Ionic reverberation modulates the cellular fate of CD8+ tissue resident memory T cells (TRMs) in patients with renal cell carcinoma: A novel mechanism.

In metastatic renal cell carcinoma (mRCC), existing treatments including checkpoint inhibitors are failed to cure and/or prevent recurrence of the disease. Therefore, in-depth understanding of tumor tissue resident memory T cells (TRMs) dysfunction are necessitated to enrich efficacy of immunotherapies and increasing disease free survival in treated patients. In patients, we observed dysregulation of K+, Ca2+, Na2+ and Zn2+ ion channels leads to excess infiltration of their respective ions in tumor TRMs, thus ionic gradients are disturbed and cells became hyperpolarized. Moreover, overloaded intramitochondrial calcium caused mitochondrial depolarization and trigger apoptosis of tumor TRMs. Decreased prevalence of activated tumor TRMs reflected our observations. Furthermore, disruptions in ionic concentrations impaired the functional activities and/or suppressed anti-tumor action of circulating and tumor TRMs in RCC. Collectively, these findings revealed novel mechanism behind dysfunctionality of tumor TRMs. Implicating enrichment of activated TRMs within tumor would be beneficial for better management of RCC patients.

Utilization of Augmented Reality Head-Mounted Display for the Surgical Management of Thoracolumbar Spinal Trauma.

Background and Objectives: Augmented reality head-mounted display (AR-HMD) is a novel technology that provides surgeons with a real-time CT-guided 3-dimensional recapitulation of a patient's spinal anatomy. In this case series, we explore the use of AR-HMD alongside more traditional robotic assistance in surgical spine trauma cases to determine their effect on operative costs and perioperative outcomes. Materials and Methods: We retrospectively reviewed trauma patients who underwent pedicle screw placement surgery guided by AR-HMD or robotic-assisted platforms at an academic tertiary care center between 1 January 2021 and 31 December 2022. Outcome distributions were compared using the Mann-Whitney U test. Results: The AR cohort (n = 9) had a mean age of 66 years, BMI of 29.4 kg/m2, Charlson Comorbidity Index (CCI) of 4.1, and Surgical Invasiveness Index (SII) of 8.8. In total, 77 pedicle screws were placed in this cohort. Intra-operatively, there was a mean blood loss of 378 mL, 0.78 units transfused, 398 min spent in the operating room, and a 20-day LOS. The robotic cohort (n = 13) had a mean age of 56 years, BMI of 27.1 kg/m2, CCI of 3.8, and SII of 14.2. In total, 128 pedicle screws were placed in this cohort. Intra-operatively, there was a mean blood loss of 432 mL, 0.46 units transfused units used, 331 min spent in the operating room, and a 10.4-day LOS. No significant difference was found between the two cohorts in any outcome metrics. Conclusions: Although the need to address urgent spinal conditions poses a significant challenge to the implementation of innovative technologies in spine surgery, this study represents an initial effort to show that AR-HMD can yield comparable outcomes to traditional robotic surgical techniques. Moreover, it highlights the potential for AR-HMD to be readily integrated into Level 1 trauma centers without requiring extensive modifications or adjustments.

Digital Patient Education on Xanthelasma Palpebrarum: A Content Analysis.

Patient education has been transformed using digital media and online repositories which disseminate information with greater efficiency. In dermatology, this transformation has allowed for patients to gain education on common cutaneous conditions and improve health literacy. Xanthelasma palpebrarum is one of the most common cutaneous conditions, yet there is a poor understanding of how digital materials affect health literacy on this condition. Our study aimed to address this paucity of literature utilizing Brief DISCERN, Rothwell's Classification of Questions, and six readability calculations. The findings of this study indicate a poor-quality profile (Brief DISCERN < 16) regarding digital materials and readability scores which do not meet grade-level recommendations in the United States. This indicates a need to improve the current body of educational materials used by clinicians for diagnosing and managing xanthelasma palpebrarum.

Optimal Cut-Off Values for Body Mass Index and Fat Mass Index Based on Age in Physically Active Males Using Receiver Operating Characteristic Curve.

