Conventional Criteria Research Articles

Unraveling the DNA methylation landscape in dog blood across breeds.

DNA methylation is a covalent bond modification that is observed mainly at cytosine bases in the context of CG pairs. DNA methylation patterns reflect the status of individual tissues, such as cell composition, age, and the local environment, in mammals. Genetic factors also impact DNA methylation, and the genetic diversity among various dog breeds provides a valuable platform for exploring this topic. Compared to those in the human genome, studies on the profiling of methylation in the dog genome have been less comprehensive. Our study provides extensive profiling of DNA methylation in the whole blood of three dog breeds using whole-genome bisulfite sequencing. The difference in DNA methylation between breeds was moderate after removing CpGs overlapping with potential genetic variation. However, variance in methylation between individuals was common and often occurred in promoters and CpG islands (CGIs). Moreover, we adopted contextual awareness methodology to characterize DNA primary sequences using natural language processing (NLP). This method could be used to effectively separate unmethylated CGIs from highly methylated CGIs in the sequences that are identified by the conventional criteria. This study presents a comprehensive DNA methylation landscape in the dog blood. Our observations reveal the similar methylation patterns across dog breeds, while CGI regions showed high variations in DNA methylation level between individuals. Our study also highlights the potential of NLP approach for analyzing low-complexity DNA sequences, such as CGIs.

Abstract A003: CD45 positive circulating tumor cells as a prognostic marker in prostate cancer

Abstract Prostate cancer is one of the most common types of cancer among male patients worldwide, making early diagnosis and effective treatment crucial for improving patient survival rates. In this regard, circulating tumor cells (CTCs) have garnered attention as an important biomarker for cancer staging and monitoring treatment response. In prostate cancer, CTCs are typically identified as keratin+/CD45- cells, with additional markers such as PSA or PSMA also being used. The conventional CTC identification way have dismissed CD45+/keratin+ double-positive cells as artifacts by nonspecific binding during the staining process. However, recent studies have reported the presence of CD45+/keratin+ CTCs in various types of cancers, highlighting metastatic potential and their ability to evade the immune system. These findings require re- examination of the role for the double positive CTCs. Therefore, this study aimed to identify the presence of CD45+ CTCs in prostate cancer and to assess their clinical significance. Blood samples were collected from 80 prostate cancer patients, followed by unbiased isolation of CTCs, which were stained using PSA, keratin, and CD45. The detected CTCs were categorized based on CD45 expression, and the clinical relevance of each group was validated using patient information. Through this study, we aimed to confirm whether the CD45+ CTCs can be a clinical indicator in prostate cancer. The results revealed that CD45+ CTCs accounted for 90% of all detected CTCs, likely due to their high immune evasion capabilities. Additionally, in 17% of the patients, only CD45+ CTCs were detected, indicating the potential to expand CTC detection even in patients where CTCs were previously undetected using conventional criteria. The number of CD45+ CTCs was significantly higher in patients with progressive disease compared to those with complete or partial response, showing greater statistical significance than analyses using CD45- CTCs. Furthermore, the number of PSA+ CTCs was closely linked to changes in plasma PSA levels, suggesting they could be used as a supporting marker to enhance the accuracy of current plasma PSA tests. These findings indicate that CD45+ CTCs in prostate cancer are not merely artifacts of nonspecific binding but are indeed meaningful cells closely related to cancer progression. This study suggests that CD45+ CTCs have the potential to be utilized as a prognostic biomarker in prostate cancer. By including CD45+ CTCs, which were previously overlooked in conventional CTC analysis methods, more sensitive and accurate cancer monitoring could be achieved. In-depth future studies on the clinical applicability of CD45+ CTCs could significantly contribute to predicting prognosis and developing personalized treatment strategies for prostate cancer patients. Citation Format: Hyeongjung Woo, Woon-Hae Kim, Hyun Young Shin, Hyerin Jung, Hyung Ho Lee, Minseok S. Kim, Jae Young Joung. CD45 positive circulating tumor cells as a prognostic marker in prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr A003.

