In Vivo Ocular Pharmacokinetics and Toxicity of Siponimod in Albino Rabbits.

Siponimod is a promising agent for the inhibition of ocular neovascularization in diabetic retinopathy and age-related macular degeneration. Siponimod's development for ophthalmological application is hindered by the limited information available on the drug's solubility, stability, ocular pharmacokinetics (PK), and toxicity in vivo. In this study, we investigated the aqueous stability of siponimod under stress conditions (up to 60 °C) and its degradation behavior in solution. Additionally, siponimod's ocular PK and toxicity were investigated using intravitreal injection of two different doses (either 1300 or 6500 ng) in an albino rabbit model. Siponimod concentration was quantified in the extracted vitreous, and the PK parameters were calculated. The drug half-life after administration of the low and high doses was 2.8 and 3.9 h, respectively. The data obtained in vivo was used to test the ability of published in silico models to predict siponimod's PK accurately. Two models that correlated siponimod's molecular descriptors with its elimination from the vitreous closely predicted the half-life. Furthermore, 24 h and 7 days after intravitreal injections, the retinas showed no signs of toxicity. This study provides important information necessary for the formulation and development of siponimod for ophthalmologic applications. The short half-life of siponimod necessitates the development of a sustained drug delivery system to maintain therapeutic concentrations over an extended period, while the lack of short-term ocular toxicity observed in the retinas of siponimod-treated rabbits supports possible clinical use.

Discovery of 9H-pyrimido[4,5-b]indole derivatives as dual RET/TRKA inhibitors.

Aberrant RET kinase signaling is activated in numerous cancers including lung, thyroid, breast, pancreatic, and prostate. Recent approvals of selective RET inhibitors, pralsetinib and selpercatinib, has shifted the focus of RET kinase drug discovery programs towards the development of selective inhibitors. However, selective inhibitors invariably lose efficacy as the selective nature of the inhibitor places Darwinian-like pressure on the tumor to bypass treatment through the selection of novel oncogenic drivers. Further, selective inhibitors are restricted for use in tumors with specific genetic backgrounds that do not encompass diverse patient classes. Here we report the identification of a pyrimido indole RET inhibitor found to also have activity against TRK. This selective dual RET/TRK inhibitor can be utilized in tumors with both RET and TRK genetic backgrounds and can also provide blockade of NTRK-fusions that are selected for from RET inhibitor treatments. Efforts towards developing dual RET/TRK inhibitors can be beneficial in terms of encompassing more diverse patient classes while also achieving blockade against emerging resistance mechanisms.

Understanding Physician's Perspectives on AI in Health Care: Protocol for a Sequential Multiple Assignment Randomized Vignette Study.

BACKGROUND: As the availability and performance of artificial intelligence (AI)-based clinical decision support (CDS) systems improve, physicians and other care providers poised to be on the front lines will be increasingly tasked with using these tools in patient care and incorporating their outputs into clinical decision-making processes. Vignette studies provide a means to explore emerging hypotheses regarding how context-specific factors, such as clinical risk, the amount of information provided about the AI, and the AI result, may impact physician acceptance and use of AI-based CDS tools. To best anticipate how such factors influence the decision-making of frontline physicians in clinical scenarios involving AI decision-support tools, hypothesis-driven research is needed that enables scenario testing before the implementation and deployment of these tools. OBJECTIVE: This study's objectives are to (1) design an original, web-based vignette-based survey that features hypothetical scenarios based on emerging or real-world applications of AI-based CDS systems that will vary systematically by features related to clinical risk, the amount of information provided about the AI, and the AI result; and (2) test and determine causal effects of specific factors on the judgments and perceptions salient to physicians' clinical decision-making. METHODS: US-based physicians with specialties in family or internal medicine will be recruited through email and mail (target n=420). Through a web-based survey, participants will be randomized to a 3-part "sequential multiple assignment randomization trial (SMART) vignette" detailing a hypothetical clinical scenario involving an AI decision support tool. The SMART vignette design is similar to the SMART design but adapted to a survey design. Each respondent will be randomly assigned to 1 of the possible vignette variations of the factors we are testing at each stage, which include the level of clinical risk, the amount of information provided about the AI, and the certainty of the AI output. Respondents will be given questions regarding their hypothetical decision-making in response to the hypothetical scenarios. RESULTS: The study is currently in progress and data collection is anticipated to be completed in 2024. CONCLUSIONS: The web-based vignette study will provide information on how contextual factors such as clinical risk, the amount of information provided about an AI tool, and the AI result influence physicians' reactions to hypothetical scenarios that are based on emerging applications of AI in frontline health care settings. Our newly proposed "SMART vignette" design offers several benefits not afforded by the extensively used traditional vignette design, due to the 2 aforementioned features. These advantages are (1) increased validity of analyses targeted at understanding the impact of a factor on the decision outcome, given previous outcomes and other contextual factors; and (2) balanced sample sizes across groups. This study will generate a better understanding of physician decision-making within this context. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/54787.

