35333 research outputs found
Sort by
Reducing Opioid Use Following Posterior Spinal Fusion Procedures: A Pilot Project
Full text linkImportance: Opioid misuse and mortality remain a prevalent problem in the United States and there is a high rate of chronic opioid-use after spinal fusions. Current guidelines recommend the optimization of non-opioid analgesics as a primary pain control strategy with opioids acting as a secondary agent. Objective: To pilot an analgesic decision tree (ADT) featuring non-opioid analgesics to reduce postoperative pain, opioid consumption, and the incidence of adverse events during the first 48 hours after patients undergo a posterior spinal fusion. Methods: A literature review of opioid-sparing analgesics was conducted and a protocol developed as an interdisciplinary collaboration. The ADT was piloted in an intensive care unit for 10 weeks. Pain control, opioid consumption, and the incidence of adverse events were compared to historical controls from a previous 10-week period. Results: In total, 12 historical control charts were reviewed and 17 patients enrolled in the ADT group. There was no significant difference in groups. The ADT did not affect NRS scores, CPOT scores, MME consumption, or ORAE in a statistically significant way. Power analyses indicate that a minimum of 9894 patients are required to detect significance. Conclusions: The ADT may be non-inferior in pain control and opioid consumption, but future testing is required. Further pilots should control confounding influences to optimize power analyses. Subsequent projects should utilize these power analyses to determine the ADT’s influence on pain control, opioid consumption, and adverse event incidence
Empowering Emerging Air Medical Leaders Through A Novel Professional Development Program Adapting National Nursing And Healthcare Management Competencies To A Multi-State Air Medical Service
Full text linkEmpowering Emerging Air Medical Leaders through a Novel Professional Development Program Adapting National Nursing and Healthcare Management Competencies to a Multi-State Air Medical ServiceHigh turnover in the nursing workforce has led to clinicians with limited experience being promoted to leadership roles without proper training or support. Nurse leaders directly impact clinical outcomes and retention. The financial burden of turnover is significant, as health systems must continually replace employees. Despite this, limited evidence exists on effective professional development and retention strategies in non-traditional, non-hospital settings. This DNP project sought to adapt and implement a novel professional development program, derived from the American Organization for Nursing Leadership’s Nurse Manager Competencies, to increase the self-efficacy of front-line, unit-level managers in a decentralized air medical organization. Emerging leaders with two years or less in their management role attended a two-day development program, conducted in-person and virtually Overall, the program demonstrated a statically significant increase (M1 = 7.15, M2 = 8.13, t = -6.47, p = .008) in the emerging leader’s self-efficacy across selected AONL nurse manager competencies and domains including: Professionalism (9.49%), Communication and Relationship Management (21.17%), Business Skills and Principles (11.68%), and Leadership (13.16%). All participants would recommend the program, with a majority (61.1%, n=11) recommending in-person delivery. This competency-based program, implemented within a large air medical organization, demonstrated a statistically significant increase in participants’ leadership self-efficacy and a high degree of participant satisfaction. Its scalable framework enables broader utilization in decentralized and non-hospital healthcare environments through the delivery of innovative curricula via both in-person and virtual modalities
Long-Term Neurocognitive And Behavioral Outcomes In Patients With Non-Syndromic Craniosynostosis
No full textIn this study, we explore the long-term cognitive capabilities and behaviors of patients in late adolescence and early adulthood who underwent corrective surgery for craniosynostosis as infants. Participants were identified from the operating records of three craniofacial plastic surgeons from a single institution. Patients 16 years of age or older who had undergone surgery as infants for any type of non-syndromic craniosynostosis were contacted via phone or email and prospectively enrolled. Participants underwent standardized neurocognitive testing using the BEERY and WASI. A subset of patients additionally underwent behavioral testing using the CAARS-2, ASR, SRS-2, and BRIEF standardized tests.A total of 32 participants were included in neurocognitive testing, with a mean age of 18.9 3.4 years old. 22 participants underwent behavioral testing with a mean age of 20 3.6 years old. The mean score for the WASI FSIQ-4 was 102, with a mean PRI score of 102 and a mean VCI score of 103, which were not significantly different than the general population. However, the mean score for BEERY VMI was 95, BEERY VP was 97, and BEERY MC was 92, all of which were significantly lower than the population average. 23% of participants scored high or very high on the CAARS-2 ADHD index, and of the 44 total patients contact, 13.6% either confirmed having a diagnosis of autism or tested moderate-severe on the SRS-2 autism screener. Patients have comparable neurocognition relative to the general population, with deficits in visual and motor integration. However, there is a significantly higher prevalence of ADHD and autism-related behaviors in this cohort. These findings are useful in counseling parents with infants who have been diagnosed with craniosynostosis, as well as in directing early screening and intervention for these patients to provide the resources and therapies families need
