The last resort requirement under REACH: From principle to practice.

REACH (Registration, Evaluation, Authorisation and Restriction of Chemicals) is a European Union regulation that aims to protect human health and the environment from the risks posed by chemicals. Article 25 clearly states that: "[i]n order to avoid animal testing, testing on vertebrate animals for the purposes of this Regulation shall be undertaken only as a last resort." In practice, however, the standard information requirements under REACH are still primarily filled using animal studies. This paper presents examples illustrating that animal testing is not always undertaken only as a last resort. Six over-arching issues have been identified which contribute to this: (1) non-acceptance of existing animal or non-animal data, (2) non-acceptance of read-across, (3) inflexible administrative processes, (4) redundancy of testing, (5) testing despite animal welfare concerns and (6) testing for cosmetic-only ingredients. We, members of the Animal-Free Safety Assessment (AFSA) Collaboration, who work together to accelerate the global adoption of non-animal approaches for chemical safety assessment, herein propose several recommendations intended to aid the European Commission, the European Chemicals Agency and registrants to protect human health and the environment while avoiding unnecessary animal tests - truly upholding the last resort requirement in REACH.

Coccidioidomycosis Seroincidence and Risk among Military Personnel, Naval Air Station Lemoore, San Joaquin Valley, California, USA1.

We conducted a retrospective cohort study that tested 2,000 US military personnel for Coccidioides antibodies in a disease-endemic region. The overall incidence of seroconversion was 0.5 cases/100 person-years; 12.5% of persons who seroconverted had illnesses requiring medical care. No significant association was found between demographic characteristics and seroconversion or disease.

Is comprehensive geriatric assessment hospital at home a cost-effective alternative to hospital admission for older people?

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.

Comprehensive Geriatric Assessment for community-dwelling, high-risk, frail, older people.

BACKGROUND: Comprehensive Geriatric Assessment (CGA) is a multidimensional interdisciplinary diagnostic process focused on determining an older person's medical, psychological and functional capability in order to develop a co-ordinated and integrated care plan. CGA is not limited simply to assessment, but also directs a holistic management plan for older people, which leads to tangible interventions. While there is established evidence that CGA reduces the likelihood of death and disability in acutely unwell older people, the effectiveness of CGA for community-dwelling, frail, older people at risk of poor health outcomes is less clear. OBJECTIVES: To determine the effectiveness of CGA for community-dwelling, frail, older adults at risk of poor health outcomes in terms of mortality, nursing home admission, hospital admission, emergency department visits, serious adverse events, functional status, quality of life and resource use, when compared to usual care. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, CINAHL, three trials registers (WHO ICTRP, ClinicalTrials.gov and McMaster Aging Portal) and grey literature up to April 2020; we also checked reference lists and contacted study authors. SELECTION CRITERIA: We included randomised trials that compared CGA for community-dwelling, frail, older people at risk of poor healthcare outcomes to usual care in the community. Older people were defined as 'at risk' either by being frail or having another risk factor associated with poor health outcomes. Frailty was defined as a vulnerability to sudden health state changes triggered by relatively minor stressor events, placing the individual at risk of poor health outcomes, and was measured using objective screening tools. Primary outcomes of interest were death, nursing home admission, unplanned hospital admission, emergency department visits and serious adverse events. CGA was delivered by a team with specific gerontological training/expertise in the participant's home (domiciliary Comprehensive Geriatric Assessment (dCGA)) or other sites such as a general practice or community clinic (community Comprehensive Geriatric Assessment (cCGA)). DATA COLLECTION AND ANALYSIS: Two review authors independently extracted study characteristics (methods, participants, intervention, outcomes, notes) using standardised data collection forms adapted from the Cochrane Effective Practice and Organisation of Care (EPOC) data collection form. Two review authors independently assessed the risk of bias for each included study and used the GRADE approach to assess the certainty of evidence for outcomes of interest. MAIN RESULTS: We included 21 studies involving 7893 participants across 10 countries and four continents. Regarding selection bias, 12/21 studies used random sequence generation, while 9/21 used allocation concealment. In terms of performance bias, none of the studies were able to blind participants and personnel due to the nature of the intervention, while 14/21 had a blinded outcome assessment. Eighteen studies were at low risk of attrition bias, and risk of reporting bias was low in 7/21 studies. Fourteen studies were at low risk of bias in terms of differences of baseline characteristics. Three studies were at low risk of bias across all domains (accepting that it was not possible to blind participants and personnel to the intervention). CGA probably leads to little or no difference in mortality during a median follow-up of 12 months (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.76 to 1.02; 18 studies, 7151 participants (adjusted for clustering); moderate-certainty evidence). CGA results in little or no difference in nursing home admissions during a median follow-up of 12 months (RR 0.93, 95% CI 0.76 to 1.14; 13 studies, 4206 participants (adjusted for clustering); high-certainty evidence). CGA may decrease the risk of unplanned hospital admissions during a median follow-up of 14 months (RR 0.83, 95% CI 0.70 to 0.99; 6 studies, 1716 participants (adjusted for clustering); low-certainty evidence). The effect of CGA on emergency department visits is uncertain and evidence was very low certainty (RR 0.65, 95% CI 0.26 to 1.59; 3 studies, 873 participants (adjusted for clustering)). Only two studies (1380 participants; adjusted for clustering) reported serious adverse events (falls) with no impact on the risk; however, evidence was very low certainty (RR 0.82, 95% CI 0.58 to 1.17). AUTHORS' CONCLUSIONS: CGA had no impact on death or nursing home admission. There is low-certainty evidence that community-dwelling, frail, older people who undergo CGA may have a reduced risk of unplanned hospital admission. Further studies examining the effect of CGA on emergency department visits and change in function and quality of life using standardised assessments are required.

