The BTLA-HVEM axis restricts CAR T cell efficacy in cancer.

The efficacy of T cell-based immunotherapies is limited by immunosuppressive pressures in the tumor microenvironment. Here we show a predominant role for the interaction between BTLA on effector T cells and HVEM (TNFRSF14) on immunosuppressive tumor microenvironment cells, namely regulatory T cells. High BTLA expression in chimeric antigen receptor (CAR) T cells correlated with poor clinical response to treatment. Therefore, we deleted BTLA in CAR T cells and show improved tumor control and persistence in models of lymphoma and solid malignancies. Mechanistically, BTLA inhibits CAR T cells via recruitment of tyrosine phosphatases SHP-1 and SHP-2, upon trans engagement with HVEM. BTLA knockout thus promotes CAR signaling and subsequently enhances effector function. Overall, these data indicate that the BTLA-HVEM axis is a crucial immune checkpoint in CAR T cell immunotherapy and warrants the use of strategies to overcome this barrier.

Streamlined measurement of chimeric antigen receptor T-cell concentration, size, viability and two-color phenotyping during manufacturing.

BACKGROUND AIMS: The successful development of CD19-targeted chimeric antigen receptor (CAR) T-cell therapies has led to an exponential increase in the number of patients recieving treatment and the advancement of novel CAR T products. Therefore, there is a strong need to develop streamlined platforms that allow rapid, cost-effective, and accurate measurement of the key characteristics of CAR T cells during manufacturing (i.e., cell number, cell size, viability, and basic phenotype). METHODS: In this study, we compared the novel benchtop cell analyzer Moxi GO II (ORFLO Technologies), which enables simultaneous evaluation of all the aforementioned parameters, with current gold standards in the field: the Multisizer Coulter Counter (cell counter) and the BD LSRFortessa (flow cytometer). RESULTS: Our results demonstrated that the Moxi GO II can accurately measure cell number and cell size (i.e., cell volume) while simultaneously assessing simple two-color flow cytometry parameters, such as CAR T-cell viability and CD4 or CAR expression. CONCLUSIONS: These measurements are comparable with those of gold standard instruments, demonstrating that the Moxi GO II is a promising platform for quickly monitoring CAR T-cell growth and phenotype in research-grade and clinical samples.

Interfacial Activity and Surface pKa of Perfluoroalkyl Carboxylic Acids (PFCAs).

Perfluoroalkyl carboxylic acids (PFCAs) are widely used synthetic chemicals that are known for their exceptional stability and interfacial activity. Despite their industrial and environmental significance, discrepancies exist in the reported pKa values for PFCAs, often spanning three to four units. These disparities stem from an incomplete understanding of how pH influences the ionized state of PFCA molecules in the bulk solution and at the air-water interface. Using pH titration and surface tension measurements, we show that the pKa values of the PFCAs adsorbed at the air-water interface differ from the bulk. Below the equivalence point, the undissociated and dissociated forms of the PFCAs exist in equilibrium, driving to the spontaneous adsorption and reduced air-water surface tension. Conversely, above the equivalence point, the complete ionization of the headgroup into the carboxylate form renders PFCAs highly hydrophilic, resulting in reduced interfacial activity of the molecules. The distinction in the chemical environments at the interface and bulk results in differences in the pKa of PFCA molecules in the bulk phase and at the air-water interface. We explore the effects of the fluoroalkyl tail length of PFCAs on their surface pKa and interfacial activity across a broad pH range. We further demonstrate the influence of pH-dependent ionized state of PFCAs on their foamability and the rate of microdroplet evaporation, understanding of which is crucial for optimizing their industrial applications and developing effective strategies for their environmental remediation. This study underscores the potential significance of pH in directing the interfacial activity of PFCAs and prompts the inclusion of pH as a key determinant in the predictions of their fate and potential risks in the environment.

Safety and efficacy of a novel anti-CD19 chimeric antigen receptor T cell product targeting a membrane-proximal domain of CD19 with fast on- and off-rates against non-Hodgkin lymphoma: a first-in-human study.

