Factors associated with Acute Limb Ischemia in Cardiogenic Shock and downstream Clinical Outcomes: Insights from the Cardiogenic Shock Working Group.

BACKGROUND: There are limited data depicting the prevalence and ramifications of acute limb ischemia (ALI) among cardiogenic shock (CS) patients. METHODS: We employed data from the Cardiogenic Shock Working Group (CSWG), a consortium including 33 sites. We constructed a multi-variable logistic regression to examine the association between clinical factors and ALI, we generated another logistic regression model to ascertain the association of ALI with mortality. RESULTS: There were 7,070 patients with CS and 399 (5.6%) developed ALI. Patients with ALI were more likely to be female (40.4% versus 29.4%) and have peripheral arterial disease (13.8% versus 8.3%). Stratified by maximum SCAI shock stage, the rates of ALI were stage B 0.0%, stage C 1.8%, stage D 4.1%, and stage E 10.3%. Factors associated with higher risk for ALI included: peripheral vascular disease OR 2.24 (95% CI: 1.53 - 3.23; p < 0.01) and ≥ 2 mechanical circulatory support (MCS) devices OR 1.66 (95% CI: 1.24 - 2.21, p < 0.01). ALI was highest for VA-ECMO patients (11.6%) or VA-ECMO + IABP/Impella CP (16.6%) yet use of distal perfusion catheters was less than 50%. Mortality was 38.0% for CS patients without ALI but 57.4% for CS patients with ALI. ALI was significantly associated with mortality, adjusted OR 1.40 (95% CI 1.01 - 1.95, p < 0.01). CONCLUSIONS: The rate of ALI was 6% among CS patients. Factors most associated with ALI include peripheral vascular disease and multiple MCS devices. The downstream ramifications of ALI were dire with a considerably higher risk of mortality.

Clinical outcomes among cardiogenic shock patients supported with high-capacity Impella axial flow pumps: A report from the Cardiogenic Shock Working Group.

BACKGROUND: The Impella 5.0 and 5.5 pumps (Abiomed, Danvers, MA) are large-bore transvalvular micro-axial assist devices used in cardiogenic shock (CS) for patients requiring high-capacity flow. Despite their increasing use, real-world data regarding indications, rates of utilization and clinical outcomes with this therapy are limited. The objective of our study was to examine clinical profiles and outcomes of patients in a contemporary, real-world CS registry of patients who received an Impella 5.0/5.5 alone or in combination with other temporary mechanical circulatory support (tMCS) devices. METHODS: The CS Working Group (CSWG) Registry includes patients from 34 US hospitals. For this analysis, data from patients who received an Impella 5.0/5.5 between 2020-2023 were analyzed. Use of Impella 5.0/5.5 with or without additional tMCS therapies, duration of support, adverse events and outcomes at hospital discharge were studied. Adverse events including stroke, limb ischemia, bleeding and hemolysis were not standardized by the registry but reported per individual CSWG Primary Investigator discretion. For those who survived, rates of native heart recovery (NHR) or heart replacement therapy (HRT) including heart transplant (HT), or durable ventricular assist device (VAD) were recorded. We also assessed outcomes based on shock etiology (acute myocardial infarction or MI-CS vs. heart failure-related CS or HF-CS). RESULTS: Among 6,205 patients, 754 received an Impella 5.0/5.5 (12.1%), including 210 MI-CS (27.8%) and 484 HF-CS (64.1%) patients. Impella 5.0/5.5 was used as the sole tMCS device in 32% of patients, while 68% of patients received a combination of tMCS devices. Impella cannulation sites were available for 524/754 (69.4%) of patients, with 93.5% axillary configuration. Survival to hospital discharge for those supported with an Impella 5.0/5.5 was 67%, with 20.4% NHR and 45.5% HRT. Compared to HF-CS, patients with MI-CS supported on Impella 5.0/5.5 had higher in-hospital mortality (45.2% vs 26.2%, p < 0.001) and were less likely to receive HRT (22.4% vs 56.6%, p < 0.001. For patients receiving a combination of tMCS during hospitalization, this was associated with higher rates of limb ischemia (9% vs. 3%, p < 0.01), bleeding (52% vs 33%, p < 0.01), and mortality (38% vs 25%; p < 0.001) compared to Impella 5.0/5.5 alone. Among Impella 5.0/5.5 recipients, the median duration of pump support was 12.9 days (IQR: 6.8-22.9) and longer in patients bridged to HRT (14 days; IQR: 7.7-28.4). CONCLUSIONS: In this multi-center cohort of patients with CS, use of Impella 5.0/5.5 was associated with an overall survival of 67.1% and high rates of HRT. Lower adverse event rates were observed when Impella 5.0/5.5 was the sole support device used. Further study is required to determine whether a strategy of early Impella 5.0/5.5 use for CS improves survival. CONDENSED ABSTRACT: High capacity Impella heart pumps are capable of provide up to 5.5 liter/min of flow while upper body surgical placement allows for ambulation. Patients with advanced cardiogenic shock from acute myocardial infarction or heart failure requiring temporary mechanical circulatory support may benefit from upfront use of Impella 5.5 to improve overall survival, including native heart recovery or successful bridge to durable left ventricular assist device surgery or heart transplantation.

