Cardiovascular toxicities associated with bispecific T-cell engager therapy.

BACKGROUND: Bispecific T-cell engagers (BTEs) are novel agents used to treat hematological malignancies. Early trials were underpowered to define cardiovascular adverse events (CVAE) and no large-scale studies systematically examined the CVAEs associated with BTEs. METHODS: Leveraging the US Food and Drug Administration's Adverse Event Reporting System-(FAERS), we identified the relative frequency of CVAEs after initiation of five BTE products approved by the Food and Drug Administration between 2014 and 2023 for the treatment of hematological malignancies. Adjusted reporting ORs (aROR) were used to identify disproportionate reporting of CVAEs with BTEs compared with background rates in the database. Fatality rates and risk ratios (RRs) for each adverse event (AE) were calculated. RESULTS: From 3668 BTE-related cases reported to FAERS, 747 (20.4%) involved CVAEs. BTEs as a class were associated with fatal CVAEs (aROR 1.29 (95% CI 1.12 to 1.50)), an association mainly driven by teclistamab (aROR 2.44 (95% CI 1.65 to 3.60)). Teclistamab was also associated with a disproportionate risk of myocarditis (aROR 25.70 (95% CI 9.54 to 69.23)) and shock (aROR 3.63 (95% CI 2.30 to 5.74)), whereas blinatumomab was associated with a disproportionate risk of disseminated intravascular coagulation (aROR 3.02 (95% CI 1.98 to 4.60)) and hypotension (aROR 1.59 (95% CI 1.25 to 2.03)). CVAEs were more fatal compared with non-CVAEs (31.1% vs 17.4%; RR 1.76 (95% CI 1.54 to 2.03)). Most CVAEs (83.3%) did not overlap with cytokine release syndrome. CONCLUSION: In the first postmarketing surveillance study of BTEs, CVAEs were involved in approximately one in five AE reports and carried a significant mortality risk.

Effect of variable left ventricular ejection fraction assessed by equilibrium radionuclide angiocardiography using different software packages on the diagnosis of cardiotoxicity in patients with cancer.

BACKGROUND: The equilibrium radionuclide angiocardiography (ERNA) scan is an established imaging modality for assessing left ventricular ejection fraction (LVEF) in oncology patients. This study aimed to explore the interchangeability of two commercially available software packages (MIM and JS) for LVEF measurement for a cancer-therapy-related cardiac dysfunction (CTRCD) diagnosis. METHODS: This is a single-center retrospective study among 322 patients who underwent ERNA scans. A total of 582 scans were re-processed using MIM and JS for cross-sectional and longitudinal LVEF measurements. RESULTS: The median LVEF for MIM and JS were 56% and 66%, respectively (P < 0.001). LVEF processed by JS was 9.91% higher than by MIM. In 87 patients with longitudinal ERNA scans, serial studies processed by MIM were classified as having CTRCD in a higher proportion than serial studies processed by JS (26.4% vs 11.4%, P = 0.020). There were no significant differences in intra- or inter-observer LVEF measurement variability (R = 0.99, P < 0.001). CONCLUSIONS: Software packages for processing ERNA studies are not interchangeable; thus, reports of ERNA studies should include details on the post-processing software. Serial ERNA studies should be processed on the same software when feasible to avoid discrepancies in the diagnosis and management of CTRCD.

Nomogram for Predicting Risk of Cancer Therapy-Related Cardiac Dysfunction in Patients With Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer.

BACKGROUND: Cancer therapy-related cardiac dysfunction (CTRCD) is an important treatment-limiting toxicity for patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer that adversely affects cancer and cardiovascular outcomes. Easy-to-use tools that incorporate readily accessible clinical variables for individual estimation of CTRCD risk are needed. METHODS AND RESULTS: From 2004 to 2013, 1440 patients with stage I to III HER2-positive breast cancer treated with trastuzumab-based therapy were identified. A multivariable Cox proportional hazards model was constructed to identify risk factors for CTRCD and included the 1377 patients in whom data were complete. Nine clinical variables, including age, race, body mass index, left ventricular ejection fraction, systolic blood pressure, coronary artery disease, diabetes, arrhythmia, and anthracycline exposure were built into a nomogram estimating risk of CTRCD at 1 year. The nomogram was validated for calibration and discrimination using bootstrap resampling. A total of 177 CTRCD events occurred within 1 year of HER2-targeted treatment. The nomogram for prediction of 1-year CTRCD probability demonstrated good discrimination, with a concordance index of 0.687. The predicted and observed probabilities of CTRCD were similar, demonstrating good model calibration. CONCLUSIONS: A nomogram composed of 9 readily accessible clinical variables provides an individualized 1-year risk estimate of CTRCD among women with HER2-positive breast cancer receiving HER2-targeted therapy. This nomogram represents a simple-to-use tool for clinicians and patients that can inform clinical decision-making on breast cancer treatment options, optimal frequency of cardiac surveillance, and role of cardioprotective strategies.

