Physiological Factors Associated with Unsatisfied Inspiration at Peak Exercise in Healthy Adults.

INTRODUCTION: Contrary to common belief, a growing body of evidence suggests that unsatisfied inspiration (UI), an inherently uncomfortable quality of dyspnea, is experienced by ostensibly healthy adults during high-intensity exercise. Based on our understanding of the mechanisms of UI among people with chronic respiratory conditions, this analysis tested the hypothesis that the experience of UI at peak exercise in young, healthy adults reflects the combination of high ventilatory demand and critical inspiratory constraints. METHODS: In a retrospective analysis design, data included 321 healthy individuals (129 females) aged 25 ± 5 yrs. Data were collected during one visit to the laboratory, which included anthropometrics, spirometry, and an incremental cardiopulmonary cycling test to exhaustion. Metabolic and cardiorespiratory variables were measured at peak exercise, and qualitative descriptors of dyspnea at peak exercise were assessed using a list of 15 descriptor phrases. RESULTS: 34% of participants (n = 109) reported sensations of UI at peak exercise. Compared to the Non-UI group, the UI group achieved a significantly higher peak work rate (243 ± 77 vs. 235 ± 69 W, P = 0.016, d = 0.10), rate of O2 consumption (3.32 ± 1.02 vs. 3.27 ± 0.96 L·min-1, P = 0.018, d = 0.05), minute ventilation (120 ± 38 vs. 116 ± 35 L·min-1, P = 0.047, d = 0.11), and breathing frequency (50 ± 9 vs. 47 ± 9 breaths·min-1, P = 0.014, d = 0.33), while having a lower exercise-induced change (peak-baseline) in inspiratory capacity (0.07 ± 0.41 vs. 0.20 ± 0.49 L, P = 0.023, d = 0.29). The inspiratory reserve volume to minute ventilation ratio at peak exercise was also lower in the UI vs. Non-UI group. Dyspnea intensity and unpleasantness ratings were significantly higher in the UI vs. Non-UI group at peak exercise (both P < 0.001). CONCLUSIONS: Healthy individuals reporting UI at peak exercise have relatively greater inspiratory constraints compared to those who do not select UI.

A Scoping Review of Personalized, Interactive, Web-Based Clinical Decision Tools Available for Breast Cancer Prevention and Screening in the United States.

Introduction. Personalized web-based clinical decision tools for breast cancer prevention and screening could address knowledge gaps, enhance patient autonomy in shared decision-making, and promote equitable care. The purpose of this review was to present evidence on the availability, usability, feasibility, acceptability, quality, and uptake of breast cancer prevention and screening tools to support their integration into clinical care. Methods. We used the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews Checklist to conduct this review. We searched 6 databases to identify literature on the development, validation, usability, feasibility, acceptability testing, and uptake of the tools into practice settings. Quality assessment for each tool was conducted using the International Patient Decision Aid Standard instrument, with quality scores ranging from 0 to 63 (lowest-highest). Results. We identified 10 tools for breast cancer prevention and 9 tools for screening. The tools included individual (e.g., age), clinical (e.g., genomic risk factors), and health behavior (e.g., alcohol use) characteristics. Fourteen tools included race/ethnicity, but no tool incorporated contextual factors (e.g., insurance, access) associated with breast cancer. All tools were internally or externally validated. Six tools had undergone usability testing in samples including White (median, 71%; range, 9%-96%), insured (99%; 97%-100%) women, with college education or higher (60%; 27%-100%). All of the tools were developed and tested in academic settings. Seven (37%) tools showed potential evidence of uptake in clinical practice. The tools had an average quality assessment score of 21 (range, 9-39). Conclusions. There is limited evidence on testing and uptake of breast cancer prevention and screening tools in diverse clinical settings. The development, testing, and integration of tools in academic and nonacademic settings could potentially improve uptake and equitable access to these tools. Highlights: There were 19 personalized, interactive, Web-based decision tools for breast cancer prevention and screening.Breast cancer outcomes were personalized based on individual clinical characteristics (e.g., age, medical history), genomic risk factors (e.g., BRCA1/2), race and ethnicity, and health behaviors (e.g., smoking). The tools did not include contextual factors (e.g., insurance status, access to screening facilities) that could potentially contribute to breast cancer outcomes.Validation, usability, acceptability, and feasibility testing were conducted mostly among White and/or insured patients with some college education (or higher) in academic settings. There was limited evidence on testing and uptake of the tools in nonacademic clinical settings.

