Occurrence Of Syndrome Research Articles

Prognostic influence of fibroblast growth factor 23 on the course of coronary heart disease in patients with chronic kidney disease

Objective: to study the prognostic impact of the level of fibroblast growth factors 23 on coronary heart disease depending on the stage of chronic kidney disease. Materials and methods: the study included 108 patients with coronary heart disease (CHD), stable angina (stress), functional class 1–3, chronic kidney disease (CKD) C1–C4, average age was 67,62±12,51 years (55 men and 53 women). The level of fibroblast growth factor 23 was assessed using the Biomedica FGF 23 multimatrix enzyme-linked immunosorbent assay. After 12 months of follow-up, the presence of a cumulative endpoint including the occurrence of acute coronary syndrome, stroke, transient ischemic attack, heart failure and death. Differences in data and correlations between them were considered statistically significant at p<0.05. Results: the developed prognostic model to determine the likelihood of cardiovascular complications in patients with coronary artery disease and CKD found that the FGF 23 level is equal to 27.9 with a sensitivity of 62.7% and specificity of 62.5% to distinguish patients with ischemic heart disease and CKD in whom a cumulative endpoint will occur over 12 months of follow-up. Conclusions: to identify patients at high risk of cardiovascular complications in coronary artery disease and CKD, it is advisable to use determination of FGF 23 level.

Identification of novel mutations in TPK1 and SLC19A3 genes in families exhibiting thiamine metabolism dysfunction syndrome

Background and aimsThe occurrence of thiamine metabolism dysfunction syndrome (THMD), a rare autosomal recessive condition, may be linked to various mutations found in the TPK1 and SLC19A3 genes. The disease chiefly manifests through ataxia, muscle hypotonia, abrupt or subacute onset encephalopathy, and a decline in developmental milestones achieved during the early stages of infancy. We present findings from an investigation that involved two individuals from Iran, both of whom experienced seizures along with ataxia and hypotonia. The underlying genetic causes were found with the use of next-generation sequencing (NGS) technology, which has facilitated the detection of causal changes in a variety of genetic disorders. Material and methodsThe selection of cases for this study was based on the phenotypic and genetic information that was obtainable from the Center for Comprehensive Genetic Services. The genetic basis for the problems observed among the participants was determined through the application of whole-exome sequencing (WES). Subsequently, sanger sequencing was employed as a means of validating any identified variations suspected to be causative. ResultsThe first patient exhibited a homozygous mutation in the TPK1 gene, NM_022445.4:c.224 T > A:p.I75 N, resulting in the substitution of isoleucine for asparagine at position 75 (p.I75 N). In our investigation, patient 2 exhibited a homozygous variant, NM_025243.4:c.1385dupA:pY462X, within the SLC19A3 gene. ConclusionsCollectively, when presented with patients showcasing ataxia, encephalopathy, and basal ganglia necrosis, it is essential to account for thiamine deficiency in light of the potential advantages of prompt intervention. At times, it may be feasible to rectify this deficiency through the timely administration of thiamine dosages. Accordingly, based on the results of the current investigation, these variations may be useful for the diagnosis and management of patients with THMD.

Linking cerebral hemodynamics and ocular microgravity-induced alterations through an in silico-in vivo head-down tilt framework

Head-down tilt (HDT) has been widely proposed as a terrestrial analog of microgravity and used also to investigate the occurrence of spaceflight-associated neuro-ocular syndrome (SANS), which is currently considered one of the major health risks for human spaceflight. We propose here an in vivo validated numerical framework to simulate the acute ocular-cerebrovascular response to 6° HDT, to explore the etiology and pathophysiology of SANS. The model links cerebral and ocular posture-induced hemodynamics, simulating the response of the main cerebrovascular mechanisms, as well as the relationship between intracranial and intraocular pressure to HDT. Our results from short-term (10 min) 6° HDT show increased hemodynamic pulsatility in the proximal-to-distal/capillary-venous cerebral direction, a marked decrease (-43%) in ocular translaminar pressure, and an increase (+31%) in ocular perfusion pressure, suggesting a plausible explanation of the underlying mechanisms at the onset of ocular globe deformation and edema formation over longer time scales.

Short Versus Regular Periods of Cast Immobilization for Distal Radial Fractures: A Systematic Review and Meta-Analysis.

