Unique Population Research Articles

Clinical Impact of Comprehensive Molecular Profiling in Adolescents and Young Adults with Sarcoma.

Sarcomas are a heterogenous group of tumours that commonly carry poor prognosis with limited therapeutic options. Adolescents and young adults (AYAs) with sarcoma are a unique and understudied patient population that have only achieved modest survival gains compared to other groups. We present our institutional experience of AYAs with sarcoma who underwent comprehensive molecular profiling (CMP) via either large-panel targeted DNA sequencing or whole genome and transcriptome sequencing and evaluated the feasibility and clinical impact of this approach. Genomic variants detected were determined to be clinically relevant and actionable following evaluation by the Molecular Tumour Board. Clinicians provided feedback regarding the utility of testing three months after reporting. Twenty-five patients who were recruited for CMP are included in this analysis. The median time from consent to final molecular report was 45 days (interquartile range: 37-57). Potentially actionable variants were detected for 14 patients (56%), and new treatment recommendations were identified for 12 patients (48%). Pathogenic germline variants were identified in three patients (12%), and one patient had a change in diagnosis. The implementation of CMP for AYAs with sarcoma is clinically valuable, feasible, and should be increasingly integrated into routine clinical practice as technologies and turnaround times continue to improve.

Oreo Cookie Treatment Lowers LDL Cholesterol More Than High-Intensity Statin therapy in a Lean Mass Hyper-Responder on a Ketogenic Diet: A Curious Crossover Experiment.

Recent research has identified a unique population of 'Lean Mass Hyper-Responders' (LMHR) who exhibit increases in LDL cholesterol (LDL-C) in response to carbohydrate-restricted diets to levels ≥ 200 mg/dL, in association with HDL cholesterol ≥ 80 mg/dL and triglycerides ≤ 70 mg/dL. This triad of markers occurs primarily in lean metabolically healthy subjects, with the magnitude of increase in LDL-C inversely associated with body mass index. The lipid energy model has been proposed as one explanation for LMHR phenotype and posits that there is increased export and subsequent turnover of VLDL to LDL particles to meet systemic energy needs in the setting of hepatic glycogen depletion and low body fat. This single subject crossover experiment aimed to test the hypothesis that adding carbohydrates, in the form of Oreo cookies, to an LMHR subject on a ketogenic diet would reduce LDL-C levels by a similar, or greater, magnitude than high-intensity statin therapy. The study was designed as follows: after a 2-week run-in period on a standardized ketogenic diet, study arm 1 consisted of supplementation with 12 regular Oreo cookies, providing 100 g/d of additional carbohydrates for 16 days. Throughout this arm, ketosis was monitored and maintained at levels similar to the subject's standard ketogenic diet using supplemental exogenous d-β-hydroxybutyrate supplementation four times daily. Following the discontinuation of Oreo supplementation, the subject maintained a stable ketogenic diet for 3 months and documented a return to baseline weight and hypercholesterolemic status. During study arm 2, the subject received rosuvastatin 20 mg daily for 6 weeks. Lipid panels were drawn water-only fasted and weekly throughout the study. Baseline LDL-C was 384 mg/dL and reduced to 111 mg/dL (71% reduction) after Oreo supplementation. Following the washout period, LDL-C returned to 421 mg/dL, and was reduced to a nadir of 284 mg/dL with 20 mg rosuvastatin therapy (32.5% reduction). In conclusion, in this case study experiment, short-term Oreo supplementation lowered LDL-C more than 6 weeks of high-intensity statin therapy in an LMHR subject on a ketogenic diet. This dramatic metabolic demonstration, consistent with the lipid energy model, should provoke further research and not be seen as health advice.

The role of self-criticism and self-compassion in the development of PTSD among midwives

ObjectiveHealthcare providers might develop emotional distress following direct and indirect exposure to traumatic events. Evidence shows that midwives, who care for women in complicated situations, are often exposed to circumstances that have a potential to lead to a variety of psychological reactions, including symptoms identified with post-traumatic stress disorder (PTSD). Nevertheless, the positive-healthy context in which childbirth is mainly perceived raises questions regarding the protective role of personality traits, which are related to processing methods of stress and pain, in the development of PTSD among this unique population. This study aimed to explore the associations between traits such as self-compassion, self-criticism, resilience, cognitive thinking, and pain catastrophizing and PTSD symptoms among Israeli midwives. SettingUsing a quantitative cross-sectional study,123 midwives from ten hospitals in Israel anonymously reported their characteristics and severity of stress and/or PTSD symptoms by filling out the Psychopathy Checklist questionnaire. Analysis of personality traits was performed via the following questionnaires: Self-Compassion Scale - Short Form, Depressive Experiences Questionnaire - Self Criticism, and the Connor-Davidson Resilience Scale. Additionally, we measured the level of catastrophizing pain by employing the Pain Catastrophizing Scale questionnaire. FindingsMost of the midwives reported existing post-trauma symptoms, among them 11.38% had been diagnosed with PTSD. Severity of the PTSD correlated with their self-criticism and the pain catastrophizing rates. Additional examination of the involvement of personality traits showed that midwives with high self-criticism, low mental resilience, besides a high rate of pain catastrophizing, were more vulnerable to developing PTSD. ConclusionsThe findings can help to refine the understanding regarding the involvement of midwives' personality characteristics in the process of PTSD onset. Vulnerable midwives have been identified as those at risk to develop PTSD symptoms. Implications for practiceThe clinical significance of these insights is to promote the ability to identify midwives who are at risk to develop PTSD. Furthermore, this information might help to produce training programs and a support network to empower self-compassion and mental resilience, and to minimize self-criticism in order establish a support network, which would help to deal with the difficult experiences they face at work.

