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PURPOSE: Transcriptional profiling of pancreatic cancers (PC) has defined two main transcriptional subtypes, classical and basal. Initial data suggest shorter survival for patients with basal tumors and differing treatment sensitivity to FOLFIRINOX (FFX) and gemcitabine nab-Paclitaxel (GnP) by transcriptional subtype. EXPERIMENTAL DESIGN: We examined 8,743 patients with RNA sequencing from PCs performed at Caris Life Sciences (Phoenix, AZ). Classical and basal subtypes were identified using PurIST algorithm on RNA-sequencing and two cohorts were analyzed: (1) Biomarker cohort included patients with complete molecular profiling data (n = 7,250); (2) Outcomes cohort included patients with metastatic disease with available survival outcomes (n=5,335). RESULTS: In the biomarker cohort, 3,063 tumors (42.2%) were strongly classical (SC), and 2,015 tumors (27.8%) were strongly basal (SB). SC and SB tumors showed strong associations with histologic phenotypes and biopsy site. SB tumors had higher rates of KRAS, TP53, and ARID1A mutations, lower rates of SMAD4 mutation, and transcriptional evidence of epithelial mesenchymal transition. Sixty of 77 cases (78%) maintained their transcriptional subtype between temporally and/or spatially disparate lesions. In the outcomes cohort, SB subtype was associated with shorter overall survival time, regardless of whether they received FFX or GnP as first line chemotherapy. Mutant KRAS allele type was prognostic of outcomes, however this impact was restricted to SC tumors, whereas all mutant KRAS alleles had similarly poor outcomes in SB tumors. CONCLUSIONS: SB subtype is a strong independent predictor of worse outcomes, irrespective of upfront chemotherapy regimen. Clinical trials should investigate PC transcriptional subtypes as a biomarker.
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BACKGROUND: American Indian/Alaska Natives (AI/ANs) disproportionately suffer from diabetes compared to non-Hispanic whites (NHW). In 2013, 69% of end-stage kidney disease (ESKD) in AI/ANs was caused by diabetes (ESKD-D) but accounts for only 44% of ESKD diagnoses in the overall USA population. Moreover, the diagnosis of diabetes and ESKD-D may be significantly related to social determinants of health. The purpose of this study was to conduct a survival analysis of AI/ANs and NHWs diagnosed with ESKD-D nationally and by Indian Health Service region and correlate the survival analysis to the Area Deprivation Index® (ADI®). METHODS: This manuscript reports a retrospective cohort analysis of 2021 United States Renal Data System data. Eligible patient records were AI/AN and NHWs with diabetes as the primary cause of ESKD and started dialysis on January 1, 2014, or later. RESULTS: A total of 81,862 patient records were included in this analysis, of which 1798 (2.2%) were AI/AN. AI/ANs survive longer, with an 18.4% decrease in risk of death compared to NHW. However, AI/ANs are diagnosed with ESKD-D and start dialysis earlier than NHWs. ADI® variables became significant as ADI® ratings increased, meaning persons with greater social disadvantage had worse survival outcomes. CONCLUSIONS: The findings reveal that AI/ANs have better survival outcomes than NWH, explained in part by initiating dialysis earlier than NHW. Additional research is needed to explore factors (e.g., social determinants; cultural; physiologic) that contribute to earlier diagnosis of ESKD-D in AI/ANs and the impact of prolonged dialysis on quality of life of those with ESKD-D.
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Background: Understanding the genetic causes for variability in chromatin accessibility can shed light on the molecular mechanisms through which genetic variants may affect complex traits. Thousands of ATAC-seq samples have been collected that hold information about chromatin accessibility across diverse cell types and contexts, but most of these are not paired with genetic information and come from diverse distinct projects and laboratories. Results: We report here joint genotyping, chromatin accessibility peak calling, and discovery of quantitative trait loci which influence chromatin accessibility (caQTLs), demonstrating the capability of performing caQTL analysis on a large scale in a diverse sample set without pre-existing genotype information. Using 10,293 profiling samples representing 1,454 unique donor individuals across 653 studies from public databases, we catalog 23,381 caQTLs in total. After joint discovery analysis, we cluster samples based on accessible chromatin profiles to identify context-specific caQTLs. We find that caQTLs are strongly enriched for annotations of gene regulatory elements across diverse cell types and tissues and are often strongly linked with genetic variation associated with changes in expression (eQTLs), indicating that caQTLs can mediate genetic effects on gene expression. We demonstrate sharing of causal variants for chromatin accessibility and diverse complex human traits, enabling a more complete picture of the genetic mechanisms underlying complex human phenotypes. Conclusions: Our work provides a proof of principle for caQTL calling from previously ungenotyped samples, and represents one of the largest, most diverse caQTL resources currently available, informing mechanisms of genetic regulation of gene expression and contribution to disease.