BACKGROUND: Commercial anti-CD19 chimeric antigen receptor T-cell therapies (CART19) are efficacious against advanced B-cell non-Hodgkin lymphoma (NHL); however, most patients ultimately relapse. Several mechanisms contribute to this failure, including CD19-negative escape and CAR T dysfunction. All four commercial CART19 products utilize the FMC63 single-chain variable fragment (scFv) specific to a CD19 membrane-distal epitope and characterized by slow association (on) and dissociation (off) rates. We hypothesized that a novel anti-CD19 scFv that engages an alternative CD19 membrane-proximal epitope independent of FMC63 and that is characterized by faster on- and off-rates could mitigate CART19 failure and improve clinical efficacy. METHODS: We developed an autologous CART19 product with 4-1BB co-stimulation using a novel humanized chicken antibody (h1218). This antibody is specific to a membrane-proximal CD19 epitope and harbors faster on/off rates compared to FMC63. We tested h1218-CART19 in vitro and in vivo using FMC63-CART19-resistant models. We conducted a first-in-human multi-center phase I clinical trial to test AT101 (clinical-grade h1218-CART19) in patients with relapsed or refractory (r/r) NHL. RESULTS: Preclinically, h1218- but not FMC63-CART19 were able to effectively eradicate lymphomas expressing CD19 point mutations (L174V and R163L) or co-expressing FMC63-CAR19 as found in patients relapsing after FMC63-CART19. Furthermore, h1218-CART19 exhibited enhanced killing of B-cell malignancies in vitro and in vivo compared with FMC63-CART19. Mechanistically, we found that h1218-CART19 had reduced activation-induced cell death (AICD) and enhanced expansion compared to FMC63-CART19 owing to faster on- and off-rates. Based on these preclinical results, we performed a phase I dose-escalation trial, testing three dose levels (DL) of AT101 (the GMP version of h1218) using a 3 + 3 design. In 12 treated patients (7 DLBCL, 3 FL, 1 MCL, and 1 MZL), AT101 showed a promising safety profile with 8.3% grade 3 CRS (n = 1) and 8.3% grade 4 ICANS (n = 1). In the whole cohort, the overall response rate was 91.7%, with a complete response rate of 75.0%, which improved to 100% in DL-2 and -3. AT101 expansion correlates with CR and B-cell aplasia. CONCLUSIONS: We developed a novel, safe, and potent CART19 product that recognizes a membrane-proximal domain of CD19 with fast on- and off-rates and showed significant efficacy and promising safety in patients with relapsed B-cell NHL. TRIAL REGISTRATION: NCT05338931; Date: 2022-04-01.

Allergic Polysensitization Clusters: Newly Recognized Severity Marker in Urban Asthmatic Adults.

INTRODUCTION: While reliable, quantitative in vitro testing for sensitivity to aeroallergens has been available for decades, such information has largely been ignored in clustering analyses of asthma. Our aim is to explore allergic polysensitization as a possible marker of asthma severity and, as such, to be considered as an integral marker in future asthma clustering analyses. METHODS: We constructed a database of sensitizations to the 25 aeroallergens in our geographic area (zone 1, Northeastern US) using the ImmunoCAP® in vitro assay. We used the Scikit-Learn® machine learning library for model-based clustering to identify allergic polysensitization clusters. Clusters were compared for differences in common office-based clinical markers of asthma. RESULTS: The database consisted of 509 patients. Unbiased machine learning identified ten clusters of increasing allergic polysensitization of varying sizes (n = 1-339) characterized by significant increases in mean serum immunoglobulin E (p < 0.001), peripheral blood eosinophil count (p < 0.001), and DLCO (p = 0.02). There was a significant decline in mean age at presentation (p < 0.001), FEV1/FVC (p = 0.01), and FEF25-75 (p = 0.002) with increasing allergic polysensitization. Finally, we identified two divergent paths for the poly-atopic march, one driven by perennial and the other by seasonal allergens. CONCLUSION: This pilot study showed that allergic polysensitization, using readily available qualitative and quantitative in vitro sensitization data, largely ignored in cluster analyses to date, may add further clinical precision in cluster analyses of asthma. We suggest the methods used here can be applied and tested using larger databases and aeroallergens present in diverse geographic regions.

