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Initiation of Guideline Directed Medical Therapy While on Microaxial Flow Pump Is Associated With Reduced In-Hospital Mortality
No full textProgram Evaluation of the Revamped HAPI Prevention Bundle Protocol in an Adult Non-Critical Inpatient Unit
No full textApplication of artificial intelligence to analyze data from randomized controlled trials: An example from DECAAF II.
No full textBACKGROUND: Causal machine learning (ML) provides an efficient way of identifying heterogeneous treatment effect groups from hundreds of possible combinations, especially for randomized trial data.
OBJECTIVE: The aim of this paper is to illustrate the potential of applying causal ML on the DECAAF II trial data. We proposed a causal ML model to predict the treatment response heterogeneity.
METHODS: We applied causal tree learning to the DECAAF II trial data as an example of real applications, identifying subgroups that may be superior when subject to one of the treatments over the other through an easily interpretable process. For each subgroup identified, the characteristics were summarized, and the relationship between treatment arms and risk for recurrence of atrial tachyarrhythmia (aTA) among subjects was assessed.
RESULTS: Causal tree learning demonstrated that, among all the preablation predictors, dividing subgroups according to age, with a cutoff of 58 years, provides the most heterogeneous subgroups in response to fibrosis-guided ablation in addition to pulmonary vein isolation (PVI) compared with PVI alone. The difference in the risk of recurrence of aTA between 2 treatments was nonsignificant in older patients (hazard ratio [HR] 1.06; 95% confidence interval [CI] 0.77-1.47; P = .72). However, among the younger patients, the risk of aTA recurrence was significantly lower in the fibrosis-guided ablation group compared with PVI-only (HR 0.50; 95% CI 0.28-0.90); P = .02).
CONCLUSION: Applying causal ML on random controlled trial datasets helped us identify groups of patients that profited from the treatment of interest in an efficient and unbiased manner
Gut phages and their interactions with bacterial and mammalian hosts.
No full textThe mammalian gut microbiome is a dense and diverse community of microorganisms that reside in the distal gastrointestinal tract. In recent decades, the bacterial members of the gut microbiome have been the subject of intense research. Less well studied is the large community of bacteriophages that reside in the gut, which number in the billions of viral particles per gram of feces, and consist of considerable unknown viral dark matter. This community of gut-residing bacteriophages, called the gut phageome, plays a central role in the gut microbiome through predation and transformation of native gut bacteria, and through interactions with their mammalian hosts. In this review, we will summarize what is known about the composition and origins of the gut phageome, as well as its role in microbiome homeostasis and host health. Furthermore, we will outline the interactions of gut phages with their bacterial and mammalian hosts, and plot a course for the mechanistic study of these systems
Comparative Analysis of Endoscope Obscuration With Utilization of an Endonasal Access Guide for Endonasal Skull Base Surgery.
No full textBACKGROUND AND OBJECTIVES: In endoscopic endonasal approaches (EEAs) for skull base pathologies, endoscope view obscuration remains a persistent, time-consuming, and distracting issue for surgeons and may result in increased operative time. The endonasal access guide (EAG) has been demonstrated as a possible adjunct to minimize these events. However, to date, there have been no comparative studies performed and the potential time savings by using EAGs have yet to be quantified. This cohort study aimed to determine the operative efficiency benefits of the EAG in EEA operations.
METHODS: Analysis of EEA operative videos from an EAG cohort (n = 20) and a control cohort (n = 20) was performed, assessing 12-minute segments in the first, middle, and last third of each operation. The first segment in each cohort was selected before EAG placement, serving as an internal control. Every endoscope lens soiling instance was counted (measured as cleaning actions per minute), timed (obscuration time %), and identified as a withdrawal, irrigation, or other cleaning action. Perioperative variables including skull base repair and postoperative cerebrospinal fluid leakage were assessed.
