Plasma biomarkers in chronic single moderate-severe traumatic brain injury.

Blood biomarkers are an emerging diagnostic and prognostic tool that reflect a range of neuropathological processes following traumatic brain injury (TBI). Their effectiveness in identifying long-term neuropathological processes after TBI is unclear. Studying biomarkers in the chronic phase is vital because elevated levels in TBI might result from distinct neuropathological mechanisms during acute and chronic phases. Here, we examine plasma biomarkers in the chronic period following TBI and their association with amyloid and tau PET, white matter microarchitecture, brain age and cognition. We recruited participants ≥40 years of age who had suffered a single moderate-severe TBI ≥10 years previously between January 2018 and March 2021. We measured plasma biomarkers using single molecule array technology [ubiquitin C-terminal hydrolase L1 (UCH-L1), neurofilament light (NfL), tau, glial fibrillary acidic protein (GFAP) and phosphorylated tau (P-tau181)]; PET tracers to measure amyloid-ß (18F-NAV4694) and tau neurofibrillary tangles (18F-MK6240); MRI to assess white matter microstructure and brain age; and the Rey Auditory Verbal Learning Test to measure verbal-episodic memory. A total of 90 post-TBI participants (73% male; mean = 58.2 years) were recruited on average 22 years (range = 10-33 years) post-injury, and 32 non-TBI control participants (66% male; mean = 57.9 years) were recruited. Plasma UCH-L1 levels were 67% higher {exp(b) = 1.67, P = 0.018, adjusted P = 0.044, 95% confidence interval (CI) [10% to 155%], area under the curve = 0.616} and P-tau181 were 27% higher {exp(b) = 1.24, P = 0.011, adjusted P = 0.044, 95% CI [5% to 46%], area under the curve = 0.632} in TBI participants compared with controls. Amyloid and tau PET were not elevated in TBI participants. Higher concentrations of plasma P-tau181, UCH-L1, GFAP and NfL were significantly associated with worse white matter microstructure but not brain age in TBI participants. For TBI participants, poorer verbal-episodic memory was associated with higher concentration of P-tau181 {short delay: b = -2.17, SE = 1.06, P = 0.043, 95% CI [-4.28, -0.07]; long delay: bP-tau = -2.56, SE = 1.08, P = 0.020, 95% CI [-4.71, -0.41]}, tau {immediate memory: bTau = -6.22, SE = 2.47, P = 0.014, 95% CI [-11.14, -1.30]} and UCH-L1 {immediate memory: bUCH-L1 = -2.14, SE = 1.07, P = 0.048, 95% CI [-4.26, -0.01]}, but was not associated with functional outcome. Elevated plasma markers related to neuronal damage and accumulation of phosphorylated tau suggest the presence of ongoing neuropathology in the chronic phase following a single moderate-severe TBI. Plasma biomarkers were associated with measures of microstructural brain disruption on MRI and disordered cognition, further highlighting their utility as potential objective tools to monitor evolving neuropathology post-TBI.

A streamlined, resource-efficient immunoprecipitation-mass spectrometry method for quantifying plasma amyloid-ß biomarkers in Alzheimer's disease.

High-performance, resource-efficient methods for plasma amyloid-ß (Aß) quantification in Alzheimer's disease are lacking; existing mass spectrometry-based assays are resource- and time-intensive. We developed a streamlined mass spectrometry method with a single immunoprecipitation step, an optimized buffer system, and ≤75% less antibody requirement. Analytical and clinical performances were compared with an in-house reproduced version of a well-known two-step assay. The streamlined assay showed high dilution linearity (r2>0.99) and precision (< 10% coefficient of variation), low quantification limits (Aß1-40: 12.5 pg/ml; Aß1-42: 3.125 pg/ml), and high signal correlation (r2~0.7) with the two-step immunoprecipitation assay. The novel single-step assay showed more efficient recovery of Aß peptides via fewer immunoprecipitation steps, with significantly higher signal-to-noise ratios, even at plasma sample volumes down to 50 pl. Both assays had equivalent performances in distinguishing non-elevated vs. elevated brain Aß-PET individuals. The new method enables simplified yet robust evaluation of plasma Aß biomarkers in Alzheimer's disease.

Impact of continuous Triazophos exposure on Labeo rohita: Physiological, biochemical, and histological alterations and IBRv2 index assessment.