Unringing the bell: Successful debriefing following a rich false memory study.

In rich false memory studies, familial informants often provide information to support researchers in planting vivid memories of events that never occurred. The goal of the current study was to assess how effectively we can retract these false memories via debriefing - i.e., to what extent can we put participants back the way we found them? We aimed to establish (1) what proportion of participants would retain a false memory or false belief following debriefing, and (2) whether richer, more detailed memories would be more difficult to retract. Participants (N = 123) completed a false memory implantation protocol as part of a replication of the "Lost in the Mall" study (Loftus & Pickrell, Psychiatric Annals, 25, 720-725, 1995). By the end of the protocol, 14% of participants self-reported a memory for the fabricated event, and a further 52% believed it had happened. Participants were then fully debriefed, and memory and belief for the false event were assessed again. In a follow-up assessment 3 days post-debriefing, the false memory rate had dropped to 6% and false belief rates also fell precipitously to 7%. Moreover, virtually all persistent false memories were found to be nonbelieved memories, where participants no longer accepted that the fabricated event had occurred. Richer, more detailed memories were more resistant to correction, but were still mostly retracted. This study provides evidence that participants can be "dehoaxed", and even very convincing false memories can be retracted.

Academic machine learning researchers' ethical perspectives on algorithm development for health care: a qualitative study.

OBJECTIVES: We set out to describe academic machine learning (ML) researchers' ethical considerations regarding the development of ML tools intended for use in clinical care. MATERIALS AND METHODS: We conducted in-depth, semistructured interviews with a sample of ML researchers in medicine (N = 10) as part of a larger study investigating stakeholders' ethical considerations in the translation of ML tools in medicine. We used a qualitative descriptive design, applying conventional qualitative content analysis in order to allow participant perspectives to emerge directly from the data. RESULTS: Every participant viewed their algorithm development work as holding ethical significance. While participants shared positive attitudes toward continued ML innovation, they described concerns related to data sampling and labeling (eg, limitations to mitigating bias; ensuring the validity and integrity of data), and algorithm training and testing (eg, selecting quantitative targets; assessing reproducibility). Participants perceived a need to increase interdisciplinary training across stakeholders and to envision more coordinated and embedded approaches to addressing ethics issues. DISCUSSION AND CONCLUSION: Participants described key areas where increased support for ethics may be needed; technical challenges affecting clinical acceptability; and standards related to scientific integrity, beneficence, and justice that may be higher in medicine compared to other industries engaged in ML innovation. Our results help shed light on the perspectives of ML researchers in medicine regarding the range of ethical issues they encounter or anticipate in their work, including areas where more attention may be needed to support the successful development and integration of medical ML tools.

Nebulised delivery of RNA formulations to the lungs: From aerosol to cytosol.

