Assessment of Embedded vs. Remote Pharmacist vs. Remote Student Pharmacist Outreach on Statin Prescribing.

BACKGROUND: The Statin Use in Persons with Diabetes (SUPD) measure is a Star measure by the Center for Medicare & Medicaid Services. The Duke Population Health Management Office (PHMO) has a team of pharmacists and pharmacy students who conduct targeted outreach to patients at risk of failing statin quality measures. Pharmacy services are embedded in select primary care clinics and other clinics are supported remotely. OBJECTIVE: The primary objective of this review is to compare the initiation rates of recommended statin prescriptions between embedded pharmacist vs remote pharmacist vs remote student pharmacist outreach groups, all of which have different levels of autonomy within pharmacy practice. The secondary objectives are to identify the barriers to the implementation of statin therapy and to assess the statin drugs and intensity of the statins prescribed. METHODS: A single-center, retrospective chart review was performed for SUPD patients with Medicare insurance. SUPD patients included patients 40-75 years of age, diagnosed with type 2 diabetes, and were not dispensed at least one statin medication of any intensity during the 6-month measurement period. The primary outcome was the initiation of recommended statin medications prescribed, or pended for the PCP to prescribe, for qualifying patients by embedded, remote, and remote student pharmacists. Secondary outcomes included the reasons for the non-implementation of statin recommendations, reasons statin therapy was not prescribed to patients contributing to the SUPD measure gap, and statin drug and dose prescribed for appropriateness. RESULTS: A total of 189 patients were included in the evaluation. In this study, 34.9% of the patients filled the prescribed or pended statin prescription and 83.3% of patients filled the prescribed or pended statin prescription at the recommended intensity according to the ACC/AHA guidelines, effectively closing the SUPD measure gap. The initiation rates of recommended statin prescriptions between the embedded pharmacist, remote pharmacist, and remote student pharmacist outreach were numerically different at 36.7%, 28.2%, and 36.7%, respectively, even though not statistically different (p=0.61). CONCLUSION: Remote student pharmacists' performance was equal to that of the embedded pharmacists when comparing the initiation rates of statin medications prescribed or pending the PCP's approval. The most common reason for non-implementation of statin therapy is that the statin was refused by the patient. Atorvastatin and rosuvastatin were the two most commonly prescribed statins.

Improving glycemic control in diabetes through virtual interdisciplinary rounds.

OBJECTIVE: A team-based disease management approach that considers comorbid conditions, social drivers of health, and clinical guidelines improves diabetes care but can be costly and complex. Developing innovative models of care is crucial to improving diabetes outcomes. The objective of this analysis was to evaluate the efficacy of virtual interdisciplinary diabetes rounds in improving glycemic control. STUDY DESIGN: Retrospective cohort study using observational data from July 2018 to December 2021. METHODS: This study employed difference-in-differences analysis to compare change in hemoglobin A1c (HbA1c) in a group of patients whose providers received advice as part of virtual interdisciplinary rounds and a group of patients whose providers did not receive rounds advice. Patients with diabetes were identified for rounding (1) based on attribution to an accountable care organization along with an upcoming primary care appointment and an HbA1c between 8% and 9% or (2) via provider referral. RESULTS: The rounded group consisted of 481 patients and the comparison group included 1806 patients. There was a 0.3-point reduction in HbA1c (95% CI, 0.1-0.4) associated with rounds overall. In a subanalysis comparing provider adoption of recommendations among those rounded, provider adoption was associated with an HbA1c reduction of 0.5 points (95% CI, 0.1-0.9) at 6 months post rounds, although there was no significant difference in the full year post rounds. CONCLUSIONS: Interdisciplinary rounds can be an effective approach to proactively provide diabetes-focused recommendations. This modality allows for efficient, low-cost, and timely access to an endocrinologist and team to support primary care providers in diabetes management.

Prediction models for hormone receptor status in female breast cancer do not extend to males: further evidence of sex-based disparity in breast cancer.

