Search

A rapid and precise modified QuEChERS method for extraction was developed for simultaneous quantitation of multi-class pesticide residues in human biological matrices, viz. blood, serum and urine. In the modified QuEChERS method, targeted analytes in biological sample were extracted using acidified solution of acetonitrile and ethyl acetate along with anhydrous MgSO4. The collected aqueous layer was evaporated and dispersive solid-phase extraction clean-up was performed. The pesticide residues were assessed using gas chromatography–tandem mass spectrometry with multiple reaction monitoring mode. The developed method was validated as per European Union SANTE/12682/2019 guidelines and the evaluated method validation parameters, viz. linearity, limit of detection, limit of quantitation, accuracy, %relative standard deviation and matrix effect were found to be satisfactory. The proposed method is easy, comprehensible and efficient for simultaneous analysis of diverse range of pesticide residues within similar class. Hence, the present solitary method can be used for systematic analysis of biological samples. [ABSTRACT FROM AUTHOR]

Background: Between 5 and 50% of atypical hemolytic uremic syndrome (aHUS) cases in children are caused by autoantibodies against complement factor H (CFH). Given the acquired autoimmune nature of the disease, plasma exchange (PE) and various immunosuppressive treatments have been used. More recently, eculizumab has been proposed. Methods: In this multicenter, retrospective study, we report outcomes of 12 children with anti-FH antibody-associated HUS treated with eculizumab associated with various immunosuppressive regimens. Results: Patients were treated with eculizumab for 15.5 [9.5;23.0] months and 3 received PE or IgG adsorption. Three patients received mycophenolate mofetil (MMF) alone, 1 patient received MMF and steroids, 1 patient received MMF and rituximab, 3 patients received MMF/steroids and rituximab, and 4 patients did not receive any immunosuppression. Anti-FH antibody levels significantly decreased but no difference was observed based on the immunosuppressive regimen. Eculizumab was discontinued in 7/10 patients after 11 [7.5;15.5] months and MMF in 6/8 patients after 36 [35;40] months. Anti-FH titers at MMF discontinuation ranged from 257 to 3425 UI/L. None of these patients relapsed and eGFR at last follow-up was above 70 mL/min/1.73 m2 in all patients. Conclusions: Eculizumab is effective and safe in inducing and maintaining remission in aHUS secondary to anti-FH antibodies and renders reduction of anti-FH titers less urgent. Anti-FH antibody titers decreased in most patients irrespective of the immunosuppressive treatment chosen, so that a strategy consisting of combining eculizumab with MMF monotherapy seems sufficient at least in non-Indian or less severe forms of anti-FH antibody-associated HUS. [ABSTRACT FROM AUTHOR]

Background: Immune Thrombocytopenia Purpura (ITP) is a hematological disorder, where its primary cause is unknown. This can be triggered through any secondary underlying diseases or other environmental agents such as drugs, vaccination, natural viral infections etc. After the introduction of COVID-19 vaccines, a 4-fold increase in ITP cases was observed globally. Many of the COVID-19 vaccines such as m-RNA and viral-vector vaccines already demonstrated a cause-effect relationship between the event of ITP and immunization. Case presentation: A 54 year old diabetic patient presented to the hospital with complaints of gum bleeding and fatigue. He was diagnosed with severe ITP following COVID-19 vaccination with a platelet count of 5000 cumm. Initially his condition was considered as idiopathic and the COVID-19 vaccine exposure (13 days prior to the clinical presentation) was not suspected. Later the immunization timeline and onset of the reaction was traced by his hematologist. The patient underwent multiple platelet transfusions and was given corticosteroid therapy. The patient was followed for a period of 1 year and throughout the follow-up period the patient had fluctuating platelets count, especially after tapering steroids. Conclusion: ITP in this case is found to have a consistent causal association to COVID-19 vaccination as per the World Health Organization Causality assessment algorithm and is categorized under vaccine product related reactions. One year follow-up conducted showed that the thrombocytopenia following COVID-19 vaccine may be prolonged. [ABSTRACT FROM AUTHOR]

Heat transfer improvement in industrial and engineering applications has attained a lot of interest from investigators in recent years. This is due to fact that the improvement of the much equipment in this sector such as electronic devices and heat exchangers are highly dependent on rate of the thermal transport. Due to their low thermal conductivity, base fluids such as oil, water, and ethylene glycol limit the heat transport rate. Because of its many functions in various manufacturing problems, hybrid convective heat transfer has piqued the interest of many engineers. The heat transfer flow with magnetic dipole features in hybrid nanoparticles $ ({\textrm{CuO} - \textrm{CoF}{\textrm{e}_\textrm{2}}{\textrm{O}_\textrm{4}}}) $ (CuO − CoF e 2 O 4 ) , $ ({\textrm{CoF}{\textrm{e}_\textrm{2}}{\textrm{O}_\textrm{4}}}) $ (CoF e 2 O 4 ) and used blood as a base fluid over a spreading sheet are investigated. The flow problem of PDEs is transmuted into structure of nonlinear ODEs by employing suitable similarity conversions. For numerical solution, bvp4c solver in MATLAB computing software is considered. Graphs depict the effects of important controlling flow parameters on velocity distribution and temperature profile. Furthermore, the table discusses the thermo physical characteristics of nanoparticles and hybrid nanofluids. [ABSTRACT FROM AUTHOR]

