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OBJECTIVE: Many patients with melanoma treated with immune checkpoint inhibitors (ICIs) do not derive response. Preclinical and retrospective studies identified that inhibition of the cyclooxygenase (COX) pathway may improve response to ICI treatment. METHODS: This prospective single site phase II trial accrued patients with advanced/metastatic melanoma. Participants underwent high-dose aspirin daily combined with pembrolizumab and ipilimumab every 3 weeks for 4 cycles followed by high-dose aspirin and pembrolizumab monotherapy. The primary endpoint was objective response rate (ORR). Longitudinal sampling of blood was performed to assess peripheral immune correlates. RESULTS: Twenty-seven subjects were enrolled with median follow-up of 32 months. An ORR of 62.9% was reached prior to discontinuation due to low likelihood of achieving the pre-specified ORR of 80%. 17 patients (63%) experienced a treatment-related adverse event (TRAEs) grade 3 or higher. A per-protocol analysis showed that patients able to continue aspirin alongside ICI through the induction period experienced significant survival benefit. Ten cytokines and increased regulatory T cells in the periphery correlated with beneficial response. CONCLUSIONS: The addition of high-dose aspirin to combination ICI within this study results in response comparable to ICI alone. Future clinical studies of COX inhibition will need to focus on mitigation of AEs to establish the clinical utility of this combination.

Current literature states the importance of mental and physical health in combating the effects of metabolic syndrome; however, there is limited information on whether providing education on the syndrome along with mental and individualized physical exercises improves perceived confidence in the older adult population. A solution to this problem would be to provide a course to this population with a primary goal of education and exercise prescription. A community case study was implemented in the spring of 2024 with the purpose of measuring perceived confidence in metabolic syndrome, management of stress and anxiety, and how to move safely with exercise. Twenty-nine older adults with an average age of 76.1 years were recruited from a local senior citizen center. A course was given to the participants that included education and prescription of exercises tailored to the needs of the individual. Before and after the course, participants completed a confidence survey investigating their confidence in lowering the risk for metabolic syndrome, managing stress/anxiety, and understanding how to move safely with exercise. Regarding the post surveys, knowing how to lower the risk of metabolic syndrome increased by 46%, learning how to manage stress and anxiety increased by 50%, and understanding how to exercise safely increased by 41%. The data from this study suggests that providing education along with specific exercise prescription improved the participant’s confidence in lowering their risk for metabolic syndrome, management of stress and anxiety, and how to move safely with exercise.

Patients that suffer from invisible chronic illness (ICI) such as autoimmune conditions, neurological conditions, and gastrointestinal problems often struggle to obtain a proper medical diagnosis due to a lack of objective indicators to help health-care providers diagnose patients with ICIs. Thus, researchers conducted interviews with 21 participants with Postural Orthostatic Tachycardia Syndrome (POTS) to determine what messages they received from health-care providers as they pursued a diagnosis, how they interpreted those messages, and what role mHealth technology may play in improving patient/provider communication and effective diagnosis/treatment of ICIs. Several themes regarding potential instructional communication intervention content emerged from the interview data, including physician communication to patients, patient interpretation of physician communication, and information-seeking via mHealth technology. Directions for future research and implications for patient and provider instruction and training, including utilizing the IDEA model, are discussed.

