Search Results (117)

Background: In the emergency setting, many diagnostic pathways incorporate change in high-sensitivity cardiac troponin (hs-cTn) concentrations (i.e., the delta) to classify patients as low-risk (rule-out) or high-risk (rule-in) for possible myocardial infarction (MI). However, the impact of analytical variation on the delta for correct classification is unknown, especially at concentrations below and around the 99th percentile. Our objective was to assess the impact of delta variation for correct risk classification across the European Society of Cardiology (ESC 0/1 h and 0/2 h), the High-STEACS, and the common change criteria (3C) pathways. Methods: A yearlong accuracy study for hs-cTnT was performed where laboratories across Canada tested three patient-based samples (level 1 target value = 6 ng/L, level 2 target value = 9 ng/L, level 3 target value = 12 ng/L) monthly across 41 different analyzers. The assigned low-delta between levels 1 and 2 was 3 ng/L (i.e., 9 − 6 = 3 ng/L) and the assigned high-delta between levels 1 and 3 was 6 ng/L (i.e., 12 − 6 = 6 ng/L). The low- and high-deltas for each analyzer were determined monthly from the measured values, with the difference calculated from the assigned deltas. The obtained deltas were then assessed via the different pathways on correct classification (i.e., percent correct with 95% confidence intervals, CI) and using non-parametric analyses. Results: The median (interquartile range) difference between the measured versus assigned low-delta (n = 436) and high-delta (n = 439) was −1 ng/L (−1 to 0). The correct classification differed among the pathways. The ESC 0/1 h pathway yielded the lowest percentage of correct classification at 35.3% (95% CI: 30.8 to 40.0) for the low-delta and 90.0% (95% CI: 86.8 to 92.6) for the high-delta. The 3C and ESC 0/2 h pathways yielded higher and equivalent estimates on correct classification: 95.2% (95% CI: 92.7 to 97.0) for the low-delta and 98.2% (95% CI: 96.4 to 99.2) for the high-delta. The High-STEACS pathway yielded 99.5% (95% CI: 98.4 to 99.9) of correct classifications for the high-delta but only 36.2% (95% CI: 31.7 to 40.9) for the low-delta. Conclusions: Analytical variation will impact risk classification for MI when using hs-cTn deltas alone per the pathways. The 3C and ESC 0/2 h pathways have <5% misclassification when using deltas for hs-cTnT in this dataset. Additional studies with different hs-cTnI assays at concentrations below and near the 99th percentile are warranted to confirm these findings. Full article

Background: The project ‘Multicenter Renal Pharmacist Group—Implementation of Pharmaceutical Care for Patients with Renal Impairment at four Non-University Hospitals in Germany’ started in the beginning of 2020 with the goal to establish high-quality pharmaceutical care to improve patient safety for hospitalized patients with renal impairment at German non-university hospitals. Pharmaceutical service quality should be optimized by intense and effective intraprofessional collaboration within the network. Methods: Over a period of two years (2020–2022), we implemented renal pharmacists (RPs) for patients with renal impairment (RI) at four non-university hospitals in Germany (Starnberg Hospital, Rudolf Virchow Hospital Glauchau, Catholic Hospital in the Märkisch District (KKiMK), and Hospital Sindelfingen-Boeblingen). The RPs conducted medication analyses identifying renal-drug-related problems (rDRPs) two to five days a week. The rDRPs, including recommendations to solve them, were forwarded to the attending physicians via written consultations or personally during ward rounds. The RPs were mentored by a renal pharmacist expert from LMU Munich and formed a multicentered team with close collaboration. Data about the RP service were collected and were retrospectively evaluated. Results: During the two-year project period, a total of 3924 patients from various disciplines were visited across all four locations. In total, 1425 patients (36.3%; with a range from 22.7 to 56.4% between hospitals) received one or more interventions by RPs concerning 2454 rDRPs (a median of one to three rDRPs per patient). In cooperation with the physicians, 77.6 to 88.2% of the rDRPs were solved. The most common causes were ‘dosage too high’ and ‘contraindication’. Conclusion: The implementation of pharmaceutical care for patients with renal impairment at four non-university hospitals in Germany increased appropriate prescribing by physicians. The multicenter team proved to be an excellent support for the newly established services. Full article

