Nevin Manimala

Front Pharmacol. 2024 Nov 18;15:1488367. doi: 10.3389/fphar.2024.1488367. eCollection 2024.

ABSTRACT

INTRODUCTION: Arylamine N-acetyltransferase 2 (NAT2) expresses a well-defined genetic polymorphism in humans that modifies drug and xenobiotic metabolism. Recent studies and genome wide association studies have reported that genetic variants of NAT2 are associated with differential risks of developing dyslipidemia and cardiometabolic disorders, suggesting a previously unrecognized role of NAT2 in pathophysiology of metabolic disorders. In support of this notion, we recently showed that human NAT2 expression is differentially regulated by glucose and insulin. Moreover, our in silico analysis showed that NAT2 is co-expressed with nuclear receptors enriched in the liver, e.g., NR1H4 (FXR) and NR1I2 (PXR), that have been previously implicated in regulation of hepatic glucose and lipid homeostasis. Identification of transcriptional regulator(s) of human NAT2 would aid in understanding novel functions that it may play in the liver. Thus, the present study was designed to investigate if NAT2 is transcriptionally regulated by hepatic nuclear receptors.

METHODS: To test this, we treated cryopreserved human hepatocytes with agonists towards four different hepatic transcription factors/nuclear hormone receptors, namely FXR (NR1H4), PXR (NR1I2), LXR (NR1H3), and PPARα (PPARA), and measured their effects on the level of NAT2 mRNA.

RESULTS: While the treatment with a FXR, PXR, or LXR agonist (i.e., GW-4064, SR-12813, or GW-3965) significantly induced their respective target genes, treatment with these agonists did not significantly alter the transcript level of NAT2 in human hepatocytes. PPARα agonist, GW-7647, treatment resulted in a statistically significant decrease in the NAT2 transcript level. However, its magnitude was marginal.

CONCLUSION: In summary, hepatic nuclear receptors we examined in the present study (FXR, PXR, LXR, and PPARα) did not significantly alter NAT2 expression in cryopreserved human hepatocytes. Additional studies are needed to identify transcriptional regulators of hepatic NAT2 expression.

PMID:39624836 | PMC:PMC11608957 | DOI:10.3389/fphar.2024.1488367

Front Endocrinol (Lausanne). 2024 Nov 18;15:1333881. doi: 10.3389/fendo.2024.1333881. eCollection 2024.

ABSTRACT

OBJECTIVE: The aim of this study was to assess the predictive capabilities of a radiomics signature obtained from arterial spin labeling (ASL) imaging in forecasting and detecting stages of kidney damage in patients with diabetes mellitus (DM), as well as to analyze the correlation between texture feature parameters and biological clinical indicators. Additionally, this study seeks to identify the imaging risk factors associated with early renal injury in diabetic patients, with the ultimate goal of offering novel insights for predicting and diagnosing early renal injury and its progression in patients with DM.

MATERIALS AND METHODS: In total, 42 healthy volunteers (Group A); 68 individuals with diabetes (Group B) who exhibited microalbuminuria, defined by a urinary albumin-to-creatinine ratio (ACR)< 30 mg/g and an estimated glomerular filtration rate (eGFR) within the range of 60-120 mL/min/1.73m²; and 53 patients with diabetic nephropathy (Group C) were included in the study. ASL using magnetic resonance imaging (MRI) at 3.0T was conducted. The radiologist manually delineated regions of interest (ROIs) on the ASL maps of both the right and left kidney cortex. Texture features from the ROIs were extracted utilizing MaZda software. Feature selection was performed utilizing a range of methods, such as the Fisher coefficient, mutual information (MI), probability of classification error, and average correlation coefficient (POE + ACC). A radiomics model was developed to detect early diabetic renal injury, extract imaging risk factors associated with early diabetic renal injury, and examine the relationship between significant texture feature parameters and biological clinical indicators. Patients with DM and kidney injury were followed prospectively. The study utilized seven machine learning algorithms to develop a detective radiomics model and a comprehensive predictive model for assessing the progression of kidney damage in patients with DM. The diagnostic efficacy of the models in detecting variations in diabetic kidney damage over time was evaluated using the area under the curve (AUC) of the receiver operating characteristic (ROC) curve. Empower (R) was used to establish a correlation between clinical biological indicators and texture feature metrics. Statistical analysis was conducted using R, Python, MedCalc 15.8, and GraphPad Prism 8.