Background Despite its importance, recruiting a sufficient sample size for randomised controlled trials (RCTs) can pose a significant challenge, which has real-world impact on reliability of evidence, trial completion and ultimately, patient care. Technology has potential to enhance the recruitment process, but there is a lack of evidence regarding its current use and effectiveness. Consistent with findings from the PRioRiTy I study, the current research aims to explore the advantages and disadvantages to using technology during the recruitment process for RCTs. Methods Semi-structured interviews (n=7) were conducted with researchers involved in RCT recruitment in Ireland. Subsequently, a Public & Patient Involvement (PPI) panel focus group (n=3) was conducted to add further depth to these findings. The data were qualitatively analysed through ‘Reflexive Thematic Analysis’ to extract prominent themes. Results A superordinate theme arose: ‘Tech is just a medium so that you can reach more people’, along with two themes, which were corroborated by the PPI focus group: ‘Technology is used if and when the benefits outweigh the costs’ and ‘Success of recruitment through technology depends on the nature of the study.’ Conclusions This study provided a deeper understanding of the factors which influence researchers to employ technology in recruitment for RCTs. Implications suggest that future researchers should aim to adapt their recruitment approaches to meet digital tool preferences of their target cohort; and engage with patient groups in the community to allow networking opportunities for future studies. This research may contribute towards maximising efficiency in RCT recruitment.

Abstract Background Interstitial lung diseases (ILD) are a group of rare lung diseases with severe outcomes. The COST Innovator Grant aims to establish a first-of-a-kind open-access Biorepository of patient-derived induced pluripotent stem cells (iPSC) and to train researchers in the skills required to generate a robust preclinical model of ILD using these cells. This study aims to describe and evaluate the effectiveness of a training course designed to train researchers in iPSC techniques to model ILD. Methods 74 researchers, physicians and stakeholders attended the training course in Dublin in May 2022 with 31 trainees receiving teaching in practical iPSC culturing skills. The training course learners were divided into the Hands-on (16 trainees) and Observer groups (15 trainees), with the Observers attending a supervised live-streamed experience of the laboratories skills directly delivered to the Hands-on group. All participants were asked to participate in an evaluation to analyse their satisfaction and knowledge gained during the Training Course, with means compared using t-tests. Results The gender balance in both groups was predominantly females (77.4%). The Hands-on group consisted mainly of researchers (75%), whereas all participants of the Observer group described themselves as clinicians. All participants in the Hands-on group were at least very satisfied with the training course compared to 70% of the participants in the Observer group. The knowledge assessment showed that the Hands-on group retained significantly more knowledge of iPSC characteristics and culturing techniques compared to the Observers (*

Abstract Background Growth hormone deficiency (GHD) has been implicated in increased cardiovascular and cerebrovascular disease risk seen in hypopituitarism, however the mechanism remains speculative. We hypothesise that platelet abnormalities may play a contributory role. Herein we examined platelet behaviour in GHD hypopituitary patients, pre- and post-growth hormone (GH) replacement. Methods This study utilizes a physiological flow-based assay to quantify platelet function in whole blood from patient cohorts under arterial shear. Thirteen GH Naïve hypopituitary adults with GHD and thirteen healthy matched controls were studied. Patients were assessed before and after GH treatment. All other pituitary replacements were optimised before the study. In addition to a full endocrine profile, whole blood was labelled and perfused over immobilised von Willibrand factor (vWF). Seven parameters of dynamic platelet-vWF interactions were recorded using digital image microscopy and analysed by customised platelet tracking software. Results We found a significantly altered profile of platelet-vWF interactions in GHD individuals compared to healthy controls. Specifically, we observed a marked increase in platelets shown to form associations such as tethering, rolling and adherence to immobilized vWF, which were reduced post GH treatment. Speed and distance platelets travelled across vWF was similar between controls and pre-therapy GHD patients, however, this was considerably increased post treatment. This may indicate reduced platelet signaling resulting in less stable adhesion of platelets post GH treatment. Conclusions Taken together observed differences in platelet behaviour may contribute to an increased risk of thrombosis in GHD which can in part be reversed by GH therapy.