RESULTS: Within the EAG cohort, obscuration time was reduced in the middle and last third compared with the first third (3.73% [CI: 2.39-5.07] vs 12.97% [CI: 10.24-15.70], P \u3c .001; 4.19% [CI: 2.83-5.55] vs 12.97% [CI: 10.24-15.70], P \u3c .001) and cleaning actions were also significantly reduced by EAG (0.69/min [CI: 0.39-0.99] vs 1.67/min [CI: 1.34-2.00], P = .001; 0.66/min [CI: 0.35-0.97] vs 1.67/min [CI: 1.34-2.00], P \u3c .001). Between the control and EAG cohorts, there was no significant difference between obscuration time and cleaning actions in the first third (9.33% vs 12.97%, P = .086; 1.34/min vs 1.67/min, P = .151) or in the middle third (6.24% vs 3.73%, P = .140; 0.80/min vs 0.69/min, P = .335), but there was a significant difference in the last third (9.25% [CI: 6.95-11.55] vs 4.19% [CI: 2.83-5.55], P \u3c .001; 0.95/min [CI: 0.73-1.17] vs 0.66/min [CI: 0.35-0.97], P = .018).
CONCLUSION: EAG significantly reduces lens obscurations and cleaning events, particularly during the intradural portion of operations. This technology may offer a greater time-saving impact with patients undergoing long EEA operations
Protective antibodies target cryptic epitope unmasked by cleavage of malaria sporozoite protein.
No full textThe most advanced monoclonal antibodies (mAbs) and vaccines against malaria target the central repeat region or closely related sequences within the Plasmodium falciparum circumsporozoite protein (PfCSP). Here, using an antigen-agnostic strategy to investigate human antibody responses to whole sporozoites, we identified a class of mAbs that target a cryptic PfCSP epitope that is only exposed after cleavage and subsequent pyroglutamylation (pGlu) of the newly formed N terminus. This pGlu-CSP epitope is not targeted by current anti-PfCSP mAbs and is not included in the licensed malaria vaccines. MAD21-101, the most potent mAb in this class, confers sterile protection against Pf infection in a human liver-chimeric mouse model. These findings reveal a site of vulnerability on the sporozoite surface that can be targeted by next-generation antimalarial interventions
Metagenomic estimation of absolute bacterial biomass in the mammalian gut through host-derived read normalization.
No full textAbsolute bacterial biomass estimation in the human gut is crucial for understanding microbiome dynamics and host-microbe interactions. Current methods for quantifying bacterial biomass in stool, such as flow cytometry, qPCR, or spike-ins (i.e., adding cells or DNA from an organism not normally found in a sample), can be labor-intensive, costly, and confounded by factors like water content, DNA extraction efficiency, PCR inhibitors, and other technical challenges that add bias and noise. We propose a simple, cost-effective approach that circumvents some of these technical challenges: directly estimating bacterial biomass from metagenomes using bacterial-to-host (B:H) read ratios. We compare B:H ratios to the standard methods outlined above, demonstrating that B:H ratios are useful proxies for bacterial biomass in stool and possibly in other host-associated substrates. We show how B:H ratios can be used to track antibiotic treatment response and recovery in both mice and humans, which showed 403-fold and 45-fold reductions in bacterial biomass during antibiotic treatment, respectively. Our results indicate that host and bacterial metagenomic DNA fractions in human stool fluctuate longitudinally around a stable mean in healthy individuals, and the average host read fraction varies across healthy individuals by \u3c 8-9 fold. B:H ratios offer a convenient alternative to other absolute biomass quantification methods, without the need for additional measurements, experimental design considerations, or machine learning algorithms, enabling retrospective absolute biomass estimates from existing stool metagenomic data
Society for Immunotherapy of Cancer: updates and best practices for multiplex immunohistochemistry (IHC) and immunofluorescence (IF) image analysis and data sharing.
No full textOBJECTIVES: Multiplex immunohistochemistry and immunofluorescence (mIHC/IF) are emerging technologies that can be used to help define complex immunophenotypes in tissue, quantify immune cell subsets, and assess the spatial arrangement of marker expression. mIHC/IF assays require concerted efforts to optimize and validate the multiplex staining protocols prior to their application on slides. The best practice guidelines for staining and validation of mIHC/IF assays across platforms were previously published by this task force. The current effort represents a complementary manuscript for mIHC/IF analysis focused on the associated image analysis and data management.
