Core requirements of frailty screening in the emergency department: an international Delphi consensus study.

INTRODUCTION: Frailty is associated with adverse outcomes among patients attending emergency departments (EDs). While multiple frailty screens are available, little is known about which variables are important to incorporate and how best to facilitate accurate, yet prompt ED screening. To understand the core requirements of frailty screening in ED, we conducted an international, modified, electronic two-round Delphi consensus study. METHODS: A two-round electronic Delphi involving 37 participants from 10 countries was undertaken. Statements were generated from a prior systematic review examining frailty screening instruments in ED (logistic, psychometric and clinimetric properties). Reflexive thematic analysis generated a list of 56 statements for Round 1 (August-September 2021). Four main themes identified were: (i) principles of frailty screening, (ii) practicalities and logistics, (iii) frailty domains and (iv) frailty risk factors. RESULTS: In Round 1, 13/56 statements (23%) were accepted. Following feedback, 22 new statements were created and 35 were re-circulated in Round 2 (October 2021). Of these, 19 (54%) were finally accepted. It was agreed that ideal frailty screens should be short (<5 min), multidimensional and well-calibrated across the spectrum of frailty, reflecting baseline status 2-4 weeks before presentation. Screening should ideally be routine, prompt (<4 h after arrival) and completed at first contact in ED. Functional ability, mobility, cognition, medication use and social factors were identified as the most important variables to include. CONCLUSIONS: Although a clear consensus was reached on important requirements of frailty screening in ED, and variables to include in an ideal screen, more research is required to operationalise screening in clinical practice.

Frailty Knowledge, Use of Screening Tools, and Educational Challenges in Emergency Departments in Ireland: A Multisite Survey.

BACKGROUND: Recognizing frailty and providing evidenced-based management in busy emergency departments is challenging. Understanding the knowledge and educational needs of ED staff is important to design training that might improve patient outcomes. OBJECTIVE: This study aimed to explore frailty knowledge of ED staff, use of frailty screening instruments in Irish emergency departments, and educational challenges in the emergency department. METHODS: A multisite survey of ED staff (different specialties) was conducted between April and September 2021. An anonymous online survey was distributed via email. Free-text sections were analyzed using content analysis. RESULTS: In total, 168 staff (nursing, medical and allied health) participated, representing 9 of 26 Irish emergency departments (35%). Most respondents were nurses (n = 78, 46%). Less than half of respondents had received frailty identification training (n = 81, 48%). One-fifth of emergency doctors and nurses (20%) were unsure how to define frailty. Major barriers to ED frailty screening were resource deficits, insufficient diagnostic pathways from the emergency departments, and lack of education on suitable instruments. CONCLUSIONS: Most of the ED staff surveyed relied on clinical judgment rather than formal training in frailty identification. A high proportion reported poor knowledge and low confidence in recognizing frailty. Dedicated staff with frailty management expertise, bespoke education initiatives, and clearly defined frailty screening pathways may help address the issues identified.

Comparing frailty prevalence between countries: validation of the Global Burden of Disease study Frailty Index (GBD-FI) in the survey of health, ageing and retirement in Europe.

BACKGROUND: Accurate comparable prevalence proportions are required to better understand the epidemiology of frailty. Estimates in many countries are missing or incomparable. The Global Burden of Disease Frailty Index (GBD-FI) applies the deficit accumulation model to generate frailty scores from items available in the Global Burden of Disease study. OBJECTIVE: To externally validate the GBD-FI. METHODS: Data were obtained from the Survey of Health Ageing and Retirement in Europe (SHARE). A 20-item modified GBD-FI was compared with established frailty measures: a 70-item frailty index (FI-70), the Clinical Frailty Scale (CFS), Frailty Phenotype (FP) and SHARE-FI. Area under receiver operating characteristic curves (AUC) were fitted to examine diagnostic accuracy for frailty and predictive validity for 2-year mortality. RESULTS: In total, 31,624 participants aged ≥50 years from 15 countries were included. Frailty prevalence was 22% using the GBD-FI (ranging from 8% in Switzerland to 41% in Poland). The GBD-FI had good to excellent diagnostic accuracy for frailty, irrespective of approach; the AUC ranged from 0.86 (95% confidence interval: 0.85-0.87) measuring frailty using the CFS to 0.94 (0.93-0.94) with the FI-70. The GBD-FI had similar accuracy for 2-year mortality (AUC 0.71, 0.69-0.74) compared with the CFS (0.73; P = 0.186), FP (0.73; P = 0.392) and SHARE-FI (0.70; P = 0.255) but lower than the FI-70 (0.76; P < 0.001). CONCLUSION: The GBD-FI demonstrated concurrent and predictive validity, suggesting it is a valid measure of frailty. It has the potential to be an efficient, replicable and consistent approach to comparing frailty between countries and regions across time using GBD data.

