Pathway-based signatures predict patient outcome, chemotherapy benefit and synthetic lethal dependencies in invasive lobular breast cancer.

BACKGROUND: Invasive Lobular Carcinoma (ILC) is a morphologically distinct breast cancer subtype that represents up to 15% of all breast cancers. Compared to Invasive Breast Carcinoma of No Special Type (IBC-NST), ILCs exhibit poorer long-term outcome and a unique pattern of metastasis. Despite these differences, the systematic discovery of robust prognostic biomarkers and therapeutically actionable molecular pathways in ILC remains limited. METHODS: Pathway-centric multivariable models using statistical machine learning were developed and tested in seven retrospective clinico-genomic cohorts (n = 996). Further external validation was performed using a new RNA-Seq clinical cohort of aggressive ILCs (n = 48). RESULTS AND CONCLUSIONS: mRNA dysregulation scores of 25 pathways were strongly prognostic in ILC (FDR-adjusted P < 0.05). Of these, three pathways including Cell-cell communication, Innate immune system and Smooth muscle contraction were also independent predictors of chemotherapy response. To aggregate these findings, a multivariable machine learning predictor called PSILC was developed and successfully validated for predicting overall and metastasis-free survival in ILC. Integration of PSILC with CRISPR-Cas9 screening data from breast cancer cell lines revealed 16 candidate therapeutic targets that were synthetic lethal with high-risk ILCs. This study provides interpretable prognostic and predictive biomarkers of ILC which could serve as the starting points for targeted drug discovery for this disease.

The osteocutaneous radial forearm free flap: A pictorial essay.

The osteocutaneous radial forearm free flap (OCRFFF) is a versatile flap with the ability to reconstruct complex defects. We detail the techniques necessary to harvest an OCRFFF, including an outline on making 90-degree osteotomies to maximize bone harvest. In this pictorial essay, we provide illustrations of the anatomy and surgical techniques necessary for OCRFFF harvest. Detailed discussion is provided on how to protect the perforators to the bone and the approach to making osteotomies in a 90-degree fashion. The approach for prophylactic plating of the radius to prevent radius fractures is outlined. A case presentation on the real-life utilization of this flap is included. The OCRFFF is an excellent head and neck reconstructive option. While there are limitations to its use for patients requiring dental rehabilitation or long/anterior mandibular defects, for the right patient and indication it has shown great success in reconstructive efforts.

Effect of CSL112 on Recurrent Myocardial Infarction and Cardiovascular Death: Insights from the AEGIS-II Trial.

BACKGROUND: The AEGIS-II trial hypothesized that CSL112, an intravenous formulation of human apoA-I, would lower the risk of plaque disruption, decreasing the risk of recurrent events such as myocardial infarction (MI) among high-risk patients with MI. OBJECTIVES: This exploratory analysis evaluates the effect of CSL112 therapy on the incidence of CV death and recurrent MI. METHODS: The AEGIS-II trial was an international, multicenter, randomized, double-blind, placebo-controlled trial that randomized 18,219 high-risk acute MI patients to 4 weekly infusions of apoA-I (6g CSL112) or placebo. RESULTS: The incidence of the composite of cardiovascular death and type 1 MI was 11-16% lower in the CSL112 group over the study period (HR of 0.84 [95% CI 0.7-1.0; p=0.056] day 90, HR 0.86, [95% CI 0.74-0.99; p=0.048] day 180, and HR 0.89, [95% CI 0.79-1.01 p=0.07; p=0.07] day 365). Similarly, the incidence of CV death or any MI was numerically lower in CSL112 treated patients throughout the follow-up period (HR 0.92 [95% CI 0.8-1.05], 0.89 [95% CI 0.79-0.996], 0.91 [0.82-1.01]. The effect of CSL112 treatment on MI was predominantly observed for type 1 MI and type 4b (MI due to stent thrombosis). CONCLUSION: While CSL112 did not significantly reduce the occurrence of the primary study endpoints, patients treated with CSL112 infusions had numerically lower rates of CV death and MI, type-1 MI, and stent thrombosis-related MI compared to placebo. These findings could suggest a role of apoA-I in reducing subsequent plaque disruption events via enhanced cholesterol efflux. Further prospective data would be needed to confirm these observations.