Abstract 4127919: Disease-associated variants in DSP -encoded desmoplakin are common, yet low penetrant alleles associated with development of myocarditis and cardiomyopathy at a population level

Intro: DSP- encoded desmoplakin is implicated in a distinct form of arrhythmic cardiomyopathy (ACM), often involving the LV and characterized by myocardial inflammation. Conventional ACM diagnostic criteria has poor sensitivity for DSP -associated ACM, thus highlighting the need to identify the full spectrum of phenotypic risk associated with disease-associated DSP variants. Objective: To analyze the genotypic and phenotypic spectrum of DSP -mediated disease at a large population level. Methods: UK Biobank participants with exome sequencing (ES) were included. Variants were filtered by gene evidence category, yielding 3 groups: predicted deleterious (pDel); subset with predicted loss of function (LOF); and ultra-filtered subset by ClinVar 2* pathogenic/likely pathogenic (P/LP). Phenotypic penetrance was analyzed with DSP -neg individuals as control. Variant location analysis assessed LOFs by susceptibility to nonsense mediated decay region and missenses by amino acid sequence to identify mutational hotspots where P/LPs localize. Results: Out of 200,580 with ES, 1407 DSP carriers had pDel, 168 with LOF, and 44 with ClinVar 2* P/LP. DSP carriers had higher burden of myocarditis, cardiomyopathy (CM), and heart failure. A progressive enrichment in myocarditis and CM was observed by more stringent variant filtering in DSP carriers compared to control. A higher proportion of DSP carriers had myocarditis – 0.28% (4) of the pDels, 1.8% (3) of LOFs, and 4.5% (2) compared to control 0.07% (p<0.05). A parallel trend noted the proportion of DSP carriers with CM growing from 1.4% (19) to 5.4% (9) and 6.8% (3) in the pDel, LOF, and ClinVar 2* P/LPs respectively compared to 0.6% in the control group (p<0.01). Location analysis of missense variants revealed that P/LPs localized in higher proportions (74%) to key domains compared to non-P/LPs (50%; p<0.001), highlighting prognostic value of predicting pathogenicity of missense DSP variants by mutation hotspots. Conclusions: While DSP variants are relatively common in the population, variant presence is associated with low penetrance. Enhancing clinical penetrance with increasingly stringent filtering of DSP variants emphasizes the importance of variant evaluation in clinical risk assessment. This first-in-kind population study of DSP provides insights into novel risk prediction factors, allowing us to predict pathogenicity by type and location of mutation and using variant filtering strategy to better assess phenotypic penetrance.

Comprehensive performance evaluation of steam generating heat pumps for industrial waste heat recovery

Steam generating heat pump (SGHP) is a key technology for industrial decarbonization. For comprehensive evaluation of the feasibility and reliability of SGHP in different industrial sector, the work develops a thorough evaluation model for assessing the performance of SGHP by considering waste heat recovery, CO2 trading value, and pollutant emission cost, in addition to the conventional evaluation criteria. This work presents a thorough comparison of the thermodynamic performance and sustainability of various types of SGHPs across different industrial sector. Additionally, the conflicting relationships between the coefficient of performance (COP) and exergy efficiency are balanced through the application of the technique for order preference by similarity to ideal solution (TOPSIS). The results show that all the indexes of SGHP connected to an open heat pump (SGHPO) with different application scenarios are higher than those of SGHP connected to a flash tank (SGHPF). At the most unfavorable operating condition of the system, the COP minimum value is 1.31 and the exergy efficiency minimum value is 20.42%. These results indicate that replacing the coal-fired boiler with SGHP is feasible and the work could provide theoretical guidance for optimal design and equipment manufacture.

NIMG-48. MEASURABLE DISEASE AS BASELINE CRITERION FOR RESPONSE ASSESSMENT IN GLIOBLASTOMA TRIALS – A COMPARATIVE STUDY OF MRI-BASED (RANO 2.0) VERSUS PET-BASED (PET RANO 1.0) ASSESSMENT