Adults face a higher risk of exposure to COVID-19 than older adults and children due to their labor force participation. This study investigated the uptake of the initial and second doses of the COVID-19 vaccine among adults, stratified by age, race, ethnicity, sex, and their combinations. Data from the Kentucky Immunization Registry were employed to evaluate temporal changes in COVID-19 vaccine uptake among adults in three age groups (college age: 18–24, prime working age: 25–44, and middle age: 45–64) in Jefferson County, Kentucky (2020 population: 782,969). The analysis explored trends by age, race, and ethnicity; intersections of age with race and ethnicity; and interactions of age–race and age–ethnicity with sex. By May 2022, the highest and lowest COVID-19 vaccination rates were observed among White and Black 45–64-year-old adults: 74.8% and 64.0%, respectively, for dose two. The highest and lowest two-dose vaccination rates at ages 25–44 and 18–24 were also among White and Black residents: 67.9% versus 46.0% and 55.2% versus 35.4%, respectively. Disparities in COVID-19 vaccination by race, ethnicity, sex, and their intersections remained evident during the study period. Efforts in vaccine distribution and promotional initiatives should focus on demographically appropriate strategies. Full article

Background: Although children can contract COVID-19, their typically lower immune reactivity appears to shield them from the intense hyperinflammatory response observed in other age groups, leading to milder disease symptoms. Nonetheless, children’s infection raises the possibility of unwanted transmission of the coronavirus to others, especially because most infected children are asymptomatic. Objectives: This study examines the uptake of the first and second doses of the COVID-19 vaccine among children by combinations of age, race, ethnicity, and sex. Methods: Data from the immunization registry were utilized to assess changes over time in COVID-19 vaccine uptake among children in Jefferson County, Kentucky’s most populous county. The analysis examined trends by age, race, ethnicity, and combinations of age-race, age-ethnicity, age-race-sex, and age-ethnicity-sex during the first six quarters of the COVID-19 vaccination rollout. Results: By May 2022, in 16–17-year-olds, the highest and lowest COVID-19 vaccination rates were observed among White and Black children (64.8% versus 41.2%, respectively, for dose two). The highest two-dose vaccination rate at ages 12–15 years was among Multiracial and White children (63.3% and 62.9%, respectively), the lowest among Black children (38.8%). The highest two-dose vaccination rate at ages 5–11 years was among children of Some Other Races, Asian, and White children (37.0%, 36.7%, and 35.5%, respectively), and the lowest among Black children (17.2%). Conclusions: Inequalities in COVID-19 vaccination based on race, ethnicity, and sex persisted throughout the study period. Efforts in vaccine distribution and promotional initiatives should focus on increasing vaccination rates among children from racial and ethnic minority groups and males. Full article

Cystic fibrosis (CF) is a life-threatening disorder caused by mutations in the CFTR gene, leading to defective chloride ion transport and thickened mucus in the respiratory and gastrointestinal systems. CFTR modulators, including ivacaftor, lumacaftor, tezacaftor, and elexacaftor, have improved patient outcomes, but interindividual pharmacokinetic variability and potential drug–drug interactions require therapeutic drug monitoring (TDM) for optimal efficacy and safety. In this context, a liquid chromatography–tandem mass spectrometry (LC-MS/MS) method has been developed and validated for the simultaneous quantification of CFTR modulators and their major active metabolites in human plasma to support pharmacokinetic studies and routine TDM. The multiplex LC-MS/MS assay was established using plasma protein precipitation, followed by chromatographic separation on an Xselect HSS T3 (Waters^®) column and positive electrospray ionization mode detection. The method was validated based on FDA and EMA guidelines for specificity, linearity, accuracy (89.8–107.8%), repeatability (1.1–8.1%), intermediate fidelity (1.3–10.9%), matrix effects, and stability, demonstrating a robust performance with excellent precision and accuracy. International interlaboratory comparisons confirmed the reliability of the assay. The developed method can be applied for the clinical monitoring of caftors’ plasma concentrations and preliminary data suggest that it can also be applied to alternative matrices, such as breast milk. This method will serve to characterize caftors’ pharmacokinetic variability and monitor drug–drug interactions to further refine personalized dosing strategies and enhance precision medicine treatments for patients with CF. Full article