Pesticides are commonly used in agriculture and aquaculture. Triazophos, an organophosphate-based pesticide, is widely used in agriculture to control many insect pests. Due to its high photochemical stability and mode of action, Triazophos could persist in the aquatic ecosystem and cause toxic effects on non-target organisms. We have studied the potential toxic effects of Triazophos on L. rohita. Primarily, we determined the median lethal concentration (LC50) of Triazophos for 24 and 96 h. Next, we studied acute (96 h, LC50-96 h) toxicity. Then, we studied chronic (35 days, 1/10th LC50-24 h Treatment I: 0.609 mg/L, 1/5th LC50-96 h Treatment II: 1.044 mg/L) toxicity. We analyzed blood biomarkers such as hematology (Hb, Hct, RBC, WBC, MCV, MCH and MCHC), prolactin, cortisol, glucose and protein levels. Concurrently, we analyzed tissue biomarkers such as glycogen, GOT, GPT, LDH and histopathology. IBRv2 index assessment method was also to evaluate the Triazophos toxicity. Studied hematological, hormonal, biochemical and enzymological biomarkers were affected in Triazophos treated groups when compare to the control group. The changes in these biomarkers were statistically significant at the 0.05 alpha level. Triazophos exposed fish shown a severe degenerated primary and secondary lamellae, lamellar fusion, hypertrophy and telangiectasia in the gills. In the hepatic tissue, it caused moderate necrosis, blood congestion, distended sinusoids with minor vacuolation, prominent pyknotic nuclei, hypertrophy, cloudy swelling of cells, lipid accumulation and fibrotic lesions. In the renal tissue, Triazophos caused thickening of Bowman's capsule, hyaline droplets degeneration, irregular renal corpuscle, congestion, cellular swelling, degeneration of tubular epithelium, necrosis, shrunken glomerulus, vacuolated glomerulus, hypertrophy, exudate and edema. IBRv2 analysis suggested that tissue biomarkers are highly sensitive to Triazophos toxicity and prolonged exposure could cause serious health effects like acute toxicity in fish. Triazophos could cause multiorgan toxicity at studied concentrations.

Role of cfDNA and ctDNA to improve the risk stratification and the disease follow-up in patients with endometrial cancer: towards the clinical application.

BACKGROUND: There has been a rise in endometrial cancer (EC) incidence leading to increased mortality. To counter this trend, improving the stratification of post-surgery recurrence risk and anticipating disease relapse and treatment resistance is essential. Liquid biopsy analyses offer a promising tool for these clinical challenges, though the best strategy for applying them in EC must be defined. This study was designed to determine the value of cfDNA/ctDNA monitoring in improving the clinical management of patients with localized and recurrent disease. METHODS: Plasma samples and uterine aspirates (UA) from 198 EC patients were collected at surgery and over time. The genetic landscape of UAs was characterized using targeted sequencing. Total cfDNA was analyzed for ctDNA presence based on the UA mutational profile. RESULTS: High cfDNA levels and detectable ctDNA at baseline correlated with poor prognosis for DFS (p-value < 0.0001; HR = 9.25) and DSS (p-value < 0.0001; HR = 11.20). This remained clinically significant when stratifying tumors by histopathological risk factors. Of note, cfDNA/ctDNA analyses discriminated patients with early post-surgery relapse and the ctDNA kinetics served to identify patients undergoing relapse before any clinical evidence emerged. CONCLUSIONS: This is the most comprehensive study on cfDNA/ctDNA characterization in EC, demonstrating its value in improving risk stratification and anticipating disease relapse in patients with localized disease. CtDNA kinetics assessment complements current strategies to monitor the disease evolution and the treatment response. Therefore, implementing cfDNA/ctDNA monitoring in clinical routines offers a unique opportunity to improve EC management. TRANSLATIONAL RELEVANCE: The study demonstrates that high levels of cfDNA and detectable ctDNA at baseline are strong indicators of poor prognosis. This enables more accurate risk stratification beyond traditional histopathological factors, allowing clinicians to identify high-risk patients who may benefit from more aggressive treatment and closer monitoring. Moreover, longitudinal analysis of cfDNA/ctDNA can detect disease recurrence months before clinical symptoms or imaging evidence appear. This early warning system offers a significant advantage in clinical practice, providing a window of opportunity for early intervention and potentially improving patient outcomes.

Blood immune profiles reveal a CXCR3/CCR5 axis of dysregulation in early sepsis.

We report on a pilot study exploring whether blood immune signatures can reveal early specific indicator profiles for patients meeting sepsis criteria upon hospital admission. We analysed samples of sepsis-suspected patients (N=20) and age-spanning healthy controls (N=12), using flow cytometry-based assays. We measured inflammatory markers from plasma fractions, and immunophenotyped freshly isolated unfixed PBMCs for leukocytes subsets representation and expression of activation markers, including chemokine receptors. We found that beside IL-6 and sCD14, CXCR3 ligands (CXCL9 and CXCL10) separated sepsis-suspected patients from healthy controls. The abundance of CD4+ T cells was significantly reduced in patients, while they displayed substantial losses of CCR5-expressing monocytes and CXCR3/CCR5 double positive T cells. Post-hoc subgrouping of patients according to their sepsis diagnosis on discharge, identified CXCR3/CCR5 double expression on T cells as a separating characteristic for confirmed cases. This work suggests a potential novel axis of dysregulation affecting CXCR3 and CCR5 in early sepsis.