The current research on the recommended durations for cast immobilization in adults with distal radial fractures (DRFs) lacks a clear consensus or definitive conclusion. The standard practice involves casting immobilization for five to six weeks. The debate revolves around the potential benefits of shorter periods (three to four weeks) without compromising patient outcomes. While previous research has delved into this subject through systematic reviews, our study stands out by conducting a meta-analysis, aiming for a more precise understanding of whether short or regular cast immobilization duration proves more effective for treating DRFs. A systematic search was conducted across PubMed, Embase, and the Cochrane Library databases to identify relevant studies. The focus was on comparing the outcomes of DRFs between short (three to four weeks) and regular (five to six weeks) periods of cast immobilization. The evaluated parameters include the shortened disabilities of the arm, shoulder, and hand questionnaire (quick (q) DASH); patient-rated wrist evaluation (PRWE); visual analog scale (VAS) score after cast removal; total complications; and the occurrence of complex regional pain syndrome (CRPS). Data synthesis employed the random-effects models, presenting the results as mean difference (MD) and weighted odds ratio (OR) with corresponding 95% confidence intervals (CI). We included three randomized controlled trials (RCTs) with 252 patients, of whom 125 (49.6%) were immobilized in a cast for three to four weeks. The average age of participants was 61.20 years, and the follow-up duration was one year. The QDASH scores were significantly lower at 12 weeks (MD -6.72; 95% CI -10.76 to -2.69; p = 0.001), six months (MD -4.46; 95% CI -7.42 to -1.50; p = 0.003), and one year (MD -4.89; 95% CI -7.45 to -2.33; p = 0.0002) in patients treated with short periods compared to those with regular periods. The PRWE scores at six months (MD -2.33; 95% CI -8.10 to 3.43; p=0.43) did not significantly differ between groups. Also, the PRWE scores were significantly lower at one year (MD -4.93; 95% CI -9.03 to -0.82; p = 0.02) in the shorter cast-immobilization-period group. There were no significant differences in VAS score after cast removal, total complications, or CRPS. The meta-analysis of RCTs on DRFs reveals that shorter periods of cast immobilization lead to better patient-reported functional outcomes (qDASH and PRWE). This suggests a potential benefit of reducing the immobilization duration for DRF patients, offering clinicians valuable insights for improved patient care and informed decision-making in clinical practice.

Capillary leak syndrome was associated with more severe multisystem inflammatory syndrome in children during the COVID-19 pandemic.

This population-based study investigated the occurrence of capillary leak syndrome (CLS) in children with multisystem inflammatory syndrome in children (MIS-C), associated with COVID-19. We also examined associations between CLS and MIS-C disease severity. All eligible individuals aged 0-18 years, who were diagnosed with MIS-C in Skåne, southern Sweden, from 1 April 2020 to 31 July 2021, were studied. They were all included in the Pediatric Rheumatology Quality Register and clinical and laboratory data were compared between patients with and without CLS. We included 31 patients (61% male) with MIS-C in the study. The median age at diagnosis was 10.6 years (range 1.99-17.15) and 45% developed CLS. All six patients who required intensive care had CLS. Patients with CLS also had a higher incidence of reduced cardiac function, measured as low ejection fraction. The CLS group exhibited significantly higher C-reactive protein values (p < 0.001) and N-terminal pro-B-type natriuretic peptide levels (p < 0.001), as well as lower platelet counts (p = 0.03), during the first week of treatment. Individuals with CLS also received more intense immunosuppression. CLS was a common complication of MIS-C in our study and these patients had a more severe disease course that required more intensive treatment.

Clavicle fractures do not increase the occurrence of later subacromial pain syndrome. A registry-based case-control study with 15-25 years of follow-up of 131.838 persons from the Danish National Patient Register