Abstract: In this article, we analyze the change in anthropogenic seismic noise level within a frequency range of 4–14 Hz, through a survey of seismic stations in California, United States, New York City, United States, and Mexicali, Baja California, Mexico from early December 2019 to late April 2020. Our analysis shows that some stations recorded a drop in anthropogenic seismic noise during the COVID-19 pandemic, and the timing of the anthropogenic noise decrease typically correlates with the timing of a strict curtailment of personal and economic activity issued by the local government. In other locations, the drop in the anthropogenic seismic noise appears not to follow the lockdown timing perfectly. During our analysis, we observed that many stations did not record a drop during the early stage of COVID-19 pandemic. Of the 19 stations of the Southern California Seismic Network that were surveyed, we found that only five show a similar extent of drop in anthropogenic seismic noise comparable to the Christmas holiday break in 2019. This suggests that the human activity that caused seismic noise did not significantly reduce during the COVID-19 pandemic near most surveyed stations in southern California. A further analysis implies that the primary seismic noise source in southern California might be traffic, and the continuation of industrial traffic, such as cargo transportation, during the COVID-19 pandemic may be the reason why many stations did not record a noise drop. Our results show that the anthropogenic seismic noise recorded by seismic stations is capable of indicating human activity, and that this metric is, particularly, powerful in measuring how localized communities initially responded to the COVID-19 pandemic.

Downscaling seasonal climate forecasts using regional climate models (RCMs) became an emerging area during the last decade owing to RCMs’ more comprehensive representation of the important physical processes at a finer resolution. However, it is crucial to test RCMs for the most appropriate model setup for a particular purpose over a given region through numerical experiments. Thus, this sensitivity study was aimed at identifying an optimum configuration in the Weather, Research, and Forecasting (WRF) model over Ethiopia. A total of 35 WRF simulations with different combinations of parameterization schemes for cumulus (CU), planetary boundary layer (PBL), cloud microphysics (MP), longwave (LW), and shortwave (SW) radiation were tested during the summer (June to August, JJA) season of 2002. The WRF simulations used a two-domain configuration with a 12 km nested domain covering Ethiopia. The initial and boundary forcing data for WRF were from the Climate Forecast System Reanalysis (CFSR). The simulations were compared with station and gridded observations to evaluate their ability to reproduce different aspects of JJA rainfall. An objective ranking method using an aggregate score of several statistics was used to select the best-performing model configuration. The JJA rainfall was found to be most sensitive to the choice of cumulus parameterization and least sensitive to cloud microphysics. All the simulations captured the spatial distribution of JJA rainfall with the pattern correlation coefficient (PCC) ranging from 0.89 to 0.94. However, all the simulations overestimated the JJA rainfall amount and the number of rainy days. Out of the 35 simulations, one that used the Grell CU, ACM2 PBL, LIN MP, RRTM LW, and Dudhia SW schemes performed the best in reproducing the amount and spatio-temporal distribution of JJA rainfall and was selected for downscaling the CFSv2 operational forecast.

BackgroundThe frequency of "exhausted" or checkpoint-positive (PD-1+CTLA-4+) cytotoxic lymphocytes (Tex) in the tumor microenvironment is associated with response to anti-PD-1 therapy in metastatic melanoma. The current study determined whether pretreatment Tex cells in locally advanced melanoma predicted response to neoadjuvant anti-PD-1 blockade.MethodsPretreatment tumor samples from 17 patients with locally advanced melanoma underwent flow cytometric analysis of pretreatment Tex and regulatory T cell frequency. Patients who met the criteria for neoadjuvant checkpoint blockade were treated with either PD-1 monotherapy or PD-1/CTLA-4 combination therapy. Best overall response was evaluated by response evaluation criteria in solid tumors version 1.1, with recurrence-free survival (RFS) calculated by the Kaplan-Meier test. The incidence and severity of adverse events were tabulated by clinicians using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.ResultsOf the neoadjuvant treated patients, 10 received anti-PD-1 monotherapy and 7 received anti-CTLA-4/PD-1 combination therapy. Of these 17 patients, 12 achieved a complete response, 4 achieved partial responses, and 1 exhibited stable disease. Surgery was subsequently performed for 11 of the 17 patients, and 8 attained a complete pathologic response. Median RFS and overall survival (OS) were not reached. Immune-related adverse events comprised four grade 3 or 4 events, including pneumonitis, transaminitis, and anaphylaxis.ConclusionThe results showed high rates of objective response, RFS, and OS for patients undergoing immune profile-directed neoadjuvant immunotherapy for locally advanced melanoma. Furthermore, the study showed that treatment stratification based upon Tex frequency can potentially limit the adverse events associated with combination immunotherapy. These data merit further investigation with a larger validation study.