Rationale and design of the AXIOMATIC-SSP phase II trial: Antithrombotic treatment with factor XIa inhibition to Optimize Management of Acute Thromboembolic events for Secondary Stroke Prevention.

BACKGROUND: Individuals with ischemic stroke or transient ischemic attack (TIA) have a high early risk of ischemic stroke despite dual antiplatelet therapy. The risk of ischemic stroke, and associated disability, represents a significant unmet clinical need. Genetic variants resulting in reduced factor XI levels are associated with reduced risk for ischemic stroke but are not associated with increased intracranial bleeding. Milvexian is an oral small-molecule inhibitor of FXIa that binds activated factor XI with high affinity and selectivity and may reduce the risk of stroke when added to antiplatelet drugs without significant bleeding. We aimed to evaluate the dose-response relationship of milvexian in participants treated with dual antiplatelets. METHODS: We began a phase II, double-blinded, randomized, placebo-controlled trial at 367 sites in 2019. Participants (N = 2366) with ischemic stroke (National Institutes of Health Stroke Scale score ≤7) or high-risk TIA (ABCD2 score ≥6) were randomized to 1 of 5 doses of milvexian or placebo for 90 days. Participants also received clopidogrel 75 mg daily for the first 21 days and aspirin 100 mg for 90 days. The efficacy endpoint was the composite of ischemic stroke or incident infarct on magnetic resonance imaging. Major bleeding, defined as type 3 or 5 bleeding according to the Bleeding Academic Research Consortium, was the safety endpoint. Participant follow-up will end in 2022. CONCLUSION: The AXIOMATIC-SSP trial will evaluate the dose-response of milvexian for ischemic stroke occurrence in participants with ischemic stroke or TIA.

Prevalence of frailty in 62 countries across the world: a systematic review and meta-analysis of population-level studies.

INTRODUCTION: The prevalence of frailty at population level is unclear. We examined this in population-based studies, investigating sources of heterogeneity. METHODS: PubMed, Embase, CINAHL and Cochrane Library databases were searched for observational population-level studies published between 1 January 1998 and 1 April 2020, including individuals aged ≥50 years, identified using any frailty measure. Prevalence estimates were extracted independently, assessed for bias and analysed using a random-effects model. RESULTS: In total, 240 studies reporting 265 prevalence proportions from 62 countries and territories, representing 1,755,497 participants, were included. Pooled prevalence in studies using physical frailty measures was 12% (95% CI = 11-13%; n = 178), compared with 24% (95% CI = 22-26%; n = 71) for the deficit accumulation model (those using a frailty index, FI). For pre-frailty, this was 46% (95% CI = 45-48%; n = 147) and 49% (95% CI = 46-52%; n = 29), respectively. For physical frailty, the prevalence was higher among females, 15% (95% CI = 14-17%; n = 142), than males, 11% (95% CI = 10-12%; n = 144). For studies using a FI, the prevalence was also higher in females, 29% (95% CI = 24-35%; n = 34) versus 20% (95% CI = 16-24%; n = 34), for males. These values were similar for pre-frailty. Prevalence increased according to the minimum age at study inclusion. Analysing only data from nationally representative studies gave a frailty prevalence of 7% (95% CI = 5-9%; n = 46) for physical frailty and 24% (95% CI = 22-26%; n = 44) for FIs. CONCLUSIONS: Population-level frailty prevalence varied by classification and sex. Data were heterogenous and limited, particularly from nationally representative studies making the interpretation of differences by geographic region challenging. Common methodological approaches to gathering data are required to improve the accuracy of population-level prevalence estimates. PROTOCOL REGISTRATION: PROSPERO-CRD42018105431.

Defining the characteristics of intermediate care models including transitional care: an international Delphi study.