BackgroundA clavicle fracture often changes the mechanical axes of the shoulder girdle due to displacement and shortening, potentially leading to scapular protraction and decreased subacromial space. If protraction of the scapula is a major risk factor for developing subacromial pain syndrome (SAPS), a previous clavicle fracture could increase the risk of later SAPS. The purpose of this study was to investigate if a previous clavicle fracture correlates with a higher occurrence or earlier diagnosis of SAPS. MethodsIn this retrospective case-control study with data from the Danish National Patient Register, all persons aged 18-60 years, with any hospital contact due to a clavicle fracture (DS420) between 1.1.1996 and 31.12.2005 were identified as cases. For each case, five controls, matched on age and sex, were identified. Primary outcome was the first hospital contact with a SAPS diagnosis (DM751-755) registered more than 180 days following fracture. Follow-up was until 01.11.2021. Results21.973 cases and 109.865 controls were included. The incidence of clavicle fractures was 76 fractures per 100.000 persons per years. 23% were female. 1.640 (7.46%) cases and 8.072 (7.35%) controls received a SAPS diagnosis within the following 15-25 years, demonstrating no significant difference in occurrence of SAPS (p=0.56).Mean time from fracture to SAPS diagnosis was shorter for cases compared to controls (4040 vs. 4442 days, p<0.001), and cases were slightly younger when receiving the diagnosis (51.3 vs 53.6 years, p<0.001).1614 cases underwent surgical fixation. This subgroup had a statistically significant higher occurrence of later SAPS diagnosis (205 cases, 13%, p<0.001). ConclusionPersons with a previous clavicle fracture did not have an increased occurrence of receiving a subacromial pain syndrome (SAPS) diagnosis compared to matched controls. However, the diagnosis was given 1-2 years earlier for people with a previous fracture. Based on these findings no strong argument for protraction of the scapula as a major risk-factor for the development of SAPS was found.

MIS-C and Kawasaki disease: Different illnesses or part of the same spectrum?

During COVID-19 pandemic pediatricians have been challenged by the occurrence of the multisystem inflammatory syndrome in children (MIS-C). This condition displays some features similar to those of Kawasaki disease (KD), but was is characterized by clinical signs and symptoms that are infrequent in this illness, such as diarrhea, abdominal pain, neurologic dysfunction and cardiac involvement, especially myocarditis. Many children with MIS-C necessitated ICU admission due to development of multiorgan failure and circulatory shock, usually of myocardial origin. Management is based on the administration of intravenous immunoglobulin, glucocorticoids and, in the most severe forms, anakinra. The clinical similarities between MIS-C and KD have raised an intense debate about whether they represent different illnesses with overlapping clinical features or are part of the same disease spectrum. Most authorities favor the assumption that MIS-C is distinct from KD, based on epidemiological, clinical and immunological differences between the two entities. Others argue that the two disorders may represent a continuum, with some differences in phenotype and severity being related to viral load or strain or magnitude or kinetics of immune response. The present article is aimed to analyze critically the rationale and evidence in favor of the second hypothesis.

Inflammation mediates the relationship between diet quality assessed by healthy eating index-2015 and metabolic syndrome.

Metabolic syndrome is a cluster of metabolic disorders, including obesity, hypertension, hyperglycemia, and abnormal lipid levels. However, researches on the association between overall dietary quality measured by the Healthy Eating Index-2015 (HEI-2015) and the risk of metabolic syndrome is still lacking. This study utilized data from four cycles (2011-2018) of the National Health and Nutrition Examination Survey (NHANES) database, including 17,582 participants. Logistic regression analysis was employed to explore the correlation between HEI and the risk of metabolic syndrome. Additionally, mediation analysis was conducted to examine the effects of Systemic Immune-Inflammation Index (SII) and serum uric acid as potential mediators between HEI and metabolic syndrome risk. Weighted quantile sum (WQS) regression evaluated the composite exposure impact of the 13 components of the HEI on metabolic syndrome, as well as the proportion of their weights. Higher dietary quality measured by HEI-2015 (at the 75th percentile) was negatively correlated with the risk of metabolic syndrome (OR=0.80, 95%CI=0.72-0.89, P=0.003). Higher SII and serum uric acid levels were identified as risk factors for metabolic syndrome (P for trend<0.001). Approximately 37.5% of the effect of HEI on metabolic syndrome occurrence was mediated by SII (Indirect effect=-0.002, 95%CI (-0.003,-0.001), Direct effect=-0.022, 95%CI (-0.0273,-0.015)). Additionally, 25% of the effect of HEI on metabolic syndrome occurrence was mediated by serum uric acid levels (Indirect effect=-0.006, 95%CI (-0.010,-0.012), Direct effect=-0.024, 95%CI (-0.041,-0.009)). WQS regression analysis revealed the highest weighted proportions for seafood and plant proteins (25.20%) and sodium (17.79%), while the weight for whole fruit was the lowest (0.25%). Better dietary quality measured by HEI-2015 was associated with a lower likelihood of metabolic syndrome. Higher SII and serum uric acid levels were identified as risk factors for metabolic syndrome and potential mediators.