CRISPR-Cas Genome Editing in Ex Vivo Human Lungs to Rewire the Translational Path of Genome-Targeting Therapeutics.

The ongoing advancements in CRISPR-Cas technologies can significantly accelerate the preclinical development of both in vivo and ex vivo organ genome-editing therapeutics. One of the promising applications is to genetically modify donor organs prior to implantation. The implantation of optimized donor organs with long-lasting immunomodulatory capacity holds promise for reducing the need for lifelong potent whole-body immunosuppression in recipients. However, assessing genome-targeting interventions in a clinically relevant manner prior to clinical trials remains a major challenge owing to the limited modalities available. This study introduces a novel platform for testing genome editing in human lungs ex vivo, effectively simulating preimplantation genetic engineering of donor organs. We identified gene regulatory elements whose disruption via Cas nucleases led to the upregulation of the immunomodulatory gene interleukin 10 (IL-10). We combined this approach with adenoviral vector-mediated IL-10 delivery to create favorable kinetics for early (immediate postimplantation) graft immunomodulation. Using ex vivo organ machine perfusion and precision-cut tissue slice technology, we demonstrated the feasibility of evaluating CRISPR genome editing in human lungs. To overcome the assessment limitations in ex vivo perfused human organs, we conducted an in vivo rodent study and demonstrated both early gene induction and sustained editing of the lung. Collectively, our findings lay the groundwork for a first-in-human-organ study to overcome the current translational barriers of genome-targeting therapeutics.

RNA/DNA Binding Protein TDP43 Regulates DNA Mismatch Repair Genes with Implications for Genome Stability.

TDP43 is an RNA/DNA binding protein increasingly recognized for its role in neurodegenerative conditions including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). As characterized by its aberrant nuclear export and cytoplasmic aggregation, TDP43 proteinopathy is a hallmark feature in over 95% of ALS/FTD cases, leading to the formation of detrimental cytosolic aggregates and a reduction in nuclear functionality within neurons. Building on our prior work linking TDP43 proteinopathy to the accumulation of DNA double-strand breaks (DSBs) in neurons, the present investigation uncovers a novel regulatory relationship between TDP43 and DNA mismatch repair (MMR) gene expressions. Here, we show that TDP43 depletion or overexpression directly affects the expression of key MMR genes. Alterations include MLH1, MSH2, MSH3, MSH6, and PMS2 levels across various primary cell lines, independent of their proliferative status. Our results specifically establish that TDP43 selectively influences the expression of MLH1 and MSH6 by influencing their alternative transcript splicing patterns and stability. We furthermore find aberrant MMR gene expression is linked to TDP43 proteinopathy in two distinct ALS mouse models and post-mortem brain and spinal cord tissues of ALS patients. Notably, MMR depletion resulted in the partial rescue of TDP43 proteinopathy-induced DNA damage and signaling. Moreover, bioinformatics analysis of the TCGA cancer database reveals significant associations between TDP43 expression, MMR gene expression, and mutational burden across multiple cancers. Collectively, our findings implicate TDP43 as a critical regulator of the MMR pathway and unveil its broad impact on the etiology of both neurodegenerative and neoplastic pathologies.

