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Purpose: screening tool of older people's prescriptions (STOPP) and screening tool to alert to right treatment (START) criteria were first published in 2008. Due to an expanding therapeutics evidence base, updating of the criteria was required.Methods: we reviewed the 2008 STOPP/START criteria to add new evidence-based criteria and remove any obsolete criteria. A thorough literature review was performed to reassess the evidence base of the 2008 criteria and the proposed new criteria. Nineteen experts from 13 European countries reviewed a new draft of STOPP & START criteria including proposed new criteria. These experts were also asked to propose additional criteria they considered important to include in the revised STOPP & START criteria and to highlight any criteria from the 2008 list they considered less important or lacking an evidence base. The revised list of criteria was then validated using the Delphi consensus methodology.Results: the expert panel agreed a final list of 114 criteria after two Delphi validation rounds, i.e. 80 STOPP criteria and 34 START criteria. This represents an overall 31% increase in STOPP/START criteria compared with version 1. Several new STOPP categories were created in version 2, namely antiplatelet/anticoagulant drugs, drugs affecting, or affected by, renal function and drugs that increase anticholinergic burden; new START categories include urogenital system drugs, analgesics and vaccines.Conclusion: STOPP/START version 2 criteria have been expanded and updated for the purpose of minimizing inappropriate prescribing in older people. These criteria are based on an up-to-date literature review and consensus validation among a European panel of experts. [ABSTRACT FROM AUTHOR]

Background: Throughout the literature, drug-related problems (DRPs), such as medication reconciliation issues and potentially inappropriate prescribing, have been reported to be associated with adverse outcomes in older individuals. Both structured pharmacist review of medication (SPRM) interventions and computerized decision support systems (CDSSs) have been shown to reduce DRPs. Objective: The objectives of this study were to (i) evaluate the impact of a specially developed SPRM/CDSS intervention on the appropriateness of prescribing in older Irish hospital inpatients, and (ii) examine the acceptance rates of these recommendations. Methods: We prospectively reviewed 361 patients, aged ≥65 years who were admitted to an Irish university teaching hospital over a 12-month period. At the point of admission, the patients received a SPRM/CDSS intervention, which screened for DRPs. Any DRPs that were identified were then communicated in writing to the attending medical team. The patient's medical records were reviewed again at 7-10 days, or at the point of discharge (whichever came first). Results: Of the 361 patients reviewed, 181 (50.1 %) were female; the median age was 77 years [interquartile range (IQR) 71-83 years). A total of 3,163 (median 9, IQR 6-12) and 4,192 (median 12, IQR 8-15) medications were prescribed at admission and discharge, respectively. The SPRM generated 1,000 recommendations in 296 patients. Of the 1,000 recommendations, 548 (54.8 %) were implemented by the medical teams accordingly. The SPRM/CDSS intervention resulted in an improvement in the appropriateness of prescribing as defined by the medication appropriateness index (MAI), with a statistically significant difference in the median summated MAI at admission (15, IQR: 7-21) and follow-up (12, IQR: 6-18); p < 0.001. However, the SPRM did not result in an improvement in appropriateness of underprescribing as defined by a modified set assessment of care of vulnerable elders (ACOVE) criteria. Conclusion: This study indicated that DRPs are prevalent in older Irish hospitalized inpatients and that a specially developed SPRM intervention supported by a CDSS can improve both the appropriateness and accuracy of medication regimens of older hospitalized inpatients. [ABSTRACT FROM AUTHOR]

Background: adverse drug reactions (ADRs) are a major cause of morbidity and healthcare utilisation in older people. The GerontoNet ADR risk score aims to identify older people at risk of ADRs during hospitalisation. We aimed to assess the clinical applicability of this score and identify other variables that predict ADRs in hospitalised older people.Methods: we prospectively studied 513 acutely ill patients aged ≥65 years. The GerontoNet ADR risk score was calculated for all patients. ADRs were identified through patient and physician consultation together with analysis of case notes. Receiver operator characteristic (ROC) curves were constructed to test the ability of the GerontoNet risk score to predict ADRs. Multivariate logistic regression examined the influence of individual variables on the presence of ADRs.Results: in-hospital ADRs were identified in 135 patients (26%). The area under the ROC curve was 0.62 (95% CI: 0.57–0.68). Variables which increased ADR risk include (i) renal failure (OR: 1.81, 95% CI: 1.12–2.92), (ii) increasing number of medications (OR: 1.09, 95% CI: 1.02–1.17) (iii) inappropriate medications (OR: 2.40, 95% CI: 1.26–4.50) and (iv) age ≥75 years (OR: 2.12, 95% CI: 1.23–3.70).Conclusion: the GerontoNet ADR risk score incorrectly classified 38% of patients as low risk. Inappropriate medications and increasing age also contribute to ADR risk. [ABSTRACT FROM PUBLISHER]