In front of bars: the occurrence of burnout syndrome in female police officers

Burnout results from chronic workplace stress that has not been successfully managed. The objective of this study was to investigate the presence of Burnout Syndrome (BS) in female criminal police officers who work in the prison system of Mato Grosso do Sul, in order to understand its triggering factors and levels of manifestation. A quantitative exploratory research was carried out, with a cross-sectional design. The data demonstrated the presence of BS in 14.7% (IC95%: 7.6% to 24.7%) of the participants, especially in younger women, those without children and those who work in the care sector. Among others, there was an association between a high level of emotional exhaustion and working in the care sector, drinking alcohol and not practicing physical activity; the results highlighted the need for attention to the mental health of these professionals and the development of strategies that minimize the harmful effects of prison work.

The occurrence of Restless Leg syndrome and attention deficit hyperactivity disorder: how about the role of age?

The occurrence of Restless Leg syndrome and attention deficit hyperactivity disorder: how about the role of age?

Association Between Thenar Musculature and Carpal Tunnel Syndrome.

Background: Dynamic forces acting on the transverse carpal ligament (TCL) may influence the mechanics of the carpal tunnel (CT), thus affecting the occurrence of CT syndrome (CTS). Previous studies demonstrated an association between muscle overlying the CT and the diagnosis of CTS. Understanding the location of insertion/origin of the thenar musculature will allow mechanical analysis of the forces applied to the TCL during performance of individual tasks. Our purpose was to determine the location of muscle overlying the CT on magnetic resonance imaging (MRI) in CTS and controls. Methods: Case-control study of 21 normal adult wrist MRI scans. MRI measurements were performed on an axial cut at the level of the hook-of-hamate. Median nerve cross-sectional area (CSA), median nerve shape and increased signal intensity within the CT were associated with CTS. The amount and length of muscle crossing the midline and the CT on the same cut was measured and the association with the occurrence of CTS was analysed. Results: We found an inverse relationship between the amount of muscle crossing the midline and the size of the CT, and a direct relationship with occurrence of CTS p less than 0.01, but no differences regarding length of muscle crossing the midline. Conclusions: This study supports an association between the thenar musculature location relative to the CT and the predictors of CTS on MRI. Since the location of muscle origin/insertion is variable, their effect may differ accordingly, therefore, further study is needed to describe the exact location of origin/insertion and its differential dynamic or static effect on the pathogenesis of CTS. Level of Evidence: Level IV (Diagnostic).

Allergic Acute Coronary Syndrome: A Case Report and Literature Review

Introduction: Kounis Syndrome was first described in 1991 by Kounis and Zavras as “the concurrence of chest pain during an allergic reaction, accompanied by clinical laboratory findings of classical angina pectoris caused by inflammatory mediators released during the allergic insult” [1].&#x0D; The mechanism of Kounis Syndrome most likely involves the release of cytokines through mast-cell degranulation, which leads to coronary vasospasm and atheromatous plaque erosion or rupture following the allergic reaction to an allergen.[2]&#x0D; The treatment is specific to acute coronary syndrome and anaphylaxis, with the added complication that the drugs used, while indicated in each of the two disorders separately, may present contradictions when administered jointly in one patient.[3]&#x0D; The purpose of this review is to briefly revise the existing literature regarding its overlooked diagnosis and contradictory joint management of anaphylaxis and acute coronary syndrome.&#x0D; We will conduct a brief review of the current literature on Kounis Syndrome while describing a suspected case of a female patient presented with both anaphylaxis symptoms and angina pectoris.&#x0D; Conclusions: Kounis syndrome is defined as the co-incidental occurrence of an acute coronary syndrome with hypersensitivity reactions following an allergic reaction. Treatment of allergic reactions may be sufficient in type I KS. In contrast, coronary intervention is needed in the other two types, accompanied by vasodilator drugs, including nitrates and calcium antagonists, each of which may have contradictory effects.