Apolipoprotein A1 Infusions and Cardiovascular Outcomes after Acute Myocardial Infarction.

BACKGROUND: Cardiovascular events frequently recur after acute myocardial infarction, and low cholesterol efflux - a process mediated by apolipoprotein A1, which is the main protein in high-density lipoprotein - has been associated with an increased risk of cardiovascular events. CSL112 is human apolipoprotein A1 derived from plasma that increases cholesterol efflux capacity. Whether infusions of CSL112 can reduce the risk of recurrent cardiovascular events after acute myocardial infarction is unclear. METHODS: We conducted an international, double-blind, placebo-controlled trial involving patients with acute myocardial infarction, multivessel coronary artery disease, and additional cardiovascular risk factors. Patients were randomly assigned to receive either four weekly infusions of 6 g of CSL112 or matching placebo, with the first infusion administered within 5 days after the first medical contact for the acute myocardial infarction. The primary end point was a composite of myocardial infarction, stroke, or death from cardiovascular causes from randomization through 90 days of follow-up. RESULTS: A total of 18,219 patients were included in the trial (9112 in the CSL112 group and 9107 in the placebo group). There was no significant difference between the groups in the risk of a primary end-point event at 90 days of follow-up (439 patients [4.8%] in the CSL112 group vs. 472 patients [5.2%] in the placebo group; hazard ratio, 0.93; 95% confidence interval [CI], 0.81 to 1.05; P = 0.24), at 180 days of follow-up (622 patients [6.9%] vs. 683 patients [7.6%]; hazard ratio, 0.91; 95% CI, 0.81 to 1.01), or at 365 days of follow-up (885 patients [9.8%] vs. 944 patients [10.5%]; hazard ratio, 0.93; 95% CI, 0.85 to 1.02). The percentage of patients with adverse events was similar in the two groups; a higher number of hypersensitivity events was reported in the CSL112 group. CONCLUSIONS: Among patients with acute myocardial infarction, multivessel coronary artery disease, and additional cardiovascular risk factors, four weekly infusions of CSL112 did not result in a lower risk of myocardial infarction, stroke, or death from cardiovascular causes than placebo through 90 days. (Funded by CSL Behring; AEGIS-II ClinicalTrials.gov number, NCT03473223.).

Usability testing of a mobile health application to support individuals with active tuberculosis: a mixed methods study.

Poor adherence to tuberculosis (TB) treatment leads to further disease transmission, worsened outcomes, and the development of drug resistance. Digital adherence technologies may facilitate a more patient-centered approach for improving TB treatment outcomes than current strategies. The objective of this study was to evaluate and explore improving usability of the TB Treatment Support Tools (TB-TST) mobile application. We used an iterative convergent mixed-method design consisting of two quantitative surveys and a qualitative think-aloud interview. Testing was conducted in three testing cycles consisting of a total of 16 interviews and 26 surveys. Results were thematically analyzed and reported to the development team during weekly team meetings. Participants rated the TB-TSTs application as having high usability and the iterative approach resulted in several refinements to the application in response to participant feedback. These refinements were well received during qualitative interviews but did not result in a statistically significant improvement in usability testing scores between cycles. Using an iterative convergent mixed-method design was an effective method for refining our mHealth application. Data collected from think-aloud interviews, the MAUQ, and the Health-ITUES identified key areas of application design that needed refinement.

Repeated Measurement of the Novel Atrial Biomarker BMP10 (Bone Morphogenetic Protein 10) Refines Risk Stratification in Anticoagulated Patients With Atrial Fibrillation: Insights From the ARISTOTLE Trial.