BACKGROUND: Although there is growing utilisation of intermediate care to improve the health and well-being of older adults with complex care needs, there is no international agreement on how it is defined, limiting comparability between studies and reducing the ability to scale effective interventions. AIM: To identify and define the characteristics of intermediate care models. METHODS: A scoping review, a modified two-round electronic Delphi study involving 27 multi-professional experts from 13 countries, and a virtual consensus meeting were conducted. RESULTS: Sixty-six records were included in the scoping review, which identified four main themes: transitions, components, benefits and interchangeability. These formed the basis of the first round of the Delphi survey. After Round 2, 16 statements were agreed, refined and collapsed further. Consensus was established for 10 statements addressing the definitions, purpose, target populations, approach to care and organisation of intermediate care models. DISCUSSION: There was agreement that intermediate care represents time-limited services which ensure continuity and quality of care, promote recovery, restore independence and confidence at the interface between home and acute services, with transitional care representing a subset of intermediate care. Models are best delivered by an interdisciplinary team within an integrated health and social care system where a single contact point optimises service access, communication and coordination. CONCLUSIONS: This study identified key defining features of intermediate care to improve understanding and to support comparisons between models and studies evaluating them. More research is required to develop operational definitions for use in different healthcare systems.

Pre-frailty as a multi-dimensional construct: A systematic review of definitions in the scientific literature.

There is as yet no widely-accepted definition of pre-frailty. We aimed to identify and examine definitions of pre-frailty in the literature to characterise important features and factors contributing to the construct using a systematic review approach with a qualitative analysis. PubMed, PsycINFO, Embase, Cochrane Library, ASSIA, and CINAHL databases were searched for studies conducted in any settings providing a definition or description of pre-frailty, published in English, between January 2000 and July 2018. Seventy-seven studies met the inclusion criteria. No consensus definition of pre-frailty was evident in the literature. Four main themes were identified using thematic analysis: (1) Pre-frailty as a prodromal, multi-factorial concept; (2) Physical, social, cognitive and nutritional subtypes; (3) Operational definitions; and (4) Outcomes. We propose a comprehensive definition suggesting that pre-frailty is a multi-dimensional concept, an early and reversible risk-state before frailty that can lead to negative healthcare outcomes, which is defined operationally by existing frailty screening and assessment tools.

Hyaluronic-Acid-Presenting Self-Assembled Nanoparticles Transform a Hyaluronidase HYAL1 Substrate into an Efficient and Selective Inhibitor.

In this study, an original method of macromolecular design was used to develop a hyaluronidase-1 (HYAL1) inhibitor from its principal substrate, hyaluronic acid (HA). HA-based nanoparticles (HA-NP) were obtained by copolymer self-assembly and their effects on HYAL1 activity were investigated by combining different analytical tools. Compared to HA, HA-NP exhibited an enhanced stability against HYAL1 degradation while maintaining its interaction with the HA receptors CD44 and aggrecan. HA-NP displayed a strong and selective inhibition of HYAL1 activity and retarded the hydrolysis of higher-molar-mass HA in solution. A co-nanoprecipitation process was used to formulate a range of hybrid nanoparticle samples, which demonstrated the specificity and efficiency of HA-NP in HYAL1 inhibition.

Burden of disease studies in the WHO European Region-a mapping exercise.

Background: The World Health Organization (WHO) and the Institute for Health Metrics and Evaluation (IHME) have produced numerous global burden of disease (GBD) estimates since the 1990s, using disability-adjusted life-years (DALYs). Here we attempt to identify studies that have either independent DALY estimates or build on the work of WHO and IHME, for the WHO European Region, categorize them by scope of disease analysis and geographic coverage, and briefly compare their methodology (age weighting, discounting and disability weights). Methods: Google and Google Scholar were used with the search terms 'DALY', 'national burden of disease', Member State names and researcher's names, covering all years. Studies were categorized as: 'specific' (fewer than five disease categories or just risk factors for a single country), 'specific, multicountry' (fewer than five disease categories or just risk factors for more than one country), 'extensive' (covering five or more but not all disease categories for one country), 'full, sub country' (covering all relevant disease categories for part of one country) and 'full, country' (covering all relevant disease categories for one country). Results: A total of 198 studies were identified: 143 'specific', 26 'specific, multicountry', 7 'extensive', 10 'full, sub country' and 12 'full, country' [England (1), Estonia (2), France (1), Romania (1), Serbia (1), Spain (3), Sweden (2) and Turkey (1)]. About 5 (20%) of the 25 examinable 'extensive', 'full, sub country' and 'full, country' studies calculated DALYs using GBD 2010 methodology. Conclusions: Independent burden of diseases studies in Europe have been located, and categorized by scope of disease analysis and geographic coverage. Methodological choices varied between independent 'full, country' studies.