Cardiac risk stratification of breast cancer patients in a cardio-oncology clinic.

PURPOSE: The field of cardio-oncology aims to optimize the cardiac health of cancer patients. The goals of this study are to (1) describe the demographics of a cardio-oncology clinic and (2) apply the American Society of Clinical Oncology (ASCO) cardiac risk stratification guidelines among breast cancer patients to assess the development of cardiovascular events, primarily heart failure (HF). METHODS: We performed a retrospective chart review on 203 consecutive cardio-oncology patients who were seen between January 2019 and March 2020. Mean follow-up for the cohort was 29.2 ± 3.1 months (range 0-113). We applied the ASCO guidelines to the breast cancer subgroup. RESULTS: The plurality of patients 82/203 (40%) referred to clinic had breast cancer. The most common reason for referral was asymptomatic left ventricular (LV) dysfunction or HF (40%). Only 36/203 (18%) of patients were referred for a pre-chemotherapy evaluation. In breast cancer patients, there was a trend toward significance in up-titrating or initiating beta-blockers in the high vs. low risk ASCO groups [46/69 (67%) vs. 5/13 (38%), p = 0.054]. Approximately 13/82 (16%) of breast cancer patients required alterations to their anti-cancer therapy. HF events occurred in 1/36 (3%) of cancer treatment naïve patients and 14/167 (8%) of those with prior therapy, specifically 9% of the breast cancer subset. CONCLUSION: Our study provides insight into referral practices, interventions, and outcomes at a cardio-oncology clinic. Furthermore, breast cancer patients continue to have high rates of HF. These findings suggest a need to shift referral practices upstream for a pre-chemotherapy evaluation to optimize cardiovascular health.

Changes in the Activity Measure for Post-Acute Care Domains in Persons With Stroke During the First Year After Discharge From Inpatient Rehabilitation.

OBJECTIVE: To describe functional changes after inpatient stroke rehabilitation using the Activity Measure for Post-Acute Care (AM-PAC), an assessment measure sensitive to change and with a low risk of ceiling effect. DESIGN: Retrospective, longitudinal cohort study. SETTING: Inpatient rehabilitation unit of an urban academic medical center. PARTICIPANTS: Among 433 patients with stroke admitted from 2012-2016, a total of 269 (62%) were included in our database and 89 of 269 patients (33.1%) discharged from inpatient stroke rehabilitation had complete data. Patients with and without complete data were very similar. The group had a mean age of 68.0±14.2 years, National Institutes of Health Stroke Score of 8.0±8.0, and rehabilitation length of stay of 14.7±7.4 days, with 84% having an ischemic stroke and 22.5% having a recurrent stroke. INTERVENTION: None. MAIN OUTCOME MEASURES: Changes in function across the first year after discharge (DC) were measured in a variety of ways. Continuous mean scores for the basic mobility (BM), daily activity (DA), and applied cognitive domains of the AM-PAC were calculated at and compared between inpatient DC and 6 (6M) and 12 months (12M) post DC. Categorical changes among individuals were classified as "improved," "unchanged," or "declined" between the 3 time points based on the minimal detectable change, (estimated) minimal clinically important difference, and a change ≥1 AM-PAC functional stage (FS). RESULTS: For the continuous analyses, the Friedman test was significant for all domains (P≤.002), with Wilcoxon signed-rank test significant for all domains from DC to 6M (all P<.001) but with no change in BM and DA between 6M and 12M (P>.60) and a decline in applied cognition (P=.002). Despite group improvements from DC to 6M, for categorical changes at an individual level 10%-20% declined and 50%-70% were unchanged. Despite insignificant group differences from 6M-12M, 15%-25% improved and 20%-30% declined in the BM and DA domains. CONCLUSIONS: Despite group gains from DC to 6M and an apparent "plateau" after 6M post stroke, there was substantial heterogeneity at an individual level. Our results underscore the need to consider individual-level outcomes when evaluating progress or outcomes in stroke rehabilitation.

Targeting mitochondrial hexokinases increases efficacy of histone deacetylase inhibitors in solid tumor models.