In the past decade RNA-based therapies such as small interfering RNA (siRNA) and messenger RNA (mRNA) have emerged as new and ground-breaking therapeutic agents for the treatment and prevention of many conditions from viral infection to cancer. Most clinically approved RNA therapies are parenterally administered which impacts patient compliance and adds to healthcare costs. Pulmonary administration via inhalation is a non-invasive means to deliver RNA and offers an attractive alternative to injection. Nebulisation is a particularly appealing method due to the capacity to deliver large RNA doses during tidal breathing. In this review, we discuss the unique physiological barriers presented by the lung to efficient nebulised RNA delivery and approaches adopted to circumvent this problem. Additionally, the different types of nebulisers are evaluated from the perspective of their suitability for RNA delivery. Furthermore, we discuss recent preclinical studies involving nebulisation of RNA and analysis in in vitro and in vivo settings. Several studies have also demonstrated the importance of an effective delivery vector in RNA nebulisation therefore we assess the variety of lipid, polymeric and hybrid-based delivery systems utilised to date. We also consider the outlook for nebulised RNA medicinal products and the hurdles which must be overcome for successful clinical translation. In summary, nebulised RNA delivery has demonstrated promising potential for the treatment of several lung-related conditions such as asthma, COPD and cystic fibrosis, to which the mode of delivery is of crucial importance for clinical success.

Lost in the mall again: a preregistered replication and extension of Loftus & Pickrell (1995).

ABSTRACTThe seminal Lost in the Mall study [Loftus, E. F., & Pickrell, J. E. (1995). The formation of false memories. Psychiatric Annals, 25(12), 720-725. https://doi.org/10.3928/0048-5713-19951201-07] has been enormously influential in psychology and is still cited in legal cases. The current study directly replicated this paper, addressing methodological weaknesses including increasing the sample size fivefold and preregistering detailed analysis plans. Participants (N = 123) completed a survey and two interviews where they discussed real and fabricated childhood events, based on information provided by an older relative. We replicated the findings of the original study, coding 35% of participants as reporting a false memory for getting lost in a mall in childhood (compared to 25% in the original study). In an extension, we found that participants self-reported high rates of memories and beliefs for the fabricated event. Mock jurors were also highly likely to believe the fabricated event had occurred and that the participant was truly remembering the event, supporting the conclusions of the original study.

Prediction of Prostate Cancer Biochemical and Clinical Recurrence Is Improved by IHC-Assisted Grading Using Appl1, Sortilin and Syndecan-1.

Gleason scoring is used within a five-tier risk stratification system to guide therapeutic decisions for patients with prostate cancer. This study aimed to compare the predictive performance of routine H&E or biomarker-assisted ISUP (International Society of Urological Pathology) grade grouping for assessing the risk of biochemical recurrence (BCR) and clinical recurrence (CR) in patients with prostate cancer. This retrospective study was an assessment of 114 men with prostate cancer who provided radical prostatectomy samples to the Australian Prostate Cancer Bioresource between 2006 and 2014. The prediction of CR was the primary outcome (median time to CR 79.8 months), and BCR was assessed as a secondary outcome (median time to BCR 41.7 months). The associations of (1) H&E ISUP grade groups and (2) modified ISUP grade groups informed by the Appl1, Sortilin and Syndecan-1 immunohistochemistry (IHC) labelling were modelled with BCR and CR using Cox proportional hazard approaches. IHC-assisted grading was more predictive than H&E for BCR (C-statistic 0.63 vs. 0.59) and CR (C-statistic 0.71 vs. 0.66). On adjusted analysis, IHC-assisted ISUP grading was independently associated with both outcome measures. IHC-assisted ISUP grading using the biomarker panel was an independent predictor of individual BCR and CR. Prospective studies are needed to further validate this biomarker technology and to define BCR and CR associations in real-world cohorts.

Siponimod As a Novel Inhibitor of Retinal Angiogenesis: In Vitro and In Vivo Evidence of Therapeutic Efficacy.