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Background: MicroRNAs (miRNAs) show promise as blood-based tumor markers for germ cell tumors (GCTs), with miRNA-371-3p being the most studied. The marginal benefit of including other candidate miRNAs to aid with the management of testicular GCTs remains unclear. Objective: To assess the performance of our combined miRNA assay (371a-3p and 372-3p) in patients with clinically localized testicular masses. Design setting and participants: This was a retrospective review of patients prospectively enrolled in an ongoing protocol collecting serum miR-371a-3p and miR-372-3p levels (together, Memorial Sloan Kettering Cancer Center [MSK] miRNA assay [MMA]) in patients with a suspected or diagnosed testicular GCT. Outcome measurements and statistical analysis: The coprimary outcomes of interest were sensitivity and specificity of miR-371a-3p and 372-3p, individually and together, to detect nonteratomatous GCTs in the orchiectomy specimen. Secondary outcomes included additional assay diagnostic parameters, the relationship of patient and disease factors with variations in miRNA levels, and temporal patterns of miRNA normalization after orchiectomy. Results and limitations: Sixty-two patients were included, 52 had a viable GCT at orchiectomy, and ten had no cancer or a non-GCT. Forty-six patients with a GCT had positive preorchiectomy MMA (sensitivity 88.5% [95% confidence interval {CI}: 79.8, 97.2]), and one patient had positive preorchiectomy MMA but no GCT (specificity 90.0% [95% CI: 71.4, 100]). The diagnostic performance of miR-371a-3-p and miR-372-3p was similar. The time for miRNA to decrease to undetectable levels varied, with some patients having positive levels up to 3 wk after orchiectomy. Conclusions: The biomarkers miR-371a-3p and miR-372-3p demonstrated high sensitivity and specificity for localized testicular GCTs, but causes of variation in relative miRNA levels and time to normalization for individual patients remain unclear. Patient summary: We studied the ability of the blood-based biomarkers miR-371a-3p and miR-372-3p to detect testicular cancer (germ cell tumors) in patients with small testicular masses. We found that together and individually these were sensitive and specific for testicular cancer.
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Virtual reality (VR) can enhance mental health care. In particular, the effectiveness of VR-based exposure therapy (VRET) has been well-demonstrated for treatment of anxiety disorders. However, most applications of VRET remain localized to clinic spaces. We aimed to explore mental health therapists' perceptions of telehealth-based VRET (tele-VRET) by conducting semi-structured, qualitative interviews with 18 telemental health therapists between October and December 2022. Interview topics included telehealth experiences, exposure therapy over telehealth, previous experiences with VR, and perspectives on tele-VRET. Therapists described how telehealth reduced barriers (88.9%, 16/18), enhanced therapy (61.1%, 11/18), and improved access to clients (38.9%, 7/18), but entailed problems with technology (61.1%, 11/18), uncontrolled settings (55.6%, 10/18), and communication difficulties (50%, 9/18). Therapists adapted exposure therapy to telehealth by using online resources (66.7%, 12/18), preparing client expectations (55.6%, 10/18), and adjusting workflows (27.8%, 5/18). Most therapists had used VR before (72.2%, 13/18) and had positive impressions of VR (55.6%, 10/18), but none had used VR clinically. In response to tele-VRET, therapists requested interactive session activities (77.8%, 14/18) and customizable interventions components (55.6%, 10/18). Concerns about tele-VRET included risks with certain clients (77.8%, 14/18), costs (50%, 9/18), side effects and privacy (22.2%, 4/18), and inappropriateness for specific forms of exposure therapy (16.7%, 3/18). These results reveal how combining telehealth and VRET may expand therapeutic options for mental healthcare providers and can help inform collaborative development of immersive health technologies.
