety about falling again. Ten falls resulted in fracture, but no strong pattern emerged in regard to the contexts of these falls. Anxiety about falling again appeared more prevalent among those that fell in urban settings and who made more visits into their neighbourhood in a typical week. CONCLUSIONS: This exploratory study has highlighted several aspects of the outdoor environment that may represent risk factors for outdoor falls and associated fear of falling. Health professionals are recommended to consider outdoor environments as well as the home setting when working to prevent falls and increase mobility among older people.

A molecular switch required for retrovirus assembly participates in the hexagonal immature lattice.

In the Rous sarcoma virus (RSV) Gag protein, the 25 amino-acid residues of the p10 domain immediately upstream of the CA domain are essential for immature particle formation. We performed systematic mutagenesis on this region and found excellent correlation between the amino-acid side chains required for in vitro assembly and those that participate in the p10-CA dimer interface in a previously described crystal structure. We introduced exogenous cysteine residues that were predicted to form disulphide bonds across the dimer interface. Upon oxidation of immature particles, a disulphide-linked Gag hexamer was formed, implying that p10 participates in and stabilizes the immature Gag hexamer. This is the first example of a critical interaction between two different Gag domains. Molecular modeling of the RSV immature hexamer indicates that the N-terminal domains of CA must expand relative to the murine leukaemia virus mature hexamer to accommodate the p10 contact; this expansion is strikingly similar to recent cryotomography results for immature human immunodeficiency virus particles.

A novel full-length isoform of murine pregnancy-specific glycoprotein 16 (psg16) is expressed in the brain but does not mediate murine coronavirus (MHV) entry.

The mouse pregnancy-specific glycoprotein 16 (PSG16) has been reported to be an alternative receptor for mouse hepatitis virus (MHV), some strains of which cause encephalitis in mice lacking the canonical receptor CEACAM1a. The known isoforms of PSG16 are N-terminally truncated relative to other PSG family proteins and are expressed in neurons as well as in the placenta. We have cloned a novel full-length isoform of psg16 that is also expressed in the brain, placenta, and retina but, like the truncated form, lacks MHV receptor activity when expressed on 293T cells, suggesting that PSG16 does not mediate CEACAM1a-independent spread of MHV.

Murine coronavirus receptors are differentially expressed in the central nervous system and play virus strain-dependent roles in neuronal spread.

Coronavirus infection of the murine central nervous system (CNS) provides a model for studies of viral encephalitis and demyelinating disease. Mouse hepatitis virus (MHV) neurotropism varies by strain: MHV-A59 causes mild encephalomyelitis and demyelination, while the highly neurovirulent strain JHM.SD (MHV-4) causes fatal encephalitis with extensive neuronal spread of virus. In addition, while neurons are the predominant CNS cell type infected in vivo, the canonical receptor for MHV, the carcinoembryonic antigen family member CEACAM1a, has been demonstrated only on endothelial cells and microglia. In order to investigate whether CEACAM1a is also expressed in other cell types, ceacam1a mRNA expression was quantified in murine tissues and primary cells. As expected, among CNS cell types, microglia expressed the highest levels of ceacam1a, but lower levels were also detected in oligodendrocytes, astrocytes, and neurons. Given the low levels of neuronal expression of ceacam1a, primary neurons from wild-type and ceacam1a knockout mice were inoculated with MHV to determine the extent to which CEACAM1a-independent infection might contribute to CNS infection. While both A59 and JHM.SD infected small numbers of ceacam1a knockout neurons, only JHM.SD spread efficiently to adjacent cells in the absence of CEACAM1a. Quantification of mRNA for the ceacam1a-related genes ceacam2 and psg16 (bCEA), which encode proposed alternative MHV receptors, revealed low ceacam2 expression in microglia and oligodendrocytes and psg16 expression exclusively in neurons; however, only CEACAM2 mediated infection in human 293T cells. Therefore, neither CEACAM2 nor PSG16 is likely to be an MHV receptor on neurons, and the mechanism for CEACAM1a-independent neuronal spread of JHM.SD remains unknown.

Conserved and variable features of Gag structure and arrangement in immature retrovirus particles.