The effects that secondary parkinsonian syndromes have on health status

Introduction and aim of work: The parkinsonian syndrome is a component of Parkinson's disease. A thorough neurological examination can detect symptoms belonging to the parkinsonian syndrome. Diagnosis using the Queen Square Brain Bank criteria is based on the presence of bradykinesia along with one additional symptom in the patient. These include muscle rigidity or resting tremors at a frequency of 4-6 Hz, or postural disturbances that cannot be explained by visual, vestibular, cerebellar, or deep sensory disorders. The parkinsonian syndrome can occur in idiopathic Parkinson's disease, hereditary disorders, secondary parkinsonism, or be part of an atypical parkinsonian syndrome. The aim of the study was to discuss the diagnostic features and differences in the occurrence of the parkinsonian syndrome as a component of Parkinson's disease, both within the context of other neurological disorders. Materials and methods: The foundation of the research was medical articles gathered from the Google Scholar database. The studies were conducted by analyzing keywords such as "parkinsonism," "drug-induced parkinsonism," and "vascular parkinsonism." Results: Secondary parkinsonism, or secondary parkinsonism syndrome, can be indicated by clinical features such as: disease onset below the age of 40, abrupt onset, rapid disease progression, symptoms related to medication use, and symptoms associated with the underlying condition. In addition to clinical evaluation, imaging studies are also employed. Various conditions can lead to the development of secondary parkinsonism, including hydrocephalus, brain tumors, encephalitis, cerebral atherosclerosis, traumatic brain injuries, medications, and poisoning. The aforementioned conditions exert different mechanisms of influence on the central nervous system.

Effective therapy for menopausal syndrome without hormones and side effects. Illusion? Reality!

The article describes the problems of the menopausal transition period that cause a woman significant discomfort and reduce her quality of life, characterizes the most common methods of treating menopausal syndrome, and suggests possible reasons for their lack of effectiveness. Femoklim, a fundamentally new anti-menopausal drug for the treatment of complications of age-related hormonal changes, is analyzed. It takes due regard to all possible mechanisms of the occurrence of menopausal syndrome, has a complex versatile effect on the female body, and does not provoke the development of cancer.

Evaluation of Restless Leg Syndrome in Patients with Non-Dialysis Dependent Chronic Kidney Disease at Fatima Memorial Hospital Lahore: A Cross-sectional Study

Objective: To determine the occurrence of restless leg syndrome in individuals with non-dialysis-dependent chronic kidney disease.Study Design: A descriptive cross-sectional study.Place and Duration of Study: The study was carried out at the Outpatient Department (OPD) of Fatima Memorial Hospital, Lahore, Pakistan, from March 2020 to August 2020.Methods: A total of 280 CKD patients not dependent on dialysis were included in the study. The data were collected through interviews containing questions from international restless leg syndrome study group (IRLSSG). Patients were stratified into different stages according to the estimated glomerular filtration rate (eGFR). Restless leg syndrome was diagnosed by analyzing the responses of the interview marked by the examiner. Results: Among 280 patients, 15.7% (n=44) of chronic kidney disease patients were noted to have restless leg syndrome. The syndrome was significantly more frequent in females and was associated with higher CKD stages (Stage V &gt; Stage III and IV). There was no association with either age or BMI.Conclusion: Restless leg syndrome is more common in chronic kidney disease stage V as compared to lower chronic kidney disease stages (III &amp; IV). If untreated, it can affect patients' quality of life and increase the risk of cardiovascular activities.&#x0D; How to cite this: Basit MB, Sabir O, Shahid AH, Kanwal A, Qadri GA, Rizvi N. Evaluation of Restless Leg Syndrome in Patients with NonDialysis Dependent Chronic Kidney Disease at Fatima Memorial Hospital Lahore: A Cross-sectional study. Life and Science. 2024; 5(1): 95-100.doi: http://doi.org/10.37185/LnS.1.1.516

Ceramides and pro-inflammatory cytokines for the prediction of acute coronary syndrome: a multi-marker approach