Evidence of a small, island-associated population of common bottlenose dolphins in the Mariana Islands

Small, island-associated populations of cetaceans have evolved around numerous oceanic islands, likely due to habitat discontinuities between nearshore and offshore waters. However, little is known about the ecology and structure of cetacean populations around the Mariana Islands, a remote archipelago in the western Pacific Ocean. We present sighting, photo-identification, and genetic data collected during twelve years of surveys around these islands that reveal the existence of a small, island-associated population of bottlenose dolphins. Nearly half of the photo-identified individuals were encountered in more than one year. Both haplotypic and nuclear genetic diversity among sampled individuals was low (haplotypic diversity = 0.701, nuclear heterozygosity = 0.658), suggesting low abundance. We used mark-recapture analysis of photo-identification data to estimate yearly abundance in the southern portion of the population’s range from 2011 to 2018. Each abundance estimate was less than 54 individuals, with each upper 95% confidence interval below 100. Additional survey effort is necessary to generate a full population abundance estimate. We found extensive introgression of Fraser’s dolphin DNA into both the mitochondrial and nuclear genomes of the population, suggesting at least two hybridization events more than two generations in the past. The Mariana Islands are used extensively by the U.S. military for land and sea training operations. Thus, this unique bottlenose dolphin population likely faces high exposure to multiple threats.

Pth1r in Neural Crest Cells Regulates Nasal Cartilage Differentiation

Neural crest cells (NCC) arise from the dorsal margin of the neural plate border and comprise a unique cell population that migrates to and creates the craniofacial region. Although factors including Shh, Fgf8, and bone morphogenetic proteins have been shown to regulate these biological events, the role of parathyroid hormone 1 receptor (Pth1r) has been less studied. We generated an NCC-specific mouse model for Pth1r and researched gene expression, function, and interaction focusing on nasal cartilage framework and midfacial development. Wnt1-Cre;Pth1rfl/fl;Tomatofl/+ mice had perinatal lethality, but we observed short snout and jaws, tongue protrusion, reduced NCC-derived cranial length, increased mineralization in nasal septum and hyoid bones, and less bone mineralization at interfrontal suture in mutants at E18.5. Importantly, the mutant nasal septum and turbinate cartilage histologically revealed gradual, premature accelerated hypertrophic differentiation. We then studied the underlying molecular mechanisms by performing RNA seq analysis and unexpectedly found that expression of Ihh and related signaling molecules was enhanced in mutant nasomaxillary tissues. To see if Pth1r and Ihh signaling are associated, we generated a Wnt1-Cre; Ihh fl/fl; Pth1r fl/fl;Tomatofl/+ (DKO) mouse and compared the phenotypes to those of each single knockout mouse: Wnt1-Cre; Ihh fl/fl;Pth1rfl/+;Tomatofl/+ (Ihh-CKO) and Wnt1-Cre;Ihhfl/+; Pth1r fl/fl;Tomatofl/+ (Pth1r-CKO). Ihh-CKO mice displayed a milder effect. Of note, the excessive hypertrophic conversion of the nasal cartilage framework observed in Pth1r-CKO was somewhat rescued DKO embryos. Further, a half cAMP responsive element and the 4 similar sequences containing 2 mismatches were identified from the promoter to the first intron in Ihh gene. Gli1-Cre ERT2 ;Pth1rfl/fl;Tomatofl/+, a Pth1r-deficient model targeted in hedgehog responsive cells, demonstrated the enlarged hypertrophic layer and significantly more Tomato-positive chondrocytes accumulated in the nasal septum and ethmoidal endochondral ossification. Collectively, the data suggest a relevant Pth1r/Ihh interaction. Our findings obtained from novel mouse models for Pth1r signaling illuminate previously unknown aspects in craniofacial biology and development.