Identification of Novel Potent NSD2-PWWP1 Ligands Using Structure-Based Design and Computational Approaches.

Dysregulation of histone methyl transferase nuclear receptor-binding SET domain 2 (NSD2) has been implicated in several hematological and solid malignancies. NSD2 is a large multidomain protein that carries histone writing and histone reading functions. To date, identifying inhibitors of the enzymatic activity of NSD2 has proven challenging in terms of potency and SET domain selectivity. Inhibition of the NSD2-PWWP1 domain using small molecules has been considered as an alternative approach to reduce NSD2-unregulated activity. In this article, we present novel computational chemistry approaches, encompassing free energy perturbation coupled to machine learning (FEP/ML) models as well as virtual screening (VS) activities, to identify high-affinity NSD2 PWWP1 binders. Through these activities, we have identified the most potent NSD2-PWWP1 binder reported so far in the literature: compound 34 (pIC50 = 8.2). The compounds identified herein represent useful tools for studying the role of PWWP1 domains for inhibition of human NSD2.

Beta blockers are associated with lower all-cause mortality among HFpEF patients.

BACKGROUND: The evidence regarding beta blocker (BB) benefit in heart failure with preserved ejection fraction (HFpEF) remains inconclusive, leading to consideration of BB withdrawal in this population. OBJECTIVES: In this study, we retrospectively analyzed the association of BB on all-cause mortality in HFpEF patients. METHODS: This is a single-center retrospective cohort study of 20,206 patients with left ventricular ejection fraction (EF) ≥ 50% who were hospitalized with decompensated HF between January 2011 and March 2020. Survival is reported at 30 days, 1 year, and 3 years. A secondary analysis comparing mortality for patients on BB with additional indications including hypertension (HTN), coronary artery disease (CAD), and atrial fibrillation (AF) was completed. Mortality was compared between patients on BB and additional therapies of spironolactone or angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEi/ARBs). RESULTS: BB showed lower all-cause mortality at 30 days, 1 year, and 3 years (p < 0.0001). This association with lower all-cause mortality was validated by a supplementary propensity score-matched analysis. At 3 years, there was significant mortality reduction with addition of BB to either spironolactone (p = 0.0359) or ACEi/ARBs (p < 0.0001). CONCLUSION: In a large single-center retrospective registry, BB use was associated with lower mortality in HFpEF patients with a recent decompensated HF hospitalization. The mortality benefit persisted in those treated with spironolactone or ACEi/ARBs, and in those with AF. This provocative data further highlights the uncertainty of the benefit of BB use in this cohort and calls for re-consideration of BB withdrawal, especially in those tolerating it well, without conclusive, large, and randomized trials showing lack of benefit or harm.

Library Screening, In Vivo Confirmation, and Structural and Bioinformatic Analysis of Pentapeptide Sequences as Substrates for Protein Farnesyltransferase.

