Clinical Relevance Research Articles

Development and Validation of a High-Performance Liquid Chromatography-Ultraviolet Spectrometry Method for Ampicillin and its Application in Routine Therapeutic Drug Monitoring of Intensive Care Patients.

Ampicillin/sulbactam, a combination of a β-lactam and β-lactamase inhibitor, is widely used in clinical settings. However, therapeutic drug monitoring (TDM) of ampicillin is not commonly performed, particularly in intensive care units (ICUs). The purpose of this study was to develop and validate a rapid and cost-effective high-performance liquid chromatography (HPLC)-ultraviolet spectrometry method to quantify ampicillin in human serum and evaluate its clinical application in ICU patients. Sample cleanup included a protein precipitation protocol, followed by chromatographic separation on a C18 reverse-phase HPLC column within 12.5 minutes using gradient elution of the mobile phase. The assay was validated according to the German Society of Toxicology and Forensic Chemistry criteria. Clinical applications involved the retrospective analysis of TDM data from ICU patients receiving continuous infusion of ampicillin/sulbactam, including the attainment of target ranges and individual predicted and observed pharmacokinetics. The method was robust, with linear relations between the peak area responses and drug concentrations in the range of 2-128 mg/L. The coefficient of variation for precision and the bias for accuracy (both interday and intraday) were less than 10%. Clinical application revealed variable pharmacokinetics of ampicillin in ICU patients (clearance of 0.5-31.2 L/h). TDM-guided dose adjustments achieved good therapeutic drug exposure, with 92.9% of the samples being within the optimal (16-32 mg/L) or quasioptimal (8-48 mg/L) range. This method provides a practical solution for the routine TDM of ampicillin, facilitating individualized dosing strategies to ensure adequate therapeutic drug exposure. Given its simplicity, cost-effectiveness, and clinical relevance, HPLC-ultraviolet spectrometry holds promise for broad implementation in hospital pharmacies and clinical laboratories.

Assessing the predictive efficacy of noninvasive liver fibrosis indices and portal vein diameter in predicting esophageal variceal bleeding in patients with cirrhosis

BackgroundThe objective of this study is to evaluate the diagnostic accuracy of noninvasive serum liver fibrosis markers and portal vein diameter (PVD) in predicting the occurrence of esophageal variceal bleeding (EVB) in patients with cirrhosis.MethodsA cohort comprising 102 individuals diagnosed with cirrhosis was divided into two groups: the P group (without EVB) and the PE group (with EVB). We conducted a comprehensive analysis comparing various noninvasive serum liver fibrosis indices, the Child-Pugh classification, ratios of aspartate aminotransferase to alanine aminotransferase, aspartate aminotransferase to platelet ratio index, fibrosis index based on four factors (FIB-4), PVD, and spleen thickness (SPT) between these groups. Receiver operating characteristic (ROC) curves were constructed for variables showing significant differences between the two groups, with subsequent calculation of the area under the ROC curve (AUROC) for each variable.ResultsSignificant distinctions were noted in the serum liver fibrosis markers between the P and PE groups, encompassing hyaluronic acid (HA), type III procollagen (PC-III), type IV collagen (IV-C), PVD, SPT, and FIB-4 (p < 0.05), as evidenced by univariate analysis findings. The respective AUROC values for these markers were 0.653, 0.706, 0.710, 0.730, 0.660, and 0.633. Additionally, upon integration with PVD, SPT, and FIB4, the AUROC values for liver fibrosis markers surged to 0.793, 0.763, and 0.706 correspondingly, highlighting the enhanced diagnostic potential.ConclusionThe integration of noninvasive liver fibrosis indices and PVD showcased remarkable diagnostic potential in EVB, underscoring its clinical relevance in predicting hemorrhagic events.

