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Decreasing Re-Intubation Rates in Mechanically Ventilated Adult Patients: A Scoping Review
Full text linkDecreasing Re-Intubation Rates in Mechanically Ventilated Adult Patients: A Scoping Review
Purpose/Background
Critically ill patients often require mechanical ventilation to support respiratory function. Prolonging mechanical ventilation can increase adverse outcomes. Weaning patients from the ventilator as soon as clinically appropriate can decrease adverse outcomes. The decision to wean mechanical ventilation lacks a standardized approach. This scoping review will evaluate the literature about the effectiveness of a standardized weaning protocol in decreasing the number of reintubations within 72 hours of extubation.
Methods
We conducted a literature search on PubMed, CINAHL, Scopus, and Medline between November 2020 and November 2023 using key terms such as adult, critically ill, intubation, mechanical ventilation, ventilator weaning, reintubation, and others. Inclusion criteria included English language, peer review, and publication within the last ten years. Ten articles were included after rapid critical appraisals.
Results
Ten articles that studied mechanically ventilated adult patients were reviewed between 2006 and 2021. None of the articles found any practices that decreased re-intubation rates. However, most of the articles in this scoping review supported practices that helped decrease time spent on mechanical ventilation, ICU length of stay, and mortality rate.
Implications for Nursing Practice
The evidence gathered from this scoping review showed no benefit in decreasing re-intubation rates in mechanically ventilated adult patients. That does not mean the data lacked benefits for future practice. The evidence showed the benefits of nurse-driven extubation protocols and early extubation to noninvasive positive pressure ventilation. ICU and Pulmonary teams should be shown the benefits of these nurse-driven extubation protocols and the effects they can have on their patients
Understanding the Mechanism of VERU-111 Resistance and Discovering Novel Mechanisms of Action of VERU-111
Full text linkTriple negative breast cancer (TNBC) has limited treatment options due to a lack of targetable markers, i.e., estrogen receptor (ER), progesterone receptor (PR) or human epidermal growth factor 2 (HER2). For this reason, hormone receptor negative (HR-) breast cancers, such as TNBC and HER2+ breast cancers, typically have worse overall prognosis than HR+ cancers. TNBC frontline therapy involves a combination of cytotoxic chemotherapies, including tubulin inhibitors like taxanes and vinca alkaloids, whereas HER2+ cancers are treated with antibody-drug conjugates in conjunction with a taxane. However, taxanes are subject to several multidrug resistance mechanisms, including drug efflux through P-gp and inhibition from β-tubulin overexpression. Taxanes also cause peripheral neuropathy and dose limiting toxicity in patients. As such, it remains critical to explore new anti-tubulin drugs that can overcome the challenges of taxane therapy. Colchicine binding site inhibitors (CBSIs) are an exciting class of tubulin inhibitors emerging as an alternative to taxanes. We have previously reported on VERU-111, an orally bioavailable, highly potent CBSI that overcomes taxane chemoresistance (TxR) in TNBC and has a beneficial safety profile in clinical trials. In this work, we report that VERU-111 is also potent against treatment-naïve and heavily pre-treated HER2-overexpressing breast cancers. Furthermore, VERU-111 can resensitize trastuzumab-resistant HER2+ breast cancer to tyrosine kinase inhibition (lapatinib) in contrast to paclitaxel. We also report that a novel VERU-111 derivative, 60c, is highly effective against heavily pretreated TNBC and curtails distant metastases with unique metastatic tropism relative to VERU-111. Understanding the mediators of chemoresistance and chemosensitivity is key to providing cancer patients with timely, effective care. Although VERU-111 chemoresistance (VeruR) has not yet been encountered during clinical trials, our group has developed several models to proactively investigate mechanisms of VeruR. Herein, we identify breast cancer resistance protein (BCRP) as a major driver of VeruR. Further, using whole genome expression data from these models, we found a putative fingerprint for VeruR in TNBC that is distinct from TxR. Notably, we show that next-generation CBSIs, like 60c, are highly potent against VeruR TNBC. Finally, we present data derived from reverse phase protein arrays and X-ray crystallography studies that reveal that members of the bromodomain (BRD) and extraterminal domain (BET) protein family are novel binding partners of VERU-111, suggesting a role for VERU-111 in bromodomain-dependent gene expression. Overall, our data reveal a potential screening tool for patients of TNBC and identify a new binding partner and potential target for VERU-111f in TNBC