A scoping review of web-based, interactive, personalized decision-making tools available to support breast cancer treatment and survivorship care.

PURPOSE: We reviewed existing personalized, web-based, interactive decision-making tools available to guide breast cancer treatment and survivorship care decisions in clinical settings. METHODS: The study was conducted using the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR). We searched PubMed and related databases for interactive web-based decision-making tools developed to support breast cancer treatment and survivorship care from 2013 to 2023. Information on each tool's purpose, target population, data sources, individual and contextual characteristics, outcomes, validation, and usability testing were extracted. We completed a quality assessment for each tool using the International Patient Decision Aid Standard (IPDAS) instrument. RESULTS: We found 54 tools providing personalized breast cancer outcomes (e.g., recurrence) and treatment recommendations (e.g., chemotherapy) based on individual clinical (e.g., stage), genomic (e.g., 21-gene-recurrence score), behavioral (e.g., smoking), and contextual (e.g., insurance) characteristics. Forty-five tools were validated, and nine had undergone usability testing. However, validation and usability testing included mostly White, educated, and/or insured individuals. The average quality assessment score of the tools was 16 (range: 6-46; potential maximum: 63). CONCLUSIONS: There was wide variation in the characteristics, quality, validity, and usability of the tools. Future studies should consider diverse populations for tool development and testing. IMPLICATIONS FOR CANCER SURVIVORS: There are tools available to support personalized breast cancer treatment and survivorship care decisions in clinical settings. It is important for both cancer survivors and physicians to carefully consider the quality, validity, and usability of these tools before using them to guide care decisions.

Opportunities, challenges, and future directions for simulation modeling the effects of structural racism on cancer mortality in the United States: a scoping review.

PURPOSE: Structural racism could contribute to racial and ethnic disparities in cancer mortality via its broad effects on housing, economic opportunities, and health care. However, there has been limited focus on incorporating structural racism into simulation models designed to identify practice and policy strategies to support health equity. We reviewed studies evaluating structural racism and cancer mortality disparities to highlight opportunities, challenges, and future directions to capture this broad concept in simulation modeling research. METHODS: We used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses-Scoping Review Extension guidelines. Articles published between 2018 and 2023 were searched including terms related to race, ethnicity, cancer-specific and all-cause mortality, and structural racism. We included studies evaluating the effects of structural racism on racial and ethnic disparities in cancer mortality in the United States. RESULTS: A total of 8345 articles were identified, and 183 articles were included. Studies used different measures, data sources, and methods. For example, in 20 studies, racial residential segregation, one component of structural racism, was measured by indices of dissimilarity, concentration at the extremes, redlining, or isolation. Data sources included cancer registries, claims, or institutional data linked to area-level metrics from the US census or historical mortgage data. Segregation was associated with worse survival. Nine studies were location specific, and the segregation measures were developed for Black, Hispanic, and White residents. CONCLUSIONS: A range of measures and data sources are available to capture the effects of structural racism. We provide a set of recommendations for best practices for modelers to consider when incorporating the effects of structural racism into simulation models.

Seronegative Autoimmune Hepatitis: A Rare Manifestation of COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for the coronavirus pandemic in 2019, commonly causes hepatic dysfunction. Liver injury ranges from mildly elevated liver enzymes to fulminant liver failure. Interestingly, there are cases that suggest a relationship between autoimmune hepatitis (AIH) in patients who either contracted coronavirus disease in 2019 (COVID-19) or were vaccinated against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We present a case of a 39-year-old female without a significant past medical history who presented with two weeks of jaundice, abdominal pain, nausea, and diarrhea. She had significantly elevated liver enzymes and conjugated hyperbilirubinemia. She also tested positive for SARS-CoV-2 but denied any respiratory symptoms; her vaccination status was up to date. She denied taking hepatotoxic agents, and the workup was negative for acute viral hepatitis. The F-actin antibody level was 22 units, but serum immunoglobulin (IgG), anti-nuclear (ANA), anti-smooth muscle, anti-mitochondrial, anti-liver/kidney microsomal-1, anti-soluble liver antigen, and anti-neutrophil cytoplasmic antibodies levels were not elevated. Computerized tomography of the abdomen and pelvis revealed hepatic hemangiomas. Eventually, a liver biopsy was performed, and histology showed active lymphoplasmacytic hepatitis with prominent regenerative changes and areas of confluent necrosis. The histologic findings, along with the patient's clinical course, were suggestive of autoimmune hepatitis. The patient was started on systemic steroids with an improvement of abdominal pain and jaundice, as well as an improvement of her liver chemical profile. She was discharged with plans for hepatology clinic follow-up. Here, we present a rare case of seronegative AIH in a patient with a recent COVID-19 infection and discuss the potential underlying mechanism. We call for further investigation into the relationship between autoimmune dysfunction and COVID-19, as well as the pathophysiology behind it. Analyzing how the virus causes autoimmune dysfunction may allow clinicians to more effectively treat patients suffering from sequelae of COVID-19 infection, and it is important not to exclude autoimmune hepatitis from the differential based on the initial autoimmune workup.