Breast cancer prognosis and management for both men and women are reliant upon estrogen receptor alpha (ERα) and progesterone receptor (PR) expression to inform therapy. Previous studies have shown that there are sex-specific binding characteristics of ERα and PR in breast cancer and, counterintuitively, ERα expression is more common in male than female breast cancer. We hypothesized that these differences could have morphological manifestations that are undetectable to human observers but could be elucidated computationally. To investigate this, we trained attention-based multiple instance learning prediction models for ERα and PR using H&E-stained images of female breast cancer from the Cancer Genome Atlas (TCGA) (n = 1085) and deployed them on external female (n = 192) and male breast cancer images (n = 245). Both targets were predicted in the internal (AUROC for ERα prediction: 0.86 ± 0.02, p < 0.001; AUROC for PR prediction = 0.76 ± 0.03, p < 0.001) and external female cohorts (AUROC for ERα prediction: 0.78 ± 0.03, p < 0.001; AUROC for PR prediction = 0.80 ± 0.04, p < 0.001) but not the male cohort (AUROC for ERα prediction: 0.66 ± 0.14, p = 0.43; AUROC for PR prediction = 0.63 ± 0.04, p = 0.05). This suggests that subtle morphological differences invisible upon visual inspection may exist between the sexes, supporting previous immunohistochemical, genomic, and transcriptomic analyses.

Transformer-based biomarker prediction from colorectal cancer histology: A large-scale multicentric study.

Deep learning (DL) can accelerate the prediction of prognostic biomarkers from routine pathology slides in colorectal cancer (CRC). However, current approaches rely on convolutional neural networks (CNNs) and have mostly been validated on small patient cohorts. Here, we develop a new transformer-based pipeline for end-to-end biomarker prediction from pathology slides by combining a pre-trained transformer encoder with a transformer network for patch aggregation. Our transformer-based approach substantially improves the performance, generalizability, data efficiency, and interpretability as compared with current state-of-the-art algorithms. After training and evaluating on a large multicenter cohort of over 13,000 patients from 16 colorectal cancer cohorts, we achieve a sensitivity of 0.99 with a negative predictive value of over 0.99 for prediction of microsatellite instability (MSI) on surgical resection specimens. We demonstrate that resection specimen-only training reaches clinical-grade performance on endoscopic biopsy tissue, solving a long-standing diagnostic problem.

Deep learning-based subtyping of gastric cancer histology predicts clinical outcome: a multi-institutional retrospective study.

INTRODUCTION: The Laurén classification is widely used for Gastric Cancer (GC) histology subtyping. However, this classification is prone to interobserver variability and its prognostic value remains controversial. Deep Learning (DL)-based assessment of hematoxylin and eosin (H&E) stained slides is a potentially useful tool to provide an additional layer of clinically relevant information, but has not been systematically assessed in GC. OBJECTIVE: We aimed to train, test and externally validate a deep learning-based classifier for GC histology subtyping using routine H&E stained tissue sections from gastric adenocarcinomas and to assess its potential prognostic utility. METHODS: We trained a binary classifier on intestinal and diffuse type GC whole slide images for a subset of the TCGA cohort (N = 166) using attention-based multiple instance learning. The ground truth of 166 GC was obtained by two expert pathologists. We deployed the model on two external GC patient cohorts, one from Europe (N = 322) and one from Japan (N = 243). We assessed classification performance using the Area Under the Receiver Operating Characteristic Curve (AUROC) and prognostic value (overall, cancer specific and disease free survival) of the DL-based classifier with uni- and multivariate Cox proportional hazard models and Kaplan-Meier curves with log-rank test statistics. RESULTS: Internal validation using the TCGA GC cohort using five-fold cross-validation achieved a mean AUROC of 0.93 ± 0.07. External validation showed that the DL-based classifier can better stratify GC patients' 5-year survival compared to pathologist-based Laurén classification for all survival endpoints, despite frequently divergent model-pathologist classifications. Univariate overall survival Hazard Ratios (HRs) of pathologist-based Laurén classification (diffuse type versus intestinal type) were 1.14 (95% Confidence Interval (CI) 0.66-1.44, p-value = 0.51) and 1.23 (95% CI 0.96-1.43, p-value = 0.09) in the Japanese and European cohorts, respectively. DL-based histology classification resulted in HR of 1.46 (95% CI 1.18-1.65, p-value < 0.005) and 1.41 (95% CI 1.20-1.57, p-value < 0.005), in the Japanese and European cohorts, respectively. In diffuse type GC (as defined by the pathologist), classifying patients using the DL diffuse and intestinal classifications provided a superior survival stratification, and demonstrated statistically significant survival stratification when combined with pathologist classification for both the Asian (overall survival log-rank test p-value < 0.005, HR 1.43 (95% CI 1.05-1.66, p-value = 0.03) and European cohorts (overall survival log-rank test p-value < 0.005, HR 1.56 (95% CI 1.16-1.76, p-value < 0.005)). CONCLUSION: Our study shows that gastric adenocarcinoma subtyping using pathologist's Laurén classification as ground truth can be performed using current state of the art DL techniques. Patient survival stratification seems to be better by DL-based histology typing compared with expert pathologist histology typing. DL-based GC histology typing has potential as an aid in subtyping. Further investigations are warranted to fully understand the underlying biological mechanisms for the improved survival stratification despite apparent imperfect classification by the DL algorithm.