Is Comprehensive Geriatric Assessment Admission Avoidance Hospital at Home an Alternative to Hospital Admission for Older Persons? : A Randomized Trial.

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).

The provision of hospital at home care: Results of a national survey of UK hospitals.

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.

Thyroid Hormone Therapy for Older Adults with Subclinical Hypothyroidism.

BACKGROUND: The use of levothyroxine to treat subclinical hypothyroidism is controversial. We aimed to determine whether levothyroxine provided clinical benefits in older persons with this condition. METHODS: We conducted a double-blind, randomized, placebo-controlled, parallel-group trial involving 737 adults who were at least 65 years of age and who had persisting subclinical hypothyroidism (thyrotropin level, 4.60 to 19.99 mIU per liter; free thyroxine level within the reference range). A total of 368 patients were assigned to receive levothyroxine (at a starting dose of 50 µg daily, or 25 µg if the body weight was <50 kg or the patient had coronary heart disease), with dose adjustment according to the thyrotropin level; 369 patients were assigned to receive placebo with mock dose adjustment. The two primary outcomes were the change in the Hypothyroid Symptoms score and Tiredness score on a thyroid-related quality-of-life questionnaire at 1 year (range of each scale is 0 to 100, with higher scores indicating more symptoms or tiredness, respectively; minimum clinically important difference, 9 points). RESULTS: The mean age of the patients was 74.4 years, and 396 patients (53.7%) were women. The mean (±SD) thyrotropin level was 6.40±2.01 mIU per liter at baseline; at 1 year, this level had decreased to 5.48 mIU per liter in the placebo group, as compared with 3.63 mIU per liter in the levothyroxine group (P<0.001), at a median dose of 50 µg. We found no differences in the mean change at 1 year in the Hypothyroid Symptoms score (0.2±15.3 in the placebo group and 0.2±14.4 in the levothyroxine group; between-group difference, 0.0; 95% confidence interval [CI], -2.0 to 2.1) or the Tiredness score (3.2±17.7 and 3.8±18.4, respectively; between-group difference, 0.4; 95% CI, -2.1 to 2.9). No beneficial effects of levothyroxine were seen on secondary-outcome measures. There was no significant excess of serious adverse events prespecified as being of special interest. CONCLUSIONS: Levothyroxine provided no apparent benefits in older persons with subclinical hypothyroidism. (Funded by European Union FP7 and others; TRUST ClinicalTrials.gov number, NCT01660126 .).

The work of older people and their informal caregivers in managing an acute health event in a hospital at home or hospital inpatient setting.

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.

Updating exposure assessment for skin sensitization quantitative risk assessment for fragrance materials.

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 patients are more likely to breach the 4-hour target in Scotland.