Clinical variability of equine asthma phenotypes and analysis of diagnostic steps in phenotype differentiation

BackgroundEquine asthma is a common, non-infectious, chronic lung disease that affects up to 80% of the horse population. Strict phenotyping and identification of subclinically asthmatic horses can be challenging. The aim of this study was to describe equine asthma phenotypes (mild, moderate, and severe asthma) defined by BALF cytology and occurrence of clinical signs in a population of privately owned horses and to identify the variables and examination steps with best discriminative potential. The standardised examination protocol included clinical examinations, blood work, airway endoscopy with bronchoalveolar lavage fluid analysis, arterial blood gas analysis and radiography under clinical conditions performed by one veterinarian.ResultsOut of 26 horses, four were diagnosed with mild (subclinical), seven with moderate, and seven with severe asthma based on clinical examination and BALF cytology. Eight horses served as controls. Cough with history of coughing was the strongest variable in phenotype differentiation. Factor analysis revealed an increasing clinical variability with disease severity and an overlapping of clinical presentations between phenotypes. Elevated mast cell (4/4 horses) and neutrophil counts (3/4 horses) in bronchoalveolar lavage cytology differentiated mild asthmatic horses from healthy horses. Moderate and severe asthmatic horses were characterised by clinical signs and neutrophil counts.ConclusionsThe results indicate that medical history, clinical examination and bronchoalveolar lavage cytology are minimum indispensable steps to diagnose equine asthma and that phenotypes are clinically overlapping. A differentiation of three phenotypes without neutrophil and mast cell counts in bronchoalveolar lavage cytology is not sufficient for clinical diagnostics. A comparably exact diagnosis cannot be achieved by relying on alternative examinations used in this study. Screenings of inconspicuous horses with bronchoalveolar lavage can aid in diagnosing subclinically affected animals, however, group size was small, the procedure is invasive and clinical relevance of slightly elevated cells in bronchoalveolar lavage remains unclear. Clinical relevance could not be clarified in this study, since follow-up examinations or lung function testing were not performed.

Predicting post-lung transplant survival in systemic sclerosis using CT-derived features from preoperative chest CT scans.

The current understanding of survival prediction of lung transplant (LTx) patients with systemic sclerosis (SSc) is limited. This study aims to identify novel image features from preoperative chest CT scans associated with post-LTx survival in SSc patients and integrate them into comprehensive prediction models. We conducted a retrospective study based on a cohort of SSc patients with demographic information, clinical data, and preoperative chest CT scans who underwent LTx between 2004 and 2020. This cohort consists of 102 patients (mean age, 50 years ± 10, 61% (62/102) females). Five CT-derived body composition features (bone, skeletal muscle, visceral, subcutaneous, and intramuscular adipose tissues) and three CT-derived cardiopulmonary features (heart, arteries, and veins) were automatically computed using 3-D convolutional neural networks. Cox regression was used to identify post-LTx survival factors, generate composite prediction models, and stratify patients based on mortality risk. Model performance was assessed using the area under the receiver operating characteristics curve (ROC-AUC). Muscle mass ratio, bone density, artery-vein volume ratio, muscle volume, and heart volume ratio computed from CT images were significantly associated with post-LTx survival. Models using only CT-derived features outperformed all state-of-the-art clinical models in predicting post-LTx survival. The addition of CT-derived features improved the performance of traditional models at 1-year, 3-year, and 5-year survival prediction with maximum AUC scores of 0.77 (0.67-0.86), 0.85 (0.77-0.93), and 0.90 (95% CI: 0.83-0.97), respectively. The integration of CT-derived features with demographic and clinical features can significantly improve t post-LTx survival prediction and identify high-risk SSc patients. Question What CT features can predict post-lung-transplant survival for SSc patients? Finding CT body composition features such as muscle mass, bone density, and cardiopulmonary volumes significantly predict survival. Clinical relevance Our individualized risk assessment tool can better guide clinicians in choosing and managing patients requiring lung transplant for systemic sclerosis.

Access for ALL in ALS: A large-scale, inclusive, collaborative consortium to unlock the molecular and genetic mechanisms of amyotrophic lateral sclerosis.