As the innermost monolayer of the vasculature, endothelial cells (ECs) serve as the interface for multiplex signal transduction. Directly exposed to blood-borne factors, both endogenous and exogenous, ECs actively mediate vascular homeostasis and represent a therapeutic target against cardiometabolic diseases. ECs act as the first-line gateway between gut-derived substances and vasculature. Additionally, ECs convert blood flow-exerted hemodynamic forces into downstream biochemical signaling to modulate vascular pathophysiology. Besides, ECs can sense other forms of stimuli, like cell extrusion, thermal stimulation, photostimulation, radiation, magnetic field, noise, and gravity. Future efforts are still needed to deepen our understanding on endothelial biology. [Display omitted] • ECs are interfaces for multiplex signal transduction in the vasculature. • ECs are gatekeepers between gut-derived substances and vasculature. • ECs convert hemodynamic forces to biochemical signals, mediating vasopathology. • ECs are sensitive to various environmental stimuli. [ABSTRACT FROM AUTHOR]

The article revisits marantic endocarditis, or non-bacterial thrombotic endocarditis (NBTE), highlighting a case series of 111 patients from the Mayo Clinic, primarily diagnosed through transesophageal echocardiography. Topics discussed include the high incidence of systemic embolism, the prevalence of mitral valve involvement, and the correlation between cancer types and significant valve regurgitation.

Background: During adolescence, individuals experience rapid changes in physical, cognitive, emotional, behavioral, and social aspects of their life. Due to certain risks which arise during the developmental period of adolescence, substance use and addiction are encountered as a public health problem. Studies on biochemical parameters and puberty are limited. In this study, adolescents with substance use disorder were compared to healthy individuals in terms of sociodemographic characteristics and serum irisin and caspase-9 levels. Methods: The study group consisted of 32 adolescents with substance use disorder and the control group was comprised of 29 healthy adolescents. The sociodemographic characteristics and serum irisin and caspase-9 levels of the groups were compared. Results: The study group performed lower than the control group in terms of duration of education and continuing education. Serum caspase-9 levels were found to be significantly higher in the study group compared to the control group. There was no difference in irisin levels of the groups. Conclusions: It was determined that substance use negatively affects educational aspects and may also lead to certain destructive biological effects in adolescents. In order to reveal the effect of substance use on adolescents in more detail, studies with larger samples are needed. [ABSTRACT FROM AUTHOR]

In the context of the modern industrialisation of poultry farming and the growing global demand for quail products, fnding effective ways to improve bird productivity and health is extremely important. One of the most promising approaches is the use of nanoselenium bio-compounds with probiotics to improve the metabolic parameters of quail. Recent research has focused on the synthesis of selenium nanoparticles using probiotics as an environmentally friendly alternative to traditional methods of adding inorganic selenium to quail feed. The advantage of this approach is the production of a biocompatible and bioavailable form of selenium, which provides birds with the ability to effectively absorb and use selenium for various physiological processes. The effect of innovative feed additives, such as selenium nanoconjugates and probiotics, on various metabolic parameters in quail was investigated. These include the activity of antioxidant defence enzymes, indicators of carbonyl oxidative stress, protein carbonyl levels and protein metabolism. By adding selenium nanoconjugates and probiotics to quail feed, an improvement in antioxidant defence mechanisms was observed, leading to a reduction in oxidative stress and an improvement in the overall health of the birds. In addition, improved protein metabolism as a result of these supplements has been shown to have a positive impact on the productivity and quality of quail products. In summary, investing in high quality feed additives such as selenium nanoconjugates and probiotics is a strategic approach to improving the productivity and proftability of poultry production. By taking advantage of the benefts of nanotechnology and probiotics, farmers can optimise the health and productivity of their poultry flocks, meeting the growing demand for quail products on the national market.

Amidst the burgeoning interest in rotating magnetic fields (RMF) within biological research, there remains a notable gap in the scientific evidence concerning the long-term safety of RMF. Thus, this study aimed to investigate the safety of protracted exposure to a 0.2 T, 4 Hz RMF over 10 months in mice. Two-month-old female C57BL/6 mice were randomly allocated to either the RMF group (exposed to 0.2 T, 4 Hz real RMF) or the SHAM group (exposed to 0 T, 4 Hz sham RMF). Throughout the experiment, the murine weekly body weights were recorded, and their behavioral traits were assessed via open field tests. In the final month, a comprehensive evaluation of the murine overall health was conducted, encompassing analyses of blood parameters, histomorphological examination of major organs, and skeletal assessments using X-ray and micro-CT imaging. The murine immune system and lipid metabolism were evaluated through immunochip analysis and metabolomics. Notably, no discernible adverse effects with RMF exposure were observed. Murine body weight, locomotor behavior, organ histomorphology, and skeletal health remained unaffected by RMF. Blood analysis revealed subtle changes in hormone and lipid levels between the SHAM and RMF groups, yet these differences did not reach statistical significance. Moreover, RMF led to elevated serum interleukin-28 (IL-28) levels, albeit within the normal range, and modest alterations in serum lipid metabolites. Conclusively, mice exposed to the 0.2 T, 4 Hz RMF for 10 months displayed no significant signs of chronic toxicity, indicating its potential clinical application as a physical therapy.