PurposeTumors with low frequencies of checkpoint positive tumor-infiltrating lymphocytes (cpTIL) have a low likelihood of response to PD-1 blockade. We conducted a prospective multicenter phase II trial of intratumoral plasmid IL-12 (tavokinogene telseplasmid; "tavo") electroporation combined with pembrolizumab in patients with advanced melanoma with low frequencies of checkpoint positive cytotoxic lymphocytes (cpCTL).Patients and methodsTavo was administered intratumorally days 1, 5, and 8 every 6 weeks while pembrolizumab (200 mg, i.v.) was administered every 3 weeks. The primary endpoint was objective response rate (ORR) by RECIST, secondary endpoints included duration of response, overall survival and progression-free survival. Toxicity was evaluated by the CTCAE v4. Extensive correlative analysis was done.ResultsThe combination of tavo and pembrolizumab was well tolerated with adverse events similar to those previously reported with pembrolizumab alone. Patients had a 41% ORR (n = 22, RECIST 1.1) with 36% complete responses. Correlative analysis showed that the combination enhanced immune infiltration and sustained the IL-12/IFNγ feed-forward cycle, driving intratumoral cross-presenting dendritic cell subsets with increased TILs, emerging T cell receptor clones and, ultimately, systemic cellular immune responses.ConclusionsThe combination of tavo and pembrolizumab was associated with a higher than expected response rate in this poorly immunogenic population. No new or unexpected toxicities were observed. Correlative analysis showed T cell infiltration with enhanced immunity paralleling the clinical activity in low cpCTL tumors.

BackgroundInterleukin 12 (IL-12) is a pivotal regulator of innate and adaptive immunity. We conducted a prospective open-label, phase II clinical trial of electroporated plasmid IL-12 in advanced melanoma patients (NCT01502293).Patients and methodsPatients with stage III/IV melanoma were treated intratumorally with plasmid encoding IL-12 (tavokinogene telseplasmid; tavo), 0.5 mg/ml followed by electroporation (six pulses, 1500 V/cm) on days 1, 5, and 8 every 90 days in the main study and additional patients were treated in two alternative schedule exploration cohorts. Correlative analyses for programmed death-ligand 1 (PD-L1), flow cytometry to assess changes in immune cell subsets, and analysis of immune-related gene expression were carried out on pre- and post-treatment samples from study patients, as well as from additional patients treated during exploration of additional dosing schedules beyond the pre-specified protocol dosing schedule. Response was measured by study-specific criteria to maximize detection of latent and potentially transient immune responses in patients with multiple skin lesions and toxicities were graded by the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0).ResultsThe objective overall response rate was 35.7% in the main study (29.8% in all cohorts), with a complete response rate of 17.9% (10.6% in all cohorts). The median progression-free survival in the main study was 3.7 months while the median overall survival was not reached at a median follow up of 29.7 months. A total of 46% of patients in all cohorts with uninjected lesions experienced regression of at least one of these lesions and 25% had a net regression of all untreated lesions. Transcriptomic and immunohistochemistry analysis showed that immune activation and co-stimulatory transcripts were up-regulated but there was also increased adaptive immune resistance.ConclusionsIntratumoral Tavo was well tolerated and led to systemic immune responses in advanced melanoma patients. While tumor regression and increased immune infiltration were observed in treated as well as untreated/distal lesions, adaptive immune resistance limited the response.

