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Background: Delivering hospital-level care with comprehensive geriatric assessment (CGA) in the home is one approach to deal with the increased demand for bed-based hospital care, but clinical effectiveness is uncertain. Objective: To assess the clinical effectiveness of admission avoidance hospital at home (HAH) with CGA for older persons. Design: Multisite randomized trial. (ISRCTN registry number: ISRCTN60477865) Setting: 9 hospital and community sites in the United Kingdom. Patients: 1055 older persons who were medically unwell, were physiologically stable, and were referred for a hospital admission. Intervention: Admission avoidance HAH with CGA versus hospital admission with CGA when available using 2:1 randomization. Measurements: The primary outcome of living at home was measured at 6 months. Secondary outcomes were new admission to long-term residential care, death, health status, delirium, and patient satisfaction. Results: Participants had a mean age of 83.3 years (SD, 7.0). At 6-month follow-up, 528 of 672 (78.6%) participants in the CGA HAH group versus 247 of 328 (75.3%) participants in the hospital group were living at home (relative risk [RR], 1.05 [95% CI, 0.95 to 1.15]; P = 0.36); 114 of 673 (16.9%) versus 58 of 328 (17.7%) had died (RR, 0.98 [CI, 0.65 to 1.47]; P = 0.92); and 37 of 646 (5.7%) versus 27 of 311 (8.7%) were in long-term residential care (RR, 0.58 [CI, 0.45 to 0.76]; P < 0.001). Limitation: The findings are most applicable to older persons referred from a hospital short-stay acute medical assessment unit; episodes of delirium may have been undetected. Conclusion: Admission avoidance HAH with CGA led to similar outcomes as hospital admission in the proportion of older persons living at home as well as a decrease in admissions to long-term residential care at 6 months. This type of service can provide an alternative to hospitalization for selected older persons. Primary Funding Source: The National Institute for Health Research Health Services and Delivery Research Programme (12/209/66).

Key summary points Aim To identify, evaluate and synthesise the evidence concerning the physical activity levels of acutely-ill older patients undergoing ‘Hospital At Home’ treatment compared to those of patients with similar characteristics in a traditional hospital inpatient setting. Findings No studies on the physical activity levels of acutely ill older adults in Hospital At Home Settings were identified. Patients managed in inpatient settings that would be eligible for Hospital At Home services spend 6.6% of their day active and perform only 881.8 daily steps, placing them at increased risk of functional decline. Message There is a lack of published research on physical activity in acutely ill older adults in Hospital At Home sttings; further research is needed. Electronic supplementary material The online version of this article (10.1007/s41999-020-00414-y) contains supplementary material, which is available to authorized users., Purpose The purpose of this review was to identify, evaluate and synthesise existing evidence reporting the physical activity levels of acutely ill older patients in a ‘Hospital At Home’ setting and compare this to patients with similar characteristics treated in a traditional hospital inpatient setting. Functional changes and any adverse outcomes due to physical activity (e.g. falls) in both settings where PA was reported or recorded were also evaluated as secondary outcomes. Methods A search strategy was devised for the MEDLINE, CINAHL, AMed, PEDRO, OT Seeker and Cochrane databases. Search results were title, abstract and full-text reviewed by two independent researchers. Data were extracted from included articles using a custom form and assessed for quality and risk of bias using the Appraisal Tool for Cross-Sectional Studies. Results No studies set in the Hospital at Home environments were identified. 16 hospital inpatient studies met the criteria for inclusion. Older patients managed in inpatient settings that would be eligible for Hospital at Home services spent 6.6% of their day active and undertook only 881.8 daily steps. Functional change was reported in four studies with both improvement and decline during admission reported. Conclusion There is a lack of published research on the physical activity levels of acutely-ill older adults in Hospital at Home settings. This review has identified a baseline level of activity for older acutely ill patients that would be suitable for Hospital at Home treatment. This data could be used as a basis of comparison in future hospital at home studies, which should also include functional change outcomes to further explore the relationship between physical inactivity and functional decline. Electronic supplementary material The online version of this article (10.1007/s41999-020-00414-y) contains supplementary material, which is available to authorized users.