Assessment of the cardiovascular safety of saxagliptin in patients with type 2 diabetes mellitus: pooled analysis of 20 clinical trials.

BACKGROUND: It is important to establish the cardiovascular (CV) safety profile of novel antidiabetic drugs. METHODS: Pooled analyses were performed of 20 randomized controlled studies (N = 9156) of saxagliptin as monotherapy or add-on therapy in patients with type 2 diabetes mellitus (T2DM) as well as a subset of 11 saxagliptin + metformin studies. Adjudicated major adverse CV events (MACE; CV death, myocardial infarction [MI], and stroke) and investigator-reported heart failure were assessed, and incidence rates (IRs; events/100 patient-years) and IR ratios (IRRs; saxagliptin/control) were calculated (Mantel-Haenszel method). RESULTS: In pooled datasets, the IR point estimates for MACE and individual components of CV death, MI, and stroke favored saxagliptin, but the 95% CI included 1. IRR (95% CI) for MACE in the 20-study pool was 0.74 (0.45, 1.25). The Cox proportional hazard ratio (95% CI) was 0.75 (0.46, 1.21), suggesting no increased risk of MACE in the 20-study pool. In the 11-study saxagliptin + metformin pool, the IRR for MACE was 0.93 (0.44, 1.99). In the 20-study pool, the IRR for heart failure was 0.55 (0.27, 1.12). CONCLUSIONS: Analysis of pooled data from 20 clinical trials in patients with T2DM suggests that saxagliptin is not associated with an increased CV risk.

Safety of saxagliptin: events of special interest in 9156 patients with type 2 diabetes mellitus.

BACKGROUND: A post hoc pooled analysis was undertaken to evaluate the safety of saxagliptin in patients with type 2 diabetes mellitus, with attention to events of special interest for dipeptidyl peptidase-4 inhibitors. METHODS: Pooled analyses were performed for 20 randomized controlled studies (N = 9156) of saxagliptin as monotherapy or add-on therapy, and a subset of 11 saxagliptin + metformin studies. Adverse events and events of special interest (gastrointestinal adverse events, infections, hypersensitivity, pancreatitis, skin lesions, lymphopenia, thrombocytopenia, hypoglycaemia, bone fracture, severe cutaneous adverse reactions, opportunistic infection, angioedema, malignancy, worsening renal function, and specific laboratory events) were assessed; incidence rates (events/100 person-years) and incidence rates ratios (saxagliptin/control) were calculated (Mantel-Haenszel method). RESULTS: In both pooled datasets, the incidence rates for deaths, serious adverse events, discontinuations due to adverse events, pancreatitis, malignancy, and most other events of special interest, excepting bone fractures and hypersensitivity, were similar between treatments, with 95% confidence intervals (CIs) for incidence rates ratios including 1. In the 20-study pool, the incidence rates per 100 person-years was higher with saxagliptin versus control for bone fractures [1.1 vs 0.6; incidence rates ratio (95% CI), 1.81 (1.04-3.28)] and hypersensitivity adverse events [1.3 vs 0.8; 1.67 (1.01-2.87)]. CONCLUSIONS: Pooled data from 20 studies confirm that saxagliptin has a favourable safety and benefit-risk profile.

The Prolyl Endopeptidase PREP Is Involved in Filaggrinolysis and Cornification.