Abstract Response assessment in glioblastoma relies on measuring contrast enhancement on MRI according to RANO 2.0 criteria, and ‘measurable disease’ often serves as inclusion criterion for clinical trials. Recently, criteria based on amino acid PET have been proposed for response assessment in clinical trials (PET RANO 1.0). Here, we compare ‘measurable disease’ as defined by PET RANO 1.0 with the standard MRI-based RANO 2.0 criteria in glioblastoma patients. In this retrospective single-center study, we identified patients with newly diagnosed IDH-wildtype glioblastoma who underwent [18F]FET PET and MRI after resection or biopsy and before chemoradiotherapy. Two independent investigators analyzed ‘measurable disease’ according to PET RANO 1.0 versus MRI-based RANO 2.0 criteria. Additionally, lesion size and uptake intensity, including maximal and mean target-to-background ratio, were assessed. We evaluated 136 patients with 76 cases after biopsy and 60 after microsurgical resection. Using RANO 2.0, 35/76 patients (46.1%) had measurable disease in the biopsy group, and 25/60 (41.6%) in the resected group (median sum of maximum cross-sectional diameters: 39.7mm and 28.0mm, respectively). Utilizing PET RANO 1.0, a significantly higher proportion (overall 123/136, 90.4%; 66/76 (86.8%) after biopsy; 57/60 (95.0%) after resection) had measurable disease (p<0.001). None of the 10 patients in the biopsy group nor of the 3 patients in the resected group without measurable disease on PET had measurable disease on MRI. Contrariwise, 32/41 patients (73.2%) in the biopsy group and 30/35 (85.7%) in the resected group without measurable disease on MRI exhibited measurable disease on PET. PET RANO 1.0 identifies a significantly higher number of patients with ‘measurable disease’ compared to conventional MRI-based criteria in the perioperative period of glioblastoma. PET-based assessment may thus serve as a novel baseline parameter for evaluating treatment response in glioblastoma trials, that may allow the enrollment of larger patient populations. Further validation in prospective trials is warranted.

Desafios diagnósticos e terapêuticos dos transtornos de ansiedade em comorbilidade com o transtorno do espectro Autista: uma revisão integrativa

Anxiety Disorders are common in children and youth with Autism Spectrum Disorder (ASD), affecting 16-40% of cases and exacerbating functional impairment by amplifying problematic behaviours such as deficits in social skills and repetitive behaviours. The article aims to explore the interaction between ASD and Anxiety Disorders, with a focus on prevalence, diagnosis, and treatment. A literature review was conducted using databases such as Medline/PubMed, highlighting the clinical implications for managing these comorbidities. Psychopathology assessment is complex, considering underlying challenges in ASD, including atypical non-verbal responses and limitations in emotional expression, as well as the frequent overlap between anxiety and ASD symptoms. Additionally, anxiety symptoms may deviate from conventional criteria in psychopathological diagnostic manuals. Differential diagnosis between ASD and Social Anxiety is challenging due to similar symptoms. There is a demand for specific therapeutic approaches, such as modified cognitive-behavioural therapy, incorporating emotional recognition and social skills training. Pharmacological interventions require caution due to limited studies on SSRIs and potential side effects in individuals with ASD.

Pharmacokinetics and bioequivalence of ezetimibe tablet in healthy Chinese subjects under fasting and fed conditions.

The purpose of this study is to evaluate the pharmacokinetics (PK) parameters of an ezetimibe 10 mg (test drug) and assess its bioequivalence to the branded reference product in healthy Chinese subjects under fasting and fed conditions. A single-center, randomized, open-label, four-period, two-sequence, full replicate crossover study was conducted in 88 healthy Chinese subjects under fasting or fed conditions. Subjects received a single oral dose of 10 mg ezetimibe tablet as test or reference formulation. There was a minimum 14-day washout period between each dose. Blood samples were collected at prescribed time intervals, the plasma concentration of free ezetimibe and total ezetimibe (ezetimibe + ezetimibe glucuronide) was determined by a validated ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method. Pharmacokinetik and bioavailability parameters were estimated via non-compartmental methods. Adverse events were also recorded. 40 and 48 eligible healthy subjects were enrolled in the fasted and fed study. Under fasting state, total ezetimibe with 90% confidence intervals (CIs) of Cmax, AUC0-t, and AUC0-∞ were 87.17% (81.99 - 92.66%), 95.98% (92.38-99.72%), and 96.04% (91.37 - 100.95%), respectively. Under fed state, total ezetimibe with 90% confidence intervals (CIs) of Cmax, AUC0-t, and AUC0-∞ were 98.71% (90.11 - 108.13%), 98.32% (94.71 - 102.06%), and 97.90% (92.68 - 103.42%), respectively. The 90% CIs of the ratio of geometric means (GMRs) of Cmax, AUC0-t, AUC0-∞ of the test and reference formulation in both fasting and fed conditions fell within the conventional bioequivalence criteria of 0.80 - 1.25. No severe adverse events were observed. The test and reference 10-mg ezetimibe tablets were bioequivalent under fasting and fed conditions in Chinese subjects. Both preparations showed good safety and tolerability.