Self-supervised attention-based deep learning for pan-cancer mutation prediction from histopathology.

The histopathological phenotype of tumors reflects the underlying genetic makeup. Deep learning can predict genetic alterations from pathology slides, but it is unclear how well these predictions generalize to external datasets. We performed a systematic study on Deep-Learning-based prediction of genetic alterations from histology, using two large datasets of multiple tumor types. We show that an analysis pipeline that integrates self-supervised feature extraction and attention-based multiple instance learning achieves a robust predictability and generalizability.

Direct prediction of genetic aberrations from pathology images in gastric cancer with swarm learning.

BACKGROUND: Computational pathology uses deep learning (DL) to extract biomarkers from routine pathology slides. Large multicentric datasets improve performance, but such datasets are scarce for gastric cancer. This limitation could be overcome by Swarm Learning (SL). METHODS: Here, we report the results of a multicentric retrospective study of SL for prediction of molecular biomarkers in gastric cancer. We collected tissue samples with known microsatellite instability (MSI) and Epstein-Barr Virus (EBV) status from four patient cohorts from Switzerland, Germany, the UK and the USA, storing each dataset on a physically separate computer. RESULTS: On an external validation cohort, the SL-based classifier reached an area under the receiver operating curve (AUROC) of 0.8092 (± 0.0132) for MSI prediction and 0.8372 (± 0.0179) for EBV prediction. The centralized model, which was trained on all datasets on a single computer, reached a similar performance. CONCLUSIONS: Our findings demonstrate the feasibility of SL-based molecular biomarkers in gastric cancer. In the future, SL could be used for collaborative training and, thus, improve the performance of these biomarkers. This may ultimately result in clinical-grade performance and generalizability.

Adversarial attacks and adversarial robustness in computational pathology.

Artificial Intelligence (AI) can support diagnostic workflows in oncology by aiding diagnosis and providing biomarkers directly from routine pathology slides. However, AI applications are vulnerable to adversarial attacks. Hence, it is essential to quantify and mitigate this risk before widespread clinical use. Here, we show that convolutional neural networks (CNNs) are highly susceptible to white- and black-box adversarial attacks in clinically relevant weakly-supervised classification tasks. Adversarially robust training and dual batch normalization (DBN) are possible mitigation strategies but require precise knowledge of the type of attack used in the inference. We demonstrate that vision transformers (ViTs) perform equally well compared to CNNs at baseline, but are orders of magnitude more robust to white- and black-box attacks. At a mechanistic level, we show that this is associated with a more robust latent representation of clinically relevant categories in ViTs compared to CNNs. Our results are in line with previous theoretical studies and provide empirical evidence that ViTs are robust learners in computational pathology. This implies that large-scale rollout of AI models in computational pathology should rely on ViTs rather than CNN-based classifiers to provide inherent protection against perturbation of the input data, especially adversarial attacks.

Impact of pharmacist outreach on glucagon prescribing.

