The cost of potentially inappropriate medications for older adults in Canada: A comparative cross-sectional study.

BACKGROUND: Potentially inappropriate medications (PIMs) are medications whereby the harms may outweigh the benefits for a given individual. Although overprescribed to older adults, their direct costs on the healthcare system are poorly described. METHODS: This was a cross-sectional study of the cost of PIMs for Canadians aged 65 and older, using adapted criteria from the American Geriatrics Society. We examined prescription claims information from the National Prescription Drug Utilization Information System in 2021 and compared these with 2013. The overall levels of inflation-adjusted total annual expenditure on PIMs, average cost per quarterly exposure, and average quarterly exposures to PIMs were calculated in CAD$. RESULTS: Exposure to most categories of PIMs decreased, aside from gabapentinoids, proton pump inhibitors, and antipsychotics, all of which increased. Canadians spent $1 billion on PIMs in 2021, a 33.6% reduction compared with 2013 ($1.5 billion). In 2021, the largest annual expenditures were on proton pump inhibitors ($211 million) and gabapentinoids ($126 million). The quarterly amount spent on PIMs per person exposed decreased from $95 to $57. In terms of mean cost per person, opioids and antipsychotics were highest ($138 and $118 per exposure). Some cost savings may have occurred secondary to an observed decline of 16.4% in the quarterly rate of exposure to PIMs (from 7301 per 10,000 in 2013 to 6106 per 10,000 in 2021). CONCLUSIONS: While expenditures on PIMs have declined in Canada, the overall cost remains high. Prescribing of some seriously harmful classes of PIMs has increased and so directed, scalable interventions are needed.

Fast intraoperative detection of primary CNS lymphoma and differentiation from common CNS tumors using stimulated Raman histology and deep learning.

Background: Accurate intraoperative diagnosis is crucial for differentiating between primary CNS lymphoma (PCNSL) and other CNS entities, guiding surgical decision-making, but represents significant challenges due to overlapping histomorphological features, time constraints, and differing treatment strategies. We combined stimulated Raman histology (SRH) with deep learning to address this challenge. We imaged unprocessed, label-free tissue samples intraoperatively using a portable Raman scattering microscope, generating virtual H&E-like images within less than three minutes. We developed a deep learning pipeline called RapidLymphoma based on a self-supervised learning strategy to (1) detect PCNSL, (2) differentiate from other CNS entities, and (3) test the diagnostic performance in a prospective international multicenter cohort and two additional independent test cohorts. We trained on 54,000 SRH patch images sourced from surgical resections and stereotactic-guided biopsies, including various CNS tumor/non-tumor lesions. Training and test data were collected from four tertiary international medical centers. The final histopathological diagnosis served as ground-truth. In the prospective test cohort of PCNSL and non-PCNSL entities (n=160), RapidLymphoma achieved an overall balanced accuracy of 97.81% ±0.91, non-inferior to frozen section analysis in detecting PCNSL (100% vs. 78.94%). The additional test cohorts (n=420, n=59) reached balanced accuracy rates of 95.44% ±0.74 and 95.57% ±2.47 in differentiating IDH-wildtype diffuse gliomas and various brain metastasis from PCNSL. Visual heatmaps revealed RapidLymphoma's capabilities to detect class-specific histomorphological key features. RapidLymphoma is valid and reliable in detecting PCNSL and differentiating from other CNS entities within three minutes, as well as visual feedback in an intraoperative setting. This leads to fast clinical decision-making and further treatment strategy planning. Importance of the study: This study introduces RapidLymphoma, a novel self-supervised-based deep-learning model for visual representations to leverage the detection of primary CNS Lymphoma (PCNSL) and differentiation from common and rare CNS entities using intraoperative label-free stimulated Raman histology. While PCNSL is rare, time-critical personalized treatment with fast intraoperative decision-making is needed. In an international multicentric clinical trial, RapidLymphoma first demonstrated its ability to detect and differentiate PCNSL from other CNS lesions with an overall diagnostic balanced accuracy of 97.81% ± 0.91 compared to formalin-fixed paraffin-embedded diagnosis and is non-inferior to frozen section analysis. It provides near real-time intraoperative feedback and guidance to the surgeon, delivering a diagnosis in under three minutes. RapidLymphoma extracts key histomorphological features for detecting and differentiating CNS lesions by utilizing the benefits of intraoperative stimulated Raman histology. This guidance is assisted through a visual prediction heatmap feedback, highlighting critical areas for the surgeon and pathologist.

Confidence sets for intraclass correlation coefficients in test-retest curve measurements.

