Mice integrate conspecific and contextual information in forming social episodic-like memories under spontaneous recognition task conditions.

The ability to remember unique past events (episodic memory) may be an evolutionarily conserved function, with accumulating evidence of episodic-(like) memory processing in rodents. In humans, it likely contributes to successful complex social networking. Rodents, arguably the most used laboratory models, are also rather social animals. However, many behavioural paradigms are devoid of sociality, and commonly-used social spontaneous recognition tasks (SRTs) are open to non-episodic strategies based upon familiarity. We address this gap by developing new SRT variants. Here, in object-in-context SRTs, we asked if context could be specified by the presence/absence of either a conspecific (experiment 1) or an additional local object (experiment 2). We show that mice readily used the conspecific as contextual information to distinguish unique episodes in memory. In contrast, no coherent behavioural response emerged when an additional object was used as a potential context specifier. Further, in a new social conspecific-in-context SRT (experiment 3) where environment-based change was the context specifier, mice preferably explored a more recently-seen familiar conspecific associated with contextual mismatch, over a less recently-seen familiar conspecific presented in the same context. The results argue that, in incidental SRT conditions, mice readily incorporate conspecific cue information into episodic-like memory. Thus, the tasks offer different ways to assess and further understand the mechanisms at work in social episodic-like memory processing.

Synthesis of LaCN3, TbCN3, CeCN5, and TbCN5 Polycarbonitrides at Megabar Pressures.

Inorganic ternary metal-C-N compounds with covalently bonded C-N anions encompass important classes of solids such as cyanides and carbodiimides, well known at ambient conditions and composed of [CN]- and [CN2]2- anions, as well as the high-pressure formed guanidinates featuring [CN3]5- anion. At still higher pressures, carbon is expected to be 4-fold coordinated by nitrogen atoms, but hitherto, such CN4-built anions are missing. In this study, four polycarbonitride compounds (LaCN3, TbCN3, CeCN5, and TbCN5) are synthesized in laser-heated diamond anvil cells at pressures between 90 and 111 GPa. Synchrotron single-crystal X-ray diffraction (SCXRD) reveals that their crystal structures are built of a previously unobserved anionic single-bonded carbon-nitrogen three-dimensional (3D) framework consisting of CN4 tetrahedra connected via di- or oligo-nitrogen linkers. A crystal-chemical analysis demonstrates that these polycarbonitride compounds have similarities to lanthanide silicon phosphides. Decompression experiments reveal the existence of LaCN3 and CeCN5 compounds over a very large pressure range. Density functional theory (DFT) supports these discoveries and provides further insight into the stability and physical properties of the synthesized compounds.

Community Pharmacy-Based Blood Pressure Screening in Newfoundland and Labrador, Canada for World Hypertension Day 2022: A Cross-Sectional Study.

Background: High blood pressure (BP) is a leading cause of cardiovascular and stroke-related events. Office-based BP measurement has declined in recent years due to the COVID-19 pandemic, which may have resulted in higher rates of undetected and uncontrolled hypertension. To gain a better idea of adult BP levels in Newfoundland and Labrador, we engaged community pharmacists in BP screening on World Hypertension Day. Methods: Data collection and BP screening occurred on May 17, 2022. Pharmacists and pharmacy students collected 3 seated BP readings from participants, using an automated device. The average of readings 2 and 3 was used to estimate BP, with elevated BP defined as ≥ 140/90 mm Hg, or ≥ 130/80 mm Hg for individuals with diabetes. Data on participant demographics, access to primary care, medical history, and antihypertensive use were also collected. Data analysis included descriptive statistics and logistic regression techniques. Results: A total of 460 participants were included in the analysis. The mean age was 56.3 years (standard deviation: 16.95); 63.3% (n = 291) were female; and 43.7% (n = 201) reported having hypertension. Elevated BP was identified in 27% (n = 123). Of those with elevated BP, 41.5% (n = 51) had no history of diagnosed hypertension. Age, sex, and diabetes were statistically significant predictors of elevated BP in the multivariable model. Conclusions: A large proportion of participants in our study had elevated BP. Targeted measures are needed to improve the detection, treatment, and control of high BP in Newfoundland and Labrador. Community pharmacists can support BP care.