BackgroundThere is a growing body of evidence supporting the significant involvement of both ceramides and pro-inflammatory cytokines in the occurrence and progression of acute coronary syndrome (ACS).MethodsThis study encompassed 216 participants whose laboratory variables were analysed using standardised procedures. Parameters included baseline serum lipid markers, comprising total cholesterol, low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol, triglycerides (TGs), lipoprotein(a) (LPa), fasting blood glucose, B-natriuretic peptide and hypersensitive C-reactive protein. Liquid chromatography-tandem mass spectrometry measured the concentrations of plasma ceramides. Enzyme-linked immunosorbent assay quantified tumour necrosis factor-α (TNF-α), interleukin 6 (IL6) and IL8. The correlation between ceramides and inflammatory factors was determined through Pearson’s correlation coefficient. Receiver operating characteristic (ROC) curve analysis and multivariate logistic regression evaluated the diagnostic potential of models incorporating traditional risk factors, ceramides and pro-inflammatory cytokines in ACS detection.ResultsAmong the 216 participants, 138 (63.89%) were diagnosed with ACS. Univariate logistic regression analysis identified significant independent predictors of ACS, including age, gender, history of diabetes, smoking history, TGs, TNF-α, IL-6, ceramide (d18:1/16:0), ceramide (d18:1/18:0), ceramide (d18:1/24:0), ceramide (d18:1/20:0) and ceramide (d18:1/22:0). Multivariate logistic regression analysis revealed significant associations between gender, diabetes mellitus history, smoking history, LPa, IL-6, ceramide (d18:1/16:0) and ACS. Receiver operating characteristic analysis indicated that model 4, which integrated traditional risk factors, IL-6 and ceramide (d18:1/16:0), achieved the highest area under the curve (AUC) of 0.827 (95% CI 0.770–0.884), compared with model 3 (traditional risk factors and ceramide [d18:1/16:0]) with an AUC of 0.782 (95% CI 0.720–0.845) and model 2 (traditional risk factors and IL-6), with an AUC of 0.785 (95% CI 0.723–0.846) in ACS detection.ConclusionsIn summary, incorporating the simultaneous measurement of traditional risk factors, pro-inflammatory cytokine IL-6 and ceramide (d18:1/16:0) can improve the diagnostic accuracy of ACS.

Non-targeted metabolomics strategy reveals the role of Geng-Nian-Shu in regulating ferroptosis in perimenopausal syndrome

Ovariectomy (OVX) is usually accompanied by the occurrence of metabolic syndrome. Previous studies have shown that Geng-Nian-Shu (GNS) plays an important regulatory role in perimenopausal syndrome (PMS) rats. GNS is a traditional Chinese medicine (TCM) prescription which composed of Suanzaoren Decoction and Ganmai Dazao Decoction in "Jingui Yaolue" and Siwu Decoction in "Heji Jufang". Recently, metabolomics analysis has been used to identify slight changes in the metabolic profile and to help understand disease progression and therapeutic interventions in PMS. However, the mechanism of GNS in the treatment of PMS is still unknown. We purposed to study the metabolic characteristics of PMS by serum and fecal metabolomics, and revealed the internal mechanism of GNS regulating ferroptosis against PMS. The PMS model was established by surgical removal of 4/5 ovaries of rats. HPLC-Q-TOF/MS was used to analyze the metabolomics of rat plasma and feces to explore the potential mechanism of GNS in PMS. The expression of ferroptosis-related proteins in rat ovaries was detected by tissue Prussian blue staining, Elisa kit and Western blotting. Cluster analysis of differential metabolites in plasma and feces between the control group and the model group showed that organic acids and their derivatives, lipids and lipid molecules were mainly disturbed during PMS in rats. After GNS administration, 17 differential metabolites were adjusted, involving several major pathways, such as the tricarboxylic acid (TCA) cycle, biosynthesis of amino acids and biosynthesis of unsaturated fatty acids. Further, we found that GNS affected ferroptosis in ovarian cells by regulating endogenous substances in OVX rats. Our study provides new insights into the mechanism of OVX-induced metabolic syndrome based on non-targeted metabolomics. It provides new ideas for the development and application of GNS and the diagnosis and treatment of PMS.

Assessment of Quinidine-Induced Torsades de Pointes Risks Using a Whole-Body Physiologically Based Pharmacokinetic Model Linked to Cardiac Ionic Current Inhibition.

