Citations

Ventricular tachycardia (VT) is a life-threatening arrhythmia that requires both relatively rapid and accurate detection in intensive care units (ICUs). Continuous monitoring systems play a crucial role in detecting them. However, previous studies have reported that nearly 9 out of 10 arrhythmia alarms in ICUs tend to be false positives, which usually transpire to a well-documented phenomenon called “alarm fatigue” that leads to desensitization, delayed responses and increased cognitive burden on healthcare providers. We developed a deep learning based, one-dimensional convolutional neural network (1D-CNN) to classify VT alarms using multiple raw waveform inputs, including two electrocardiogram (ECG) leads, photoplethysmogram (PPG) and arterial blood pressure (ABP) signals. The model was trained using the publicly available VTaC Arrhythmia Benchmark Dataset. Ten-second waveform segments preceding each alarm were pre-processed and used to train the model to correctly classify the VT alarm. On the test set, the model achieved an area under the receiver operating characteristic curve (AUC-ROC) of 0.901, overall accuracy of 83.22%, F1-score of 73.3%, sensitivity of 77.53%, specificity of 85.63%, and positive predictive value (PPV) of 69.57%. The model successfully detected over three-quarters of them while significantly reducing false positive rates for the detection of VT. This study demonstrates that a deep learning based 1D-CNN model using short segments of raw waveform data can achieve robust performance in distinguishing true and false VT alarms.

OBJECTIVE: To identify distinct phenotypes of acute respiratory distress syndrome (ARDS) developing after hematopoietic cell transplantation (HCT), using routinely available clinical data at ICU admission. DESIGN: Multicenter retrospective cohort study using latent class analysis. SETTING: ICUs across three Mayo Clinic campuses (Minnesota, Florida, and Arizona). PATIENTS: A total of 166 adult patients who developed ARDS within 120 days following HCT (96 allogeneic, 70 autologous). INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Model selection was based on multiple metrics including Bayesian information criteria, entropy, and Vuong-Lo-Mendell-Rubin Likelihood Ratio testing. A two-class model optimally described the cohort. Class 1 (n = 81) was characterized by worse hypoxemia (P/F ratio 157 vs. 210, p = 0.002), higher Pco 2 (41 vs. 36 mm Hg, p < 0.001), and higher bilirubin (1.4 vs. 0.9 mg/dL, p < 0.001) compared with class 2 (n = 85). Both classes included a mix of transplant types, transcending a simple autologous/allogeneic dichotomy, although class 1 had more allogeneic recipients (70.4% vs. 45.9%, p = 0.001). Although time-from-transplant was not a class-defining variable, class 1 occurred later after transplant (30.0 vs. 11.9 d, p < 0.001) with higher frequency of idiopathic pneumonia syndrome (14.8% vs. 2.4%, p = 0.004). Class 2 had more frequent neutropenia (leukocytes 0.4 vs. 5.9 × 109, p < 0.001) and higher frequency of peri-engraftment respiratory distress syndrome (29.4% vs. 9.9%, p = 0.005). Outcomes were significantly worse for class 1 (90-d mortality: 72.8% vs. 48.2%, p = 0.001). An exploratory parsimonious model had good classification accuracy (0.90) using just six variables: leukocyte count, platelet count, bilirubin, Pco 2, body mass index, and temperature. CONCLUSIONS: ARDS after HCT comprises two distinct phenotypes with distinct clinical characteristics and outcomes. These phenotypes align with recognized post-HCT lung injury syndromes and may reflect different underlying biological processes. This framework provides a foundation for investigating targeted therapeutic approaches.