OBJECTIVE: To 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. METHODS: We 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. RESULTS: The likelihood of breaching the 4-hour target increased linearly with age from 15 to 19 years upward. Patients ≥85 years were significantly (p<0.001) more likely to have breached than patients aged 20 to 24 years (OR 3.80, 95% CI: 3.73 to 3.86). When considering major incidents, patients aged ≥85 years were more likely to have breached than those aged 20 to 24 years (OR 2.05, 95% CI: 2.01 to 2.09, p<0.001). The same was true of minor incidents (OR 2.85, 95% CI: 2.73 to 2.98, p<0.001). CONCLUSIONS: Older 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.

Real-world experience using hydroxyurea in children with sickle cell disease in Lilongwe, Malawi.

INTRODUCTION: Sickle cell disease (SCD) is among the most common inherited hematologic diseases in sub-Saharan Africa (SSA). Historically, hydroxyurea administration in SSA has been restricted due to limited region-specific evidence for safety and efficacy. METHODS: We conducted a prospective observational cohort study of pediatric patients with SCD in Malawi. From January 2015 to November 2017, hydroxyurea at doses of 10-20 mg/kg/day was administered to children with clinically severe disease (targeted use policy). From December 2017 to July 2018, hydroxyurea was prescribed to all patients (universal use policy). RESULTS: Of 187 patients with SCD, seven (3.7%) died and 23 (12.3%) were lost to follow-up. The majority (135, 72.2%) were prescribed hydroxyurea, 59 (43.7%) under the targeted use policy and 76 (56.3%) under the universal use policy. There were no documented severe toxicities. Under the targeted use policy, children with SCD demonstrated absolute decreases in the rates of hospitalization (-4.1 per 1000 person-days; -7.2, -1.0; P = .004), fevers (-4.2 per 1000 person-days; -7.2, -1.1; P = .002), transfusions (-2.3 per 1000 person-days; 95% confidence interval: -4.9, 0.3; P = .06), and annual school absenteeism (-51.2 per person-year; -60.1, -42.3; P < .0001) within 6 months of hydroxyurea commencement. CONCLUSION: We successfully implemented universal administration of hydroxyurea to children with SCD at a tertiary hospital in Malawi. Similar to recently reported trials, hydroxyurea was safe and effective during routine programmatic experience, with clinical benefits particularly among high-risk children. This highlights the importance of continued widespread scale-up of hydroxyurea within SCD programs across SSA.

Understanding and improving multidisciplinary team working in geriatric medicine.

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).

Nephrin as a biomarker of sickle cell glomerulopathy in Malawi.

BACKGROUND: Glomerulopathy is an increasingly identified complication in young patients with sickle cell disease (SCD). Hyperfiltration and albuminuria followed by declining glomerular filtration rates and eventual end-stage renal disease (ESRD) is assumed to be the typical progression of glomerular disease. There are only a few reported biomarkers to identify early-stage renal disease in SCD. PROCEDURES: We detail the renal profile of 101 children with SCD in Malawi and propose a novel urinary biomarker for the identification of early renal disease. RESULTS: Among children with sickle cell anemia, 24.8% had a urine albumin-creatinine ratio of 30 mg/g or above. In univariate analysis, only patients with higher urinary nephrin, a urinary marker of glomerular injury, had significantly greater odds of having albuminuria. In multivariable analysis, nephrin remained significantly associated with albuminuria. A nephrin-creatinine ratio (NCR) cut-point of 622 ng/mg, the 50th percentile, was associated with a 45.8 times greater odds of having albuminuria in children with nephrinuria above this value. Further analysis revealed this urinary NCR cut-point to have 96% sensitivity, 64% specificity, 47% positive predictive value, and 98% negative predictive value for the presence of albuminuria. CONCLUSIONS: These data suggest that a substantial number of children with SCD in Malawi have renal disease and could be at risk for worsening nephropathy and ESRD as they age. Our data suggest that urinary nephrin could be utilized as an early marker of glomerular disease in SCD.

Substantial fibrin amyloidogenesis in type 2 diabetes assessed using amyloid-selective fluorescent stains.

