Citations

Background: Paroxysmal atrial fibrillation (AF) is a common arrhythmogenic complication in the intensive care unit (ICU) associated with significant costs and morbidity. AF detection models in the literature have utilized entropic analyses of telemetry to diagnose AF, but they have not been utilized to forecast its onset. Hypothesis: Deep learning techniques applied to high-frequency telemetry data can be utilized to forecast AF with clinically significant lead time. Methods: Telemetry data were collected from 72 ICU monitored beds in a tertiary care center from 4/2018-12/2023. Coefficient of sample entropy (COSEn), a metric of heart rate variability complexity, was calculated on successive 1-minute windows and utilized to identify areas of AF initiation as well as control windows without AF. ECG lead II (256Hz) and beat-to-beat (B2B) measurements were analyzed by the MOMENT time-series foundational model to generate representation embeddings. A binary classification multilayer perceptron (MLP) was trained on these embeddings to forecast AF onset 5m in advance. All results were reported on separate test sets. Group-based trajectory modelling (GBTM) was performed on risk score trajectories from the 20m before AF onset or absence. Results: Over 230,000 hours of B2B data from 2263 patients was analyzed using COSEn to identify 287 transitions to AF from 136 patients. The same number of AF-absent windows were randomly selected. COSEn alone as a forecaster produced an area under the receiver operating characteristic curve (AUC) of 0.65 (95% CI: 0.61-0.69). The MOMENT + MLP model (MMM) achieved an AUC of 0.81 (0.78-0.83) (Fig. 1). COSEn and MMM were subsequently applied to the two hours preceding AF onset or absence. For COSEn, the mean risk trajectory dipped in the baseline period whereas the MMM risk trajectory sustained a high level through the baseline, highlighting its capacity to forecast AF (Fig. 2). For AF patients, GBMT yielded two types of trajectories: one with elevated risk throughout, and another with a rising trend 5 minutes prior to AF onset (Fig. 3). Conclusions: Deep learning techniques can forecast the onset of AF with up to 5 minutes of lead-time and GBTM allowed for the identification of different pre-AF risk trajectory phenotypes.The ability to forecast AF onset has potential to clinically prevent poor outcomes in the ICU, though further refinements to augment the amount of lead time are warranted.

The objective of this project was to develop a standardized list of renally eliminated and potentially nephrotoxic drugs that will help inform initiatives to improve medication safety. Several available lists of medications from the published literature including original research articles and reviews, and from regulatory agencies, tertiary references, and clinical decision support systems were compiled, consolidated, and compared. Only systemically administered medications were included. Medication combinations were included if at least 1 active ingredient was considered renally dosed or potentially nephrotoxic. The medication list was reviewed for completeness and clinical appropriateness by a multidisciplinary team of individuals with expertise in critical care, nephrology, and pharmacy. An initial list of renally dosed and nephrotoxic drugs was created. After reconciliation and consensus from clinical experts, a standardized list of 681 drugs is proposed. The proposed evidence-based standardized list of renally dosed and potentially nephrotoxic drugs will be useful to harmonize epidemiologic and medication quality improvement studies. In addition, the list can be used for clinical purposes with surveillance in nephrotoxin stewardship programs. We suggest an iterative re-evaluation of the list with emerging literature and new medications on an approximately annual basis.

TPS5125 Background: B7-H3 is a member of the B7 superfamily, which includes PD-L1 (B7-H1) and PD-L2 (B7-DC). Enoblituzumab is a humanized Fc-optimized B7-H3–targeting antibody that induces antibody-dependent cellular cytotoxicity (ADCC). A recent investigator-initiated trial demonstrated that enoblituzumab therapy, used in the neoadjuvant prostate cancer setting, is feasible, safe, may enhance short-term clinical outcomes, and appears to stimulate intratumoral immune activation including CD8+ T cell infiltration and peripheral expansion of tumor-infiltrating T-cell clones that correlated with undetectable PSA at 1-year post-prostatectomy. To assess the impact of enoblituzumab on recurrence-free survival following prostatectomy, a phase 2, randomized, neoadjuvant clinical trial in high-risk localized prostate cancer patients has been started. We hypothesize that targeting B7-H3 with enoblituzumab will delay or prevent recurrence following prostatectomy compared to standard of care (SOC) . Methods: The HEAT trial is an investigator-initiated, multi-center, randomized, phase 2 study that is presently enrolling (NCT06014255). Eligible patients will undergo a pre-treatment prostate biopsy and conventional imaging (CT and bone scan) as well as PSMA-PET. Patients who have clinical stage cT1c-T3b, cN0 cM0 disease by conventional imaging (N1 by PSMA allowed with up to 3 LNs each ≤1 cm) will be eligible as long as concurrent hormonal or radiation therapy is not given. Prostate biopsy, within 3 months of enrollment, needs to show at least 3 positive cores containing at least 1 core with at least 50% disease involvement with Gleason ≥4+3=7 disease (with at least 1 additional high-risk feature such as PSA>20 ng/ml or cT3) or a Gleason sum ≥8. Patients will receive enoblituzumab at a dose of 15mg/kg IV biweekly for 6 doses (12 weeks) on the treatment arm, followed by prostatectomy, or will be scheduled for prostatectomy directly within 4-8 weeks on the SOC arm. 219 patients will be randomized (2:1) to treatment versus SOC. Pre-treatment, on-treatment, and post-treatment biomarkers of response and resistance will be collected. Patients will be followed according to standard institutional practices, but will require PSA evaluations every 3 (±1) months during year 1 and every 6 (±2) months during years 2-5. In both arms, salvage or adjuvant therapy will occur after biochemical or radiographic progression. The primary endpoint is recurrence-free survival (RFS) defined as any metastasis events, local pelvic visceral or lymph node recurrence, detectable prostate-specific antigen (PSA), or start of subsequent local or systemic therapy (including salvage or adjuvant therapy), or death for any cause, whichever occurs first. Secondary endpoints include additional clinical and immunologic correlates. Clinical trial information: NCT06014255 .