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PURPOSE: Non-steroidal anti-inflammatory drugs (NSAID) are associated with increased stress fracture risk, potentially due to inhibiting the adaptive bone formation responses to exercise. This study investigated if a single, maximal dose of three different NSAIDs alters bone formation biomarker response to strenuous exercise. METHODS: In a randomized, counter-balanced order, 12 participants (10 male, 2 female), performed four bouts of plyometric jumps, each separated by at least one week. Two hours before exercise, participants consumed either placebo (PLA) or NSAID: Ibuprofen (IBU, 800 mg), celecoxib (CEL, 200 mg), flurbiprofen (FLU, 100 mg). Blood was collected before (PRE), and at 0, 15, 60, 120, and 240 minutes post-exercise. Parathyroid hormone (PTH), ionized calcium (iCa), procollagen type 1 N-terminal propeptide (P1NP), bone alkaline phosphatase (BAP), osteocalcin (OCN), C-terminal telopeptide of type 1 collagen (CTX), tartrate resistant acid phosphatase (TRAP5b), and sclerostin (SCL) were measured. Prostaglandin E2 metabolite (PGE2M) and creatinine (Cr) were measured in urine. Data were analyzed using repeated measures ANOVA and area under the curve analysis (AUC). Data are mean ± SD. RESULTS: There was an exercise effect for P1NP, BAP, OCN, CTX, TRAP5b, SCL, OPG, PTH, and iCa (all p < 0.05), but no NSAID treatment effect for any biomarker (all p > 0.05). AUC analyses were not different for any biomarker (p > 0.05). PGE2M was higher during the PLA trial (322 ± 153 pg/mg Cr, p < 0.05) compared to IBU (135 ± 83 pg/mg), CEL (202 ± 107 pg/mg), and FLU (159 ± 74 pg/mg). CONCLUSIONS: Plyometric exercise induced changes in bone metabolism, but the responses were unaltered by consuming NSAIDs two hours before exercise.
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OBJECTIVE: Fetal imaging often identifies signs of upper airway obstruction due to micrognathia that may require airway intervention at delivery. This study investigated the role of quantitative fetal imaging measurements in predicting the need for otolaryngology consultation and intervention within a multidisciplinary Fetal Center. METHODS: Data were retrospectively collected from expectant mothers attending a multidisciplinary Fetal Center from January 2017 to October 2023. Cases of fetal micrognathia associated with potential upper airway obstruction were analyzed, focusing on prenatal ultrasound and magnetic resonance imaging (MRI) findings, genetic testing results, and interventions at birth. RESULTS: Among 25 pregnancies identified, diverse prenatal diagnoses were observed. Post hoc quantitative fetal ultrasound/MRI measurements included inferior facial angle, anteroposterior diameter, biparietal distance, and Jaw Index. Otolaryngology teams were present at delivery for a subset of cases, with various interventions performed, including tracheostomy and intubation. Lower gestational age at birth, rather than more severe quantitative measurements, was associated with the need for intervention. Intubation failure due to airway difficulty was also predicted by lower gestational age. CONCLUSION: While certain quantitative fetal imaging measurements are often used for clinical decision-making regarding airway management at birth, they did not clearly predict the need for airway intervention in our sample. Gestational age is an important consideration in decision-making for fetal teams and should be considered in preterm fetuses to plan for airway difficulties. The findings highlight the complexity of fetal micrognathia management and highlight the need for further research to refine predictive models and optimize clinical decision-making in this challenging clinical scenario. LEVEL OF EVIDENCE: Level 3 Laryngoscope, 2024.
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Despite the unmet needs for chemical tools to study biological roles of tryptophan in living systems, there has been a lack of chemical modification methods for tryptophan residues that can be used in cellular environments. Driven by a preliminary computational study of our previous research, this work experimentally examined our hypotheses to translate the metal-catalyzed tryptophan modification method in hexafluoroisopropanol (HFIP) into a metal-free process. While one of the hypotheses merely confirmed the superiority of the thiophene-ethanol reagent developed in the previous report, the second hypothesis resulted in the identification of a trifluoroborate salt and an acidic ionic liquid as alternatives for the catalysis. Labeling of lysates of a human cell line was achieved with the acidic ionic liquid catalyst, where negative impacts of the tryptophan labeling and HFIP medium on the cellular samples were apparently insignificant. Because the labeling process does not require any redox mediators and is a formal redox-neutral reaction, the metal-free approach would be of use for tryptophan biology research potentially related to their various redox roles.