Evaluating test-retest reliability is crucial in biomechanical research, as it validates experimental results. While methods for reliability of scalar outcome variables are well-established, methods to assess reliability of continuous curve data (such as joint angle trajectories during gait) remain less explored. This study investigates methods for constructing confidence sets for curve-level intraclass correlation coefficients (ICC), which can be expressed as either an ICC curve or an integrated ICC. Currently, no standardised guidelines exist in biomechanics for reporting curve-level ICC uncertainty. Nonparametric bootstrapping techniques are proposed for both the ICC curve's confidence bands and the integrated ICC's confidence intervals, and these methods are validated through Monte Carlo simulations, covering various effect sizes and curve characteristics. Additionally, these methods are applied to assess the test-retest reliability of knee kinematics in three different planes during landing of one-leg hops, where less uncertainty is observed for the ICC curve and integrated ICC in the frontal plane compared to other planes. When the entire time domain is of primary empirical interest, we recommend using a rank-based bootstrap confidence band to express ICC uncertainty, as it yields increasingly precise and valid results as the number of individuals increases, with the coverage rate approaching the correct level of 95%. When a single summary metric is of primary interest, we recommend using the integrated ICC along with a typical bootstrap confidence interval based on the normal distribution, as the coverage rate remains adequately accurate and stable at around the correct level of 95% across varying number of individuals.

Assessing the risk of climate maladaptation for Canadian polar bears.

The Arctic is warming four times faster than the rest of the world, threatening the persistence of many Arctic species. It is uncertain if Arctic wildlife will have sufficient time to adapt to such rapidly warming environments. We used genetic forecasting to measure the risk of maladaptation to warming temperatures and sea ice loss in polar bears (Ursus maritimus) sampled across the Canadian Arctic. We found evidence for local adaptation to sea ice conditions and temperature. Forecasting of genome-environment mismatches for predicted climate scenarios suggested that polar bears in the Canadian high Arctic had the greatest risk of becoming maladapted to climate warming. While Canadian high Arctic bears may be the most likely to become maladapted, all polar bears face potentially negative outcomes to climate change. Given the importance of the sea ice habitat to polar bears, we expect that maladaptation to future warming is already widespread across Canada.

Racial, ethnic, and socioeconomic disparities in rates of stage IV prostate cancer after USPSTF category "D" recommendation against prostate-specific antigen screening: a retrospective cohort study.

Background: In 2012 the United States Preventative Services Task Force (USPSTF) changed its prostate-specific antigen (PSA) screening recommendation to a category "D". The purpose of this study is to examine racial, ethnic, and socioeconomic differences in risk of presentation with metastatic prostate cancer (mPCa) at time of diagnosis before and after the 2012 USPSTF category "D" recommendation. Methods: This is a population-based cohort study. We identified patients with mPCa at diagnosis within the National Cancer Database from 2004-2017. Logistic regression models were used to examine associations of mPCa with age, race, ethnicity, geographic location, education level, income, and insurance status. Linear regression models assuming underlying binomial distribution were fitted to annual percentage of mPCa at diagnosis for years 2012-2017 to evaluate the post category "D" recommendation era. Results: From 2004 to 2017, 88,987 patients presented with mPCa. A higher percentage of mPCa was noted post-USPSTF category "D" recommendation, with a disproportionately greater increase observed among Hispanics and non-Hispanic Blacks [Δslope/year: Hispanics (0.0092), non-Hispanic Blacks (0.0073) and non-Hispanic Whites (0.0070)]. Insurance status impacts race/ethnicity differently: uninsured Hispanics were 3.66 times more likely to present with mPCa than insured Hispanics, while uninsured non-Hispanic Blacks were 2.62 times more likely to present with mPCa than insured non-Hispanic Blacks. Household income appears to be associated with differences in mPCa, particularly among non-Hispanic Blacks. Those earning <$30,000 were more likely to present with mPCa compared to higher income brackets. Conclusions: Since the USPSTF grade "D" recommendation against PSA screening, the percentage of mPCa at diagnosis has increased, with a higher rate of increase among Hispanic and non-Hispanic Blacks compared to non-Hispanic Whites.

Brief report: incidence and outcomes of pediatric tracheal intubation-associated cardiac arrests in the ICU-RESUS clinical trial.