Protein farnesylation is a post-translational modification where a 15-carbon farnesyl isoprenoid is appended to the C-terminal end of a protein by farnesyltransferase (FTase). This process often causes proteins to associate with the membrane and participate in signal transduction pathways. The most common substrates of FTase are proteins that have C-terminal tetrapeptide CaaX box sequences where the cysteine is the site of modification. However, recent work has shown that five amino acid sequences can also be recognized, including the pentapeptides CMIIM and CSLMQ. In this work, peptide libraries were initially used to systematically vary the residues in those two parental sequences using an assay based on Matrix Assisted Laser Desorption Ionization-Mass Spectrometry (MALDI-MS). In addition, 192 pentapeptide sequences from the human proteome were screened using that assay to discover additional extended CaaaX-box motifs. Selected hits from that screening effort were rescreened using an in vivo yeast reporter protein assay. The X-ray crystal structure of CMIIM bound to FTase was also solved, showing that the C-terminal tripeptide of that sequence interacted with the enzyme in a similar manner as the C-terminal tripeptide of CVVM, suggesting that the tripeptide comprises a common structural element for substrate recognition in both tetrapeptide and pentapeptide sequences. Molecular dynamics simulation of CMIIM bound to FTase further shed light on the molecular interactions involved, showing that a putative catalytically competent Zn(II)-thiolate species was able to form. Bioinformatic predictions of tetrapeptide (CaaX-box) reactivity correlated well with the reactivity of pentapeptides obtained from in vivo analysis, reinforcing the importance of the C-terminal tripeptide motif. This analysis provides a structural framework for understanding the reactivity of extended CaaaX-box motifs and a method that may be useful for predicting the reactivity of additional FTase substrates bearing CaaaX-box sequences.

Clinical Outcomes Associated With Diltiazem Use in Heart Failure With Reduced Ejection Fraction After Implementation of a Clinical Support System.

BACKGROUND: Despite atrial fibrillation guideline recommendations, many patients with heart failure with reduced ejection fraction (EF) continue to receive IV diltiazem for acute rate control. OBJECTIVE: Our institution recently implemented a clinical decision support system (CDSS)-based tool that recommends against the use of diltiazem in patients with an EF ≤ 40%. The objective of this study was to evaluate outcomes of adherence to the aforementioned CDSS-based tool. METHODS: This multi-hospital, retrospective study assessed patients who triggered the CDSS alert and compared those who did and did not discontinue diltiazem. The primary outcome was the occurrence of clinical deterioration. The primary endpoint was compared utilizing a Fisher's Exact Test, and a multivariate logistic regression model was developed to confirm the results of the primary analysis. RESULTS: A total of 246 patients were included in this study with 146 patients in the nonadherent group (received diltiazem) and 100 patients in the adherent group (did not receive diltiazem). There was a higher proportion of patients experiencing clinical deterioration in the alert nonadherence group (33% vs 21%, P = 0.044), including increased utilization of inotropes and vasopressors, and higher rate of transfer to ICU. CONCLUSION AND RELEVANCE: In patients with heart failure with reduced EF, diltiazem use after nonadherence to a CDSS alert resulted in an increased risk of clinical deterioration. This study highlights the need for improved provider adherence to diltiazem clinical decision support systems.

Appropriateness of Ophthalmology Recommendations From an Online Chat-Based Artificial Intelligence Model.

Objective: To determine the appropriateness of ophthalmology recommendations from an online chat-based artificial intelligence model to ophthalmology questions. Patients and Methods: Cross-sectional qualitative study from April 1, 2023, to April 30, 2023. A total of 192 questions were generated spanning all ophthalmic subspecialties. Each question was posed to a large language model (LLM) 3 times. The responses were graded by appropriate subspecialists as appropriate, inappropriate, or unreliable in 2 grading contexts. The first grading context was if the information was presented on a patient information site. The second was an LLM-generated draft response to patient queries sent by the electronic medical record (EMR). Appropriate was defined as accurate and specific enough to serve as a surrogate for physician-approved information. Main outcome measure was percentage of appropriate responses per subspecialty. Results: For patient information site-related questions, the LLM provided an overall average of 79% appropriate responses. Variable rates of average appropriateness were observed across ophthalmic subspecialties for patient information site information ranging from 56% to 100%: cataract or refractive (92%), cornea (56%), glaucoma (72%), neuro-ophthalmology (67%), oculoplastic or orbital surgery (80%), ocular oncology (100%), pediatrics (89%), vitreoretinal diseases (86%), and uveitis (65%). For draft responses to patient questions via EMR, the LLM provided an overall average of 74% appropriate responses and varied by subspecialty: cataract or refractive (85%), cornea (54%), glaucoma (77%), neuro-ophthalmology (63%), oculoplastic or orbital surgery (62%), ocular oncology (90%), pediatrics (94%), vitreoretinal diseases (88%), and uveitis (55%). Stratifying grades across health information categories (disease and condition, risk and prevention, surgery-related, and treatment and management) showed notable but insignificant variations, with disease and condition often rated highest (72% and 69%) for appropriateness and surgery-related (55% and 51%) lowest, in both contexts. Conclusion: This LLM reported mostly appropriate responses across multiple ophthalmology subspecialties in the context of both patient information sites and EMR-related responses to patient questions. Current LLM offerings require optimization and improvement before widespread clinical use.