Abstract B043: Dual epigenetic therapy combined with anti-PD1 rescues HMA-induced suppressive myeloid phenotype and reduces tumor growth in a PDAC model

Abstract INTRODUCTION. We previously showed, using the PDAC mouse model KPC (KrasLSL G12D/+; p53 r172H/+; Pdx1-Cre), that sequential treatment with the DNA hypomethylating drug decitabine (5aza-dC; DAC) followed by anti-PD-1 led to increased tumor necrosis, slower tumor growth, increased tumor-infiltrating CD8+ and CD4+ T-cells (TILs), and significantly increased mean survival time. However, despite these positive outcomes, the KPC tumors eventually escaped from treatment. We identified a unique myeloid population as a specific subtype of M2-polarized putatively immunosuppressive Chil3+ macrophages (TAMs). Here we further characterize the recruitment mechansism of these cells and show that HDAC inhibition can further improve the efficacy of DAC+PD-1 treatment. METHODS. Primary macrophages were isolated from bone marrow (BMDM) or the peritoneum of 6-8 weeks mice and RAW264.7 cells were also used and exposed to conditioned media from primary KPC cell lines after HMA treatment (KPC-SN-DAC). Gene set enrichemnt analysis was done on RNASeq data from myeloid cells and validated by RT-qPCR. We used cytokine arrays to identify secreted cytokines from KPC cells. KPC cells were orthtopically injected in C57BL/6 mice, and tumor growth was followed by untrasound. Treatments were started when tumor reaced a size of 1 mm3. RESULTS. Expression profiling reveled that exposure of the myeloid cells to KPC-SN-DAC resulted in an HMA-specific M2-like gene signature. Notably DAC alone had minimal effect on myeloid cells polarization. To assess which factors might trigger this polarization we employed cytokine arrays and identified a number of candidate cytokines induced or secreted from KPC cells specifically following HMA treatment. In order to revert this unfavorable cytokine profile, we have evaluated the combination of DAC with four different HDAC inhibitors with reported immunomodulatory effects: Romidepsin (ROMI), Domatinostat (DOMA), Pracinostat (PRAC) and Entinostat (ENT). In vitro synergy studies through cell viability assays showed that ROMI, PRAC and DOMA synergized at low doses with DAC. Pofiling of supernatants from KPC cells treated with a combination of DAC+HDACis showed that, while ROMI had limited effect, PRAC and DOMA reverted DAC-induced cytokine secretion. Lastly, we tested in vivo the combination of DAC+ROMI/DOMI/PRAC+PD1 using mice orthotopically injected with KPC cells. The combination DAC+PRAC+PD1 showed reduced tumor volume compared to DAC+PD1. Moreover, PRAC+PD1 significantly improved overall survival. Interestingly, HDAC inhibition rescued the increased Chil3 expression in DAC+PD1 treated tumors. CONCLUSIONS. Our results show that paracrine rather than direct effect of hypomethylating therapy is responsible for suppressive myeloid polarization and characterize a specific effect of hypomethylating therapy on immature myeloid cells. Moreover, we have identified HDAC inhibition as a viable strategy to prevent unfavorable myeloid polarization and improve the therapeutic efficacy of the DAC+PD1 paradigm. Citation Format: Arturo Orlacchio, Stephen Muzyka, Catherine Do, Diane M. Simeone, Tamas Gonda. Dual epigenetic therapy combined with anti-PD1 rescues HMA-induced suppressive myeloid phenotype and reduces tumor growth in a PDAC model [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B043.

Abstract B067: Patient-specific differences in cancer-associated fibroblasts alter tumor organoid phenotype and chemosensitivity in pancreatic ductal adenocarcinoma