Recent progress in therapeutics for amyotrophic lateral sclerosis (ALS) has spurred development and imbued the field of ALS with hope for more breakthroughs, yet substantial scientific gaps persist. This unmet need remains a stark reminder that innovative paradigms are needed to invigorate ALS research. To move toward more informative, targeted, and personalized drug development, the National Institutes of Health (NIH) established a national ALS clinical research consortium called Access for ALL in ALS (ALL ALS). This new consortium is a multi-institutional effort that aims to organize the ALS clinical research landscape in the United States. ALL ALS is operating in partnership with several stakeholders to operationalize the recommendations of the Accelerating Access to Critical Therapies for ALS Act (ACT for ALS) Public Private Partnership. ALL ALS will provide a large-scale, centralized, and readily accessible infrastructure for the collection and storage of a wide range of data from people living with ALS (symptomatic cohort) or who may be at risk of developing ALS (asymptomatic ALS gene carriers). Importantly, ALL ALS is designed to encourage community engagement, equity, and inclusion. The consortium is prioritizing the enrollment of geographically, ethnoculturally, and socioeconomically diverse participants. Collected data include longitudinal clinical data and biofluids, genomic, and digital biomarkers that will be harmonized and linked to the central Accelerating Medicines Partnership for ALS (AMP ALS) portal for sharing with the research community. The aim of ALL ALS is to deliver a comprehensive, inclusive, open-science dataset to help researchers answer important scientific questions of clinical relevance in ALS.

A chart-based test of contrast sensitivity in noise: reference ranges, effects of age and optical abnormality

ABSTRACT Clinical relevance Contrast sensitivity plays an important role in the comprehensive assessment of visual function; however, measurement with standard eye charts can be affected by age and optical abnormality. Background This study describes a novel chart-based test of letter contrast sensitivity (CS) in luminance noise (the Illinois Eye and Ear Noise CS test), defines normal reference ranges, estimates test-retest repeatability, and assesses the effects of age and simulated optical abnormalities. Methods Seventy-five individuals with normal visual function (age 18–85 years) participated. Subjects identified letter optotypes that spanned a broad contrast range (0.9% to 59.6%) printed in a book-based test. Letters were presented against a grey background (no-noise condition) and in luminance noise that consisted of light and dark checks (noise condition). A subset of 10 subjects repeated the test to define short-term variability and performed the test under three additional conditions: simulated cataract, +2.00D defocus, and low room illuminance. Results In the no-noise condition, CS was independent of age (mean log CS of 1.74) until approximately 54 years, and declined for older subjects (CS loss of 0.1 log unit/decade). CS measured in noise was independent of age across the range of ages tested (mean log CS of 0.91). The 95% limits of agreement for test-retest repeatability was 0.19 log units. Simulated cataract, +2.00D defocus, and reduced illumination significantly reduced CS in the no-noise condition (F = 102.6, p < 0.001), whereas these optical manipulations did not significantly affect CS in noise (F = 2.58, p = 0.074). Conclusions Measurements of CS in luminance noise may be valuable, as these measures are largely independent of age and certain forms of optical degradation. CS measurements in noise may provide useful insight into visual function in patients who have combined neural and optical abnormality, as noise minimises CS loss from optical defects.

Decoding machine learning in nursing research: A scoping review of effective algorithms.

The rapid evolution of artificial intelligence (AI) technology has revolutionized healthcare, particularly through the integration of AI into health information systems. This transformation has significantly impacted the roles of nurses and nurse practitioners, prompting extensive research to assess the effectiveness of AI-integrated systems. This scoping review focuses on machine learning (ML) used in nursing, specifically investigating ML algorithms, model evaluation methods, areas of focus related to nursing, and the most effective ML algorithms. The scoping review followed the Preferred Reporting Items for Systematic Review and Meta-Analysis Extension for Scoping Reviews (PRISMA-ScR) guidelines. A structured search was performed across seven databases according to PRISMA-ScR: PubMed, EMBASE, CINAHL, Web of Science, OVID, PsycINFO, and ProQuest. The quality of the final reviewed studies was assessed using the Medical Education Research Study Quality Instrument (MERSQI). Twenty-six articles published between 2019 and 2023 met the inclusion and exclusion criteria, and 46% of studies were conducted in the US. The average MERSQI score was 12.2, indicative of moderate- to high-quality studies. The most used ML algorithm was Random Forest. The four second-most used were logistic regression, least absolute shrinkage and selection operator, decision tree, and support vector machine. Most ML models were evaluated by calculating sensitivity (recall)/specificity, accuracy, receiver operating characteristic (ROC), area under the ROC (AUROC), and positive/negative prediction value (precision). Half of the studies focused on nursing staff or students and hospital readmission or emergency department visits. Only 11 articles reported the most effective ML algorithm(s). The scoping review provides insights into the current status of ML research in nursing and recognition of its significance in nursing research, confirming the benefits of ML in healthcare. Recommendations include incorporating experimental designs in research studies to optimize the use of ML models across various nursing domains. The scoping review demonstrates substantial clinical relevance of ML applications for nurses, nurse practitioners, administrators, and researchers. The integration of ML into healthcare systems and its impact on nursing practices have important implications for patient care, resource management, and the evolution of nursing research.