Hexokinase 1 and 2 have been shown to inhibit Bak- and Bax-mediated apoptosis, leading us to combine the histone deacetylase inhibitor romidepsin with clotrimazole or bifonazole, two compounds that reportedly decrease mitochondrial localization of hexokinases. Cancer cell lines derived from breast, kidney, lung, colon or ovarian cancers were treated with a short-term exposure to 25 ng/ml romidepsin combined with either clotrimazole or bifonazole. The combination of romidepsin with 25 µM clotrimazole or bifonazole resulted in increased annexin staining compared to cells treated with any of the drugs alone. Cell death was caspase-mediated, as the pan-caspase inhibitor Q-VD-OPh was found to inhibit apoptosis induced by the combination. A549 lung cancer cells or HCT-116 cells deficient in Bak and Bax were also resistant to apoptosis with the combination implicating the intrinsic apoptotic pathway. We found that a 24 h treatment with clotrimazole or bifonazole decreased total hexokinase 2 expression, resulting in a 76% or 60% decrease, respectively, of mitochondrial expression of hexokinase 2. Mitochondrial hexokinase 1 levels increased 2-fold or less. Our work suggests that the combination of a short-term romidepsin treatment with bifonazole or clotrimazole leads to increased apoptosis, most likely due to decreased mitochondrial expression of hexokinase 2.

Longitudinal profiling of the lung microbiome in the AERIS study demonstrates repeatability of bacterial and eosinophilic COPD exacerbations.

BACKGROUND: Alterations in the composition of the lung microbiome associated with adverse clinical outcomes, known as dysbiosis, have been implicated with disease severity and exacerbations in COPD. OBJECTIVE: To characterise longitudinal changes in the lung microbiome in the AERIS study (Acute Exacerbation and Respiratory InfectionS in COPD) and their relationship with associated COPD outcomes. METHODS: We surveyed 584 sputum samples from 101 patients with COPD to analyse the lung microbiome at both stable and exacerbation time points over 1 year using high-throughput sequencing of the 16S ribosomal RNA gene. We incorporated additional lung microbiology, blood markers and in-depth clinical assessments to classify COPD phenotypes. RESULTS: The stability of the lung microbiome over time was more likely to be decreased in exacerbations and within individuals with higher exacerbation frequencies. Analysis of exacerbation phenotypes using a Markov chain model revealed that bacterial and eosinophilic exacerbations were more likely to be repeated in subsequent exacerbations within a subject, whereas viral exacerbations were not more likely to be repeated. We also confirmed the association of bacterial genera, including Haemophilus and Moraxella, with disease severity, exacerbation events and bronchiectasis. CONCLUSIONS: Subtypes of COPD have distinct bacterial compositions and stabilities over time. Some exacerbation subtypes have non-random probabilities of repeating those subtypes in the future. This study provides insights pertaining to the identification of bacterial targets in the lung and biomarkers to classify COPD subtypes and to determine appropriate treatments for the patient. TRIAL REGISTRATION NUMBER: Results, NCT01360398.

Management of post-myocardial infarction ventricular septal defects: A critical assessment.

BACKGROUND: Post-myocardial infarction (MI) ventricular septal defects (PIVSD) are an uncommon but life-threatening complication of acute MI. Although surgical closure has been the standard of care, mortality, and recurrence of VSD remain high even after emergent surgery. Transcatheter VSD closure (TCC) devices have become an alternative or adjunct to surgical closure. METHODS: Online database search was performed for studies that included adults with PIVSD who underwent medical treatment (MT) alone, surgical closure (SC) (early or late), and TCC (early, late, or for post-surgical residual VSD). RESULTS: Twenty-six studies were included with a total of 737 patients who underwent either MT (N = 100), SC (early (n = 167), late (n = 100)), and TCC (early (n = 176), late (n = 115), or post-surgical residual VSD (n = 79)). The 30-day mortality among MT group was 92 ± 6.3%, among SC was 61 ± 22.5% (early 56 ± 23%, late 41 ± 30%), and for all TCC patients was 33 ± 24% (early 54 ± 32.7%, late 16 ± 26%), and TCC for post-surgical residual VSD 11 ± 34.9%. The mortality among overall SC, overall TCC and early TCC groups was significantly lower as compared with the MT (P < 0.001 for all comparisons). The overall mortality among all TCC, and late TCC groups was significantly lower when compared with the late SC (P < 0.0001, P < 0.0001, respectively). CONCLUSION: Closure of PIVSD decreases mortality as compared with MT alone and should be attempted as early as possible after diagnosis. Selection of TCC versus SC should be based on factors including complexity of the defect, availability of closure devices, expertise of the operator, and clinical condition of patient.