The Effect Of The Ketogenic Diet On The Circadian Rhythmicity Of Glymphatic Function In Mice
No full textThe glymphatic system is a network of perivascular spaces that coordinates removal of waste products from brain parenchyma. It is known that the glymphatic system is under control of the circadian rhythm, however little is known about factors that influence this control. Data has shown that the expression of specific circadian rhythm genes is altered when exposed to the ketogenic diet. In this experiment, we show that the day-night rhythmicity of glymphatic function is extinguished in mice exposed to the ketogenic diet through the up-regulation of influx of cerebrospinal fluid to brain parenchyma and the reduction in cervical lymph node drainag
Tigit And Gdf-15 As Biomarkers And Targets In Renal Cell Carcinoma Resistant To Immune Checkpoint Inhibitors
No full textImmune checkpoint inhibitors have become the standard of care treatment for local and systemic clear cell renal cell carcinoma (RCC). However, a subset of patients fail these therapies due to the development of disease refractory to such treatments. Therefore, it is imperative that we study the potential mechanisms of resistance to immune checkpoint inhibition within the tumor microenvironment. Likewise, establishing biomarkers indicative of treatment resistance may benefit clinicians and patients when it comes to the initial selection of treatment. Moreover, biomarkers of resistance might also serve as potential drug targets. In this study we analyzed expression of TIGIT and GDF-15, two proteins expressed within the tumor microenvironment, as potential biomarkers for increased immune tolerance in RCC. TIGIT is believed to act as a coinhibitory immune checkpoint promoting T cell anergy and increased tumor immune tolerance, while GDF-15 is a secreted cytokine hypothesized to downregulate tumor infiltration by immune and pro-inflammatory cells, though its mechanism is not yet fully elucidated. We hypothesized a role for these proteins in metastatic seeding, and thus increased expression at metastatic sites. Additionally, we expected worsened clinical outcomes such as overall survival and response to therapy with increased TIGIT and GDF-15. We used both quantitative immunofluorescence and immunohistochemistry to identify and quantify the expression of these proteins in tissue microarrays of renal cell carcinoma, including primary tumors, metastases, and normal renal tissue. We found no significant differences in TIGIT positivity in T cells between primary RCC tumors and patient matched metastases, and found that TIGIT positivity in RCC is comparable to lung cancer, but lower than in other malignancies such as cervical, melanoma, and head and neck cancer. We revealed an inverse association between TIGIT positivity and two other checkpoint proteins PD-1 and LAG3. Immunological staining of patient tumors for GDF-15 did not reveal differences in expression when comparing primary tumor versus metastatic sites or normal renal parenchyma. However, quantification of GDF-15 using quantitative immunofluorescence revealed an association with poorer therapeutic response, including decreased progression free survival in patients with high GDF-15 expression at metastatic sites. Furthermore, correlation studies with previously published spatial proteomic data revealed a decrease in tumor B and T cell infiltration with increased GDF-15 expression. The expression of TIGIT and GDF-15 in immune checkpoint inhibitor resistant tumors has made these proteins conceivable targets for novel therapies with neutralizing monoclonal antibodies or small molecule inhibitors. As patients continue to be enrolled in basket clinical trials targeting TIGIT or GDF-15 in conjunction with other immune checkpoint inhibitors, our findings support continued consideration for evaluating these markers in patients with RCC. We showed that in RCC expression of GDF-15 and TIGIT was variable and thus blockading therapies may require selective employment in this patient population
Evaluating Nebulizer Efficiency For Phage Therapy In Drug-Resistant Pseudomonas Infections
Full text linkBackground
The global rise of multidrug-resistant (MDR) Pseudomonas aeruginosa necessitates novel therapeutic approaches, particularly for patients with cystic fibrosis (CF). Bacteriophage therapy, delivered via inhalation, offers a targeted and potentially transformative treatment for pulmonary infections caused by MDR pathogens. This study aimed to evaluate the effects of nebulizer type and bacteriophage morphology on viable phage recovery and aerosol particle size distribution, hypothesizing that nebulizer-phage compatibility significantly influences the delivery of viable phages to the lower respiratory tract.
