Citations

AbstractDespite the pivotal role of communication skills in genetic counseling, communication strategies employed by genetic counselors in their current practice remain largely unexplored. The field of genetic counseling could benefit from updated simulated genetic counseling sessions conducted by genetic counselors illustrating a diversity of skills. This paper outlines the development and evaluation of updated simulations used to develop an online training course to identify genetic counseling skills and to assess how commonly these skills are used. Practicing genetic counselors in the United States were recruited to counsel trained standardized patients across six pretest and posttest simulated sessions in cancer, prenatal, and cardiology genetics settings. Sessions were coded using the novel Genetic Counseling Skills Checklist to identify which communication and counseling skills were utilized. Standardized patients were asked to provide session quality ratings and written feedback, which were analyzed using descriptive statistics and content analysis, respectively. Results from 64 recorded sessions involving 20 counselors from a variety of training programs, racial and ethnic backgrounds, states of residence, and with varying years of clinical experience revealed utilization of a broad array of skills across specialty types and clinical indications. The total number of unique skills used varied widely from 12 to 49, with an average of 35.8 out of 56 possible skills checked per session. Differences in skill usage were observed between pretest and posttest sessions. Standardized patient comments were predominantly positive with a focus on information delivery and empathetic responses. Perceptions of areas of improvement were giving less information, having clearer delivery, and expressing more empathy. This work led to the creation of a training course showcasing various skills used by practicing genetic counselors, which summarizes commonly used skills and other promising but less frequently utilized ones.

Introduction Artificial intelligence (AI), particularly large-language models like Chat Generative Pre-Trained Transformer (ChatGPT), has demonstrated potential in streamlining research methodologies. Systematic reviews and meta-analyses, often considered the pinnacle of evidence-based medicine, are inherently time-intensive and demand meticulous planning, rigorous data extraction, thorough analysis, and careful synthesis. Despite promising applications of AI, its utility in conducting systematic reviews with meta-analysis remains unclear. This study evaluated ChatGPT’s accuracy in conducting key tasks of a systematic review with meta-analysis. Methods This validation study used data from a published meta-analysis on emotional functioning after spinal cord stimulation. ChatGPT-4o performed title/abstract screening, full-text study selection, and data pooling for this systematic review with meta-analysis. Comparisons were made against human-executed steps, which were considered the gold standard. Outcomes of interest included accuracy, sensitivity, specificity, positive predictive value, and negative predictive value for screening and full-text review tasks. We also assessed for discrepancies in pooled effect estimates and forest plot generation. Results For title and abstract screening, ChatGPT achieved an accuracy of 70.4%, sensitivity of 54.9%, and specificity of 80.1%. In the full-text screening phase, accuracy was 68.4%, sensitivity 75.6%, and specificity 66.8%. ChatGPT successfully pooled data for five forest plots, achieving 100% accuracy in calculating pooled mean differences, 95% CIs, and heterogeneity estimates ( I 2 score and tau-squared values) for most outcomes, with minor discrepancies in tau-squared values (range 0.01–0.05). Forest plots showed no significant discrepancies. Conclusion ChatGPT demonstrates modest to moderate accuracy in screening and study selection tasks, but performs well in data pooling and meta-analytic calculations. These findings underscore the potential of AI to augment systematic review methodologies, while also emphasizing the need for human oversight to ensure accuracy and integrity in research workflows.

Abstract Background In predynamic or dynamic scapholunate (SL) instability, standard diagnostic imaging may not identify SL interosseous ligament (SLIL) injury, leading to delayed detection and intervention. This study describes the use of four-dimensional computed tomography (4DCT) in identifying early SLIL injury and following injured wrists to 1-year postoperatively. Description of Technique 4DCT acquires a series of three-dimensional volume data with high temporal resolution (66 ms). 4DCT-derived arthrokinematic data can be used as biomarkers of ligament integrity. Patients and Methods This study presents the use of 4DCT in a two-participant case series to assess changes in arthrokinematics following unilateral SLIL injury preoperatively and 1-year postoperatively. Patients were treated with volar ligament repair with volar capsulodesis and arthroscopic dorsal capsulodesis. Arthrokinematics were compared between uninjured, preoperative injured, and postoperative injured (repaired) wrists. Results 4DCT detected changes in interosseous distances during flexion-extension and radioulnar deviation. Generally, radioscaphoid joint distances were greatest in the uninjured wrist during flexion-extension and radioulnar deviation, and SL interval distances were smallest in the uninjured wrist during flexion-extension and radioulnar deviation. Conclusion 4DCT provides insight into carpal arthrokinematics during motion. Distances between the radioscaphoid joint and SL interval can be displayed as proximity maps or as simplified descriptive statistics to facilitate comparisons between wrists and time points. These data offer insight into areas of concern for decreased interosseous distance and increased intercarpal diastasis. This method may allow surgeons to assess whether (1) injury can be visualized during motion, (2) surgery repaired the injury, and (3) surgery restored normal carpal motion. Level of Evidence Level IV, Case series.