A Complete Response in a Metastatic Melanoma Patient After a Single Dose of Dual Checkpoint Inhibitors Blockade Could Be Predictable: A Case Report.

Cutaneous malignant melanoma is one of the most aggressive forms of skin cancer and thus, a high mortality has been reported over decades. The prognosis for melanoma varies widely based on several factors, including the stage at which it is diagnosed, the location and thickness of the tumor, the patient's age and overall health, and specific genetic factors associated with melanoma. Therapeutic options include checkpoint inhibitors, regardless of V-Raf Murine Sarcoma Viral Oncogene Homolog B status (BRAF), and targeted therapy (anti-BRAF) in the adjuvant or metastatic setting. Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment but predicting which patients will benefit from these therapies remains challenging. Biomarkers like leukocytes, neutrophils, eosinophils, basophils, platelets, and other peripheral blood biomarkers have been investigated for their potential to predict responses to ICIs. Tumor mutational burden (TMB), circulating tumor DNA (ctDNA), and soluble PD-L1 (sPD-L1) have emerged as potential biomarkers for predicting responses to ICIs. Elevated baseline levels of ctDNA and elevated sPD-L1 levels have been associated with worse prognosis in melanoma patients. High TMB is often associated with better responses to ICIs in melanoma. Here we present a case from our department, of a 57-year-old patient, diagnosed in 2019 with stage IV - pT4cNx cM1 (lymph nodes metastases) and suspicion of lung metastases, BRAF wild-type right hallux malignant melanoma. Due to impressive results, first-line treatment with ICIs nivolumab and ipilimumab was the preferred treatment of choice, which showed a favorable response, with regression of oncological disease after the first cycle, and achieving complete response afterward. Unfortunately, the treatment was discontinued due to severe hepatic and pancreatic toxicity, but the favorable response to immunotherapy has been maintained for four years and is ongoing. Identifying predictive biomarkers is important to achieve the best response for the patient, with minimal adverse events, especially if long-term clinical benefit can be reached.

A randomized, triple-blinded, placebo-controlled clinical trial evaluating immune responses of Typhim Vi and PPSV23 vaccines in healthy adults: The PREP study.

Rapid and early identification of emergent infections is essential for delivering prompt clinical care. To advance the development of algorithms for the clinical management of infection identification, we performed a vaccination clinical trial to investigate the potential of using vaccination as a model for studying mild inflammation responses associated with different infections (NCT05346302). We collected data at various time points over 4 weeks from blood samples, wearable devices, and questionnaires. Following a 2-week baseline period, 210 healthy participants, aged 18-40 years, were administered either a Pneumococcal Polysaccharide vaccine (PPSV23), Typhoid Vi Polysaccharide vaccine (Typhim Vi), or placebo. In longitudinal analyses of blood biomarkers, we found that CRP was significantly higher at 2 days post-vaccination, whereas basophils, IL-10, IL-12p40, and MIG were significantly higher at 7 days post-vaccination in the PPSV23 group compared to both other groups (all p < 0.05). MIP-1ß was significantly lower in the PPSV23 group than in the placebo group, while monocytes and MPV were significantly lower in the Typhim Vi group than in the placebo group at 7 days post-vaccination (all p < 0.05). The PPSV3 group showed a higher inflammatory profile, suggesting that PPSV23 induces a stronger immune response compared to Typhim Vi. The distinct immune responses induced by the two vaccines indicate the potential for utilizing vaccines as models for studying inflammation responses associated with different infectious pathogens.

Risk factors and predictive indicators of rupture in cerebral aneurysms.

Cerebral aneurysms are abnormal dilations of blood vessels in the brain that have the potential to rupture, leading to subarachnoid hemorrhage and other serious complications. Early detection and prediction of aneurysm rupture are crucial for effective management and prevention of rupture-related morbidities and mortalities. This review aims to summarize the current knowledge on risk factors and predictive indicators of rupture in cerebral aneurysms. Morphological characteristics such as aneurysm size, shape, and location, as well as hemodynamic factors including blood flow patterns and wall shear stress, have been identified as important factors influencing aneurysm stability and rupture risk. In addition to these traditional factors, emerging evidence suggests that biological and genetic factors, such as inflammation, extracellular matrix remodeling, and genetic polymorphisms, may also play significant roles in aneurysm rupture. Furthermore, advancements in computational fluid dynamics and machine learning algorithms have enabled the development of novel predictive models for rupture risk assessment. However, challenges remain in accurately predicting aneurysm rupture, and further research is needed to validate these predictors and integrate them into clinical practice. By elucidating and identifying the various risk factors and predictive indicators associated with aneurysm rupture, we can enhance personalized risk assessment and optimize treatment strategies for patients with cerebral aneurysms.

