Charting the future of patient care: A strategic leadership guide to harnessing the potential of artificial intelligence.

Artificial Intelligence (AI) applications have the potential to revolutionize conventional healthcare practices, creating a more efficient and patient-centred approach with improved outcomes. This guide discuses eighteen AI-based applications in clinical decision-making, precision medicine, operational efficiency, and predictive analytics, including a real-world example of AI's role in public health during the early stages of the COVID-19 pandemic. Additionally, we address ethical questions, transparency, data privacy, bias, consent, accountability, and liability, and the strategic measures that must be taken to align AI with ethical principles, legal frameworks, legacy information technology systems, and employee skills and knowledge. We emphasize the importance of informed and strategic approaches to harness AI's potential and manage its challenges. Moreover, this guide underscores the importance of evaluating and integrating new skills and competencies to navigate and use AI-based technologies in healthcare management, such as technological literacy, long-term strategic vision, change management skills, ethical decision-making, and alignment with patient needs.

Angiopathic activity of LRG1 is induced by the IL-6/STAT3 pathway.

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.

Zenocutuzumab, a HER2xHER3 Bispecific Antibody, Is Effective Therapy for Tumors Driven by NRG1 Gene Rearrangements.

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.

LRG1 destabilizes tumor vessels and restricts immunotherapeutic potency.

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).

Social media networks and leadership ethics in healthcare.

Social media has penetrated intrapersonal and professional communication, particularly among a younger generation of healthcare professionals and patients who have grown up in the digital age of communication. Social media tools provide a unique set of opportunities in healthcare, but with these new opportunities come a number of potential challenges. As health leaders navigate the increasingly complex world of social media, concerns have arisen regarding questions of ethics and professionalism and how the use of social media fits within the social contract between the medical profession and society. This article describes the changing parameters of professional conduct in digital environments and proposes a set of considerations and recommendations for health leaders to navigate this new frontier.

Prescriber Implementation of STOPP/START Recommendations for Hospitalised Older Adults: A Comparison of a Pharmacist Approach and a Physician Approach.

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.

Cost-Effectiveness Analysis of a Physician-Implemented Medication Screening Tool in Older Hospitalised Patients in Ireland.

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.

The adverse drug reaction risk in older persons (ADRROP) prediction scale: derivation and prospective validation of an ADR risk assessment tool in older multi-morbid patients.

BACKGROUND: Adverse drug reactions (ADRs) cause serious morbidity and mortality in multi-morbid older adults. Reliable ADR risk prediction would improve patient safety in this at-risk population. We aimed to derive and validate a new predictive tool for assessing ADR Risk in Older People (acronym ADRROP). DESIGN: We combined four databases describing 2217 older people hospitalized with acute illness in order to determine risk factor variables significantly associated with ADRs. We identified the independent ADR risk factors from 1687 patients (derivation cohort) and used them to construct the ADRROP scale. We prospectively validated ADRROP using data from 530 patients (validation cohort). We applied area under the curve (AUC) analysis to test ADRROP's ADR predictive power. We also compared ADRROP's performance to the GerontoNet ADR risk scale. RESULTS: Eight independent ADR risk factors were identified in the derivation patient cohort: female gender, age > 70 years, estimated GFR < 30 ml/min/1.73 m2, assistance required for ≥ 1 daily activity, ≥ 4 co-morbidities, liver disease, presence and number of STOPP criteria-defined potentially inappropriate medications, and ≥ 1 fall in the previous year. The ADRROP predictive scale constructed from these combined variables ranged from 0 to 27. The derivation cohort AUC value was 0.623 (95% CI 0.598-0.665); the validation cohort AUC was 0.592 (95% CI 0.532-0.652). Applying the GerontoNet ADR risk scale to the combined cohorts yielded an AUC of 0.566 (95% CI 0.537-0.596). CONCLUSIONS AND RELEVANCE: Neither ADRROP nor the GerontoNet ADR risk scale predicted ADRs to a high level in hospitalized older people with multi-morbidity.

Prevention of Hospital-Acquired Adverse Drug Reactions in Older People Using Screening Tool of Older Persons' Prescriptions and Screening Tool to Alert to Right Treatment Criteria: A Cluster Randomized Controlled Trial.

OBJECTIVES: To determine whether use of the Screening Tool of Older Persons' Prescriptions (STOPP) and Screening Tool to Alert to Right Treatment (START) criteria reduces incident hospital-acquired adverse drug reactions (ADRs), 28-day medication costs, and median length of hospital stay in older adults admitted with acute illness. DESIGN: Single-blind cluster randomized controlled trial (RCT) of unselected older adults hospitalized over a 13-month period. SETTING: Tertiary referral hospital in southern Ireland. PARTICIPANTS: Consecutively admitted individuals aged 65 and older (N = 732). INTERVENTION: Single time point presentation to attending physicians of potentially inappropriate medications according to the STOPP/START criteria. MEASUREMENTS: The primary outcome was the proportion of participants experiencing one or more ADRs during the index hospitalization. Secondary outcomes were median length of stay (LOS) and 28-day total medication cost. RESULTS: One or more ADRs occurred in 78 of the 372 control participants (21.0%; median age 78, interquartile range (IQR) 72-84) and in 42 of the 360 intervention participants (11.7%; median age 80, IQR 73-85) (absolute risk reduction = 9.3%, number needed to treat = 11). The median LOS in the hospital was 8 days (IQR 4-14 days) in both groups. At discharge, median medication cost was significantly lower in the intervention group (€73.16, IQR €38.68-121.72) than in the control group (€90.62, IQR €49.38-162.53) (Wilcoxon rank test Z statistic = -3.274, P < .001). CONCLUSION: Application of STOPP/START criteria resulted in significant reductions in ADR incidence and medication costs in acutely ill older adults but did not affect median LOS.