Validating the Definition of Lumbar Instability-A Cross-Sectional Study with 420 Healthy Volunteers.

Background/Objectives: Low back pain is thought to be caused by lumbar instability. To date, multiple definitions of radiological lumbar instability have been used without verifying the "normal range" of the lumbar segmental mobility. Ideally, normative data for lumbar mobility in healthy individuals are required to establish an acceptable threshold for lumbar instability. This study aims to elucidate (i) the prevalence of so-called radiological lumbar instability at each lumbar spine level in conventional criteria and (ii) a practical radiological threshold for lumbar instability in healthy individuals. Methods: Participants completed a questionnaire and underwent standard active dynamic radiography of the lumbar spine in the standing position. Intervertebral range of motion (IROM) and sagittal translation distance (ΔST) were measured at each intervertebral level. Nachemson's criteria of radiological lumbar instability were applied. Results: This study involved four hundred and twenty participants (249 males and 171 females); 76% (320/420) met the criteria for radiological lumbar instability. The definition of lumbar instability based on IROM and ΔST was achieved by 0.2% and 1.7% of participants at the L5-sacrum (L5-S) level, respectively. Conclusions: The normative data of lumbar mobility were obtained from a large number of participants who had less LBP-related ADL disability. The widely accepted criteria for lumbar instability were not applicable except for the L5-S level. Further studies of lumbar mobility, including patients with severe LBP, might prove the relationship between hypermobility of the lumbar spine and LBP.

Eleven Years of Change: Disease Progression in Biomarker-Defined Sporadic Parkinson's Disease.

Long-term longitudinal data on outcomes in sporadic Parkinson's Disease are limited, especially from cohorts with extensive biological characterization. Recent advances in biomarkers characterization of Parkinson's Disease necessitate an updated examination of long-term progression within contemporary cohorts like the Parkinson's Progression Markers Initiative, which enrolled individuals within 2 years of clinical diagnosis of Parkinson's Disease. Our study leverages the Neuronal Synuclein Disease framework, which defines the disease based on biomarker assessed presence of neuronal alpha-synuclein and dopamine deficit, rather than based on conventional clinical diagnostic criteria. In this study we aimed to provide a comprehensive long-term description of disease progression using the integrated biological and clinical staging system framework. We analyzed data from 344 participants from the sporadic Parkinson's Disease cohort in the Parkinson's Progression Markers Initiative, who met Neuronal Synuclein Disease criteria. We assessed 11-year progression in a spectrum of clinical measures. We used Cox proportional hazards models to assess the association between baseline stage and time to key outcomes, including survival, postural instability (Hoehn & Yahr ≥ 3), loss of independence (Schwab & England < 80%), cognitive decline, and domain-based milestones such as walking and balance, motor complications, autonomic dysfunction, and activities of daily living. Additional analyses were completed to account for death and participant dropout. Biomarker analysis included dopamine transporter binding measures, as well as serum urate, neurofilament light chain and CSF amyloid-beta, phosphorylated tau and total tau. At baseline, despite the cohort consisting of individuals within 2 years of clinical diagnosis, there was clear separation of participants in Neuronal Synuclein Disease Stages (23% Stage 2b, 67% Stage 3, 10% Stage 4). At 11 years, data were available for 153 participants; 35 participants had died over the follow up period. Of retained participants, 59% presented normal cognition, 24% had evidence of postural instability and mean Schwab & England score was 78.5. Serum neurofilament light chain consistently increased over time. No other biofluids had a consistent change in trajectory. Of importance, baseline Neuronal Synuclein Disease Stage predicted progression to clinically meaningful milestones. This study provides data on longitudinal, 11-year progression in Neuronal Synuclein Disease participants within 2 years of clinical diagnosis. We observed better long-term outcomes in this contemporary observational study cohort. It highlights the heterogeneity in the early Parkinson's Disease population as defined by clinical diagnostic criteria and underscores the importance of shifting from clinical to biologically and functionally based inclusion criteria in the design of new clinical trials.