Exercise effects on brain health and learning from minutes to months: The brain EXTEND trial.

Despite evidence that aerobic exercise benefits the aging brain, in particular the hippocampus and memory, controlled clinical trials have not comprehensively evaluated effects of aerobic exercise training on human memory in older adults. The central goal of this study was to determine chronic effects of moderate-to-vigorous intensity aerobic exercise on the hippocampus and memory in non-demented, inactive adults ages 55-80 years. We determine effects of aerobic exercise training with a 6-month randomized controlled trial (RCT) comparing 150 min/week of home-based, light intensity exercise with progressive moderate-to-vigorous intensity aerobic exercise. For the first time in a large trial, we examined temporal mechanisms by determining if individual differences in the rapid, immediate effects of moderate intensity exercise on hippocampal-cortical connectivity predict chronic training-related changes over months in connectivity and memory. We examined physiological mechanisms by testing the extent to which chronic training-related changes in cardiorespiratory fitness are a critical factor to memory benefits. The Exercise Effects on Brain Connectivity and Learning from Minutes to Months (Brain-EXTEND) trial is conceptually innovative with advanced measures of hippocampal-dependent learning and memory processes combined with novel capture of the physiological changes, genetic components, and molecular changes induced by aerobic exercise that change hippocampal-cortical connectivity. Given that hippocampal connectivity deteriorates with Alzheimer's and aerobic exercise may contribute to reduced risk of Alzheimer's, our results could lead to an understanding of the physiological mechanisms and moderators by which aerobic exercise reduces risk of this devastating and costly disease.

Machine learning approach to predict blood-secretory proteins and potential biomarkers for liver cancer using omics data.

Identifying non-invasive blood-based biomarkers is crucial for early detection and monitoring of liver cancer (LC), thereby improving patient outcomes. This study leveraged computational approaches to predict potential blood-based biomarkers for LC. Machine learning (ML) models were developed using selected features from blood-secretory proteins collected from the curated databases. The logistic regression (LR) model demonstrated the optimal performance. Transcriptome analysis across 7 LC cohorts revealed 231 common differentially expressed genes (DEGs). The encoded proteins of these DEGs were compared with the ML dataset, revealing 29 proteins overlapping with the blood-secretory dataset. The LR model also predicted 29 additional proteins as blood-secretory with the remaining protein-coding genes. As a result, 58 potential blood-secretory proteins were obtained. Among the top 20 genes, 13 common hub genes were identified. Further, area under the receiver operating characteristic curve (ROC AUC) analysis was performed to assess the genes as potential diagnostic blood biomarkers. Six genes, ESM1, FCN2, MDK, GPC3, CTHRC1 and COL6A6, exhibited an AUC value higher than 0.85 and were predicted as blood-secretory. This study highlights the potential of an integrative computational approach for discovering non-invasive blood-based biomarkers in LC, facilitating for further validation and clinical translation. SIGNIFICANCE: Liver cancer is one of the leading causes of premature death worldwide, with its prevalence and mortality rates projected to increase. Although current diagnostic methods are highly sensitive, they are invasive and unsuitable for repeated testing. Blood biomarkers offer a promising non-invasive alternative, but their wide dynamic range of protein concentration poses experimental challenges. Therefore, utilizing available omics data to develop a diagnostic model could provide a potential solution for accurate diagnosis. This study developed a computational method integrating machine learning and bioinformatics analysis to identify potential blood biomarkers. As a result, ESM1, FCN2, MDK, GPC3, CTHRC1 and COL6A6 biomarkers were identified, holding significant promise for improving diagnosis and understanding of liver cancer. The integrated method can be applied to other cancers, offering a possible solution for early detection and improved patient outcomes.

Blood-based protein biomarkers during the acute ischemic stroke treatment window: a systematic review.

