Biomarkers Of Disease Severity Research Articles

The Role of Uromodulin in Chronic Kidney Disease – A Systematic Review and Meta-Analysis

Background: Numerous studies have investigated the function of the biomarker uromodulin (UMD), which has shown promise in the diagnosis and severity assessment of chronic kidney disease (CKD). However, the results continue to be contradictory and inconclusive. Consequently, our goal was to investigate the connection between UMD and CKD patients, with a focus on their diagnostic utility and association with the severity of CKD based on the Kidney Disease Improving Global Outcomes (KDIGO) classification. Methods: We systematically searched PubMed, EMBASE, and Scopus using a predefined string to identify relevant studies. Included studies diagnosed CKD based on GFR according to Kidney Disease Outcomes Quality Initiative KDOQI guidelines or by calculating eGFR using the MDRD formula, meeting predefined criteria. Quality assessment was conducted using the Newcastle Ottawa Scale (NOS). The main outcome was the mean difference (MD) in serum UMD levels across CKD stages. Results: A total of 5 articles involving 1,094 subjects fulfilled our inclusion criteria and were included in our systematic review and meta-analysis. Significant differences in UMD levels were observed across multiple comparisons. When comparing CKD patients to controls, UMD levels showed a substantial MD of –115.719 (95% CI –163.297, -68.141). Similarly, UMD levels exhibited significant MDs when comparing controls vs. CKD 1 71.185 (95% CI 39.572, 102.798), controls vs. CKD 2 81.531 (95% CI 40.570, 122.491), controls vs. CKD 3 130.886 (95% CI 99.095, 162.677), controls vs. CKD 4 180.317 (95% CI 141.373, 219.262), controls vs. CKD 5 198.033 (95% CI 155.573, 240.494) and CKD 1-2-3 vs. CKD 4-5 89.540 (95% CI 47.561, 131.518). Conclusions: In conclusion, our systematic review and meta-analysis highlights pronounced differences in UMD levels across multiple comparisons in CKD. When comparing CKD patients with controls, a significant decrease in UMD levels is evident, indicative of potential implications in renal pathology. Moreover, the observed variations in UMD levels between different CKD stages underscore its potential utility as a biomarker for disease severity and progression. These findings contribute to our understanding of UMD dynamics in CKD and suggest avenues for further research into its diagnostic and prognostic significance in clinical practice.

Single-step colorimetric detection of acid phosphatase in human urine using an oxidase-mimic platinum nanozyme

A nanozyme sensor for rapid detection of urinary acid phosphatase with high sensitivity and a broad dynamic range that is relevant to human pathophysiology is proposed.

Mn-ferrite nanoparticles as promising magnetic tags for radiofrequency inductive detection and quantification in lateral flow assays.

Lateral flow assays are low-cost point-of-care devices that are stable, easy to use, and provide quick results. They are mostly used as qualitative screening tests to detect biomarkers for several diseases. Quantification of the biomarkers is sometimes desirable but challenging to achieve. Magnetic nanoparticles can be used as tags, providing both visual and magnetic signals that can be detected and quantified by magnetic sensors. In the present work, we synthesized superparamagnetic MnFe2O4 nanoparticles using the hydrothermal coprecipitation route. MnFe2O4 presents low magnetic anisotropy and high saturation magnetization, resulting in larger initial magnetic susceptibility, which is crucial for optimizing the signal in inductive sensors. We functionalized the coprecipitated nanoparticles with citric acid to achieve colloidal stability in a neutral pH and to provide carboxyl groups to their surface to bioconjugate with biomolecules, such as proteins and antibodies. The nanomaterials were characterized by several techniques, and we correlated their magnetic properties with their sensitivity and resolution for magnetic detection in radiofrequency inductive sensors. We considered the NeutrAvidin/biotin model of biorecognition to explore their potential as magnetic labels in lateral flow assays. Our results show that MnFe2O4 nanoparticles are more sensitive to inductive detection than magnetite nanoparticles, the most used nanotags in magnetic lateral flow assays. These nanoparticles present high potential as magnetic tags for the development of sensitive lateral flow immunoassays for detecting and quantifying biomarkers.

Isolation of Extracellular Vesicles Using Titanium Dioxide Microspheres.