BACKGROUND: BMP10 (bone morphogenic protein 10) has emerged as a novel biomarker associated with the risk of ischemic stroke and other outcomes in patients with atrial fibrillation (AF). The study aimed to determine if repeated BMP10 measurements improve prognostication of cardiovascular events in patients with AF. METHODS AND RESULTS: BMP10 was measured using a prototype Elecsys immunoassay in plasma samples collected at randomization and after 2 months in patients with AF randomized to apixaban or warfarin in the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial (n=2878). Adjusted Cox-regression models were used to evaluate the association between 2-month BMP10 levels and outcomes. BMP10 levels increased by 7.8% (P<0.001) over 2 months. The baseline variables most strongly associated with BMP10 levels at 2 months were baseline BMP10 levels, body mass index, sex, age, creatinine, diabetes, warfarin treatment, and AF-rhythm. During median 1.8 years follow-up, 34 ischemic strokes/systemic embolism, 155 deaths, and 99 heart failure hospitalizations occurred. Comparing the third with the first sample quartile, higher BMP10 levels at 2 months were associated with higher risk of ischemic stroke (hazard ratio [HR], 1.33 [95% CI, 0.67-2.63], P=0.037), heart failure (HR, 1.91 [95% CI, 1.17-3.12], P=0.012) and all-cause death (HR, 1.61 [95% CI, 1.17-2.21], P<0.001). Adding BMP10 levels at 2 months on top of established risk factors and baseline BMP10 levels improved the C-indices for ischemic stroke/systemic embolism (from 0.73 to 0.75), heart failure hospitalization (0.76-0.77), and all-cause mortality (0.70-0.72), all P<0.05. CONCLUSIONS: Elevated levels of BMP10 at 2 months strengthened the associations with the risk of ischemic stroke, hospitalization for heart failure, and all-cause mortality. Repeated measurements of BMP10 may further refine risk stratification in patients with AF.

Outcomes by sex in the International Study of Comparative Health Effectiveness With Medical and Invasive Approaches (ISCHEMIA) trial.

BACKGROUND: In the International Study of Comparative Health Effectiveness With Medical and Invasive Approaches (ISCHEMIA) trial, among participants with stable coronary artery disease, the risk of cardiac events was similar between an invasive (INV) strategy of angiography and coronary revascularisation and a conservative (CON) strategy of initial medical therapy alone. Outcomes according to participant sex were not reported. AIMS: We aimed to analyse the outcomes of ISCHEMIA by participant sex. METHODS: We evaluated 1) the association between participant sex and the likelihood of undergoing revascularisation for participants randomised to the INV arm; 2) the risk of the ISCHEMIA primary composite outcome (cardiovascular death, any myocardial infarction [MI] or rehospitalisation for unstable angina, heart failure or resuscitated cardiac arrest) by participant sex; and 3) the contribution of the individual primary outcome components to the composite outcome by participant sex. RESULTS: Of 5,179 randomised participants, 1,168 (22.6%) were women. Female sex was independently associated with a lower likelihood of revascularisation when assigned to the INV arm (adjusted odds ratio 0.75, 95% confidence interval [CI]: 0.57-0.99; p=0.04). The INV versus CON effect on the primary composite outcome was similar between sexes (women: hazard ratio [HR] 0.96, 95% CI: 0.70-1.33; men: HR 0.90, 95% CI: 0.76-1.07; pinteraction=0.71). The contribution of the individual components to the composite outcome was similar between sexes except for procedural MI, which was significantly lower in women (9/151 [5.9%]) than men (67/519 [12.9%]; p=0.01). CONCLUSIONS: In ISCHEMIA, women assigned to the INV arm were less likely to undergo revascularisation than men. The effect of an INV versus CON strategy was consistent by sex, but women had a significantly lower contribution of procedural MI to the primary outcome.

Bleeding Outcomes in Patients Treated With Asundexian in Phase II Trials.