IMPORTANCE: Propofol is a first-line sedative for adults receiving invasive mechanical ventilation (IMV). However, it can contribute to hemodynamic instability, especially during intubation. The magnitude, timing, risk factors, and variability of sedation-associated mean arterial pressure (MAP) changes remain poorly characterized in ICU settings. OBJECTIVES: To quantify MAP changes following propofol sedation, identify risk factors for hemodynamic instability, and characterize associated interventions. DESIGN: Retrospective cohort study. The primary outcome was MAP change within 2 hours following sedation. Secondary outcomes included vasopressor use and hypotension (MAP ≤ 60 mm Hg). Mixed-effects modeling was used to account for individual patient differences. SETTING AND PARTICIPANTS: Adults (≥ 18 yrs old) who required IMV and received greater than or equal to 6 consecutive hours of propofol infusion, between May 5th, 2018, and July 31st, 2024, in 11 ICUs across the Mayo Clinic, spanning 5 hospitals in 4 states. MAIN OUTCOMES AND MEASURES: The primary outcome was the change in MAP within 2 hours following the initiation of propofol-based sedation. RESULTS: Across 16,418 patients, 25.2% were on vasopressors before sedation initiation. Among the remaining 12,281 patients, 40.3% required vasopressors and 7.7% experienced hypotension within 2 hours of sedation. Propofol-based sedation was associated with a MAP reduction within the first 30 minutes (–6.58 mm Hg; 95% CI, –6.85 to –6.32; p < 0.001). There was substantial interpatient variability in both baseline MAP, and MAP decline after sedation (9.5 and 40.9% between-patient differences, respectively). Higher Sequential Organ Failure Assessment (SOFA) scores (–0.31 mm Hg/point), older age (–0.04 mm Hg/yr), and male sex (–0.47 mm Hg) were associated with lower MAP. Patients with higher illness severity experienced progressively greater MAP decline over time (–0.20 mm Hg/hr/SOFA point; p < 0.001). CONCLUSIONS AND RELEVANCE: Propofol-based sedation was associated with clinically significant hemodynamic effects requiring intervention in the early post-intubation period. The marked interpatient variability in hemodynamic responses highlights the importance of personalized management approaches, including risk stratification based on age, sex, and illness severity.

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy characterized by the clonal proliferation of myeloid precursors and rapid progression. Historically consisting of intensive chemotherapy, AML management has evolved significantly due to advances in molecular diagnostics and risk stratification. This review discusses current therapeutic paradigms in AML, emphasizing the growing role of personalized medicine across age and risk groups. For younger, fit patients, intensive regimens such as the “7 + 3” protocol remain the standard, often enhanced by targeted agents like FMS-like tyrosine kinase 3 (FLT3) and IDH inhibitors. Older or unfit individuals benefit from low-intensity treatments such as hypomethylating agents combined with venetoclax, now considered a frontline standard of care. The use of liposomal chemotherapy (CPX-351), measurable residual disease (MRD) monitoring, and maintenance therapy further refine post-remission strategies. Emerging therapies, including menin inhibitors, antibody–drug conjugates, and immunotherapies like CAR-T cells and vaccines, offer additional options, especially in relapsed/refractory settings. This comprehensive review outlines the current landscape and future directions in AML therapy, emphasizing the transition toward individualized, mutation-driven treatment strategies.

Background: The impact of multiple substance use on the risk of pancreatitis remains underexplored. Objective: To systematically review peer-reviewed observational studies assessing the association of multiple substance use with the risk of acute pancreatitis (AP) or chronic pancreatitis (CP) in adults. Design: We conducted a systematic review informed by the Preferred Reporting Items for Systematic Review and Meta-Analyses guideline. Data sources and methods: EMBASE, MEDLINE, and PsycINFO were searched up to March 2024. Reference lists of included studies were reviewed. From 5205 records identified, 181 relevant records were evaluated in full text. Studies evaluating the association of ⩾2 substances, including tobacco, alcohol, cannabis, and illicit substances, with AP or CP were included. Data were extracted by one reviewer, with quality control by a second reviewer. Quality assessments were independently conducted by two reviewers, with differences resolved by a third. Results: Of 11 included studies, 6 investigated AP as the outcome and 5 examined CP. Among AP studies, 5 comparing smoking and alcohol to alcohol-only use showed high heterogeneity ( I 2 = 90.9%), with relative risks (RRs) from 1.40 to 11.40. One study examining cannabis and alcohol versus alcohol found a lower risk of AP in cannabis users. Among CP studies, four comparing smoking and alcohol to alcohol-only use were heterogeneous ( I 2 = 81%) with odds ratios 1.21–31.50. Where examined, smoking increases the risk of AP and CP in a dose-dependent fashion. Heavy alcohol users demonstrated a significant increase in CP risk across all smoking categories in one study. Conclusion: Combined alcohol and tobacco use increases pancreatitis risk compared to single substance use, despite heterogeneity in RRs and exposure definitions. Evidence suggests a dose-dependent impact of smoking on pancreatitis risk when added to alcohol. Studies on the impact of a combination of other substance use on pancreatitis risk are needed. Trial registration (PROSPERO): CRD42024503677.