BACKGROUND: Hypoglycemia is a major limiting factor in the glycemic management of diabetes. As a method of treating hypoglycemia, the American Diabetes Association recommends glucagon to be prescribed for all individuals at increased risk of clinically impactful hypoglycemia. Glucagon Emergency Kits have been shown to reduce emergency department visits and overall health care costs. Despite these known benefits, glucagon continues to be underprescribed. Previous pharmacist-led interventions embedded in a single clinic have been shown to positively affect the rate of glucagon prescribing in patients with diabetes. OBJECTIVE: This study aimed to compare the rate of glucagon prescribing between quality improvement remote pharmacist outreach to multiple primary care and endocrinology specialty clinics and the control group in 1 month following a pharmacist-led provider outreach. METHODS: This was a single-center, 2-arm study with a simple randomization design. RESULTS: On pharmacist outreach, 61 of 109 patients (56.0%) in the outreach group were prescribed a glucagon product within 1 month of their primary care provider (PCP) or endocrinology appointment compared with 1 of 113 (0.9%) of patients in the control group (P < 0.001). Glucagon prescribing occurred in 25 of 35 Black patients (71.4%) compared with 36 of 73 white patients (49.3%) in the outreach group. Glucagon prescribing was associated with race (P = 0.03; chi-square test). CONCLUSIONS: The pharmacist-led provider outreach before a PCP or endocrinology appointment has a positive and statistically significant impact on glucagon prescribing rates. The pharmacist outreach had a higher impact on Black patients than white patients, possibly because of a lower rate of glucagon prescribing in Black patients before the outreach.

Impact of a clinical pharmacist on provider prescribing patterns in a primary care clinic.

BACKGROUND: Sodium-glucose transporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) agonists have demonstrated beneficial outcomes in patients with type 2 diabetes at high cardiovascular risk. Unfortunately, these agents are still underutilized in primary care practice. A clinical pharmacist was embedded at a primary care clinic to provide diabetes and hypertension management under a collaborative practice agreement with a supervising physician. OBJECTIVES: This study will evaluate whether the presence of an embedded pharmacist in a primary care clinic affects prescribing patterns of novel, evidence-based diabetes therapies. METHODS: We abstracted information on SGLT2 inhibitor and GLP-1 agonist prescribing patterns from 3 primary care clinics across 2 time periods as a single-center, retrospective cohort study. We used a difference-in-difference analysis to compare prescription rates and assess the impact of embedding the pharmacist into clinical practice. Prescriptions written by the pharmacist were excluded. RESULTS: Across all 3 clinics, 1309 and 1489 patients were included in the pre-intervention and postintervention periods, respectively. The percentage of patients prescribed either an SGLT2 inhibitor or GLP-1 agonist, similar between both groups at baseline, rose to 11.6% in the nonintervention clinics and 15.0% in the intervention clinic. There was a statistically significant increase in SGLT2 inhibitor and GLP-1 agonist prescribing in the intervention clinic compared with nonintervention clinics (P = 0.034). This change in prescribing patterns appeared even greater when excluding prescribers who were not present during both pre-intervention and postintervention periods (P = 0.009). CONCLUSION: The presence of a pharmacist is associated with increased SGLT2 inhibitor and GLP-1 agonist prescribing within a clinic, even in patients not seen directly by the pharmacist. These results suggest that an on-site clinical pharmacist providing care for patients with diabetes may indirectly influence the prescribing behavior of co-located primary care providers, increasing the adoption of novel noninsulin diabetic medications.

Retinal imaging using adaptive optics optical coherence tomography with fast and accurate real-time tracking.

One of the main obstacles in high-resolution 3-D retinal imaging is eye motion, which causes blur and distortion artifacts that require extensive post-processing to be corrected. Here, an adaptive optics optical coherence tomography (AOOCT) system with real-time active eye motion correction is presented. Correction of ocular aberrations and of retinal motion is provided by an adaptive optics scanning laser ophthalmoscope (AOSLO) that is optically and electronically combined with the AOOCT system. We describe the system design and quantify its performance. The AOOCT system features an independent focus adjustment that allows focusing on different retinal layers while maintaining the AOSLO focus on the photoreceptor mosaic for high fidelity active motion correction. The use of a high-quality reference frame for eye tracking increases revisitation accuracy between successive imaging sessions, allowing to collect several volumes from the same area. This system enables spatially targeted retinal imaging as well as volume averaging over multiple imaging sessions with minimal correction of motion in post processing.