This study aims to redefine obesity cut-off points for body mass index (BMI) and fat mass index (FMI) according to the different age groups of physically active males. Healthy physically active volunteers (N = 1442) aged 18-57 years (y), with a mean BMI = 22.7 ± 2.8 kg/m2, and mean FMI = 4.3 ± 1.7 kg/m2 were recruited from various fitness centers. BMI was calculated and individuals were categorized according to the Asia-Pacific BMI criterion of ≤22.9 kg/m2 and the previous WHO-guided BMI criterion of ≤24.9 kg/m2. FMI was also calculated for the study participants with a cut-off of 6.6 kg/m2. Redefining of BMI and FMI cut-off values was carried out based on different age groups categorized with a difference of 10 y and 5 y using the receiver operating characteristic (ROC) curve and Youden's index. For the entire study population, BMI redefined cut-off points for overweight and obesity were 23.7 kg/m2 and 24.5 kg/m2, respectively, while FMI redefined cut-off points for overweight and obesity were 4.6 kg/m2 and 5.7 kg/m2, respectively. With 10 y of age group difference, a constant BMI and FMI values were observed, while with 5 y of age group difference, a constant increase in the BMI cut-offs was observed as the age group increased, i.e., from 23.3 kg/m2 in 20-24 y to 26.6 kg/m2 in ≥45 y and a similar trend was seen in FMI cut-offs. To conclude, our study suggests that age-dependent BMI and FMI cut-off points may provide appropriate measurements for physically active males as the age group increases.

Improvements in Physical Function and Pain Interference and Changes in Mental Health Among Patients Seeking Musculoskeletal Care.

Importance: Among patients seeking care for musculoskeletal conditions, there is mixed evidence regarding whether traditional, structure-based care is associated with improvement in patients' mental health. Objective: To determine whether improvements in physical function and pain interference are associated with meaningful improvements in anxiety and depression symptoms among patients seeking musculoskeletal care. Design, Setting, and Participants: This cohort study included adult patients treated by an orthopedic department of a tertiary care US academic medical center from June 22, 2015, to February 9, 2022. Eligible participants presented between 4 and 6 times during the study period for 1 or more musculoskeletal conditions and completed Patient-Reported Outcomes Measurement Information System (PROMIS) measures as standard care at each visit. Exposure: PROMIS Physical Function and Pain Interference scores. Main Outcomes and Measures: Linear mixed effects models were used to determine whether improvements in PROMIS Anxiety and PROMIS Depression scores were associated with improved PROMIS Physical Function or Pain Interference scores after controlling for age, gender, race, and PROMIS Depression (for the anxiety model) or PROMIS Anxiety (for the depression model). Clinically meaningful improvement was defined as 3.0 points or more for PROMIS Anxiety and 3.2 points or more for PROMIS Depression. Results: Among 11 236 patients (mean [SD] age, 57 [16] years), 7218 (64.2%) were women; 120 (1.1%) were Asian, 1288 (11.5%) were Black, and 9706 (86.4%) were White. Improvements in physical function (ß = -0.14; 95% CI, -0.15 to -0.13; P < .001) and pain interference (ß = 0.26; 95% CI, 0.25 to 0.26; P < .001) were each associated with improved anxiety symptoms. To reach a clinically meaningful improvement in anxiety symptoms, an improvement of 21 PROMIS points or more (95% CI, 20-23 points) on Physical Function or 12 points or more (95% CI, 12-12 points) on Pain Interference would be required. Improvements in physical function (ß = -0.05; 95% CI, -0.06 to -0.04; P < .001) and pain interference (ß = 0.04; 95% CI, 0.04 to 0.05; P < .001) were not associated with meaningfully improved depression symptoms. Conclusions and Relevance: In this cohort study, substantial improvements in physical function and pain interference were required for association with any clinically meaningful improvement in anxiety symptoms, and were not associated with any meaningful improvement in depression symptoms. Patients seeking musculoskeletal care clinicians providing treatment cannot assume that addressing physical health will result in improved symptoms of depression or potentially even sufficiently improved symptoms of anxiety.

A Cross-Sectional Study of Graduate Medical Education in Radiological Fellowships using Accessible Content.