Background: Rapid and accurate acute ischemic stroke (AIS) diagnosis is needed to expedite emergent thrombolytic and mechanical thrombectomy treatment. Changes in blood-based protein biomarkers during the first 24 h of AIS, the time window for treatment, could complement imaging techniques and facilitate rapid diagnosis and treatment. Methods: We performed a systematic review according to PRISMA guidelines. MEDLINE, EMBASE, Cochrane Library, and Web of Science databases were searched for eligible studies comparing levels of blood-based protein biomarkers in AIS patients with levels in healthy controls and stroke mimics. Protein biomarkers from the following pathophysiological categories were included: neurovascular inflammation (MMP-9, TNF-alpha), endothelial integrity (VCAM-1, ICAM-1), cell migration (E-Selectin, P-Selectin, L-Selectin), markers of glial and neuronal origin (GFAP, S100, S100B, NSE), and cardiac dysfunction (BNP, NT-proBNP). The literature search was limited to English-language publications before November 7th, 2023. Results: A total of 61 studies from 20 different countries were identified, which included in total, 4,644 AIS patients, 2,242 stroke mimics, and 2,777 controls. Studies investigating TNF-alpha, MMP-9, VCAM-1, ICAM-1, E-Selectin, L-Selectin, GFAP, NSE, and S100B showed pronounced methodological heterogeneity, making between-study comparisons difficult. However, in 80% of NT-proBNP and BNP studies, and all P-selectin studies, higher biomarker levels were observed in AIS patients compared to healthy controls and/or patients with stroke mimics. Conclusion: None of the biomarkers included showed sufficient evidence for additional diagnostic benefit for AIS. Comprehensive standardized global multicenter studies are needed to (1) permit comparability, (2) enable valid statements about protein-based biomarkers, and (3) reflect real-world scenarios.

Clinical Application of Blood Biomarkers in Neurodegenerative Diseases-Present and Future Perspectives.

Neurodegenerative diseases are a group of complex diseases characterized by a progressive loss of neurons and degeneration in different areas of the nervous system. They share similar mechanisms, such as neuroinflammation, oxidative stress, and mitochondrial injury, resulting in neuronal loss. One of the biggest challenges in diagnosing neurodegenerative diseases is their heterogeneity. Clinical symptoms are usually present in the advanced stages of the disease, thus it is essential to find optimal biomarkers that would allow early diagnosis. Due to the development of ultrasensitive methods analyzing proteins in other fluids, such as blood, huge progress has been made in the field of biomarkers for neurodegenerative diseases. The application of protein biomarker measurement has significantly influenced not only diagnosis but also prognosis, differentiation, and the development of new therapies, as it enables the recognition of early stages of disease in individuals with preclinical stages or with mild symptoms. Additionally, the introduction of biochemical markers into routine clinical practice may improve diagnosis and allow for a stratification group of people with higher risk, as well as an extension of well-being since a treatment could be started early. In this review, we focus on blood biomarkers, which could be potentially useful in the daily medical practice of selected neurodegenerative diseases.

Association of early blood-based biomarkers and six-month functional outcomes in conventional severity categories of traumatic brain injury: capturing the continuous spectrum of injury.

BACKGROUND: Traumatic brain injury is conventionally categorised as mild, moderate, or severe on the Glasgow Coma Scale (GCS). Recently developed biomarkers can provide more objective and nuanced measures of the extent of brain injury. METHODS: Exposure-response relationships were investigated in 2479 patients aged ≥16 enrolled in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) prospective observational cohort study. Neurofilament protein-light (NFL), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), and glial fibrillary acidic protein (GFAP) were assayed from serum sampled in the first 24 h; concentrations were divided into quintiles within GCS severity groups. Relationships with the Glasgow Outcome Scale-Extended were examined using modified Poisson regression including age, sex, major extracranial injury, time to sample, and log biomarker concentration as covariates. FINDINGS: Within severity groups there were associations between biomarkers and outcomes after adjustment for covariates: GCS 13-15 and negative CT imaging (relative risks [RRs] from 1.28 to 3.72), GCS 13-15 and positive CT (1.21-2.81), GCS 9-12 (1.16-2.02), GCS 3-8 (1.09-1.94). RRs were associated with clinically important differences in expectations of prognosis. In patients with GCS 3 (RRs 1.51-1.80) percentages of unfavourable outcome were 37-51% in the lowest quintiles of biomarker levels and reached 90-94% in the highest quintiles. Similarly, for GCS 15 (RRs 1.83-3.79), the percentages were 2-4% and 19-28% in the lowest and highest biomarker quintiles, respectively. INTERPRETATION: Conventional TBI severity classification is inadequate and underestimates heterogeneity of brain injury and associated outcomes. The adoption of circulating biomarkers can add to clinical assessment of injury severity. FUNDING: European Union 7th Framework program (EC grant 602150), Hannelore Kohl Stiftung, One Mind, Integra LifeSciences, Neuro-Trauma Sciences, NIHR Rosetrees Trust.