Filaggrin (FLG) is a well-known biomarker of atopic dermatitis and skin dryness. Its full proteolysis (or filaggrinolysis) produces the major constituents of the natural moisturizing factor. Some proteases/peptidases remain to be identified in this multistep process. Mining 16 omics analyses, we identified prolyl endopeptidase (PREP) as a candidate peptidase. Indirect immunofluorescence and confocal analysis demonstrated its localization in the granular and deep cornified layers, where it co-localized with FLG. Tandem mass spectroscopy and fluorescent quenching activity assays showed that PREP cleaved several synthetic peptides derived from the FLG sequence, at the carboxyl side of an internal proline. Deimination of these peptides increased PREP enzymatic efficiency. Specific inhibition of PREP in reconstructed human epidermis (RHEs) using benzyloxycarbonyl-Pro-Prolinal (ZPP) induced the accumulation of FLG monomers. Down-regulation of PREP expression in RHEs using RNA interference confirmed the impact of PREP on FLG metabolism, and highlighted a more general role of PREP in keratinocyte differentiation. Indeed, quantitative global proteomic, Western blotting and RT-qPCR analyses showed a strong reduction in the expression of bleomycin hydrolase, known to be involved in filaggrinolysis, and of several other actors of cornification like loricrin. Consequently, at the functional level, the trans-epidermal electric resistance was drastically reduced.

Apixaban versus no anticoagulation for the prevention of venous thromboembolism in children with newly diagnosed acute lymphoblastic leukaemia or lymphoma (PREVAPIX-ALL): a phase 3, open-label, randomised, controlled trial.

BACKGROUND: Paediatric patients with acute lymphoblastic leukaemia or lymphoma are at increased risk of venous thromboembolism resulting in increased mortality and morbidity. We hypothesised that apixaban, a direct oral anticoagulant, would safely reduce venous thromboembolism in this patient population. METHODS: PREVAPIX-ALL was a phase 3, open-label, randomised, controlled trial conducted in 74 paediatric hospitals in 9 countries. Participants aged 1 year or older to younger than 18 years with newly diagnosed acute lymphoblastic leukaemia (pre-B cell or T cell) or lymphoblastic lymphoma (B cell or T cell immunophenotype) and a central venous line in place throughout induction were randomly assigned 1:1 to standard of care (SOC, ie, no systemic anticoagulation) or weight-adjusted twice-daily apixaban during induction. Randomisation was performed centrally and stratified by age (those <10 years or those ≥10 years). Participants weighing 35 kg or less were administered 2·5 mg twice daily of apixaban as a 2·5 mg tablet, 0·5 mg tablets, or 0·4 mg/mL oral solution, while those weighing more than 35 kg were administered weight-adjusted prophylactic doses using 0·5 mg tablets or the 0·4 mg/mL oral solution twice daily. Primary outcomes were assessed by a blinded central adjudication committee. The primary efficacy outcome for the intention to treat population was the composite of symptomatic or clinically unsuspected venous thromboembolism, the primary safety outcome was major bleeding, and secondary safety outcomes included clinically relevant non-major (CRNM) bleeding. Patients were screened for venous thromboembolism by ultrasound and echocardiogram at the end of induction. The trial was registered with ClinicalTrials.gov (NCT02369653) and is now complete. FINDINGS: Between Oct 22, 2015, and June 4, 2021, 512 participants were randomly assigned and included in analyses (222 [43%] female and 290 [57%] male; 388 [76%] White, 52 [10%] Asian, 24 [5%] Black or African American, and 48 [9%] other races; and 122 [24%] Hispanic or Latino ethnicity). During a median follow-up period of 27 days (IQR 26-28), 31 (12%) of 256 patients on apixaban had a composite venous thromboembolism compared with 45 (18%) of 256 participants receiving SOC (relative risk [RR] 0·69, 95% CI 0·45-1·05; p=0·080). Two major bleeding events occurred in each group (RR 1·0, 95% CI 0·14-7·01; p=1·0). A higher incidence of CRNM bleeding, primarily grade 1 or 2 epistaxis, occurred in the apixaban group (11 [4%] of 256 participants) compared with the SOC group (3 [1%] of 256; RR 3·67, 95% CI 1·04-12·97, p=0·030). The most frequent grade 3-5 adverse events in both groups were thrombocytopenia (n=28 for the apixaban group and n=20 for the SOC group) or platelet count decreased (n=49 and n=45), anaemia (n=77 and n=74), febrile neutropenia (n=27 and n=20), and neutropenia (n=16 and n=17) or neutrophil count decreased (n=22 and n=25). Five deaths occurred, which were due to infection (n=3 in the SOC group), cardiac arrest (n=1 in apixaban group), and haemorrhagic cerebral sinus vein thrombosis (n=1 in the SOC group). There was one apixaban-related death (coagulopathy and haemorrhage after cardiac arrest of unknown cause). INTERPRETATION: PREVAPIX-ALL is, to our knowledge, the first trial assessing primary thromboprophylaxis using a direct oral anticoagulant in paediatric patients with acute lymphoblastic leukaemia or lymphoma. No statistically significant treatment benefit was identified in participants receiving apixaban. Major and CRNM bleeding were infrequent overall, but a higher incidence of CRNM bleeding (primarily epistaxis in younger children) occurred in participants receiving apixaban. For patients deemed to be at particularly high risk of thrombosis, PREVAPIX-ALL provides encouraging safety data for the use of apixaban in clinical settings in which the potential benefits are thought to outweigh the risk of bleeding. FUNDING: Bristol Myers Squibb-Pfizer Alliance.