BACKGROUND: Phase II trials of asundexian were underpowered to detect important differences in bleeding. OBJECTIVES: The goal of this study was to obtain best estimates of effects of asundexian vs active control/placebo on major and clinically relevant nonmajor (CRNM) and all bleeding, describe most common sites of bleeding, and explore association between asundexian exposure and bleeding. METHODS: We performed a pooled analysis of 3 phase II trials of asundexian in patients with atrial fibrillation (AF), recent acute myocardial infarction (AMI), or stroke. Bleeding was defined according to the International Society on Thrombosis and Hemostasis (ISTH) criteria. RESULTS: In patients with AF (n = 755), both asundexian 20 mg and 50 mg once daily vs apixaban had fewer major/CRNM events (3 of 249; incidence rate [IR] per 100 patient-years 5.47 vs 1 of 254 [IR: not calculable] vs 6 of 250 [IR: 11.10]) and all bleeding (12 of 249 [IR: 22.26] vs 10 of 254 [IR: 18.21] vs 26 of 250 [IR: 50.56]). In patients with recent AMI or stroke (n = 3,409), asundexian 10 mg, 20 mg, and 50 mg once daily compared with placebo had similar rates of major/CRNM events (44 of 840 [IR: 7.55] vs 42 of 843 [IR: 7.04] vs 56 of 845 [IR: 9.63] vs 41 of 851 [IR: 6.99]) and all bleeding (107 of 840 [IR: 19.57] vs 123 of 843 [IR: 22.45] vs 130 of 845 [IR: 24.19] vs 129 of 851 [IR: 23.84]). Most common sites of major/CRNM bleeding with asundexian were gastrointestinal, respiratory, urogenital, and skin. There was no significant association between asundexian exposure and major/CRNM bleeding. CONCLUSIONS: Analyses of phase II trials involving >500 bleeds highlight the potential for improved safety of asundexian compared with apixaban and similar safety compared with placebo. Further evidence on the efficacy of asundexian awaits the results of ongoing phase III trials.

Hypoglycemia and Cardiovascular Outcomes in the CARMELINA and CAROLINA Trials of Linagliptin: A Secondary Analysis of Randomized Clinical Trials.

Importance: Previous studies have reported an association between hypoglycemia and cardiovascular (CV) events in people with type 2 diabetes (T2D), but it is unclear if this association is causal or identifies a high-risk patient phenotype. Objective: To evaluate the associations between hypoglycemia and CV outcomes. Design, Setting, and Participants: This secondary analysis was a post hoc assessment of the multinational, double-blind CARMELINA (Cardiovascular and Renal Microvascular Outcome Study With Linagliptin; 2013-2016) and CAROLINA (Cardiovascular Outcome Trial of Linagliptin vs Glimepiride in Type 2 Diabetes; 2010-2018) randomized clinical trials of the antihyperglycemic drug, linagliptin, a dipeptidyl peptidase 4 inhibitor. Participants were adults with T2D at high CV risk with or without high kidney risk. By design, participants in the CARMELINA trial had longer duration of T2D and had a higher CV risk than participants in the CAROLINA trial. Data analyses were conducted between June 2021 and June 2023. Intervention: Linagliptin or placebo in the CARMELINA trial, and linagliptin or glimepiride in the CAROLINA trial. Main Outcomes and Measures: The primary outcome for both trials was CV death, myocardial infarction (MI), or stroke (3-point major adverse CV events [3P-MACE]). For the present analyses, hospitalization for heart failure (HF) was added. Hypoglycemia was defined as plasma glucose less than 54 mg/dL or severe hypoglycemia (episodes requiring the assistance of another person). Associations between the first hypoglycemic episode and subsequent CV events and between nonfatal CV events (MI, stroke, hospitalization for HF) and subsequent hypoglycemic episodes were assessed using multivariable Cox proportional hazards regression models. Sensitivity analyses explored the risk of CV events within 60 days after each hypoglycemic episode. Results: In the CARMELINA trial (6979 patients; 4390 males [62.9%]; mean [SD] age, 65.9 [9.1] years), there was an association between hypoglycemia and subsequent 3P-MACE plus hospitalization for HF (hazard ratio [HR], 1.23; 95% CI, 1.04-1.46) as well as between nonfatal CV events and subsequent hypoglycemia (HR, 1.39; 95% CI, 1.06-1.83). In the CAROLINA trial (6033 patients; 3619 males (60.0%); mean [SD] age, 64.0 [9.5] years), there was no association between hypoglycemia and subsequent 3P-MACE plus hospitalization for HF (HR, 1.00; 95% CI, 0.76-1.32) and between nonfatal CV events and subsequent hypoglycemia (HR, 1.44; 95% CI, 0.96-2.16). In analyses of CV events occurring within 60 days after hypoglycemia, there was either no association or too few events to analyze. Conclusions and Relevance: This study found bidirectional associations between hypoglycemia and CV outcomes in the CARMELINA trial but no associations in either direction in the CAROLINA trial, challenging the notion that hypoglycemia causes adverse CV events. The findings from the CARMELINA trial suggest that both hypoglycemia and CV events more likely identify patients at high risk for both. Trial Registration: ClinicalTrials.gov Identifier: NCT01897532 (CARMELINA) and NCT01243424 (CAROLINA).