Sphingosine-1-phosphate (S1P) receptors control endothelial cell proliferation, migration, and survival. Evidence of the ability of S1P receptor modulators to influence multiple endothelial cell functions suggests their potential use for antiangiogenic effect. The main purpose of our study was to investigate the potential of siponimod for the inhibition of ocular angiogenesis in vitro and in vivo. We investigated the effects of siponimod on the metabolic activity (thiazolyl blue tetrazolium bromide assay), cell toxicity (lactate dehydrogenase release), basal proliferation and growth factor-induced proliferation (bromodeoxyuridine assay), and migration (transwell migration assay) of human umbilical vein endothelial cells (HUVEC) and retinal microvascular endothelial cells (HRMEC). The effects of siponimod on HRMEC monolayer integrity, barrier function under basal conditions, and tumor necrosis factor alpha (TNF-α)-induced disruption were assessed using the transendothelial electrical resistance and fluorescein isothiocyanate-dextran permeability assays. Siponimod's effect on TNF-α-induced distribution of barrier proteins in HRMEC was investigated using immunofluorescence. Finally, the effect of siponimod on ocular neovascularization in vivo was assessed using suture-induced corneal neovascularization in albino rabbits. Our results show that siponimod did not affect endothelial cell proliferation or metabolic activity but significantly inhibited endothelial cell migration, increased HRMEC barrier integrity, and reduced TNF-α-induced barrier disruption. Siponimod also protected against TNF-α-induced disruption of claudin-5, zonula occludens-1, and vascular endothelial-cadherin in HRMEC. These actions are mainly mediated by sphingosine-1-phosphate receptor 1 modulation. Finally, siponimod prevented the progression of suture-induced corneal neovascularization in albino rabbits. In conclusion, the effects of siponimod on various processes known to be involved in angiogenesis support its therapeutic potential in disorders associated with ocular neovascularization. SIGNIFICANCE STATEMENT: Siponimod is an extensively characterized sphingosine-1-phosphate receptor modulator already approved for the treatment of multiple sclerosis. It inhibited retinal endothelial cell migration, potentiated endothelial barrier function, protected against tumor necrosis factor alpha-induced barrier disruption, and also inhibited suture-induced corneal neovascularization in rabbits. These results support its use for a novel therapeutic indication in the management of ocular neovascular diseases.

Circumstances of suicide after registration with a national digital mental health service: an analysis of coroners' reports.

BACKGROUND: Little is known about the safety of mental healthcare provided remotely by digital mental health services (DMHS), which do not offer face-to-face contact. AIMS: To examine the circumstances of suicide by patients registered with a national DMHS. METHOD: Data from 59 033 consenting patients registered with a national DMHS, the MindSpot Clinic, between 1 January 2013 and 31 December 2016 were linked with the Australian National Death Index and documents held by the National Coronial Information System (NCIS). Data extracted included demographic information, the nature of contact, duration between last contact and death, symptom scores and information in police, autopsy, toxicology and coroners' reports. RESULTS: Of the 59 033 patients, 90 (0.15%) died by suicide in a follow-up period of up to 5 years. The mean time between last contact and death was 560 days. Coroners' reports were located for 81/90 patients. Most (87.0%) were receiving face-to-face care around the time of death, 60.9% had a documented previous suicide attempt, 52.2% had been in hospital in the previous 6 months and 22.2% had severe mental illness, mainly schizophrenia or bipolar disorder. Other common findings were current treatment with psychotropic medication (79.2%) and the presence of alcohol (41.6%), benzodiazepines (31.2%), and illegal drugs and non-prescribed opioids (20.8%) at time of death. CONCLUSIONS: Those who died by suicide after contact with the DMHS had more severe illness, were mostly engaged with face-to-face services and often had disinhibiting substances, especially benzodiazepines, present at the time of death.

Lost in the mall again: a preregistered replication and extension of Loftus & Pickrell (1995).

The seminal Lost in the Mall study has been enormously influential in psychology and is still cited in legal cases. The current study directly replicated this paper, addressing methodological weaknesses including increasing the sample size fivefold and preregistering detailed analysis plans. Participants (N = 123) completed a survey and two interviews where they discussed real and fabricated childhood events, based on information provided by an older relative. We replicated the findings of the original study, coding 35% of participants as reporting a false memory for getting lost in a mall in childhood (compared to 25% in the original study). In an extension, we found that participants self-reported high rates of memories and beliefs for the fabricated event. Mock jurors were also highly likely to believe the fabricated event had occurred and that the participant was truly remembering the event, supporting the conclusions of the original study.

An open trial of the Things You Do Questionnaire: Changes in daily actions during internet-delivered treatment for depressive and anxiety symptoms.