Contexte: L'hypertension artérielle est une cause majeure d'événements cardiovasculaires et d'AVC. Or, la mesure de la pression artérielle (PA) en clinique a connu un déclin ces dernières années en raison de la pandémie de COVID-19, de sorte que les taux d'hypertension artérielle non détectée et non maîtrisée pourraient avoir augmenté. Afin de nous faire une idée plus précise de l'état de la PA des adultes de Terre-Neuve-et-Labrador, nous avons organisé une campagne de mesure de la PA dans les pharmacies de détail à l'occasion de la Journée mondiale de l'hypertension artérielle. Méthodologie: La collecte des données et les mesures ont eu lieu le 17 mai 2022. Les pharmaciens aidés par des étudiants en pharmacie ont pris 3 relevés en position assise par participant à l'aide d'un dispositif de mesure automatisé. La moyenne des 2 derniers relevés a été utilisée pour obtenir la PA estimative. La PA était considérée comme élevée si les valeurs étaient égales ou supérieures à 140/90 mmHg, ou à 130/80 mmHg chez les personnes diabétiques. D'autres renseignements ont été recueillis, notamment les caractéristiques démographiques des participants, leur accès aux soins primaires, leurs antécédents médicaux et leur prise d'antihypertenseurs. Les données ont ensuite été analysées à l'aide de statistiques descriptives et de techniques de régression logistique. Résultats: Au total, 460 participants ont été inclus dans l'analyse. L'âge moyen était de 56,3 ans (écart-type : 16,95); 63,3 % (n = 291) étaient de sexe féminin et 43,7 % (n = 201) ont indiqué être atteints d'hypertension. Une PA élevée a été observée chez 27 % des participants (n = 123), dont 41,5 % (n = 51) qui n'avaient jamais reçu un diagnostic d'hypertension artérielle. L'âge, le sexe et le diabète se sont avérés des facteurs de prédiction de PA élevée statistiquement significatifs dans un modèle multivarié. Conclusions: Un pourcentage important des participants à notre étude présentait une PA élevée. Des mesures ciblées s'imposent pour mieux dépister, traiter et maîtriser l'hypertension artérielle à Terre-Neuve-et-Labrador. Les pharmaciens de proximité pourraient également jouer un rôle dans la surveillance de la PA.

Case-finding for HPV vaccination eligibility within a dental office with concurrent development of a dialogue tool.

Background: Human papillomavirus (HPV) immunization can prevent cancers, but uptake has been incomplete (and worse with the COVID-19 pandemic). Dental clinicians already screen for oral cancers, many of which are caused by HPV, and could identify vaccination candidates, but this requires a case-finding strategy. Objective: The purpose of this study was (1) to develop and test a case-finding approach to identify patients who were candidates for HPV vaccinations, (2) to test an HPV vaccination intervention by dental professionals on vaccination uptake. Methods: Design: Prospective, non-randomized feasibility case finding study with a 4-week enrollment period and a 6 week follow up period in general dental offices.Setting: Two general and non-commercial dentistry offices in Edmonton, Alberta Canada.Subjects: Consecutive scheduled (non-emergent) patients who met the Health Canada criteria for HPV vaccination: immunocompetent males and females aged 9-45 years and those who are immunocompromised. Consent for the discussion was obtained from each subject or parent.Intervention: Scheduled dental patients meeting the inclusion criteria were flagged by a research assistant who reviewed the appointment schedule each week for 4 weeks. For these subjects, dental clinicians (dentists and dental hygienists) used our Dental Dialogue Tool to discuss HPV vaccination and answer questions. Participating patients who consented to receive the HPV vaccine were given a prescription by the attending dentist and were directed to follow-up with a local pharmacy to have the vaccine administered. Each participant that was provided with an HPV prescription was contacted after 6 weeks to identify if they received the first dose of vaccine.Outcomes: Yield of our case-finding strategy and receipt of a patient's first HPV vaccine dose during 6 weeks post vaccine prescription. Results: Our case-finding strategy assessed 656 scheduled patients over 4 weeks. From this screening,179 (a case-finding yield of 20.4 %), were candidates for HPV vaccine discussion. Forty-three of these 179 patients (24 %) were already vaccinated.. Two patients (1.1 %) did not consent to be spoken with and 134 (74.8 %) consented to the HPV vaccine discussion.. Forty-eight of 134 patients (35.8 %) of patients accepted a prescription from the dentist after speaking with the dental clinician. Ultimately, 8/48 (16 %) (patients received their first dose of the HPV vaccine by the 6 week of follow-up call. However, this is only 4.5 % (8/177) of those patients who did consent for the discussion of HPV cancers and vaccination from their dentist. Conclusion: We demonstrated that case-finding for HPV vaccine candidates in general dental offices was feasible, with a reasonable yield. While the dental dialogue tool was described as a great resource to explain the facts and answer questions, very few patients were vaccinated after 6 weeks of follow-up. Further work is necessary to sharpen the intervention, perhaps including follow-up discussions with the dental clinicians.