Abstract Synucleinopathies such as Parkinson’s disease (PD) are defined by the accumulation and aggregation of the α-synuclein protein in neurons, glia and other tissues. We have previously shown that destabilization of α-synuclein tetramers is associated with familial PD due to SNCA mutations and demonstrated brain-region specific alterations of α-synuclein multimers in sporadic PD patients following the classical Braak spreading theory. In this study, we assessed relative levels of disordered and higher-ordered multimeric forms of cytosolic α-synuclein in blood from familial PD with G51D mutations and sporadic PD patients. We used an adapted in vitro-cross-linking protocol for human EDTA-whole blood. The relative levels of higher-ordered α-synuclein tetramers were diminished in blood from familial PD and sporadic PD patients compared to controls. Interestingly, the relative amount of α-synuclein tetramers was already decreased in asymptomatic G51D carriers, supporting the hypothesis that α-synuclein multimer destabilization precedes the development of clinical PD. Our data, therefore suggest that measuring α-synuclein tetramers in blood may have potential as a facile biomarker assay for early detection and quantitative tracking of PD progression.

Bladder cancer (BCa) is the most common malignancy of the urinary system. It has a high recurrence rate and requires longterm follow-up. Significant advances in BCa research have been made in recent years; however, the initial diagnosis and follow-up of BCa relies on cystoscopy, which is an invasive and expensive procedure. Over the past decade, liquid biopsies (e.g., blood and urine) have proven to be highly efficient methods for the discovery of BCa biomarkers. This noninvasive sampling method is used to analyze unique tumor components released into body fluids and enables serial sampling and longitudinal monitoring of tumor progression. Several liquid biopsy biomarkers have been studied extensively and have shown promising results in the clinical applications of BCa, including early detection, microscopic residual disease detection, recurrence prediction, and treatment response. Therefore, this review aims to provide an update on various new liquid biopsy markers and the advantages and current limitations of liquid biopsy in the diagnosis of BCa.

Abstract Background Recently developed blood markers for Alzheimer's disease (AD) detection have high accuracy but usually require ultra-sensitive analytic tools not commonly available in clinical laboratories, and their performance in clinical practice is unknown. Methods We analyzed plasma samples from 290 consecutive participants that underwent lumbar puncture in routine clinical practice in a specialized memory clinic (66 cognitively unimpaired, 130 participants with mild cognitive impairment, and 94 with dementia). Participants were classified as amyloid positive (A +) or negative (A-) according to CSF Aβ1–42/Aβ1–40 ratio. Plasma pTau217, pTau181, Aβ1–42 and Aβ1–40 were measured in the fully-automated LUMIPULSE platform. We used linear regression to compare plasma biomarkers concentrations between A + and A- groups, evaluated Spearman’s correlation between plasma and CSF and performed ROC analyses to assess their diagnostic accuracy to detect brain amyloidosis as determined by CSF Aβ1–42/Aβ1–40 ratio. We analyzed the concordance of pTau217 with CSF amyloidosis. Results Plasma pTau217 and pTau181 concentration were higher in A + than A- while the plasma Aβ1–42/Aβ1–40 ratio was lower in A + compared to A-. pTau181 and the Aβ1–42/Aβ1–40 ratio showed moderate correlation between plasma and CSF (Rho = 0.66 and 0.69, respectively). The areas under the ROC curve to discriminate A + from A- participants were 0.94 (95% CI 0.92–0.97) for pTau217, and 0.88 (95% CI 0.84–0.92) for both pTau181 and Aβ1–42/Aβ1–40. Chronic kidney disease (CKD) was related to increased plasma biomarker concentrations, but ratios were less affected. Plasma pTau217 had the highest fold change (× 3.2) and showed high predictive capability in discriminating A + from A-, having 4–7% misclassification rate. The global accuracy of plasma pTau217 using a two-threshold approach was robust in symptomatic groups, exceeding 90%. Conclusion The evaluation of blood biomarkers on an automated platform exhibited high diagnostic accuracy for AD pathophysiology, and pTau217 showed excellent diagnostic accuracy to identify participants with AD in a consecutive sample representing the routine clinical practice in a specialized memory unit.