The assembly of retroviruses is driven by oligomerization of the Gag polyprotein. We have used cryo-electron tomography together with subtomogram averaging to describe the three-dimensional structure of in vitro-assembled Gag particles from human immunodeficiency virus, Mason-Pfizer monkey virus, and Rous sarcoma virus. These represent three different retroviral genera: the lentiviruses, betaretroviruses and alpharetroviruses. Comparison of the three structures reveals the features of the supramolecular organization of Gag that are conserved between genera and therefore reflect general principles of Gag-Gag interactions and the features that are specific to certain genera. All three Gag proteins assemble to form approximately spherical hexameric lattices with irregular defects. In all three genera, the N-terminal domain of CA is arranged in hexameric rings around large holes. Where the rings meet, 2-fold densities, assigned to the C-terminal domain of CA, extend between adjacent rings, and link together at the 6-fold symmetry axis with a density, which extends toward the center of the particle into the nucleic acid layer. Although this general arrangement is conserved, differences can be seen throughout the CA and spacer peptide regions. These differences can be related to sequence differences among the genera. We conclude that the arrangement of the structural domains of CA is well conserved across genera, whereas the relationship between CA, the spacer peptide region, and the nucleic acid is more specific to each genus.

Cognitive impairment negatively impacts allied health service uptake: Investigating the association between health and service use.

There is widespread concern about the potential impact on health and social care services of the ageing population and long-term health conditions, such as dementia. To effectively plan services it is important to understand current need and use and identify gaps in provision. Using data from the Cognitive Function and Ageing Study Wales (CFAS Wales), we used logistic regression to model the relationship between health (self-rated health, cognitive impairment, and activities of daily living), and the use of health and care services. CFAS Wales is a longitudinal cohort study of people aged 65 years and over, in two areas in Wales, UK, over-sampling those aged 75 years and over. Participants (n = 3593) answered a wide range of health and lifestyle questions and completed a variety of cognitive and physical health assessments. Data from 3153 people from wave 1 and 1968 people from wave 2 were analysed. As anticipated we found poorer health, on some indicators, predicted greater service use, including social care, hospital, general practitioner, and nursing services. However, cognitive impairment did not predict greater service use, except for social care. Controlling for age, sex, socio-economic status, social connection indices and area environment, conversely we found lower reported uptake of allied health services by people with cognitive impairment. Further analysis showed that people with a cognitive impairment were less likely to report having a sight-check or seeing a dentist in the previous year, a finding replicated in wave 2. These differences were not explained by transportation issues. In contrast, we did not find a significant difference in reported uptake of hearing checks or physiotherapist use, with mixed evidence of differences in chiropodist visits. Not accessing these preventative services may not only exacerbate existing conditions but have further downstream negative consequences for health and well-being in people who are cognitively impaired.

Support and Assessment for Fall Emergency Referrals (SAFER 1) trial protocol. Computerised on-scene decision support for emergency ambulance staff to assess and plan care for older people who have fallen: evaluation of costs and benefits using a pragmatic cluster randomised trial.

BACKGROUND: Many emergency ambulance calls are for older people who have fallen. As half of them are left at home, a community-based response may often be more appropriate than hospital attendance. The SAFER 1 trial will assess the costs and benefits of a new healthcare technology--hand-held computers with computerised clinical decision support (CCDS) software--to help paramedics decide who needs hospital attendance, and who can be safely left at home with referral to community falls services. METHODS/DESIGN: Pragmatic cluster randomised trial with a qualitative component. We shall allocate 72 paramedics ('clusters') at random between receiving the intervention and a control group delivering care as usual, of whom we expect 60 to complete the trial.Patients are eligible if they are aged 65 or older, live in the study area but not in residential care, and are attended by a study paramedic following an emergency call for a fall. Seven to 10 days after the index fall we shall offer patients the opportunity to opt out of further follow up. Continuing participants will receive questionnaires after one and 6 months, and we shall monitor their routine clinical data for 6 months. We shall interview 20 of these patients in depth. We shall conduct focus groups or semi-structured interviews with paramedics and other stakeholders.The primary outcome is the interval to the first subsequent reported fall (or death). We shall analyse this and other measures of outcome, process and cost by 'intention to treat'. We shall analyse qualitative data thematically. DISCUSSION: Since the SAFER 1 trial received funding in August 2006, implementation has come to terms with ambulance service reorganisation and a new national electronic patient record in England. In response to these hurdles the research team has adapted the research design, including aspects of the intervention, to meet the needs of the ambulance services.In conclusion this complex emergency care trial will provide rigorous evidence on the clinical and cost effectiveness of CCDS for paramedics in the care of older people who have fallen. TRIAL REGISTRATION: ISRCTN10538608.

How older people as pedestrians perceive the outdoor environment - methodological issues derived from studies in two European countries.