Evaluation of direct oral anticoagulants for the treatment of venous thromboembolism in the oncology population.

Direct oral anticoagulants (DOACs) have become an attractive option for the treatment of venous thromboembolism (VTE) in cancer patients. However, their use is currently not recommended as first-line treatment by national guidelines due to limited data in this patient population. The objective of this study was to evaluate the practice and safety patterns of DOACs when used for VTE treatment in the oncology population. This study was a retrospective chart review of adult cancer patients treated at Hackensack University Medical Center from January 2013 to October 2015 who received dabigatran, rivaroxaban, or apixaban for VTE treatment. Of 126 patients screened, 39 patients were included. Thirty-five patients received rivaroxaban and four patients received apixaban. Ten of 39 patients (26%) were not receiving a DOAC dosage consistent with the package insert. No patients experienced clinically significant bleeding, while four patients experienced a minor bleed. Four of 14 thrombocytopenic patients (29%) did not have their DOAC dose held for thrombocytopenia. All patients had their DOACs appropriately held for procedures. Increased education on dosing DOACs according to the package insert is warranted for oncology prescribers. Despite the increased risk for bleeding in cancer patients, no clinically significant bleeding events were identified in our patient cohort. This data suggests that the use of DOACs may be safe to use for VTE treatment in cancer patients and may provide foundation for larger, randomized controlled trials to determine whether DOACs should be used for VTE treatment in cancer patients.

Vancomycin-resistant enterococcal bacteremia pharmacotherapy.

OBJECTIVE: To review the literature on the pharmacotherapy of bloodstream infections (BSI) caused by vancomycin-resistant enterococci (VRE). DATA SOURCES: A MEDLINE literature search was performed for the period 1946 to May 2014 using the search terms Enterococcus, enterococci, vancomycin-resistant, VRE, bacteremia, and bloodstream infection. References were also identified from selected review articles. STUDY SELECTION AND DATA EXTRACTION: English-language case series, cohort studies, and meta-analyses assessing the options in the pharmacotherapy of VRE BSIs in adult patients were evaluated. DATA SYNTHESIS: Studies were identified that utilized linezolid, quinupristin/dalfopristin (Q/D), and daptomycin. In all, 8 comparative retrospective cohort studies, 2 meta-analyses of daptomycin and linezolid, and 3 retrospective comparisons of linezolid and Q/D were included for review. Mortality associated with VRE BSIs was high across studies, and the ability to determine differences in outcomes between agents was confounded by the complex nature of the patients included. Two meta-analyses comparing daptomycin with linezolid for VRE BSIs found modest advantages for linezolid, but these conclusions may be hampered by heterogeneity within the included studies. CONCLUSIONS: VRE BSIs remain a difficult-to-treat clinical situation. Differences in toxicity between the agents used to treat it are clear, but therapeutic differences are more difficult to discern. Meta-analyses suggest that a moderate advantage for linezolid over daptomycin may exist, but problems with the nature of studies that they included make definitive conclusions difficult.

Barotrauma: Tooth under Pressure.

With the growing number of air passengers, flight attendants, leisure pilots, as well as military and airline pilots, dentists may encounter physiological and pathological phenomena precipitated by high altitude. With the introduction of the self-contained breathing apparatus (SCUBA), many of these manifestations caused by changes in atmospheric pressure were reported in association with diving as well. Limited literature exists on this subject. Hence, this article aims to review literature concerning the classification, etiology and manifestations of barodontalgia, as well as important clinical considerations for its management.

Barotrauma: Tooth Under Pressure.