Dietary flavonoid intake and risk of hormone-related cancers: A population-based prospective cohort study.

BACKGROUND: Dietary flavonoids may have potential effects on hormone-related cancers (HRCs) due to their anti-cancer properties via regulating hormones and suppressing inflammation and oxidative stress. We aimed to examine the association of flavonoid intake with risks of HRCs and whether this association was mediated by blood biomarkers involved in biological mechanisms. METHODS: This prospective cohort study from UK Biobank included 187,350 participants free of cancer when the last dietary recall was completed. The dietary intakes of flavonoids and subclasses were assessed using 24-hour dietary recalls. Venous blood was collected at baseline and assayed for biomarkers of inflammation, hormones, and oxidative stress. Hazard ratios (HR) and 95 % confidential intervals (CI) for the associations between flavonoid intake and HRCs risk were estimated by the cause-specific Cox proportional hazards model. The role of blood biomarkers in the flavonoids-HRCs association was investigated through mediation analysis. RESULTS: Over a median follow-up of 9.5 years, 3,392 female breast cancer, 417 ovarian cancer, 516 endometrial cancer, 4,305 prostate cancer, 45 testicular cancer, and 146 thyroid cancer cases were documented. Compared to the lowest quintile, multivariable-adjusted HRs (95 % CIs) in the highest quintile of total flavonoid intake were 0.89 (0.80-0.99) for breast cancer, 0.68 (0.50-0.92) for ovarian cancer, and 0.88 (0.80-0.98) for female-specific cancers. For subclasses, intakes of flavonols and anthocyanidins were inversely associated with the risk of female-specific cancers (Ptrend <0.05). Anthocyanidin intake was positively related to prostate cancer risk, whereas isoflavone intake was inversely linked to thyroid cancer risk (Ptrend <0.05). Additionally, certain biomarkers of inflammation, hormones and oxidative stress jointly mediated the association of flavonoid intake with the risk of female-specific cancers and prostate cancer. CONCLUSIONS: Our findings highlighted the importance of dietary flavonoids for the prevention of HRCs in the general population, providing epidemiological evidence for dietary guidelines.

Predictive factors for manual detorsion success in testicular torsion.

PURPOSE: In cases of testicular torsion (TT), prompt diagnosis and treatment are highly associated with organ salvage, and manual detorsion (MD) is a recommended maneuver as a first intervention. In our study, we aimed to investigate the effect of predictive factors of TT in predicting the success of MD. METHODS: A retrospective, 2-center study was conducted on patients diagnosed with TT between January 2015 and 2024. Demographic, clinical, ultrasound, and laboratory characteristics at presentation were analyzed. MD was routinely performed as the first intervention in all patients. Predictive parameters were compared in the MD success and failure groups. Univariate and multiple logistic regression analysis was used to identify risk factors for MD failure. RESULTS: A total of 94 patients were included in the study. The median age of the patients was 20 (IQR: 12-69) years, and the median symptom duration was 6 (IQR: 4-12) hours. MD confirmed by Doppler ultrasonography was successful in 52 (55.3%) patients and unsuccessful in 42 (44.7%). Age, symptom duration, Testicular Workup for Ischemia and Suspected Torsion (TWIST) score, TWIST risk groups, WBC, neutrophil, monocyte counts, and Monocyte/Eosinophil ratio (MER) were statistically different between the two groups. In multiple logistic regression analysis, the risk factors for failure of MD were found to be being over 18 years of age, the duration of symptoms being longer than 9 h, and MER > 28. CONCLUSION: Current urology guidelines suggest that age, symptom duration, and MER are reliable predictors of the success of MD, which is recommended in all cases of TT.

FCER1G as a novel immune-associated blood biomarker in cardiogenic stroke.