Tumor Genomic Profile Is Associated With Arterial Thromboembolism Risk in Patients With Solid Cancer.

Background: Patients with cancer have an increased risk for arterial thromboembolism (ATE). Scant data exist about the impact of cancer-specific genomic alterations on the risk for ATE. Objectives: The aim of this study was to determine whether individual solid tumor somatic genomic alterations influence the incidence of ATE. Methods: A retrospective cohort study was conducted using tumor genetic alteration data from adults with solid cancers who underwent Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets testing between 2014 and 2016. The primary outcome, ATE, was defined as myocardial infarction, coronary revascularization, ischemic stroke, peripheral arterial occlusion, or limb revascularization and identified through systematic electronic medical record assessments. Patients were followed from date of tissue-matched blood control accession to first ATE event or death, for up to 1 year. Cause-specific Cox proportional hazards regression was used to determine HRs of ATE for individual genes adjusted for pertinent clinical covariates. Results: Among 11,871 eligible patients, 74% had metastatic disease, and there were 160 ATE events. A significantly increased risk for ATE independent of tumor type was noted for the KRAS oncogene (HR: 1.98; 95% CI: 1.34-2.94; multiplicity-adjusted P = 0.015) and the STK11 tumor suppressor gene (HR: 2.51; 95% CI: 1.44-4.38; multiplicity-adjusted P = 0.015). Conclusions: In a large genomic tumor-profiling registry of patients with solid cancers, alterations in KRAS and STK11 were associated with an increased risk for ATE independent of cancer type. Further investigation is needed to elucidate the mechanism by which these mutations contribute to ATE in this high-risk population.

Biomarkers and cardiovascular outcomes in chimeric antigen receptor T-cell therapy recipients.

AIMS: Chimeric antigen receptor T-cell therapy (CAR-T) harnesses a patient's immune system to target cancer. There are sparse existing data characterizing death outcomes after CAR-T-related cardiotoxicity. This study examines the association between CAR-T-related severe cardiovascular events (SCE) and mortality. METHODS AND RESULTS: From a multi-centre registry of 202 patients receiving anti-CD19 CAR-T, covariates including standard baseline cardiovascular and cancer parameters and biomarkers were collected. Severe cardiovascular events were defined as a composite of heart failure, cardiogenic shock, or myocardial infarction. Thirty-three patients experienced SCE, and 108 patients died during a median follow-up of 297 (interquartile range 104-647) days. Those that did and did not die after CAR-T were similar in age, sex, and prior anthracycline use. Those who died had higher peak interleukin (IL)-6 and ferritin levels after CAR-T infusion, and those who experienced SCE had higher peak IL-6, C-reactive protein (CRP), ferritin, and troponin levels. The day-100 and 1-year Kaplan-Meier overall mortality estimates were 18% and 43%, respectively, while the non-relapse mortality (NRM) cumulative incidence rates were 3.5% and 6.7%, respectively. In a Cox model, SCE occurrence following CAR-T was independently associated with increased overall mortality risk [hazard ratio (HR) 2.8, 95% confidence interval (CI) 1.6-4.7] after adjusting for age, cancer type and burden, anthracycline use, cytokine release syndrome grade ≥ 2, pre-existing heart failure, hypertension, and African American ancestry; SCEs were independently associated with increased NRM (HR 3.5, 95% CI 1.4-8.8) after adjusting for cancer burden. CONCLUSION: Chimeric antigen receptor T-cell therapy recipients who experience SCE have higher overall mortality and NRM and higher peak levels of IL-6, CRP, ferritin, and troponin.

The Role of Multimodality Cardiac Imaging in Patients Undergoing Cancer Treatment.