Abstract This study introduces a novel approach in the realm of liquid biopsies, employing a 3D Mueller-matrix (MM) image reconstruction technique to analyze dehydrated blood smear polycrystalline structures. Our research centers on exploiting the unique optical anisotropy properties of blood proteins, which undergo structural alterations at the quaternary and tertiary levels in the early stages of diseases such as cancer. These alterations manifest as distinct patterns in the polycrystalline microstructure of dried blood droplets, offering a minimally invasive yet highly effective method for early disease detection. We utilized a groundbreaking 3D MM mapping technique, integrated with digital holographic reconstruction, to perform a detailed layer-by-layer analysis of partially depolarizing dry blood smears. This method allows us to extract critical optical anisotropy parameters, enabling the differentiation of blood films from healthy individuals and prostate cancer patients. Our technique uniquely combines polarization-holographic and differential MM methodologies to spatially characterize the 3D polycrystalline structures within blood films. A key advancement in our study is the quantitative evaluation of optical anisotropy maps using statistical moments (first to fourth orders) of linear and circular birefringence and dichroism distributions. This analysis provides a comprehensive characterization of the mean, variance, skewness, and kurtosis of these distributions, crucial for identifying significant differences between healthy and cancerous samples. Our findings demonstrate an exceptional accuracy rate of over $$90\%$$ 90 % for the early diagnosis and staging of cancer, surpassing existing screening methods. This high level of precision and the non-invasive nature of our technique mark a significant advancement in the field of liquid biopsies. It holds immense potential for revolutionizing cancer diagnosis, early detection, patient stratification, and monitoring, thereby greatly enhancing patient care and treatment outcomes. In conclusion, our study contributes a pioneering technique to the liquid biopsy domain, aligning with the ongoing quest for non-invasive, reliable, and efficient diagnostic methods. It opens new avenues for cancer diagnosis and monitoring, representing a substantial leap forward in personalized medicine and oncology.

Abstract Background The hypothalamus plays a crucial role in the health and productivity of dairy cows, yet studies on its functionality and its impact on peripheral circulation in these animals are relatively scarce, particularly regarding dietary interventions. Therefore, our study undertook a comprehensive analysis, incorporating both metabolomics and transcriptomics, to explore the effects of a grain-based diet on the functionality of the hypothalamus, as well as on blood and milk in dairy cows. Results The hypothalamic metabolome analysis revealed a significant reduction in prostaglandin E2 (PGE2) level as a prominent response to the grain-based diet introduction. Furthermore, the hypothalamic transcriptome profiling showed a notable upregulation in amino acid metabolism due to the grain-based diet. Conversely, the grain-based diet led to the downregulation of genes involved in the metabolic pathway from lecithin to PGE2, including phospholipase A2 (PLA2G4E, PLA2G2A, and PLA2G12B), cyclooxygenase-2 (COX2), and prostaglandin E synthase (PTGES). Additionally, the plasma metabolome analysis indicated a substantial decrease in the level of PGE2, along with a decline in adrenal steroid hormones (tetrahydrocortisol and pregnenolone) following the grain-based diet introduction. Analysis of the milk metabolome showed that the grain-based diet significantly increased uric acid level while notably decreasing PGE2 level. Importantly, PGE2 was identified as a critical metabolic marker in the hypothalamus, blood, and milk in response to grain intervention. Correlation analysis demonstrated a significant correlation among metabolic alterations in the hypothalamus, blood, and milk following the grain-based diet. Conclusions Our findings suggest a potential link between hypothalamic changes and alterations in peripheral circulation resulting from the introduction of a grain-based diet.

Background: Acute hemorrhage is fatal in equines with a complication of severe hypovolemic shock that causes a sudden death in such cases. Aim: This study was designed to report the influences of acute bleeding in conscious non-sedated donkeys (Equus asinus) on the hematobiochemical variables, acid-base, blood gas elements and markers of inflammation and bone metabolism. Methods: Eight healthy donkeys were used where a total of 900mL of whole blood was collected. Five blood samples were collected from each animal: just before collection of blood (T0); (2) 30min (T1), 60min (T2), 120min (T3) and 240min (T4) later. The blood panels including total white blood cells, lymphocytes, neutrophils, red blood cell counts (RBCs), HCT, hemoglobin (Hg) and RBCs indices were measured. Biochemical parameters and electrolytes were evaluated. The activity of aspartate aminotransferase (AST), creatine kinase (CK) and γ-glutamyl transferase (GGT) were also determined. Complete acid-base and blood gas panel were assessed. Serum amyloid A (SAA), haptoglobin (Hp), osteocalcin (OC), bone alkaline phosphatase (b-ALP) and pyridinoline cross-links (PYD) were measured. Results: The RBCs, Hg and HCT increased significantly at points T1, T2 and T3 compared to T0. The concentrations of total proteins and albumin decreased significantly at points T3 and T4. The blood urea nitrogen concentrations increased significantly at T4. Creatinine concentrations increased significantly at T2 and T3. The AST, GGT and CK decreased significantly. On the other hand, glucose increased significantly at T3 and T4. The pH decreased significantly at points T1, T2, T3 and T4. The PCO2 increased significantly at T 3 and T4. The BE, HCO3 and TCO2 values decreased significantly at T2, T3 and T4. Contrary, the AG increased significantly at points T3 and T4. The potassium increased significantly at T1-T4 and chloride decreased significantly at T3 and T4. Lactate showed significant increases at T1-T4. The SAA, Hp, OC, b-ALP and PYD did not differ significantly at T1-T4. Conclusion: In conscious non-sedated donkeys, induced bleeding resulted in significant changes in the hematobiochemical elements, the acid-base status and blood gas and electrolyte parameters. However, it did not change the markers of inflammation and bone metabolism. [Open Vet J 2024; 14(5.000): 1146-1153]