Genotypes of SNPs of Key Genes Regulate Susceptibility and Drug Sensitivity to Neovascular AMD
Full text linkAge-related macular degeneration (AMD), particularly its neovascular form, stands as a leading cause of blindness globally, with its prevalence in our country on a steady rise. This underscores the critical impact of neovascular AMD (nAMD) management on patient quality of life and societal burden. Current optimal treatments hinge on anti-vascular endothelial growth factor (anti-VEGF) therapies, though their efficacy varies across different drugs and individuals, highlighting the importance of precise drug selection in clinical outcomes. Research suggests that factors such as baseline vision, age, disease duration, lesion size, central retina thickness, neovascularization type, and demographic differences influence nAMD prognosis. In addition, Genetic predispositions and environmental factors also contribute to nAMD development, with increasing focus on molecular genetics to understand treatment responses. Single nucleotide polymorphisms (SNPs), as primary genomic variations, are linked to disease susceptibility and treatment sensitivity, including in nAMD. This study posits that SNP interactions within human genes may influence anti-VEGF drug’s efficacy, supported by evidence on the distinct molecular functions and pathways of VEGF family genes. We aimed to analyze nAMD susceptibility and sensitivity to VEGF inhibitors and explore gene polymorphisms at the molecular level, demonstrating that SNP presence could elucidate variances in anti-VEGF drug performance, thereby optimizing clinical drug selection and minimizing treatment failures. Given the high costs associated with anti-VEGF therapies, adopting a precision medicine approach, guided by genetic insights, is crucial for economic and clinical efficiency. This study provides a foundation for personalized treatment strategies, efficacy monitoring, individual variability assessment, biologic development, and etiological analysis in nAMD management. We investigated the presence of SNPs in nAMD patients, examining the correlation between gene SNPs, genetic susceptibility, and anti-VEGF drug efficacy. Selecting 30 SNP sites from 14 genes associated with nAMD, we analyzed their contribution to disease occurrence and treatment response, revealing significant SNP-related individual differences in drug sensitivity and cross-efficacy. Our research encompasses three main aspects: firstly, reviewing pathogenic factors of nAMD and anti-VEGF drug effects; secondly, conducting a retrospective study comparing the effectiveness and safety of conbercept and ranibizumab; thirdly, analyzing the association between gene SNPs and nAMD etiology and drug efficacy. Significant genotype differences were found, underscoring the potential of genotype-based personalized treatments for enhanced clinical outcomes in nAMD management
On Thymic Regulatory T-Cell Ontogeny
Full text linkRegulatory T (Treg) cells play a pivotal role in maintaining immune homeostasis and preventing autoimmunity. Like most T cells, Treg development occurs primarily in the thymus, where T-cell precursors undergo a series of developmental stages, including double-negative (DN), double-positive (DP), and single-positive (SP) stages, leading to the formation of distinct mature T cells. To ensure a diverse and self-tolerant T-cell repertoire capable of effectively responding to a wide range of pathogens while preventing autoimmunity, the differentiation process of thymocytes is closely supervised by sequential programs, including the rearrangement of T-cell receptor (TCR) gene segments, β-selection of cells expressing a functional TCRβ chain, positive selection of cells followed by CD4/CD8 lineage specificity, and negative selection or clonal deletion to eliminate autoreactive T cells. The induction of the Treg population is triggered when autoreactive cells escape from negative selection. Despite significant progress in our understanding of thymic T-cell differentiation, investigating how thymic Treg cells differentiate in their native settings remains a key conceptual and technical challenge. One major issue is that previous investigations have been limited by technological constraints. First, studies often rely on predefined markers, which can introduce bias in defining developmental stages. Second, techniques such as adoptive T-cell transfer and in vitro culture of TCR transgenic can induce stress on the cells, emphasizing the necessity of studying T-cell development under native physiological conditions. Third, the thymic T-cell pool is a mix of cells derived at any developmental stages as well as mature T cells recirculating back into thymus. Such heterogeneity complexes the assessment focusing on differentiating thymocytes. To address these challenges, we