Inappropriate prescribing is highly prevalent in older people and is a major healthcare concern because of its association with negative healthcare outcomes including adverse drug events, related morbidity and hospitalization. With changing population demographics resulting in increasing proportions of older people worldwide, improving the quality and safety of prescribing in older people poses a global challenge. To date a number of different strategies have been used to identify potentially inappropriate prescribing in older people. Over the last two decades, a number of criteria have been published to assist prescribers in detecting inappropriate prescribing, the majority of which have been explicit sets of criteria, though some are implicit. The majority of these prescribing indicators pertain to overprescribing and misprescribing, with only a minority focussing on the underprescribing of indicated medicines. Additional interventions to optimize prescribing in older people include comprehensive geriatric assessment, clinical pharmacist review, and education of prescribers as well as computerized prescribing with clinical decision support systems. In this review, we describe the inappropriate prescribing detection tools or criteria most frequently cited in the literature and examine their role in preventing inappropriate prescribing and other related healthcare outcomes. We also discuss other measures commonly used in the detection and prevention of inappropriate prescribing in older people and the evidence supporting their use and their application in everyday clinical practice. [ABSTRACT FROM AUTHOR]

Leucine-rich α-2-glycoprotein 1 (LRG1) is a secreted glycoprotein that under physiological conditions is produced predominantly by the liver. In disease, its local induction promotes pathogenic neovascularisation while its inhibition leads to reduced dysfunctional angiogenesis. Here we examine the role of interleukin-6 (IL-6) in defective angiogenesis mediated by LRG1. IL-6 treatment induced LRG1 expression in endothelial cells and ex vivo angiogenesis cultures and promoted vascular growth with reduced mural cell coverage. In Lrg1−/− explants, however, IL-6 failed to stimulate angiogenesis and vessels exhibited improved mural cell coverage. IL-6 activated LRG1 transcription through the phosphorylation and binding of STAT3 to a conserved consensus site in the LRG1 promoter, the deletion of which abolished activation. Blocking IL-6 signalling in human lung endothelial cells, using the anti-IL6 receptor antibody Tocilizumab, significantly reduced LRG1 expression. Our data demonstrate that IL-6, through STAT3 phosphorylation, activates LRG1 transcription resulting in vascular destabilisation. This observation is especially timely in light of the potential role of IL-6 in COVID-19 patients with severe pulmonary microvascular complications, where targeting IL-6 has been beneficial. However, our data suggest that a therapy directed towards blocking the downstream angiopathic effector molecule LRG1 may be of greater utility. [ABSTRACT FROM AUTHOR]

Background: Two randomised controlled trials (RCTs) conducted simultaneously in the same Irish university teaching hospital have shown that provision of Screening Tool of Older Persons' Prescriptions (STOPP)/Screening Tool to Alert doctors to Right Treatment (START) recommendations to attending prescribers by a physician or a pharmacist can reduce in-hospital adverse drug reactions (ADRs) in older adults (≥ 65 years). The aims of this study were to compare the prescriber implementation rates of STOPP/START recommendations between the physician approach and the pharmacist approach in these two RCTs and to provide a narrative summary of the comparable clinical outcomes.Methods: Data were extracted from the two RCT published papers and their associated computerised databases to calculate the percentage prescriber implementation rates for the STOPP/START recommendations. The Chi-square test was used to quantify the differences in prescriber implementation rates, with differences considered statistically significant where p < 0.05.Results: Prescriber implementation rates of the STOPP and START recommendations made by the physician were 81.2% and 87.4% respectively, significantly higher than those made by the pharmacist (39.2% and 29.5% respectively), p < 0.0001. A greater absolute risk reduction in patients with ADRs was shown with the physician's intervention compared to the pharmacist's intervention (9.3% vs 6.8%).Conclusion: This study shows that the methods of communication and the medium through which the STOPP/START recommendations are delivered significantly affect their implementation. Non-implementation of some pharmacist-delivered recommendations may be contributing to preventable ADRs in older adults. Thus, future research should aim to identify the factors influencing prescriber implementation of pharmacist recommendations in order to inform the design of more effective pharmacist interventions in optimising older patients' pharmacotherapy. [ABSTRACT FROM AUTHOR]

In turn, the LRG1-mediated induction of angiocrine factors may result in indirect angiopathic effects on endothelial cells and mural cells. LRG1 may then act in an autocrine loop on endothelial cells through the TGF receptor complex to activate canonical and non-canonical signalling that will modify endothelial cell function and induce vascular destabilising genes. [Extracted from the article]