The lethality of torsades de pointes (TdP) by drugs is one of main reasons that some drugs were withdrawn from the market. In order to assess drug-induced TdP risks, a model of cardiac ionic current suppression in human ventricular myocytes (ToR-ORd model), combined with the maximum effective free therapeutic plasma concentration or the maximum effective free therapeutic myocyte concentration was often used, with the latter proved to be more relevant and more accurate. We aimed to develop a whole-body physiologically-based pharmacokinetic (PBPK) model, incorporated with a human cardiomyocyte pharmacodynamic (PD) model, to provide a comprehensive assessment of drug-induced TdP risks in normal and specific scenarios. Quinidine served as an example to validate the PBPK-PD model via predicting plasma quinidine concentrations and quinidine-induced changes in QT interval (ΔQTc). The predicted plasma quinidine concentrations and ΔQTc values following oral administration or intravenous administration of quinidine were comparable to clinic observations. Visual predictive checks showed that most of the observed plasma concentrations and ΔQTc values fell within the 5th and 95th percentiles of simulations. The validated PBPK-PD model was further applied to assess the TdP risks using frequencies of early afterdepolarization and long-QT syndrome occurrence in 4 scenarios, such as therapeutic dose, supra-therapeutic dose, alkalosis, and hyperkalemia in 200 human subjects. In conclusion, the developed PBPK-PD model may be applied to predict the quinidine pharmacokinetics and quinidine-induced TdP risks in healthy subjects, but also simulate quinidine-induced TdP risks under disease conditions, such as hypokalemia and alkalosis.

Cellular dynamics following CAR T cell therapy are associated with response and toxicity in relapsed/refractory myeloma

B-cell maturation antigen (BCMA)-targeting chimeric antigen receptor (CAR) T cells revolutionized the treatment of relapsed/refractory multiple myeloma (RRMM). However, data on cellular (CAR) T cell dynamics and the association with response, resistance or the occurrence of cytokine release syndrome (CRS) are limited. Therefore, we performed a comprehensive flow cytometry analysis of 27 RRMM patients treated with Idecabtagene vicleucel (Ide-cel) to assess the expansion capacity, persistence and effects on bystander cells of BCMA-targeting CAR T cells. Additionally, we addressed side effects, like cytokine release syndrome (CRS) and cytopenia. Our results show that in vivo expansion of CD8+ CAR T cells is correlated to response, however persistence is not essential for durable remission in RRMM patients. In addition, our data provide evidence, that an increased fraction of CD8+ T cells at day of leukapheresis in combination with successful lymphodepletion positively influence the outcome. We show that patients at risk for higher-grade CRS can be identified already prior to lymphodepletion. Our extensive characterization contributes to a better understanding of the dynamics and effects of BCMA-targeting CAR T cells, in order to predict the response of individual patients as well as side effects, which can be counteracted at an early stage or even prevented.

Incidence and Risk Factors for the Development of Axial Symptoms Following Posterior Single-Door Laminoplasty: A Retrospective Analysis

PurposePosterior single-door laminoplasty(PSLP) is a widely practiced clinical procedure, but the occurrence of postoperative axial syndrome(AS) remains a significant concern. The aim of this study was to identify risk factors associated with AS and develop a risk prediction model. MethodsClinical data from 226 patients who underwent PSLP between June 2017 and June 2022 were collected. Through Logistic model analysis, the risk factors of AS are clarified and the intensity of each risk factor is explained in the form of forest plot. Subsequently, we constructed a predictive model and plotted Receiver Operating Characteristic(ROC) curves to assess the model's predictive value. ResultsIn the end, 87 cases were diagnosed with AS, resulting in an incidence rate of 38.5%. Logistic regression analysis revealed that preoperative encroachment rate of anterior spinal canal(Pre-op ERASC), intraoperative facet joints destruction(Intra-op FJD), intraoperative open-door angle(Intra-op OA), postoperative loss of cervical curvature(Post-op LCC), and postoperative loss of cervical range of motion(Post-op LCROM) were independent risk factors for AS. Conversely, preoperative cervical curvature(Pre-op CC) and postoperation early function training(Post-op EFT) were protective factors against AS. The Youden index indicated that the cut-off values for Pre-op ERASC and Pre-op CC were 26.6°and 16.5, respectively. The risk prediction model for AS was constructed and a nomogram was plotted. The model has high clinical value. ConclusionPre-op ERASC, Pre-op CC, Intra-op FJD, Intra-op OA, Post-op LCC, Post-op LCROM, and Post-op EFT are independent influencing factors for AS occurrence. The risk model has good practicability.