Empagliflozin to prevent progressive adverse remodelling after myocardial infarction (EMPRESS-MI): rationale and design.

AIMS: Patients with a reduced left ventricular ejection fraction (LVEF) following an acute myocardial infarction (MI) are at risk of progressive adverse cardiac remodelling that can lead to the development of heart failure and death. The early addition of a sodium-glucose cotransporter 2 (SGLT2) inhibitor to standard treatment may delay or prevent progressive adverse remodelling in these patients. METHODS AND RESULTS: EMpagliflozin to PREvent worSening of left ventricular volumes and Systolic function after Myocardial Infarction (EMPRESS-MI) is a randomized, double-blind, placebo-controlled, multi-centre trial designed to assess the effect of empagliflozin on cardiac remodelling evaluated using cardiovascular magnetic resonance (CMR) in 100 patients with left ventricular systolic dysfunction following MI. Eligible patients were those ≥12 h and ≤14 days following acute MI, with an LVEF <45% by CMR. Patients were randomized to empagliflozin 10 mg once a day or matching placebo. The primary outcome will be change in left ventricular end-systolic volume indexed to body surface area over 24 weeks from randomization. Secondary endpoints include measures of left ventricular and atrial volumes, left ventricular mass, LVEF, and circulating cardiac biomarkers. CONCLUSIONS: EMPRESS-MI will assess the effect of the SGLT2 inhibitor empagliflozin on cardiac remodelling in patients with left ventricular systolic dysfunction after an acute MI.

Liver and pancreatic-targeted interleukin-22 as a therapeutic for metabolic dysfunction-associated steatohepatitis.

Metabolic dysfunction-associated steatohepatitis (MASH) is the most prevalent cause of liver disease worldwide, with a single approved therapeutic. Previous research has shown that interleukin-22 (IL-22) can suppress ß-cell stress, reduce local islet inflammation, restore appropriate insulin production, reverse hyperglycemia, and ameliorate insulin resistance in preclinical models of diabetes. In clinical trials long-acting forms of IL-22 have led to increased proliferation in the skin and intestine, where the IL-22RA1 receptor is highly expressed. To maximise beneficial effects whilst reducing the risk of epithelial proliferation and cancer, we designed short-acting IL-22-bispecific biologic drugs that successfully targeted the liver and pancreas. Here we show 10-fold lower doses of these bispecific biologics exceed the beneficial effects of native IL-22 in multiple preclinical models of MASH, without off-target effects. Treatment restores glycemic control, markedly reduces hepatic steatosis, inflammation, and fibrogenesis. These short-acting IL-22-bispecific targeted biologics are a promising new therapeutic approach for MASH.