Extracellular vesicles (EVs) are bilayer membrane particles released from several cell types to the extracellular environment. EVs have a crucial role in cell-cell communication, involving different biological processes in health and diseases. Due to the potential of biomarkers for several diseases as diagnostic and therapeutic tools, it is relevant to understand the biology of the EVs and their content. One of the current challenges involving EVs is regarding the purification method, which is a critical step for EV's functional and characterization studies. Ultracentrifugation is the most used method for EV isolation, where the nanoparticles are separated in sequential centrifugation to isolate the EVs based on their size. However, for viscous biofluids such as plasma, there is a co-isolation of the most abundant proteins, which can impair the EV's protein identification due to the low abundance of these proteins and signal suppression by the most abundant plasma proteins. Emerging techniques have gained attention in recent years. Titanium dioxide (TiO2) is one of the most promising techniques due to its property for selective isolation based on the interaction with phospholipids in the EV membrane. Using a small amount of TiO2 beads and a low volume of plasma, it is possible to isolate EVs with reduced plasma protein co-isolation. This study describes a comprehensive workflow for the isolation and characterization of plasma extracellular vesicles (EVs) using mass spectrometry-based proteomics techniques. The aim of this chapter is describe the EV isolation using TiO2 beads enrichment and high-throughput mass spectrometry techniques to efficiently identify the protein composition of EVs in a fast and straightforward manner.

Contrast enhanced photoacoustic detection of fibrillar collagen in the near infrared region-I.

Fibrillar collagen accumulation emerges as a promising biomarker in several diseases, such as desmoplastic tumors and unstable atherosclerotic plaque. Gold nanorods (GNRs) hold great potential as contrast agents in high-resolution, biomedically safe, and non-invasive photoacoustic imaging (PAI). This study presents the design and characterization of a specialized imaging tool which exploits GNR assisted targeted photoacoustic imaging that is tailored for the identification of fibrillar collagen. In addition to the photoacoustic characterization of collagen in the NIR 1 and 2 regions, we demonstrate the detailed steps of conjugating a decoy to GNRs. This study serves as a proof of concept, that demonstrates that conjugated collagenase-1 (MMP-1) generates a distinct and collagen-specific photoacoustic signal, facilitating real-time visualization in the wavelength range of 700-970 nm (NIR I). As most of the reported studies utilized the endogenous contrast of collagen in the NIR II wavelength that has major limitations to perform in vivo deep tissue imaging, the approach that we are proposing is unique and it highlights the promise of MMP-1 decoy-functionalized GNRs as novel contrast agents for photoacoustic imaging of collagen in the NIR 1 region. To our knowledge this is the first time functionalized GNRs are optimized for the detection of fibrillar collagen and utilized in the field of non-invasive photoacoustic imaging that can facilitate a better prognosis of desmoplastic tumors and broken atherosclerotic plaques.

D-Dimer a biomarker for disease severity in COVID-19 patients

D-Dimer a biomarker for disease severity in COVID-19 patients

Quantitative muscle ultrasound in adult spinal muscular atrophy. A pilot study.

Muscle ultrasound has been investigated in children with spinal muscular atrophy (SMA) and proposed as a potential biomarker of disease severity. We studied the ultrasound properties in adults with SMA to see whether they also have potential as markers of disease severity in older patients. Thickness and quantitative echogenicity of muscle and subcutaneous tissue were compared between eight prospectively recruited adult patients with SMA and eight age, sex and body mass index-matched controls. Measurements were made in the dominant deltoid, biceps, triceps, forearm extensors, first dorsal interosseous, quadriceps, tibialis anterior, and gastrocnemius muscles. The muscle-to-subcutaneous (M:S) thickness and echogenicity ratios were also calculated. A mean value across all muscles as well as the individual values for each muscle were then calculated for each parameter in each subject and compared between the two groups. Significance was set at 0.05 after Bonferroni correction. In the SMA patients, mean muscle thickness was significantly smaller (1.3 vs. 1.9 cm), muscle echogenicity higher (106 vs. 67 on the grayscale level), and subcutaneous thickness larger (0.9 vs. 0.3 cm) than in controls; M:S echogenicity ratio was significantly increased and M:S thickness ratio reduced in the patients. The most abnormal scores were found in the nonambulatory patients and the least abnormal in the ambulatory patients. Ultrasound can detect and quantify the severity of muscle atrophy and structure in adult SMA, suggesting a potential role as a marker of disease severity, which will require validation by larger studies.