Quality of life of women with a screen-detected versus clinically detected breast cancer in the Netherlands: a prospective cohort study.

Breast cancer (BC) screening enables early detection of BC, which may lead to improved quality of life (QoL). We aim to compare QoL between women with a screen-detected and clinically detected BC in the Netherlands. We used data from the 'Utrecht cohort for Multiple BREast cancer intervention studies and Long-term evaluation' (UMBRELLA) between October 2013 and March 2022. Patients were categorized as screen-detected or clinically detected. We analysed three questionnaires, namely EORTC QLQ C-30, BR23, and HADS (Hospital Anxiety and Depression Scale) completed by BC patients shortly after diagnosis (T1) and one-year after treatment (T2). Independent t-tests were performed to compare QoL average differences between the two groups. Bonferroni-corrected p-value significance threshold of 0.00057 was used. The magnitude of differences was calculated using Cohen's d. The clinical relevance of QLQ-C30 differences was assessed based on interpretation guideline of EORTC-QLQ-C30 results. After applying inclusion and exclusion criteria, there were 691 women with screen-detected BC and 480 with clinically detected BC. Generally, screen-detected BC patients reported a better QoL. At T1, their average QLQ-C30 summary score was higher (86.1) than clinically detected BC patients (83.0) (p < 0.0001). Cohen's d for all items ranged between 0.00 and 0.39. A few QLQ-C30 score differences were clinically relevant, indicating better outcomes in emotional functioning, general health, constipation, and fatigue for women with screen-detected BC. In the Netherlands, women with screen-detected BC reported statistically significant and better QoL than women with clinically detected BC. However, clinical relevance of the differences is limited.

Vascular mimicry and mosaic vessels in parathyroid tumours: a new diagnostic approach?

AimsEvaluation of ‘alternative’ vascularisation in human cancer is considered an important prognostic parameter; the 2022 WHO classification of parathyroid tumours despite progresses in clinical triaging of patients strongly emphasises new...

Hallmarks of aging in age-related macular degeneration and age-related neurological disorders: novel insights into common mechanisms and clinical relevance.

Age-related macular degeneration (AMD) and age-related neurological diseases (ANDs), such as Alzheimer's and Parkinson's Diseases, are increasingly prevalent conditions that significantly contribute to global morbidity, disability, and mortality. The retina, as an accessible part of the central nervous system (CNS), provides a unique window to study brain aging and neurodegeneration. By examining the associations between AMD and ANDs, this review aims to highlight novel insights into fundamental mechanisms of aging and their role in neurodegenerative disease progression. This review integrates knowledge from the emerging field of aging research, which identifies common denominators of biological aging, specifically loss of proteostasis, impaired macroautophagy, mitochondrial dysfunction, and inflammation. Finally, we emphasize the clinical relevance of these pathways and the potential for cross-disease therapies that target common aging hallmarks. Identifying these shared pathways could open avenues to develop therapeutic strategies targeting mechanisms common to multiple degenerative diseases, potentially attenuating disease progression and promoting the healthspan.

A critical review of management of allogeneic transplant-eligible adults with Ph+ acute lymphoblastic leukaemia.