BACKGROUND: We have previously shown that many chronic, inflammatory diseases are accompanied, and possibly partly caused or exacerbated, by various coagulopathies, manifested as anomalous clots in the form of 'dense matted deposits'. More recently, we have shown that these clots can be amyloid in nature, and that the plasma of healthy controls can be induced to form such clots by the addition of tiny amounts of bacterial lipopolysaccharide or lipoteichoic acid. Type 2 diabetes (T2D) is also accompanied by raised levels of LPS. METHODS: We use superresolution and confocal microscopies to investigate the amyloid nature of clots from healthy and T2D individuals. RESULTS: We show here, with the established stain thioflavin T and the novel stains Amytracker™ 480 and 680, that the clotting of plasma from type 2 diabetics is also amyloid in nature, and that this may be prevented by the addition of suitable concentrations of LPS-binding protein. CONCLUSION: This implies strongly that there is indeed a microbial component to the development of type 2 diabetes, and suggests that LBP might be used as treatment for it and its sequelae.

Comprehensive geriatric assessment for older adults admitted to hospital.

BACKGROUND: Comprehensive geriatric assessment (CGA) is a multi-dimensional, multi-disciplinary diagnostic and therapeutic process conducted to determine the medical, mental, and functional problems of older people with frailty so that a co-ordinated and integrated plan for treatment and follow-up can be developed. This is an update of a previously published Cochrane review. OBJECTIVES: We sought to critically appraise and summarise current evidence on the effectiveness and resource use of CGA for older adults admitted to hospital, and to use these data to estimate its cost-effectiveness. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, three other databases, and two trials registers on 5 October 2016; we also checked reference lists and contacted study authors. SELECTION CRITERIA: We included randomised trials that compared inpatient CGA (delivered on geriatric wards or by mobile teams) versus usual care on a general medical ward or on a ward for older people, usually admitted to hospital for acute care or for inpatient rehabilitation after an acute admission. DATA COLLECTION AND ANALYSIS: We followed standard methodological procedures expected by Cochrane and Effective Practice and Organisation of Care (EPOC). We used the GRADE approach to assess the certainty of evidence for the most important outcomes. For this update, we requested individual patient data (IPD) from trialists, and we conducted a survey of trialists to obtain details of delivery of CGA. We calculated risk ratios (RRs), mean differences (MDs), or standardised mean differences (SMDs), and combined data using fixed-effect meta-analysis. We estimated cost-effectiveness by comparing inpatient CGA versus hospital admission without CGA in terms of cost per quality-adjusted life year (QALY) gained, cost per life year (LY) gained, and cost per life year living at home (LYLAH) gained. MAIN RESULTS: We included 29 trials recruiting 13,766 participants across nine, mostly high-income countries. CGA increases the likelihood that patients will be alive and in their own homes at 3 to 12 months' follow-up (risk ratio (RR) 1.06, 95% confidence interval (CI) 1.01 to 1.10; 16 trials, 6799 participants; high-certainty evidence), results in little or no difference in mortality at 3 to 12 months' follow-up (RR 1.00, 95% CI 0.93 to 1.07; 21 trials, 10,023 participants; high-certainty evidence), decreases the likelihood that patients will be admitted to a nursing home at 3 to 12 months follow-up (RR 0.80, 95% CI 0.72 to 0.89; 14 trials, 6285 participants; high-certainty evidence) and results in little or no difference in dependence (RR 0.97, 95% CI 0.89 to 1.04; 14 trials, 6551 participants; high-certainty evidence). CGA may make little or no difference to cognitive function (SMD ranged from -0.22 to 0.35 (5 trials, 3534 participants; low-certainty evidence)). Mean length of stay ranged from 1.63 days to 40.7 days in the intervention group, and ranged from 1.8 days to 42.8 days in the comparison group. Healthcare costs per participant in the CGA group were on average GBP 234 (95% CI GBP -144 to GBP 605) higher than in the usual care group (17 trials, 5303 participants; low-certainty evidence). CGA may lead to a slight increase in QALYs of 0.012 (95% CI -0.024 to 0.048) at GBP 19,802 per QALY gained (3 trials; low-certainty evidence), a slight increase in LYs of 0.037 (95% CI 0.001 to 0.073), at GBP 6305 per LY gained (4 trials; low-certainty evidence), and a slight increase in LYLAH of 0.019 (95% CI -0.019 to 0.155) at GBP 12,568 per LYLAH gained (2 trials; low-certainty evidence). The probability that CGA would be cost-effective at a GBP 20,000 ceiling ratio for QALY, LY, and LYLAH was 0.50, 0.89, and 0.47, respectively (17 trials, 5303 participants; low-certainty evidence). AUTHORS' CONCLUSIONS: Older patients are more likely to be alive and in their own homes at follow-up if they received CGA on admission to hospital. We are uncertain whether data show a difference in effect between wards and teams, as this analysis was underpowered. CGA may lead to a small increase in costs, and evidence for cost-effectiveness is of low-certainty due to imprecision and inconsistency among studies. Further research that reports cost estimates that are setting-specific across different sectors of care are required.