This paper has re-analysed and compared data between three studies conducted in the United Kingdom and in Sweden (the OPUS 'Older People's Use of Unfamiliar Space' study in the United Kingdom and the Swedish studies 'Let's Go for a Walk' and 'Walking in Old Age') to provide a comprehensive account of the issues facing older people in the outdoor environment. All three studies draw on the 'fit' between the person and their environment as a guiding conceptual base - capturing the dynamics of the relationship between older people's personal needs and their wider environmental context. This common conceptual base allowed us to test theory against practice, and to explore the utility of this concept across different geographical contexts. Participatory research was also applied, highlighting the importance of the voice of older people and involving older people in research. The studies also used a mixed-method approach involving both quantitative and qualitative methods. The paper highlights that although not generalisable, you can compare cross-locales and cross-nationally using different methodology; it investigates the challenges of cross-national comparative analysis and draws on findings from the three studies to illustrate the different challenges and solutions and finally looks at lessons that are transferable.

Support and Assessment for Fall Emergency Referrals (SAFER) 2: a cluster randomised trial and systematic review of clinical effectiveness and cost-effectiveness of new protocols for emergency ambulance paramedics to assess older people following a fall with referral to community-based care when appropriate.

BACKGROUND: Emergency calls are frequently made to ambulance services for older people who have fallen, but ambulance crews often leave patients at the scene without any ongoing care. We evaluated a new clinical protocol which allowed paramedics to assess older people who had fallen and, if appropriate, refer them to community-based falls services. OBJECTIVES: To compare outcomes, processes and costs of care between intervention and control groups; and to understand factors which facilitate or hinder use. DESIGN: Cluster randomised controlled trial. PARTICIPANTS: Participating paramedics at three ambulance services in England and Wales were based at stations randomised to intervention or control arms. Participants were aged 65 years and over, attended by a study paramedic for a fall-related emergency service call, and resident in the trial catchment areas. INTERVENTIONS: Intervention paramedics received a clinical protocol with referral pathway, training and support to change practice. Control paramedics continued practice as normal. OUTCOMES: The primary outcome comprised subsequent emergency health-care contacts (emergency admissions, emergency department attendances, emergency service calls) or death at 1 month and 6 months. Secondary outcomes included pathway of care, ambulance service operational indicators, self-reported outcomes and costs of care. Those assessing outcomes remained blinded to group allocation. RESULTS: Across sites, 3073 eligible patients attended by 105 paramedics from 14 ambulance stations were randomly allocated to the intervention group, and 2841 eligible patients attended by 110 paramedics from 11 stations were randomly allocated to the control group. After excluding dissenting and unmatched patients, 2391 intervention group patients and 2264 control group patients were included in primary outcome analyses. We did not find an effect on our overall primary outcome at 1 month or 6 months. However, further emergency service calls were reduced at both 1 month and 6 months; a smaller proportion of patients had made further emergency service calls at 1 month (18.5% vs. 21.8%) and the rate per patient-day at risk at 6 months was lower in the intervention group (0.013 vs. 0.017). Rate of conveyance to emergency department at index incident was similar between groups. Eight per cent of trial eligible patients in the intervention arm were referred to falls services by attending paramedics, compared with 1% in the control arm. The proportion of patients left at scene without further care was lower in the intervention group than in the control group (22.6% vs. 30.3%). We found no differences in duration of episode of care or job cycle. No adverse events were reported. Mean cost of the intervention was £17.30 per patient. There were no significant differences in mean resource utilisation, utilities at 1 month or 6 months or quality-adjusted life-years. In total, 58 patients, 25 paramedics and 31 stakeholders participated in focus groups or interviews. Patients were very satisfied with assessments carried out by paramedics. Paramedics reported that the intervention had increased their confidence to leave patients at home, but barriers to referral included patients' social situations and autonomy. CONCLUSIONS: Findings indicate that this new pathway may be introduced by ambulance services at modest cost, without risk of harm and with some reductions in further emergency calls. However, we did not find evidence of improved health outcomes or reductions in overall NHS emergency workload. Further research is necessary to understand issues in implementation, the costs and benefits of e-trials and the performance of the modified Falls Efficacy Scale. TRIAL REGISTRATION: Current Controlled Trials ISRCTN60481756 and PROSPERO CRD42013006418. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 13. See the NIHR Journals Library website for further project information.

Enhanced trauma program commitment at a level I trauma center: effect on the process and outcome of care.