Acute lymphoblastic leukaemia (ALL) in 20%-30% of adult patients contains the Philadelphia (Ph+) chromosome. Historically, Ph+ ALL denoted a markedly inferior outcome and long-term survival in the absence of an allograft was uncommon. However, the advent of targeted therapy directed against the BCR::ABL1 fusion protein with various tyrosine kinase inhibitors (TKIs) has markedly improved the prognosis, resulting in a number of treatment controversies in allograft-eligible patients. Which is the best TKI to use in induction? What is the clinical relevance of the subdivision of Ph+ ALL into multilineage vs lymphoid types? Do all patients in first morphological complete remission (CR1) after induction and consolidation with chemotherapy/TKI require an allograft? If not, what risk factors predict a poor outcome without an allograft? Can chemotherapy-free approaches, such as blinatumomab in conjunction with more potent TKIs, obviate the need for an allograft in high-risk patients? What is the best strategy to deal with persistent or emerging minimal residual disease both pre- and post-transplant? Is maintenance TKI indicated in all patients post allograft? Can salvage therapy and a subsequent allograft cure patients who relapse after not being transplanted in CR1? This manuscript reviews the latest data influencing contemporary management and discusses these controversies.

The development and evanescence of red blood cell antibodies after transfusion: A multi-institutional prospective study in Japan.

Despite several reports on red blood cell (RBC) alloimmunization, the actual prevalence and factors contributing to RBC alloimmunization in transfused patients remain poorly investigated. We examined the association between clinical factors and the development and evanescence of RBC antibodies after transfusion. Each participating institution performed antibody screens before and after RBC transfusion. A survey including patient characteristics, results of antibody screen and identification, antibody screen methods, total amount of RBC transfused, and adverse reactions, was conducted. Between October 2018 and March 2023, 1194 patients were registered at five institutions. Overall, 958 patients underwent at least one follow-up RBC antibody screen after transfusion, revealing new antibody development in 44 (4.6%). Anti-E was identified in 25 patients, anti-Jka in 5, and anti-c in 4. The number of RBC units transfused was significantly associated with antibody development after transfusion (p < .001). Among 55 patients in whom antibodies were identified after transfusion, including historical antibodies, antibodies evanesced in 18 (33%); anti-E in 7, anti-Jka in 4, and anti-Lea in 2. Evanescent antibodies were identified more frequently by saline and/or enzyme methods than persistent antibodies (p = .012). The number of RBC units transfused can impact antibody development, and antibodies identified only by saline and/or enzyme methods, deemed clinically insignificant, are likely to have a high evanescence rate. Antibody screen should be carefully performed, especially in those receiving a large number of RBC units. Confirming previous antibody screen results should be performed to prevent omitting evanesced antibodies regardless of clinical relevance.

Relevance of lesion size in navigator-triggered and free-breathing diffusion-weighted liver MRI.

The purpose of this study was to investigate the relevance of focal liver lesions (FLL) size for lesion detection comparing navigator triggering (TRIG) to free breathing (FB) liver Diffusion-weighted magnetic resonance imaging (DWI). Patients with known or suspected FLL were prospectively (registry number 276_19 B) included from October to December 2019 in this study, out of which 32 had liver lesions. Echo planar spin-echo DWI data both with TRIG and FB were with approximately constant acquisition times acquired at 1.5 T. Lesions were segmented in the b = 800 s/mm² images in both the TRIG and FB images. The lesion size, location (liver segment), liver lesion visibility, as well as contrast-to-noise ratio (CNR) were recorded. The CNR was assessed with the Wilcoxon-Mann-Whitney test and the number of visible lesions with the Fisher test. Data from 43 patients (22 female) were analyzed. The mean patient age was 58 ± 14 years. A total of 885 FLL (Ntotal) were segmented. Among these, 811 lesions (Nboth) were detected with TRIG and FB, 65 lesions exclusively with TRIG (NTRIG_Only), and nine exclusively in FB (NFB_Only). The largest additional lesion in TRIG/FB had a diameter of 10.4 mm/7.6 mm. The number of additional lesions detected with TRIG decreased with size. Among all lesions ≤ 4.7 mm, the relative number of additional lesions was 15.6%. Additional lesions were found in all liver segments with TRIG. In the left liver lobe, the relative proportion was 9.2%, and in the right liver lobe 5.4%. CNR and visibility were significantly higher in TRIG than in FB (p < 0.001). In relation to size, the difference is significant in terms of visibility and CNR for lesion diameters ≤ 8 mm. Respiration triggering can improve the detection of small liver lesions with diameters up to approx. 1 cm in the whole liver. Question Can respiration triggering (TRIG) improve the detection of small FLL compared to FB diffusion-weighted imaging? Findings Among 885 segmented FLL, TRIG was superior to FB for lesions smaller than 8 mm and had improved CNR and visibility. Clinical relevance Diffusion-weighted magnetic resonance imaging is used for the detection of focal liver lesions and image quality is influenced by breathing motion. Navigator triggering becomes more important for smaller lesions, and seems recommendable for the detection of small focal liver lesions.