Many psychological treatments aim to reduce symptoms of depression and anxiety by modifying maladaptive patterns of cognitions, behavior, and other actions. The Things You Do Questionnaire (TYDQ) was developed to measure the frequency of actions that are associated with psychological health in a reliable and valid manner. The present study examined treatment-related change in the frequency of actions measured by the TYDQ. Using an uncontrolled single-group design, 409 participants with self-reported symptoms of depression, anxiety, or both received access to an 8-week internet-delivered treatment course based on cognitive behavior therapy. Most (77 %) participants completed the treatment, completed questionnaires at post-treatment (83 %), and obtained significant reductions in symptoms of depression (d = 0.88) and anxiety at post-treatment (d = 0.97), as well as improvement in a measure of satisfaction with life (d = 0.36). Factor analyses supported the five-factor structure of the TYDQ, including Realistic Thinking, Meaningful Activities, Goals and Plans, Healthy Habits, and Social Connections. Those participants who, on average, engaged in the identified actions on the TYDQ at least half the days of the week reported lower symptoms of depression and anxiety at post-treatment. The psychometric properties of both a longer 60-item (TYDQ-60) and shorter 21-item (TYDQ-21) version were acceptable. These findings provide further evidence that there are modifiable activities that are strongly associated with psychological health. Future studies will test the replicability to these results in in a broader range of samples, including those seeking psychological treatment.

Nano-Hydroxyapatite/PLGA Mixed Scaffolds as a Tool for Drug Development and to Study Metastatic Prostate Cancer in the Bone.

(1) Background: Three-dimensional (3D) in vitro, biorelevant culture models that recapitulate cancer progression can help elucidate physio-pathological disease cues and enhance the screening of more effective therapies. Insufficient research has been conducted to generate in vitro 3D models to replicate the spread of prostate cancer to the bone, a key metastatic site of the disease, and to understand the interplay between the key cell players. In this study, we aim to investigate PLGA and nano-hydroxyapatite (nHA)/PLGA mixed scaffolds as a predictive preclinical tool to study metastatic prostate cancer (mPC) in the bone and reduce the gap that exists with traditional 2D cultures. (2) Methods: nHA/PLGA mixed scaffolds were produced by electrospraying, compacting, and foaming PLGA polymer microparticles, +/- nano-hydroxyapatite (nHA), and a salt porogen to produce 3D, porous scaffolds. Physicochemical scaffold characterisation together with an evaluation of osteoblastic (hFOB 1.19) and mPC (PC-3) cell behaviour (RT-qPCR, viability, and differentiation) in mono- and co-culture, was undertaken. (3) Results: The results show that the addition of nHA, particularly at the higher-level impacted scaffolds in terms of mechanical and degradation behaviour. The nHA 4 mg resulted in weaker scaffolds, but cell viability increased. Qualitatively, fluorescent imaging of cultures showed an increase in PC-3 cells compared to osteoblasts despite lower initial PC-3 seeding densities. Osteoblast monocultures, in general, caused an upregulation (or at least equivalent to controls) in gene production, which was highest in plain scaffolds and decreased with increases in nHA. Additionally, the genes were downregulated in PC3 and co-cultures. Further, drug toxicity tests demonstrated a significant effect in 2D and 3D co-cultures. (4) Conclusions: The results demonstrate that culture conditions and environment (2D versus 3D, monoculture versus co-culture) and scaffold composition all impact cell behaviour and model development.

How do participants feel about the ethics of rich false memory studies?

ABSTRACTDeception is often a necessity in rich false memory studies, but is this deception acceptable to participants? In the current study, we followed up with 175 participants who had taken part in a replication of the Lost in the Mall childhood false memory study (Loftus & Pickrell, 1995), as either a research subject or a familial informant. We found that both participants and informants were generally very positive about their experience, did not regret taking part and found the deceptive methods acceptable. Importantly, the vast majority reported that they would still have taken part had they known the true objectives from the beginning. Participants also reported learning something interesting about memory and enjoying the nostalgia and family discussions that were prompted by the study. We would encourage other researchers to assess the ethical implications of false memory research paradigms and to incorporate the valuable feedback from participants and informants.