Aims: To assess the alterations in cell-specific DNA methylation associated with chondroitin sulphate response using peripheral blood collected from Kashin-Beck disease (KBD) patients before initiation of chondroitin sulphate treatment. Methods: Peripheral blood samples were collected from KBD patients at baseline of chondroitin sulphate treatment. Methylation profiles were generated using reduced representation bisulphite sequencing (RRBS) from peripheral blood. Differentially methylated regions (DMRs) were identified using MethylKit, while DMR-related genes were defined as those annotated to the gene body or 2.2-kilobase upstream regions of DMRs. Selected DMR-related genes were further validated by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) to assess expression levels. Tensor composition analysis was performed to identify cell-specific differential DNA methylation from bulk tissue. Results: This study revealed 21,060 hypermethylated and 44,472 hypomethylated DMRs, and 13,194 hypermethylated and 22,448 hypomethylated CpG islands for differential global methylation for chondroitin sulphate treatment response. A total of 12,666 DMR-related genes containing DMRs were identified in their promoter regions, such as CHL1 (false discovery rate (FDR) = 2.11 × 10-11), RIC8A (FDR = 7.05 × 10-4), and SOX12 (FDR = 1.43 × 10-3). Additionally, RIC8A and CHL1 were hypermethylated in responders, while SOX12 was hypomethylated in responders, all showing decreased gene expression. The patterns of cell-specific differential global methylation associated with chondroitin sulphate response were observed. Specifically, we found that DMRs located in TESPA1 and ATP11A exhibited differential DNA methylation between responders and non-responders in granulocytes, monocytes, and B cells. Conclusion: Our study identified cell-specific changes in DNA methylation associated with chondroitin sulphate response in KBD patients. Cite this article: Bone Joint Res 2024;13(5):237–246.

The investigation and clarification of the properties of surface-functionalized superparamagnetic nanoparticles in a biological environment are key challenges prior to their medical applications. In the present work, electron paramagnetic resonance spectroscopy (EPR) combined with the spin labeling technique was utilized to better understand the behavior of nitroxides attached to magnetite nanoparticles dispersed in body fluid. EPR spectra of spin-labeled, silane-coated Fe3O4 nanoparticles in human serum and whole blood were recorded and analyzed for both room- and low-temperature values. In all cases, the obtained EPR signal consisted of a broad line from magnetite cores and a characteristic signal from the attached 4-Amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO). Even for liquid samples, the anisotropic components of magnetic tensors did not fully average out, which was reflected in the differences in the intensity of three narrow hyperfine lines from nitroxide. At 230 K the irregular slow-motion signal from the attached radical was also simulated using the EasySpin toolbox, which allowed to determine the parameters related to magnetic tensors and the dynamics of the spin label. The study showed that the anisotropy of the motion of the spin label 4-amino-TEMPO reflects its interactions with the surrounding medium and the manner of the attachment of the nitroxide to the surface of nanoparticles.

Aims: Gram-negative infections are associated with comorbid patients, but outcomes are less well understood. This study reviewed diagnosis, management, and treatment for a cohort treated in a tertiary spinal centre. Methods: A retrospective review was performed of all gram-negative spinal infections (n = 32; median age 71 years; interquartile range 60 to 78), excluding surgical site infections, at a single centre between 2015 to 2020 with two- to six-year follow-up. Information regarding organism identification, antibiotic regime, and treatment outcomes (including clinical, radiological, and biochemical) were collected from clinical notes. Results: All patients had comorbidities and/or non-spinal procedures within the previous year. Most infections affected lumbar segments (20/32), with Escherichia coli the commonest organism (17/32). Causative organisms were identified by blood culture (23/32), biopsy/aspiration (7/32), or intraoperative samples (2/32). There were 56 different antibiotic regimes, with oral (PO) ciprofloxacin being the most prevalent (13/56; 17.6%). Multilevel, contiguous infections were common (8/32; 25%), usually resulting in bone destruction and collapse. Epidural collections were seen in 13/32 (40.6%). In total, five patients required surgery, three for neurological deterioration. Overall, 24 patients improved or recovered with a mean halving of CRP at 8.5 days (SD 6). At the time of review (two to six years post-diagnosis), 16 patients (50%) were deceased. Conclusion: This is the largest published cohort of gram-negative spinal infections. In older patients with comorbidities and/or previous interventions in the last year, a high level of suspicion must be given to gram-negative infection with blood cultures and biopsy essential. Early organism identification permits targeted treatment and good initial clinical outcomes; however, mortality is 50% in this cohort at a mean of 4.2 years (2 to 6) after diagnosis. Cite this article: Bone Jt Open 2024;5(5):435–443.