COVID-19 has increased the emphasis on social emotional learning (SEL) in our schools. Unfortunately, the current approaches to SEL can often perpetuate racial hierarchies, apply a deficit lens toward students, and emphasize the need for student-level change while ignoring the historical, social, and cultural influences that created and actively maintain oppressive environments through which students are required to navigate. Therefore, the authors offer an Antiracist Social Emotional Justice Learning (ASEJL) approach for educators to apply to promote freedom and justice for students through empowerment, hope, and joy. The AEJL approach emphasizes applying Critical Theoretical Frameworks, Anti-Bias Building Blocks, Student and Family Voice, Strengths Based Empowerment, and Homeplace to combat the current colorblind approach to SEL while cultivating the interests and talents of students and families from diverse backgrounds.

Brian Goldstein, Willie H Oglesby Thomas Jefferson University, Philadelphia, PA, USACorrespondence: Brian Goldstein, Thomas Jefferson University Student, 901 Walnut Street, 10th Street, Philadelphia, PA, 19107, USA, Tel +1 215-287-7688, Fax +1 866-330-2654, Email BDG107@students.jefferson.eduIntroduction: From the early days of the pandemic, US cities have implemented a variety of public health measures to reduce the spread of COVID-19. This study investigates which policies were most effective in reducing cases of COVID-19 in four major cities: Philadelphia, New York City, Baltimore, and Chicago.Methods: Through a cross-comparative analysis, we developed a timeline that tracked the implementation of a range of public health measures along with changes in COVID-19 cases, hospitalizations, and deaths. Data were collected from publicly available government sites and from press releases.Results: The results from the stay-at-home orders illustrate the delayed impact it has in reducing COVID-19 cases and hospitalizations. The mask mandate led to the immediate and sustained reduction in cases across all four cities. During the spike of COVID-19 in the Fall of 2020, restrictions on indoor dining contributed significantly to reducing COVID-19 cases.Discussion: Of all the measures that were examined, the implementation of mask mandates was most closely associated with a decline in COVID-19 cases, hospitalizations, and deaths across all four cities. Restrictions on indoor dining were also associated with a reduction in COVID-19 cases. Future studies should further investigate the adherence to different policies to better understand their impacts.Keywords: public policy, healthcare, reform, health system, population health

Chemical exchange saturation transfer (CEST) is a relatively novel magnetic resonance imaging (MRI) technique with an image contrast designed for in vivo measurement of certain endogenous molecules with protons that are exchangeable with water protons, such as amide proton transfer commonly used for neuro-oncology applications. Recent technological advances have made it feasible to implement CEST on clinical grade scanners within practical acquisition times, creating new opportunities to integrate CEST in clinical workflow. In addition, the majority of CEST applications used in neuro-oncology are performed without the use gadolinium-based contrast agents which are another appealing feature of this technique. This review is written for clinicians involved in neuro-oncologic care (nonphysicists) as the target audience explaining what they need to know as CEST makes its way into practice. The purpose of this article is to (1) review the basic physics and technical principles of CEST MRI, and (2) review the practical applications of CEST in neuro-oncology.

ABSTRACT Pseudomonas aeruginosa is an opportunistic pathogen that requires iron for growth and virulence, yet this nutrient is sequestered by the innate immune system during infection. When iron is limiting, P. aeruginosa expresses the PrrF1 and PrrF2 small RNAs (sRNAs), which post-transcriptionally repress expression of nonessential iron-containing proteins, thus sparing this nutrient for more critical processes. The genes for the PrrF1 and PrrF2 sRNAs are arranged in tandem on the chromosome, allowing for the transcription of a longer heme-responsive sRNA, termed PrrH. While the functions of PrrF1 and PrrF2 have been extensively studied, the role of PrrH in P. aeruginosa physiology and virulence is not well understood. In this study, we performed transcriptomic and proteomic studies to identify the PrrH regulon. In shaking cultures, the pyochelin synthesis proteins were increased in two distinct prrH mutants compared to the wild type, while the mRNAs for these proteins were not affected by the prrH mutation. We identified complementarity between the PrrH sRNA and the sequence upstream of the pchE mRNA, suggesting the potential for PrrH to directly regulate the expression of genes for pyochelin synthesis. We further showed that pchE mRNA levels were increased in the prrH mutants when grown in static but not shaking conditions. Moreover, we discovered that controlling for the presence of light was critical for examining the impact of PrrH on pchE expression. As such, our study reports on the first likely target of the PrrH sRNA and highlights key environmental variables that will allow for future characterization of PrrH function. IMPORTANCE In the human host, iron is predominantly in the form of heme, which Pseudomonas aeruginosa can acquire as an iron source during infection. We previously showed that the iron-responsive PrrF small RNAs (sRNAs) are critical for mediating iron homeostasis during P. aeruginosa infection; however, the function of the heme-responsive PrrH sRNA remains unclear. In this study, we identified genes for pyochelin siderophore biosynthesis, which mediates uptake of inorganic iron, as a novel target of PrrH regulation. This study therefore highlights a novel relationship between heme availability and siderophore biosynthesis in P. aeruginosa.