Circulating soluble fibroblast activation protein (FAP) levels are independent of cardiac and extra-cardiac FAP expression determined by targeted molecular imaging in patients with myocardial FAP activation.

INTRODUCTION: Tissue Fibroblast Activation Protein alpha (FAP) is overexpressed in various types of acute and chronic cardiovascular disease. A soluble form of FAP has been detected in human plasma, and low circulating FAP concentrations are associated with increased risk of death in patients with acute coronary syndrome. However, little is known about the regulation and release of FAP from fibroblasts, and whether circulating FAP concentration is associated with tissue FAP expression. This study characterizes the release of FAP in human cardiac fibroblasts (CF) and analyzes the association of circulating FAP concentrations with in vivo tissue FAP expression in patients with acute (ST-segment elevation myocardial infarction, STEMI) and chronic (severe aortic stenosis, AS) myocardial FAP expression. METHODS AND RESULTS: FAP was released from CF in a time- and concentration-dependent manner. FAP concentration was higher in supernatant of TGFß-stimulated CF, and correlated with cellular FAP concentration. Inhibition of metallo- and serine-proteases diminished FAP release in vitro. Median FAP concentrations of patients with acute (77 ng/mL) and chronic (75 ng/mL, p = 0.50 vs. STEMI) myocardial FAP expression did not correlate with myocardial nor extra-myocardial nor total FAP volume (P ≥ 0.61 in all cases) measured by whole-body FAP-targeted positron emission tomography. CONCLUSION: We describe a time- and concentration dependent, protease-mediated release of FAP from cardiac fibroblasts. Circulating FAP concentrations were not associated with increased in vivo tissue FAP expression determined by molecular imaging in patients with both chronic and acute myocardial FAP expression. These data suggest that circulating FAP and tissue FAP expression provide complementary, non-interchangeable information.

Predictors of heart failure readmission and all-cause mortality in patients with acute heart failure.

BACKGROUND: Predischarge risk stratification of patients with acute heart failure (AHF) could facilitate tailored treatment and follow-up, however, simple scores to predict short-term risk for HF readmission or death are lacking. METHODS: We sought to develop a congestion-focused risk score using data from a prospective, two-center observational study in adults hospitalized for AHF. Laboratory data were collected on admission. Patients underwent physical examination, 4-zone, and in a subset 8-zone, lung ultrasound (LUS), and echocardiography at baseline. A second LUS was performed before discharge in a subset of patients. The primary endpoint was the composite of HF hospitalization or all-cause death. RESULTS: Among 350 patients (median age 75 years, 43% women), 88 participants (25%) were hospitalized or died within 90 days after discharge. A stepwise Cox regression model selected four significant independent predictors of the composite outcome, and each was assigned points proportional to its regression coefficient: NT-proBNP ≥2000 pg/mL (admission) (3 points), systolic blood pressure < 120 mmHg (baseline) (2 points), left atrial volume index ≥60 mL/m2 (baseline) (1 point) and ≥ 9 B-lines on predischarge 4-zone LUS (3 points). This risk score provided adequate risk discrimination for the composite outcome (HR 1.48 per 1 point increase, 95% confidence interval: 1.32-1.67, p < 0.001, C-statistic: 0.70). In a subset of patients with 8-zone LUS data (n = 176), results were similar (C-statistic: 0.72). CONCLUSIONS: A four-variable risk score integrating clinical, laboratory and ultrasound data may provide a simple approach for risk discrimination for 90-day adverse outcomes in patients with AHF if validated in future investigations.

Dapagliflozin and Days of Full Health Lost in the DAPA-HF Trial.