BACKGROUND: Tracheal intubation (TI)-associated cardiac arrest (TI-CA) occurs in 1.7% of pediatric ICU TIs. Our objective was to evaluate resuscitation characteristics and outcomes between cardiac arrest patients with and without TI-CA. METHODS: Secondary analysis of cardiac arrest patients in both ICU-RESUS trial and ancillary CPR-NOVA study. The primary exposure was TI-CA, defined as cardiac arrest occurred during TI procedure or within 20 min after endotracheal tube placement. The primary outcome was survival to hospital discharge with favorable neurological outcome (Pediatric Cerebral Performance Category score 1-3 or unchanged). RESULTS: Among 315 children with cardiac arrests, 48 (15.2%) met criteria for TI-CA. Pre-existing medical conditions were similar between groups. Pre-arrest non-invasive mechanical ventilation was more common among TI-CA patients (18/48, 37.5%) compared to non-TI-CA patients (35/267, 13.1%). In 48% (23/48), the TI-CA occurred within 20 min after intubation (i.e., not during intubation). Duration of CPR was longer in TI-CA patients (median 11.0 min, interquartile range [IQR]: 2.5, 35.5) than non-TI-CA patients (median 5.0 min, IQR 2.0, 21.0), p = 0.03. Return of spontaneous circulation occurred in 32/48 (66.7%) TI-CA versus 186/267 (69.7%) non-TI-CA, p = 0.73. Survival to hospital discharge with favorable neurological outcome occurred in 29/48 (60.4%) TI-CA versus 146/267 (54.7%) non-TI-CA, p = 0.53. CONCLUSIONS: Fifteen percent of these pediatric ICU cardiac arrests were associated with TI. Half of TI-CA occurred after endotracheal tube placement. While duration of CPR was longer in TI-CA patients, there were no differences in unadjusted outcomes following TI-CA versus non-TI-CA. TRIAL REGISTRATION: The ICU-RESUS (ClinicalTrials.gov Identifier: NCT02837497).

Initial development of the Sugar-Sweetened Fruit Drink Questionnaire for examining beliefs, knowledge, and behaviors in an intervention to reduce sugar-sweetened fruit drink intake in Alaska Native children.

OBJECTIVE: Alaska Native children may be at increased risk for dental caries because of added sugar intake from sugar-sweetened fruit drinks. This study describes development of a questionnaire to (a) assess Alaska Native caregivers' beliefs, knowledge, and behaviors regarding sugar-sweetened fruit drinks, and (b) describe behavior changes within a community-based intervention. METHODS: Questionnaire development was conducted in three phases with Yup'ik Alaska Native caregivers in Southwest Alaska: (1) initial selection and adaptation of questionnaire items; (2) cognitive testing; and (3) data collection. The Sugar-Sweetened Fruit Drink Questionnaire (SFDQ) contains 31 culturally-tailored items across six areas: beliefs/values, environment/skills, knowledge, motivation, self-efficacy, and behaviors. RESULTS: Eighty-one percent of caregivers gave their children sugar-sweetened fruit drinks. Motivations included: what they grew up with (52%), few other options (46%), makes child happy (46%), healthier than soda (45%), and others in community drink them (42%). On average, 93% of caregivers believed drinking a lot of sugar-sweetened fruit drinks leads to cavities in children and caregivers agreed (mean 4.1 on 5-point scale, 5 = strongly agree) it is important to limit sugar-sweetened fruit drinks. Among a sub-sample of respondents (n = 20), we found low to moderate temporal stability in some SFDQ items over a 10-14 day period, indicating respondent ambivalence and/or uncertainty. CONCLUSIONS: Using community-based participatory research methods, we developed a culturally tailored exploratory questionnaire that will be used to describe changes in caregiver knowledge, beliefs, attitudes, self-efficacy, and behavior within a planned intervention to reduce sugar-sweetened fruit drink intake in Alaska Native children.

Serum miRNA improves the accuracy of a multivariate index assay for triage of an adnexal mass.

OBJECTIVE: To determine whether a multimodal assay combining serum microRNA with protein biomarkers and metadata improves triage assessment of an adnexal mass. METHODS: Serum samples from 468 training subjects (191 cancer cases and 277 benign adnexal mass controls or healthy controls) were analyzed for seven protein biomarkers and 180 miRNA. Circulating analyte data were combined with age and menopausal status (metadata) into a neural network model to classify samples as cases or controls. Forward regression with ten-fold cross-validation minimized the dimensionality of the model while maximizing linear separation between cases and controls. Model validation proceeded using both internal (44 cases and 56 controls) and external validation sets (51 cases and 59 controls). RESULTS: The total study population comprised 678 subjects, including 286 cases and 392 controls. Overall, 290 (43%) of the subjects were premenopausal. A panel of 10 miRNA delivered optimal performance when combined with protein and metadata features. The combined model improved the Receiver Operator Characteristic Area Under the Curve (ROC AUC) on the internal (AUC = 0.9; 95% CI 0.81-0.95) and external validation sets (AUC = 0.95; 95% CI 0.90-0.98) compared to miRNA alone or proteins plus metadata (without miRNA). On external validation, the combined model offered 92% sensitivity at 80% specificity overall, with 80% and 100% sensitivity for early and late-stage cancers, respectively, including 78% sensitivity for early-stage, serous ovarian cancers and 82% sensitivity for early-stage, non-serous cancers. CONCLUSIONS: A multimodal assay combining miRNA with protein biomarkers, age, and menopausal status improves surgical triage of an adnexal mass.

