Pharmacogenomic augmented machine learning in electronic health record alerts: A health system-wide usability survey of clinicians.

Pharmacogenomic (PGx) biomarkers integrated using machine learning can be embedded within the electronic health record (EHR) to provide clinicians with individualized predictions of drug treatment outcomes. Currently, however, drug alerts in the EHR are largely generic (not patient-specific) and contribute to increased clinician stress and burnout. Improving the usability of PGx alerts is an urgent need. Therefore, this work aimed to identify principles for optimal PGx alert design through a health-system-wide, mixed-methods study. Clinicians representing multiple practices and care settings (N = 1062) in urban, rural, and underserved regions were invited to complete an electronic survey comparing the usability of three drug alerts for citalopram, as a case study. Alert 1 contained a generic warning of pharmacogenomic effects on citalopram metabolism. Alerts 2 and 3 provided patient-specific predictions of citalopram efficacy with varying depth of information. Primary outcomes included the System's Usability Scale score (0-100 points) of each alert, the perceived impact of each alert on stress and decision-making, and clinicians' suggestions for alert improvement. Secondary outcomes included the assessment of alert preference by clinician age, practice type, and geographic setting. Qualitative information was captured to provide context to quantitative information. The final cohort comprised 305 geographically and clinically diverse clinicians. A simplified, individualized alert (Alert 2) was perceived as beneficial for decision-making and stress compared with a more detailed version (Alert 3) and the generic alert (Alert 1) regardless of age, practice type, or geographic setting. Findings emphasize the need for clinician-guided design of PGx alerts in the era of digital medicine.

Ensuring safe and equitable discharge: a quality improvement initiative for individuals with hypertensive disorders of pregnancy.

OBJECTIVE: To improve timely and equitable access to postpartum blood pressure (BP) monitoring in individuals with hypertensive disorders of pregnancy (HDP). METHODS: A quality improvement initiative was implemented at a large academic medical centre in the USA for postpartum individuals with HDP. The primary aim was to increase completed BP checks within 7 days of hospital discharge from 40% to 70% in people with HDP in 6 months. Secondary aims included improving rates of scheduled visits, completed visits within 3 days for severe HDP and unattended visits. The balancing measure was readmission rate. Statistical process control charts were used, and data were stratified by race and ethnicity. Direct feedback from birthing individuals was obtained through phone interviews with a focus on black birthing people after a racial disparity was noted in unattended visits. RESULTS: Statistically significant improvements were noted across all measures. Completed and scheduled visits within 7 days of discharge improved from 40% to 76% and 61% to 90%, respectively. Completed visits within 3 days for individuals with severe HDP improved from 9% to 49%. The unattended visit rate was 26% at baseline with non-Hispanic black individuals 2.3 times more likely to experience an unattended visit than non-Hispanic white counterparts. The unattended visit rate decreased to 15% overall with an elimination of disparity. A need for BP devices at discharge and enhanced education for black individuals was identified through patient feedback. CONCLUSION: Timely follow-up of postpartum individuals with HDP is challenging and requires modification to our care delivery. A hospital-level quality improvement initiative using birthing individual and frontline feedback is illustrated to improve equitable, person-centred care.

Submentalis Rapid Eye Movement Sleep Muscle Activity: A Potential Biomarker for Synucleinopathy.

Accurate antemortem diagnosis of parkinsonism is primarily based on clinical evaluation with limited biomarkers. We evaluated the diagnostic utility of quantitative rapid eye movement (REM) sleep without atonia analysis in the submentalis and anterior tibialis muscles in parkinsonian patients (53 synucleinopathy, 24 tauopathy). Receiver operating characteristic curves determined REM sleep without atonia cutoffs distinguishing synucleinopathies from tauopathies. Elevated submentalis muscle activity was highly sensitive (70-77%) and specific (95-100%) in distinguishing synucleinopathy from tauopathy. In contrast, anterior tibialis synucleinopathy discrimination was poor. Our results suggest that elevated submentalis REM sleep without atonia appears to be a potentially useful biomarker for presumed synucleinopathy etiologies in parkinsonism. ANN NEUROL 2019;86:969-974.

Depression Outcomes in Smokers and Nonsmokers: Comparison of Collaborative Care Management Versus Usual Care.