68Ga-grazytracer PET for noninvasive assessment of response to immunotherapy in solid tumors and lymphomas: a phase 1/2 clinical trial

To tackle the clinical challenge of noninvasively assessing immunotherapy efficacy in patients, here we used positron emission tomography (PET) with 68Ga-grazytracer, which targets granzyme B, a crucial effector molecule secreted by activated CD8+ T cells. In this phase 1/2 clinical trial (NCT05000372) involving a diverse cohort of 24 patients with solid tumors and lymphomas who received immunotherapies, including immune checkpoint inhibitors (either alone or with chemotherapies) and chimeric antigen receptor-T cell therapy, we examined the in vivo behaviors of 68Ga-grazytracer. Primary endpoints were safety, biodistribution, granzyme B specificity, and the predictive utility of 68Ga-grazytracer, while secondary endpoint was the relationship between 68Ga-grazytracer uptake and tumor immune phenotype. 68Ga-grazytracer exhibited a safe profile and specifically targeted granzyme B in patients. 68Ga-grazytracer PET showed superior predictive value for short-term prognosis and progression-free survival than those of conventional assessment criteria, including RECIST 1.1 and PERCIST. Moreover, the uptake of 68Ga-grazytracer in tumors was significantly higher in those with a “non-desert” immune phenotype than those with an immune “desert” phenotype, thereby meeting the primary and secondary endpoints of this trial. Collectively, we successfully visualized CD8+ T cell effector function in humans using 68Ga-grazytracer PET, offering insights for enhancing immunotherapy assessment, patient stratification and treatment planning.

Targeting Hypoglycemic Natural Products from the Cloud Forest Plants Using Chemotaxonomic Computer-Assisted Selection.

The cloud forest (CF), a hugely biodiverse ecosystem, is a hotspot of unexplored plants with potential for discovering pharmacologically active compounds. Without sufficient ethnopharmacological information, developing strategies for rationally selecting plants for experimental studies is crucial. With this goal, a CF metabolites library was created, and a ligand-based virtual screening was conducted to identify molecules with potential hypoglycemic activity. From the most promising botanical families, plants were collected, methanolic extracts were prepared, and hypoglycemic activity was evaluated through in vitro enzyme inhibition assays on α-amylase, α-glucosidase, and dipeptidyl peptidase IV (DPP-IV). Metabolomic analyses were performed to identify the dominant metabolites in the species with the best inhibitory activity profile, and their affinity for the molecular targets was evaluated using ensemble molecular docking. This strategy led to the identification of twelve plants (in four botanical families) with hypoglycemic activity. Sida rhombifolia (Malvaceae) stood out for its DPP-IV selective inhibition versus S. glabra. A comparison of chemical profiles led to the annotation of twenty-seven metabolites over-accumulated in S. rhombifolia compared to S. glabra, among which acanthoside D and cis-tiliroside were noteworthy for their potential selective inhibition due to their specific intermolecular interactions with relevant amino acids of DPP-IV. The workflow used in this study presents a novel targeting strategy for identifying novel bioactive natural sources, which can complement the conventional selection criteria used in Natural Product Chemistry.

Revolutionizing LVH detection using artificial intelligence: the AI heartbeat project.

Many studies have shown the utility and promise of artificial intelligence (AI), for the diagnosis of left ventricular hypertrophy (LVH). The aim of the present study was to conduct a meta-analysis to compare the accuracy of AI tools to electrocardiographic criteria, including Sokolow-Lyon and the Cornell, most commonly used for the detection of LVH in clinical practice. Nine studies meeting the inclusion criteria were selected, comprising a sample size of 31 657 patients in the testing and 100 271 in the training datasets. Meta-analysis was performed using a hierarchal model, calculating the pooled sensitivity, specificity, accuracy, along with the 95% confidence intervals (95% CIs). To ensure that the results were not skewed by one particular study, a sensitivity analysis using the 'leave-out-one approach' was adopted for all three outcomes. AI was associated with greater pooled estimates; accuracy, 80.50 (95% CI: 80.4-80.60), sensitivity, 89.29 (95% CI: 89.25-89.33) and specificity, 93.32 (95% CI: 93.26-93.38). Adjusting for weightage of individual studies on the outcomes, the results showed that while accuracy and specificity were unchanged, the adjusted pooled sensitivity was 53.16 (95% CI: 52.92-53.40). AI demonstrates higher diagnostic accuracy and sensitivity compared with conventional ECG criteria for LVH detection. AI holds promise as a reliable and efficient tool for the accurate detection of LVH in diverse populations. Further studies are needed to test AI models in hypertensive populations, particularly in low resource settings.