Background: Cardioembolic stroke (CE) exhibits the highest recurrence rate and mortality rate among all subtypes of cerebral ischemic stroke (CIS), yet its pathogenesis remains uncertain. The immune system plays a pivotal role in the progression of CE. Growing evidence indicates that several immune-associated blood biomarkers may inform the causes of stroke. The study aimed to identify new immune-associated blood biomarkers in patients with CE and create an online predictive tool in distinguishing CE from noncardioembolic stroke (non-CE) in CIS. Methods: Gene expression profiles that were publicly available were obtained from the Gene Expression Omnibus (GEO). The identification of differentially expressed genes (DEGs) was conducted using the Limma package. The hub module and hub genes were identified through the application of weighted gene coexpression network analysis (WGCNA). In order to identify potential diagnostic biomarkers for CE, both the random forest (RF) model and least absolute shrinkage and selection operator (LASSO) regression analysis were employed. Concurrently, the CIBERSORT algorithm was employed to evaluate the infiltration of immune cells in CE samples and examine the correlation between the biomarkers and the infiltrating immune cells. The diagnostic gene expression in blood samples was confirmed using qRT-PCR in a self-constructed dataset. Univariate and multiple logistic regression analyses were used to identify the risk factors for CE. Subsequently, the mathematical model of the nomogram was employed via Java's "Spring Boot" framework to develop the corresponding online tool, which was then deployed on a cloud server utilizing "nginx". Results: Eleven differentially expressed genes (DEGs) that were upregulated and seven DEGs that were downregulated were identified. Through bioinformatics analysis and clinical sample verification, it was discovered that Fc Fragment of IgE Receptor Ig (FCER1G) could serve as a novel potential blood biomarker for CE. FCER1G, along with other risk factors associated with CE, were utilized to develop a nomogram. The training and validation sets, which consisted of 65 CIS patients, yielded areas under the curve (AUCs) of 0.9722 and 0.9689, respectively. These results indicate a high level of precision in risk delineation by the nomogram. Furthermore, the associated online predictive platform has the potential to serve as a more efficacious and appropriate predictive instrument (https://www.origingenetic.com/CardiogenicStroke-FCER1G) for distinguishing between CE and non-CE. Conclusion: Blood biomarker FCER1G has the potential to identify patients who are at a higher risk of cardioembolism and direct the search for occult AF.The utilization of this online tool is anticipated to yield significant implications in terms of distinguishing between CE and non-CE, as well as enhancing the optimization of treatment decision support.

A multi-ethnic proteomic profiling analysis in Alzheimer's disease identifies the disparities in dysregulation of proteins and pathogenesis.

Background: Alzheimer's disease (AD) is the most common type of dementia that affects the elderly population. Lately, blood-based proteomics have been intensively sought in the discovery of AD biomarkers studies due to the capability to link external environmental factors with the development of AD. Demographic differences have been shown to affect the expression of the proteins in different populations which play a vital role in the degeneration of cognitive function. Method: In this study, a proteomic study focused on Malaysian Chinese and Malay prospects was conducted. Differentially expressed proteins (DEPs) in AD patients and normal controls for Chinese and Malays were identified. Functional enrichment analysis was conducted to further interpret the biological functions and pathways of the DEPs. In addition, a survey investigating behavioural practices among Chinese and Malay participants was conducted to support the results from the proteomic analysis. Result: The variation of dysregulated proteins identified in Chinese and Malay samples suggested the disparities of pathways involved in this pathological condition for each respective ethnicity. Functional enrichment analysis supported this assumption in understanding the protein-protein interactions of the identified protein signatures and indicate that differentially expressed proteins identified from the Chinese group were significantly enriched with the functional terms related to Aß/tau protein-related processes, oxidative stress and inflammation whereas neuroinflammation was associated with the Malay group. Besides that, a significant difference in sweet drinks/food intake habits between these two groups implies a relationship between sugar levels and the dysregulation of protein APOA4 in the Malay group. Additional meta-analysis further supported the dysregulation of proteins TF, AHSG, A1BG, APOA4 and C4A among AD groups. Conclusion: These findings serve as a preliminary understanding in the molecular and demographic studies of AD in a multi-ethnic population.

Clinical application of plasma P-tau217 to assess eligibility for amyloid-lowering immunotherapy in memory clinic patients with early Alzheimer's disease.