Background There is limited understanding of the contribution made by older people and their caregivers to acute healthcare in the home and how this compares to hospital inpatient healthcare. Objectives To explore the work of older people and caregivers at the time of an acute health event, the interface with professionals in a hospital and hospital at home (HAH) and how their experiences relate to the principles underpinning comprehensive geriatric assessment (CGA). Design A qualitative interview study within a UK multi-site participant randomised trial of geriatrician-led admission avoidance HAH, compared with hospital inpatient care. Methods We conducted semi-structured interviews with 34 older people (15 had received HAH and 19 hospital care) alone or alongside caregivers (29 caregivers; 12 HAH, 17 hospital care), in three sites that recruited participants to a randomised trial, during 2017–2018. We used normalisation process theory to guide our analysis and interpretation of the data. Results Patients and caregivers described efforts to understand changes in health, interpret assessments and mitigate a lack of involvement in decisions. Practical work included managing risks, mobilising resources to meet health-related needs, and integrating the acute episode into longer-term strategies. Personal, relational and environmental factors facilitated or challenged adaptive capacity and ability to manage. Conclusions Patients and caregivers contributed to acute healthcare in both locations, often in parallel to healthcare providers. Our findings highlight an opportunity for CGA-guided services at the interface of acute and chronic condition management to facilitate personal, social and service strategies extending beyond an acute episode of healthcare.

Odanacatib (ODN), a selective oral inhibitor of cathepsin K, was an investigational agent previously in development for the treatment of osteoporosis. In this analysis, the effects of ODN on bone remodeling/modeling and structure were examined in the randomized, double-blind, placebo-controlled, event-driven, Phase 3, Long-term Odanacatib Fracture Trial (LOFT; NCT00529373) and planned double-blind extension in postmenopausal women with osteoporosis. A total of 386 transilial bone biopsies, obtained from consenting patients at baseline (ODN n = 17, placebo n = 23), month 24 (ODN n = 112, placebo n = 104), month 36 (ODN n = 42, placebo n = 41), and month 60 (ODN n = 27, placebo n = 20) were assessed by dynamic and static bone histomorphometry. Patient characteristics at baseline and BMD changes over 5 years for this subset were comparable to the overall LOFT population. Qualitative assessment of biopsies revealed no abnormalities. Consistent with the mechanism of ODN, osteoclast number was higher with ODN versus placebo over time. Regarding bone remodeling, dynamic bone formation indices in trabecular, intracortical, and endocortical surfaces were generally similar in ODN-treated versus placebo-treated patients after 2 years of treatment. Regarding periosteal modeling, the proportion of patients with periosteal double labels and the bone formation indices increased over time in the ODN-treated patients compared with placebo. This finding supported the observed numerical increase in cortical thickness at month 60 versus placebo. In conclusion, ODN treatment for 5 years did not reduce bone remodeling and increased the proportion of patients with periosteal bone formation. These results are consistent with the mechanism of action of ODN, and are associated with continued BMD increases and reduced risk of fractures compared with placebo in the LOFT Phase 3 fracture trial. © 2020 American Society for Bone and Mineral Research.

Background Alirocumab reduces low-density lipoprotein cholesterol (LDL-C) levels by up to 61%. The ODYSSEY Open-Label Extension study investigated the effect of alirocumab in patients with heterozygous familial hypercholesterolaemia (HeFH) over 144 weeks. Methods Eligible patients with HeFH had completed an earlier double-blind, randomised, placebo-controlled parent study. Patients were initiated on 75 mg alirocumab Q2W subcutaneous (SC) unless baseline LDL-C was > 8.9 mmol/l, in which case they received 150 mg alirocumab Q2W. Dose titration to 150 mg Q2W was at the investigator's discretion. Results The study enrolled 167 patients and the parent study mean (± SD) baseline LDL-C level was 3.65 ± 1.9 mmol/l. Mean LDL-C level was reduced by 48.7% at week 144; mean on-treatment LDL-C was 2.30 ± 1.24 mmol/l. Eight patients reported injection-site reactions, with one treatment discontinuation. Treatment emergent anti-drug antibodies were identified in five patients but these did not affect the efficacy. Conclusions Alirocumab effectively and safely reduced LDL-C in these patients.