Safety and efficacy of factor XIa inhibition with milvexian for secondary stroke prevention (AXIOMATIC-SSP): a phase 2, international, randomised, double-blind, placebo-controlled, dose-finding trial.

BACKGROUND: People with factor XI deficiency have lower rates of ischaemic stroke than the general population and infrequent spontaneous bleeding, suggesting that factor XI has a more important role in thrombosis than in haemostasis. Milvexian, an oral small-molecule inhibitor of activated factor XI, added to standard antiplatelet therapy, might reduce the risk of non-cardioembolic ischaemic stroke without increasing the risk of bleeding. We aimed to estimate the dose-response of milvexian for recurrent ischaemic cerebral events and major bleeding in patients with recent ischaemic stroke or transient ischaemic attack (TIA). METHODS: AXIOMATIC-SSP was a phase 2, randomised, double-blind, placebo-controlled, dose-finding trial done at 367 hospitals in 27 countries. Eligible participants aged 40 years or older, with acute (<48 h) ischaemic stroke or high-risk TIA, were randomly assigned by a web-based interactive response system in a 1:1:1:1:1:2 ratio to receive one of five doses of milvexian (25 mg once daily, 25 mg twice daily, 50 mg twice daily, 100 mg twice daily, or 200 mg twice daily) or matching placebo twice daily for 90 days. All participants received clopidogrel 75 mg daily for the first 21 days and aspirin 100 mg daily for the first 90 days. Investigators, site staff, and participants were masked to treatment assignment. The primary efficacy endpoint was the composite of ischaemic stroke or incident covert brain infarct on MRI at 90 days, assessed in all participants allocated to treatment who completed a follow-up MRI brain scan, and the primary analysis assessed the dose-response relationship with Multiple Comparison Procedure-Modelling (MCP-MOD). The main safety outcome was major bleeding at 90 days, assessed in all participants who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov (NCT03766581) and the EU Clinical Trials Register (2017-005029-19). FINDINGS: Between Jan 27, 2019, and Dec 24, 2021, 2366 participants were randomly allocated to placebo (n=691); milvexian 25 mg once daily (n=328); or twice-daily doses of milvexian 25 mg (n=318), 50 mg (n=328), 100 mg (n=310), or 200 mg (n=351). The median age of participants was 71 (IQR 62-77) years and 859 (36%) were female. At 90 days, the estimates of the percentage of participants with either symptomatic ischaemic stroke or covert brain infarcts were 16·8 (90·2% CI 14·5-19·1) for placebo, 16·7 (14·8-18·6) for 25 mg milvexian once daily, 16·6 (14·8-18·3) for 25 mg twice daily, 15·6 (13·9-17·5) for 50 mg twice daily, 15·4 (13·4-17·6) for 100 mg twice daily, and 15·3 (12·8-19·7) for 200 mg twice daily. No significant dose-response was observed among the five milvexian doses for the primary composite efficacy outcome. Model-based estimates of the relative risk with milvexian compared with placebo were 0·99 (90·2% CI 0·91-1·05) for 25 mg once daily, 0·99 (0·87-1·11) for 25 mg twice daily, 0·93 (0·78-1·11) for 50 mg twice daily, 0·92 (0·75-1·13) for 100 mg twice daily, and 0·91 (0·72-1·26) for 200 mg twice daily. No apparent dose-response was observed for major bleeding (four [1%] of 682 participants with placebo, two [1%] of 325 with milvexian 25 mg once daily, two [1%] of 313 with 25 mg twice daily, five [2%] of 325 with 50 mg twice daily, five [2%] of 306 with 100 mg twice daily, and five [1%] of 344 with 200 mg twice daily). Five treatment-emergent deaths occurred, four of which were considered unrelated to the study drug by the investigator. INTERPRETATION: Factor XIa inhibition with milvexian, added to dual antiplatelet therapy, did not substantially reduce the composite outcome of symptomatic ischaemic stroke or covert brain infarction and did not meaningfully increase the risk of major bleeding. Findings from our study have informed the design of a phase 3 trial of milvexian for the prevention of ischaemic stroke in patients with acute ischaemic stroke or TIA. FUNDING: Bristol Myers Squibb and Janssen Research & Development.