Aberrant protein expression of Appl1, Sortilin and Syndecan-1 during the biological progression of prostate cancer.

Diagnosis and assessment of patients with prostate cancer is dependent on accurate interpretation and grading of histopathology. However, morphology does not necessarily reflect the complex biological changes occurring in prostate cancer disease progression, and current biomarkers have demonstrated limited clinical utility in patient assessment. This study aimed to develop biomarkers that accurately define prostate cancer biology by distinguishing specific pathological features that enable reliable interpretation of pathology for accurate Gleason grading of patients. Online gene expression databases were interrogated and a pathogenic pathway for prostate cancer was identified. The protein expression of key genes in the pathway, including adaptor protein containing a pleckstrin homology (PH) domain, phosphotyrosine-binding (PTB) domain, and leucine zipper motif 1 (Appl1), Sortilin and Syndecan-1, was examined by immunohistochemistry (IHC) in a pilot study of 29 patients with prostate cancer, using monoclonal antibodies designed against unique epitopes. Appl1, Sortilin, and Syndecan-1 expression was first assessed in a tissue microarray cohort of 112 patient samples, demonstrating that the monoclonal antibodies clearly illustrate gland morphologies. To determine the impact of a novel IHC-assisted interpretation (the utility of Appl1, Sortilin, and Syndecan-1 labelling as a panel) of Gleason grading, versus standard haematoxylin and eosin (H&E) Gleason grade assignment, a radical prostatectomy sample cohort comprising 114 patients was assessed. In comparison to H&E, the utility of the biomarker panel reduced subjectivity in interpretation of prostate cancer tissue morphology and improved the reliability of pathology assessment, resulting in Gleason grade redistribution for 41% of patient samples. Importantly, for equivocal IHC-assisted labelling and H&E staining results, the cancer morphology interpretation could be more accurately applied upon re-review of the H&E tissue sections. This study addresses a key issue in the field of prostate cancer pathology by presenting a novel combination of three biomarkers and has the potential to transform clinical pathology practice by standardising the interpretation of the tissue morphology.

Modelling acute myeloid leukemia (AML): What's new? A transition from the classical to the modern.

Acute myeloid leukemia (AML) is a heterogeneous malignancy affecting myeloid cells in the bone marrow (BM) but can spread giving rise to impaired hematopoiesis. AML incidence increases with age and is associated with poor prognostic outcomes. There has been a disconnect between the success of novel drug compounds observed in preclinical studies of hematological malignancy and less than exceptional therapeutic responses in clinical trials. This review aims to provide a state-of-the-art overview on the different preclinical models of AML available to expand insights into disease pathology and as preclinical screening tools. Deciphering the complex physiological and pathological processes and developing predictive preclinical models are key to understanding disease progression and fundamental in the development and testing of new effective drug treatments. Standard scaffold-free suspension models fail to recapitulate the complex environment where AML occurs. To this end, we review advances in scaffold/matrix-based 3D models and outline the most recent advances in on-chip technology. We also provide an overview of clinically relevant animal models and review the expanding use of patient-derived samples, which offer the prospect to create more "patient specific" screening tools either in the guise of 3D matrix models, microphysiological "organ-on-chip" tools or xenograft models and discuss representative examples.

Physicians' and Machine Learning Researchers' Perspectives on Ethical Issues in the Early Development of Clinical Machine Learning Tools: Qualitative Interview Study.