NRG1 rearrangements are recurrent oncogenic drivers in solid tumors. NRG1 binds to HER3, leading to heterodimerization with other HER/ERBB kinases, increased downstream signaling, and tumorigenesis. Targeting ERBBs, therefore, represents a therapeutic strategy for these cancers. We investigated zenocutuzumab (Zeno; MCLA-128), an antibody-dependent cellular cytotoxicity-enhanced anti-HER2xHER3 bispecific antibody, in NRG1 fusion-positive isogenic and patient-derived cell lines and xenograft models. Zeno inhibited HER3 and AKT phosphorylation, induced expression of apoptosis markers, and inhibited growth. Three patients with chemotherapy-resistant NRG1 fusion-positive metastatic cancer were treated with Zeno. Two patients with ATP1B1-NRG1-positive pancreatic cancer achieved rapid symptomatic, biomarker, and radiographic responses and remained on treatment for over 12 months. A patient with CD74-NRG1-positive non-small cell lung cancer who had progressed on six prior lines of systemic therapy, including afatinib, responded rapidly to treatment with a partial response. Targeting HER2 and HER3 simultaneously with Zeno is a novel therapeutic paradigm for patients with NRG1 fusion-positive cancers., Significance: NRG1 rearrangements encode chimeric ligands that activate the ERBB receptor tyrosine kinase family. Here we show that targeting HER2 and HER3 simultaneously with the bispecific antibody Zeno leads to durable clinical responses in patients with NRG1 fusion-positive cancers and is thus an effective therapeutic strategy. This article is highlighted in the In This Issue feature, p. 1171., (©2022 The Authors; Published by the American Association for Cancer Research.)

Background: A poorly functioning tumor vasculature is pro-oncogenic and may impede the delivery of therapeutics. Normalizing the vasculature, therefore, may be beneficial. We previously reported that the secreted glycoprotein leucine-rich α-2-glycoprotein 1 (LRG1) contributes to pathogenic neovascularization. Here, we investigate whether LRG1 in tumors is vasculopathic and whether its inhibition has therapeutic utility., Methods: Tumor growth and vascular structure were analyzed in subcutaneous and genetically engineered mouse models in wild-type and Lrg1 knockout mice. The effects of LRG1 antibody blockade as monotherapy, or in combination with co-therapies, on vascular function, tumor growth, and infiltrated lymphocytes were investigated., Findings: In mouse models of cancer, Lrg1 expression was induced in tumor endothelial cells, consistent with an increase in protein expression in human cancers. The expression of LRG1 affected tumor progression as Lrg1 gene deletion, or treatment with a LRG1 function-blocking antibody, inhibited tumor growth and improved survival. Inhibition of LRG1 increased endothelial cell pericyte coverage and improved vascular function, resulting in enhanced efficacy of cisplatin chemotherapy, adoptive T cell therapy, and immune checkpoint inhibition (anti-PD1) therapy. With immunotherapy, LRG1 inhibition led to a significant shift in the tumor microenvironment from being predominantly immune silent to immune active., Conclusions: LRG1 drives vascular abnormalization, and its inhibition represents a novel and effective means of improving the efficacy of cancer therapeutics., Funding: Wellcome Trust (206413/B/17/Z), UKRI/MRC (G1000466, MR/N006410/1, MC/PC/14118, and MR/L008742/1), BHF (PG/16/50/32182), Health and Care Research Wales (CA05), CRUK (C42412/A24416 and A17196), ERC (ColonCan 311301 and AngioMature 787181), and DFG (CRC1366)., Competing Interests: Declaration of interests J.G. and S.E.M. are founders of a company spun out by UCL Business to commercialize a LRG1 function-blocking therapeutic antibody developed through the UK Medical Research Council DPFS funding scheme. This is currently directed toward treating ocular disease. J.G. and S.E.M. are members of the scientific advisory board and are shareholders of this company and named inventors on three patents related to LRG1 as a therapeutic target., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: A recent randomised controlled trial conducted in an Irish University teaching hospital that evaluated a physician-implemented medication screening tool, demonstrated positive outcomes in terms of a reduction in incident adverse drug reactions., Objective: The present study objective was to evaluate the cost effectiveness of physicians applying this screening tool to older hospitalised patients compared with usual hospital care in the context of the earlier randomised controlled trial., Method: We used a cost-effectiveness analysis alongside a conventional outcome analysis in a cluster randomised controlled trial. Patients in the intervention arm (n = 360) received a multifactorial intervention consisting of medicines reconciliation, communication with patients' senior medical team, and generation of a pharmaceutical care plan in addition to usual medical and pharmaceutical care. Control arm patients (n = 372) received usual medical and pharmaceutical care only. Incremental cost effectiveness was examined in terms of costs to the healthcare system and an outcome measure of adverse drug reactions during inpatient hospital stay. Uncertainty in the analysis was explored using a cost-effectiveness acceptability curve., Results: On average, the intervention arm was more costly but was also more effective. Compared with usual care (control), the intervention was associated with a non-statistically significant increase of €877 (95% confidence interval - €1807, €3561) in the mean healthcare cost, and a statistically significant decrease of - 0.164 (95% confidence interval - 0.257, - 0.070) in the mean number of adverse drug reaction events per patient. The associated incremental cost-effectiveness ratio per adverse drug reaction averted was €5358. The probability of the intervention being cost effective at threshold values of €0, €5000 and €10,000 was 0.236, 0.455 and 0.680, respectively., Conclusion: Based on the evidence presented, this physician-led intervention is not likely to be cost effective compared with usual hospital care. To inform future healthcare policy decisions in this field, more economic analyses of structured medication reviews by other healthcare professionals and by computerised clinical decision support software need to be conducted.