A novel coupling technique based on thermal desorption gas chromatography with mass spectrometry and ion mobility spectrometry for breath analysis

Exhaled breath analysis is evolving into an increasingly important non-invasive diagnostic tool. Volatile organic compounds (VOCs) in breath contain information about health status and are promising biomarkers for several diseases, including respiratory infections caused by bacteria. To monitor the composition of VOCs in breath or the emission of VOCs from bacteria, sensitive analytical techniques are required. Next to mass spectrometry, ion mobility spectrometry (IMS) is considered a promising analytical tool for detecting gaseous analytes in the parts per billion by volume to parts per trillion by volume range. This work presents a new, dual coupling of thermal desorption gas chromatography to a quadrupole mass spectrometer (MS) and an IMS by operating a simple splitter. Nearly identical retention times can be reached in the range of up to 30 min with slight deviations of 0.06 min–0.24 min. This enables the identification of unknown compounds in the IMS chromatogram using unambiguous mass spectral identification, as there are still no commercially available databases for IMS. It is also possible to discriminate one of the detectors using the splitter to improve detection limits. Using a test liquid mixture of seven ketones, namely 2-butanone, 2-pentanone, 2-hexanone, 2-heptanone, 2-octanone, 2-nonanone, and 2-decanone with a concentration of 0.01 g l−1 reproducibilities ranging from 3.0% to 7.6% for MS and 2.2%–5.3%, for IMS were obtained, respectively. In order to test the system optimized here for the field of breath analysis, characteristic VOCs such as ethanol, isoprene, acetone, 2-propanol, and 1-propanol were successfully identified in exhaled air using the dual detector system due to the match of the corresponding IMS, and MS spectra. The presented results may be considered to be a starting point for the greater use of IMS in combination with MS within the medical field.

Vascular Endothelial Growth Factor A VEGFA Inhibition: An Effective Treatment Strategy for Psoriasis.

Psoriasis is an inflammatory skin disease mediated by the immune system and characterized by an inflammatory ring, also known as an epithelial immune microenvironment (EIME). The interaction between the epithelial tissue of the skin and the immune system has a crucial role in the immune cycle of psoriasis. Although the formation of new blood vessels in skin lesions provides energy support for the proliferation of epidermal keratinocytes, the role of angiogenesis in psoriasis has not been extensively studied. Vascular endothelial growth factor A (VEGFA) is a key regulator of angiogenesis that has an important role in the development of psoriasis. VEGFA promotes angiogenesis and directly stimulates epidermal keratinocytes and infiltrating immune cells, thus contributing to the progression of psoriasis. Measuring VEGFA levels to identify angiogenic characteristics in psoriasis patients may be a predictive biomarker for disease severity and response to anti-angiogenic therapy. Clinical data have shown that anti-angiogenic therapy can improve skin lesions in psoriasis patients. Therefore, this study aimed to uncover the underestimated role of blood vessels in psoriasis, explore the relationship between VEGFA and keratinocytes in the EIME, and inspire innovative drug therapies for the treatment of psoriasis.

Deep Learning-Assisted Single-Molecule Detection of Protein Post-translational Modifications with a Biological Nanopore.

Protein post-translational modifications (PTMs) play a crucial role in countless biological processes, profoundly modulating protein properties on both spatial and temporal scales. Protein PTMs have also emerged as reliable biomarkers for several diseases. However, only a handful of techniques are available to accurately measure their levels, capture their complexity at a single molecule level, and characterize their multifaceted roles in health and disease. Nanopore sensing provides high sensitivity for the detection of low-abundance proteins, holding the potential to impact single-molecule proteomics and PTM detection, in particular. Here, we demonstrate the ability of a biological nanopore, the pore-forming toxin aerolysin, to detect and distinguish α-synuclein-derived peptides bearing single or multiple PTMs, namely, phosphorylation, nitration, and oxidation occurring at different positions and in various combinations. The characteristic current signatures of the α-synuclein peptide and its PTM variants could be confidently identified by using a deep learning model for signal processing. We further demonstrate that this framework can quantify α-synuclein peptides at picomolar concentrations and detect the C-terminal peptides generated by digestion of full-length α-synuclein. Collectively, our work highlights the advantage of using nanopores as a tool for simultaneous detection of multiple PTMs and facilitates their use in biomarker discovery and diagnostics.