Kidney transplantation (KT) represents a pivotal intervention for patients with chronic kidney disease (CKD), significantly improving survival and quality of life. However, KT recipients face an array of non-immunological complications, collectively amplifying cardiovascular (CV) and metabolic risks. This review explores the intersection of cardio-metabolic syndrome and KT, emphasizing the recently introduced cardiovascular–kidney–metabolic (CKM) syndrome. CKM syndrome integrates metabolic risk factors, CKD, and CV disease, with KT recipients uniquely predisposed due to immunosuppressive therapies and pre-existing CKD-related risks. Key issues include post-transplant hypertension, obesity, dyslipidemia, post-transplant diabetes mellitus (PTDM), and anemia. Immunosuppressive agents such as corticosteroids, calcineurin inhibitors, and mTOR inhibitors contribute significantly to these complications, exacerbating metabolic dysfunction, insulin resistance, and lipid abnormalities. For instance, corticosteroids and calcineurin inhibitors heighten the risk of PTDM, while mTOR inhibitors are strongly associated with dyslipidemia. These pharmacologic effects underscore the need for tailored immunosuppressive strategies. The management of these conditions requires a multifaceted approach, including lifestyle interventions, pharmacological therapies like SGLT2 inhibitors and GLP-1 receptor agonists, and close monitoring. Additionally, emerging therapies hold promise in addressing metabolic complications in KT recipients. Proactive risk stratification and early intervention are essential to mitigating CKM syndrome and improving outcomes. This comprehensive review highlights the importance of integrating cardio-metabolic considerations into KT management, offering insights into optimizing long-term recipient health and graft survival. Full article

Diabetes mellitus (DM) in kidney transplant recipients (KTR) is a risk factor for mortality, increases the risk of infections and, in the long term, can lead to graft loss due to diabetic kidney disease. A preventive approach applied to those on the waiting list could decrease the incidence of post-transplant DM (PTDM) by detecting those patients at risk, thus allowing strategies to minimize the probability of developing a New Onset Diabetes After Transplant (NODAT). On the other hand, modifications of immunosuppressive therapy may improve glucose control in patients with KTR. In recent years, two new classes of antidiabetic drugs and non-steroidal mineralocorticoid receptor antagonists have demonstrated cardiovascular and renal benefits in randomized clinical trials where the transplant population has not been represented. Because of the potential benefit expected in this population, the clinical use of glucagon-like peptide-1 receptor agonists (GLP-1RA), sodium-glucose cotransporter 2 inhibitors (SGLT2i) and finerenone is increasing in the kidney transplant setting. This review focuses on comprehensive pharmacological interventions in KTR with glucose metabolism disorders. In-depth knowledge in this area will allow prevention and identification of potential adverse effects or drug interactions in the clinical course of KTR with DM. Full article