Background: Anticholinergic burden (ACB), is defined as the cumulative effect of anticholinergic medication which are widely prescribed to older adults despite increasing ACB being associated with adverse effects such as: falls, dementia and increased mortality. This research explores the views of health care professionals (HCPs) and patients on a planned trial to reduce ACB by stopping or switching anticholinergic medications. The objectives were to explore the views of key stakeholders (patients, the public, and HCPs) regarding the potential acceptability, design and conduct of an ACB reduction trial.Materials and Methods: We conducted qualitative interviews and focus groups with 25 HCPs involved in prescribing medication with anticholinergic properties and with 22 members of the public and patients who were prescribed with the medication. Topic guides for the interviews and focus groups explored aspects of feasibility including: 1) views of a trial of de-prescribing/medication switching; 2) how to best communicate information about such a trial; 3) views on who would be best placed and preferred to undertake such medication changes, e.g., pharmacists or General Practitioners (GPs)? 4) perceived barriers and facilitators to trial participation and the smooth conduct of such a trial; 5) HCP views on the future implementability of this approach to reducing ACB and 6) patients’ willingness to be contacted for participation in a future trial. Qualitative data analysis was underpinned by Normalization Process Theory.Results: The public, patients and HCPs were supportive of an ACB reduction trial. There was consensus among the different groups that key points to consider with such a trial included: 1) ensuring patient engagement throughout to enable concerns/potential pitfalls to be addressed from the beginning; 2) ensuring clear communication to minimise potential misconceptions about the reasons for ACB reduction; and 3) provision of access to a point of contact for patients throughout the life of a trial to address concerns; The HCPs in particular suggested two more key points: 4) minimise the workload implications of any trial; and 5) pharmacists may be best placed to carry out ACB reviews, though overall responsibility for patient medication should remain with GPs.Conclusion: Patients, the public and HCPs are supportive of trials to reduce ACB. Good communication and patient engagement during design and delivery of a trial are essential as well as safety netting and minimising workload.

Background hospital level healthcare in the home guided by comprehensive geriatric assessment (CGA) might provide a less costly alternative to hospitalisation for older people. Objective to determine the cost-effectiveness of CGA admission avoidance hospital at home (HAH) compared with hospital admission. Design/intervention a cost-effectiveness study alongside a randomised trial of CGA in an admission avoidance HAH setting, compared with admission to hospital. Participants/setting older people considered for a hospital admission in nine locations across the UK were randomised using a 2:1 randomisation schedule to admission avoidance HAH with CGA (N = 700), or admission to hospital with CGA when available (N = 355). Measurements quality adjusted life years, resource use and costs at baseline and 6 months; incremental cost-effectiveness ratios were calculated. The main analysis used complete cases. Results adjusting for baseline covariates, HAH was less costly than admission to hospital from a health and social care perspective (mean −£2,265, 95% CI: −4,279 to −252), and remained less costly with the addition of informal care costs (mean difference −£2,840, 95% CI: −5,495 to −185). There was no difference in quality adjusted survival. Using multiple imputation for missing data, the mean difference in health and social care costs widened to −£2,458 (95% CI: −4,977 to 61) and societal costs remained significantly lower (−£3,083, 95% CI: −5,880 to −287). There was little change to quality adjusted survival. Conclusions CGA HAH is a cost-effective alternative to admission to hospital for selected older people.

Geriatric medicine is a speciality that has historically relied on team working to best serve patients. The nature of frailty in older people means that people present with numerous comorbidities, which in turn require a team-based approach to be managed, including allied health professionals, social work and nursing alongside medicine. The 'engine room' of the speciality has thus for many years been the multidisciplinary team (MDT) meeting-something other specialities have discovered only recently. Yet, rather paradoxically, the speciality has been slow compared to others (e.g. trauma, surgery, cancer) to reflect more formally on how team working can be enhanced, trained and supported in geriatric teams. This paper is a reflective review, grounded on our respective expertise in geriatric medicine and improvement science, on practice and its changing patterns within geriatric medicine, and the role of MDTs within it (Part 1). It offers a perspective from behavioural safety science, which has been studying team-working in healthcare for the last 20 years (Part 2) and concludes with practical suggestions, based on evidence, on how to integrate evidence and best practice into modern geriatric medicine-to address current and future challenges (Part 3).