Graduate medical education in radiology serves an imperative role in training the next generation of specialists. Given the regularity of virtual interviews, the website of a fellowship programs remains a critical first-line source of information of applicants. The aim of this study is to systematically evaluate 7 radiology fellowship programs utilizing a systematic process. A cross-sectional descriptive 286 graduate medical education fellowship programs in radiology were screened from the Fellowship and Residency Electronic Interactive Database (FREIDA). Extracted data was evaluated for comprehensiveness using 20 content criteria, and a readability score is calculated. The mean comprehensiveness among all fellowship program websites was 55.8% (n = 286), and the average FRE among the program overview sections was 11.9 (n = 214). ANOVA revealed no statistical significance in program website comprehensiveness between radiology fellowships (P = 0.33). The quality of a program's website data continues to serve an important role in an applicant's decision-making. Fellowship programs have improved in their content availability overtime, but content reevaluation needs to be continued for tangible improvement.

Transient Receptor Potential (TRP) Channels in Pain, Neuropsychiatric Disorders, and Epilepsy.

Pharmacomodulation of membrane channels is an essential topic in the study of physiological conditions and disease status. Transient receptor potential (TRP) channels are one such family of nonselective cation channels that have an important influence. In mammals, TRP channels consist of seven subfamilies with a total of twenty-eight members. Evidence shows that TRP channels mediate cation transduction in neuronal signaling, but the full implication and potential therapeutic applications of this are not entirely clear. In this review, we aim to highlight several TRP channels which have been shown to mediate pain sensation, neuropsychiatric disorders, and epilepsy. Recent findings suggest that TRPM (melastatin), TRPV (vanilloid), and TRPC (canonical) are of particular relevance to these phenomena. The research reviewed in this paper validates these TRP channels as potential targets of future clinical treatment and offers patients hope for more effective care.

Relationships between improvement in physical function, pain interference, and mental health in musculoskeletal patients.

Importance: Among patients seeking care for musculoskeletal conditions, there is mixed evidence regarding whether traditional, structure-based care is associated with improvement in patients' mental health. Objective: To determine whether improvements in physical function and pain interference are associated with meaningful improvements in anxiety and depression symptoms among patients seeking musculoskeletal care. Design: Retrospective cohort study from June 22, 2015 to February 9, 2022. Setting: Orthopedic department of a tertiary care US academic medical center. Participants: Consecutive sample of adult patients who presented to the musculoskeletal clinic 4 to 6 times during the study period and completed Patient-Reported Outcomes Measurement Information System (PROMIS) measures as standard care at each visit. Exposure: PROMIS Physical Function and Pain Interference scores. Main Outcomes and Measures: Linear mixed effects models were used to determine whether: 1) PROMIS Anxiety and 2) PROMIS Depression scores improved as a function of improved PROMIS Physical Function or Pain Interference scores, after controlling for age, gender, race, and PROMIS Depression (for the Anxiety model) and PROMIS Anxiety (for the Depression model). Clinically meaningful improvement was defined as ≥3.0 points for PROMIS Anxiety and ≥3.2 points for PROMIS Depression. Results: Among 11,236 patients (mean [SD] age 57 [16] years), 9,706 (86%) were White, and 7,218 (64%) were women. Improvements in physical function (ß=-0.14 [95% CI -0.15- -0.13], p<0.001) and pain interference (ß=0.26 [0.25-0.26], p<0.001) were each associated with improved anxiety symptoms. To reach a clinically meaningful improvement in anxiety symptoms, an improvement of ≥21 [20-23] PROMIS points on Physical Function or ≥12 [12-12] points on Pain Interference would be required. Improvements in physical function (ß=-0.05 [- 0.06- -0.04], p<0.001) and pain interference (ß=0.04 [0.04-0.05], p<0.001) were not associated with meaningfully improved depression symptoms. Conclusions and Relevance: In this cohort study, substantial improvements in physical function and pain interference were required for association with any clinically meaningful improvement in anxiety symptoms and were not associated with any meaningful improvement in depression symptoms. Among patients seeking musculoskeletal care, musculoskeletal clinicians and patients cannot assume that addressing physical health will result in improved symptoms of depression or potentially even sufficiently improved symptoms of anxiety. Key Points: Question: Among patients seeking musculoskeletal care, are improvements in physical function and pain interference associated with meaningful changes in symptoms of anxiety and depression?Findings: In this large cohort study, improvement by ≥2.3 population-level standard deviations (SD) on PROMIS Physical Function or ≥1.2 SD on PROMIS Pain Interference were required for any association with meaningful improvement in anxiety symptoms. Improvements in physical function and pain interference were not associated with meaningfully improved depression symptoms.Meaning: Musculoskeletal clinicians and patients cannot assume that exclusively addressing the physical aspect of a musculoskeletal condition will improve symptoms of depression or potentially even anxiety.