Abstract Pancreatic adenocarcinoma (PDAC) is the 3rd leading cause of cancer-related deaths in Canada with a 5-year survival rate ~10%. Unfortunately, only 20% of patients are eligible for surgical resection while the other 80% of patients are treated with chemotherapy (i.e. nab-paclitaxel, Gemcitabine, or FOLFIRINOX) that shows limited efficiency. Also, the tumor microenvironment (TME), and specifically cancer-associated fibroblasts (CAFs), contribute to PDAC chemoresistance. Recent studies suggest heterogeneity of CAF subtypes in patients, including myofibroblast (my), inflammatory (i), and antigen-presenting (ap) CAFs, is linked to more aggressive PDAC. While there is clear evidence CAFs effect tumor growth, chemoresistance and metastasis, the mechanisms underlying these effects are unknown. Given the involvement of environmental cues from the TME and the recent literature involving HDACs and epigenetic regulators in chemoresistance, we propose epigenetic reprogramming occurs in pancreatic cancer cells in response to CAFs, thereby affecting their response to chemotherapy. Using patient-derived tumor cells we examine the cross talk that occurs between cancer cells and CAFs in a patient-specific manner. We hypothesized that patient-specific CAF populations alter cancer cell phenotypes and chemosensitivity through epigenetic reprograming. Supported by the Baker Centre for Pancreatic Cancer, we established a living biobank of patient-derived organoids (PDO) grown in 3D cultures and CAFs grown in 2D cultures. These samples are linked to DERIVE (Determination of Response to Therapy in Individual Patients), a clinical database that includes patient response to therapy. Characterization of low passage, patient CAFs by flow cytometry shows significant heterogeneity between samples based on the proportions of myCAFs, iCAFs and apCAFs, and also identified CAFs that do not belong to any of these subtypes. Incubation of PDOs with CAF-conditioned media showed an increase in growth regardless of the CAF samples but, interestingly, myCAF-high (myCAFHI) conditioned media promoted a cystic-like phenotype in PDOs while iCAF-high conditioned media promoted a more complex PDO phenotype. myCAFHI-conditioned media also sensitized resistant PDOs to gemcitabine. Characterization of epigenetic mediators showed variable expression of histone deacetylases (HDACs), and combinatorial treatment with gemcitabine and the HDAC5 inhibitor, LMK-235 sensitized resistant PDOs to gemcitabine. We are currently performing single-cell RNA-seq, ATAC-seq and DNA methylation profiling on PDOs before and after treatment with CAF-conditioned media to identify unique CAF populations and examine the epigenetic targets underlying these outcomes. This study (1) shows CAFs present with significant heterogeneity between patients and secreted factors from CAFs induce responses in a patient-specific fashion that may change chemosensitivity, and (2) suggest targeting epigenetic mediators in PDOs and CAFs may help sensitize tumors to chemotherapy. Citation Format: Emilie Jaune-Pons, Zachary Klassen, Rachel Lu, Ye Shen, Nadeem Hussain, Michael Sey, Ken Leslie, Ephraim Tang, Anton Skaro, Matthew Cecchini, Crystal Engelage, Danielle Porplycia, Stephen Welch, Brian Yan, Christopher Pin. Patient-specific differences in cancer-associated fibroblasts alter tumor organoid phenotype and chemosensitivity in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B067.

Abstract B022: A platform to characterize hepatic immunity reveals variation in hepatic infiltration of tumor expanded T cells in “localized” PDAC

Abstract Even in its earliest stages, pancreatic ductal adenocarcinoma (PDAC) is an essentially incurable disease due to the presence of disseminated, yet radiographically occult cancer cells in the setting of an otherwise “localized” primary tumor. The vast majority (~80%) of patients who undergo curative-intent surgery develop liver metastases, often within six months of surgery, and these hepatic metastases dominate survival outcomes, even in the presence of multisite recurrence. What drives hepatic organotropism remains unknown, in large part due to the exclusion of “normal” liver tissue from PDAC biobanking programs. While recent work in animal models suggests that suppression of the hepatic immune microenvironment may facilitate metastatic progression, confirmatory studies in human patients are lacking, due to a paucity of relevant model systems. To address this deficit, we developed an experimental pipeline to profile hepatic immunity at single-cell resolution vis-à-vis the peripheral and intratumoral immune compartments. We hypothesized that this platform could be leveraged to identify tissue- and patient-specific immunophenotypes associated with hepatic recurrence prior to the development of overt metastases. Patients with localized PDAC at Duke University were enrolled in an IRB-approved (Pro00108288) biobanking program to obtain multisegment liver biopsies, primary tumor specimen, and peripheral blood at the time of curative-intent resection. Immune (CD45+) cells were sorted following enzymatic digestion (tissues) or Ficoll separation (blood) and single-cell gene expression and T cell receptor libraries were created. Data was processed using CellRanger and aligned, filtered, and normalized using R. In total, we identified 32 unique immune cell populations conserved across patients, with both shared and site-specific cell types identified in the T cell, B cell, NK cell, and myeloid compartments. Additionally, we identified expanded T cell clones within the tumor microenvironment and traced a subset of these clonotypes to the premetastatic liver. These tumor-expanded T cells (TTE cells) presumably arise from recognition of a specific tumor antigen, which then instigates activation and proliferation of the clone. Notably, we identified a subset of our patients without known liver metastases who nonetheless demonstrated hepatic infiltration of TTE cells. While the significance of these hepatic TTE cells is still unclear, we hypothesize that this is evidence of a primed immune response to tumor antigens already present in the liver at the time of surgery. This experimental platform has now been implemented within an ongoing window-of-opportunity trial (NCT05634720) testing neoadjuvant hepatic artery chemotherapy in patients undergoing resection of localized PDAC. The correlative scientific objectives will focus on quantifying the variation of hepatic TTE infiltration across patients, determining the function and activation state of hepatic TTE cells, and testing the association between hepatic TTE cell infiltration and clinical outcomes. Citation Format: Elishama N. Kanu, Ashley A. Fletcher, Jiayin Bao, Austin M. Eckhoff, Karrie Comatas, Tao Wang, Bin-Jin Hwang, Michael E. Lidsky, Sabino Zani, Dan G. Blazer, Peter J. Allen, Zhicheng Ji, Daniel P. Nussbaum, Erika J. Crosby. A platform to characterize hepatic immunity reveals variation in hepatic infiltration of tumor expanded T cells in “localized” PDAC [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B022.