With the growing number of air passengers, flight attendants, leisure pilots, as well as military and airline pilots, dentists may encounter physiological and pathological phenomena precipitated by high altitude. With the introduction of the self-contained breathing apparatus (SCUBA), many of these manifestations caused by changes in atmospheric pressure were reported in association with diving as well. Limited literature exists on this subject. Hence, this article aims to review literature concerning the classification, etiology and manifestations of barodontalgia, as well as important clinical considerations for its management.

Antimicrobial and antibiofilm potential of biosurfactants isolated from lactobacilli against multi-drug-resistant pathogens.

BACKGROUND: Biosurfactants (BS) are amphiphilic compounds produced by microbes, either on the cell surface or secreted extracellularly. BS exhibit strong antimicrobial and anti-adhesive properties, making them good candidates for applications used to combat infections. In this study, our goal was to assess the in vitro antimicrobial, anti-adhesive and anti-biofilm abilities of BS produced by Lactobacillus jensenii and Lactobacillus rhamnosus against clinical Multidrug Resistant (MDR) strains of Acinetobacter baumannii, Escherichia coli, and Staphylococcus aureus (MRSA). Cell-bound BS from both L. jensenii and L. rhamnosus were extracted and isolated. The surface activities of crude BS samples were evaluated using an oil spreading assay. The antimicrobial, anti-adhesive and anti-biofilm activities of both BS against the above mentioned MDR pathogens were determined. RESULTS: Surface activities for both BS ranged from 6.25 to 25 mg/ml with clear zones observed between 7 and 11 cm. BS of both L. jensenii and L. rhamnosus showed antimicrobial activities against A. baumannii, E. coli and S. aureus at 25-50 mg/ml. Anti-adhesive and anti-biofilm activities were also observed for the aforementioned pathogens between 25 and 50 mg/ml. Finally, analysis by electron microscope indicated that the BS caused membrane damage for A. baumannii and pronounced cell wall damage in S. aureus. CONCLUSION: Our results indicate that BS isolated from two Lactobacilli strains has antibacterial properties against MDR strains of A. baumannii, E. coli and MRSA. Both BS also displayed anti-adhesive and anti-biofilm abilities against A. baumannii, E. coli and S. aureus. Together, these capabilities may open up possibilities for BS as an alternative therapeutic approach for the prevention and/or treatment of hospital-acquired infections.

Progress and Pitfalls of Chimeric Antigen Receptor T Cell Immunotherapy against T Cell Malignancies.

Chimeric antigen receptor T cell (CAR-T) immunotherapy has revolutionized the treatment of relapsed and refractory B cell-derived hematologic malignancies. Currently, there are 6 Food and Drug Administration-approved commercial CAR-T products that target antigens exclusively expressed on malignant B cells or plasma cells. However, concurrent advancement for patients with rarer and more aggressive T cell-derived hematologic malignancies have not yet been achieved. CAR-T immunotherapies are uniquely limited by challenges related to CAR-T product manufacturing and intrinsic tumor biology. In this review tailored for practicing clinician-scientists, we discuss the major barriers of CAR-T implementation against T cell-derived neoplasms and highlight specific scientific advancements poised to circumvent these obstacles. We summarize salient early-stage clinical trials implementing novel CAR-T immunotherapies specifically for patients with relapsed and/or refractory T cell neoplasms. Finally, we highlight novel manufacturing and treatment strategies that are poised to have a meaningful future clinical impact.

The risk vs. benefit calculus of anticoagulation in patients with ibrutinib-related atrial fibrillation.

For ibrutinib-related atrial fibrillation (IRAF), guidelines for anticoagulation do not exist. We sought to describe stroke, bleeding, and anticoagulation rates among patients with IRAF. We performed a single-center retrospective review of 168 patients treated with ibrutinib followed from 2013 to 2022. Over a median follow-up of 6.4 years, 44 (26.0%) patients developed IRAF of which 38 (86.4%) had a CHA2DS2-VASc ≥2 and 7 (15.9%) had a HAS-BLED ≥3. Anticoagulation was initiated in 20 (45.5%) without a clear pattern in scores, risk factors, or cumulative dose, besides having another reason for anticoagulation. Few patients with IRAF developed non-hemorrhagic CVA (n = 3, 6.8%) or significant bleeding (n = 3, 6.8%). Among those with each adverse outcome, 2 in each group were anticoagulated and all were older than 65 years old. In conclusion, decisions for anticoagulation vary widely and patients who are elderly or with HTN may be most at risk for CVA or significant bleed.