PURPOSE OF REVIEW: Modern therapeutics have led to improved survival for many types of cancer but have also been associated with adverse effects including potentially life-threatening cardiotoxicities. We sought to review the uses of multimodality cardiac imaging for risk stratification, prevention, and identification of cardiotoxicities in patients undergoing cancer treatment. RECENT FINDINGS: Advancements in both echocardiography and emerging modalities, like cardiac magnetic resonance imaging and cardiac computed tomography, continue to improve the pre- and during therapy cardiac evaluation of cancer patients. Echocardiography and cardiac magnetic resonance imaging, with the incorporation of global longitudinal strain, can identify overt and subclinical cancer therapy-related cardiac dysfunction and myocarditis, and stress echocardiography and cardiac computed tomography can noninvasively screen and monitor for coronary artery disease. Multimodality cardiac imaging is an evolving and critical tool for the pre-therapy screening and risk stratification, as well as during therapy surveillance of cancer treatment-related cardiotoxicity.

Differentiation syndrome-induced Myopericarditis in the induction therapy of acute Promyelocytic leukemia: a case report.

BACKGROUND: All trans retinoic acid (ATRA) has revolutionized the treatment and outcomes of patients with Acute Promyelocytic Leukemia (APL). Induction therapy with ATRA is associated with the rare but potentially fatal complication of differentiation syndrome. While the presentation of this syndrome is varied, myopericarditis as a manifestation of differentiation syndrome is often fatal and rarely reported in literature. We present a case of myopericarditis as the sole manifestation of differentiation syndrome in a patient on induction therapy with ATRA and arsenic trioxide for APL. CLINICAL PRESENTATION: A 62 year old woman with remote history of breast and uterine cancer presented to the hospital for expedited work up of easy bruising and expanding hematomas. She was diagnosed with APL with peripheral blood and bone marrow cytogenetics revealing t (15;17) translocation and initiated on induction therapy with ATRA and ATO as well as steroids for differentiation syndrome prophylaxis. Eighteen days into induction therapy, patient developed pleuritic chest pain, elevated cardiac biomarkers, ECG changes suggestive of pericarditis. Cardiac magnetic resonance imaging showed patchy multifocal sub-epicardial late gadolinium enhancement and elevated T2 signal consistent with acute myopericarditis. Given the timing of symptom onset and lack of other identifiable cause, patient was diagnosed with differentiation syndrome- induced myopericarditis and promptly initiated on high dose steroids with rapid improvement in symptoms, ECG, and cardiac biomarkers. Patient successfully resumed dose-reduced ATRA and arsenic trioxide without complication. CONCLUSION: Myopericarditis can be the sole manifestation of differentiation syndrome and the presentation may be atypical owing to the use of prophylactic steroids as illustrated in our patient's case. A high index of suspicion for differentiation syndrome, multimodality imaging, and prompt input from multidisciplinary providers is crucial for making the timely diagnosis and initiating life-saving treatment.

Cardio-oncology Training in the COVID-19 Era.

OPINION STATEMENT: Cardio-oncology is a field dedicated to the prevention, diagnosis, and management of cardiovascular disease in cancer patients before, during, and after cancer therapy. It is an emerging field with limited opportunities for structured education and training. In the year 2021, we cannot define the requirements of cardio-oncology training without acknowledging the impact of the global coronavirus disease 19 (COVID-19) pandemic. While this pandemic poses significant health risks to patients with cancer and cardiovascular disease as well as the providers who care for them, it also allows novel opportunities for the nascent field of cardio-oncology to readily adapt. In this article, we detail how the COVID-19 pandemic has impacted all aspects of cardio-oncology training, how programs and trainees can adapt to these challenges, and how lessons learned from the COVID-19 era can continue to positively impact cardio-oncology training for the foreseeable future.

Risk assessment of acute pulmonary embolism utilizing coronary artery calcifications in patients that have undergone CT pulmonary angiography and transthoracic echocardiography.