A novel simulated media system for in vitro evaluation of bioequivalent intestinal drug solubility.

Orally administered solid drug must dissolve in the gastrointestinal tract before absorption to provide a systemic response. Intestinal solubility is therefore crucial but difficult to measure since human intestinal fluid (HIF) is challenging to obtain, varies between fasted (Fa) and fed (Fe) states and exhibits inter and intra subject variability. A single simulated intestinal fluid (SIF) cannot reflect HIF variability, therefore current approaches are not optimal. In this study we have compared literature Fa/FeHIF drug solubilities to values measured in a novel in vitro simulated nine media system for either the fasted (Fa9SIF) or fed (Fe9SIF) state. The manuscript contains 129 literature sampled human intestinal fluid equilibrium solubility values and 387 simulated intestinal fluid equilibrium solubility values. Statistical comparison does not detect a difference (Fa/Fe9SIF vs Fa/FeHIF), a novel solubility correlation window enclosed 95% of an additional literature Fa/FeHIF data set and solubility behaviour is consistent with previous physicochemical studies. The Fa/Fe9SIF system therefore represents a novel in vitro methodology for bioequivalent intestinal solubility determination. Combined with intestinal permeability this provides an improved, population based, biopharmaceutical assessment that guides formulation development and indicates the presence of food based solubility effects. This transforms predictive ability during drug discovery and development and may represent a methodology applicable to other multicomponent fluids where no single component is responsible for performance.

Exploring attitudinal barriers to participation in inpatient fall risk assessment using the Theoretical Domains Framework: A survey of providers.

Background and Aims: Lack of provider (physicians and advanced practice providers) participation in fall risk assessment was theorized to be contributing to rising rates of falls with injury at our institution. This project sought to identify if attitudinal barriers to inpatient provider participation in fall risk assessment were similar to those identified in other clinical settings. Methods: Barriers to provider participation in fall risk assessment were identified in the literature. These were mapped to the Theoretical Domains Framework (TDF) domains to assist with interpretation of the data. A 10-item survey using a 5-point Likert scale (strongly agree to strongly disagree) with two open-ended questions was developed using these barriers. The survey was distributed via email to all providers on the Medical Staff in July 2021. Results: The response rate was 9.1% (188/2062). 72.6% (95% confidence interval [CI]: 65.6, 78.5) of providers at our institution did agree that fall risk assessment was within their role and 72% (95% CI: 66.1, 78.5) agreed that assessment can prevent falls. Nearly half felt that they lacked formal training in fall risk assessment (48.1% [95% CI: 41.1, 55.1]) and 52.2% (95% CI: 44.6, 58.6) agreed that other aspects of patient care took priority over falls assessment. These barriers correlated best with the TDF domains of Beliefs about Capabilities and Beliefs about Consequences. Conclusions: Survey results indicate that interventions focused on increasing provider motivation and capability regarding fall risk assessment and helping providers prioritize fall risk assessment are potential targets for future quality improvement projects.

A Canadian Simulation Model for Major Depressive Disorder: Study Protocol.