BACKGROUND Hospital at home (HaH) replicates elements of hospital-based care in the community, to facilitate the safe management of a broad spectrum of acute illness in the patient's usual environment. The extent to which this model of care has been adopted in the United Kingdom is unknown. METHODS The Society for Acute Medicine Benchmarking Audit is a day of care survey undertaken annually within the United Kingdom. Participation is open to all hospital in the United Kingdom receiving acutely unwell medical patients. A questionnaire is used to collect hospital-level data on the structure and organisation of acute care delivery. The survey included questions designed to quantify the number of hospitals that offered HaH. When present, further questions were asked to clarify the characteristics of the HaH service in terms of workforce, range of diagnostic test and interventions. This information was used to build a picture of HaH service provision on a national scale. RESULTS A total of 130 hospitals contributed organisational data to SAMBA19. The capability to refer to a hospital at home service was recognised by 46.9% (n = 61) of units. The majority of these services, 83.3% (n = 50) were nurse-led. The capability to provide a physician review at home was reported in 23.3% (n = 14). The majority of services could provide intravenous antibiotics at home, but access to other simple interventions, such as intravenous diuretics or acute supplemental oxygen, is limited. CONCLUSION At present, few acute hospitals for consitency in the United Kingdom have access to a hospital at home service capable of replicating essential elements of inpatient care. Our study suggests organisational change in acute care delivery and significant investment would be required to establish equal access to hospital-at-home care within the United Kingdom.

In 2008, a proposal for assessing the risk of induction of skin sensitization to fragrance materials Quantitative Risk Assessment 1 (QRA1) was published. This was implemented for setting maximum limits for fragrance materials in consumer products. However, there was no formal validation or empirical verification after implementation. Additionally, concerns remained that QRA1 did not incorporate aggregate exposure from multiple product use and included assumptions, e.g. safety assessment factors (SAFs), that had not been critically reviewed. Accordingly, a review was undertaken, including detailed re-evaluation of each SAF together with development of an approach for estimating aggregate exposure of the skin to a potential fragrance allergen. This revision of QRA1, termed QRA2, provides an improved method for establishing safe levels for sensitizing fragrance materials in multiple products to limit the risk of induction of contact allergy. The use of alternative non-animal methods is not within the scope of this paper. Ultimately, only longitudinal clinical studies can verify the utility of QRA2 as a tool for the prevention of contact allergy to fragrance materials.

Older people usually present to hospital because of a crisis: a sudden change in health, function, or circumstances that causes worry, distress, or overwhelms independence or care provision. Crises may relate to the individual, the carer, care systems, or the environment. At the point of presentation it may not be clear which, or what combination, of these is responsible. It is necessary to identify all relevant factors for hospital care to be effective and efficient. Admission to hospital for an acute illness can have a major negative impact on an older person’s ongoing functional abilities, hence systems of care need to know when to expect and how to manage functional deterioration.

Cosmetic regulations prohibit animal testing for the purpose of safety assessment and recent registration, evaluation and authorization of chemicals guidance states that the local lymph node assay (LLNA) in mice shall only be conducted if in vitro data cannot give sufficient information for classification and labeling. However, Quantitative Risk Assessment for fragrance ingredients requires an NESIL (no expected sensitization induction level), a dose not expected to cause induction of skin sensitization in humans. In absence of human data, this is derived from the LLNA and it remains a key challenge for risk assessors to derive this value from nonanimal data. Here we present a workflow using structural information, reactivity data and KeratinoSens results to predict an LLNA result as a point of departure. Specific additional tests (metabolic activation, complementary reactivity tests) are applied in selected cases depending on the chemical domain of a molecule. Finally, in vitro and in vivo data on close analogues are used to estimate uncertainty of the prediction in the specific chemical domain. This approach was applied to three molecules which were subsequently tested in the LLNA and 22 molecules with available and sometimes discordant human and LLNA data. Four additional case studies illustrate how this approach is being applied to recently developed molecules in the absence of animal data. Estimation of uncertainty and how this can be applied to determine a final NESIL for risk assessment is discussed. We conclude that, in the data-rich domain of fragrance ingredients, sensitization risk assessment without animal testing is possible in most cases by this integrated approach.