Impaired cerebral interstitial fluid dynamics in cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy, caused by cysteine-altering variants in NOTCH3, is the most prevalent inherited cerebral small vessel disease. Impaired cerebral interstitial fluid dynamics has been proposed as one of the potential culprits of neurodegeneration and may play a critical role in the initiation and progression of cerebral small vessel disease. In the present study, we aimed to explore the cerebral interstitial fluid dynamics in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy and to evaluate its association with clinical features, imaging biomarkers and disease severity of cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy. Eighty-one participants carrying a cysteine-altering variant in NOTCH3, including 44 symptomatic cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy patients and 37 preclinical carriers, and 21 age- and sex-matched healthy control individuals were recruited. All participants underwent brain MRI studies and neuropsychological evaluations. Cerebral interstitial fluid dynamics was investigated by using the non-invasive diffusion tensor image analysis along the perivascular space method. We found that cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy patients exhibited significantly lower values of diffusion tensor image analysis along the perivascular space index comparing to preclinical carriers and healthy controls. For the 81 subjects carrying NOTCH3 variants, older age and presence of hypertension were independently associated with decreased diffusion tensor image analysis along the perivascular space index. The degree of cerebral interstitial fluid dynamics was strongly related to the severity of cerebral small vessel disease imaging markers, with a positive correlation between diffusion tensor image analysis along the perivascular space index and brain parenchymal fraction and negative correlations between diffusion tensor image analysis along the perivascular space index and total volume of white matter hyperintensity, peak width of skeletonized mean diffusivity, lacune numbers and cerebral microbleed counts. In addition, diffusion tensor image analysis along the perivascular space index was a significant risk factor associated with the development of clinical symptoms of stroke or cognitive dysfunction in individuals carrying NOTCH3 variants. In cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy patients, diffusion tensor image analysis along the perivascular space index was significantly associated with Mini-Mental State Examination scores. Mediation analysis showed that compromised cerebral interstitial fluid dynamics was not only directly associated with cognitive dysfunction but also had an indirect effect on cognition by influencing brain atrophy, white matter disruption, lacunar lesions and cerebral microbleeds. In conclusion, cerebral interstitial fluid dynamics is impaired in cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy and its disruption may play an important role in the pathogenesis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy. Diffusion tensor image analysis along the perivascular space index may serve as a biomarker of disease severity for cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy.

Differential cellular immune responses against Orientia tsutsugamushi Karp and Gilliam strains following acute infection in mice.

Scrub typhus is a leading cause of febrile illness in endemic countries due to infection with Orientia tsutsugamushi (Ot), a seriously understudied intracellular bacterium. Pulmonary involvement associated with vascular parasitism in patients is common and can develop into life threatening interstitial pneumonia. The diverse antigenicity of Ot genotypes and inter-strain differences in genome content are connected to varied virulence and clinical outcomes; however, detailed studies of strain-related pulmonary immune responses in human patients or small animal models of infection are lacking. In this study, we have used two clinically prevalent bacterial strains (Karp and Gilliam) to reveal cellular immune responses in inflamed lungs and potential biomarkers of disease severity. The results demonstrate that outbred CD-1 mice are highly susceptible to both Karp and Gilliam strains; however, C57BL/6 (B6) mice were susceptible to Karp, but resistant to Gilliam (with self-limiting infection), corresponding to their tissue bacterial burdens and lung pathological changes. Multicolor flow cytometric analyses of perfused B6 mouse lungs revealed robust and sustained influx and activation of innate immune cells (macrophages, neutrophils, and NK cells), followed by CD4+ and CD8+ T cells, during Karp infection, but such responses were greatly attenuated during Gilliam infection. The robust cellular responses in Karp-infected B6 mice positively correlated with significantly early and high levels of serum cytokine/chemokine protein levels (CXCL1, CCL2/3/5, and G-CSF), as well as pulmonary gene expression (Cxcl1/2, Ccl2/3/4, and Ifng). In vitro infection of B6 mouse-derived primary macrophages also revealed bacterial strain-dependent immune gene expression profiles. This study provided the lines of evidence that highlighted differential tissue cellular responses against Karp vs. Gilliam infection, offering a framework for future investigation of Ot strain-related mechanisms of disease pathogenesis vs. infection control.

Inflammatory immune profiles associated with disease severity in pulmonary tuberculosis patients with moderate to severe clinical TB or anemia.