OBJECTIVE: To evaluate the relation of coronary artery calcifications (CAC) on non-ECG-gated CT pulmonary angiography (CTPA) with short-term mortality in patients with acute pulmonary embolism (PE). METHODS: We retrospectively included all in-patients between May 2007 and December 2014 with an ICD-9 code for acute PE and CTPA and transthoracic echocardiography available. CAC was qualitatively graded as absent, mild, moderate, or severe. Relations of CAC with overall and PE-related 30-day mortality were assessed using logistic regression analyses. The independence of those relations was assessed using a nested approach, first adjusting for age and gender, then for RV strain, peak troponin T, and cardiovascular risk factors for an overall model. RESULTS: Four hundred seventy-nine patients were included (63 ± 16 years, 52.8% women, 47.2% men). In total, 253 (52.8%) had CAC-mild: 143 (29.9%); moderate: 89 (18.6%); severe: 21 (4.4%). Overall mortality was 8.8% (n = 42) with higher mortality with any CAC (12.6% vs. 4.4% without; odds ratio [OR] 3.1 [95%CI 2.1-14.5]; p = 0.002). Mortality with severe (19.0%; OR 5.1 [95%CI 1.4-17.9]; p = 0.011), moderate (11.2%; OR 2.7 [95%CI 1.1-6.8]; p = 0.031), and mild CAC (12.6%; OR 3.1 [95%CI 1.4-6.9]; p = 0.006) was higher than without. OR adjusted for age and gender was 2.7 (95%CI 1.0-7.1; p = 0.050) and 2.6 (95%CI 0.9-7.1; p = 0.069) for the overall model. PE-related mortality was 4.0% (n = 19) with higher mortality with any CAC (5.9% vs. 1.8% without; OR 3.5 [95%CI 1.1-10.7]; p = 0.028). PE-related mortality with severe CAC was 9.5% (OR 5.8 [95%CI 1.0-34.0]; p = 0.049), with moderate CAC 6.7% (OR 4.0 [95%CI 1.1-14.6]; p = 0.033), and with mild 4.9% (OR 2.9 [95%CI 0.8-9.9]; p = 0.099). OR adjusted for age and gender was 4.2 (95%CI 0.9-20.7; p = 0.074) and 3.4 (95%CI 0.7-17.4; p = 0.141) for the overall model. Patients with sub-massive PE showed similar results. CONCLUSION: CAC is frequent in acute PE patients and associated with short-term mortality. Visual assessment of CAC may serve as an easy, readily available tool for early risk stratification in those patients. KEY POINTS: • Coronary artery calcification assessed on computed tomography pulmonary angiography is frequent in patients with acute pulmonary embolism. • Coronary artery calcification assessed on computed tomography pulmonary angiography is associated with 30-day overall and PE-related mortality in patients with acute pulmonary embolism. • Coronary artery calcification assessed on computed tomography pulmonary angiography may serve as an additional, easy readily available tool for early risk stratification in those patients.

Mitral annular plane systolic excursion and tricuspid annular plane systolic excursion for risk stratification of acute pulmonary embolism.

INTRODUCTION: Risk stratification for acute pulmonary embolism (PE) incorporates metrics of right ventricle (RV) function. Significant RV dysfunction influences left ventricular (LV) function, though LV function metrics are not utilized for stratifying outcomes in patients with PE. Mitral annular plane systolic excursion (MAPSE) is a linear echocardiographic (TTE) measure that evaluates longitudinal LV function and may aid in risk stratification for acute PE. METHODS: Using a single-center database of patients with PE from 2007 to 2014, MAPSE was calculated for all TTE's available with sufficient quality (n = 362). A MAPSE of ≥11 mm was used as a normal reference. Thirty-day adverse outcomes were defined as administration of vasopressor, fibrinolytic therapy, open embolectomy, or 30-day PE-related mortality. Odds ratios (OR) and adjusted OR (AOR) were calculated using logistic regression analysis. Tricuspid annular plane systolic excursion (TAPSE) measurements were incorporated to determine the additive benefit of MAPSE. RESULTS: Compared with the reference MAPSE ≥ 11 mm and LVEF > 50%, patients with MAPSE < 11 mm and an LVEF > 50% had worse outcomes (AOR 2.94 [95% CI: 1.08-7.98], P = 0.035). Among patients with LVEF > 50%, the presence of both a MAPSE < 11 mm and TAPSE < 16 mm was associated with greater odds of adverse outcomes compared with isolated depressed TAPSE (AOR 10.75 [95% CI: 3.06-37.8], P < 0.01 vs AOR 1.68 [95% CI: 0.18-15.6], P = 0.65). CONCLUSION: A depressed MAPSE, in patients with preserved LVEF, is associated with worse outcomes in patients with acute PE. The addition of MAPSE to TAPSE appears to have a greater prognostic value than either alone and may further aid in risk stratification, but for confirmation further prospective data are needed.

Right ventricular strain in patients with pulmonary embolism and syncope.