Abstract Background and Aims The TRISCEND II trial demonstrated superior clinical benefits for patients with ≥severe tricuspid regurgitation (TR) treated with the EVOQUE transcatheter tricuspid valve replacement (TTVR) system plus medical therapy vs medical therapy alone. This work reports 1-year and 18-month outcomes in patients stratified by baseline TR severity. Methods The multicentre, prospective TRISCEND II trial enrolled 400 patients with symptomatic, ≥severe TR, and randomized 2:1 to TTVR (n = 267) or control (n = 133). In a post hoc analysis, patients were stratified into severe TR (n = 172) and massive/torrential TR (n = 220) cohorts. Clinical and quality-of-life outcomes were reported at 1 year, with Kaplan–Meier estimates for all-cause mortality and heart failure (HF) hospitalization assessed at 18 months. Study oversight included an independent echocardiographic core laboratory, clinical events committee, and data safety monitoring board. Results One year after TTVR, TR was ≤mild in 95.2% of severe TR and 95.3% of massive/torrential TR patients. The primary safety and effectiveness endpoint (win ratio) favoured TTVR over control regardless of baseline TR severity: severe {1.64 [95% confidence interval (CI): 1.11, 2.43]} and massive/torrential [2.20 (1.55, 3.14)]. At 18 months, TTVR patients had similar mortality to controls [rate difference: severe 0.2% (−11.6, 11.9), massive/torrential −5.8% (−17.6, 6.0)], whereas HF hospitalization rates favoured TTVR in the massive/torrential cohort [vs control, severe 9.8% (−3.0, 22.7), massive/torrential -15.2% (−28.9, −1.5)]. Conclusions Patients with ≥severe TR benefit from TTVR, experiencing improvements in TR severity, functional capacity, and quality of life regardless of baseline TR severity, with a signal for greater benefit in patients with more advanced disease.

Abstract Purpose: Germline pathogenic variants (PV) in ATM increase the risk of pancreatic ductal adenocarcinoma (PDAC), but the underlying tumor biology of PDAC associated with germline PV in ATM has not been adequately explored. Experimental Design: Whole-genome, whole-exome, and RNA sequencing were performed on PDAC tumors from 25 germline ATM PV carriers diagnosed at Mayo Clinic between 2007 and 2017. Somatic and copy-number alterations, mutational signatures, transcriptomic subtypes, and the immune landscape were evaluated. Results: High-quality whole-exome and whole-genome sequencing were obtained from 21 and 15 tumors, respectively. Biallelic inactivation of ATM was observed in 87%, KRAS PV in 90%, CDKN2A homozygous loss in 60%, and TP53 alterations in &lt;10% of these tumors. A predominant clock-like mutational signature was present in all samples. Whole-transcriptome analysis identified that the aberrantly differentiated endocrine exocrine subtype accounted for 18% of PDAC and was consistently associated with &gt;5-year overall survival. In addition, a 28-gene expression–based signature associated with overall survival was identified and further validated in The Cancer Genome Atlas cohort. Immune landscape analysis through CODEX identified enriched CD4 T-helper cell/tumor interactions and reduced B7H3-high cell/tumor interactions in ATM PV carriers compared with noncarriers. Conclusions: The observed absence of TP53 PV and enrichment for CDKN2A alterations in ATM tumors, along with differences in the mutational signatures, transcriptomic subtypes and immune landscape, improve our understanding of the mechanistic pathways involved in PDAC development in germline ATM PV carriers and help identify potential targeted therapeutic strategies.