Factors associated with persistent postsurgical pain after total knee or hip joint replacement: a systematic review and meta-analysis.

Studies have identified demographic, clinical, psychosocial, and perioperative variables associated with persistent pain after a variety of surgeries. This study aimed to perform a systematic review and meta-analysis of factors associated with persistent pain after total knee replacement (TKR) and total hip replacement (THR) surgeries. To meet the inclusion criteria, studies were required to assess variables before or at the time of surgery, include a persistent postsurgical pain (PPSP) outcome measure at least 2 months after a TKR or THR surgery, and include a statistical analysis of the effect of the risk factor(s) on the outcome measure. Outcomes from studies implementing univariate and multivariable statistical models were analyzed separately. Where possible, data from univariate analyses on the same factors were combined in a meta-analysis. Eighty-one studies involving 171,354 patients were included in the review. Because of the heterogeneity of assessment methods, only 44% of the studies allowed meaningful meta-analysis. In meta-analyses, state anxiety (but not trait anxiety) scores and higher depression scores on the Beck Depression Inventory were associated with an increased risk of PPSP after TKR. In the qualitative summary of multivariable analyses, higher preoperative pain scores were associated with PPSP after TKR or THR. This review systematically assessed factors associated with an increased risk of PPSP after TKR and THR and highlights current knowledge gaps that can be addressed by future research.

KCMF1 regulates autophagy and ion channels' function in renal cell carcinoma: a future therapeutic target.

INTRODUCTION: In RCC, systematic procedures such as surgery, chemo-radiation therapy, and application of target-based inhibitors increase the risk of several comorbidities such as chronic kidney disease, hemorrhage, and cardiac arrest that may increase the mortality rate. Even though immune-based checkpoint inhibitor therapies have an overall good response rate, it is restricted to only 30-40% of patients. Hence, an in-depth study of tumor pathophysiology in RCC is needed to identify the new therapeutic target. In RCC, persisted hypoxia is an essential phenomenon for tumor growth and progression. KCMF1 is a newly identified ubiquitin ligase whose domain interacts with destabilized proteins and reprogrammed the ubiquitin coding for lysosome-mediated degradation and autophagy under hypoxic conditions/oxidative stress and maintaining cellular homeostasis. But in RCC, the functional role of KCMF1 remains undefined to date. METHOD: We determined KCMF1 and its associated proteins RAD6 and UBR4 expression and their co-localization using confocal microscopy in tumor and non-tumor tissues samples. Further, immunofluorescence staining was performed to determine autophagy (LC3B, p62), hypoxia-inducible factor (HIF-1A) and ion channel markers (Kv1.3, KCNN4) in RCC patients (n-10). Inductively coupled plasma mass spectrophotometry (ICPMS) was performed to estimate the concentration of potassium (K+), sodium (Na+) and Zinc (zn2+) in tumor and non-tumor cells of RCC patients (n-20). Lastly, images were analyzed using ZEN3.1, and ImageJ software. RESULT AND CONCLUSION: We observed a discrepancy in the formation of ubiquitin ligase, autophagosome via KCMF1, and ionic concentration in tumor cells, which might be one of the possible factors for cancer evolution. KCMF1-associated ubiquitin ligase system could be considered as a novel therapeutic target for RCC in the future.

Health Literacy Analytics of Accessible Patient Resources in Cardiovascular Medicine: What are Patients Wanting to Know?