PRC2 Inhibitors Overcome Glucocorticoid Resistance Driven by NSD2 Mutation in Pediatric Acute Lymphoblastic Leukemia.

Mutations in epigenetic regulators are common in relapsed pediatric acute lymphoblastic leukemia (ALL). Here, we uncovered the mechanism underlying the relapse of ALL driven by an activating mutation of the NSD2 histone methyltransferase (p.E1099K). Using high-throughput drug screening, we found that NSD2-mutant cells were specifically resistant to glucocorticoids. Correction of this mutation restored glucocorticoid sensitivity. The transcriptional response to glucocorticoids was blocked in NSD2-mutant cells due to depressed glucocorticoid receptor (GR) levels and the failure of glucocorticoids to autoactivate GR expression. Although H3K27me3 was globally decreased by NSD2 p.E1099K, H3K27me3 accumulated at the NR3C1 (GR) promoter. Pretreatment of NSD2 p.E1099K cell lines and patient-derived xenograft samples with PRC2 inhibitors reversed glucocorticoid resistance in vitro and in vivo. PRC2 inhibitors restored NR3C1 autoactivation by glucocorticoids, increasing GR levels and allowing GR binding and activation of proapoptotic genes. These findings suggest a new therapeutic approach to relapsed ALL associated with NSD2 mutation. SIGNIFICANCE: NSD2 histone methyltransferase mutations observed in relapsed pediatric ALL drove glucocorticoid resistance by repression of the GR and abrogation of GR gene autoactivation due to accumulation of K3K27me3 at its promoter. Pretreatment with PRC2 inhibitors reversed resistance, suggesting a new therapeutic approach to these patients with ALL.This article is highlighted in the In This Issue feature, p. 1.

Case Studies in Physiology: Cardiopulmonary exercise testing and inspiratory muscle training in a 59-year-old, 4 years after an extrapleural pneumonectomy.

This case report characterizes the physiological responses to incremental cycling and determines the effects of 12 wk of inspiratory muscle training (IMT) on respiratory muscle strength, exercise capacity, and dyspnea in a physically active 59-yr-old female, 4 years after a left-sided extrapleural pneumonectomy (EPP). On separate days, a symptom-limited incremental exercise test and a constant work rate (CWR) test at 75% of peak work rate (WR) were completed, followed by 12 wk of IMT and another CWR test. IMT consisted of two sessions of 30 repetitions twice daily for 5 days per week. Physiological and perceptual variables were measured throughout each exercise test. The participant had a total lung capacity that was 43% predicted post-EPP. A rapid and shallow breathing pattern was adopted throughout exercise, and the ratio of minute ventilation to carbon dioxide output was elevated for a given work rate. Oxygen uptake was 71% predicted and WR was 88% predicted. Following IMT, maximal inspiratory pressure improved by 36% (-27.1 cmH2O) and endurance time by 31 s, with no observable changes in any submaximal or peak cardiorespiratory variables during exercise. The intensity and unpleasantness of dyspnea increased by 2 and 3 Borg 0-10 units, respectively, at the highest equivalent submaximal exercise time achieved on both tests. Despite having undergone a significant reduction in lung volume post-EPP, the participant achieved a relatively normal peak incremental WR, which may reflect a high level of physical conditioning. This case report also demonstrates that IMT can effectively increase respiratory muscle strength several years following EPP.NEW & NOTEWORTHY Constraints on tidal volume expansion and the adoption of a rapid and shallow breathing pattern result in a ventilatory limitation and increased ventilatory inefficiency during exercise in a patient several years after extrapleural pneumonectomy (EPP). Inspiratory muscle training can effectively increase respiratory muscle strength after EPP.