Exploring the interconnectedness between health-related quality of life factors among long-term adolescent and young adult cancer survivors (AYAs): a network analysis

PurposeAdolescent and young adult cancer survivors (AYAs) are at increased risk of long-term and late effects, and experience unmet needs, impacting their health-related quality of life (HRQoL). In order to provide and optimize supportive care and targeted interventions for this unique population, it is important to study HRQoL factors’ interconnectedness on a population level. Therefore, this network analysis was performed with the aim to explore the interconnectedness between HRQoL factors, in the analysis described as nodes, among long-term AYAs.MethodsThis population-based cohort study used cross-sectional survey data of long-term AYAs, who were identified by the Netherlands Cancer Registry (NCR). Participants completed a one-time survey (SURVAYA study), including the EORTC survivorship questionnaire (QLQ-SURV111) to assess their long-term HRQoL outcomes and sociodemographic characteristics. The NCR provided the clinical data. Descriptive statistics and a network analysis, including network clustering, were performed.ResultsIn total, 3596 AYAs (on average 12.4 years post diagnosis) were included in our network analysis. The network was proven stable and reliable and, in total, four clusters were identified, including a worriment, daily functioning, psychological, and sexual cluster. Negative health outlook, part of the worriment cluster, was the node with the highest strength and its partial correlation with health distress was significantly different from all other partial correlations.ConclusionThis study shows the results of a stable and reliable network analysis based on HRQoL data of long-term AYAs, and identified nodes, correlations, and clusters that could be intervened on to improve the HRQoL outcomes of AYAs.

Mobile health in the aging surgical patient

Mobile health includes the use of mobile devices, patient monitoring devices, and digital assistants to improve the delivery of healthcare. Aging surgical patients (ie, 65 years and older) represent a unique patient population that demands increased resources to prepare for surgery and optimize recovery. Mobile health has the potential to improve surgical patient outcomes by increasing the accessibility of personalized care and reducing costs. However, there are some challenges to consider when using mobile health in older surgical patients, such as technological literacy, visual and hearing impairment, and cognitive changes before or after anesthesia. Despite the rapid uptake of mobile health in medical specialties, its application in the surgical field is gradual. The complexity of aging surgical patients requires surgical care teams, surgical leaders, and healthcare policymakers to consider unique solutions, such as mobile health, to address this growing population’s needs before and after surgery. This article will discuss the potential benefits and challenges of mobile health among aging surgical patients, as well as opportunities to support these patients and families with customizable tools to meet their preferences and needs.

The Military Health History: An Educational Initiative to Improve Veteran Healthcare.

As a result of the nature of military service, veterans are a unique patient population with many special health considerations. For various reasons, measures are often not taken by clinicians to address such special considerations. This results in a healthcare disparity for veterans first described by Dr. Jeffrey Brown in 2012. To address this disparity, we introduced "the military health history" to third-year medical students at a large medical school in the southeastern United States. Our objective was to assess the effectiveness of this educational intervention and determine its potential role in creating a future in which veteran healthcare is of the highest quality. This study was approved as a quality assurance/quality improvement project by both Louisiana State University Health Science Center and Southeast Louisiana Veteran Healthcare System IRB offices. A short lecture outlining the components of the military health history was presented to 186 third-year medical students. The students were given the opportunity to answer five survey questions before and after the lecture. These questions assessed the students' current confidence performing a military health history, perceived importance of doing so, and likelihood of future implementation. To determine useful retention of the lecture material, the post-lecture survey was readministered to the same population sample 6 months after the lecture. A series of repeated measures analyses of variance were conducted to examine changes in mean levels of confidence, importance, and likelihood of ascertaining military history during a patient encounter at pre- and post-presentation as well as at the 6 month follow-up. Results revealed a significant effect of time on importance, Wilks' Lambda = 0.74, F (2, 87) = 15.41, P < 0.001; confidence, Wilks' Lambda = 0.61, F (2, 87) = 27.58, P < 0.001; and likelihood of ascertaining a military history during a future patient encounter, Wilks' Lambda = 0.46, F (2, 88) = 50.58, P < 0.001. Results are demonstrated in detail in Table I of the manuscript. The lecture resulted in a statistically significant increase over 6 months in both the likelihood and confidence parameters. The team believes that this result indicates that the students demonstrated useful retention of the lecture material. Our hope is that these students continue to employ the military health history throughout their years of clinical work. In the future, we plan to survey veterans immediately following Veterans Health Administration clinic visits with members of our study population to assess the patient's perceived benefit of the military health history. The team will continue to investigate ways in which military health curricula can be implemented in undergraduate medical education.