Introduction: There remains an increasing utilization of internet-based resources as a first line of medical knowledge. Among patients with cardiovascular disease, these resources often are relied upon for numerous diagnostic and therapeutic modalities. However, the reliability of this information is not fully understood. The aim of this study was to provide a descriptive profile on the literacy quality, readability, and transparency of publicly available educational resources in cardiology. Methods: The frequently asked questions and associated online educational articles on common cardiovascular diagnostic and therapeutic interventions were investigated using publicly available data from the Google RankBrain machine learning algorithm after applying inclusion and exclusion criteria. Independent raters evaluated questions for Rothwell's Classification and readability calculations. Results: Collectively, 520 questions and articles were evaluated across 13 cardiac interventions, resulting in 3,120 readability scores. The sources of articles were most frequently from academic institutions followed by commercial sources. Most questions were classified as "Fact" at 76.0% (n = 395), and questions regarding "Technical Details" of each intervention were the most common subclassification at 56.3% (n = 293). Conclusions: Our data show that patients most often are using online search query programs to seek information regarding specific knowledge of each cardiovascular intervention rather than form an evaluation of the intervention. Additionally, these online patient educational resources continue to not meet grade-level reading recommendations.

Hemodynamic Effects of Ketamine Infusion in the Intensive Care Unit for Maintenance Sedation Compared With Propofol and Midazolam: A Retrospective Cohort Study.

Background: Sedation and analgesia in the intensive care unit (ICU) are major clinical challenges, and several continuous infusion medications have been used for these purposes. The use of these sedative medications has been associated with hemodynamic effects that complicate the patient's critical illness. Continuous ketamine infusion is an emerging sedative option that has been used more frequently in the ICU since 2017. The purpose of this study was to characterize the hemodynamic differences between 3 continuous sedative infusions: ketamine, propofol, and midazolam. Methods: For this single-center retrospective cohort study, we collected data for patients hospitalized between January 2015 and April 2020 at Saint Luke's Health System in Kansas City, Missouri. Adult patients in the ICU requiring a norepinephrine infusion and sedation were included. The change in norepinephrine requirement from baseline at 1 hour was the primary outcome. The change in vasopressor requirement at 3 and 30 hours after initiation of the infusion was also tabulated. Results: Sixty-eight critically ill patients with several types of shock requiring vasopressor support with norepinephrine were enrolled in our study. Patients who received ketamine had an increase in norepinephrine requirement compared to midazolam and propofol, although this difference was not statistically significant. Conclusion: In our study, continuous ketamine infusion did not reveal a statistically significant favorable hemodynamic effect compared with propofol and midazolam because of the small sample size. A trend toward an unfavorable hemodynamic effect is not expected, but large randomized trials are needed to further evaluate the hemodynamic effects of continuous ketamine infusion in the ICU.

Catheter-based renal sympathetic nerve denervation on hypertension management outcomes.

BACKGROUND: Renal sympathetic denervation (RSD) provides a minimally invasive interventional treatment modality for patients with resistant hypertension. However, the post-operative outcomes remain a key area of investigation since its earliest clinical trials. AIM: To evaluate patient outcomes after RSD intervention among peer-reviewed patient cases. METHODS: A systematic review of literature on MEDLINE, Google Scholar, and the Cochrane Database of Systematic Reviews for RSD case studies to assess post-operative hypertension readings and medical management. RESULTS: Among 51 RSD cases, the post-operative RSD patients report an apparent reduction with a mean number of 3.1 antihypertensive medications. The mean systolic arterial blood pressure 1 year following RSD was 136.0 mmHg (95%CI: 118.7-153.3). CONCLUSION: The apparent improvements in office systolic blood pressure after 12 month post-operative RSD can support the therapeutic potential of this intervention for blood pressure reduction. Additional studies which utilized a uniform methodology for blood pressure measurement can further support the findings of this systematic review.

Insight into the role of myokines and myogenic regulatory factors under hypobaric hypoxia induced skeletal muscle loss.