Weibel-Palade bodies (WPBs) are endothelial storage organelles that mediate the release of molecules involved in thrombosis, inflammation and angiogenesis, including the pro-thrombotic glycoprotein von Willebrand factor (VWF). Although many protein components required for WPB formation and function have been identified, the role of lipids is almost unknown. We examined two key phosphatidylinositol kinases that control phosphatidylinositol 4-phosphate levels at the trans-Golgi network, the site of WPB biogenesis. RNA interference of the type II phosphatidylinositol 4-kinases PI4KIIα and PI4KIIβ in primary human endothelial cells leads to formation of an increased proportion of short WPB with perturbed packing of VWF, as exemplified by increased exposure of antibody-binding sites. When stimulated with histamine, these cells release normal levels of VWF yet, under flow, form very few platelet-catching VWF strings. In PI4KIIα-deficient mice, immuno-microscopy revealed that VWF packaging is also perturbed and these mice exhibit increased blood loss after tail cut compared to controls. This is the first demonstration that lipid kinases can control the biosynthesis of VWF and the formation of WPBs that are capable of full haemostatic function., (© 2016. Published by The Company of Biologists Ltd.)

Within the healthy population, there is substantial, heritable, and interindividual variability in the platelet response. We explored whether a proportion of this variability could be accounted for by interindividual variation in gene expression. Through a correlative analysis of genome-wide platelet RNA expression data from 37 subjects representing the normal range of platelet responsiveness within a cohort of 500 subjects, we identified 63 genes in which transcript levels correlated with variation in the platelet response to adenosine diphosphate and/or the collagen-mimetic peptide, cross-linked collagen-related peptide. Many of these encode proteins with no reported function in platelets. An association study of 6 of the 63 genes in 4235 cases and 6379 controls showed a putative association with myocardial infarction for COMMD7 (COMM domain-containing protein 7) and a major deviation from the null hypo thesis for LRRFIP1 [leucine-rich repeat (in FLII) interacting protein 1]. Morpholino-based silencing in Danio rerio identified a modest role for commd7 and a significant effect for lrrfip1 as positive regulators of thrombus formation. Proteomic analysis of human platelet LRRFIP1-interacting proteins indicated that LRRFIP1 functions as a component of the platelet cytoskeleton, where it interacts with the actin-remodeling proteins Flightless-1 and Drebrin. Taken together, these data reveal novel proteins regulating the platelet response.

In this study, we demonstrate the suitability of the vertebrate Danio rerio (zebrafish) for functional screening of novel platelet genes in vivo by reverse genetics. Comparative transcript analysis of platelets and their precursor cell, the megakaryocyte, together with nucleated blood cell elements, endothelial cells, and erythroblasts, identified novel platelet membrane proteins with hitherto unknown roles in thrombus formation. We determined the phenotype induced by antisense morpholino oligonucleotide (MO)-based knockdown of 5 of these genes in a laser-induced arterial thrombosis model. To validate the model, the genes for platelet glycoprotein (GP) IIb and the coagulation protein factor VIII were targeted. MO-injected fish showed normal thrombus initiation but severely impaired thrombus growth, consistent with the mouse knockout phenotypes, and concomitant knockdown of both resulted in spontaneous bleeding. Knockdown of 4 of the 5 novel platelet proteins altered arterial thrombosis, as demonstrated by modified kinetics of thrombus initiation and/or development. We identified a putative role for BAMBI and LRRC32 in promotion and DCBLD2 and ESAM in inhibition of thrombus formation. We conclude that phenotypic analysis of MO-injected zebrafish is a fast and powerful method for initial screening of novel platelet proteins for function in thrombosis.