Abstract High-altitude cerebral edema (HACE) is a severe neurological condition that can occur at high altitudes. It is characterized by the accumulation of fluid in the brain, leading to a range of symptoms, including severe headache, confusion, loss of coordination, and even coma and death. Exosomes play a crucial role in intercellular communication, and their contents have been found to change in various diseases. This study analyzed the metabolomic characteristics of blood exosomes from HACE patients compared to those from healthy controls (HCs) with the aim of identifying specific metabolites or metabolic pathways associated with the development of HACE conditions. A total of 21 HACE patients and 21 healthy controls were recruited for this study. Comprehensive metabolomic profiling of the serum exosome samples was conducted using ultraperformance liquid chromatography–tandem mass spectrometry (UPLC‒MS/MS). Additionally, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was performed to identify the metabolic pathways affected in HACE patients. Twenty-six metabolites, including ( +)-camphoric acid, choline, adenosine, adenosine 5′-monophosphate, deoxyguanosine 5′-monophosphate, guanosine, and hypoxanthine-9-β-D-arabinofuranoside, among others, exhibited significant changes in expression in HACE patients compared to HCs. Additionally, these differentially abundant metabolites were confirmed to be potential biomarkers for HACE. KEGG pathway enrichment analysis revealed several pathways that significantly affect energy metabolism regulation (such as purine metabolism, thermogenesis, and nucleotide metabolism), estrogen-related pathways (the estrogen signaling pathway, GnRH signaling pathway, and GnRH pathway), cyclic nucleotide signaling pathways (the cGMP-PKG signaling pathway and cAMP signaling pathway), and hormone synthesis and secretion pathways (renin secretion, parathyroid hormone synthesis, secretion and action, and aldosterone synthesis and secretion). In patients with HACE, adenosine, guanosine, and hypoxanthine-9-β-D-arabinofuranoside were negatively correlated with height. Deoxyguanosine 5′-monophosphate is negatively correlated with weight and BMI. Additionally, LPE (18:2/0:0) and pregnanetriol were positively correlated with age. This study identified potential biomarkers for HACE and provided valuable insights into the underlying metabolic mechanisms of this disease. These findings may lead to potential targets for early diagnosis and therapeutic intervention in HACE patients.

Abstract The use of biomarker-led clinical trial designs has been transformative for investigating amyloid-targeting therapies for Alzheimer’s disease (AD). The designs have ensured the correct selection of patients on these trials, supported target engagement and have been used to support claims of disease modification and clinical efficacy. Ultimately, this has recently led to approval of disease-modifying, amyloid-targeting therapies for AD; something that should be noted for clinical trials investigating tau-targeting therapies for AD. There is a clear overlap of the purpose of biomarker use at each stage of clinical development between amyloid-targeting and tau-targeting clinical trials. However, there are differences within the potential context of use and interpretation for some biomarkers in particular measurements of amyloid and utility of soluble, phosphorylated tau biomarkers. Given the complexities of tau in health and disease, it is paramount that therapies target disease-relevant tau and, in parallel, appropriate assays of target engagement are developed. Tau positron emission tomography, fluid biomarkers reflecting tau pathology and downstream measures of neurodegeneration will be important both for participant recruitment and for monitoring disease-modification in tau-targeting clinical trials. Bespoke design of biomarker strategies and interpretations for different modalities and tau-based targets should also be considered.

Abstract Background High blood eosinophils seem to predict exacerbations and response to inhaled corticosteroids (ICS) treatment in patients with chronic obstructive pulmonary disease (COPD). The aim of our study was to prospectively evaluate for 2 years, blood and sputum eosinophils in COPD patients treated with bronchodilators only at recruitment. Methods COPD patients in stable condition treated with bronchodilators only underwent monitoring of lung function, blood and sputum eosinophils, exacerbations and comorbidities every 6 months for 2 years. ICS was added during follow-up when symptoms worsened. Results 63 COPD patients were enrolled: 53 were followed for 1 year, 41 for 2 years, 10 dropped-out. After 2 years, ICS was added in 12/41 patients (29%) without any statistically significant difference at time points considered. Blood and sputum eosinophils did not change during follow-up. Only FEV1/FVC at T0 was predictive of ICS addition during the 2 year-follow-up (OR:0.91; 95% CI: 0.83–0.99, p = 0.03). ICS addition did not impact on delta (T24-T0) FEV1, blood and sputum eosinophils and exacerbations. After 2 years, patients who received ICS had higher blood eosinophils than those in bronchodilator therapy (p = 0.042). Patients with history of ischemic heart disease increased blood eosinophils after 2 years [p = 0.03 for both percentage and counts]. Conclusions Blood and sputum eosinophils remained stable during the 2 year follow-up and were not associated with worsened symptoms or exacerbations. Almost 30% of mild/moderate COPD patients in bronchodilator therapy at enrollment, received ICS for worsened symptoms in a 2 year-follow-up and only FEV1/FVC at T0 seems to predict this addition. History of ischemic heart disease seems to be associated with a progressive increase of blood eosinophils.