A Partial Discharge Study of Medium-Voltage Motor Winding Insulation Under Two-Level Voltage Pulses With High Dv/Dt.

Medium-voltage (e.g., 10 kV rated) silicon carbide (SiC) devices have great potentials in medium-voltage variable speed drives. But their high switching dv/dt can increase the voltage stress on motor windings and cause partial discharges. This paper presents a partial discharge study of a medium-voltage form-wound winding under two-level square-wave voltage pulses. A 10 kV SiC device-based test platform is built to generate voltage pulses with high dv/dt. A three-step test approach is proposed and employed to systematically investigate the effects of various voltage parameters on partial discharges. These include voltage rise/fall time, voltage pulse width, pulse repetitive rate, duty ratio, voltage polarity, fundamental frequency, and modulation index. Partial discharge inception voltages (PDIVs) and repetitive partial discharge inception voltages (RPDIVs) of the sample are measured with varied voltage parameters. Test results show that voltage rise/fall time is a major affecting factor which reduces PDIVs of the winding sample by 6.5% when it decreases from 800 ns to 100 ns. Based on test results, a hypothetical partial discharge mechanism is presented to explain the effects of fast voltage rise/fall edges. An empirical equation is also derived to estimate PDIVs of a winding sample under various voltage rise/fall time and pulse width conditions.

A sensitive HPLC-MS/MS method for the detection, resolution and quantitation of cathinone enantiomers in horse blood plasma and urine.

Resolution of cathinone enantiomers in equine anti-doping analysis is becoming more important to distinguish the inadvertent ingestion of plant-based products from those of deliberate administration of designer synthetic analogs. With this in mind, a rapid and sensitive method was developed and validated for the detection, resolution and quantitative determination of cathinone enantiomers in horse blood plasma and urine. The analytes were recovered from the blood plasma and urine matrices by using a liquid-liquid extraction after adjusting the pH to 9. The recovered analytes were derivatized with Nα-(2,4-dinitro-5-fluorophenyl)-L-valinamide, a chiral derivatizing agent analogous to Marfey's reagent. The resulting diastereoisomers were baseline resolved under a reversed-phase liquid chromatographic condition. Derivatization of the analytes not only allowed the separation of the enantiomers using cost-effective traditional liquid chromatography conditions and reversed-phase columns but also increased the sensitivity, at least to an order of magnitude, when tandem mass spectrometry is used for the detection. A limit of detection of 0.05 ng/mL was achieved for cathinone enantiomers for both matrices. Acceptable intraday and interday precision and accuracy along with satisfactory dilution accuracy and precision were observed during the method validation. The method suitability was tested using the post administration urine samples collected after single doses of cathinone and ephedrine as single-enantiomeric form and methcathinone as racemic form. Finally, a proof of concept of the isomeric ratio in urine samples to distinguish the presence of cathinone as a result of accidental ingestion of plant-based product from that of an illicit use of a designer product is demonstrated. To the best of our knowledge, this is the first such work where cathinone enantiomers were resolved and quantified in horse blood plasma and urine at sub nanogram levels.

Deformable Liposomal Hydrogel for Dermal and Transdermal Delivery of Meloxicam.

BACKGROUND AND AIM: Meloxicam (MX) is a potent hydrophobic non-steroidal anti-inflammatory drug used to reduce inflammation and pain. However, its oral dosage form can cause many adverse gastrointestinal effects. In the present study, a poloxamer P407 based hydrogel system containing transfersomes or flavosomes has been prepared as a potential therapeutic vehicle for the topical delivery of MX. METHODS: In this study, MX was encapsulated in conventional liposomes, transfersomes, and flavosomes. The obtained liposomal vesicles were characterized in terms of size, drug entrapment efficiency, zeta potential, and stability. These MX-loaded liposomal formulations were further incorporated into a poloxamer P407 gel and evaluated using rheological properties, a stability study and an ex vivo permeation study through human cadaver skin by both HPLC analysis and confocal laser scanning microscopy (CLSM). RESULTS: The developed deformable liposomes exhibited homogeneous vesicle sizes less than 120 nm with a higher entrapment efficiency as compared to conventional liposomes. The deformable liposomal gel formulations showed improved permeability compared to a conventional liposomal gel and a liposome-free gel. The enhancement effect was also clearly visible by CLSM. CONCLUSION: These deformable liposomal hydrogel formulations can be a promising alternative to conventional oral delivery of MX by topical administration. Notably, flavosome-loaded gel formulations displayed the highest permeability through the deeper layers of the skin and shortened lag time, indicating a potential faster on-site pain relief and anti-inflammatory effect.