ABSTRACT Adsorption-based extracorporeal therapies have been subject to technical developments and clinical application for close to five decades. More recently, new technological developments in membrane and sorbent manipulation have made it possible to deliver more biocompatible extracorporeal adsorption therapies to patients with a variety of conditions. There are several key rationales based on physicochemical principles and clinical considerations that justify the application and investigation of such therapies as evidenced by multiple ex vivo, experimental and clinical observations. Accordingly, unspecific adsorptive extracorporeal therapies have now been applied to the treatment of a wide array of conditions from poisoning to drug overdoses, to inflammatory states and sepsis, and acute or chronic liver and kidney failure. In response to the rapidly expanding knowledge base and increased clinical evidence, we convened an Acute Disease Quality Initiative consensus conference dedicated to such treatment. The data show that hemoadsorption has clinically acceptable short-term biocompatibility and safety, technical feasibility and experimental demonstration of specified target molecule removal. Pilot studies demonstrate potentially beneficial effects on physiology and larger studies of endotoxin-based hemoadsorption have identified possible target phenotypes for larger randomized controlled trials. Moreover, in a variety of endogenous and exogenous intoxications, removal of target molecules has been confirmed in vivo. However, some studies have raised concerns about harm, or failed to deliver benefits. Thus, despite many achievements, modern hemoadsorption remains a novel and experimental intervention with limited data, and a large research agenda.

AbstractBackgroundThe role of microbes in chronic rhinosinusitis (CRS) is poorly understood. We hypothesize that analyzing prior microbial exposures via assessing microbial protein serological reactivity in CRS versus controls may offer insights for CRS etiopathogenesis.MethodsWe profiled IgG and IgA antibodies to individual microbial proteins in serum samples of CRS patients and controls using a novel high‐throughput microarray protein technology, Nucleic Acid Programmable Protein Array (NAPPA). The study was conducted on 118 subjects (39 CRS, 79 controls). A CRS‐focused NAPPA array, with 1557 potentially sero‐reactive microbial proteins elected from a pre‐screening of 6500 genes of interest was constructed. It included membrane‐associated proteins from 47 bacterial species and all proteins from 43 viral strains. Differences between CRS and controls were compared across individual antimicrobial antibodies and the species.ResultsChronic rhinosinusitis patients had significantly elevated antimicrobial antibodies compared with controls. One bacterium (Staphylococcus aureus) and three viral strains (human metapneumovirus, human herpesvirus 5, and human herpesvirus 4) were identified as sources of the proteins that showed significantly elevated sero‐reactivity in CRS patients. Within CRS, patients with polyps had elevated antibodies against S. aureus, influenza A virus (H1N1, H3N2), and rhinovirus B14. CRS patients without polyps showed more antibodies against human herpesvirus 1 and vaccinia virus WR.ConclusionsCompared with healthy controls, CRS patients’ serum samples showed significantly increased sero‐reactivity to both bacterial and viral proteins, reflecting recent or current infection or active colonization. Significantly higher antibodies against S. aureus, human metapneumovirus, human herpesvirus 5, and human herpesvirus 4 in CRS need further study.