Utility of Ga68 prostate-specific membrane antigen positron-emission tomography for pre-operative staging of high-risk prostate cancer in a prospective cohort.

INTRODUCTION: To assess the yield of Ga68 PSMA PET/CT added to the conventional staging of high-risk prostate cancer in terms of altered staging and changes to management. METHODS: Patients with high-risk prostate cancer without metastatic disease on conventional staging referred for Ga68 PSMA PET/CT at Mercy Radiology, Auckland, New Zealand, were prospectively recruited. Conventional staging was double read in a blinded fashion by oncology fellowship-trained radiologists, who were also experienced in PET/CT, followed by interpretation of the PSMA PET/CT by the same radiologists. Confirmation of changes in management decision was obtained from the treating surgeon and multidisciplinary team meeting records. Ethical approval was obtained from the Health and Disability Ethics Committee. All patients gave written informed consent. RESULTS: A total of 49 patients were scanned. Three who were otherwise eligible for radical prostatectomy elected alternative treatments, leaving 46 patients included for analysis in the study. The addition of PSMA PET/CT was associated with highly statistically significant changes in both staging and management. The stage was changed in 32.6% (95% CI 20.8-47.1%, P < 0.001) patients upstaging in 60% and downstaging in 40%; clinical management in 34.8% (95% CI 22.6-49.3%; P < 0.001), with intramodality change in 25% and intermodality change in 75%. Factors predictive of a change in management with PSMA PET/CT included higher Gleason score and a greater proportion of prostatic cores positive for tumour. CONCLUSION: The addition of Ga68 PSMA PET/CT to conventional staging in high-risk prostate cancer frequently leads to changes in staging and management.

Dissemination of results from medical student public health research training and factors associated with publication.

PURPOSE: To examine factors associated with successful publications resulting from mandatory public health research training attachment, the Trainee Intern Health Care Evaluation (TIHE) projects, at the University of Otago, Dunedin School of Medicine, New Zealand. METHODS: A total of 227 TIHE projects completed during the period from January 1985 to December 2013 were included in the study. In February 2016, Medline and Google Scholar databases were searched independently by both authors for publications using predefined search criteria. RESULTS: Overall, 25 (11.1%) out of 227 projects resulted in 19 articles, 3 conference presentations/abstracts and 4 cited report abstracts. Nineteen (8.4%) projects resulted in 22 peer-reviewed journal publications, the majority of which were original articles (86.4%). The number of projects commissioned by a client was independently associated with the likelihood of publication, conference abstract or citation of the project report (OR 1.40; P<0.01, 95% CI 1.14 to 1.71). The number of authors and the number of non-student authors were positively associated with publication in higher impact journals, while student first-authored articles were more likely to be published in lower impact journals. Projects completed in more recent years were more likely to be published. CONCLUSIONS: Mandatory medical student research experiences promote tangible research output. These findings may help to influence policy around the introduction of required medical school research and facilitate encouraging academic careers among medical students. Future research could focus on examining how different student-related, supervisor-related and programme-related factors influence publication rates from mandatory medical student research attachments.

Interferometric mapping of material properties using thermal perturbation.

Optical phase changes induced by transient perturbations provide a sensitive measure of material properties. We demonstrate the high sensitivity and speed of such methods, using two interferometric techniques: quantitative phase imaging (QPI) in transmission and phase-resolved optical coherence tomography (OCT) in reflection. Shot-noise-limited QPI can resolve energy deposition of about 3.4 mJ/cm2 in a single pulse, which corresponds to 0.8 °C temperature rise in a single cell. OCT can detect deposition of 24 mJ/cm2 energy between two scattering interfaces producing signals with about 30-dB signal-to-noise ratio (SNR), and 4.7 mJ/cm2 when SNR is 45 dB. Both techniques can image thermal changes within the thermal confinement time, which enables accurate single-shot mapping of absorption coefficients even in highly scattering samples, as well as electrical conductivity and many other material properties in biological samples at cellular scale. Integration of the phase changes along the beam path helps increase sensitivity, and the signal relaxation time reveals the size of hidden objects. These methods may enable multiple applications, ranging from temperature-controlled retinal laser therapy or gene expression to mapping electric current density and characterization of semiconductor devices with rapid pump-probe measurements.