Metabolomic Profiling of Pulmonary Neuroendocrine Neoplasms

Background/Objectives: Pulmonary neuroendocrine neoplasms (NENs) account for 20% of malignant lung tumors. Their management is challenging due to their diverse clinical features and aggressive nature. Currently, metabolomics offers a range of potential cancer biomarkers for diagnosis, monitoring tumor progression, and assessing therapeutic response. However, a specific metabolomic profile for early diagnosis of lung NENs has yet to be identified. This study aims to identify specific metabolomic profiles that can serve as biomarkers for early diagnosis of lung NENs. Methods: We measured 153 metabolites using liquid chromatography combined with mass spectrometry (LC-MS) in the plasma of 120 NEN patients and compared them with those of 71 healthy individuals. Additionally, we compared these profiles with those of 466 patients with non-small-cell lung cancers (NSCLCs) to ensure clinical relevance. Results: We identified 21 metabolites with consistently altered plasma concentrations in NENs. Compared to healthy controls, 18 metabolites were specific to carcinoid tumors, 5 to small-cell lung carcinomas (SCLCs), and 10 to large-cell neuroendocrine carcinomas (LCNECs). These findings revealed alterations in various metabolic pathways, such as fatty acid biosynthesis and beta-oxidation, the Warburg effect, and the citric acid cycle. Conclusions: Our study identified biomarker metabolites in the plasma of patients with each subtype of lung NENs and demonstrated significant alterations in several metabolic pathways. These metabolomic profiles could potentially serve as biomarkers for early diagnosis and better management of lung NENs.

“You’re Ugly and Bad!“: a path analysis of the interplay between self-criticism, alexithymia, and specific symptoms

AbstractSelf-criticism is a transdiagnostic factor of significant clinical relevance. Research has studied its detrimental role on mental health without discriminating how this differs based on individual psychological functioning. Furthermore, little research has considered the lack of emotional awareness as an essential competence that contributes to dysfunctional self-critical processes and, consequently, to psychopathological outcomes. The objective of the study was to investigate how different forms of self-criticism are associated with specific symptoms, considering social anxiety, obsessive-compulsive, and eating disorder symptoms. Furthermore, we wanted to explore the role of alexithymia in this relationship. The sample comprised 564 subjects (M = 35.12, SD = 12.8), 389 females and 175 males. Participants completed online questionnaires to investigate levels of self-criticism, alexithymia, and specific symptoms. Hierarchical regression and path analyses showed that aspects of self-criticism have different importance in psychopathological features. Furthermore, the subscales of alexithymia differently mediate the relationship between self-criticism and symptomatological features, depending on the type of feature considered (social anxiety, eating or obsessive-compulsive). In light of the results, since self-criticism is a contributing factor to the onset and maintenance of many mental disorders, it becomes important to distinguish its specific characteristics and how they are linked to the disorders. A better understanding of these processes would help to prepare more targeted interventions.

Alterations in circulating immunoregulatory proteins discriminate poor CD4 T lymphocyte trajectories in people with HIV on suppressive antiretroviral therapy.