Background: Depression is common in the primary care setting and tobacco use is more prevalent among individuals with depression. Recent research has linked smoking to poorer outcomes of depression treatment. We hypothesized that in adult primary care patients with the diagnosis of depression, current smoking would have a negative impact on clinical outcomes, regardless of treatment type (usual primary care [UC] vs collaborative care management [CCM]). Methods: A retrospective chart review study of 5155 adult primary care patients with depression in a primary care practice in southeast Minnesota was completed. Variables obtained included age, gender, marital status, race, smoking status, initial Patient Health Questionnaire-9 (PHQ-9), and 6-month PHQ-9. Clinical remission (CR) was defined as 6-month PHQ-9 <5. Persistent depressive symptoms (PDS) were defined as PHQ-9 ≥10 at 6 months. Treatment in both CCM and UC were compared. Results: Using intention to treat analysis, depressed smokers treated with CCM were 4.60 times as likely (95% CI 3.24-6.52, P < .001) to reach CR and were significantly less likely to have PDS at 6 months (adjusted odds ratio [AOR] 0.19, 95% CI 0.14-0.25, P < .001) compared with smokers in UC. After a 6-month follow-up, depressed smokers treated with CCM were 1.75 times as likely (95% CI 1.18-2.59, P = .006) to reach CR and were significantly less likely to have PDS (AOR 0.45, 95% CI 0.31-0.64, P < .001) compared with smokers in UC. Conclusions: CCM significantly improved depression outcomes for smokers at 6 months compared with UC. However, in the UC group, smoking outcomes were not statistically different at 6 months for either remission or PDS. Also, nonsmokers in CCM had the best clinical outcomes at 6 months in both achieving clinical remission and reduction of PDS when compared with smokers in UC as the reference group.

Immobilization of American Beaver (Castor canadensis) with Nalbuphine, Medetomidine, and Azaperone.

Thirty-two American beavers (Castor canadensis) were immobilized with a mixture of nalbuphine, medetomidine, and azaperone (NalMedA) for tail transmitter placement and health assessments prior to translocation. Inductions and reversals were very smooth, but regardless of the dose administered, which ranged from 0.02 to 0.06 mL/kg, many beavers reacted to mild stimuli such as being lifted out of the cage, drawing blood from the tail, expressing anal glands for sex determination, and turning on isoflurane to deepen anesthesia before placement of tail transmitters. On a scale from 1 to 5, a sedation score of 4 was achieved in 8/32 beavers and a sedation score of 5 in 1/32 of beavers given a mean (SD) dosage of 0.04 (0.01) mL/kg NalMedA, which equated to a mean of 1.09 (0.21) mg/kg nalbuphine, 0.43 (0.09) mg/kg medetomidine, and 0.36 (0.07) mg/kg azaperone. All other animals achieved lower sedation scores. Supplementary isoflurane was needed to deepen anesthesia before tail transmitter placement. Although Nal-MedA appeared to be safe for use in American beavers, the level of sedation achieved was quite variable. Supplementary oxygen is recommended to reduce hypoxemia.

A Mixture of Butorphanol, Azaperone, and Medetomidine for the Immobilization of American Beavers ( Castor canadensis).

A total of 58 American beavers ( Castor canadensis) was immobilized with butorphanol, azaperone, and medetomidine (BAM) for the purpose of health assessments, sex determination, and placement of very high-frequency tail transmitters in a subset of animals. Isoflurane gas anesthesia was available to aid with induction when needed, and all animals received supplementary oxygen. Thirty-one beavers immobilized with a mean (SD) dose of 0.65 (0.15) mg/kg butorphanol, 0.22 (0.05) mg/kg azaperone, and 0.26 (0.06) mg/kg medetomidine did not require supplemental isoflurane during induction and the mean induction time was 8 min (range: 3-21 min). This dose was equivalent to 0.024 (0.005) mL of BAM per kilogram. A total of 29 beavers that were immobilized with a mean (SD) of 0.51 (0.07) mg/kg butorphanol, 0.17 (0.02) mg/kg azaperone, and 0.2 (0.03) mg/kg medetomidine needed supplementary isoflurane at 5% and 5 L/min for <1 min to induce full anesthesia. In none of the beavers did BAM alone provide sufficient depth of anesthesia to drill a hole in the tail for transmitter placement, and supplementary isoflurane was administered to reach a sufficient level of analgesia for the procedure. The beavers were reversed with 5 mg of atipamezole per milligram of medetomidine and 1 mg of naltrexone per milligram of butorphanol. No adverse effects or mortalities were observed. Butorphanol-azaperone-medetomidine can be considered safe for use in American beavers for minor procedures.

Allosteric regulation of DNA cleavage and sequence-specificity through run-on oligomerization.

SgrAI is a sequence specific DNA endonuclease that functions through an unusual enzymatic mechanism that is allosterically activated 200- to 500-fold by effector DNA, with a concomitant expansion of its DNA sequence specificity. Using single-particle transmission electron microscopy to reconstruct distinct populations of SgrAI oligomers, we show that in the presence of allosteric, activating DNA, the enzyme forms regular, repeating helical structures characterized by the addition of DNA-binding dimeric SgrAI subunits in a run-on manner. We also present the structure of oligomeric SgrAI at 8.6 Å resolution, demonstrating the conformational state of SgrAI in its activated form. Activated and oligomeric SgrAI displays key protein-protein interactions near the helix axis between its N termini, as well as allosteric protein-DNA interactions that are required for enzymatic activation. The hybrid approach reveals an unusual mechanism of enzyme activation that explains SgrAI's oligomerization and allosteric behavior.