Background Lateral flow device (LFD) viral antigen immunoassays have been developed around the world as diagnostic tests for SARS-CoV-2 infection. They have been proposed to deliver an infrastructure-light, cost-economical solution giving results within half an hour. Methods LFDs were initially reviewed by a Department of Health and Social Care team, part of the UK government, from which 64 were selected for further evaluation from 1st August to 15th December 2020. Standardised laboratory evaluations, and for those that met the published criteria, field testing in the Falcon-C19 research study and UK pilots were performed (UK COVID-19 testing centres, hospital, schools, armed forces). Findings 4/64 LFDs so far have desirable performance characteristics (orient Gene, Deepblue, Abbott and Innova SARS-CoV-2 Antigen Rapid Qualitative Test). All these LFDs have a viral antigen detection of >90% at 100,000 RNA copies/ml. 8951 Innova LFD tests were performed with a kit failure rate of 5.6% (502/8951, 95% CI: 5.1–6.1), false positive rate of 0.32% (22/6954, 95% CI: 0.20–0.48). Viral antigen detection/sensitivity across the sampling cohort when performed by laboratory scientists was 78.8% (156/198, 95% CI 72.4–84.3). Interpretation Our results suggest LFDs have promising performance characteristics for mass population testing and can be used to identify infectious positive individuals. The Innova LFD shows good viral antigen detection/sensitivity with excellent specificity, although kit failure rates and the impact of training are potential issues. These results support the expanded evaluation of LFDs, and assessment of greater access to testing on COVID-19 transmission. Funding Department of Health and Social Care. University of Oxford. Public Health England Porton Down, Manchester University NHS Foundation Trust, National Institute of Health Research.

Erworben im Rahmen der Schweizer Nationallizenzen (http://www.nationallizenzen.ch) Several aromatic aldehydes such as 3-(4-tert-butylphenyl)-2-methylpropanal were shown to adversely affect the reproductive system in male rats following oral gavage dose of ≥ 25 mg/kg bw/d. It was hypothesized that these aldehydes are metabolized to benzoic acids such as p-tert-butylbenzoic acid as key toxic principle and that Coenzyme A (CoA) conjugates may be formed from such acids. Here we performed a detailed structure activity relationship study on the formation of benzoic acids from p-alkyl-phenylpropanals and related chemicals in rat hepatocytes in suspension. Formation of CoA conjugates from either p-alkyl-phenylpropanals directly or from their benzoic acid metabolites was further assessed in plated rat hepatocytes using high resolution LC-MS. All of the test chemicals causing reproductive adverse effects in male rats formed p-alkyl-benzoic acids in rat hepatocytes in suspension. Compounds metabolized to p-alkyl-benzoic acids led to accumulation of p-alkyl-benzoyl-CoA conjugates at high and steady levels in plated rat hepatocytes, whereas CoA conjugates of most other xenobiotic acids were only transiently detected in this in vitro system. The correlation between this metabolic fate and the toxic outcome may indicate that accumulation of the alkyl-benzoyl-CoA conjugates in testicular cells could impair male reproduction by adversely affecting CoA-dependent processes required for spermatogenesis. This hypothesis prompted a search for new p-alkyl-phenylpropanal derivatives which do not form benzoic acid metabolites and the corresponding CoA conjugates. It was found that such metabolism did not occur with a derivative containing an o-methyl substituent, ie, 3-(4-isobutyl-2-methylphenyl)propanal. This congener preserved the fragrance quality but lacked the male reproductive toxicity in a 28-day rat study, as predicted from its in vitro metabolism.

In order to accurately assess aggregate exposure to a fragrance material in consumers, data are needed on consumer habits and practices, as well as the concentration of the fragrance material in those products. The present study describes the development of Phase 2 Creme RIFM model by expanding the previously developed Phase 1 model to include an additional six product types. Using subject-matching algorithms, the subjects in the Phase 1 Creme RIFM database were paired with subjects in the SUPERB and BodyCare surveys based on age and gender. Consumption of the additional products was simulated to create a seven day diary allowing full data integration in a consistent format. The inhalation route was also included for air care and other products where a fraction of product used is inhaled, derived from the RIFM 2-box model. The expansion of the Phase 1 Creme RIFM model has resulted in a more extensive and refined model, which covers a broader range of product categories and now, includes all relevant routes of exposure. An evaluation of the performance of the model has been carried out in an accompanying publication to this one.