Abstract Brain voltage-gated sodium channel NaV1.1 (SCN1A) loss-of-function variants cause the severe epilepsy Dravet syndrome, as well as milder phenotypes associated with genetic epilepsy with febrile seizures plus. Gain of function SCN1A variants are associated with familial hemiplegic migraine type 3. Novel SCN1A-related phenotypes have been described including early infantile developmental and epileptic encephalopathy with movement disorder, and more recently neonatal presentations with arthrogryposis. Here we describe the clinical, genetic and functional evaluation of affected individuals. Thirty-five patients were ascertained via an international collaborative network using a structured clinical questionnaire and from the literature. We performed whole-cell voltage-clamp electrophysiological recordings comparing sodium channels containing wild-type versus variant NaV1.1 subunits. Findings were related to Dravet syndrome and familial hemiplegic migraine type 3 variants. We identified three distinct clinical presentations differing by age at onset and presence of arthrogryposis and/or movement disorder. The most severely affected infants (n = 13) presented with congenital arthrogryposis, neonatal onset epilepsy in the first 3 days of life, tonic seizures and apnoeas, accompanied by a significant movement disorder and profound intellectual disability. Twenty-one patients presented later, between 2 weeks and 3 months of age, with a severe early infantile developmental and epileptic encephalopathy and a movement disorder. One patient presented after 3 months with developmental and epileptic encephalopathy only. Associated SCN1A variants cluster in regions of channel inactivation associated with gain of function, different to Dravet syndrome variants (odds ratio = 17.8; confidence interval = 5.4–69.3; P = 1.3 × 10−7). Functional studies of both epilepsy and familial hemiplegic migraine type 3 variants reveal alterations of gating properties in keeping with neuronal hyperexcitability. While epilepsy variants result in a moderate increase in action current amplitude consistent with mild gain of function, familial hemiplegic migraine type 3 variants induce a larger effect on gating properties, in particular the increase of persistent current, resulting in a large increase of action current amplitude, consistent with stronger gain of function. Clinically, 13 out of 16 (81%) gain of function variants were associated with a reduction in seizures in response to sodium channel blocker treatment (carbamazepine, oxcarbazepine, phenytoin, lamotrigine or lacosamide) without evidence of symptom exacerbation. Our study expands the spectrum of gain of function SCN1A-related epilepsy phenotypes, defines key clinical features, provides novel insights into the underlying disease mechanisms between SCN1A-related epilepsy and familial hemiplegic migraine type 3, and identifies sodium channel blockers as potentially efficacious therapies. Gain of function disease should be considered in early onset epilepsies with a pathogenic SCN1A variant and non-Dravet syndrome phenotype.

Polygenic diseases, which are genetic disorders caused by the combined action of multiple genes, pose unique and significant challenges for the diagnosis and management of affected patients. A major goal of cardiovascular medicine has been to understand how genetic variation leads to the clinical heterogeneity seen in polygenic cardiovascular diseases (CVDs). Recent advances and emerging technologies in artificial intelligence (AI), coupled with the ever-increasing availability of next generation sequencing (NGS) technologies, now provide researchers with unprecedented possibilities for dynamic and complex biological genomic analyses. Combining these technologies may lead to a deeper understanding of heterogeneous polygenic CVDs, better prognostic guidance, and, ultimately, greater personalized medicine. Advances will likely be achieved through increasingly frequent and robust genomic characterization of patients, as well the integration of genomic data with other clinical data, such as cardiac imaging, coronary angiography, and clinical biomarkers. This review discusses the current opportunities and limitations of genomics; provides a brief overview of AI; and identifies the current applications, limitations, and future directions of AI in genomics.

Coronavirus disease (COVID-19) is a novel disease with multi-system involvement, but majority of patients have pulmonary and cardiovascular involvement in the acute stages. The cardiovascular impact of acute COVID-19 is well recognized ranging from myocarditis arrhythmias, thrombotic occlusion of coronary arteries, spontaneous coronary artery dissection and micro-thrombi in small coronary vessels on autopsy findings. We report a case of young male who recovered from probable mild covid-19 infection presenting few weeks later with devastating cardiovascular involvement with severe left ventricular (LV) impairment due to non-ischemic cardiomyopathy, multiple LV thrombi and embolic stroke.

Abstract Traumatic injury to the spinal cord initiates a series of pathological cellular processes that exacerbate tissue damage at and beyond the original site of injury. This secondary damage includes oxidative stress and inflammatory cascades that can lead to further neuronal loss and motor deficits. Microglial activation is an essential component of these secondary signaling cascades. The voltage-gated proton channel, Hv1, functionally expressed in microglia has been implicated in microglia polarization and oxidative stress in ischemic stroke. Here, we investigate whether Hv1 mediates microglial/macrophage activation and aggravates secondary damage following spinal cord injury (SCI). Following contusion SCI, wild-type (WT) mice showed significant tissue damage, white matter damage and impaired motor recovery. However, mice lacking Hv1 (Hv1-/-) showed significant white matter sparing and improved motor recovery. The improved motor recovery in Hv1-/- mice was associated with decreased interleukin-1β, reactive oxygen/ nitrogen species production and reduced neuronal loss. Further, deficiency of Hv1 directly influenced microglia activation as noted by decrease in microglia numbers, soma size and reduced outward rectifier K+ current density in Hv1-/- mice compared to WT mice at 7 d following SCI. Our results therefore implicate that Hv1 may be a promising potential therapeutic target to alleviate secondary damage following SCI caused by microglia/macrophage activation.