Oxidative tryptophan modification by terpene- and squalene-hydroperoxides and a possible link to cross-reactions in diagnostic tests.

Hydroperoxides can act as specific haptens and oxidatively modify proteins. Terpene hydroperoxides trigger unusually high frequencies of positive skin reactions in human patients if tested at high concentrations. It is unknown whether this is due to specific hapten formation. Here, we show that both terpene hydroperoxides and the endogenous hydroperoxide formed from squalene can oxidatively modify tryptophan. Oxidative modifications of Trp were recently postulated to explain cross-sensitization between unrelated photosensitizers. Current observations may extend this hypothesis: Oxidative events triggered by endogenous hydroperoxides and hydroperoxides/oxidants derived from xenobiotics might lead to a sensitized state detected by patch tests with high concentrations of hydroperoxides.

Knowledge sharing to facilitate regulatory decision-making in regard to alternatives to animal testing: Report of an EPAA workshop.

The European Partnership for Alternative Approaches to Animal Testing (EPAA) convened a workshop Knowledge sharing to facilitate regulatory decision-making. Fifty invited participants from the European Commission, national and European agencies and bodies, different industry sectors (chemicals, cosmetics, fragrances, pharmaceuticals, vaccines), and animal protection organizations attended the workshop. Four case studies exemplarily revealed which procedures are in place to obtain regulatory acceptance of new test methods in different sectors. Breakout groups discussed the status quo identifying the following facilitators for regulatory acceptance of alternatives to animal testing: Networking and communication (including cross-sector collaboration, international cooperation and harmonization); involvement of regulatory agencies from the initial stages of test method development on; certainty on prerequisites for test method acceptance including the establishment of specific criteria for regulatory acceptance. Data sharing and intellectual property issues affect many aspects of test method development, validation and regulatory acceptance. In principle, all activities should address replacement, reduction and refinement methods (albeit animal testing is generally prohibited in the cosmetics sector). Provision of financial resources and education support all activities aiming at facilitating the acceptance and use of alternatives to animal testing. Overall, workshop participants recommended building confidence in new methodologies by applying and gaining experience with them.

Detection of potentially skin sensitizing hydroperoxides of linalool in fragranced products.

On prolonged exposure to air, linalool can form sensitizing hydroperoxides. Positive hydroperoxide patch tests in dermatitis patients have frequently been reported, but their relevance has not been established. Owing to a lack of analytical methods and data, it is unclear from which sources the public might be exposed to sufficient quantities of hydroperoxides for induction of sensitization to occur. To address this knowledge gap, we developed analytical methods and performed stability studies for fine fragrances and deodorants/antiperspirants. In parallel, products recalled from consumers were analysed to investigate exposure to products used in everyday life. Liquid chromatography-mass spectrometry with high mass resolution was found to be optimal for the selective and sensitive detection of the organic hydroperoxide in the complex product matrix. Linalool hydroperoxide was detected in natural linalool, but the amount was not elevated by storage in a perfume formulation exposed to air. No indication of hydroperoxide formation in fine fragrances was found in stability studies. Aged fine fragrances recalled from consumers contained a geometric mean linalool concentration of 1,888 µg/g and, corrected for matrix effects, linalool hydroperoxide at a concentration of around 14 µg/g. In antiperspirants, we detected no oxidation products. In conclusion, very low levels of linalool hydroperoxide in fragranced products may originate from raw materials, but we found no evidence for oxidation during storage of products. The levels detected are orders of magnitude below the levels inducing sensitization in experimental animals, and these results therefore do not substantiate a causal link between potential hydroperoxide formation in cosmetics and positive results of patch tests.