Methods
We conducted an in vitro study utilizing two clinically relevant nebulizer systems: the Pari LC Plus jet nebulizer and the Altera eFlow vibrating mesh nebulizer. Four phages with varying morphologies—OMKO-1, TIVP-H6, LPS-5, and MS2—were aerosolized through each device. The Next Generation Cascade Impactor was employed to measure aerosolized particle sizes and recover viable phages across defined aerodynamic size fractions. Data on viable phage recovery, particle size distribution, and respirable fractions (≤5.0 μm) were collected and analyzed using factorial ANOVA to assess the effects of phage morphology and nebulizer type.
Results
The results demonstrated significant variability in viable phage recovery and particle size distribution across nebulizer-phage combinations. The Pari LC Plus produced aerosols with a lower mass median aerodynamic diameter (MMAD) than the Altera eFlow (4.27 ± 1.03 μm vs. 5.85 ± 0.90 μm; p \u3c 0.001), delivering a higher proportion of viable phages to the respirable fraction for all phage types except LPS-5. The OMKO-1 phage exhibited the greatest difference in viability between nebulizers, with the Pari LC Plus preserving 47.3% ± 5.0% of viable phages compared to 28.3% ± 22.1% for the Altera eFlow. In contrast, the control phage MS2 achieved the highest overall recovery, highlighting the structural advantages of tailless phages in maintaining viability during nebulization.
Conclusions
This study concluded that phage morphology and nebulizer type are critical determinants of aerosol delivery efficacy. Jet nebulizers, such as the Pari LC Plus, may be more effective for larger, tailed phages, while vibrating mesh nebulizers can deliver tailless phages with greater efficiency. These findings underscore the importance of tailoring phage-nebulizer pairings to optimize therapeutic outcomes. Future studies should focus on in vivo validation and the development of standardized protocols to advance the clinical application of inhaled phage therapy for MDR P. aeruginosa infections
Macrophage Migration Inhibitory Factor And D-Dopachrome Tautomerase As Biomarkers And Key Modulators Of Tumor Progression In Head And Neck Cancer And Melanoma
Full text linkMacrophage Migration Inhibitory Factor (MIF) and its homolog D-dopachrome Tautomerase (DDT) are pro-inflammatory cytokines implicated in tumor progression across multiple cancers. Both MIF and DDT act through canonical CD74 and non-canonical CXCR2/4/7 signaling pathways, which contribute to immune suppression and tumor progression. Elevated MIF levels are associated with metastasis and poor prognosis in HNC and contribute to immune checkpoint inhibitor (ICI) resistance in melanoma. DDT’s role in cancer is not well understood. This study aims to evaluate the expression and therapeutic potential of MIF and DDT inhibition, focusing on their ability to modulate immune responses and improve survival outcomes as novel therapeutic targets. We focused on HNC and melanoma for our studies given the preclinical data implicating MIF in the pathogenesis of these malignancies. In the HNC arm of our study, we utilized immune-sensitive (MOC1) and immune-resistant (MOC2) mouse oropharyngeal carcinoma tumor in vivo models to assess the efficacy of dual MIF and DDT inhibition. Genetically modified mice engineered to express human low (CATT5) and high (CATT7) MIF expression promoters were also used to evaluate the impact of MIF levels on HNC progression and survival. We also performed a retrospective analysis of 524 unique bulk RNA sequencing samples from patients with HNC from The Cancer Genome Atlas (TCGA) to correlate tumor cytokine expression with patient outcomes. We evaluated how MIF, DDT, and CD74 expression correlate with survival outcomes, and how expression changes when stratified by HPV status. For the melanoma arm of this project, we obtained bulk RNA sequencing from 97 patient-derived tumor samples collected by the Yale Skin Cancer SPORE Biorepository from 2002-2020. Gene expression of MIF, DDT, CD74, and inflammatory markers were correlated with patient survival outcomes. In murine models of HNC, dual inhibition of MIF and DDT with anti-PD-1/cisplatin significantly delayed tumor growth and improved survival compared to cisplatin/anti-PD-1 treatment alone. Monotherapy with anti-MIF or anti-DDT delayed tumor growth but was less effective than combination treatment. Additionally, MOC2-bearing mice did not benefit from anti-MIF/anti-DDT therapy. Genetically modified