Calmodulin-like skin protein level increases in the differentiated epidermal layers in atopic dermatitis.

In atopic dermatitis (AD), the skin barrier is disturbed, and the expression of calcium-dependent S100 proteins and the calcium gradient is also altered in the epidermis. The calmodulin-like skin protein (CLSP), which is expressed in the differentiated epidermis, is believed to modulate the function of calcium-dependent proteins involved in barrier formation and is significantly increased in the epidermis of psoriatic patients. We, therefore, investigated the CLSP level in skin biopsies taken from patients with acute exacerbated and non-exacerbated AD as well as from healthy control subjects. Immunohistochemical, Western blot and ELISA analyses showed significant increases (P < 0.03) in CLSP level in the epidermis from patients with acute exacerbated AD as compared to that from patients with non-exacerbated AD and from control subjects. Such increased expression of CLSP may help re-establish a functional epidermal barrier in acute AD.

Validation of a Harmonised, Three-Item Cognitive Screening Instrument for the Survey of Health, Ageing and Retirement in Europe (SHARE-Cog).

More accurate and standardised screening and assessment instruments are needed for studies to better understand the epidemiology of mild cognitive impairment (MCI) and dementia in Europe. The Survey of Health, Ageing and Retirement in Europe (SHARE) does not have a harmonised multi-domain cognitive test available. The current study proposes and validates a new instrument, the SHARE cognitive instrument (SHARE-Cog), for this large European longitudinal cohort. Three cognitive domains/sub-tests were available across all main waves of the SHARE and incorporated into SHARE-Cog; these included 10-word registration, verbal fluency (animal naming) and 10-word recall. Subtests were weighted using regression analysis. Diagnostic accuracy was assessed from the area under the curve (AUC) of receiver operating characteristic curves. Diagnostic categories included normal cognition (NC), subjective memory complaints (SMC), MCI and dementia. A total of 20,752 participants were included from wave 8, with a mean age of 75 years; 55% were female. A 45-point SHARE-Cog was developed and validated and had excellent diagnostic accuracy for identifying dementia (AUC = 0.91); very good diagnostic accuracy for cognitive impairment (MCI + dementia), (AUC = 0.81); and good diagnostic accuracy for distinguishing MCI from dementia (AUC = 0.76) and MCI from SMC + NC (AUC = 0.77). SHARE-Cog is a new, short cognitive screening instrument developed and validated to assess cognition in the SHARE. In this cross-sectional analysis, it has good-excellent diagnostic accuracy for identifying cognitive impairment in this wave of SHARE, but further study is required to confirm this in previous waves and over time.

Poroelastic behavior and water permeability of human skin at the nanoscale.

Topical skin care products and hydrating compositions (moisturizers or injectable fillers) have been used for years to improve the appearance of, for example facial wrinkles, or to increase "plumpness". Most of the studies have addressed these changes based on the overall mechanical changes associated with an increase in hydration state. However, little is known about the water mobility contribution to these changes as well as the consequences to the specific skin layers. This is important as the biophysical properties and the biochemical composition of normal stratum corneum, epithelium, and dermis vary tremendously from one another. Our current studies and results reported here have focused on a novel approach (dynamic atomic force microscopy-based nanoindentation) to quantify biophysical characteristics of individual layers of ex vivo human skin. We have discovered that our new methods are highly sensitive to the mechanical properties of individual skin layers, as well as their hydration properties. Furthermore, our methods can assess the ability of these individual layers to respond to both compressive and shear deformations. In addition, since human skin is mechanically loaded over a wide range of deformation rates (frequencies), we studied the biophysical properties of skin over a wide frequency range. The poroelasticity model used helps to quantify the hydraulic permeability of the skin layers, providing an innovative method to evaluate and interpret the impact of hydrating compositions on water mobility of these different skin layers.