We describe the basic ingredients of a general computational framework for performing machine calculations in the cohomology of groups. This has been implemented in the GAP system for computational algebra and the paper is intended to aid those wishing to extend that implementation to their own needs.

ObjectiveTo determine if age is a factor in a patients’ likelihood of breaching the 4 hour time target to admission/discharge in emergency departments (EDs) within NHS Scotland.MethodsWe used data from the Information Service Division Scotland to analyse all ED attendances in Scotland between January 2015 and September 2018 (n=5 596 642). We assessed the likelihood of time to admission/discharge being within 4 hours, 8 hours and 12 hours for all age categories (reference category 20 to 24 years). Univariable logistic regressions were carried out for sex, Scottish Index of Multiple Deprivation level and both major (potentially life threatening) and minor (not immediately life threatening) incidences.ResultsThe likelihood of breaching the 4-hour target increased linearly with age from 15 to 19 years upward. Patients ≥85 years were significantly (pConclusionsOlder age is associated with a higher probability of breaching waiting time targets in a linear fashion within NHS Scotland, which is consistent with previous single hospital or regional studies. This association may be due to the higher proportion of elderly patients being admitted or a more systemic issue, but regardless, the elderly are being put more at risk.

This book is an introduction to elementary algebraic topology for students with an interest in computers and computer programming. Its aim is to illustrate how the basics of the subject can be implemented on a computer. The transition from basic theory to practical computation raises a range of non-trivial algorithmic issues and it is hoped that the treatment of these will also appeal to readers already familiar with basic theory who are interested in developing computational aspects. The book covers a subset of standard introductory material on fundamental groups, covering spaces, homology, cohomology and classifying spaces as well as some less standard material on crossed modules, homotopy 2- types and explicit resolutions for an eclectic selection of discrete groups. It attempts to cover these topics in a way that hints at potential applications of topology in areas of computer science and engineering outside the usual territory of pure mathematics, and also in a way that demonstrates how computers can be used to perform explicit calculations within the domain of pure algebraic topology itself. The initial chapters include examples from data mining, biology and digital image analysis, while the later chapters cover a range of computational examples on the cohomology of classifying spaces that are likely beyond the reach of a purely paper-and-pen approach to the subject. The applied examples in the initial chapters use only low-dimensional and mainly abelian topological tools. Our applications of higher dimensional and less abelian computational methods are currently confined to pure mathematical calculations. The approach taken to computational homotopy is very much based on J.H.C. Whitehead’s theory of combinatorial homotopy in which he introduced the fundamental notions of CW-space, simple homotopy equivalence and crossed module. The book should serve as a self-contained informal introduction to these topics and their computer implementation. It is written in a style that tries to lead as quickly as possible to a range of potentially useful machine computations.

This chapter introduces some of the basic ingredients in the classification of homotopy 2-types and describes datatypes and algorithms for implementing them on a computer. These are illustrated using computer examples involving: the fundamental crossed modules of a CW-complex, cat-1-groups, simplicial groups, Moore complexes, the Dold-Kan correspondence, integral homology of simplicial groups, homological perturbation theory. A manual classification of homotopy classes of maps from a surface to the projective plane is also included.

This chapter introduces some of the basic concepts of algebraic topology and describes datatypes and algorithms for implementing them on a computer. The basic concepts include: regular CW-complex, non-regular CW-complex, simplicial complex, cubical complex, permutahedral complex, simple homotopy, set of path-components, fundamental group, van Kampen’s theorem, knot quandle, Alexander polynomial of a knot, covering space. These are illustrated using computer examples involving digital images, protein backbones, high-dimensional point cloud data, knot complements, discrete groups, and random simplicial complexes.

This chapter introduces the basic ingredients of the cohomology of groups and describes datatypes and algorithms for implementing them on a computer. These are illustrated using computer examples involving: integral homology of finite groups such as the Mathieu groups, homology of crystallographic groups, homology of nilpotent groups, homology of Coxeter groups, transfer homomorphism, homological perturbation theory, mod-p comology rings of small finite p-groups, Lyndon-Hocshild-Serre spectral sequence, Bokstein operation, Steenrod squares, Stiefel-Whitney classes, Lie algebras, the modular isomorphism problem, and Bredon homology.