Our ability to accurately predict the delivery date of term pregnancies is limited by shortcomings of modern-day clinical tools and due date estimation methods. The pregnancy clock is a series of coordinated and harmonized signals between mother, fetus, and placenta that regulate the length of gestation. Clock proteins are thought to be important mediators of these signals, yet few studies have investigated their potential utility as predictors of term delivery date. In this study, we performed a cross-sectional proteome analysis of 2648 serum samples collected between 18 and 28 weeks of gestation from mothers who delivered at term. The cohort included pregnancies both with and without complications. A total of 15 proteins of diverse functionalities were shown to have a direct association with time to birth (TTB), 11 of which have not been previously linked to gestational age. The protein A Distintegrin and Metalloproteinase 12 (ADA12) was one of the 15 proteins shown to have an association with TTB. Mothers who expressed the highest levels of ADA12 in the cohort (90th percentile) gave birth earlier than mothers who expressed the lowest levels of ADA12 (10th percentile) at a statistically significant rate (median gestational age at birth 39^0/7 weeks vs. 39^3/7 weeks, p < 0.001). Altogether, these findings suggest that ADA12, as well as potentially other clock proteins, have the potential to serve as clinical predictors of term delivery date in uncomplicated pregnancies and represent an important step towards characterizing the role(s) of clock proteins in mediating pregnancy length. Full article

Measuring exercise intensity for safety and to inform prescription in acute burn survivors, is challenging. This study aimed to assess the validity of adult patient end-of-workout rating of session perceived exertion (sRPE); and calculated training load (TL) (sRPE × session duration) as measures of exercise intensity. Secondly, the study aimed to compare clinician and patient perception of exercise effort during physiotherapist-led sessions. Repeated RPE data were collected every 5-min during two resistance exercise sessions completed by 25 burns patients. Physiological (heart rate [HR], blood lactate [BLa]) and perceptual measures (sRPE, ratings of pain, fatigue, delayed onset muscle soreness, sleep quality and stress) were also captured. Adjusted, multivariable linear regression models were used to determine the associations between sRPE and TL and significant predictor variables. Paired t-tests were performed to compare clinician and participant sRPE. Results: Average RPE calculated from 5-min repeats, after adjustment for age and %TBSA, was significantly associated with sRPE, F(1, 45) = 100.82, (p < 0.001, adjusted R² = 0.64) and TL, F(1, 45) = 33.66, (p < 0.001, adjusted R² = 0.39). No significant differences between patient and clinician sRPE were apparent (p = 0.948). Thus, one-off reporting of sRPE and calculated TL may be appropriate markers to monitor exercise intensity and aid prescription in individuals with burn injuries, regardless of patient and burn characteristics or time since burn. There was also no difference between patient and clinician’s perceptions of exercise effort. Full article

Background: Chemotherapy-induced peripheral neuropathy (CIPN) from oxaliplatin and taxane drugs is a bothersome toxicity. Palmitoylethanolamide (PEA) has been reported to improve myelinated nerve fiber function in patients experiencing painful CIPN. We conducted a double-blind, placebo-controlled, randomized trial of PEA in patients with established CIPN. Methods: Eligible patients were adults who had pain, numbness, tingling, or other symptoms of CIPN for at least three months following completion of paclitaxel, oxaliplatin, or cisplatin-based chemotherapy. Study patients were randomized to one of the two treatment groups (PEA versus placebo, both administered either once or twice daily). The CIPN20 questionnaire was assessed weekly. Results: A total of 17 males and 71 females participated in the study; most had neuropathy from paclitaxel. Most (85%) finished 8 weeks of treatment. There was no suggestion that either of the PEA arms did any better than the combined placebo arms. There was no signal of significant toxicity differences between the three study arms. Quality of life outcome measures were similar between the study arms, as were cognitive function evaluations. Discussion: PEA failed to improve established CIPN. Future trials might explore whether PEA may be effective in preventing CIPN or cognitive changes based on data that suggest it may be helpful in this situation. Conclusions: PEA failed to improve established chemotherapy-induced neuropathy. Full article