Mindfulness and Imagery Enhanced Behavioral Parenting: Effectiveness Pilot of the Confident Carers Cooperative Kids Program.

Mindfulness is increasingly offered to parents of children presenting with behavioral problems, either as a stand-alone intervention, or integrated within existing behavioral parenting interventions. There is relatively modest support for mindful parenting, with small to medium effect size improvements demonstrated across child and parent outcome measures. Here we introduce a mindfulness and imagery enhanced behavioral parenting program. We argue blending mindfulness, imagery and behavioral skills could produce improved parenting engagement and perseverance, leading to stronger outcomes. Pilot data is presented from two contrasting real world clinical settings. Parents attending the 8-week Confident Carers Cooperative Kids (CCCK) group program in a university clinic setting were invited to be included in the study (n = 20). Permission was also gained to use archival data from a community organisation offering CCCK groups to parents who were at risk of child welfare involvement (n = 14). Pre- and post-intervention measures were completed across both groups on parent-reported child behavior, parent wellbeing, adaptive parenting, and mindful parenting. Parents from both groups achieved significant pre- to post-intervention improvements in child behavior problems, parent wellbeing, adaptive parenting, and mindful parenting, with large effect sizes. Larger improvements in child behavior problems were reported by parents from the community group compared with the university group. The CCCK intervention appears beneficial across child and parent outcomes, including for families most in need. A larger sample is required to replicate and extend these promising findings.

Diagnostic Accuracy of Frailty Screening Instruments Validated for Use among Older Adults Attending Emergency Departments: A Systematic Review and Meta-Analysis.

Early identification of frailty can prevent functional decline. Although multiple frailty screens exist for use in Emergency Departments (EDs), few are validated against diagnostic standards such as comprehensive geriatric assessment. To examine the diagnostic accuracy of ED screens for frailty, scientific databases were searched for prospective diagnostic accuracy test studies from January 2000 to September 2022. Studies were assessed for risk of bias using QUADAS-C. Psychometric properties were extracted and analysed using R. Six studies involving 1,663 participants describing seven frailty screening instruments (PRISMA-7, CFS, VIP, FRESH, BPQ, TRST, and ISAR), representing 13 unique data points, were included. The mean age of participants ranged from 76 to 86 years. The proportion that was female ranged from 45 to 60%. The pooled prevalence rate of frailty was high at 59%. The pooled estimate for sensitivity was 0.85 (95% CI: 0.76-0.91) versus 0.77 (95% CI: 0.62-0.88) for specificity. Pooled accuracy based on area under the ROC curve was 0.89 (95% CI: 0.86-0.90). Although few studies were found, limiting the ability to conduct a meta-analysis of individual instruments, available frailty screens can accurately diagnose frailty in older adults attending the ED. As specificity was comparatively low, additional assessment may be required to identify those requiring inpatient management or onward community referral. Further study is therefore required.

Proteomic analysis identifies new biomarkers for postmenopausal and dry skin.

A proteomic analysis of stratum corneum (SC) samples of normal healthy skin revealed the presence of more than 70 proteins by 2D electrophoresis. The majority of these proteins to our knowledge have not yet been described in normal SC. We analysed by Western blot the levels of 25 proteins in the SC taken from postmenopausal and dry skin compared with young and normal skin, respectively. In postmenopausal skin, there was a significantly increased amount of heat shock protein 27, plakoglobin and desmoglein 1, whereas transglutaminase 3, apolipoprotein D and acid ceramidase levels were significantly reduced compared with the SC of young skin. We confirmed corneodesmosin as a marker of dry skin. In addition, we showed for the first time that the levels of both phosphatidylethanolamine-binding protein 1 and annexin A2 were significantly increased in the SC of dry skin compared with the SC of normal skin. These results suggest that a proteomic analysis of the SC obtained using a non-invasive varnish stripping method is an attractive alternative to invasive methods to better characterize changes in the physiology of ageing and dry skin.