BACKGROUND: Conventional time-to-first-event analyses cannot incorporate recurrent hospitalizations and patient well-being in a single outcome. OBJECTIVES: To overcome this limitation, we tested an integrated measure that includes days lost from death and hospitalization, and additional days of full health lost through diminished well-being. METHODS: The effect of dapagliflozin on this integrated measure was assessed in the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) trial, which examined the efficacy of dapagliflozin, compared with placebo, in patients with NYHA functional class II to IV heart failure and a left ventricular ejection fraction ≤40%. RESULTS: Over 360 days, patients in the dapagliflozin group (n = 2,127) lost 10.6 ± 1.0 (2.9%) of potential follow-up days through cardiovascular death and heart failure hospitalization, compared with 14.4 ± 1.0 days (4.0%) in the placebo group (n = 2,108), and this component of all measures of days lost accounted for the greatest between-treatment difference (-3.8 days [95% CI: -6.6 to -1.0 days]). Patients receiving dapagliflozin also had fewer days lost to death and hospitalization from all causes vs placebo (15.5 ± 1.1 days [4.3%] vs 20.3 ± 1.1 days [5.6%]). When additional days of full health lost (ie, adjusted for Kansas City Cardiomyopathy Questionnaire-overall summary score) were added, total days lost were 110.6 ± 1.6 days (30.7%) with dapagliflozin vs 116.9 ± 1.6 days (32.5%) with placebo. The difference in all measures between the 2 groups increased over time (ie, days lost by death and hospitalization -0.9 days [-0.7%] at 120 days, -2.3 days [-1.0%] at 240 days, and -4.8 days [-1.3%] at 360 days). CONCLUSIONS: Dapagliflozin reduced the total days of potential full health lost due to death, hospitalizations, and impaired well-being, and this benefit increased over time during the first year. (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure; NCT03036124).

Prognostic Models for Mortality and Morbidity in Heart Failure With Preserved Ejection Fraction.

Importance: Accurate risk prediction of morbidity and mortality in patients with heart failure with preserved ejection fraction (HFpEF) may help clinicians risk stratify and inform care decisions. Objective: To develop and validate a novel prediction model for clinical outcomes in patients with HFpEF using routinely collected variables and to compare it with a biomarker-driven approach. Design, Setting, and Participants: Data were used from the Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure (DELIVER) trial to derive the prediction model, and data from the Angiotensin Receptor Neprilysin Inhibition in Heart Failure With Preserved Ejection Fraction (PARAGON-HF) and the Irbesartan in Heart Failure With Preserved Ejection Fraction Study (I-PRESERVE) trials were used to validate it. The outcomes were the composite of HF hospitalization (HFH) or cardiovascular death, cardiovascular death, and all-cause death. A total of 30 baseline candidate variables were selected in a stepwise fashion using multivariable analyses to create the models. Data were analyzed from January 2023 to June 2023. Exposures: Models to estimate the 1-year and 2-year risk of cardiovascular death or hospitalization for heart failure, cardiovascular death, and all-cause death. Results: Data from 6263 individuals in the DELIVER trial were used to derive the prediction model and data from 4796 individuals in the PARAGON-HF trial and 4128 individuals in the I-PRESERVE trial were used to validate it. The final prediction model for the composite outcome included 11 variables: N-terminal pro-brain natriuretic peptide (NT-proBNP) level, HFH within the past 6 months, creatinine level, diabetes, geographic region, HF duration, treatment with a sodium-glucose cotransporter 2 inhibitor, chronic obstructive pulmonary disease, transient ischemic attack/stroke, any previous HFH, and heart rate. This model showed good discrimination (C statistic at 1 year, 0.73; 95% CI, 0.71-0.75) in both validation cohorts (C statistic at 1 year, 0.71; 95% CI, 0.69-0.74 in PARAGON-HF and 0.75; 95% CI, 0.73-0.78 in I-PRESERVE) and calibration. The model showed similar discrimination to a biomarker-driven model including high-sensitivity cardiac troponin T and significantly better discrimination than the Meta-Analysis Global Group in Chronic (MAGGIC) risk score (C statistic at 1 year, 0.60; 95% CI, 0.58-0.63; delta C statistic, 0.13; 95% CI, 0.10-0.15; P < .001) and NT-proBNP level alone (C statistic at 1 year, 0.66; 95% CI, 0.64-0.68; delta C statistic, 0.07; 95% CI, 0.05-0.08; P < .001). Models derived for the prediction of all-cause and cardiovascular death also performed well. An online calculator was created to allow calculation of an individual's risk. Conclusions and Relevance: In this prognostic study, a robust prediction model for clinical outcomes in HFpEF was developed and validated using routinely collected variables. The model performed better than NT-proBNP level alone. The model may help clinicians to identify high-risk patients and guide treatment decisions in HFpEF.