Nanoparticle-mediated co-delivery of inflammasome inhibitors provides protection against sepsis.

The NLRP3 inflammasome, a multiprotein complex responsible for triggering the release of pro-inflammatory cytokines, plays a crucial role in inducing the inflammatory response associated with sepsis. While small molecule inhibitors of the NLRP3 inflammasome have been investigated for sepsis management, delivering NLRP3 inhibitors has been accompanied by several challenges, primarily related to the drug formulation, delivery route, stability, and toxicity. Many existing inflammasome inhibitors either show higher liver toxicity or require a high dosage to efficiently impede the inflammasome complex assembly. Moreover, the potential synergistic effects of combining multiple inflammasome inhibitors in sepsis therapy remain largely unexplored. Therefore, a rational approach is essential for presenting the potential administration of NLRP3 small molecule inhibitors to inhibit NLRP3 inflammasome activation effectively. In this context, we present a lipid nanoparticle-based dual-drug delivery system loaded with MCC 950 and disulfiram, demonstrating markedly higher efficiency compared to an equivalent amount of free-drug combinations and individual drug nanoparticles in vitro. This combination therapy substantially improved the in vivo survival rate of mice for LPS-induced septic peritonitis. Additionally, the synergistic approach illustrated a significant reduction in the expression of active caspase-1 as well as IL-1ß inhibition integral components in the NLRP3 pathway. This study underscores the importance of integrating combination therapies facilitated by nanoparticle delivery to address the limitations of small molecule inflammasome inhibitors.

Is There a Baby in the Lung? A Case of Placental Transmogrification of the Lung.

Pulmonary nodules are commonly encountered in pulmonary practice. Etiologies could include infectious, inflammatory, and malignant. Placental transmogrification of the lung is an extremely rare etiology of pulmonary nodules. Such condition often presents as unilateral lesions in asymptomatic men. In general, such nodules are generally stable and grow extremely slowly. We highlight an unusual case of placental transmogrification of the lung (PLC) identified in a young female. The patient's bilateral nodules were larger than what has been previously cited in the literature and exhibited growth over an 8-year follow-up period.

Prioritizing the primary prevention of heart failure: Measuring, modifying and monitoring risk.

With the rising incidence of heart failure (HF) and increasing burden of morbidity, mortality, and healthcare expenditures, primary prevention of HF targeting individuals in at-risk HF (Stage A) and pre-HF (Stage B) Stages has become increasingly important with the goal to decrease progression to symptomatic (Stage C) HF. Identification of risk based on traditional risk factors (e.g., cardiovascular health which can be assessed with the American Heart Association's Life's Essential 8 framework), adverse social determinants of health, inherited risk of cardiomyopathies, and identification of risk-enhancing factors, such as patients with viral disease, exposure to cardiotoxic chemotherapy, and history of adverse pregnancy outcomes should be the first step in evaluation for HF risk. Next, use of guideline-endorsed risk prediction tools such as Pooled Cohort Equations to Prevent Heart Failure provide quantification of absolute risk of HF based in traditional risk factors. Risk reduction through counseling on traditional risk factors is a core focus of implementation of prevention and may include the use of novel therapeutics that target specific pathways to reduce risk of HF, such as mineralocorticoid receptor agonists (e.g., fineronone), angiotensin-receptor/neprolysin inhibitors, and sodium glucose co-transporter-2 inhibitors. These interventions may be limited in at-risk populations who experience adverse social determinants and/or individuals who reside in rural areas. Thus, strategies like telemedicine may improve access to preventive care. Gaps in the current knowledge base for risk-based prevention of HF are highlighted to outline future research that may target approaches for risk assessment and risk-based prevention with the use of artificial intelligence, genomics-enhanced strategies, and pragmatic trials to develop a guideline-directed medical therapy approach to reduce risk among individuals with Stage A and Stage B HF.