Abstract The PD-1:PD-L1 axis is a major immune regulatory pathway that blunts T cell activation in the tumor microenvironment. We recently identified that PD-1 is also upregulated on ovarian mouse tumor-infiltrating myeloid dendritic cells (TIDCs) that exhibit an immune suppressive phenotype. Extending those observations in this study, we now report that PD-1 is also expressed on human myeloid TIDCs of ovarian cancer patients, on which it suppresses the expression of co-stimulatory molecules (CD40 and CD80) as well as production of inflammatory cytokines. Mechanistic studies revealed that PD-1 on TIDCs is associated with Src homology domain-containing phosphatase-2 (SHP-2) and that PD-1-mediated blockade of NFkB-dependent cytokine release is SHP-2 dependent. PD-1 also inhibits NFkB-mediated antigen presentation which appears, however, to be independent of SHP-2. Thus, suppression of NFkB is critical in mediating PD-1-induced paralysis of ovarian tumor-associated immune TIDCs and is mediated through multiple signaling circuits that are both SHP-2 dependent and independent.

Abstract Ovarian cancer is an immune reactive tumor with a complex suppressive network that blunts immune eradication. One putative pathway of evasion may be recruitment of CD4 regulatory T cells (Treg) into the tumor microenvironment. This study investigated the association of tumor infiltrating Tregs in ovarian cancer patients with poor survival. Methods: Immunofluorescence of intraepithelial CD4+CD25+FOXP3+ Tregs, CD3+ and CD8+ cells was performed in tumors of 52 ovarian cancer patients. Average and maximum count of cells were associated with survival via Cox regression models and summarized with hazard ratios (HR) and 95% confidence intervals (CIs). Results: The maximum counts of Tregs in these patients suggests an association between higher number of Tregs and poor clinical outcome (HR=1.48, CI=0.97, 2.28), although not statistically significant (p=0.07). Moreover, presence of high CD8/Treg ratio (HR=0.7, CI=0.53, 0.91; p=0.008) as well as high CD8/CD4 ratio (HR=0.76, CI=0.57, 1.0; p=0.05) appear to be associated with good outcome. The CD3 lymphocyte count was not associated with survival (HR=0.9, CI=0.66, 1.24; p=0.52). Conclusion: Although the present pilot study was conducted with a limited number of patients, our data suggests that higher numbers of infiltrating Tregs might be associated with poor survival and low CD8/Treg ratio may be correlated with improved survival in patients with epithelial ovarian carcinoma. We plan to confirm these results in a larger set of patients.

The poly(ADP-ribose) binding protein CHFR regulates cellular responses to mitotic stress. The deubiquitinase UBC13, which regulates CHFR levels, has been associated with better overall survival in paclitaxel-treated ovarian cancer. Despite the extensive use of taxanes in the treatment of ovarian cancer, little is known about expression of CHFR itself in this disease. In the present study, tissue microarrays containing ovarian carcinoma samples from 417 women who underwent initial surgical debulking were stained with anti-CHFR antibody and scored in a blinded fashion. CHFR levels, expressed as a modified H-score, were examined for association with histology, grade, time to progression (TTP) and overall survival (OS). In addition, patient-derived xenografts from 69 ovarian carcinoma patients were examined for CHFR expression and sensitivity to paclitaxel monotherapy. In clinical ovarian cancer specimens, CHFR expression was positively associated with serous histology (p = 0.0048), higher grade (p = 0.000014) and higher stage (p = 0.016). After correction for stage and debulking, there was no significant association between CHFR staining and overall survival (p = 0.62) or time to progression (p = 0.91) in patients with high grade serous cancers treated with platinum/taxane chemotherapy (N = 249). Likewise, no association between CHFR expression and paclitaxel sensitivity was observed in ovarian cancer PDXs treated with paclitaxel monotherapy. Accordingly, differences in CHFR expression are unlikely to play a major role in paclitaxel sensitivity of high grade serous ovarian cancer.