It is essential to track immune perturbations related to insufficient CD4 T-cell recovery in PWH on suppressive ART as those with incomplete reconstitution are at a greater risk of non-AIDS-related morbidity and mortality. Several inflammatory soluble mediators have associated with poor immune reconstitution and adverse morbid outcomes in PWH, yet their implementation into routine clinical care to guide management remains inconsistent. Circulating immune checkpoint proteins have been linked to dysregulated immune pathways during suppressive ART and may serve as improved surrogate markers of clinical relevance. Here we investigate soluble lymphocyte-associated immunoregulatory proteins in virally suppressed PWH with no reported co-morbid outcomes and varying CD4 T-cell counts, to reveal underlying pathways that remain perturbed despite ART. This novel signature of immunoregulatory markers pertaining to poor CD4 T-cell trajectories uncover previously overlooked immune checkpoints as important targets for clinical monitoring of PWH in the setting of durable viral suppression by ART.

Factors affecting intraperitoneal pressure (IPP) and its prognostic value in predicting leak risk and gastrointestinal symptoms in adult peritoneal dialysis patients: a systematic review and meta-analysis.

Intraperitoneal pressure measurementoffers therapeutic and prognostic benefits in predicting leak risks and gastrointestinal symptoms in Peritoneal Dialysis (PD) patients. This systematic review aims to evaluate the prognostic utility of intraperitoneal pressure measurements and different estimated intraperitoneal pressure equations in predicting the risk of non-infectious complications in PD patients. Databases including MEDLINE, EMBASE and Cochrane were searched up to July 2023. Randomised and non-randomised trials were included, focusing on End-Stage Kidney Disease (ESKD) patients undergoing PD. Primary outcomes were variables associated with intraperitoneal pressure, while secondary outcomes included PD-related non-infectious complications and gastrointestinal symptoms. Data synthesis combined meta-analysis with narrative synthesis.This review has been registered on PROSPERO (CRD42023475138). Out of 1828 identified studies, 12 were included for systematic review and 10 for meta-analysis. Body Mass Index (BMI) and Body Surface Area (BSA) showed a consistent positive correlation with intraperitoneal pressure (BMI: r = 0.49, 95% CI 0.35-0.61, I2 = 67.39%, p = 0.003; BSA: r = 0.2, 95% CI 0.08-0.31, I2 = 14.10%, p = 0.324). Conversely, the association between intraperitoneal pressure and age, intraperitoneal volume, and Charlson Comorbidity Index were less consistent. Subgroup analysis demonstrated an association between higher intraperitoneal pressure in patients with increased BMI and BSA. However, the relationship between intraperitoneal pressure and non-infectious mechanical complications remained inconclusive. This review underscores a significant association between intraperitoneal pressure and anthropometric measures (BMI and BSA). The majority of the studies identified included a small sample and considerable bias. However, the association between intraperitoneal pressure and clinically relevant outcomes was not clear. While increasing body mass index and body surface areas are associated with increasing intraperitoneal pressure, the clinical relevance of measuring intraperitoneal pressure in an adult population remains unclear, particularly given the absence of an association with clinically relevant non-infectious outcomes.

PBPK modeling of recombinant factor IX Fc fusion protein (rFIXFc) and rFIX to characterize the binding to type 4 collagen in the extravascular space.

Patients with severe and sometimes moderate hemophilia B are prophylactically treated with factor IX concentrates to prevent bleeding. For some time now, various extended terminal half-life (EHL) recombinant factor IX concentrates are available allowing less frequent administration during prophylaxis in comparison to standard half-life recombinant FIX (rFIX). Especially, recombinant FIX-Fc fusion protein (rFIXFc; Alprolix®) exhibits a rapid distribution phase, potentially due to binding to type IV collagen (Col4) in the extravascular space. Studies suggest that the presence of extravascular rFIXFc is protective against bleeding as without measurable FIX activity in plasma, and no extra bleeding seems to occur. The physiologically based pharmacokinetic (PBPK) model for rFIXFc which we describe in this study, is able to accurately predict the observed concentration-time profiles of rFIXFc in plasma and is able to quantify the binding of rFIXFc to Col4 in the extravascular space after an intravenous dose of 50 IU/kg rFIXFc in a male population. Our model predicts that the total AUC of rFIXFc bound to Col4 in the extravascular space is approximately 19 times higher compared to the AUC of rFIXFc in plasma. This suggests that rFIXFc present in the extravascular compartment may play an important role in achieving hemostasis after rFIXFc administration. Further studies on extravascular distribution of rFIXFc and the distribution profile of other EHL-FIX concentrates are needed to evaluate the predictions of our PBPK model and to investigate its clinical relevance.