Implementing a pragmatic clinical trial to tailor opioids for chronic pain on behalf of the IGNITE ADOPT PGx investigators.

Chronic pain is a prevalent condition with enormous economic burden. Opioids such as tramadol, codeine, and hydrocodone are commonly used to treat chronic pain; these drugs are activated to more potent opioid receptor agonists by the hepatic CYP2D6 enzyme. Results from clinical studies and mechanistic understandings suggest that CYP2D6-guided therapy will improve pain control and reduce adverse drug events. However, CYP2D6 is rarely used in clinical practice due in part to the demand for additional clinical trial evidence. Thus, we designed the ADOPT-PGx (A Depression and Opioid Pragmatic Trial in Pharmacogenetics) chronic pain study, a multicenter, pragmatic, randomized controlled clinical trial, to assess the effect of CYP2D6 testing on pain management. The study enrolled 1048 participants who are taking or being considered for treatment with CYP2D6-impacted opioids for their chronic pain. Participants were randomized to receive immediate or delayed (by 6 months) genotyping of CYP2D6 with clinical decision support (CDS). CDS encouraged the providers to follow the CYP2D6-guided trial recommendations. The primary study outcome is the 3-month absolute change in the composite pain intensity score assessed using Patient-Reported Outcomes Measurement Information System (PROMIS) measures. Follow-up will be completed in July 2024. Herein, we describe the design of this trial along with challenges encountered during enrollment.

Recovery after Exercise-Induced Muscle Damage in Subjects Following a Vegetarian or Mixed Diet.

It is unclear if following a vegetarian diet affects muscle recovery after exercise-induced muscle damage (EIMD). Sixteen vegetarians (VEG) and sixteen mixed dieters (MIX) performed a vertical jump, quadriceps femoris maximal isometric, and isokinetic concentric strength tests prior to and five days following the EIMD protocol. The quadriceps muscle was injured by performing eccentric contractions. Diet: MIX consumed more g/kg of animal protein (p < 0.001) and EAA (p < 0.05) except for isoleucine. VEG consumed more plant protein (p = 0.001). Isometric strength: MIX recovered post-day 2, VEG recovered post-day 4 (group (p = 0.07), time (p < 0.001)). Concentric contractions at 60 degrees per second: Both recovered post-day 1 (group (p = 0.27), time (p = 0.05)); 180 degrees per second: MIX recovered post-day 2, VEG recovered post-day 5 (group (p = 0.10), time (p < 0.001)); and 240 degrees per second: MIX recovered post-day 1, VEG did not recover by post-day 5 (group (p = 0.01), time (p < 0.001)). Vertical jump: Both recovered post-day 3 (group (p = 0.45), time (p < 0.001)). MIX recovered isometric strength 2 days faster, concentric strength was up to 5 days faster, and soreness was 1-4 days faster when compared to VEG. Both groups had similar recovery time for power.

Development of a Multifaceted Program for Pharmacogenetics Adoption at an Academic Medical Center: Practical Considerations and Lessons Learned.

In 2019, Indiana University launched the Precision Health Initiative to enhance the institutional adoption of precision medicine, including pharmacogenetics (PGx) implementation, at university-affiliated practice sites across Indiana. The overarching goal of this PGx implementation program was to facilitate the sustainable adoption of genotype-guided prescribing into routine clinical care. To accomplish this goal, we pursued the following specific objectives: (i) to integrate PGx testing into existing healthcare system processes; (ii) to implement drug-gene pairs with high-level evidence and educate providers and pharmacists on established clinical management recommendations; (iii) to engage key stakeholders, including patients to optimize the return of results for PGx testing; (iv) to reduce health disparities through the targeted inclusion of underrepresented populations; (v) and to track third-party reimbursement. This tutorial details our multifaceted PGx implementation program, including descriptions of our interventions, the critical challenges faced, and the major program successes. By describing our experience, we aim to assist other clinical teams in achieving sustainable PGx implementation in their health systems.