Background/Objectives: Recent studies, typically using patient cerebrospinal fluid (CSF), have suggested that different autoantibodies (Aabs) acting on their respective receptors, may underlie neuropsychiatric disorders. The GluN1 (NR1) subunit of the N-methyl-D-aspartate receptor (NMDAR) has been identified as a target of anti-NMDAR Aabs in a number of central nervous system (CNS) diseases, including encephalitis and autoimmune epilepsy. However, the role or the nature of Aabs responsible for effects on neuronal excitability and synaptic plasticity is yet to be established fully. Methods: Peptide immunisation was used to generate Aabs against selected specific GluN1 extracellular sequences based on patient-derived anti-NMDAR Aabs that have been shown to bind to specific regions within the GluN1 subunit. ‘Protein A’ purification was used to obtain the total IgG, and further peptide purification was used to obtain a greater percentage of NMDAR-target specific IgG Aabs. The binding and specificity of these anti-NMDAR Aabs were determined using a range of methodologies including enzyme-linked immunosorbent assays, immunocytochemistry and immunoblotting. Functional effects were determined using different in vitro electrophysiology techniques: two-electrode voltage-clamps in Xenopus oocytes and measures of long-term potentiation (LTP) in ex vivo hippocampal brain slices using multi-electrode arrays (MEAs). Results: We show that anti-NMDAR Aabs generated from peptide immunisation had specificity for GluN1 immunisation peptides as well as target-specific binding to the native protein. Anti-NMDAR Aabs had no clear effect on isolated NMDARs in an oocyte expression system. However, peptide-purified anti-NMDAR Aabs prevented the induction of LTP at Schaffer collateral-CA1 synapses in ex vivo brain slices, consistent with causing synaptic NMDAR hypofunction at a network level. Conclusions: This work provides a solid basis to address outstanding questions regarding anti-NMDAR Aab mechanisms of action and, potentially, the development of therapies against CNS diseases. Full article

Objectives: This study evaluated the psychometric properties of the ceroid lipofuscinosis type 2 Quality of Life (CLN2 QoL) questionnaire. Methods: Data from children with CLN2 disease aged 3–16 years receiving cerliponase alfa in the BMN 190-201 and BMN 190-202 clinical studies, collected via purposive sampling, were used to assess convergent and divergent validity, internal consistency and reliability. The clinically important difference (CID) was estimated with distribution- and anchor-based methods. Descriptive and inferential statistical analyses were conducted using IBM SPSS. Results: CLN2 QoL data of 22 participants were analysed. Ceiling effects were observed in 22 items (35% threshold); no floor effects were observed. Internal consistency analysis showed good reliability (Cronbach’s alpha and Omega reliability >0.7) for four domains at study completion; only one domain had good reliability at baseline. All domains had good test–retest reliability (correlation >0.5) except Feeding With G-Tube and Seizures. Convergent and divergent correlation analysis showed moderate-strong correlations (>0.4) between PedsQL and CLN2 QoL total scores, between the Pediatric Quality of Life Inventory (PedsQL) total score and most CLN2 QoL domains at baseline, and between CLN2 QoL total score and most PedsQL domains at week 97. Known groups validity showed a significant difference in means for the Behaviour domain (p = 0.05) for reasons that could not be clarified. CID was 6.79–12.94 for domains; total score CID was 6.91 using distribution-based and 6.13–13.05 using anchor-based methods. Conclusions: This study is the first to validate the CLN2 QoL and to estimate the CID of this instrument in CLN2 patients. Our results show good validity and reliability of this tool. Full article

During responses to outbreaks, the collection and analysis of data on employed case patients’ industry and occupation are necessary to better understand the relationship between work and health outcomes. The occurrence of mpox by occupation and industry has not previously been assessed in the context of the 2022 outbreak. We analyzed employment data from 2548 mpox cases reported to the U.S. Centers for Disease Control and Prevention from surveillance systems in seven U.S. jurisdictions and population-based reference data on employment patterns from the U.S. Bureau of Labor Statistics to describe the differential proportionate distribution of cases across occupation and industry groups using the proportionate morbidity ratio. In gender-specific analyses, we found that men employed in certain occupations and industries had a higher relative risk of mpox than others. While occupational transmission cannot be ruled out, it is more likely that individuals with personal and behavioral risk factors for mpox were more likely to work in these occupations and industries. This analysis provides an example of collecting and analyzing occupation and industry data in case reports to understand possible differences in risk by occupation and industry in infectious disease outbreak investigation and help inform resource allocation, messaging, and response. Full article