INTRODUCTION: Chronic pancreatitis (CP) is a disease associated with chronic inflammation, fibrosis, and pain. There is a lack of tools available that facilitate early diagnosis, when intervention could prevent irreversible damage. Pilot data suggested prostaglandin E2 (PGE2) as a candidate biomarker for early CP. PGE2 activates signaling pathways that promote inflammation, pain, and fibrosis. METHODS: We assessed PGE2, metabolites, and downstream targets in pancreatic fluid collected endoscopically 0–10 (n = 110) and 10–20 (n = 111) minutes after intravenous secretin administration. PGE2 and metabolites were measured in plasma (n = 75) and urine (n = 71) from the same subjects. Subjects were enrolled in the PROCEED study and classified symptomatic controls, acute/recurrent acute pancreatitis (AP/RAP), or CP. RESULTS: A significant main effect was detected in 10–20 minutes pancreas fluid ( P = 0.027) and plasma ( P = 0.046); post hoc testing showed PGE2 was lower in the AP/RAP group compared with symptomatic controls. There was also trend toward lower PGE2 in urine ( P = 0.062). To elucidate the active downstream pathways, calcitonin gene-related peptide, substance P, and matrix metalloproteinases (MMPs) 1, 2, 3, 7, 9, and 13 were measured in pancreas fluid. A significant difference between the 3 groups was detected for both MMP7 and MMP9. MMP7 was elevated in individuals with CP vs AP/RAP ( P = 0.012) for samples collected early but both time points for MMP9 ( P = 0.027, P = 0.002). DISCUSSION: While PGE2 is detectable in pancreas fluid, these data suggest that it may not be sensitive enough to distinguish between AP/RAP and CP. However, MMPs may distinguish between stages of pancreatitis and require further testing as potential diagnostic biomarkers.

PURPOSE Testing for germline BRCA1 and/or BRCA2 mutations (gBRCAm) is recommended for patients with human epidermal growth factor receptor 2–negative (HER2–) breast cancer (BC) to guide treatment selection with poly (ADP-ribose) polymerase inhibitors (PARPis). However, real-world data on germline BRCA1 and/or BRCA2 (gBRCA) testing and PARPi treatment patterns in metastatic BC (mBC) are limited. METHODS Deidentified patient data from adults diagnosed with HER2– mBC between 2014 and 2022 were captured from electronic health records in the US Flatiron Health database. gBRCA testing patterns and prevalence were examined by tumor subtype (hormone receptor–positive [HR+]/triple-negative) and disease stage at diagnosis. Demographic and clinical characteristics were described by receipt of gBRCA testing and PARPi. PARPi treatment patterns were assessed, and real-word overall survival (OS) was estimated in patients with gBRCAm diagnosed with mBC after January 1, 2018. RESULTS Of the 15,006 total patients, 4,654 (31.0%) received a gBRCA test. gBRCA testing rates mostly increased from 2014 to 2022 and were lower in patients with HR+ than triple-negative tumors. Of the patients who underwent gBRCA testing, 337 (7.2%) had gBRCAm. From 2018 to 2022, PARPi was initiated in 94 (45.6%) of 206 patients with gBRCAm. With a median follow-up of 22.8 months across patients with available first-line treatment start dates, real-world OS was numerically longer among 94 patients with gBRCAm who received PARPi (32.3 months [95% CI, 22.7 to 47.4]) than among 99 patients who did not (21.9 months [95% CI, 18.4 to not reached]). CONCLUSION Although gBRCA testing increased over time, testing and PARPi utilization rates remained suboptimal in potentially eligible patients with HER2– mBC. Exploratory analysis showed numerically longer OS in patients who received PARPi. Wider and timelier gBRCA testing is warranted to inform potentially optimal treatment decisions.