BACKGROUND: With the approval of disease-modifying treatments (DMTs) for early Alzheimer's disease (AD), there is an increased need for efficient and non-invasive detection methods for cerebral amyloid-ß (Aß) pathology. Current methods, including positron emission tomography (PET) and cerebrospinal fluid (CSF) analysis, are costly and invasive methods that may limit access to new treatments. Plasma tau phosphorylated at threonine-217 (P-tau217) presents a promising alternative, yet optimal cutoffs for treatment eligibility with DMTs like aducanumab require further investigation. This study evaluates the efficacy of one- and two-cutoff strategies for determining DMT eligibility at the Butler Hospital Memory & Aging Program (MAP). METHODS: In this retrospective, cross-sectional diagnostic cohort study, we first developed P-tau217 cutoffs using site-specific and BioFINDER-2 training data, which were then tested in potential DMT candidates from Butler MAP (total n = 150). ROC analysis was used to calculate the area under the curve (AUC) and accuracy of P-tau217 interpretation strategies, using Aß-PET/CSF testing as the standard of truth. RESULTS: Potential DMT candidates at Butler MAP (n = 50), primarily diagnosed with mild cognitive impairment (n = 29 [58%]) or mild dementia (21 [42%]), were predominantly Aß-positive (38 [76%]), and half (25 [50%]) were subsequently treated with aducanumab. Elevated P-tau217 predicted cerebral Aß positivity in potential DMT candidates (AUC = 0.97 [0.92-1]), with diagnostic accuracy ranging from 0.88 (0.76-0.95, p = 0.028) to 0.96 (0.86-1, p < .001). When using site-specific cutoffs, a subset of DMT candidates (10%) exhibited borderline P-tau217 (between 0.273 and 0.399 pg/mL) that would have potentially required confirmatory testing. CONCLUSIONS: This study, which included participants treated with aducanumab, confirms the utility of one- and two-cutoff strategies for interpreting plasma P-tau217 in assessing DMT eligibility. Using P-tau217 could potentially replace more invasive diagnostic methods, and all aducanumab-treated participants would have been deemed eligible based on P-tau217. However, false positives remain a concern, particularly when applying externally derived cutoffs that exhibited lower specificity which could have led to inappropriate treatment of Aß-negative participants. Future research should focus on prospective validation of P-tau217 cutoffs to enhance their generalizability and inform standardized treatment decision-making across diverse populations.

A Randomized, Crossover Trial Assessing Appetite, Energy Metabolism, Blood Biomarkers, and Ad Libitum Food Intake Responses to a Mid-Morning Pecan Snack vs. an Equicaloric High-Carbohydrate Snack in Healthy Volunteers with Overweight/Obesity.

BACKGROUND: The differential effects of pecans versus other popular snack foods on appetite and blood markers of metabolism and satiety have not been well studied. This study investigated the effects of a single mid-morning snack of pecans or tortilla chips on subjective appetite, food intake, blood measures of hormones and metabolites, and resting energy expenditure. METHODS: Twenty participants with overweight and obesity were enrolled in a within-participants, randomized crossover trial. Participants had indwelling catheters placed for blood sampling and were fed a standardized breakfast, followed two hours later by a 250 kcal snack of either pecans or tortilla chips, and then by a self-selected lunch. Visual analog scale (VAS) appetite measures, blood markers, and energy expenditure were taken at intervals after food consumption. RESULTS: VAS ratings, energy, food intake and macronutrient composition did not differ between treatment conditions, but glucose and insulin were significantly more elevated after tortilla chips. Free fatty acids (FFA), triglycerides (TG), peptide YY (PYY), and glucagon-like peptide-1 (GLP-1) were higher after consuming pecans compared to tortilla chips. CONCLUSIONS: Pecan consumption improves postprandial glucose and insulin profiles which would be beneficial to individuals at risk of developing type 2 diabetes. Further studies are needed to investigate whether increased relative secretion of PYY and GLP-1 after eating pecans versus tortilla chips may affect subjective appetite and energy intake if consumed chronically.

Assessment of leukocyte and systemic inflammation index ratios in dyslipidemia patients with dry eye disease: a retrospective case‒control study.

BACKGROUND: Dry eye disease (DED) is a complication of dyslipidemia (DLP) that is caused by metabolic syndrome and increased inflammation. This research aimed to assess leukocyte and systemic inflammation index ratios as potential biomarkers for systemic inflammation in dyslipidemia patients with dry eye disease (DLP-DED). METHODS: Several blood biomarkers were studied in 32 patients with DLP-DED (study group) and 63 patients with DLP-only (control group). The evaluated blood biomarkers included specific systemic inflammation index ratios, such as the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), and neutrophil-to-lymphocyte and platelet ratio (NLPR), and lipid profiles, such as total cholesterol (TC), high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), triglyceride (TG), albumin (ALB), and C-reactive protein (CRP) levels. RESULTS: Lymphocyte levels were significantly greater in the DLP-DED group than in the DLP-only group (P = 0.044). In addition, a significant negative correlation between HDL and the NLPR (P = 0.007; r= -0.428) and a significant negative correlation between the serum ALB concentration and the PLR (P = 0.008; r= -0.420) were identified as potential inflammatory predictors of DLP-DED. CONCLUSION: The findings of this study suggest that patients with DLP-DED may benefit from routine blood monitoring of their elevated lipid profile and blood inflammatory biomarkers, such as CRP, leukocytes, and systemic inflammation index ratios (NLR, PLR, MLR, and NLPR), to reduce the complications of DLP on ocular health. The correlation data suggest that the NLPR, PLR, serum ALB concentration, and serum HDL concentration may be valuable inflammatory biomarkers in DLP-DED patients. More research is required to ascertain the significance of the NLR, PLR, MLR, and NLPR and the additive role that leukocytes play.