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Virtual reality (VR) is an emerging technology that can enhance experiences and outcomes in mental healthcare. However, mental health therapists have been slow to adopt VR into practice. Implementation of telehealth-based VR therapy (tele-VR) could catalyze adoption and innovation in mental healthcare. To explore therapists' perspectives on tele-VR, we conducted a cross-sectional survey of practicing mental health providers in the United States in June-July 2023. We analyzed 176 completed surveys from therapists, of whom 51.14% had no prior experience with VR, only 6.25% had used VR clinically, and 56.82% had neutral impressions of VR for therapy. Despite therapists' general inexperience with VR, therapists indicated a wide variety of tele-VR simulations (e.g., social situations, flying, heights) and features (e.g., personalized spaces, homework, interactivity) would be moderately to extremely useful for their practices. Therapists also requested additional VR simulations and features for their telehealth clients such as behavioral skills training, exposure therapy, gender identity therapy, and psychological assessments in VR. Therapists rated Health Insurance Portability and Accountability Act compliance, the ability to try VR before buying, affordability for therapists, accessibility for clients, and insurance coverage as the five most influential implementation factors for tele-VR. Overall, therapists were generally inexperienced and neutral about VR for telehealth therapy, but were interested in tele-VR for specific applications. These findings provide actionable directions for future research and collaborative development of therapeutic VR content and features.
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Objectives: The purpose of this study was to investigate the effects of contamination of venous blood with a lipid-containing solution on parameters measured by a modern blood gas analyzer. Methods: We collected venous blood from 17 healthcare workers (46 ± 11 years; 53â¯% women) into three blood gas syringes containing 0â¯, 5 and 10â¯% lipid-containing solution. Blood gas analysis was performed within 15â¯min from sample collection on GEM Premier 5000, while triglycerides and serum indices were assays on Roche COBAS C702. Results: Triglycerides concentration increased from 1.0 ± 0.3â¯mmol/L in the uncontaminated blood gas syringe, to 39.4 ± 7.8 and 65.3 ± 14.4â¯mmol/L (both p<0.001) in syringes with 5 and 10â¯% final lipid contamination. The lipemic and hemolysis indices increased accordingly. Statistically significant variation was noted for all analytes except hematocrit and COHb in the syringe with 5â¯% lipids, while only COHb did not vary in the syringe with 10â¯% lipids. Significant increases were observed from 5â¯% lipid contamination for pO2, SO2 and lactate, while the values of pH, pCO2, sodium, potassium, chloride, ionized calcium, glucose, hematocrit (10â¯% contamination), hemoglobin and MetHB decreased. All these changes except lactate and CoHb exceeded their relative performance specifications. Conclusions: Artifactual hyperlipidemia caused by contamination with exogenous lipids can have a clinically significant impact on blood gas analysis. Manufacturers of blood gas analyzers must be persuaded to develop new instruments equipped with serum indices.
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INTRODUCTION: The Defense Health Agency aims to ensure that military surgical residents have the expeditionary general surgical skills necessary to deploy to a combat environment and maintains the Clinical Investigation Programs (CIPs) that foster research during graduate medical education. This project evaluates the potential to achieve both aims simultaneously through a large animal Combat Casualty Care Research Program (CCCRP). MATERIALS AND METHODS: Large animal experimental protocols within a single CIP's CCCRP were collected from July 1, 2017, to June 30, 2022. Operations performed were tabulated and categorized by Emergency General Surgery procedure equivalent. In addition, procedures performed by a single resident from July 1, 2020, to June 30, 2022, were separately indexed for a more granular analysis. RESULTS: The results are presented with total 5-year numbers listed first, followed by single resident 2-year numbers in parentheses. The residents at the CIP carried out 8676 (1,609) tabulated procedures. Major surgical procedures included 573 (154) laparotomies, 364 (129) thoracotomies, 279 (125) splenectomies, 219 (108) craniotomies, 206 (81) hepatorrhaphies, 363 (62) nephrectomies, 383 (48) bowel resections, 215 (48) spine exposures with laminectomies, and 173 (9) sternotomies. Additional procedures included 1028 (127) central venous lines, 878 (127) arterial lines, 90 (67) tube thoracostomies, 199 (37) carotid artery exposures, 394 (29) suprapubic urostomies, and placement of 278 (10) aortic occlusion catheters. At this time, the residents had 17 (10) presentations at national meetings, 8 (7) research awards, and published 20 peer-reviewed manuscripts. Additionally, the residents involved in the CCCRP gained valuable experience in critical care, including management of 110 traumatic brain injuries, 121 Intercranial Pressure catheters, 316 cases of hemorrhagic shock, and 211 massive transfusion protocols, among a variety of other vital critical care skills. CONCLUSIONS: This large animal CCCRP represents a unique training model that not only achieves its primary goal of fostering graduate medical education research but also bolsters Emergency General Surgery readiness for military surgical residents.