A multidimensional assessment of dyspnoea in healthy adults during exercise.

PURPOSE: (1) To determine whether healthy humans can distinguish between the intensity and unpleasantness of exertional dyspnoea; (2) to evaluate the reliability of qualitative dyspnoea descriptors during exercise; and (3) to assess the reliability of the Multidimensional Dyspnoea Profile (MDP) METHODS: Forty-four healthy participants (24M:20F, 25 ± 5 years) completed maximal incremental cycling tests on three visits. During visit 1, participants rated the intensity and unpleasantness of dyspnoea simultaneously throughout exercise using the modified 0-10 category-ratio Borg scale. On visits 2 and 3, participants rated either the intensity or unpleasantness of dyspnoea alone at the same measurement times as visit 1. On all visits, participants selected qualitative descriptors throughout all exercise intensities from a list of 4, selected relevant qualitative descriptors from a list of 15 at peak exercise, and completed the MDP. RESULTS: Participants rated their dyspnoea intensity significantly higher for a given minute ventilation ([Formula: see text]) compared to dyspnoea unpleasantness (dyspnoea-[Formula: see text] slope: 0.08 ± 0.02 vs. 0.07 ± 0.03 Borg 0-10/L min-1, p < 0.001) during visit 1. The onset of intensity ratings occurred at a significantly lower work rate compared to unpleasantness ratings measured on the same exercise test (52 ± 41 vs. 91 ± 53 watts, p < 0.001). Dyspnoea intensity and unpleasantness remained significantly different for a given ventilation even when measured independently on separate exercise tests (p < 0.05). There was good-to-excellent reliability (ICC > 0.60) for the use of qualitative dyspnoea descriptors and the MDP to measure dyspnoea at peak exercise. CONCLUSION: Exercise-induced dyspnoea in healthy adults can differ in the sensory and affective dimensions, and can be measured reliably using qualitative descriptors and the MDP.

Topical Delivery of Meloxicam using Liposome and Microemulsion Formulation Approaches.

The aim of this study is to develop, characterize and compare conventional liposome, deformable liposome (transfersome) and microemulsion formulations as potential topical delivery systems for meloxicam. Liposomes were characterized in terms of vesicle size, zeta potential and entrapment efficiency. For microemulsions, particle size, electrical conductivity and viscosity studies were performed to assess the structure of the investigated systems. An ex vivo skin permeation study has been conducted to compare these formulations. The dermal and transdermal delivery of meloxicam using these formulations can be a promising alternative to conventional oral delivery of non-steroidal anti-inflammatory drugs (NSAIDs) with enhanced local and systemic onset of action and reduced side effects.

Clinical Updates in Primary Biliary Cholangitis: Trends, Epidemiology, Diagnostics, and New Therapeutic Approaches.

Primary biliary cholangitis, formerly known as primary biliary cirrhosis, is a chronic, autoimmune, and cholestatic disease ameliorating the biliary epithelial system causing fibrosis and end-stage liver disease, over time. Patients range from an asymptomatic phase early in the disease course, to symptoms of decompensated cirrhosis later in its course. This review focuses on the current consensus on the epidemiology, diagnosis, and management of patients with primary biliary cholangitis. We also discuss established medical management as well as novel and investigational therapeutics in the pipeline for management of PBC.

A Comprehensive Analysis of Liver Transplantation Outcomes Among Ethnic Minorities in the United States.