Cancer-associated FBXW7 loss is synthetic lethal with pharmacological targeting of CDC7.

The F-box and WD repeat domain containing 7 (FBXW7) tumour suppressor gene encodes a substrate-recognition subunit of Skp, cullin, F-box (SCF)-containing complexes. The tumour-suppressive role of FBXW7 is ascribed to its ability to drive ubiquitination and degradation of oncoproteins. Despite this molecular understanding, therapeutic approaches that target defective FBXW7 have not been identified. Using genome-wide clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 screens, focussed RNA-interference screens and whole and phospho-proteome mass spectrometry profiling in multiple FBXW7 wild-type and defective isogenic cell lines, we identified a number of FBXW7 synthetic lethal targets, including proteins involved in the response to replication fork stress and proteins involved in replication origin firing, such as cell division cycle 7-related protein kinase (CDC7) and its substrate, DNA replication complex GINS protein SLD5 (GINS4). The CDC7 synthetic lethal effect was confirmed using small-molecule inhibitors. Mechanistically, FBXW7/CDC7 synthetic lethality is dependent upon the replication factor telomere-associated protein RIF1 (RIF1), with RIF1 silencing reversing the FBXW7-selective effects of CDC7 inhibition. The delineation of FBXW7 synthetic lethal effects we describe here could serve as the starting point for subsequent drug discovery and/or development in this area.

Outcomes According to Coronary Revascularization Modality in the ISCHEMIA Trial.

BACKGROUND: In the ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) trial, the risk of ischemic events was similar in patients with stable coronary artery disease treated with an invasive (INV) strategy of angiography and percutaneous coronary intervention (PCI) or surgical (coronary artery bypass grafting [CABG]) coronary revascularization and a conservative (CON) strategy of initial medical therapy. OBJECTIVES: The authors analyzed separately the outcomes of INV patients treated with PCI or CABG. METHODS: Patients without preceding primary outcome events were categorized as INV-PCI or INV-CABG from the time of revascularization. The ISCHEMIA primary outcome (composite of cardiovascular death, protocol-defined myocardial infarction or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest) was used. RESULTS: Among INV-CABG patients, primary outcome events occurred in 84 of 512 (16.4%) at a median follow-up of 2.85 years; 48 events (57.1%) occurred within 30 days after CABG, including 40 procedural MIs. Among INV-PCI patients, primary outcome events occurred in 147 of 1,500 (9.8%) at median follow-up of 2.94 years; 31 of which (21.1%) occurred within 30 days after PCI, including 24 procedural MIs. In comparison, 352 of 2,591 CON patients (13.6%) had primary outcome events at a median follow-up of 3.2 years, 22 of which (6.3%) occurred within 30 days of randomization. The adjusted primary outcome risks were higher after both CABG and PCI within 30 days (HR: 16.25 [95% CI: 11.44-23.07] and HR: 2.99 [95% CI: 1.97-4.53]) and lower thereafter (0.63 [95% CI: 0.44-0.89] and 0.66 [95% CI: 0.53-0.82]). CONCLUSIONS: In ISCHEMIA, early revascularization by PCI and CABG was associated with higher early risks and lower long-term risks of cardiovascular events compared with CON. The early risk was greatest after CABG, owing to protocol-defined procedural MIs.

Targeting Transcriptional Regulation with a CDK9 Inhibitor Suppresses Growth of Endocrine- and Palbociclib-Resistant ER+ Breast Cancers.