Bone marrow edema-like signal after cartilage repair does not affect outcomes in a five-year follow-up.

Bone marrow edema-like signal (BMELS) after cartilage repair is common, but its clinical significance remains uncertain. This study aimed to investigate the clinical and structural significance of BMELS following microfracturing (MFX) and matrix-induced autologous chondrocyte implantation (MACI). In this multicenter study, MRI examinations were performed over a period of 5 years after cartilage repair surgery (MFX n = 17; MACI n = 28) in 45 patients. Morphological assessments, including the MOCART 2.0 (magnetic resonance observation of cartilage repair tissue), quantitative imaging biomarkers (QIB) with T2 mapping of the repair tissue, and, specifically, assessment of the presence and size of BMELS, were conducted along with patient-reported outcome measures, such as the Knee injury and Osteoarthritis Outcome Score (KOOS) and the International Knee Documentation Committee (IKDC). BMELS structural and clinical assessments were obtained after 3 months, 12 months, and 60 months. Statistical analysis included the Mann-Whitney U-test, Wilcoxon rank test, Shapiro-Wilk test, and simulation-based power analysis. BMELS were a common finding 60 months after cartilage repair. The size of BMELS differed significantly only between MACI and MFX patients after 3 months, with larger BMELS occurring in the MFX group. There were no significant differences in patients with or without BMELS regarding the T2 ratio of the treated area, the MOCART 2.0, or clinical scores. BMELS frequently appeared after cartilage repair procedures. We could show that the postoperative size and change in the size of BMELS after MACI and MFX did not affect clinical scores, morphological MRI results, or biochemical properties of the treated area after 60 months. Question What is the clinical significance of bone marrow edema-like signal (BMELS) appearance after matrix-induced autologous chondrocyte implantation (MACI) or microfracture (MFX)? Finding There were no significant differences in patients with or without BMELS regarding the T2 ratio of the treated area, the MOCART 2.0, or clinical scores. Clinical relevance BMELS frequently appeared after cartilage repair, the appearance or the size dynamic after MACI and MFX did not affect clinical scores, morphological MRI results, or biochemical properties after 60 months.

Small bowel neuroendocrine tumors: Unique features and low lethality compared with small bowel adenocarcinoma.

Population-based studies comparing clinical characteristics and survival disparities between patients with small bowel adenocarcinoma (SBA) and small bowel neuroendocrine tumors (SBNETs) in the United States are limited. Data for patients with SBA or SBNETs, obtained from the Surveillance, Epidemiology, and End Results database for the years between 2000 and 2018 were analyzed. Between 2000 and 2018, the age-adjusted incidence of SBA experienced a marginal increase whereas SBNETs demonstrated a significant increase, emerging as the predominant subtype of small bowel cancer (SBC). Diagnoses peaked at ages 65-69years for SBA and 60-64years for SBNETs, with the latter exhibiting a heightened age-specific incidence and maintaining equilibrium in gender distribution. Clinicopathologic disparities revealed SBA's duodenal predilection, larger tumor size, and advanced stages, contrasting with SBNETs' ileal predilection, early-stage presentation, and superior outcomes. SBNETs patients underwent surgery more frequently but received less chemotherapy and radiation than SBA patients. Factors intricately correlated with a diagnosis of SBNETs included female gender, White race, advanced age, marital status, recent diagnoses, superior tumor differentiation, smaller size, distal location, and early-stage presentation. Survival analysis unveiled a remarkable 79% reduction in the mortality risk for SBNETs compared with SBA. Subgroup analysis further confirmed the consistently favorable survival advantages of SBNETs, highlighting the clinical relevance of histological classification in prognostication. Compared with SBA, SBNETs exhibited distinctive clinicopathological features characterized by a higher inclination toward low-grade and early-stage manifestations, thereby contributing to superior survival outcomes.