Personalised virtual reality in palliative care: clinically meaningful symptom improvement for some.

OBJECTIVES: This study examined the effects of virtual reality (VR) among palliative care patients at an acute ward. Objectives included evaluating VR therapy benefits across three sessions, assessing its differential impact on emotional versus physical symptoms and determining the proportion of patients experiencing clinically meaningful improvements after each session. METHODS: A mixed-methods design was employed. Sixteen palliative inpatients completed three personalised 20 min VR sessions. Symptom burden was assessed using the Edmonton Symptom Assessment Scale-Revised and quality of life with the Functional Assessment of Chronic Illness Therapy (FACIT-Pal-14). Standardised criteria assessed clinically meaningful changes. Quantitative data were analysed using linear mixed models. RESULTS: Quality of life improved significantly pre-VR to post-VR with a large effect size (Cohen's d: 0.98). Total symptom burden decreased after 20 min VR sessions (Cohen's d: 0.75), with similar effect sizes for emotional (Cohen's d: 0.67) and physical symptoms (Cohen's d: 0.63). Over 50% of patients experienced clinically meaningful improvements per session, though substantial individual variability occurred. CONCLUSIONS: This study reveals the nuanced efficacy of personalised VR therapy in palliative care, with over half of the patients experiencing meaningful benefits in emotional and physical symptoms. The marked variability in responses underscores the need for realistic expectations when implementing VR therapy.

Validity of Home Blood Pressure Devices Sold in Canada.

Background: Measurement of home blood pressure is an important tool for the management of hypertension. However, the validity of home devices is of concern. The Recommended Blood Pressure Devices Program of Hypertension Canada reviews and recommends blood pressure devices using international validation standards. We sought to determine the proportion of Hypertension Canada-recommended devices available for purchase in pharmacies and online. Methods: We visited 16 community pharmacies in the Edmonton area to record the blood pressure devices they sold. We also reviewed the 50 most popular devices from online retailers (Amazon, Walmart, Best Buy, and Canadian Tire). All devices were referenced against the Recommended Blood Pressure Device Program of Hypertension Canada (www.hypertension.ca/bpdevices) to determine if the models were recommended. Results: We reviewed 170 devices. Of those sold in pharmacies, 61 of 68 (89.7%) were Hypertension Canada-recommended devices, whereas online retailers had only 46 of 102 (45.1%) recommended devices; P < 0.001. Conclusions: Most blood pressure devices sold in pharmacies are Hypertension Canada recommended, in contrast to less than one-half from online retailers. The lack of validation of many home blood pressure devices could have important clinical implications, leading to over- or undertreatment of hypertension. Clinicians should advise patients on the importance of home blood pressure device validation and direct them to resources such as Hypertension Canada (https://hypertension.ca/public/recommended-devices) for guidance.