Type II PI4-kinases control Weibel-Palade body biogenesis and von Willebrand factor structure in human endothelial cells.

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 PI4KIIß 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.

Prevention of Adverse Drug Reactions in Hospitalised Older Patients Using a Software-Supported Structured Pharmacist Intervention: A Cluster Randomised Controlled Trial.

BACKGROUND: Proven interventions to reduce adverse drug reactions (ADRs) in older hospitalised patients are lacking. Previous randomised controlled trial (RCT) data indicate that a structured pharmacist review of medication (SPRM) can reduce inappropriate prescribing in older hospitalised patients. However, no RCT data show that an SPRM reduces ADRs in this population. METHODS: We performed a cluster RCT comparing a clinical decision support software (CDSS)-supported SPRM intervention with standard pharmaceutical care in older patients hospitalised with an acute unselected illness. Over 13 months, we screened 1833 patients aged ≥65 years admitted to specialist services other than geriatric medicine for study inclusion. We randomised 361 patients to the trial intervention arm and 376 patients to the control arm, applying the intervention at a single timepoint within 48 h of admission. The primary endpoint (ADR incidence) was assessed at 7-10 days post-admission or at discharge (whichever came first). The secondary endpoints were the median hospital length of stay (LOS) and hospital mortality rate. RESULTS: Attending clinicians in the intervention group implemented 54.8% of SPRM/CDSS prescribing recommendations. Ninety-one ADRs occurred in 78 control patients (20.7%) compared with 61 ADRs in 50 intervention patients (13.9%), i.e., an absolute risk reduction of 6.8%. The number needed to treat (NNT) to prevent one patient having one ADR was 15; the total NNT to prevent one ADR was 14. The median LOS and hospital mortality were not significantly different. CONCLUSION: An SPRM delivered on a CDSS platform significantly reduces ADR incidence in acutely hospitalised older people.

Regulation of melanosome number, shape and movement in the zebrafish retinal pigment epithelium by OA1 and PMEL.

Analysis of melanosome biogenesis in the retinal pigment epithelium (RPE) is challenging because it occurs predominantly in a short embryonic time window. Here, we show that the zebrafish provides an ideal model system for studying this process because in the RPE the timing of melanosome biogenesis facilitates molecular manipulation using morpholinos. Morpholino-mediated knockdown of OA1 (also known as GPR143), mutations in the human homologue of which cause the most common form of human ocular albinism, induces a major reduction in melanosome number, recapitulating a key feature of the mammalian disease where reduced melanosome numbers precede macromelanosome formation. We further show that PMEL, a key component of mammalian melanosome biogenesis, is required for the generation of cylindrical melanosomes in zebrafish, which in turn is required for melanosome movement into the apical processes and maintenance of photoreceptor integrity. Spherical and cylindrical melanosomes containing similar melanin volumes co-exist in the cell body but only cylindrical melanosomes enter the apical processes. Taken together, our findings indicate that melanosome number and shape are independently regulated and that melanosome shape controls a function in the RPE that depends on localisation in the apical processes.

STOPP/START criteria for potentially inappropriate prescribing in older people: version 2.

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.

The impact of a structured pharmacist intervention on the appropriateness of prescribing in older hospitalized patients.

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.

Delirium in an adult acute hospital population: predictors, prevalence and detection.

BACKGROUND: To date, delirium prevalence and incidence in acute hospitals has been estimated from pooled findings of studies performed in distinct patient populations. OBJECTIVE: To determine delirium prevalence across an acute care facility. DESIGN: A point prevalence study. SETTING: A large tertiary care, teaching hospital. PATIENTS: 311 general hospital adult inpatients were assessed over a single day. Of those, 280 had full data collected within the study's time frame (90%). MEASUREMENTS: Initial screening for inattention was performed using the spatial span forwards and months backwards tests by junior medical staff, followed by two independent formal delirium assessments: first the Confusion Assessment Method (CAM) by trained geriatric medicine consultants and registrars, and, subsequently, the Delirium Rating Scale-Revised-98 (DRS-R98) by experienced psychiatrists. The diagnosis of delirium was ultimately made using DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) criteria. RESULTS: Using DSM-IV criteria, 55 of 280 patients (19.6%) had delirium versus 17.6% using the CAM. Using the DRS-R98 total score for independent diagnosis, 20.7% had full delirium, and 8.6% had subsyndromal delirium. Prevalence was higher in older patients (4.7% if <50 years and 34.8% if >80 years) and particularly in those with prior dementia (OR=15.33, p<0.001), even when adjusted for potential confounders. Although 50.9% of delirious patients had pre-existing dementia, it was poorly documented in the medical notes. Delirium symptoms detected by medical notes, nurse interview and patient reports did not overlap much, with inattention noted by professional staff, and acute change and sleep-wake disturbance noted by patients. CONCLUSIONS: Our point prevalence study confirms that delirium occurs in about 1/5 of general hospital inpatients and particularly in those with prior cognitive impairment. Recognition strategies may need to be tailored to the symptoms most noticed by the detector (patient, nurse or primary physician) if formal assessments are not available.

Inappropriate prescribing: criteria, detection and prevention.

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.