GOALS: The aim of this study was to perform a comprehensive assessment of liver transplant (LT) outcomes among US adults with a specific focus on understanding race/ethnicity-specific disparities. BACKGROUND: Despite improvements in the liver allocation and LT-related care, disparities in LT outcomes persist. STUDY: Using data from the 2005 to 2016 United Networks for Organ Sharing LT registry, we evaluated waitlist survival, probability of receiving LT, and post-LT survival among US adults stratified by race/ethnicity and liver disease etiology. Kaplan-Meier methods evaluated unadjusted waitlist and post-LT outcomes, and multivariate regression models evaluated adjusted waitlist and post-LT outcomes. RESULTS: Among 88,542 listed for LT patients (41.3% hepatitis C virus, 25.3% alcoholic liver disease, 22.3% nonalcoholic steatohepatitis, 11.1% hepatitis C virus/alcoholic liver disease), significant race/ethnicity-specific disparities were observed. Compared with non-Hispanic whites, Hispanics had a significantly lower risk of waitlist death [hazard ratio (HR)=0.84, 95% confidence interval (CI): 0.79-0.90, P<0.001]. Compared with non-Hispanic whites, significantly lower likelihood of receiving LT was observed in African Americans (HR=0.94, 95% CI: 0.91-0.98, P<0.001), Hispanics (HR=0.70, 95% CI: 0.68-0.73, P<0.001) and Asians (HR=0.74, 95% CI: 0.69-0.80, P<0.001). Compared with non-Hispanic whites, African Americans had a significantly higher risk of 5-year post-LT death (HR=1.31, 95% CI: 1.23-1.39, P<0.001). CONCLUSION: Among US adults awaiting LT, significant race/ethnicity-specific disparities in LT outcomes were observed. Despite evaluating an era after implementation of the Model for End-Stage Liver Disease, ethnic minorities continue to demonstrate a lower probability of receiving LT, and significantly higher risk of death post-LT in African Americans.

The Notorious Soilborne Pathogenic Fungus Sclerotinia sclerotiorum: An Update on Genes Studied with Mutant Analysis.

Ascomycete Sclerotinia sclerotiorum (Lib.) de Bary is one of the most damaging soilborne fungal pathogens affecting hundreds of plant hosts, including many economically important crops. Its genomic sequence has been available for less than a decade, and it was recently updated with higher completion and better gene annotation. Here, we review key molecular findings on the unique biology and pathogenesis process of S. sclerotiorum, focusing on genes that have been studied in depth using mutant analysis. Analyses of these genes have revealed critical players in the basic biological processes of this unique pathogen, including mycelial growth, appressorium establishment, sclerotial formation, apothecial and ascospore development, and virulence. Additionally, the synthesis has uncovered gaps in the current knowledge regarding this fungus. We hope that this review will serve to build a better current understanding of the biology of this under-studied notorious soilborne pathogenic fungus.

Lymphocyte-Specific Chromatin Accessibility Pre-determines Glucocorticoid Resistance in Acute Lymphoblastic Leukemia.

Glucocorticoids play a critical role in the treatment of lymphoid malignancies. While glucocorticoid efficacy can be largely attributed to lymphocyte-specific apoptosis, its molecular basis remains elusive. Here, we studied genome-wide lymphocyte-specific open chromatin domains (LSOs), and integrated LSOs with glucocorticoid-induced RNA transcription and chromatin modulation using an in vivo patient-derived xenograft model of acute lymphoblastic leukemia (ALL). This led to the identification of LSOs critical for glucocorticoid-induced apoptosis. Glucocorticoid receptor cooperated with CTCF at these LSOs to mediate DNA looping, which was inhibited by increased DNA methylation in glucocorticoid-resistant ALL and non-lymphoid cell types. Our study demonstrates that lymphocyte-specific epigenetic modifications pre-determine glucocorticoid resistance in ALL and may account for the lack of glucocorticoid sensitivity in other cell types.

Oral and intratympanic steroid therapy for idiopathic sudden sensorineural hearing loss.