BACKGROUND: Innovative tools leveraging artificial intelligence (AI) and machine learning (ML) are rapidly being developed for medicine, with new applications emerging in prediction, diagnosis, and treatment across a range of illnesses, patient populations, and clinical procedures. One barrier for successful innovation is the scarcity of research in the current literature seeking and analyzing the views of AI or ML researchers and physicians to support ethical guidance. OBJECTIVE: This study aims to describe, using a qualitative approach, the landscape of ethical issues that AI or ML researchers and physicians with professional exposure to AI or ML tools observe or anticipate in the development and use of AI and ML in medicine. METHODS: Semistructured interviews were used to facilitate in-depth, open-ended discussion, and a purposeful sampling technique was used to identify and recruit participants. We conducted 21 semistructured interviews with a purposeful sample of AI and ML researchers (n=10) and physicians (n=11). We asked interviewees about their views regarding ethical considerations related to the adoption of AI and ML in medicine. Interviews were transcribed and deidentified by members of our research team. Data analysis was guided by the principles of qualitative content analysis. This approach, in which transcribed data is broken down into descriptive units that are named and sorted based on their content, allows for the inductive emergence of codes directly from the data set. RESULTS: Notably, both researchers and physicians articulated concerns regarding how AI and ML innovations are shaped in their early development (ie, the problem formulation stage). Considerations encompassed the assessment of research priorities and motivations, clarity and centeredness of clinical needs, professional and demographic diversity of research teams, and interdisciplinary knowledge generation and collaboration. Phase-1 ethical issues identified by interviewees were notably interdisciplinary in nature and invited questions regarding how to align priorities and values across disciplines and ensure clinical value throughout the development and implementation of medical AI and ML. Relatedly, interviewees suggested interdisciplinary solutions to these issues, for example, more resources to support knowledge generation and collaboration between developers and physicians, engagement with a broader range of stakeholders, and efforts to increase diversity in research broadly and within individual teams. CONCLUSIONS: These qualitative findings help elucidate several ethical challenges anticipated or encountered in AI and ML for health care. Our study is unique in that its use of open-ended questions allowed interviewees to explore their sentiments and perspectives without overreliance on implicit assumptions about what AI and ML currently are or are not. This analysis, however, does not include the perspectives of other relevant stakeholder groups, such as patients, ethicists, industry researchers or representatives, or other health care professionals beyond physicians. Additional qualitative and quantitative research is needed to reproduce and build on these findings.

Strategies to Mitigate and Treat Orthopaedic Device-Associated Infections.

Orthopaedic device implants play a crucial role in restoring functionality to patients suffering from debilitating musculoskeletal diseases or to those who have experienced traumatic injury. However, the surgical implantation of these devices carries a risk of infection, which represents a significant burden for patients and healthcare providers. This review delineates the pathogenesis of orthopaedic implant infections and the challenges that arise due to biofilm formation and the implications for treatment. It focuses on research advancements in the development of next-generation orthopaedic medical devices to mitigate against implant-related infections. Key considerations impacting the development of devices, which must often perform multiple biological and mechanical roles, are delineated. We review technologies designed to exert spatial and temporal control over antimicrobial presentation and the use of antimicrobial surfaces with intrinsic antibacterial activity. A range of measures to control bio-interfacial interactions including approaches that modify implant surface chemistry or topography to reduce the capacity of bacteria to colonise the surface, form biofilms and cause infections at the device interface and surrounding tissues are also reviewed.

GW5074 Increases Microglial Phagocytic Activities: Potential Therapeutic Direction for Alzheimer's Disease.

Microglia, the resident immune cells of the central nervous system (CNS), are responsible for maintaining homeostasis in the brain by clearing debris and are suggested to be inefficient in Alzheimer's Disease (AD), a progressive neurodegenerative disorder for which there is no disease-modifying drug. Besides pathological approaches, unbiased evidence from genome-wide association studies (GWAS) and gene network analysis implicate genes expressed in microglia that reduce phagocytic ability as susceptibility genes for AD. Thus, a central feature toward AD therapy is to increase the microglial phagocytic activities while maintaining synaptic integrity. Here, we developed a robust unbiased high content screening assay to identify potential therapeutics which can reduce the amyloid-beta (Aß1-42) load by increasing microglial uptake ability. Our screen identified the small-molecule GW5074, an inhibitor of c-RAF, a serine/threonine kinase, which significantly increased the Aß1-42 clearance activities in human monocyte-derived microglia-like (MDMi) cells, a microglia culture model that recapitulates many genetic and phenotypic aspects of human microglia. Notably, GW5074 was previously reported to be neuroprotective for cerebellar granule cells and cortical neurons. We found that GW5074 significantly increased the expression of key AD-associated microglial molecules known to modulate phagocytosis: TYROBP, SIRPß1, and TREM2. Our results demonstrated that GW5074 is a potential therapeutic for AD, by targeting microglia.