From ''Dependent Translation" to "Creative Translation'' by Taha Abdurrahman

This paper undertakes a critical and analytical examination of the transformative dimensions of translation as conceptualized by the Moroccan philosopher Taha Abdurrahman. Central to Abdurrahman’s intellectual project is the call to transcend the pervasive Eurocentrism that characterizes contemporary translation theories. Abdurrahman offers a nuanced critique of the translation methodologies employed during the Abbasid period, particularly the uncontextualized appropriation of Greek philosophy. He contends that this approach led to the marginalization of Islamic philosophy, reducing it to a mode of mere transmission and dependency, initially on ancient Greece and subsequently on the modern West. To address these historical inadequacies, Abdurrahman advocates for an innovative translation strategy termed taʾṣīliyya, which translates literally to “authenticating.” This strategy emphasizes a transformative process whereby the source text is integrated into the receiving culture, aligning with its specific epistemic and cultural needs, irrespective of the original context. Abdurrahman posits that this method is essential for fostering an autonomous Arab/Islamic philosophical tradition, one that is not subsumed under external theoretical paradigms, even if this necessitates deviating from conventional criteria of accuracy and faithfulness. This paper critically engages with the theoretical foundations and proposes practical applications of Abdurrahman’s translation paradigm. It situates his framework within the broader historical trajectory of translation in the Arabic intellectual tradition and contemporary translation studies. Furthermore, it interrogates the theoretical and methodological ramifications of eschewing conventional norms of fidelity and accuracy, notwithstanding their entrenched and restrictive nature.

Integrating theory and practice in value engineering within Egypt’s construction industry

Egypt’s economy is unstable, marked by high unemployment, low incomes, and safety concerns, which impede its rapid development. One crucial sector that faces difficulties is construction, dealing with issues like funding shortages, payment disputes, and ineffective project management. Conventional project success criteria strongly emphasize efficient resource use and waste minimization. These criteria are symbolized by the iron triangle of cost, time, and quality. A key instrument for obtaining value for money in building projects is value engineering (VE). Even though VE is acknowledged in theory, its application is still limited in most developing countries, including the Egyptian construction industry. Therefore, to bridge the gap between theory and practice, this paper attempts to investigate the current state and application of VE in Egypt. The study further outlines strategies for integrating VE into construction practices and identifies obstacles to their implementation. This study employed both qualitative and quantitative research approaches to attain the research aim, beginning with a thorough literature review to assess the application of value engineering (VE) in both local and international construction industries. Then, a web-based survey was conducted to gather diverse perspectives on VE’s role and its current practice in Egyptian construction projects. The gathered data were analyzed mainly using descriptive and thematic analysis approaches. The paper’s findings revealed that there is a large gap between VE in theory and practice in Egypt. Reasons include lack of awareness and understanding, time and financial constraints, and resistance to change. Bridging the gap to enhance VE in Egypt includes a focus on the role of educational institutions and training, public awareness and recognition, and early project lifecycle integration. This research has gained insights about VE environment, process, duration, types of projects applied, and effectiveness, aiming to get a comprehensive overview of VE in Egypt. Furthermore, this research has identified a significant gap between VE theory and practice in Egypt. To bridge this gap and enhance the implementation of VE in Egypt, strategies such as focusing on the role of educational institutions, increasing public awareness and recognition, and integrating VE approach early in the project lifecycle are suggested. These findings will guide construction industry practitioners to deeply understand the current state of VE in Egypt and practically integrate VE in the construction industry to minimize unnecessary costs, enhance functionality requirements, and achieve value for client’s money.

Pharmacokinetics, Safety, and Immunogenicity of a Biosimilar of Nivolumab (LY01015): A Randomized, Double-Blind, Parallel-Controlled Phase I Clinical Trial in Healthy Chinese Male Subjects.