The combination of endocrine therapy and CDK4/6 inhibitors such as palbociclib is an effective and well-tolerated treatment for estrogen receptor-positive (ER+) breast cancer, yet many patients relapse with therapy-resistant disease. Determining the mechanisms underlying endocrine therapy resistance is limited by the lack of ability to fully recapitulate inter- and intratumor heterogeneity in vitro and of availability of tumor samples from women with disease progression or relapse. In this study, multiple cell line models of resistant disease were used for both two-dimensional (2D)- and three-dimensional (3D)-based inhibitor screening. The screens confirmed the previously reported role of pro-proliferative pathways, such as PI3K-AKT-mTOR, in endocrine therapy resistance and additionally identified the transcription-associated cyclin-dependent kinase CDK9 as a common hit in ER+ cell lines and patient-derived organoids modeling endocrine therapy-resistant disease in both the palbociclib-sensitive and palbociclib-resistant settings. The CDK9 inhibitor, AZD4573, currently in clinical trials for hematologic malignancies, acted synergistically with palbociclib in these ER+in vitro 2D and 3D models. In addition, in two independent endocrine- and palbociclib-resistance patient-derived xenografts, treatment with AZD4573 in combination with palbociclib and fulvestrant resulted in tumor regression. Tumor transcriptional profiling identified a set of transcriptional and cell-cycle regulators differentially downregulated only in combination-treated tumors. Together, these findings identify a clinically tractable combination strategy for overcoming resistance to endocrine therapy and CDK4/6 inhibitors in breast cancer and provide insight into the potential mechanism of drug efficacy in targeting treatment-resistant disease. SIGNIFICANCE: Targeting transcription-associated CDK9 synergizes with CDK4/6 inhibitor to drive tumor regression in multiple models of endocrine- and palbociclib-resistant ER+ breast cancer, which could address the challenge of overcoming resistance in patients.

Awake caudal anesthesia in ex-premature infants undergoing lower abdominal surgery: A narrative review.

BACKGROUND AND OBJECTIVES: The aim of this narrative review is to evaluate the literature describing the use of caudal anesthetic-based techniques in premature and ex-premature infants undergoing lower abdominal surgery. METHODS: All available literature from inception to August 2023 was retrieved according to Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines from Medline, PubMed, Embase, and the Cochrane Library. Two authors reviewed all references for eligibility, abstracted data, and appraised quality. RESULTS: Of the 211 articles identified, 45 met our inclusion criteria yielding 1548 cases with awake caudal anesthesia. The review included 558 (36.0%) cases of awake caudal anesthesia, 837 cases (54.1%) of "awake" caudal anesthesia with sedation, and 153 cases (9.9%) of combined spinal caudal epidural anesthesia without sedation. The overall anesthetic failure rate was 7.2% (71.9:1000 caudals). Failure rates were highest for CSEA (13.7%, 7.7-18.4), intermediate for awake caudal (6.6%, 5.26-9.51), and lowest for sedated caudal anesthesia (5.85%, 4.48-7.82). The incidence (range) of perioperative apnea was highest for sedated caudal anesthesia (8.16, 0%-24%), intermediate for awake caudal (7.62%, 0%-60%), and lowest for CSEA (5.53%, 0%-14.3%). High spinal anesthesia occurred in 0.84%, or 8.35:1000 caudals overall. The incidence was highest in awake caudal anesthesia cases (1.97% or 19.7:1000 caudals), intermediate with caudal with sedation (1.07% or 10.7:1000 caudals), and lowest in CSEA (0.7% or 6.6:1000 caudals). Our review was confounded by incomplete data reporting and small sample sizes as most were case reports. There were no high-quality randomized controlled trials, and the eight single-center retrospective data reviews lacked sufficient data to perform meta-analysis. CONCLUSIONS: There is insufficient evidence to validate or refute the benefits of the use of "awake" caudal anesthesia in premature and ex-premature infants. The high doses of local anesthetics used, the high failure rate, and the increased incidence of high spinal anesthesia would suggest that the techniques offer no real advantages over awake spinal anesthesia or general anesthesia with a regional block.

Prospective Study of Risk Factors for Postoperative Atrial Fibrillation After Cardiac Surgery.