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OBJECTIVE: Foreign body ingestion is an increasingly prevalent issue for children who are in the preverbal to early verbal stages of life. Foreign bodies lodged in the gastrointestinal tract can cause issues such as obstruction, perforation, and fistulae. Radiographic imaging can often locate most foreign bodies; however, radiolucent objects may be missed. Ultrasound is an alternative imaging modality that can be used to locate and track foreign objects as they pass through the bowel. The objective of this study was to characterize the sonographic appearance of various ingested foreign bodies of varying characteristics in an ex vivo gastrointestinal tract segment. METHODS: A GE Logiq 9 ultrasound machine with a linear transducer at a frequency of 15 MHz was used to examine various ingested foreign bodies placed in a segment of pig intestinal tract. RESULTS: Imaged objects varied in visual appearance from echogenicity, texture, size, and shape; acoustic shadows and reverberation artifacts cast were particularly distinguishing characteristics. CONCLUSIONS: Ultrasound evaluation to assess foreign body ingestion in the pediatric population may provide a useful alternative or supportive imaging modality in confirming the location and real-time tracking of the ingested item. This may be especially useful for objects of varying radiodensities that cannot always be reliably seen in traditional radiographs.
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Ge-Sb-Se-Te chalcogenides, namely Se-substituted Ge-Sb-Te, have been developed as an alternative optical phase change material (PCM) with a high figure-of-merit. A need for the integration of such new PCMs onto a variety of photonic platforms has necessitated the development of fabrication processes compatible with diverse material compositions as well as substrates of varying material types, shapes, and sizes. This study explores the application of chemical solution deposition as a method capable of creating conformally coated layers and delves into the resulting modifications in the structural and optical properties of Ge-Sb-Se-Te PCMs. Specifically, we detail the solution-based deposition of Ge-Sb-Se-Te layers and present a comparative analysis with those deposited via thermal evaporation. We also discuss our ongoing endeavor to improve available choice of processing-material combinations and how to realize solution-derived high figure-of-merit optical PCM layers, which will enable a new era for the development of reconfigurable photonic devices.
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Alignment in total ankle replacement is important for success and implant survival. Recently there has been the introduction and adoption of patient specific instrumentation for implantation in total ankle replacement. Current literature does not evaluate the effect of preoperative deformity on accuracy of patient specific instrumentation. A retrospective radiographic analysis was performed on 97 consecutive patients receiving total ankle replacement with patient specific instrumentation to assess the accuracy and reproducibility of the instrumentation. Subgroup analysis evaluated the effect of preoperative deformity. All surgeries were performed by fellowship trained foot and ankle surgeons without industry ties to the implants used. Preoperative and postoperative films were compared to plans based on computerized tomography scans to assess how closely the plan would be implemented in patients. Overall postoperative coronal plane alignment was within 2° of predicted in 87.6% (85 patients). Similarly, overall postoperative sagittal plane alignment was within 2° of predicted in 88.7% (86 patients). Tibial implant size was accurately predicted in 81.4% (79 patients), and talus implant size was correct in 75.3% (73 patients). Patients with preoperative varus deformity had a higher difference between predicted and actual postoperative alignment compared to valgus deformity (1.1° compared to 0.3°, p = .02). A higher average procedure time was found in varus patients, and more adjunctive procedures were needed in patients with varus or valgus deformity, but these were not significant, p > .5. Surgeons can expect a high degree of accuracy when using patient specific instrumentation overall, but less accurate in varus deformity.
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Purpose: The specialty of Laboratory Genetics and Genomics (LGG) was created in 2017 in an effort to reflect the increasing convergence in technologies and approaches between clinical molecular genetics and clinical cytogenetics. However, there has not yet been any formal evaluation of the merging of these disciplines and the challenges faced by Program Directors (PDs) tasked with ensuring the successful training of laboratory geneticists under the new model. Methods: An electronic multi-question Qualtrics survey was created and was sent to the PD for each of the Accreditation Council for Graduate Medical Education-accredited LGG fellowship programs at the time. The data were collected, and the responses were aggregated for each question. Results: All of the responding PDs had started training at least 1 LGG fellow. PDs noted challenges with funding, staff shortages, molecular/cytogenetics content integration, limited total training time, increased remote work, increased sendout testing, and a lack of prior cytogenetics knowledge among incoming fellows. Conclusion: This survey attempted to assess the challenges that LGG PDs have been facing in offering and integrating clinical molecular genetics and clinical cytogenetics fellowship training. Common challenges between programs were noted, and a set of 6 concluding comments are provided to facilitate future discussion.