Nivolumab (Opdivo®) is the first anti-PD-1 antibody approved in the world. LY01015 is a potential biosimilar of nivolumab. This phase I study aimed to establish the pharmacokinetic equivalence between LY01015 and the original investigational nivolumab (Opdivo®) in healthy Chinese male subjects. Additionally, safety and immunogenicity were assessed. A randomized, double-blind, parallel-controlled, phase I trial was conducted with 176 healthy male adults receiving a single intravenous infusion of LY01015 or nivolumab at 0.3mg/kg. Pharmacokinetics, safety, and immunogenicity were evaluated over a 99-day period. The primary pharmacokinetics endpoint was AUC0-∞, and the secondary pharmacokinetic endpoints included AUC0-t and Cmax. Pharmacokinetic bioequivalence was confirmed using standard equivalence margins of 80.00-125.00%. This study is the first to report on the pharmacokinetics, safety, and immunogenicity of Opdivo® in healthy individuals. The pharmacokinetics profiles of LY01015 and Opdivo® were found to be comparable. The geometric mean ratios (90% confidence intervals) for the AUC0-∞, AUC0-t, and Cmax of LY01015 to Opdivo® were 94.49% (90.29-98.88%), 94.92% (88.73-101.54%), and 96.55% (93.32-99.90%), respectively, falling within the conventional bioequivalence criteria of 80.00-125.00%. The safety and immunogenicity were also comparable between the two groups. LY01015 demonstrated highly similar pharmacokinetics to nivolumab in healthy Chinese male subjects. Both drugs exhibited comparable safety and immunogenicity profiles. This trial is registered at the Chinese Clinical Trial Registry website ( https://www.chictr.org.cn/ #ChiCTR2200064771).

Antibiotic prophylaxis practice in gastrointestinal surgery in five hospitals in southern Benin

BackgroundBenin’s healthcare system is characterized by a lack of local guidelines for surgical antibiotic prophylaxis (SAP), which is essential to prevent surgical site infection. AimTo audit compliance for SAP practices in gastrointestinal surgery. MethodsData were prospectively collected from gastrointestinal surgery departments in five hospitals. Over a four month period, SAP was assessed using five conventional criteria (indication, choice of antibiotic, dosage, timing, and duration of administration) among patients admitted for Altemeier class 1 or 2 procedures. Three guidelines were used as reference: World Health Organization (WHO), American Society of Health-System Pharmacists (ASHP)and French Society of Anaesthesia and Intensive Care Medicine (SFAR). FindingsOf 68 surgical interventions, overall compliance with WHO, ASHP, and SFAR was observed in zero (0.0%), one case (1.5%) and two cases (2.9%), respectively. Compliance with indication varied according to the guidelines: 65 (95.6%) were compliant with WHO and ASHP and 47 cases (69.11%) with SFAR. Among compliant cases, the antibiotics administered were rarely selected according to guidelines: WHO, 2 (2.9%) and ASHP, 2 (2.9%), and SFAR, 3 (4.4%). Drug dosage compliance varied from 20 (29.4%) (SFAR) to 49 (72.0%) (ASHP). Timings were respected in 47 (69.1%; WHO), 45 (66.2%; ASHP) and 9 cases (13.2%; SFAR). The number of cases compliant with antibiotic prophylaxis duration were 13 (19.1%; WHO), 17 (25.0%; ASHP) and 16 (23.5%; SFAR). ConclusionThe SAP compliance rate in gastrointestinal surgery based on the five conventional criteria was very low. SAP guidelines must be implemented appropriately for local bacteriological epidemiology.

18F]FDG PET/CT Integration in Evaluating Immunotherapy for Lung Cancer: A Clinician's Practical Approach.

The advent of immune checkpoint inhibitors (ICIs) has revolutionized the treatment paradigm of lung cancer, resulting in notable enhancements in patient survival. Nevertheless, evaluating treatment response in patients undergoing immunotherapy poses distinct challenges due to unconventional response patterns like pseudoprogressive disease (PPD), dissociated response (DR), and hyperprogressive disease (HPD). Conventional response criteria such as the RECIST 1.1 may not adequately address these complexities. To tackle this issue, novel response criteria such as the iRECIST and imRECIST have been proposed, enabling a more comprehensive assessment of treatment response by incorporating additional scans and considering the best overall response even after radiologic progressive disease evaluation. Additionally, [18F]FDG PET/CT imaging has emerged as a valuable modality for evaluating treatment response, with various metabolic response criteria such as the PERCIMT, imPERCIST, and iPERCIST developed to overcome the limitations of traditional criteria, particularly in detecting pseudoprogression. A multidisciplinary approach involving oncologists, radiologists, and nuclear medicine specialists is crucial for effectively navigating these complexities and enhancing patient outcomes in the era of immunotherapy for lung cancer. In this review, we delineate the key components of these guidelines, summarizing essential aspects for radiologists and nuclear medicine physicians. Furthermore, we provide insights into how imaging can guide the management of individual lung cancer patients in real-world multidisciplinary settings.