developed a Rag1CreER timestamping mouse model. This model is based on the CreER-loxp system and enables tracing thymocytes at their earlier stage by tamoxifen-induced Cre recombinase. When combined with Rosa reporter strains, this genetic tool enables inducible labeling of early T cells at the T-cell receptor (TCR) rearrangement stage at any time, allowing temporal tracking of their developmental trajectories. By integrating timestamp tracing with single-cell technology, our deconvolution of thymic cells delineated the dynamic processes of developmental stages, and transcriptome profiles during thymic T-cell differentiation. This method provides a comprehensive and high-resolution view of thymic T-cell differentiation under natural conditions. We identified intermediate CD4 SP thymocytes that precede Treg induction, these cells are featured with Treg-associated gene signatures such as high levels of Tnfrsf9, Tnfrsf4, Ikzf2, Ikzf4 and Il2ra. These cells are induced by TCR signaling through various levels and can differentiate into Treg cells both in vitro and in vivo. We also pulse-chased nascent thymic Treg cells and specified their maturation process. We captured a sharp increase of activation markers such as GITR, CD44, CD25 and CD73 after Foxp3 induction. The acquisition of these markers was further found to occur within the thymus by parabiosis experiment, highlighting a potential transition process of newly derived Treg cells. Further transcriptome and epigenome analysis revealed profound gene expression changes, and demethylation of Treg-specific gene regions is involved in such transition process, thus highlighting a maturation process. Furthermore, we also extended our studies of our timestamp tracing tool. We tracked thymic Treg cells for a longer time and determined the features of recirculating or retained mature thymic Treg cells. These data provide a detailed picture of thymic Treg-cell ontogeny in native conditions. Finally, we applied our timestamping strategy to compare the function difference of T cells derived at neonatal and adult stages and demonstrated that neonatal-derived cells are more active. Thus, the developmental processes of thymic regulatory T cells in native physiological conditions are resolved by a novel genetic tool combined with unbiased approaches, providing a foundation for further exploration
Procedural Oxygen Mask Use for Inpatient Bariatric Endoscopy: A Scoping Review
Full text linkPurpose/Background
Hypoxia is a severe adverse event that is often associated with sedated endoscopy procedures, and bariatric patients have a significantly higher risk for complications related to oxygenation during sedation due to pathophysiological changes to the respiratory system. This scoping review compares the rate of hypoxemic events with the use of a binasal cannula versus a procedural oxygen mask during inpatient endoscopic procedures in patients aged 19-64 with a BMI greater than 40.
Methods
The scoping review includes control trials with and without randomization, case-control/cohort studies, systematic reviews, and qualitative/descriptive studies. With limited research regarding the PICOT, extending the age of qualifying articles beyond the desired five years was necessary. This scoping review focuses on utilizing the POM mask to prevent hypoxia during upper endoscopies and some alternative approaches. Databases utilized for this review include EBSCO, CINAHL, Pubmed, and Medline. The literature search initially resulted in 10,525 articles, which then were narrowed down to 10 based on their pertinence to the PICOT question.
Results
Many outcomes were reported, the most commonly being hypoxemic events with a BMI \u3e30 without preoxygenation, hypoxemic events with a BMI \u3e30 with preoxygenation, hypoxia with a bi-nasal cannula, and procedural termination with preoxygenation. Data from randomized control trials and case-control studies showed a decrease in both hypoxemic events and early termination of the procedure with adequate preoxygenation. Four reports of decreased instances of hypoxemia were reported with the bi-nasal cannula; however, there were also four reports of increased instances, leaving mixed results.
Implications for nursing practice
A summary of the evidence supports using the procedural oxygen mask in the bariatric population undergoing endoscopy procedures. Current research indicates that the POM should be the new standard of care due to this population\u27s dramatic decrease in hypoxemic events. Anesthesia providers should stay updated on the standard of care and best practices related to bariatric endoscopies
Examining the Shared Decision-Making Preferences of Adult Black Men with Hypertension in the U.S. Mid-South Region: A Mixed Methods Approach