Influence of maternal α-lipoic acid supplementation in Sprague Dawley rats on maternal and fetal metabolic health in pregnancies complicated by obesity.

The objective of this study was to investigate the influence of α-lipoic acid (LA; R enantiomer) supplementation on maternal and fetal metabolic health in pregnancies complicated by maternal obesity. Forty female Sprague-Dawley rats were randomized to one of 4 treatment groups (n=10/group) throughout prepregnancy (3 weeks) and gestation (20 days): (1) a low calorie control (CON); (2) a high calorie obesity-inducing diet (HC); (3) the HC diet with 0.25% LA (HC+LA) or; (4) the HC diet pair-fed to match the caloric intake of the HC+LA group (HC+PF). On gestation day 20, pregnant rats were placed under anesthesia for collection of maternal/fetal blood and tissues. Compared with the HC group, LA-supplemented mothers demonstrated lower maternal prepregnancy and gestational weight gain (GWG), improved glycemic control (lower homeostatic model assessment for insulin resistance), and higher cholesterol concentrations in serum [high-density lipoprotein cholesterol (HDL-C) and low-and very-low density lipoprotein cholesterol (LDL/VLDL) fractions] and liver. Male and female fetuses from LA-supplemented mothers exhibited lower body weight, improved insulin sensitivity, and evidence of altered lipid metabolism including lower serum HDL-C, lower serum triglyceride (TG), and increased hepatic TG accumulation. Although maternal LA supplementation showed some benefit for both mothers and fetuses with respect to obesity and glycemic control, concern about the potential longer-term implications of liver cholesterol (mothers) and TG accumulation (fetuses) needs further investigation.

Reconstructing 120 years of climate change impacts on Joshua tree flowering.

Quantifying how global change impacts wild populations remains challenging, especially for species poorly represented by systematic datasets. Here, we infer climate change effects on masting by Joshua trees (Yucca brevifolia and Y. jaegeriana), keystone perennials of the Mojave Desert, from 15 years of crowdsourced observations. We annotated phenophase in 10,212 geo-referenced images of Joshua trees on the iNaturalist crowdsourcing platform, and used them to train machine learning models predicting flowering from annual weather records. Hindcasting to 1900 with a trained model successfully recovers flowering events in independent historical records and reveals a slightly rising frequency of conditions supporting flowering since the early 20th Century. This reflects increased variation in annual precipitation, which drives masting events in wet years-but also increasing temperatures and drought stress, which may have net negative impacts on recruitment. Our findings reaffirm the value of crowdsourcing for understanding climate change impacts on biodiversity.

Emerging Pathway to a Precision Medicine Approach for Angina With Nonobstructive Coronary Arteries in Women.

Women are disproportionately affected by symptoms of angina with nonobstructive coronary arteries (ANOCA) which is associated with significant mortality and economic impact. Although distinct endotypes of ANOCA have been defined, it is underdiagnosed and is often incompletely characterized when identified. Patients are often unresponsive to traditional therapeutic options, which are typically antianginal, and the current ability to guide treatment modification by specific pathways is limited. Studies have associated specific genetic loci, transcriptomic features, and biomarkers with ANOCA. Such panomic data, in combination with known imaging and invasive diagnostic techniques, should be utilized to define more precise pathophysiologic subtypes of ANOCA in women, which will in turn help to identify targeted, effective therapies. A precision medicine-based approach to managing ANOCA incorporating these techniques in women has the potential to significantly improve their clinical care.

Is misokinesia sensitivity explained by visual attentional orienting? ERP evidence from an emotional oddball task suggests no.

Misokinesia is a prevalent condition characterized by strong, negative emotional reactions to the sight of repetitive fidgeting movements in others. Here we present the results of a study designed to explore the relationship between misokinesia sensitivity (MKS) and attentional sensitivity to affectively-valenced visual stimuli. In particular, we asked participants with either high or low levels of MKS to perform an emotional oddball task that included responding to faces that had either angry or happy expressions, while we recorded event-related potentials. We found that there were no significant differences between the two MKS groups in attentional sensitivity to these faces, as indexed by the amplitude of the P300 ERP component they elicited. Importantly, we could not ascribe this null ERP finding to either low statistical power or the idiosyncrasies of our ERP analysis parameters. As such, our findings add to growing evidence that MKS may not be the simple result of heightened attentional orienting responses to visual events, but rather, it may be associated with other aspects of cognitive-affective processing.