Patients with acute pulmonary embolism (PE) can present with various clinical manifestations including syncope. The mechanism of syncope in PE is not fully elucidated and data of right ventricular (RV) function in patients has been limited. We retrospectively identified 477 consecutive patients hospitalized with acute PE diagnosed with a computed tomogram (CT) who also had a transthoracic echocardiogram (TTE) 24 h prior to or 48 h after diagnosis. Parameters of RV strain on CT, TTE, electrocardiogram (ECG), and clinical characteristics and adverse outcomes were collected. Patients with all three studies available for assessment were included (n = 369) and those with syncope (n = 34) were compared to patients without syncope (n = 335). Patients with syncope were more likely to demonstrate RV strain on all three modes of assessment compared to those without syncope [17 (50%) vs. 67 (20%); p = 0.001], and those patients were more likely to receive advanced therapies [9 (53%) vs. 15 (22%); p = 0.02]. PE-related mortality was highest among those presenting with high-risk PE and syncope (36%, OR 20.1, 95% CI 5.3-81.1; p < 0.001) and was low in patients with syncope without criteria for high-risk PE (3%, OR 1.2, 95% CI 0.2-10.0; p < 0.001). In conclusion, acute PE patients with syncope are more likely to demonstrate multimodality evidence of RV strain and to receive advanced therapies. Syncope was only associated with increased PE-related mortality in patients presenting with a high-risk PE. Syncope alone without evidence of RV strain is associated with low short-term adverse events and is similar to those without syncope.

Randomized controlled trial of a gluten-free diet in patients with schizophrenia positive for antigliadin antibodies (AGA IgG): a pilot feasibility study

Background: Approximately one-third of people with schizophrenia have elevated levels of anti-gliadin antibodies of the immunoglobulin G type (AGA IgG) ­ a higher rate than seen in healthy controls. We performed the first double-blind clinical trial of gluten-free versus gluten-containing diets in a subset of patients with schizophrenia who were positive for AGA IgG. Methods: In this pilot feasibility study, 16 participants with schizophrenia or schizoaffective disorder who had elevated AGA IgG (≥ 20 U) but were negative for celiac disease were admitted to an inpatient unit for a 5-week trial. All participants received standardized gluten-free meals and were randomized in a double-blind fashion to receive a shake containing 10 g of gluten flour or 10 g of rice flour each day. Participants were rated for psychiatric, cognitive and gastrointestinal symptoms at baseline and endpoint. Results: Of the 16 participants, 14 completed the 5-week trial (2 discontinued early for administrative reasons). Compared with participants on the gluten-containing diet, participants on the gluten-free diet showed improvement on the Clinical Global Impressions scale (Cohen d = ­0.75) and in negative symptoms (Cohen d = ­0.53). We noted no improvement in positive or global cognitive symptoms, but did observe an improvement in attention favouring the gluten-free diet (Cohen d = 0.60). Robust improvements in gastrointestinal adverse effects occurred in the gluten-free group relative to the glutencontaining group. Adverse effects were similar between groups. Limitations: This study was limited by its small sample size; larger studies are needed. Conclusion: This feasibility study suggests that removal of gluten from the diet is associated with improvement in psychiatric and gastrointestinal symptoms in people with schizophrenia or schizoaffective disorder.

Gut permeability and mimicry of the Glutamate Ionotropic Receptor NMDA type Subunit Associated with protein 1 (GRINA) as potential mechanisms related to a subgroup of people with schizophrenia with elevated antigliadin antibodies (AGA IgG).

About one third of people with schizophrenia have elevated IgG antibodies to gliadin (AGA IgG) and increased inflammation. Understanding the mechanism by which this immune response occurs is critical to the development of personalized treatments. We examined gut permeability and mimicry to the glutamate receptor as possible mechanisms related to high gliadin antibodies (AGA IgG) seen in some people with schizophrenia. The Glutamate Ionotropic Receptor NMDA type Subunit Associated with protein 1 (GRINA) has a similar protein structure to gliadin representing a potential target for cross reactivity or mimicry. In a population of schizophrenia subjects (N = 160) and healthy controls (N = 80) we analyzed serum samples for both GRINA and Anti-Saccharomyces Cerevisiae antibodies (ASCA), related to gut permeability. Schizophrenia patients compared to controls had a higher prevalence of positivity to ASCA IgA (p = 0.004) and IgG (p < 0.001). Multinomial logistic regression showed an association between AGA IgG and ASCA IgG in schizophrenia (p = 0.05 for the estimated regression coefficient) but not in healthy controls (p = 0.13). GRINA IgG was higher in schizophrenia patients than in healthy controls (0.43 ±â€¯0.30 vs. 0.22 ±â€¯0.24, p < 0.001). Logistic regressions showed an association between AGA IgG and GRINA IgG in schizophrenia (p = 0.016 for the estimated regression coefficient) but not for the controls (p = 0.471). Thus, we propose that mimicry through the presence of cross-reactivity between gliadin and GRINA might disrupt the functions of the glutamate system and relate to illness pathophysiology in those with schizophrenia and elevated AGA IgG.