Abstract Background Breast cancers exhibit considerable heterogeneity in their biology, immunology, and prognosis. Currently, no validated, serum protein-based tools are available to evaluate the prognosis of patients with early breast cancer. Methods The study population consisted of 521 early-stage breast cancer patients with a median follow-up of 8.9 years. Additionally, 61 patients with breast fibroadenoma or atypical ductal hyperplasia were included as controls. We used a proximity extension assay to measure the preoperative serum levels of 92 proteins associated with inflammatory and immune response processes. The invasive cancers were randomly split into discovery (n = 413) and validation (n = 108) cohorts for the statistical analyses. Results Using LASSO regression, we identified a nine-protein signature (CCL8, CCL23, CCL28, CSCL10, S100A12, IL10, IL10RB, STAMPB2, and TNFβ) that predicted various survival endpoints more accurately than traditional prognostic factors. In the time-dependent analyses, the prognostic power of the model remained rather stable over time. We also developed and validated a 17-protein model with the potential to differentiate benign breast lesions from malignant lesions (Wilcoxon p

Introduction: Neutrophils play a complex and important role in the immunopathology of TB. Data suggest they are protective during early infection but become a main driver of immunopathology if infection progresses to active disease. Neutrophils are now recognized to exist in functionally diverse states, but little work has been done on how neutrophil states or subsets are skewed in TB disease. Methods: To address this, we carried out comprehensive phenotyping by flow cytometry of neutrophils in the blood and airways of individuals with active pulmonary TB with and without HIV co-infection recruited in Durban, South Africa. Results: Active TB was associated with a profound skewing of neutrophils in the blood toward phenotypes associated with activation and apoptosis, reduced phagocytosis, reverse transmigration, and immune regulation. This skewing was also apparently in airway neutrophils, particularly the regulatory subsets expressing PDL-1 and LOX-1. HIV co-infection did not impact neutrophil subsets in the blood but was associated with a phenotypic change in the airways and a reduction in key neutrophil functional proteins cathelicidin and arginase 1. Discussion: Active TB is associated with profound skewing of blood and airway neutrophils and suggests multiple mechanisms by which neutrophils may exacerbate the immunopathology of TB. These data indicate potential avenues for reducing neutrophil-mediated lung pathology at the point of diagnosis. [ABSTRACT FROM AUTHOR]

Background: Recently developed blood markers for Alzheimer's disease (AD) detection have high accuracy but usually require ultra-sensitive analytic tools not commonly available in clinical laboratories, and their performance in clinical practice is unknown. Methods: We analyzed plasma samples from 290 consecutive participants that underwent lumbar puncture in routine clinical practice in a specialized memory clinic (66 cognitively unimpaired, 130 participants with mild cognitive impairment, and 94 with dementia). Participants were classified as amyloid positive (A +) or negative (A-) according to CSF Aβ1–42/Aβ1–40 ratio. Plasma pTau217, pTau181, Aβ1–42 and Aβ1–40 were measured in the fully-automated LUMIPULSE platform. We used linear regression to compare plasma biomarkers concentrations between A + and A- groups, evaluated Spearman's correlation between plasma and CSF and performed ROC analyses to assess their diagnostic accuracy to detect brain amyloidosis as determined by CSF Aβ1–42/Aβ1–40 ratio. We analyzed the concordance of pTau217 with CSF amyloidosis. Results: Plasma pTau217 and pTau181 concentration were higher in A + than A- while the plasma Aβ1–42/Aβ1–40 ratio was lower in A + compared to A-. pTau181 and the Aβ1–42/Aβ1–40 ratio showed moderate correlation between plasma and CSF (Rho = 0.66 and 0.69, respectively). The areas under the ROC curve to discriminate A + from A- participants were 0.94 (95% CI 0.92–0.97) for pTau217, and 0.88 (95% CI 0.84–0.92) for both pTau181 and Aβ1–42/Aβ1–40. Chronic kidney disease (CKD) was related to increased plasma biomarker concentrations, but ratios were less affected. Plasma pTau217 had the highest fold change (× 3.2) and showed high predictive capability in discriminating A + from A-, having 4–7% misclassification rate. The global accuracy of plasma pTau217 using a two-threshold approach was robust in symptomatic groups, exceeding 90%. Conclusion: The evaluation of blood biomarkers on an automated platform exhibited high diagnostic accuracy for AD pathophysiology, and pTau217 showed excellent diagnostic accuracy to identify participants with AD in a consecutive sample representing the routine clinical practice in a specialized memory unit. [ABSTRACT FROM AUTHOR]