Full text linkPurpose. This study aimed to explore what factors are related to Black men’s shared decision-making (SDM) preferences for selecting hypertension (HTN) treatment and management options with a healthcare clinician. Methods. Researchers employed an exploratory sequential mixed methods design to explore factors influencing Black adult men\u27s preferences for involvement in SDM regarding HTN treatment. Qualitative interviews with N=16 Black men identified factors related to SDM involvement, while a quantitative phase with N=105 Black men examined factors that could predict the level of involvement in SDM for HTN treatment. Results. Trust and having a female clinician were a significant independent predictor of decision-making involvement among men in this study (b = 9.09; t(102) = 3.07; p = .003). Engaging in the SDM process with a female clinician increased the desired level of decision-making involvement for HTN treatment and management. Conclusion. Findings from this study suggest that clinician gender is a key factor that influences SDM involvement preferences. Future research should focus on targeted questions to delve deeper into the specific aspects of SDM in gender-discordant patient-clinician relationships
The Role of Scribble in Activating the Sonic Hedgehog (SHH) Pathway and Its Role in the Progression of SHH-Medulloblastoma
No full textOur current knowledge of regulators in vertebrates’ Hedgehog (HH) pathway is incomplete. Gaining a better understanding of HH pathway components is appealing due to the key role of the Sonic Hedgehog (SHH) pathway in modulating the developmental proliferation of granule neuron progenitors (GNPs) in the cerebellum. Aberrant activation of SHH pathway in GNPs promotes the formation of SHH-Medulloblastoma (SHH-MB), a common pediatric brain tumor. Though SHH-MB is genetically understood, current therapies are ineffective. Recently, we identified a scaffold protein, Scribble (Scrib), as a novel interactor of our previously identified SHH pathway regulator—Abcc4. Scrib’s reported expression in the brain also suggested that Scrib had a potential connection to the SHH pathway. However, so far it is unknown whether Scrib regulates the SHH pathway. In this study, I first provided evidence that Scrib is expressed in the developing cerebellum most prominently when the HH pathway is most active. Scrib\u27s enrichment in proliferating GNPs and purified SHH-MB tumor cells led to my hypothesis that Scrib contributes to SHH pathway activation. This hypothesis was further supported by both in vitro and in vivo studies using preclinical SHH-MB models. These studies showed that suppression of Scrib diminished the intensity of the SHH pathway and reduced tumor growth. I then used the NIH-3T3 cell line, a model system that robustly responds to SHH ligand, to elucidate Scrib\u27s role in the SHH pathway regulation. Surprisingly, in an Abcc4-independent fashion, Scrib potently modulated the SHH pathway by affecting SHH-induced amount of nuclear Gli2, a transcription factor which is a downstream activator of the SHH pathway cascade. Next, to determine why nuclear Gli2 expression is affected, a phospho-proteomic study was conducted. This study found that Scrib influences the phosphorylation at multiple Gli2 sites. Follow-up investigations, including site-directed mutagenesis and subcellular fractionation, showed that phosphorylation of S232 is critical to both optimal Gli2 activity and nuclear Gli2 expression. These findings narrowed down the Scrib effect to Gli2 phosphorylation at a single residue —S232. In addition, I extended these studies to identify the kinase mediating the phosphorylation of Gli2 at S232. Among the candidate kinases screened, CK1ε was the most likely kinase that phosphorylates Gli2-S232
The Impact of Local Physiology on the Corrosion of Orthopedic Alloys
Full text linkIntroduction. Total knee arthroplasty (TKA) is used in the treatment of end-stage osteoarthritis of the knee. It is one of the most common elective surgeries performed with predictions expecting significant increases in the number of procedures performed over the next decade. However, the patient satisfaction rate after TKA is as low as 80%. Cobalt-chromium-molybdenum (CoCrMo) is regularly used for TKA protheses due to the alloy’s mechanical strength, biocompatibility, and corrosion resistance. The corrosion resistance of this alloy relies on a passive oxide layer. This oxide layer can be impacted by phagocytic cells which can leave pits and craters on implant surfaces in a process termed inflammatory cell-induced corrosion (ICIC). Additionally, the corrosion resistance of implant alloys can be analyzed using electrochemistry. This thesis aims to investigate the effects of local physiology on the corrosion of CoCrMo. The first study in this thesis investigates the relationship between the physical and electrochemical properties of preoperative synovial fluid (SF) and postoperative patient-reported outcomes. The second study investigates the effects of simulated wear particles on ICIC.