OBJECTIVE: To investigate the role of intratympanic (IT) therapy in the treatment of idiopathic sudden sensorineural hearing loss (ISSNHL). METHODS: This study was a retrospective review. Patients were treated for ISSNHL from January 1, 2011 to April 12, 2015 with the following: pre/posttreatment audios, treatment initiated ≤90 days and idiopathic etiology. Fifty-three ISSNHL patients were analyzed in the following subgroups: oral steroids (n = 8), combination oral+IT (n = 39), and IT (n = 6). Main outcomes measured were pre/posttreatment pure tone average (PTA) scores. RESULTS: The PTA changes for all treatment groups improved by 8.0 ± 19.5 dB (P = .004); for 31 patients treated ≤2 weeks after onset, PTA improved by 13.8 ± 16.6 dB (P < .001). Multivariable generalized linear model for repeated measures was conducted to investigate the association between PTA changes for treatment groups adjusted for age, gender, time-to-treatment, and vertigo. Earlier time-to-treatment and older age were statistically correlated towards improved outcomes. As time-to-treatment increased by each day, change in PTA decreased by 0.324 (95% CI [0.12, 0.52], P = .002). As age increased by each year, PTA changes increased by 0.802 (95% CI [0.36, 1.24], P < .001). For the oral+IT group, PTA changes for concurrent oral+IT (n = 20, 7.10 dB) and delayed/salvage oral+IT (n = 19, 5.43 dB) were not statistically different (P = .79); earlier time-to-treatment (P = .001), and older age (P = .006) remained statistically correlated towards improved outcomes. CONCLUSION: Results suggest outcomes can be improved with early identification and oral steroid therapy by primary care providers. Poorer prognosis for younger patients potentially suggests a need for more aggressive diagnostic and therapeutic management for this subgroup. LEVEL OF EVIDENCE: 3b.

Late recurrence of hepatocellular carcinoma after liver transplantation.

AIMS: Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide and liver transplant (LT) prolongs survival. However, 15-20% will experience recurrent HCC, most occurring within 2 years of LT. HCC patients with late recurrences (>5 years after LT) may have distinctive clinical/biological characteristics. METHODS: A retrospective review was conducted of 88 patients who underwent LT for HCC between 1993-2015, analyzing demographics, clinical factors, explant pathology, and outcome. RESULTS: Median follow-up was 6.4 years. HCC recurred in 15 (17.0%) patients with mean time to recurrence of 3.96 +/- 3.99 years. Five patients recurred >5 years post-LT. All late recurrences involved males in their 50s, recurring at 8.5 years on average. Recurrences occurred in chest wall (2), liver (2), lung (2), bone (1) and pelvis (1), with multifocal involvement in 2 patients. Four patients died within 18 months of late recurrence. The fifth patient is alive after ablation of liver recurrence and treatment with sorafenib and everolimus. CONCLUSIONS: One-third of post-LT patients with recurrent HCC experienced late recurrence. Although the sample size makes it difficult to identify significant risk factors, this study highlights the importance of long-term follow up and need for biomarkers to identify patients at risk for late recurrences.

Quantitation of γ-aminobutyric acid in equine plasma by hydrophilic interaction liquid chromatography with tandem mass spectrometry.

γ-Aminobutyric acid is the principal inhibitory neurotransmitter in the central nervous system and regulates the neuronal excitability. There has been anecdotal evidence that γ-aminobutyric acid has been used within a few hours prior to competition in equine sports to calm down nervous horses. However, regulating the use of γ-aminobutyric acid is challenging because it is an endogenous substance in the horse. γ-Aminobutyric acid is usually present at low ng/mL levels in equine plasma; therefore, a sensitive method has to be developed to quantify these low background levels. Measuring low concentrations of endogenous γ-aminobutyric acid is essential to establish a threshold that can be used to differentiate levels attributable to exogenous administrations of γ-aminobutyric acid. A hydrophilic interaction liquid chromatography coupled with tandem mass spectrometry method was developed and validated for the quantitation of γ-aminobutyric acid in equine plasma. Calibrators were prepared in artificial surrogate matrix consisting of 35 mg/mL equine serum albumin in phosphate buffered saline. Samples were prepared by protein precipitation with acetonitrile. Utilizing this methodology, a total of 403 equine plasma samples collected post-competition from horses participating in equestrian events in Canada were analyzed.

Sudden Sensorineural Hearing Loss: Primary Care Update.

The primary care physician's role in recognizing sudden sensorineural hearing (SSNHL) loss and delivering initial treatment is critical in the management of the syndrome. This role involves recognizing its clinical symptoms, distinguishing it from conductive hearing loss with the Weber tuning fork or the Rauch hum test, and urgent administration of high dose oral corticosteroids. Diagnosis and treatment should not be delayed for audiometric testing or referral to otolaryngology. This paper provides an update on the initial evaluation and treatment of this syndrome based on the literature and clinical guideline recommendations.