mice with low MIF expression (CATT5) showed better survival than high MIF-expressing (CATT7) mice in MOC1 tumors, while the opposite was observed in MOC2-bearing mice. For HNC, TCGA analysis revealed significantly elevated MIF and DDT expression in tumor tissues compared to benign tissues, with higher expression linked to poorer survival outcomes. In the Yale melanoma cohort, higher levels of MIF and DDT and lower levels of CD74 were correlated with worse survival. Lower MIF and DDT expression, alongside higher CD74:MIF and CD74:DDT ratios, correlated with improved survival in melanoma patients. Specifically, high CD74:MIF and CD74:DDT ratios were associated with increased immune cell infiltration. These findings suggest that MIF and DDT are promising therapeutic targets, particularly in melanoma and HNC. Dual inhibition of MIF and DDT not only suppresses tumor growth but also enhances immune cell infiltration, reshaping the tumor microenvironment (TME). These results support dual MIF and DDT inhibition as a synergistic approach to overcome treatment resistance in melanoma and HNC. The identification of MIF and DDT as therapeutic targets opens new avenues for combination therapies that could benefit patients with resistant cancers. Further investigation is needed to optimize patient stratification and refine therapeutic combinations to maximize clinical benefits
Towards Multi-Modal Multi-Document Understanding Capabilities in Foundation Models
Full text linkContemporary foundation models are predominantly evaluated on isolated documentor image-understanding tasks, thereby overlooking the inherent multimodal multi-document reasoning that characterizes scientific inquiry. To bridge this gap, M3SCIQA is introduced, aMulti-Modal,Multi-document Scientific Question Answering benchmark crafted to test foundation models in practical scientific research settings. A comprehensive evaluation of 18 leading foundation models shows a substantial performance gap between models and human experts. Detailed error analysis reveals persistent deficiencies in both scientific visual reasoning tasks and long-range retrieval. Addressing the former, SPACECUE offers a concise yet effective visual prompting that overlays grid coordinates and Semantic-SAM masks on scientific images to direct model attention to query-relevant regions. This strategy yields accuracy improvements for GPT-4V and Claude 3 Opus on the Physics and Biology subset of the MMMU benchmark
Fatigue, Recovery, and the Economics of Remote Work
Full text linkI propose a model in which workers experience fatigue over time and can restore productivity by taking breaks. Optimal schedules feature evenly spaced, full-recovery breaks; when breaks are costless, they should occur frequently, but switching costs make the optimal number finite. The model is embedded in a principal-agent framework with contractual frictions. When employers control the schedule, workers overwork; when workers self-manage, they overrest. Both lead to inefficiencies. These results shed light on the trade-offs in remote work arrangements, especially following COVID-19. The analysis highlights how control rights, incentive design, and recovery constraints interact—and why neither rigid supervision nor full autonomy guarantees efficiency
Scalable Targeting of Social Protection: When Do Algorithms Out-Perform Surveys and Community Knowledge?
Full text linkInnovations in big data and algorithms are enabling new approaches to target interventions at scale. We compare the accuracy of three different systems for identifying the poor to receive benefit transfers — proxy means-testing, nominations from community members, and an algorithmic approach using machine learning to predict poverty using mobile phone usage behavior — and study how their cost-effectiveness varies with the scale and scope of the program. We collect mobile phone records from all major telecom operators in Bangladesh and conduct community-based wealth rankings and detailed consumption surveys of 5,000 households, to select the 22,000 poorest households for $300 transfers from 106,000 listed households. While proxy-means testing is most accurate, algorithmic targeting becomes more cost-effective for national-scale programs where large numbers of households have to be screened. We explore the external validity of these insights using survey data and mobile phone records data from Togo, and cross-country information on benefit transfer programs from the World Bank