Background and purpose: Differentiating pediatric posterior fossa (PF) tumors such as medulloblastoma (MB), ependymoma (EP), and pilocytic astrocytoma (PA) remains relevant, because of important treatment and prognostic implications. Diffusion kurtosis imaging (DKI) has not yet been investigated for discrimination of pediatric PF tumors. Estimating diffusion values from whole-tumor-based (VOI) segmentations may improve diffusion measurement repeatability compared to conventional region-of-interest (ROI) approaches. Our purpose was to compare repeatability between ROI and VOI DKI-derived diffusion measurements and assess DKI accuracy in discriminating among pediatric PF tumors. Materials and methods: We retrospectively analyzed 34 children (M, F, mean age 7.48 years) with PF tumors who underwent preoperative examination on a 3 Tesla magnet, including DKI. For each patient, two neuroradiologists independently segmented the whole solid tumor, the ROI of the area of maximum tumor diameter, and a small 5 mm ROI. The automated analysis pipeline included inter-observer variability, statistical, and machine learning (ML) analyses. We evaluated inter-observer variability with coefficient of variation (COV) and Bland–Altman plots. We estimated DKI metrics accuracy in discriminating among tumor histology with MANOVA analysis. In order to account for class imbalances, we applied SMOTE to balance the dataset. Finally, we performed a Random Forest (RF) machine learning classification analysis based on all DKI metrics from the SMOTE dataset by partitioning 70/30 the training and testing cohort. Results: Tumor histology included medulloblastoma (15), pilocytic astrocytoma (14), and ependymoma (5). VOI-based measurements presented lower variability than ROI-based measurements across all DKI metrics and were used for the analysis. DKI-derived metrics could accurately discriminate between tumor subtypes (Pillai’s trace: p < 0.001). SMOTE generated 11 synthetic observations (10 EP and 1 PA), resulting in a balanced dataset with 45 instances (34 original and 11 synthetic). ML analysis yielded an accuracy of 0.928, which correctly predicted all but one lesion in the testing set. Conclusions: VOI-based measurements presented improved repeatability compared to ROI-based measurements across all diffusion metrics. An ML classification algorithm resulted accurate in discriminating PF tumors on a SMOTE-generated dataset. ML techniques based on DKI-derived metrics are useful for the discrimination of pediatric PF tumors. Full article

Purpose: Genetic counselors (GCs) increasingly play key roles in advancing genomic medicine through innovative research. Here, we examine one large cohort of GCs’ evolving contributions to the literature, with the goal of facilitating worldwide professional development for GCs through scholarly activities. Methods: Publications were cataloged by members of the Section of Genetic Counseling (Section), established at the Children’s Hospital of Philadelphia and the University of Pennsylvania in 2014, including publication year, journal, impact factor, and author position. Data were organized using the “My Bibliography” tool on the National Center for Biotechnology Information website and a Research Electronic Data Capture database created to initially collect manuscripts published through 30 June 2020. A subsequent survey captured publications through 5 February 2024. Results: An amount of 52 of 120 (43%) GCs shared their curriculum vitae/papers. 992 unique publications were identified from 1986 to 2024. Since 2013, no less than 32 papers were published annually by Section members and no less than 10 GCs contributed to publications yearly. Impact factors typically averaged >5.0 per year. Areas of foci diversified considerably since 2015. Conclusions: Here, we establish that GCs indeed contribute to scholarly work as evidenced by the number of publications alone. The establishment of an academic home may have contributed, given publications increased concurrent to launching the Section, providing a model for organizing GCs at institutions nationally and internationally. Highlighting such achievements will foster the expansion of GC roles in the era of precision genomic medicine and therapy. Considering ways to support GCs towards expanding these activities is equally important. Full article