INTRODUCTION: To examine risk factors for new-onset postoperative atrial fibrillation (POAF) after cardiac surgery. METHODS: Patients enrolled in the Cardiothoracic Surgical Trials Network multicenter, randomized trial of rate control versus rhythm control for POAF were included. Predictors of POAF were determined using multivariable logistic regression. RESULTS: Among the 2104 patients who were enrolled preoperatively, 695 developed POAF (33.0%). Rates of POAF were 28.1% after isolated coronary artery bypass grafting (CABG), 33.7% after isolated valve repair or replacement, and 47.3% after CABG plus valve repair or replacement. Baseline characteristics associated with an increased risk of POAF identified on multivariable analysis included older age (odds ratio [OR] 1.57; 95% confidence interval [CI] 1.42-1.73, per 10 y), White race or non-Hispanic ethnicity (OR 1.52; CI: 1.11-2.07), history of heart failure (OR 1.55; CI: 1.16-2.08), and history of hypothyroidism (OR 1.42; CI 1.04-1.94). The type of cardiac procedure was associated with an increased risk of POAF with both isolated valve repair or replacement (OR 1.33, CI 1.08-1.64) and combined CABG plus valve repair or replacement (OR 1.64, CI 1.24-2.17) having increased risk of POAF compared to isolated CABG. No preoperative cardiac medication was associated with POAF. CONCLUSIONS: In this prospective cohort of patients, older age, a history of hypothyroidism, a history of heart failure, and valve repair or replacement, with or without CABG, and White non-Hispanic race were associated with an increased risk of POAF.

Cardiovascular Effects of GnRH Antagonists Compared With Agonists in Prostate Cancer: A Systematic Review.

Background: Androgen deprivation therapy is the cornerstone of treatment for patients with advanced prostate cancer. Meta-analysis of small, oncology-focused trials suggest gonadotropin-releasing hormone (GnRH) antagonists may be associated with fewer adverse cardiovascular outcomes compared with GnRH agonists. Objectives: This study sought to determine whether GnRH antagonists were associated with fewer major adverse cardiovascular events compared with GnRH agonists. Methods: Electronic databases were searched for all prospective, randomized trials comparing GnRH antagonists with agonists. The primary outcome was a major adverse cardiovascular event as defined by the following standardized Medical Dictionary for Regulatory Activities terms: "myocardial infarction," "central nervous system hemorrhages and cerebrovascular conditions," and all-cause mortality. Bayesian meta-analysis models with random effects were fitted. Results: A total of 11 eligible studies of a maximum duration of 3 to 36 months (median = 12 months) enrolling 4,248 participants were included. Only 1 trial used a blinded, adjudicated event process, whereas potential bias persisted in all trials given their open-label design. A total of 152 patients with primary outcome events were observed, 76 of 2,655 (2.9%) in GnRH antagonist-treated participants and 76 of 1,593 (4.8%) in agonist-treated individuals. Compared with GnRH agonists, the pooled OR of GnRH antagonists for the primary endpoint was 0.57 (95% credible interval: 0.37-0.86) and 0.58 (95% credible interval: 0.32-1.08) for all-cause death. Conclusions: Despite the addition of the largest, dedicated cardiovascular outcome trial, the volume and quality of available data to definitively answer this question remain suboptimal. Notwithstanding these limitations, the available data suggest that GnRH antagonists are associated with fewer cardiovascular events, and possibly mortality, compared with GnRH agonists.

Restrictive or Liberal Transfusion Strategy in Myocardial Infarction and Anemia.

BACKGROUND: A strategy of administering a transfusion only when the hemoglobin level falls below 7 or 8 g per deciliter has been widely adopted. However, patients with acute myocardial infarction may benefit from a higher hemoglobin level. METHODS: In this phase 3, interventional trial, we randomly assigned patients with myocardial infarction and a hemoglobin level of less than 10 g per deciliter to a restrictive transfusion strategy (hemoglobin cutoff for transfusion, 7 or 8 g per deciliter) or a liberal transfusion strategy (hemoglobin cutoff, <10 g per deciliter). The primary outcome was a composite of myocardial infarction or death at 30 days. RESULTS: A total of 3504 patients were included in the primary analysis. The mean (±SD) number of red-cell units that were transfused was 0.7±1.6 in the restrictive-strategy group and 2.5±2.3 in the liberal-strategy group. The mean hemoglobin level was 1.3 to 1.6 g per deciliter lower in the restrictive-strategy group than in the liberal-strategy group on days 1 to 3 after randomization. A primary-outcome event occurred in 295 of 1749 patients (16.9%) in the restrictive-strategy group and in 255 of 1755 patients (14.5%) in the liberal-strategy group (risk ratio modeled with multiple imputation for incomplete follow-up, 1.15; 95% confidence interval [CI], 0.99 to 1.34; P = 0.07). Death occurred in 9.9% of the patients with the restrictive strategy and in 8.3% of the patients with the liberal strategy (risk ratio, 1.19; 95% CI, 0.96 to 1.47); myocardial infarction occurred in 8.5% and 7.2% of the patients, respectively (risk ratio, 1.19; 95% CI, 0.94 to 1.49). CONCLUSIONS: In patients with acute myocardial infarction and anemia, a liberal transfusion strategy did not significantly reduce the risk of recurrent myocardial infarction or death at 30 days. However, potential harms of a restrictive transfusion strategy cannot be excluded. (Funded by the National Heart, Lung, and Blood Institute and others; MINT ClinicalTrials.gov number, NCT02981407.).