BACKGROUND: Intrathecal drug delivery systems (IDDS) have been utilized for over 3 decades for management of chronic pain and spasticity. Patients with IDDS may present for surgical procedures unrelated to the IDDS device, although data are limited regarding perioperative outcomes. METHODS: This is a historical matched cohort study conducted between January 1, 2007 and December 31, 2016 of patients with an opioid-based IDDS versus matched control patients undergoing surgery excluding interventional pain procedures. Patients in the IDDS group were matched with up to 2 patients without an IDDS. Multivariable regression analyses were utilized to assess differences in the primary outcome of cumulative perioperative opioid consumption (ie, intraoperative and postanesthesia care unit [PACU] opioid consumption), and opioid consumption during the first 24 and 72 postoperative hours. Postoperative clinical outcomes were also assessed including escalating oxygen requirements, naloxone administration, pain-sedation mismatch, and perioperative pain service consultation. RESULTS: A total of 321 surgeries were included, 112 with IDDS and 209 controls, with median (interquartile range [IQR]) age of 57 (49–64) years. Compared to matched controls, patients with an IDDS had greater perioperative opioid consumption (median [IQR] oral morphine milligram equivalents [OME] of 110 [60–163] vs 93 [IQR, 53–142]; adjusted multiplicative increase 1.28 [95% confidence interval {CI}, 1.03–1.59]; P = .026). IDDS patients also had greater opioid consumption in the first 24 and 72 postoperative hours (multiplicative increases of 2.23 [95% CI, 1.36–3.63], P = .001, and 2.46 [95% CI, 1.41–4.32], P = .002, respectively). There were no significant differences in postoperative oxygen requirements, naloxone administration, or pain-sedation mismatch. Inpatient pain medicine consultation was more frequent in IDDS patients compared to controls (51.8% vs 6.2%; P < .001). CONCLUSIONS: Patients with opioid-based IDDS received more perioperative opioids and were more likely to receive postoperative pain service consultation compared to matched controls. There were no significant differences in clinical safety outcomes, suggesting tolerance for higher opioid doses. Further research is warranted to optimize perioperative outcomes in those with IDDS.

Abstract Aging is the biggest risk factor for the most serious chronic diseases and disabilities. Cellular senescence, a state in which cells stop dividing but release factors that damage other cells, may contribute to both age-related and chronic diseases. Removal of senescent cells from aged mice has been shown to delay aging and age–related disabilities. Our goal was to determine the ability of potential senolytic agents to remove senescent cells in a primate model. Several agents and combinations were tested including Fisetin, Navitoclax, combined Dasatinib and Quercetin, and combined Dasatinib and Fisetin. Here we describe the Dasatinib and Fisetin trial. Dasatinib is an FDA approved oral anticancer drug that has been used to treat chronic myelogenous leukemia in humans. Fisetin is a flavonoid that can be found in many plants, particularly strawberries, and acts as a coloring agent. After baseline measurements, six older (mean age=21 years) female rhesus monkeys (Macaca mulatta) were given a combined oral dose of Dasatinib (5 mg/kg) and Fisetin (100 mg/kg) on two consecutive days. Animals were additionally assessed at 1- and 7-weeks following dosing. At 7 weeks post dosing, there were fewer (p&lt;0.05) p16+ cells in the epidermis compared to baseline. Similarly, there was a reduction (p&lt;0.05) in p21+ cells in the epidermis at 1- and 7-weeks post dosing compared to baseline. There were no negative outcomes associated with treatment. This study provides preliminary evidence for the senolytic potential of combined Dasatinib and Fisetin treatment and indicates that pharmacological mitigation of age-related changes is possible.

Abstract Purpose Peripheral nerve stimulation (PNS) is a rapidly expanding field within neuromodulation; however, there is limited data on therapeutic efficacy. This study describes the indications and clinical outcomes for patients undergoing PNS for chronic pain states. Patients and Methods This is a retrospective case series of adults undergoing PNS implantation from 2004 to 2017 at an academic medical center. The primary outcomes were changes in numeric rating scale (NRS) pain scores, opioid utilization in oral morphine milligram equivalent (MME), and self‐reported patient functioning at 6 months postoperatively. Infectious and device‐related complications were also assessed. Results A total of 72 patients underwent PNS implantation, including 59 patients that received a preceding PNS trial (59/78; 76% progression rate) and 13 that did not receive a PNS trial. The most common indication for stimulation was occipital neuralgia (47%) followed by lower‐extremity neuropathies (17%). PNS implantation was associated with 6‐month reductions in pain scores (7 [6, 8] baseline vs. 4 [2, 5] 6 months; P < 0.001) and opioid utilization (eg, median 60 [31, 104] vs. 18 [0, 52] MME among those with baseline opioid use; P < 0.001). Median functional improvement was 73% (50%, 88%). Seven patients (10%) suffered a postoperative surgical site infection at a median of 50 (30, 124) days, of which five devices were removed. Conclusion Peripheral nerve stimulation was associated with reduced pain scores, lower opioid utilization, and improved patient function at 6 months. These data support PNS as a potentially effective nonopioid analgesic modality in chronic pain, though prospective multicenter evaluation is warranted to evaluate longer‐term outcomes.