Increased circulating regulatory T cells in medicated people with schizophrenia.

Immunological abnormalities are increasingly reported in people with schizophrenia, but no clear functional biomarkers associated with genetic correlates of the disease have been found. Regulatory T cells (Tregs) are key immunoregulatory cells involved in the control of inflammatory processes and their functions are directly related to the human leucocyte antigen (HLA) gene, which has been implicated in schizophrenia genetic studies. However, there is a lack of studies reporting Treg status in people with schizophrenia. In the current study, the proportion of circulating Tregs was examined using flow cytometry in 26 medicated participants with schizophrenia and 17 healthy controls. Psychiatric symptoms and cognitive function were evaluated using the Scale for the Assessment of Negative Symptoms, the Brief Psychiatric Rating Scale, and the MATRICS Consensus Cognitive Battery. The proportion of Tregs was found to be significantly greater in the schizophrenia group compared to healthy controls. No differences were observed in total lymphocyte counts or CD3+ and CD4+ T cells, confirming a specific effect for Tregs. Elevated Tregs in schizophrenia correlated with fewer negative symptoms, a core domain of the illness. These results suggest that Tregs may contribute to improved negative symptoms in schizophrenia, possibly by counteracting on-going inflammatory processes.

Adjunct Aripiprazole Reduces Prolactin and Prolactin-Related Adverse Effects in Premenopausal Women With Psychosis: Results From the DAAMSEL Clinical Trial.

PURPOSE/BACKGROUND: Prolactin-related adverse effects contribute to nonadherence and adverse health consequences, particularly in women with severe mental illness. Treating these adverse effects may improve treatment acceptability, adherence, and long-term outcomes. METHODS/PROCEDURES: Premenopausal women with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision diagnosis of schizophrenia, schizoaffective disorder, or bipolar disorder were recruited for a randomized, double-blind, placebo-controlled 16-week trial of adjunct aripiprazole (5-15 mg/d). Participants had elevated prolactin (>24 ng/mL) and were experiencing galactorrhea, amenorrhea, oligomenorrhea, or sexual dysfunction on a prolactin-elevating antipsychotic. Participants were evaluated biweekly for prolactin elevation and galactorrhea and completed a menstrual diary review. Psychiatric symptoms and adverse effects were closely monitored. FINDINGS/RESULTS: Forty-six women were randomized (n = 25 aripiprazole, n = 21 placebo). Thirty-seven completed at least 8 weeks of the study (n = 20 [80%] aripiprazole and n = 17 [81%] placebo). Aripiprazole (mean dose, 11.7 ± 2.4 mg/d) was effective for lowering prolactin relative to placebo (P = 0.04). In addition, 45% (9/20) of the aripiprazole group had a normalized prolactin (<24 mg/mL) compared with 12% (2/17) of the placebo group (P = 0.028). Galactorrhea resolved in 77% (10/13) of the aripiprazole-treated participants compared with 33% (4/12) in the placebo group (P = 0.028). Normalization of sexual function (<16 on the Arizona Sexual Experience Scale) occurred in 50% on aripiprazole (7/14) versus 9% (1/11) on placebo (P = 0.030). No differences between groups in symptoms or adverse effects were noted. Overall, women rated a mean score of 4.6 ± 0.6 on a 5-point Likert scale for sexual function improvement, suggesting their particular satisfaction with improvement in this domain. IMPLICATIONS/CONCLUSIONS: Building upon prior studies, this rigorous evaluation confirms the utility of adjunctive aripiprazole as a strategy for improving prolactin and managing prolactin-related adverse effects in premenopausal women with psychosis.

Multimodality Assessment of Right Ventricular Strain in Patients With Acute Pulmonary Embolism.