RESULTS: A total of 367 texture features were extracted from the ROIs in the kidneys and refined based on selection criteria using MaZda software across groups A, B, and C. The renal blood flow (RBF) values of the renal cortex in groups A, B, and C exhibited a decreasing trend, with values of 256.458 ± 54.256 mL/100g/min, 213.846 ± 52.109 mL/100g/min, and 170.204 ± 34.992 mL/100g/min, respectively. There was a positive correlation between kidney RBF and eGFR (r = 0.439, P<0.001). The negative correlation between RBF and various clinical parameters including urinary albumin-to-creatinine ratio (UACR), body mass index (BMI), diastolic blood pressure (DBP), blood urea nitrogen (BUN), and serum creatinine (SCr) was investigated. Through the use of a least absolute shrinkage and selection operator (LASSO) regression model, the study identified the eight most significant texture features and biological indicators, namely GeoY, GeoRf, GeoRff, GeoRh, GeoW8, GeoW12, S (0, 4) Entropy, and S (5, -5) Entropy. Spearman correlation analysis revealed associations between imaging markers in early diabetic patients with kidney damage and factors such as age, systolic blood pressure (SBP), Alanine Transaminase (ALT), Aspartate Amino Transferase (AST) albumin, uric acid (UA), microalbuminuria (UMA), UACR, 24h urinary protein, fasting blood glucose (FBG), two hours postprandial blood glucose (P2BG), and HbA1c. The study utilized ASL imaging as a detection model to identify renal injury in patients with DM across different stages, achieving a sensitivity of 85.1%, specificity of 65.5%, and an AUC of 0.865. Additionally, a comprehensive prediction model combining imaging labels and biological indicators, with the naive Bayes machine learning algorithm as the best model, demonstrated an AUC of 0.734, accuracy of 0.74, and precision of 0.43.

CONCLUSION: ASL imaging sequences demonstrated the ability to accurately detect alterations in kidney function and blood flow in patients with DM. Strong associations were observed between renal blood flow values in ASL imaging and established clinical biomarkers. These values show promise in detecting early microstructural changes in the kidneys of diabetic patients. Utilizing image markers in conjunction with clinical indicators was effective in identifying early renal dysfunction and its progression in individuals with DM. Furthermore, the integration of imaging texture feature parameters with clinical biomarkers holds significant potential for predicting early renal damage and its progression in patients with diabetes.

PMID:39624821 | PMC:PMC11608948 | DOI:10.3389/fendo.2024.1333881

Front Endocrinol (Lausanne). 2024 Nov 18;15:1501818. doi: 10.3389/fendo.2024.1501818. eCollection 2024.

ABSTRACT

PURPOSE: here is a general consensus that an inverse relationship exists between vitamin D status and body mass index (BMI) in overweight and obese individuals, leading to the hypothesis that vitamin D deficiency may contribute to the development of unfavorable metabolic phenotypes. However, evidence from non-obese adults remains limited. This study measured energy metabolism in non-obese adults using a metabolic chamber and explored its association with vitamin D status.

METHODS: Sixty-nine healthy adults (mean age = 22.8 years, mean BMI = 20.7 kg/m²) participated in this cross-sectional study. Participants were categorized into vitamin D-deficient, insufficient, and sufficient groups based on the Chinese classification for total 25(OH)D levels (WS/T 677-2020). They performed typical daily activities in a metabolic chamber, where their baseline lipid profile, 24-hour energy expenditure, and substrate oxidation were measured.

RESULTS: A two-way ANOVA (seasonality × 25(OH)D) revealed no statistically significant differences in total energy expenditure, resting energy expenditure, sleeping energy expenditure, walking energy expenditure, carbohydrate oxidation rate, or fat oxidation rate among the three groups (p > 0.05). These results remained consistent even after adjusting for fat-free mass. Although statistically significant correlations were found between 25(OH)D status and certain lipid profile markers (i.e., total cholesterol, high-density lipoprotein, and free fatty acid) (p < 0.05), these correlations were weak, with Pearson’s correlation coefficients below 0.3.

CONCLUSIONS: Total 25(OH)D status does not affect energy metabolism in young, healthy, non-obese adults. Along with existing evidence, this suggests that low 25(OH)D status is more likely a consequence of unfavorable metabolic phenotypes rather than a contributing factor.

CLINICAL TRIAL REGISTRATION: https://www.chictr.org.cn, identifier ChiCTR-IIR-17010604.

PMID:39624819 | PMC:PMC11608976 | DOI:10.3389/fendo.2024.1501818

Front Endocrinol (Lausanne). 2024 Nov 18;15:1461103. doi: 10.3389/fendo.2024.1461103. eCollection 2024.