The Effect of Posterior Pericardiotomy on the Incidence of Atrial Fibrillation After Cardiac Surgery-Extended Follow-Up study (PALACS-EF): rationale and design.

Aims: Postoperative atrial fibrillation (POAF) is the most common complication of cardiac surgery and has been associated with increased postoperative morbidity and hospital costs. The Posterior left pericardiotomy for the prevention of AtriaL fibrillation After Cardiac Surgery (PALACS) trial found that posterior pericardiotomy significantly reduced the incidence of POAF (17% vs. 32%, P < 0.001). We present the protocol for The Effect of Posterior Pericardiotomy on the Incidence of Atrial Fibrillation After Cardiac Surgery-Extended Follow-Up study (PALACS-EF): a prospective, extended follow-up of the original PALACS trial. The aim of PALACS-EF is to gain more data regarding the effect of posterior pericardiotomy on postdischarge clinical outcomes. The primary outcome is the time to the first occurrence of the composite of all-cause mortality or hospital cardiovascular readmission. The key secondary outcome is the time to the first occurrence of the composite of all-cause mortality and all-cause hospital readmission. Hospital readmission, myocardial infarction, stroke, transient ischaemic attack, heart failure, systemic embolism, or new arrhythmias with onset since 30-day follow-up will also be recorded. Methods and results: All 420 patients enrolled in the PALACS trial will be included; extended follow-up will be conducted via telephone by blinded research personnel utilizing a standardized script to ensure uniformity and completeness of follow-up. If an event has occurred, documentation will be obtained, and an independent adjudication committee blinded to group assignment will adjudicate outcome events. Results will be reported when a median follow-up of 5 years is achieved. Conclusion: PALACS-EF will provide data to answer the question of whether posterior pericardiotomy improves postdischarge outcomes in patients undergoing cardiac surgery, and it will provide information on the relationship between POAF and adverse postdischarge outcomes including mortality, hospitalization, heart failure, and stroke. Registration: PALACS: NCT02875405, PALACS-EF: NCT05903222.

Cannabis use during pregnancy and hemodynamic responses to infant cues in pregnancy: an exploratory study.

Introduction: Cannabis is one of the most commonly used substances during pregnancy and has the potential to negatively impact parent-infant relationships. The prefrontal cortex (PFC) response to infant cues during pregnancy has been associated with subsequent positive parenting behaviors. However, PFC activation is altered in individuals who use cannabis. As the potency of cannabis has changed over the years, little is known about the specific role of cannabis use on gestational parent brain responses to infant cues. Materials and methods: Using functional Near-Infrared Spectroscopy (fNIRS) in the second trimester of pregnancy, we measured hemodynamic responses to an infant cry task and an infant faces task among individuals who were using cannabis (N = 14) and compared them with those who were not using cannabis (N = 45). For the infant cry task, pregnant individuals listened to cry sounds and matched white noise. For the infant faces task, they viewed happy, sad, and neutral faces. Results: There was no significant difference between the two groups after adjusting for multiple comparisons. Without adjusting for multiple comparisons, we found preliminary evidence for the differences in the dorsomedial PFC associated with heightened response to infant cry among individuals who use cannabis. The groups were also different in the dorsolateral PFC associated with decreased response to infant sad faces among individuals who use cannabis. Discussion: Our preliminary data suggests that cannabis use during pregnancy was associated with brain activation in the regions involved in the emotional regulation and information processes. However, the results did not survive after adjustment for multiple comparisons, thus future research with larger sample sizes is needed to confirm potential differences in brain function among cannabis-using pregnant individuals.