The goal of the current article is to conduct a widescale empirical investigation on the (in)efficacy of Harman's single-factor test by showing that the approach is insensitive to aspects of research design known to influence common method bias (CMB). Our systematic literature review of 1,619 sources demonstrates that the amount of variance explained by the first factor of Harman's single-factor test does not differ between cross-sectional and multi-wave, single-source and multi-source, or mono-method and multi-method studies. We instead find that extraneous aspects of studies influence the amount of variance explained, including the number of studied indicators and retained factors. These results therefore suggest that Harman's single-factor test is not a reliable assessment of CMB, and we hope these results prevent future researchers from applying the analysis. Our discussion concludes with alternative suggestions for identifying and addressing CMB, such as the application of sophisticated research designs and marker variable techniques. [ABSTRACT FROM AUTHOR]

Context: Burnout is a psychological syndrome consisting of increased emotional exhaustion (EE), depersonalization (DP), and decreased personal accomplishment (PA). To date, examinations of burnout among athletic training students (ATS) is limited. Objective: To determine prevalence and antecedents of burnout among ATS. Design: Cross-sectional study. Setting: Web-based survey. Patients or Other Participants: Students enrolled in athletic training programs (ATP). Intervention(s): A survey assessed demographics, stressors, and burnout measured by the Maslach Burnout Inventory-Human Services Survey. Main Outcome Measure(s): Multiple regression analyses were used to determine relationships between variables. Results: A total of 725 students participated. Most respondents were undergraduates (n = 582, 80%), female (n = 518, 71%), Caucasian (n = 564, 78%), and single (n = 422, 58%). Mean burnout scores for EE, DP, and PA were 33 ± 10, 17 ± 4.5, and 39 ± 5.8, respectively. Survey responses showed that 70.8% of undergraduate and 62.9% of graduate students reported high EE. All the students (100%) in both samples reported high DP. Undergraduates pursuing internships or residencies (b = -7.69, P < 0.001) and who were currently enrolled in non-Division I institutions (b = -2.90, P < 0.01) had decreased EE. Increased stress revealed increased EE (overall stress: b = 3.11, P < 0.001; social stress: b = 1.32, P < 0.05; class stress: b = 1.45, P < 0.05). Increases in clinical hours also related to increased EE (b = 1.49, P < 0.001). Those pursuing internships or residencies (b = -2.10, P < 0.05) and who were female (b = -2.10, P < 0.05) reported decreased DP. Being married (b = 2.87, P < 0.01), increased clinical hours (b = 0.77, P < 0.001), and social stress (b = 0.59, P < 0.05) resulted in increased DP. Increased PA was seen in students intending to pursue graduate education (b = 1.76, P < 0.05) and female students (b = 1.17, P < 0.05). Graduate students' stress levels revealed increased EE (b = 6.57, P < 0.01) and DP (b = 0.98, P < 0.05). Conclusions: Differences exist between undergraduate and graduate burnout scores and associated predictors. Further research is needed to identify student responses to burnout.