Intracranial recordings reveal high-frequency activity in the human temporal-parietal cortex supporting non-literal language processing.

Non-literal expressions such as sarcasm, metaphor and simile refer to words and sentences that convey meanings or intentions that are different and more abstract than literal expressions. Neuroimaging studies have shown activations in a variety of frontal, parietal and temporal brain regions implicated in non-literal language processing. However, neurophysiological correlates of these brain areas underlying non-literal processing remain underexplored. To address this, we investigated patterns of intracranial EEG activity during non-literal processing by leveraging a unique patient population. Seven neurosurgical patients with invasive electrophysiological monitoring of superficial brain activity were recruited. Intracranial neural responses were recorded over the temporal-parietal junction (TPJ) and its surrounding areas while patients performed a language task. Participants listened to vignettes that ended with non-literal or literal statements and were then asked related questions to which they responded verbally. We found differential neurophysiological activity during the processing of non-literal statements as compared to literal statements, especially in low-Gamma (30-70 Hz) and delta (1-4 Hz) bands. In addition, we found that neural responses related to non-literal processing in the high-gamma band (>70 Hz) were significantly more prominent at TPJ electrodes as compared to non-TPJ (i.e., control) electrodes in most subjects. Moreover, in half of patients, high-gamma activity related to non-literal processing was accompanied by delta-band modulation. These results suggest that both low- and high-frequency electrophysiological activities in the temporal-parietal junction play a crucial role during non-literal language processing in the human brain. The current investigation, utilizing better spatial and temporal resolution of human intracranial electrocorticography, provides a unique opportunity to gain insights into the localized brain dynamics of the TPJ during the processing of non-literal language expressions.

Research on Medical Coverage for Disabled Children in China

Every country has numerous disabled individuals, and throughout their lives, they typically face more difficulties and challenges than the general population. Disabled children, in particular, face even greater challenges. These children are born with noticeable differences and require significant external support. While in many European and American countries, people often see children with disabilities integrated into schools, in China however, it is often difficult for disabled children to live and learn alongside their peers. They usually require support from medicine and doctors due to their physical and mental conditions, which can incur substantial expenses, placing a significant financial burden on most families. Therefore, the Chinese government should pay closer attention to the health and well-being of this particular group. This unique population needs a better healthcare system. We urgently need to focus on and allocate more resources to ensure that every disabled child can access the healthcare and opportunities they rightfully deserve.

Dual Management: Diabetes and Sickle Cell Anemia in Patient Care

The coexistence of diabetes mellitus (DM) and sickle cell anemia (SCA) presents a complex medical challenge, necessitating an integrated approach to patient care. This review explores the interplay between diabetes and sickle cell anemia, addressing the epidemiology, pathophysiological intricacies, and the compounded complications associated with these comorbidities. Emphasizing the need for an interdisciplinary care model, the review discusses the challenges in patient care, encompassing both physiological and psychosocial dimensions. Furthermore, it outlines innovative treatment strategies, including medication management and lifestyle interventions, aiming to optimize outcomes for individuals navigating the dual management of diabetes and sickle cell anemia. By synthesizing current research findings and highlighting areas for future investigation, this review provides valuable insights into the complexities of dual management and offers a foundation for enhancing the quality of care for this unique patient population

Psoriasis as a Risk Factor for Skin Cancer: An International, Propensity-Matched Retrospective Cohort Study

Psoriasis, a chronic immune-mediated skin disorder impacting millions globally, is increasingly recognized for its links to various disease processes. As our understanding of immune dysregulation in psoriasis progresses, acknowledging the pivotal role of dysregulated T-cells in the pathogenic development of the persistent inflammatory state becomes crucial. This immune dysregulation and the resulting prevalent inflammatory state have raised concerns about psoriasis potentially serving as a significant comorbidity in cancer development among patients. To contribute to this discussion, we conducted a global retrospective cohort study with propensity score matching (PSM) using the TriNetX Analytics platform. The study aimed to investigate whether patients diagnosed with psoriasis face an elevated risk in the development of cutaneous malignancies, encompassing both melanoma and non-melanoma skin cancers. Our findings confirmed a noteworthy concern, revealing a significantly increased risk of developing cutaneous neoplasms in individuals with psoriasis. In conclusion, our study underscores the importance of heightened awareness and the necessity for routine skin cancer screenings in this unique patient population. The observed association between psoriasis and an increased risk of cutaneous neoplasms highlights the need for proactive medical interventions and emphasizes the potential impact of psoriasis as a comorbidity in the context of cancer development.