BACKGROUND: Major depressive disorder (MDD) is a common, often recurrent condition and a significant driver of healthcare costs. People with MDD often receive pharmacological therapy as the first-line treatment, but the majority of people require more than one medication trial to find one that relieves symptoms without causing intolerable side effects. There is an acute need for more effective interventions to improve patients' remission and quality of life and reduce the condition's economic burden on the healthcare system. Pharmacogenomic (PGx) testing could deliver these objectives, using genomic information to guide prescribing decisions. With an already complex and multifaceted care pathway for MDD, future evaluations of new treatment options require a flexible analytic infrastructure encompassing the entire care pathway. Individual-level simulation models are ideally suited for this purpose. We sought to develop an economic simulation model to assess the effectiveness and cost effectiveness of PGx testing for individuals with major depression. Additionally, the model serves as an analytic infrastructure, simulating the entire patient pathway for those with MDD. METHODS AND ANALYSIS: Key stakeholders, including patient partners, clinical experts, researchers, and modelers, designed and developed a discrete-time microsimulation model of the clinical pathways of adults with MDD in British Columbia (BC), including all publicly-funded treatment options and multiple treatment steps. The Simulation Model of Major Depression (SiMMDep) was coded with a modular approach to enhance flexibility. The model was populated using multiple original data analyses conducted with BC administrative data, a systematic review, and an expert panel. The model accommodates newly diagnosed and prevalent adult patients with MDD in BC, with and without PGx-guided treatment. SiMMDep comprises over 1500 parameters in eight modules: entry cohort, demographics, disease progression, treatment, adverse events, hospitalization, costs and quality-adjusted life-years (payoff), and mortality. The model predicts health outcomes and estimates costs from a health system perspective. In addition, the model can incorporate interactive decision nodes to address different implementation strategies for PGx testing (or other interventions) along the clinical pathway. We conducted various forms of model validation (face, internal, and cross-validity) to ensure the correct functioning and expected results of SiMMDep. CONCLUSION: SiMMDep is Canada's first medication-specific, discrete-time microsimulation model for the treatment of MDD. With patient partner collaboration guiding its development, it incorporates realistic care journeys. SiMMDep synthesizes existing information and incorporates provincially-specific data to predict the benefits and costs associated with PGx testing. These predictions estimate the effectiveness, cost-effectiveness, resource utilization, and health gains of PGx testing compared with the current standard of care. However, the flexible analytic infrastructure can be adapted to support other policy questions and facilitate the rapid synthesis of new data for a broader search for efficiency improvements in the clinical field of depression.

Long-Term Blood Pressure Reductions Following Catheter-Based Renal Denervation: A Systematic Review and Meta-Analysis.

BACKGROUND: Renal denervation is a recognized adjunct therapy for hypertension with clinically significant blood pressure (BP)-lowering effects. Long-term follow-up data are critical to ascertain durability of the effect and safety. Aside from the 36-month follow-up data available from randomized control trials, recent cohort analyses extended follow-up out to 10 years. We sought to analyze study-level data and quantify the ambulatory BP reduction of renal denervation across contemporary randomized sham-controlled trials and available long-term follow-up data up to 10 years from observational studies. METHODS: A systematic review was performed with data from 4 observational studies with follow-up out to 10 years and 2 randomized controlled trials meeting search and inclusion criteria with follow-up data out to 36 months. Study-level data were extracted and compared statistically. RESULTS: In 2 contemporary randomized controlled trials with 36-month follow-up, an average sham-adjusted ambulatory systolic BP reduction of -12.7±4.5 mm Hg from baseline was observed (P=0.05). Likewise, a -14.8±3.4 mm Hg ambulatory systolic BP reduction was found across observational studies with a mean long-term follow-up of 7.7±2.8 years (range, 3.5-9.4 years; P=0.0051). The observed reduction in estimated glomerular filtration rate across the long-term follow-up was in line with the predicted age-related decline. Antihypertensive drug burden was similar at baseline and follow-up. CONCLUSIONS: Renal denervation is associated with a significant and clinically meaningful reduction in ambulatory systolic BP in both contemporary randomized sham-controlled trials up to 36 months and observational cohort studies up to 10 years without adverse consequences on renal function.