Inverse regulation of the cytosolic Ca²âº buffer parvalbumin and mitochondrial volume in muscle cells via SIRT1/PGC-1α axis.

Skeletal muscles show a high plasticity to cope with various physiological demands. Different muscle types can be distinguished by the force, endurance, contraction/relaxation kinetics (fast-twitch vs. slow-twitch muscles), oxidative/glycolytic capacity, and also with respect to Ca²âº-signaling components. Changes in Ca²âº signaling and associated Ca²âº-dependent processes are thought to underlie the high adaptive capacity of muscle fibers. Here we investigated the consequences and the involved mechanisms caused by the ectopic expression of the Ca²âº-binding protein parvalbumin (PV) in C2C12 myotubes in vitro, and conversely, the effects caused by its absence in in fast-twitch muscles of parvalbumin null-mutant (PV⁻/⁻) mice in vivo. The absence of PV in fast-twitch muscle tibialis anterior (TA) resulted in an increase in the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) and of its positive regulator, the deacetylase sirtuin 1 (SIRT1). TA muscles from PV⁻/⁻ mice also have an increased mitochondrial volume. Mild ionophore treatment of control (PV-devoid) C2C12 myotubes causing a moderate elevation in [Ca²âº](c) resulted in an increase in mitochondrial volume, together with elevated PGC-1α and SIRT1 expression levels, whilst it increased PV expression levels in myotubes stably transfected with PV. In PV-expressing myotubes the mitochondrial volume, PGC-1α and SIRT1 were significantly lower than in control C2C12 myotubes already at basal conditions and application of ionophore had no effect on either one. SIRT1 activation causes a down-regulation of PV in transfected myotubes, whilst SIRT1 inhibition has the opposite effect. We conclude that PV expression and mitochondrial volume in muscle cells are inversely regulated via a SIRT1/PGC-1α signaling axis.

Death feigning by grass snakes (Natrix natrix) in response to handling by human "predators.".

Death feigning, a variant of tonic immobility, is usually interpreted as a last-resort antipredator measure. The authors describe death feigning in grass snakes (Natrix natrix) and test some of its potential correlates. Death feigning was seen in 66% of wild-caught snakes but was not seen in hatchlings from laboratory-incubated eggs. Minimal indication of death feigning was mouth gaping, often with the tongue hanging free, but more dramatic cases involved voluntary supination and/or lack of muscle tone. Aside from hatchlings, which did not feign death, there was little variation in frequency or intensity of death feigning with body size. There was no effect of body temperature on death feigning nor were snakes that were moving when caught less likely to feign death than those that were not moving. Interpretation of the adaptive value of death feigning in grass snakes or in other animals is hampered by lack of evidence of this behavior in the field in response to natural predators.

Differences in locomotor behavior revealed in mice deficient for the calcium-binding proteins parvalbumin, calbindin D-28k or both.

We investigated the role of the two calcium-binding proteins parvalbumin (PV) and calbindin D-28k (CB) in the locomotor activity and motor coordination using null-mutant mice for PV (PV-/-), CB (CB-/-) or both proteins (PV-/-CB-/-). These proteins are expressed in distinct, mainly non-overlapping populations of neurons of the central and peripheral nervous system and PV additionally in fast-twitch muscles. In a test measuring repeated locomotor activity during 18-20 days, the analysis revealed a slightly increased activity in mice lacking either protein, while the lack of both decreased the number of beams crossed during active periods. An increase in the characteristic speed during the first 8 days could be attributed to PV-deficiency, while the elimination of CB in CB-/- and double-KO mice decreased the percentage of fast movements at all time points. In the latter, additionally a reduction of the fastest speed was observed. The alterations in locomotor activity (fast movements, fastest speed) strongly correlate with the impairment in locomotor coordination in mice deficient for CB evidenced in the runway assay and the rotarod assay. The graded locomotor phenotype (CB>PV) is qualitatively correlated with alterations in Purkinje cell firing reported previously in these mice. The presence or absence of either protein did not affect the spontaneous locomotor activity when animals were placed in a novel environment and tested only once for 30 min. In summary, the lack of these calcium-binding proteins yields characteristic, yet distinct phenotypes with respect to locomotor activity and coordination.