Comparison of American Thyroid Association and Conventional Criteria in Diagnosing Hypothyroidism among Pregnant Ladies Attending a Tertiary Care Hospital

ABSTRACT Background: There is continuing debate regarding universal screening, the use of a thyroid-stimulating hormone (TSH) cutoff value, and levothyroxine replacement in frequently encountered issues like subclinical hypothyroidism in pregnancy. The study was intended to compare the American Thyroid Association (ATA)-2011 defined trimester-specific TSH with conventional TSH values in the diagnosis of newly detected hypothyroidism in pregnancy, as there are no trimester-specific reference ranges of TSH in Bangladesh. Methods: This cross-sectional, observational study enrolled 175 pregnant women recruited by convenient sampling from the Department of Obstetrics and Gynecology, BIRDEM General Hospital. As per the study protocol, investigations were advised. TSH, free thyroxine, and antithyroid antibodies were tested using the chemiluminescent technique. Data were analyzed by SPSS version 25. Nonparametric tests were chosen for statistical analysis. Results: The majority (53%) of the participants, were 30 years of age or younger. Using the ATA-2011 defined trimester-specific reference ranges of TSH, 32% had hypothyroidism. While using the conventional criteria (TSH – 0.4–4 mIU/L), hypothyroidism was diagnosed in 20.6% of cases. Conclusions: There is statistically significant discordance in diagnosing hypothyroidism in pregnancy between the two criteria.

Morphological Prediction of CPAP Associated Acute Respiratory Instability.

Multiple mechanisms are involved in the pathogenesis of obstructive sleep apnea (OSA). Elevated loop gain is a key target for precision OSA care and may be associated with treatment intolerance when the upper airway is the sole therapeutic target. Morphological or computational estimation of LG is not yet widely available or fully validated - there is a need for improved phenotyping/endotyping of apnea to advance its therapy and prognosis. This study proposes a new algorithm to assess self-similarity as a signature of elevated loop gain using respiratory effort signals and presents its use to predict the probability of acute failure (high residual event counts) of continuous positive airway pressure (CPAP) therapy. Effort signals from 2145 split-night polysomnography studies from the Massachusetts General Hospital were analyzed for SS and used to predict acute CPAP therapy effectiveness. Logistic regression models were trained and evaluated using 5-fold cross-validation. Receiver operating characteristic (ROC) and precision-recall (PR) curves with AUC values of 0.82 and 0.84, respectively, were obtained. Self-similarity combined with the central apnea index (CAI) and hypoxic burden outperformed CAI alone. Even in those with a low CAI by conventional scoring criteria or only mild desaturation, SS was related to poor therapy outcomes. The proposed algorithm for assessing SS as a measure of expressed high loop gain is accurate, non-invasive, and has the potential to improve phenotyping/endotyping of apnea, leading to more precise sleep apnea treatment strategies.

Information Criteria for Signal Extraction Using Singular Spectrum Analysis: White and Red Noise

In singular spectrum analysis, which is applied to signal extraction, it is of critical importance to select the number of components correctly in order to accurately estimate the signal. In the case of a low-rank signal, there is a challenge in estimating the signal rank, which is equivalent to selecting the model order. Information criteria are commonly employed to address these issues. However, singular spectrum analysis is not aimed at the exact low-rank approximation of the signal. This makes it an adaptive, fast, and flexible approach. Conventional information criteria are not directly applicable in this context. The paper examines both subspace-based and information criteria, proposing modifications suited to the Hankel structure of trajectory matrices employed in singular spectrum analysis. These modifications are initially developed for white noise, and a version for red noise is also proposed. In the numerical comparisons, a number of scenarios are considered, including the case of signals that are approximated by low-rank signals. This is the most similar to the case of real-world time series. The criteria are compared with each other and with the optimal rank choice that minimizes the signal estimation error. The results of numerical experiments demonstrate that for low-rank signals and noise levels within a region of stable rank detection, the proposed modifications yield accurate estimates of the optimal rank for both white and red noise cases. The method that considers the Hankel structure of the trajectory matrices appears to be a superior approach in many instances. Reasonable model orders are obtained for real-world time series. It is recommended that a transformation be applied to stabilize the variance before estimating the rank.