METHODS: The Society for Immunotherapy of Cancer convened a task force of pathologists and laboratory leaders from academic centers as well as experts from pharmaceutical and diagnostic companies to develop best practice guidelines for the quantitative image analysis of mIHC/IF output and data management considerations.
RESULTS: Best-practice approaches for image acquisition, color deconvolution and spectral unmixing, tissue and cell segmentation, phenotyping, and algorithm verification are reviewed. Additional quality control (QC) measures such as batch-to-batch correction and QC for assembled images are also discussed. Recommendations for sharing raw outputs, processed results, key analysis programs and source code, and representative photomicrographs from mIHC/IF assays are included. Lastly, multi-institutional harmonization efforts are described.
CONCLUSIONS: mIHC/IF technologies are maturing and are routinely included in research studies and moving towards clinical use. Guidelines for how to perform and standardize image analysis on mIHC/IF-stained slides will likely contribute to more comparable results across laboratories and pave the way for clinical implementation. A checklist encompassing these two-part guidelines for the generation of robust data from quantitative mIHC/IF assays will be provided in a third publication from this task force. While the current effort is mainly focused on best practices for characterizing the tumor microenvironment, these principles are broadly applicable to any mIHC/IF assay and associated image analysis
Treatment-Emergent Major Adverse Cardiovascular and Thromboembolic Events were Infrequent During Clinical Trials of Pegloticase.
No full textOBJECTIVES: Long-term maintenance of serum urate (SU) levels/dl reduces gout flare frequency. However, urate-lowering therapy (ULT) initiation can induce gout flare. The incidence of thromboembolic (TE) and cardiovascular (CV) events has been shown to increase in the 30 and 120 days following gout flare, respectively; therefore, the question of ULT initiation increasing patient risk for CV/TE events has been raised. Here, we investigate CV/TE event incidence following pegloticase initiation in clinical trials.
METHODS: This post hoc analysis of pooled data from 4 trials examined treatment-emergent gout flare and CV/TE events in patients with uncontrolled gout. Studies included two phase 3 trials (NCT00325195), the MIRROR open-label trial (NCT03635957), and the MIRROR randomized controlled trial (NCT03994731). Per protocol, pegloticase (8 mg) was administered every 2 (all trials) or 4 weeks (phase 3 trials); data from the first 24 weeks of therapy were included in this analysis. Some MIRROR patients received methotrexate (15 mg/week) as co-therapy. Based on prior studies, the high-risk window for CV/TE events was defined as 120 days following flare onset.
RESULTS: Overall, 5/328 (1.5%) patients experienced ≥1 CV/TE event during pegloticase treatment, including 3/244 (1.2%) patients who received on-label (biweekly) dosing (35.4 events/1000 person-years). All events occurred within the 120-day gout flare exposure window.
CONCLUSIONS: CV/TE event incidence during pegloticase treatment was similar to the general gout population (31.7 events/1000 person-years). These findings suggest that pegloticase initiation does not put patients at a higher risk for CV/TE events
Revealing the dance of NLRP3: spatiotemporal patterns in inflammasome activation.
No full textThe nucleotide-binding domain, leucine-rich repeat, and pyrin domain containing-protein 3 (NLRP3) inflammasome is a multiprotein complex that plays a critical role in the innate immune response to both infections and sterile stressors. Dysregulated NLRP3 activation has been implicated in a variety of autoimmune and inflammatory diseases, including cryopyrin-associated periodic fever syndromes, diabetes, atherosclerosis, Alzheimer\u27s disease, inflammatory bowel disease, and cancer. Consequently, fine-tuning NLRP3 activity holds significant therapeutic potential. Studies have implicated several organelles, including mitochondria, lysosomes, the endoplasmic reticulum (ER), the Golgi apparatus, endosomes, and the centrosome, in NLRP3 localization and inflammasome assembly. However, reports of conflict and many factors regulating interactions between NLRP3 and subcellular organelles remain unknown. This review synthesizes the current understanding of NLRP3 spatiotemporal dynamics, focusing on recent literature that elucidates the roles of subcellular localization and organelle stress in NLRP3 signaling and its crosstalk with other innate immune pathways converging at these organelles