Outcomes of Impella 5.0 and 5.5 for cardiogenic shock: A single-center 137 patient experience.

BACKGROUND: This study evaluated the outcomes of patients with cardiogenic shock (CS) supported with Impella 5.0 or 5.5 and identified risk factors for in-hospital mortality. METHODS: Adults with CS who were supported with Impella 5.0 or 5.5 at a single institution were included. Patients were stratified into three groups according to their CS etiology: (1) acute myocardial infarction (AMI), (2) acute decompensated heart failure (ADHF), and (3) postcardiotomy (PC). The primary outcome was survival, and secondary outcomes included adverse events during Impella support and length of stay. Multivariable logistic regression was performed to identify risk factors for in-hospital mortality. RESULTS: One hundred and thirty-seven patients with CS secondary to AMI (n = 47), ADHF (n = 86), and PC (n = 4) were included. The ADHF group had the highest survival rates at all time points. Acute kidney injury (AKI) was the most common complication during Impella support in all 3 groups. Increased rates of AKI and de novo renal replacement therapy were observed in the PC group, and the AMI group experienced a higher incidence of bleeding requiring transfusion. Multivariable analysis demonstrated diabetes mellitus, elevated pre-insertion serum lactate, and elevated pre-insertion serum creatinine were independent predictors of in-hospital mortality, but the etiology of CS did not impact mortality. CONCLUSIONS: This study demonstrates that Impella 5.0 and 5.5 provide effective mechanical support for patients with CS with favorable outcomes, with nearly two-thirds of patients alive at 180 days. Diabetes, elevated pre-insertion serum lactate, and elevated pre-insertion serum creatinine are strong risk factors for in-hospital mortality.

Concomitant use of extracorporeal membrane oxygenation and percutaneous microaxial assist device support for cardiogenic shock.

Objectives: Venoarterial extracorporeal membrane oxygenation (VA-ECMO) with concomitant percutaneous microaxial left ventricular assist device support is an emerging treatment modality for cardiogenic shock (CS). Survival outcomes by CS etiology with this support strategy have not been well described. Methods: This study was a retrospective, single-center analysis of patients with CS due to acute myocardial infarction (AMI-CS) or decompensated heart failure (ADHF-CS) supported with VA-ECMO with concomitant percutaneous microaxial left ventricular assist device support from December 2020 to January 2023. Results: A total of 44 patients were included (AMI-CS, n = 20, and ADHF-CS, n = 24). Patients with AMI-CS and ADHF-CS had similar survival at 90 days postdischarge (P = .267) with similar destinations after support (P = .220). Patients with AMI-CS initially supported with VA-ECMO were less likely to survive 90 days postdischarge (P = .038) when compared with other cohorts. Limb ischemia and acute kidney injury occurred more frequently in patients presenting with AMI-CS (P =.013; P = .030). Subanalysis of ADHF-CS patients into acute-on-chronic decompensated HF and de novo HF demonstrated no difference in survival or destination. Conclusions: VA-ECMO with concomitant percutaneous microaxial left ventricular assist device support can be used to successfully manage patients with CS. There is no difference in survival or destination for AMI-CS and ADHF-CS with this support strategy. AMI-CS patients with initial VA-ECMO support have increased mortality in comparison to other cohorts. Future multicenter studies are required to fully analyze the differences between AMI-CS and ADHF-CS with this support strategy.

Permanent ocular remodeling in the setting of chronic hypotony after trabeculectomy: A case report.