ABSTRACT

INTRODUCTION: Turner syndrome (TS) is associated with significant neuropsychological challenges, and screening is recommended at key transition stages. Our goal was to describe the institutional experience of formal neuropsychological assessments in TS and assess differences by karyotype.

METHODS: Data were abstracted by retrospective chart review of completed assessments between January 1, 2019, and October 31, 2022, referred from the newly established multidisciplinary clinic, and descriptive statistical analyses were presented (SAS V9.4).

RESULTS: Of 114 patients, 38 (33%) had completed neuropsychological assessment at a median age of 11.3 years (IQR 6.5-14.9). Median full-scale IQ (FSIQ) was lower in those with a 45,X karyotype compared with other karyotypes (p = 0.027) but did not meet statistical significance at the adjusted significance level for multiple comparisons. Lower median non-verbal IQ [performance intelligence quotient (PIQ)] relative to verbal IQ (VIQ) was observed. Diagnoses of attention-deficit hyperactivity disorder (ADHD) (26%) and anxiety disorder (26%) were common followed by specific learning disorder (mathematics; 18%) and autism spectrum disorder (16%).

DISCUSSION: The prevalence of neuropsychological abnormalities in our diverse clinic underscores the importance of early and routine neuropsychological testing in TS.

PMID:39624818 | PMC:PMC11608949 | DOI:10.3389/fendo.2024.1461103

Front Endocrinol (Lausanne). 2024 Nov 18;15:1461865. doi: 10.3389/fendo.2024.1461865. eCollection 2024.

ABSTRACT

OBJECTIVE: This study aimed to assess the viability of a multivariate regression model utilizing ultrasound findings and serum markers for predicting thyroid cancer metastasis.

METHODS: A retrospective analysis of 98 thyroid patients admitted from January 2022 to October 2022 was conducted to categorize them into a metastasis group (n=20) and a non-metastasis group (n=78) based on postoperative pathological results. Both groups underwent ultrasound examination and serum marker testing. Correlative analysis was performed to explore the association between various indicators and thyroid cancer metastasis. A multivariate regression model was developed, and receiver operating characteristic (ROC) curves were used to assess the predictive value of ultrasound findings, serum markers, and their combination for thyroid cancer metastasis.

RESULTS: Statistically significant differences were found in the levels of ultrasound findings and serum markers between the two groups. Nodule boundaries, presence or absence of halos, margins, lobulation, capsular invasion, surface smoothness, nodule aspect ratio, uric acid, total cholesterol, triglyceride, and LDL cholesterol levels were predictors of metastasis in thyroid cancer. The AUC value of 0.950 for the prediction of thyroid cancer metastasis by ultrasound signs combined with serologic indicators was significantly higher than 0.728 and 0.711 predicted by ultrasound signs or serologic indicators alone.

CONCLUSION: The multivariate regression model incorporating ultrasound findings and serum markers enhances the predictive accuracy for thyroid cancer metastasis, offering essential guidance for early prediction and intervention in a clinical setting.

PMID:39624817 | PMC:PMC11608942 | DOI:10.3389/fendo.2024.1461865

Cureus. 2024 Dec 1;16(12):e74888. doi: 10.7759/cureus.74888. eCollection 2024 Dec.

ABSTRACT

Introduction Mind The Bleep (MTB) is an online medical education organisation run by United Kingdom-based resident doctors. It represents one of a number of free-open access online medical resources (FOAMed) that have increased in popularity, especially since the COVID-19 pandemic. The surgical team of MTB works to produce high-quality surgical educational resources aimed at early postgraduate doctors. This paper provides an appraisal of the teams’ current methods of teaching and the learning points identified from these. Methods This was a retrospective mixed-method review analysing quantitative and qualitative data sources including website analytics and feedback surveys. Wilcoxon signed-rank tests were used to identify significant differences between pre- and post-session confidence levels in the subject matter. Results A total of 22 online targeted education programmes, with a total of 140 webinars were completed between November 2021 and August 2024. The total live viewership was 6733 participants with a mean of 48.1 per webinar. The total attendance including live and watched later was 10221 participants, with a mean of 73 total viewers per webinar. Of the total viewers, 4714 provided feedback (46.1%). Across all webinar series, we identified a statistically significant increase in participant-rated confidence (p<0.05). Discussion Our ability to produce consistent high-quality content is due to leveraging a near-peer teaching model and recruiting resident doctors as teachers. This method ensures cognitive congruence between participant and educator and provides doctors an opportunity to gain teaching experience. Our social media advertising has ensured wide reach. To the best of our knowledge, we provide the first large-scale breakdown of the work done by an online surgical education organisation. Limitations include a low feedback rate and feedback limited to Kirkpatrick type 1 learner reaction.