Methods. In the first study, SF was collected from 146 patients immediately prior to TKA (IRB approval number: 16-04802-XP and 21-08403-XP). SF volume and pH were recorded. SF was transferred into a three-electrode electrochemical cell with an ASTM F1537 CoCrMo working electrode to perform open circuit potential (OCP), electrochemical impedance spectroscopy (EIS), and linear polarization (LP) testing. The approximate instantaneous corrosion rate (1/RP) was obtained from EIS testing. The potentiodynamic curves from LP testing were used to find the corrosion potential (Ecorr) and to determine the existence of a passive region. The Knee injury and Osteoarthritis Outcome Score for Joint Replacement (KOOSJR) was obtained at 3-11 months, 1-3 years, and 3+ years. Patients self-reported knee stiffness, pain, and functionality on a scale from 0 to 100 with 100 being the optimal outcome. Spearman rank correlation tests were done to assess if there was a correlation between KOOSJR scores and volume, pH, OCP, Ecorr, and 1/RP. A Mann-Whitney test was used to determine if there was a difference between the KOOSJR scores of samples with a passive region compared to samples without a passive region. In the second study, a 30-day macrophage-lymphocyte co-culture experiment on ASTM F1537 CoCrMo disks was performed. Simulated CoCrMo wear particles were added to groups in none, low (1:10), medium (1:100), and high (1:500) cell-particle ratios. The activators interferon gamma (IFNγ) and lipopolysaccharide (LPS) were added to select groups. Supernatants were collected on days 10 and 30 to determine tissue necrosis factor alpha (TNFα) and interleukin 6 (IL-6) levels using enzyme-linked immunosorbent assays (ELISA). Cleaned disks were examined for ICIC damage features using scanning electron microscopy (SEM) and the percent weight oxygen on disk surfaces was found using energy dispersion X-ray spectroscopy (EDS). Welch’s one-way ANOVA with Dunnett’s post-hoc tests were used to compare cytokine means between groups. Kruskal-Wallis one-way ANOVA was used to determine if there were differences between the mean percent weight oxygen of groups.
Results. Patients with more synovial fluid had higher long-term KOOSJR scores (1-3 years: r=0.124, p=0.016) (3+ years: r=0.499, p=0.043). Additionally, the KOOSJR scores of patients with at least 2 mL synovial fluid were statistically higher than the scores of patients with less than 2 mL synovial fluid at 1-3 years (p=0.007) and at 3 or more years (p=0.039). No significant correlations were found between KOOSJRs and pH, OCP, Ecorr, and 1/RP. Approximately two-thirds of samples did not have a passive region. Short-term KOOSJRs were significantly higher for samples with passive regions than without passive regions (3-11 months: p=0.047). Damage consistent with previous reports of ICIC was found on most disks. However, there were no significant differences in the mean percent weight oxygen between groups (p=0.772). When compared to groups without particles, day 10 TNFα levels were higher for groups with medium and high particle concentrations, but not for groups with low particle concentrations. TNFα and IL-6 levels were higher in activated groups than non-activated groups for groups with medium and high particle concentrations. Unexpectedly, day 10 IL-6 levels were lower for groups with medium and high particle concentrations than with no particles. However, the activated group with medium particles had higher IL-6 levels than the activated group with no particles on day 30.
Conclusion. The SF study found that CoCrMo appears to exhibit active corrosion behavior in approximately two-thirds of SF samples. Patients whose SF elicited passive corrosion behavior reported better short-term patient satisfaction scores than patients whose SF elicited active corrosion behavior. Additionally, higher SF volumes at time of surgery were associated with higher long-term patient satisfaction scores. Future research will investigate the differences in SF composition which may lead to these differences in corrosion behavior and patient satisfaction. The cell culture study used an in vitro model of ICIC to investigate the effects of simulated wear particles on the cellular response and the extent of ICIC damage. The addition of simulated wear particles showed no difference in the extent of damage to the alloy surfaces. However, there were differences in the cellular response measured by TNFα and IL-6. The 30-day study may have been too short to demonstrate any differences in ICIC damage caused by the addition of simulated wear particles
Real-world Pharmacological Anticoagulation and Clinical Outcomes of Venous Thromboembolism in Adults with Sickle Cell Disease
Full text linkSickle cell disease (SCD) is an inherited disease characterized by sickle-shaped red blood cells that can slow or block blood flow. It affects about 100,000 people in the United States, and occurs more commonly in people of African descent. SCD is considered as a hypercoagulable state and venous thromboembolism (VTE) is a serious disease-specific complication. However, there have been limited real-world studies on VTE in SCD patients. This work aims to provide a comprehensive assessment of the risk factors and treatment of VTE in adults with SCD by using longitudinal real-world data. First, a retrospective cohort study on 30-day readmission was conducted to give a general understanding of the treatment of SCD. It was found that SCD patients were at high risk of readmission, and younger adults had higher risk than older adults. The risk factors vary significantly by age. These findings suggest that multifaceted, age-specific interventions are needed to improve the clinical outcomes of SCD patients. Second, the treatment patterns of pharmacological anticoagulation in adults with SCD was studied by using a retrospective, repeated cross-sectional design. The results may contribute to the optimal selection of regimens or dosing and informed decision making on anticoagulant utilization in routine care. Third, the incidence of VTE and its associated risk factors and clinical outcomes were examined. Several SCD-related complications and treatments were found to be significantly associated with VTE. Landmark survival analysis demonstrated that early management of VTE may improve the overall survival of SCD patients