Optimal risk stratification is essential in managing patients with an acute pulmonary embolism (PE). There are limited data evaluating the potential additive value of various methods of evaluation of right ventricular (RV) strain in PE. We retrospectively evaluated RV strain by computed tomography (CT), transthoracic echocardiography (TTE), electrocardiography (ECG), and troponin levels in consecutive hospitalized patients with acute PE (May 2007 to December 2014). Four-hundred and seventy-seven patients met inclusion criteria. RV strain on ECG (odds ratio [OR] 1.9, confidence interval [CI] 1.1 to 3.3; p = 0.03), CT (OR 2.7, CI 1.5 to 4.8, p <0.001), TTE (OR 2.8, CI 1.5 to 5.4, p <0.001), or a positive troponin (OR 2.7, CI 2.0 to 6.9, p <0.001) were associated with adverse events. In patients with ECG, CT, and TTE data, increased risk was only elevated with RV strain on all 3 parameters (OR 4.6, CI 1.8 to 11.3, p <0.001). In all patients with troponin measurements, risk was only elevated with RV strain on all 3 parameters plus a positive troponin (OR 8.8, CI 2.8 to 28.1, p <0.001) and was similar in intermediate-risk PE (OR 11.1, CI 1.2 to 103.8, p = 0.04). In conclusion, in patients with an acute PE and evaluation of RV strain by ECG, CT, and TTE, risk of adverse events is only elevated when RV strain is present on all 3 modalities. Troponin further aids in discriminating high-risk patients. Multimodality assessment of RV strain is identified as a superior approach to risk assessment.

Blood Draw Barriers for Treatment with Clozapine and Development of a Point-of-Care Monitoring Device.

BACKGROUND: While clozapine (CLZ) is the most effective antipsychotic drug for schizophrenia treatment, it remains underused. In order to understand the barriers of frequent blood draws for white blood cell counts (WBCs) and clozapine levels, we developed a psychiatrist survey and began an integrative approach of designing a point-of-care device that could eventually have real-time monitoring with immediate results. METHODS: We ascertained barriers related to CLZ management and the acceptance of possible solutions by sending an anonymous survey to physicians in psychiatric practice (n=860). In parallel, we tested CLZ sensing using a prototype point-of-care monitoring device. RESULTS: 255 responses were included in the survey results. The two barriers receiving mean scores with the highest agreement as being a significant barrier were patient nonadherence to blood work and blood work's burden on the patient (out of 28). Among nine solutions, the ability to obtain lab results in the physician's office or pharmacy was top ranked (mean±sd Likert scale [4.0±1.0]). Physicians responded that a point-of-care device to measure blood levels and WBCs would improve care and increase CLZ use. Residents ranked point-of-care devices higher than older physicians (4.07±0.87 vs. 3.47±1.08, p<0.0001). Also, the prototype device was able to detect CLZ reliably in 1.6, 8.2, and 16.3 µg/mL buffered solutions. DISCUSSION: Survey results demonstrate physicians' desire for point-of-care monitoring technology, particularly among younger prescribers. Prototype sensor results identify that CLZ can be detected and integrated for future device development. Future development will also include integration of WBCs for a complete detection device.

Adjunctive Minocycline in Clozapine-Treated Patients with Schizophrenia: Analyzing the Effects of Minocycline on Clozapine Plasma Levels.

Clozapine is the sole antipsychotic agent effective for the treatment of refractory schizophrenia. Sixty percent of clozapine-treated patients, however, fail to adequately respond. Minocycline, a tetracycline antibiotic, possesses antiinflammatory and neuroprotective properties that may play a role in schizophrenia. Clozapine is mainly metabolized by CYP1A2 enzymes, and minocycline may potentially inhibit CYP1A2 as hypothesized by case report data. To date, no pharmacokinetic interaction has been reported between minocycline and clozapine. This is a secondary analysis of a 10-week controlled study of adjunctive minocycline to clozapine in treatment refractory schizophrenia. Clozapine plasma levels were collected every two weeks during the study. 28 participants assigned to receive minocycline and 22 assigned to placebo were included. No differences existed in baseline demographics, clozapine dose or plasma levels. Average changes from baseline in clozapine plasma level (p = 0.033) were significantly higher in the minocycline group despite maintenance of stable doses. No statistically significant treatment differences were found in the norclozapine (p = 0.754) or total clozapine (p = 0.053) changes in plasma levels, although possible changes in total clozapine levels require further investigation. This analysis suggests that minocycline administration may lead to increased clozapine plasma levels. Further study is needed to examine possible explanations.