HYPOTHESIS: With advances in surgical care, the occurrences of major adverse outcomes have become a rare event. The effect of a surgical service can be more comprehensively evaluated by following the Donabedian model, looking at the triad of structure, process, and outcome. It is hypothesized that the implementation of a focused program commitment at a trauma center is associated with improvements in process of care and patient outcomes. DESIGN: Evaluation of prospectively collected information in a trauma registry for the 3-year periods immediately before (1995-1997) and after (1999-2001) the implementation (in 1998) of the full-time trauma service. SETTING: Level I university-affiliated trauma center. PATIENTS: Patients meeting criteria for major trauma. INTERVENTION: The implementation of a full-time trauma service, featuring 24-hour in-house attending coverage, dedicated trauma admitting unit, regular trauma core curriculum, regular multidisciplinary quality assurance meetings, and state designation for level I status. MAIN OUTCOME MEASURES: Process of care measures, including time in the emergency department (ED) and trauma "bypass" hours (ie, time spent in the trauma resuscitation area). Outcome measures, including lengths of stay, overall mortality and mortality, excluding ED deaths. RESULTS: The total number of patients with major trauma increased from 2240 (1995-1997) to 2513 (1999-2001). The average time in the ED for patients going to the operating room, intensive care unit, and observation wards all decreased significantly (84 vs 52 minutes, 197 vs 118 minutes, and 300 vs 140 minutes, respectively; all with P<.01). The number of hours that the trauma center was closed owing to ED overcrowding also decreased significantly, from 56 to 2.7 hours per month (P<.01). After excluding ED deaths, there was a trend on bivariate analyses toward lower overall mortality rates (4.5% vs 3.4%, P =.07) and mortality rates among patients with severe head injury (23.8% vs 17.2%, P =.07). On further analyses with multiple logistic regression, controlling for age, Injury Severity Score, Abbreviated Injury Score (for a head injury), and admission blood pressure, the later period is associated with a 31% decrease in overall odds of death (P =.047) and a 42% decrease in odds of death among patients with severe head injury (an Abbreviated Injury Score, >or=3; P =.03). CONCLUSION: The implementation of a full-time trauma service is associated with improved timeliness of triage and therapeutic interventions and improved patient outcomes.

Community characteristics and demographic information as determinants for a hospital-based injury prevention outreach program.

HYPOTHESIS: To focus the efforts of a hospital-based injury prevention outreach program, information on patient demographics, community characteristics, and catchment area must be known. DESIGN AND SETTING: Evaluation of prospectively collected data maintained in the Trauma Registry of a level I university-based trauma center. PATIENTS AND MAIN OUTCOME MEASURES: Demographics, mechanism of injury, mortality, and home ZIP codes of patients admitted to the Adult Trauma Service, The Johns Hopkins Medical Institution, Baltimore, Md, were compared for 2 separate calendar years, at 2 years before (1995) and at 2 years after (2000) the implementation of a dedicated trauma program that includes an injury prevention outreach program. RESULTS: The list of common patient ZIP codes varied minimally from 1995 to 2000. The 18 most common ZIP codes represent (1) 80% of patients, (2) total area of 99 square miles (257.4 km2) (5.7-mile [9.1-km] radius), and (3) a region with a mean household income that is 67% of the statewide median. An increasingly disproportionate percentage of patients with gunshot wounds (GSWs) were the youngest patients (ages 15-24 years) treated by the Adult Trauma Service. While overall survival of trauma patients improved in 2000, no improvement was seen among patients with GSWs. Over half of the nonsurviving patients (37/65 [57%]) seen in 2000 and more than two thirds of patients with lethal GSWs (25/37 [67.6%]) were declared dead in the emergency department, suggesting nonpreventability from a clinical care standpoint. CONCLUSIONS: The catchment area represented by the bulk of patients admitted to a level I urban trauma center is compact and economically disadvantaged. While overall trauma mortality has decreased, GSWs are more lethal and prevalent in teenagers and young men. This identifies violence prevention as an area of emphasis.

Early leukocytosis in trauma patients: what difference does it make?

OBJECTIVE: To determine the association of the admission white blood cell count in trauma patients with demographics, severity and mechanism of injury, and need for therapeutic intervention. METHODS: Evaluation of prospectively collected registry data (admissions to a Level I trauma center in 2001). Differences in mean white blood cell count on admission were evaluated with t tests. Multiple linear regressions were performed with forward stepwise selection of variables. RESULTS: Of the 882 patients admitted for greater than 24 hours, white blood cell count was available for 786. Variations in white blood cell count were noted on bivariate analysis among different races, injury mechanisms and severities, Glasgow Coma Scores, blood pressures, and between patients requiring early transfusions versus those who did not. No difference was noted between patients who went to the operating room in the first 24 hours versus those who did not, or for patients who died in the hospital. On multiple linear regression analyses, only ISS greater than 15, GCS less than or equal to 8, and white race were associated with increases in white blood cell count. Leukocytosis was found not to be associated with mechanism of injury, specific organ injury, shock on admission, or the need for transfusion or surgery. CONCLUSION: Variations in white blood cell count in trauma patients are associated with race and injury severity, but they are not beneficial in predicting the need for volume resuscitation, transfusion, or surgery.