Background: Rehabilitation after critical illness improves functional outcomes, but in some countries, specialised rehabilitation wards are closed during holidays. Objective: This study aimed to compare the length of hospital stay, discharge destination and survival in sepsis patients who were hospitalised during and outside holiday periods over 10 years. Method: In a registry-based cohort study, 1,552 consecutive patients who had their first-time admission due to sepsis between 2003 and 2013 were included. Length of hospital stay, discharge destination and survival in patients hospitalised during (n=481% and outside (n=1071% holiday periods were compared. Results: Patients hospitalised during holiday periods had a longer length of stay compared with patients hospitalised outside holiday periods (median 9 vs. 7 days, p<0.001, mean 14.5 vs. 11.2 days, 95% CI 1.675.0, p<0.001%. The difference was even larger in a subgroup of patients (n=332% who were admitted to an intensive care unit or a monitoring unit (median 13.5 vs. 9 days, p<0.001, mean 22.8 vs. 15.2 days, 95% CI 2.5712.8, p=0.004%. There were no differences in discharge destination or survival between the groups. Conclusion: We found that closing a rehabilitation ward during holidays prolongs the length of hospital stay in patients with sepsis. This may lead to increased costs and increased risk of complications, and it may be a burden for sepsis patients who want to return to normal life as soon as possible. [ABSTRACT FROM AUTHOR]

Simple Summary: Circulating tumor DNA (ctDNA) is a non-invasive method of identifying and monitoring genitourinary cancers, including prostate, bladder, and renal cell carcinoma, via blood or urine samples. CtDNA introduces a potential method for cancer screening. If detected, ctDNA may reveal genetic alterations that have prognostic value. As treatment options for genitourinary cancers progress towards accounting for tumor genetic profiles, ctDNA may predict which patients have improved responses to therapeutic targets. CtDNA may play an important role in surveillance after tumor resection and may be used to reveal mechanisms of treatment resistance. The clinical utility of ctDNA has yet to be established. Significantly more research is needed to understand the utility ctDNA has in clinical practice. CtDNA is emerging as a non-invasive clinical detection method for several cancers, including genitourinary (GU) cancers such as prostate cancer, bladder cancer, and renal cell carcinoma (RCC). CtDNA assays have shown promise in early detection of GU cancers, providing prognostic information, assessing real-time treatment response, and detecting residual disease and relapse. The ease of obtaining a "liquid biopsy" from blood or urine in GU cancers enhances its potential to be used as a biomarker. Interrogating these "liquid biopsies" for ctDNA can then be used to detect common cancer mutations, novel genomic alterations, or epigenetic modifications. CtDNA has undergone investigation in numerous clinical trials, which could address clinical needs in GU cancers, for instance, earlier detection in RCC, therapeutic response prediction in castration-resistant prostate cancer, and monitoring for recurrence in bladder cancers. The utilization of liquid biopsy for ctDNA analysis provides a promising method of advancing precision medicine within the field of GU cancers. [ABSTRACT FROM AUTHOR]

Simple Summary: We investigated whether the baseline plasma cell-free DNA might help to differentiate malignant nodules from benign lesions observed in screening low-dose computed tomography (LDCT) examinations. Plasma cell-free DNA was determined before the first LDCT in 137 participants in the ITALUNG trial, including 29 with screen-detected malignant nodules (17 prevalent and 12 incident) and 108 with benign nodules. In subjects with prevalent lung cancers (LC), the radiological characteristics well differentiated the malignant nodule, and the cell-free DNA was markedly increased. A total of 75% of subjects with incident LC showed a baseline cell-free DNA ≥ 3.15 ng/mL, compared to 34% of subjects with benign nodules (p = 0.006). Moreover, the cell-free DNA correlated (p = 0.001) with the tumor growth measured with nodular volume doubling time. The baseline plasma cell-free DNA is an independent, potentially useful biomarker in the LC screening process and should be further investigated. The role of total plasma cell-free DNA (cfDNA) in lung cancer (LC) screening with low-dose computed tomography (LDCT) is uncertain. We hypothesized that cfDNA could support differentiation between malignant and benign nodules observed in LDCT. The baseline cfDNA was measured in 137 subjects of the ITALUNG trial, including 29 subjects with screen-detected LC (17 prevalent and 12 incident) and 108 subjects with benign nodules. The predictive capability of baseline cfDNA to differentiate malignant and benign nodules was compared to that of Lung-RADS classification and Brock score at initial LDCT (iLDCT). Subjects with prevalent LC showed both well-discriminating radiological characteristics of the malignant nodule (16 of 17 were classified as Lung-RADS 4) and markedly increased cfDNA (mean 18.8 ng/mL). The mean diameters and Brock scores of malignant nodules at iLDCT in subjects who were diagnosed with incident LC were not different from those of benign nodules. However, 75% (9/12) of subjects with incident LC showed a baseline cfDNA ≥ 3.15 ng/mL, compared to 34% (37/108) of subjects with benign nodules (p = 0.006). Moreover, baseline cfDNA was correlated (p = 0.001) with tumor growth, measured with volume doubling time. In conclusion, increased baseline cfDNA may help to differentiate subjects with malignant and benign nodules at LDCT. [ABSTRACT FROM AUTHOR]