PMID:39624814 | PMC:PMC11608416 | DOI:10.7759/cureus.74888

Cureus. 2024 Dec 2;16(12):e74990. doi: 10.7759/cureus.74990. eCollection 2024 Dec.

ABSTRACT

Background The use of automatic external defibrillators (AEDs) by lay rescuers can reduce the time to defibrillation and improve survival in out-of-hospital cardiac arrest (OHCA). AEDs use voice prompts to guide users through the defibrillation process, creating a potential barrier for deaf and hard-of-hearing (HoH) individuals. The objective of this study is to assess familiarity with and concerns regarding AED use among members of these communities. Methods A 19-question Qualtrics survey was distributed to adults in the United States who self-identified as deaf or HoH. The questions included seven demographics, eight yes/no/unsure, three Likert scales, and one multiple-response question. Quantitative analysis was performed using 95% confidence intervals to compare familiarity with and concerns about AED use among deaf, HoH, and combined groups of respondents. Results Of the responses, 500 met the inclusion criteria; 130 (26%) self-identified as deaf, and 370 (74%) self-identified as HoH. Around 460 (92%) were in the 18-40 age group. AED recognition was high among both deaf (90.77%) and HoH (84.59%) respondents, though deaf respondents were less likely than HoH respondents to have seen an AED in a public place (p=0.03) or know how to safely use one (p=0.001). In both the deaf and HoH groups, the top concern regarding AED use was that AEDs were too technical or complicated (61.86% and 56.8%). Of all respondents, 36.4% reported that AEDs were not user-friendly (p=0.034). All participants identified some concerns regarding AED use in emergencies. In addition, 56.15% of deaf and 39.19% of HoH respondents were concerned that AED use is potentially dangerous (p<0.001). There was no statistically significant difference between the two groups in knowing when to use an AED or where to find more information about AEDs. Conclusion Deaf and HoH people have specific concerns about AEDs, including the safety and complexity of operating an AED and the accessibility (user-friendliness). In this study, the deaf population is less familiar with using an AED than the HoH population. Possible interventions to address concerns of the deaf and HoH communities include AED training given in American Sign Language (ASL) and updating AED designs with improved visual and non-verbal directions.

PMID:39624811 | PMC:PMC11611321 | DOI:10.7759/cureus.74990

Pharmacoepidemiol Drug Saf. 2024 Dec;33(12):e70066. doi: 10.1002/pds.70066.

ABSTRACT

PURPOSE: The largest rural outbreak of human immunodeficiency virus (HIV) in the US was centered in Scott County, Indiana, and linked to injection practices involving the opioid Opana ER (oxymorphone extended release [ER] reformulated). We examined supply trends using pharmacy transactions of Opana ER in Scott and all US counties from January 2007 to December 2019.

METHODS: We calculated the monthly morphine milligram equivalents (MME) of Opana ER (and its competitor OxyContin) in pharmacies using the Automation of Reports and Consolidated Orders System (ARCOS) database from the Washington Post. We modeled the MME rate per capita in Scott County and five geographic comparators in seven distinct time periods including the market introduction of abuse deterrent formulations of both drugs and the HIV outbreak period (circa 2014).

RESULTS: After Opana ER introduction, transaction rates surged in Scott County, where annual OxyContin MMEs were already seven-fold higher than Indiana overall (CY2009: 46.8 vs. 6.8 MME/pop., respectively). Immediately after OxyContin’s reformulation, the Opana ER growth rate in Scott County surpassed all geographic comparators modeled (~27 times faster than the US, 1.28 vs. 0.047 MME/pop/month, respectively). By 2012, prior to the outbreak, MMEs from Opana ER almost perfectly replaced the diminishing OxyContin supply. When Opana ER with INTAC was subsequently introduced, pharmacy transactions declined precipitously by nearly 50%, persisting through the HIV outbreak period and market withdrawal.

CONCLUSIONS: Opana ER rapidly supplanted OxyContin in a vulnerable population that was at heightened risk for HIV who subsequently faced an immediate supply shock after its reformulation. Pharmacy transactions are critical for suspicious order monitoring and pharmacovigilance by US and international agencies especially during deleterious supply shocks in legal and illicit drug markets.