Variable climate-growth relationships of quaking aspen (Populus tremuloides) among Sky Island mountain ranges in the Great Basin, Nevada, USA

The Great Basin is an arid province located in the interior western United States. The region encompasses millions of hectares and quaking aspen (Populus tremuloides Michx.) forests comprise a minor portion of the total area. However, montane aspen forests play a disproportionately large role in providing ecosystem services in the region, including water retention, biodiversity, wildlife habitat, livestock forage, and recreational uses. With warming temperatures, increasing evaporative demand, and heightened precipitation variability, the future of aspen has become a critical concern. Using dendroecological approaches, we assessed growth patterns of 20 aspen stands across three geographically isolated “sky island” mountain ranges spanning portions of the north-central Great Basin. We anticipated that the growth of Great Basin aspen would be strongly influenced by regional climatic patterns and largely in synchrony. Results revealed a more complex growth dynamic that varied among mountain ranges and across environmental gradients. In particular, aspen climate-growth relationships in the slightly dryer Ruby Mountains were strongly and positively correlated (r > 0.5) with previous fall to winter moisture availability. The Jarbidge Mountains had a positive but modest relationship with previous fall to winter moisture availability (r > 0.3). Climate-growth response in the Santa Rosa Mountains, the wettest range, showed no significant response to moisture availability during any time period examined but had greater tree-ring growth with warmer May temperatures. Although tree-ring centennial (1910 – 2010) growth trends were positive for all three mountain ranges, only the Santa Rosa Mountains maintained a positive recent growth trend (1970 – 2010). Moreover, distinct temporal shifts in tree growth-climate relationships in each mountain range suggest potentially unique aspen population adaptations to climate variability. For instance, in two of the mountain ranges, there was a shift from positive/neutral to negative growth relationships with temperature starting around the 1963 – 1987 time period, while tree growth also began simultaneously responding more positively to moisture availability. These growth shifts and observed enhanced sensitivities to monthly and seasonal climate variables over time may reflect dynamic tree growth responses caused by ongoing global climate change, but that may be tempered by local or regional factors, such as the relative availability and timing of soil moisture provided by spring snowmelt. A better understanding of biogeographic variation and causality in aspen growth could provide multiple management pathways governed by resilience characteristics in the face of future anthropogenic and climatic threats.

Exploration of the advanced preparation nurse-mother role in care of children with chronic disease: A narrative inquiry.

To explore the lived experience of advanced preparation nurses (APNs) who are mothers (APN-mothers) as they seek care in the Emergency Department for a child with a chronic disease. Qualitative, Narrative Inquiry. Narrative Inquiry was used to examine critical self-reflections of four (n = 4) APN-mothers. Directed by a question guide, participants engaged in the Narrative Reflective Process through metaphoric and artistic means. Participants identified salient challenges associated with their experiences. Narrative threads that emerged include feelings around being discovered, unfair expectations by healthcare providers, feelings of guilt and the tension from competing roles: APN and mother. APN-mothers represent a unique population with enhanced knowledge, skills and judgement; however, they indicate that there is insufficient communication and interprofessional collaboration between parents and Emergency Department staff. Further research is needed to foster and improve therapeutic relationships between APN-mothers and healthcare providers. Findings can inform the development of family centred care guidelines for healthcare professional parents and their children. This study explores the experiences of an understudied population. This research will impact APN-mothers, healthcare professionals in the Emergency Department as well as nursing students and researchers. EQUATOR guidelines and SRQR reporting method used. APN-mothers, caregivers and support persons of children with chronic disease enacted investigator-participant roles and were involved in each step of the study process. In addition, some patients (participants' children with chronic diseases) were included in data collected.

The Exploration of the GWOT Combat Amputee's Experience With Longitudinal Care: A Qualitative Study.