Purpose: Trabeculectomy surgery is a commonly performed procedure for treatment of glaucoma. While the goal is to lower intraocular pressure, over-filtration may cause hypotony with ocular structural changes and vision loss. Observations: A 53-year-old woman with primary open-angle glaucoma was referred to our service for further evaluation. The patient previously underwent trabeculectomy 9 years prior and was found to have a cataract and hypotony maculopathy in the right eye. Treatment options included cataract surgery alone, bleb revision alone, or combined cataract extraction and bleb revision. Biometry revealed corneal astigmatism in the right eye, and significant disparity in axial length between the two eyes. Since the axial length and corneal astigmatic changes were presumed to be at least partially reversible, measurements from the non-operative left eye influenced the lens selection for the hypotonous right eye. The patient underwent combined phacoemulsification and bleb revision. While IOP increased and hypotony was partly reversed, there was hyperopic and astigmatic refractive surprise after surgery.The patient subsequently underwent intraocular lens exchange using biometric values of the previously hypotonous eye and met the target post-operative refractive goal. Conclusions and importance: This case demonstrates changes to the axial length and ocular structure following longstanding hypotony maculopathy may be permanent, even after restoration of normotensive intraocular pressure.

Oligourea helix bundle binds detergents with diverse polar head groups.

Here we report a series of crystal structures (and accompanying biophysical data) of an array of diverse detergent guests bound to an oligourea foldamer helix bundle. These results significantly increase our structural and chemical understanding of aqueous guest recognition by oligourea foldamers and will aid the design of further functionalised oligourea-based self-assemblies.

Screening Ultra-Large Encoded Compound Libraries Leads to Novel Protein-Ligand Interactions and High Selectivity.

The DNA-encoded library (DEL) discovery platform has emerged as a powerful technology for hit identification in recent years. It has become one of the major parallel workstreams for small molecule drug discovery along with other strategies such as HTS and data mining. For many researchers working in the DEL field, it has become increasingly evident that many hits and leads discovered via DEL screening bind to target proteins with unique and unprecedented binding modes. This Perspective is our attempt to analyze reports of DEL screening with the purpose of providing a rigorous and useful account of the binding modes observed for DEL-derived ligands with a focus on binding mode novelty.

Salt sensitivity risk derived from nocturnal dipping and 24-h heart rate predicts long-term blood pressure reduction following renal denervation.

BACKGROUND: Renal denervation (RDN) has been consistently shown in recent sham-controlled clinical trials to reduce blood pressure (BP). Salt sensitivity is a critical factor in hypertension pathogenesis, but cumbersome to assess by gold-standard methodology. Twenty-four-hour average heart rate (HR) and mean arterial pressure (MAP) dipping, taken by ambulatory blood pressure monitoring (ABPM), stratifies patients into high, moderate, and low salt sensitivity index (SSI) risk categories. OBJECTIVES: We aimed to assess whether ABPM-derived SSI risk could predict the systolic blood pressure reduction at long-term follow-up in a real-world RDN patient cohort. METHODS: Sixty participants had repeat ABPM as part of a renal denervation long-term follow-up. Average time since RDN was 8.9 ±â€Š1.2 years. Based on baseline ABPM, participants were stratified into low (HR < 70 bpm and MAP dipping > 10%), moderate (HR ≥70 bpm or MAP dipping ≤ 10%), and high (HR ≥ 70 bpm and MAP dipping ≤ 10%) SSI risk groups, respectively. RESULTS: One-way ANOVA indicated a significant treatment effect ( P  = 0.03) between low ( n  = 15), moderate ( n  = 35), and high ( n  = 10) SSI risk with systolic BP reduction of 9.6 ±â€Š3.7 mmHg, 8.4 ±â€Š3.5 mmHg, and 28.2 ±â€Š9.6 mmHg, respectively. Baseline BP was not significantly different between SSI Risk groups ( P  = 0.18). High SSI risk independently correlated with systolic BP reduction ( P  = 0.02). CONCLUSIONS: Our investigation indicates that SSI risk may be a simple and accessible measure for predicting the BP response to RDN. However, the influence of pharmacological therapy on these participants is an important extraneous variable requiring testing in prospective or drug naive RDN cohorts.