PMID:39623517 | DOI:10.1002/pds.70066

Health Qual Life Outcomes. 2024 Dec 2;22(1):104. doi: 10.1186/s12955-024-02316-0.

ABSTRACT

BACKGROUND: To assess fatigue in cancer patients, several patient-reported outcome measures (PROMs) are available that differ in content. To support the selection of suitable measures for specific applications and to evaluate possibilities of quantitative linking, the present study provides a content comparison of common fatigue measures, scales, and item banks. We included the EORTC CAT Core, EORTC QLQ-FA12, EORTC QLQ-C30, FACIT-F, PROMIS Fatigue (Cancer item bank v1.0), Brief Fatigue Inventory (BFI), Multidimensional Fatigue Inventory (MFI-20), Piper Fatigue Scale (PFS-12), and PRO-CTCAE.

METHODS: All items of the included measures were linked to the International Classification of Functioning, Disability and Health (ICF). Additionally, they were categorized as assessing general, physical, emotional, or cognitive fatigue. Descriptive statistics were used to display the contents covered in each measure and to allow for a qualitative comparison.

RESULTS: The measures consist of 160 items in total and covered primarily contents of the ICF components ‘Body functions’, ‘Activities and participation’, and ‘Environmental Factors’. Most ICF codings refer to ‘b1300 Energy level’ (9-67% of the codings per instrument; 47% of all coded content). Within the broad categorization of types of fatigue, most items were classified as general fatigue (33-100% of the codings per instrument; 49% of the overall item pool). While the EORTC CAT Core focuses exclusively on physical and general fatigue, FACIT and BFI additionally assess emotional fatigue. The EORTC QLQ-FA12, PROMIS, MFI-20, and PFS-12 cover all fatigue components, including cognitive fatigue.

DISCUSSION: The review provides an in-depth content comparison of PROMs assessing cancer-related fatigue. This can inform the selection of suitable measures in different clinical contexts. Furthermore, it will inform quantitative analyses to facilitate comparison of scores obtained with different PROMs.

PMID:39623483 | DOI:10.1186/s12955-024-02316-0

Scand J Trauma Resusc Emerg Med. 2024 Dec 2;32(1):122. doi: 10.1186/s13049-024-01297-9.

ABSTRACT

BACKGROUND: Helicopter hoist operations (HHO) are an important option for rescue operations in rugged and challenging terrain. German mid-range mountains are characterized by the versatility of ground conditions, few urban structures, and frequent use for local leisure activities, including the practice of more or less high-risk outdoor sports. This retrospective analysis aims to investigate the incidence of rescue missions in German mid-range mountains requiring HHO. The contributing air rescue bases’ operational tactics and the underlying medical characteristics, such as injury patterns and the provided medical care, are also reported.

METHODS: This study is a retrospective analysis of the documentation of HHO missions carried out at the air rescue bases in Freiburg, Nuremberg, and Bautzen staffed by emergency physicians between 01/2020 and 07/2022. Data was extracted from the German Air Rescue database. To assess the topics of interest, we conducted basic descriptive statistics.

RESULTS: Data selection retrieved 410 HHO-associated rescue missions. A total of 304 datasets, including HHO, were suitable for further statistical processing. Air rescue base Freiburg contributed 152, Nuremberg 63, and Bautzen 89 missions. HHO missions showed an increased frequency in the summer season and from Friday to Sunday. In this collective, 75% of the underlying diagnoses were trauma-associated; in 33% of all patients, traumatic injury of the pelvis or lower limb occurred. 28% of the patients were in a potential or actual life-threatening condition and were scored NACA 4 or higher. The rates of invasive medical treatment, such as endotracheal intubation (5%) or venous access (79%), were considerably higher than in overall emergency missions. In terms of mission tactics and cooperation with mountain rescue services, different approaches of the three air bases resulted in differences regarding first-on-scene rates and time spans.

CONCLUSION: The results show a relevant year-round need to deploy emergency medical expertise to inaccessible terrain in the three regions examined. Detailed analysis showed relevant differences in operational tactics between the three bases and potential for optimization. Simultaneous alerting of the hoist helicopter and reliable and precise coordination with other rescue organizations involved, especially the local mountain rescue service and the rescue coordination center, can help to shorten both the treatment-free interval and the prehospital time for patients in inaccessible terrain.

TRIAL REGISTRATION: The study is registered at DRKS (DRKS00033493).

PMID:39623469 | DOI:10.1186/s13049-024-01297-9