Contemporary advances in combat medicine have allowed greater numbers of wounded service members to survive their injuries. An estimated 1,705 combat veterans sustained major lower or upper extremity amputations between 2001 and 2017 during the Global War on Terror. This study intends to answer the following question utilizing a qualitative study design: What were the common and abnormal experiences of the Global War on Terror combat amputees relative to their mechanism of injury, perception of injury, and systems of care utilized during their recovery and rehabilitation process?. During the months of December 2022 and January 2023, individual semi-structured interviews were conducted with U.S. Marines that served in the Global War on Terror (total n = 10). Deductive and inductive approaches were employed to identify codes, themes, and meta-themes in the data. All participants deployed to Afghanistan between the years 2010 and 2014 and were assigned to the following military occupational specialties: Explosive Ordnance Disposal technicians (total n = 2); combat engineers (total n = 2); and infantrymen (total n = 6). Analysis of data collected from interviews highlighted these key observations: (1) Themes in the combat amputee experience include support, systems of care, and mindset and (2) the themes synergistically contribute to the meta-themes mental health and pain and vice versa. As all participants were subjected to a blast mechanism of injury, it is difficult to determine if this played a role in deviating rehabilitation and recovery processes. Perception of injury and how well participants adapted to their new lifestyle, meaning how optimistic they were, appeared to play a significant role in recovery. Participants had mixed feelings about the care they had received but generally spoke favorably of military hospitals and were frustrated with the Veteran Affairs, and there was no clear consensus on their relationship with civilian health care, though most participants chose to seek most of their care through the Veteran Affairs. Based on the research question, this study found an intricate relationship between mental health, pain, and the experiences of the participants regarding their care and rehabilitation. However, the nature of qualitative research makes it impossible to determine generalizations that can be used to create meaningful change to address improving combat amputee veteran care. Further research into long-term health outcomes based on hypotheses not evaluated in existing literature would further improve the ability of health care providers to care for this unique patient population.

Expedition 5300: limits of human adaptations in the highest city in the world.

Exposure to chronic hypobaric hypoxia imposes a significant physiological burden to more than 80 million humans living above 2500m throughout the world. Among them, 50000 live in the world's highest city, La Rinconada, located at 5000-5300m in southern Peru. Expedition 5300 is the first scientific and medical programme led in La Rinconada to investigate the physiological adaptations and altitude-related health issues in this unique population. Dwellers from La Rinconada have very high haemoglobin concentration (20.3±2.4g/dL; n=57) and those with chronic mountain sickness (CMS) exhibit even higher concentrations (23.1±1.7g/dL; n=150). These values are associated with large total haemoglobin mass and blood volume, without an associated iron deficit. These changes in intravascular volumes lead to a substantial increase in blood viscosity, which is even larger in CMS patients. Despite these large haematological changes, 24h blood pressure monitoring is essentially normal in La Rinconada, but some results suggest impaired vascular reactivity. Echocardiography revealed large right heart dilatation and high pulmonary arterial pressure as well as left ventricle concentric remodelling and grade I diastolic dysfunction. These changes in heart dimension and function tend to be more severe in highlanders with CMS. Polygraphy evaluations revealed a large reduction in nocturnal pulse oxygen saturation (median SpO2 =79%), which is even more severe in CMS patients who also tended to show a higher oxygen desaturation index. The population of La Rinconada offers a unique opportunity to investigate the human responses to chronic severe hypoxia, at an altitude that is probably close to the maximum altitude human beings can permanently tolerate without presenting major health issues.

Jones Fracture in the National Football League.

Background: Jones fracture, or proximal fifth metatarsal fracture, is a common injury in National Football League (NFL)-caliber athletes. Combine draft performance can greatly impact the long-term success of these athletes, and substantial emphasis has been placed on early return to play (RTP) and the minimization of post-operative complications after Jones fracture in these athletes. To date, no study has specifically described the treatment and outcomes of this injury specifically in NFL-caliber players, considering factors relevant to this unique population. Thus, the purpose of this review is to delve into Jones fracture in NFL-caliber athletes, evaluating the diagnostic, treatment, and RTP considerations. Methods: We searched Medline (PubMed), Embase (Elsevier), Scopus (Elsevier), and SPORTDiscus (EBSCOhost) for the concept of Jones fractures in the NFL. Using the PRISMA guidelines, a team of three reviewers conducted abstract screenings, full-text screenings, and the extraction of studies describing Jones fractures specifically in the NFL. Results: Of the 1911 studies identified, 6 primary retrospective studies met the inclusion and exclusion criteria. The heterogeneity of the outcome reporting precluded a meta-analysis; thus, a qualitative review of manuscripts describing Jones fracture was carried out. Classification, diagnosis, and treatment considerations, RTP statistics and outcomes, and complications were discussed. Amongst the primary studies, there were 285 Jones fractures, all athletes were able to RTP, and the average time to RTP ranged from 6 weeks to 27 weeks. For complications, with operative treatment, the refracture rate ranged from 4 to 12%, and incomplete healing ranged from 7 to 50%. RTP was 15 weeks for refractures. There were no patient-reported outcomes. Conclusions: The vast majority of Zone 2/3 Jones fractures are treated with IM screw fixation with or without adjunctive orthobiologics, such as bone marrow aspirate concentrate, in NFL-caliber athletes. The six major series investigating outcomes after the operative treatment of Jones fractures in NFL players reveal very positive findings overall with regard to RTP, reoperation, and career continuation.