BACKGROUND: The present study aimed to analyse the role of myokines and the regeneration capacity of skeletal muscle during chronic hypobaric hypoxia (CHH). METHODS: Male Sprague-Dawley rats were exposed to hypobaric hypoxia (HH) for 1d, 3d and 7d. RESULTS: Exposure to HH enhanced the levels of decorin, irisin, IL-6 and IL-15 till 3 days of hypoxia and on 7 day of exposure, no significant changes were observed in relation to control. A significant upregulation in myostatin, activated protein kinase, SMAD3, SMAD4, FOXO-1, MURF-1 expression was observed with prolonged HH exposure as compared to normoxic control. Further, myogenesis-related markers, PAX-7, Cyclin D1 and myogenin were downregulated during CHH exposure in comparison to control. Energy metabolism regulators such as Sirtuin 1, proliferator-activated receptor gamma coactivator-1α and GLUT-4, were also increased on 1-d HH exposure that showed a declining trend on CHH exposure. CONCLUSIONS: These results indicated the impairment in the levels of myokines and myogenesis during prolonged hypoxia. CHH exposure enhanced the levels of myostatin and reduced the regeneration or repair capacity of the skeletal muscles. Myokine levels could be a predictive biomarker for evaluating skeletal muscle performance and loss at high altitudes.

Amylin and Secretases in the Pathology and Treatment of Alzheimer's Disease.

Alzheimer's disease remains a prevailing neurodegenerative condition which has an array physical, emotional, and financial consequences to patients and society. In the past decade, there has been a greater degree of investigation on therapeutic small peptides. This group of biomolecules have a profile of fundamentally sound characteristics which make them an intriguing area for drug development. Among these biomolecules, there are four modulatory mechanisms of interest in this review: alpha-, beta-, gamma-secretases, and amylin. These protease-based biomolecules all have a contributory role in the amyloid cascade hypothesis. Moreover, the involvement of various biochemical pathways intertwines these peptides to have shared regulators (i.e., retinoids). Further clinical and translational investigation must occur to gain a greater understanding of its potential application in patient care. The aim of this narrative review is to evaluate the contemporary literature on these protease biomolecule modulators and determine its utility in the treatment of Alzheimer's disease.

Comprehension Profile of Patient Education Materials in Endocrine Care.

Introduction: The internet is an ever-evolving resource to improve healthcare literacy among patients. The nature of the internet can make it difficult to condense educational materials in a manner applicable to a worldwide patient audience. Within the realm of endocrinology, there is lack of a comprehensive analysis regarding these pathologies in addition to education materials related to their medical work-up or management. The aim of this study was to assess contemporary online patient education material in endocrinology and management of care. Methods: Analysis of the readability of 1,500 unique online education materials was performed utilizing seven readability measures: Flesch Reading Ease (FRE), Flesch-Kincaid Grade Level (FKGL), Gunning Fog Index Readability Formula (FOG), Simple Measure of Gobbledygook Index (SMOG), Coleman-Liau Index (CLI), automated readability index (ARI), and Linsear Write Formula (LWF). Results: The average grade level readability scores from six measures (e.g., FKGL, FOG, SMOG, CLI, ARI, LWF) was more than or equal to 11 which corresponds to a reading level at or above the 11th grade. The average FRE between adrenal, diabetes, and thyroid-related education m aterial ranged between "fairly difficult" to "very difficult". Conclusions: The readability of contemporary online endocrine education material did not meet current readability recommendations for appropriate comprehension of the general audience.

Behavior of KCNQ Channels in Neural Plasticity and Motor Disorders.

The broad distribution of voltage-gated potassium channels (VGKCs) in the human body makes them a critical component for the study of physiological and pathological function. Within the KCNQ family of VGKCs, these aqueous conduits serve an array of critical roles in homeostasis, especially in neural tissue. Moreover, the greater emphasis on genomic identification in the past century has led to a growth in literature on the role of the ion channels in pathological disease as well. Despite this, there is a need to consolidate the updated findings regarding both the pharmacotherapeutic and pathological roles of KCNQ channels, especially regarding neural plasticity and motor disorders which have the largest body of literature on this channel. Specifically, KCNQ channels serve a remarkable role in modulating the synaptic efficiency required to create appropriate plasticity in the brain. This role can serve as a foundation for clinical approaches to chronic pain. Additionally, KCNQ channels in motor disorders have been utilized as a direction for contemporary pharmacotherapeutic developments due to the muscarinic properties of this channel. The aim of this study is to provide a contemporary review of the behavior of these channels in neural plasticity and motor disorders. Upon review, the behavior of these channels is largely dependent on the physiological role that KCNQ modulatory factors (i.e., pharmacotherapeutic options) serve in pathological diseases.