Contexte: La mesure de la pression artérielle au domicile est un outil important dans la prise en charge de l'hypertension. Or, il semble que les appareils utilisés à la maison à cette fin ne soient pas toujours des dispositifs validés. Dans le cadre de son Programme de recommandation d'appareils de mesure de la pression artérielle, Hypertension Canada analyse et recommande des tensiomètres selon des normes de validation internationales. Nous avons donc cherché à déterminer la proportion des tensiomètres recommandés par Hypertension Canada qu'il est possible d'acheter dans les pharmacies et en ligne. Méthodologie: Nous avons rendu visite à 16 pharmacies communautaires dans la région d'Edmonton pour recenser les tensiomètres qui y étaient vendus. Nous avons également analysé les 50 tensiomètres les plus vendus par des détaillants en ligne (Amazon, Walmart, Best Buy et Canadian Tire). Nous avons vérifié si chacun des modèles faisait partie de la liste des appareils recommandés par Hypertension Canada (www.hypertension.ca/bpdevices). Résultats: Nous avons passé en revue 170 appareils. Dans les pharmacies, 61 appareils sur 68 (89,7 %) étaient recommandés par Hypertension Canada, alors qu'en ligne, cette proportion n'était que de 46 sur 102 (45,1 %); p < 0,001. Conclusions: La plupart des tensiomètres vendus dans les pharmacies sont recommandés par Hypertension Canada, contrairement à moins de la moitié de ceux qui sont vendus en ligne. L'absence de validation pour de nombreux tensiomètres pourrait avoir d'importantes conséquences cliniques, menant à un traitement excessif ou insuffisant de l'hypertension. Les cliniciens doivent informer les patients de l'importance d'utiliser un tensiomètre validé à la maison et les orienter vers des ressources comme Hypertension Canada (https://hypertension.ca/public/recommended-devices) pour guider leur choix.

HistoEM: A Pathologist-Guided and Explainable Workflow Using Histogram Embedding for Gland Classification.

Pathologists have, over several decades, developed criteria for diagnosing and grading prostate cancer. However, this knowledge has not, so far, been included in the design of convolutional neural networks (CNN) for prostate cancer detection and grading. Further, it is not known whether the features learned by machine-learning algorithms coincide with diagnostic features used by pathologists. We propose a framework that enforces algorithms to learn the cellular and subcellular differences between benign and cancerous prostate glands in digital slides from hematoxylin and eosin-stained tissue sections. After accurate gland segmentation and exclusion of the stroma, the central component of the pipeline, named HistoEM, utilizes a histogram embedding of features from the latent space of the CNN encoder. Each gland is represented by 128 feature-wise histograms that provide the input into a second network for benign vs cancer classification of the whole gland. Cancer glands are further processed by a U-Net structured network to separate low-grade from high-grade cancer. Our model demonstrates similar performance compared with other state-of-the-art prostate cancer grading models with gland-level resolution. To understand the features learned by HistoEM, we first rank features based on the distance between benign and cancer histograms and visualize the tissue origins of the 2 most important features. A heatmap of pixel activation by each feature is generated using Grad-CAM and overlaid on nuclear segmentation outlines. We conclude that HistoEM, similar to pathologists, uses nuclear features for the detection of prostate cancer. Altogether, this novel approach can be broadly deployed to visualize computer-learned features in histopathology images.

Managing Medications During "Sick Days" in Patients With Diabetes, Kidney, and Cardiovascular Conditions: A Theory-informed Approach to Intervention Design and Implementation.

OBJECTIVES: Our aim in this work was to 1) explore barriers and enablers to patient and health-care provider (HCP) behaviours related to sick-day medication guidance (SDMG), 2) identify theory-informed strategies to advise SDMG intervention design, and 3) obtain perspectives on an eHealth tool for this purpose. METHODS: A qualitative descriptive study using qualitative conventional content analysis was undertaken. Interviews and focus groups were held with patients and HCPs from January 2021 to April 2022. Data were analyzed using the Behaviour Change Wheel and Theoretical Domains Framework to inform intervention design. RESULTS: Forty-eight people (20 patients, 13 pharmacists, 12 family physicians, and 3 nurse practitioners) participated in this study. Three interventions were designed to address the identified barriers and enablers: 1) prescriptions provided by a community-based care provider, 2) pharmacists adding a label to at-risk medications, and 3) built-in prompts for prescribing and dispensing software. Most participants accepted the concept of an eHealth tool and identified pharmacists as the ideal point-of-care provider. Challenges for an eHealth tool were raised, including credibility, privacy of data, medical liability, clinician remuneration and workload impact, and equitable access to use of the tool. CONCLUSIONS: Patients and HCPs endorsed non-technology and eHealth innovations as strategies to aid in the delivery of SDMG. These findings can guide the design of future theory-informed SDMG interventions.