Immune control of Mycobacterium tuberculosis (Mtb) infection is largely influenced by the extensive disease heterogeneity that is typical for tuberculosis (TB). In this study, the peripheral inflammatory immune profile of different sub-groups of pulmonary TB patients was explored based on clinical disease severity, anemia of chronic disease, or the radiological extent of lung disease. Plasma samples were obtained from n=107 patients with active pulmonary TB at the time of diagnosis and after start of standard chemotherapy. A composite clinical TB symptoms score, blood hemoglobin status and chest X-ray imaging were used to sub-group TB patients into 1.) mild and moderate-severe clinical TB, 2.) anemic and non-anemic TB, or 3.) limited and extensive lung involvement. Plasma levels of biomarkers associated with inflammation pathways were assessed using a Bio-Plex Magpix 37-multiplex assay. In parallel, Th1/Th2 cytokines were quantified with a 27-multiplex in matched plasma and cell culture supernatants from whole blood stimulated with M. tuberculosis-antigens using the QuantiFERON-TB Gold assay. Clinical TB disease severity correlated with low blood hemoglobin levels and anemia but not with radiological findings in this study cohort. Multiplex protein analyses revealed that distinct clusters of inflammation markers and cytokines separated the different TB disease sub-groups with variable efficacy. Several top-ranked markers overlapped, while other markers were unique with regards to their importance to differentiate the TB disease severity groups. A distinct immune response profile defined by elevated levels of BAFF, LIGHT, sTNF-R1 and 2, IP-10, osteopontin, chitinase-3-like protein 1, and IFNα2 and IL-8, were most effective in separating TB patients with different clinical disease severity and were also promising candidates for treatment monitoring. TB patients with mild disease displayed immune polarization towards mixed Th1/Th2 responses, while pro-inflammatory and B cell stimulating cytokines as well as immunomodulatory mediators predominated in moderate-severe TB disease and anemia of TB. Our data demonstrated that clinical disease severity in TB is associated with anemia and distinct inflammatory immune profiles. These results contribute to the understanding of immunopathology in pulmonary TB and define top-ranked inflammatory mediators as biomarkers of disease severity and treatment prognosis.

Clinical stage and plasma neurofilament concentration in adults with Friedreich ataxia

ObjectivesFriedreich Ataxia (FRDA) is the most common recessive ataxia disorder. Yet, little is known of the prevalence in Sweden. In the future, there may be effective disease-modifying therapies, and use of clinical rating scales as well as possible biomarkers in serum or cerebrospinal fluid may be of importance. We evaluated the axonal protein neurofilament light in plasma (p-NfL) as a possible biomarker for disease severity in FRDA. Materials & methodsWe searched for all possible genetically confirmed FRDA cases in the Västra Götaland Region (VGR) of Sweden, and investigated each patient clinically and obtained blood sample for analysis of p-NfL. ResultsWe found eight patients corresponding to 1/170.000 adults in the VGR, and 5 of these participated in the study. Three out of the five FRDA patients displayed a small or moderate increase in the p-NfL value, compared to the age-adjusted cut-offs for p-NfL established in the Clinical Neurochemistry Laboratory at our hospital. The two others were the oldest and most severely affected, displayed normal values according the cut-off values. The cohort is too small to make any statistically significant correlation between the five p-NfL values with regard to disease severity. ConclusionsFRDA is less prevalent in our region of Sweden than could be assumed. In concordance with previous studies from other authors, we find that p-NfL may be increased in patients with FRDA, but less so in older more clinically affected patients. Thus, we conclude that on an individual basis, p-NFL is of uncertain clinical value as a suitable biomarker.

Tissue Interleukin-33: A Novel Potential Regulator of Innate Immunity and Biomarker of Disease Severity in Chronic Rhinosinusitis with Nasal Polyps.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a disease of real interest for researchers due to its heterogenicity and complex pathophysiological mechanisms. Identification of the factors that ensure success after treatment represents one of the main challenges in CRSwNP research. No consensus in this direction has been reached so far. Biomarkers for poor outcomes have been noted, but nonetheless, their prognostic value has not been extensively investigated, and needs to be sought. We aimed to evaluate the correlation between potential prognostic predictors for recalcitrant disease in patients with CRSwNP. The study group consisted of CRSwNP patients who underwent surgical treatment and nasal polyp (NP) tissue sampling. The preoperative workup included Lund-Mackay assessment, nasal endoscopy, eosinophil blood count, asthma, and environmental allergy questionnaire. Postoperatively, in subjects with poor outcomes, imagistic osteitis severity was evaluated, and IL-33 expression was measured. IL-33 expression in NP was positively and significantly correlated with postoperative osteitis on CT scans (p = 0.01). Furthermore, high osteitis CT scores were related to high blood eosinophilia (p = 0.01). A positive strong correlation was found between postoperative osteitis and the Lund-Mackay preoperative score (p = 0.01), as well as the nasal endoscopy score (p = 0.01). Our research analyzed the levels of polyp IL-33, relative to blood eosinophilia, overall disease severity score, and osteitis severity, in patients with CRSwNP. These variables are prognostic predictors for poor outcomes and recalcitrant disease. Considering the importance of bone involvement in CRSwNP, this research aims to provide a better insight into the correlations of osteitis with clinical and biological factors.

Progression of Retinal Ganglion Cell and Nerve Fiber Layer Loss in Spinocerebellar Ataxia 3 Patients.

Spectral domain optical coherence tomography (SD-OCT) allows noninvasive measurements of retinal neuron layers. Here, we evaluate the relationship between clinical features and anatomical SD-OCT measurements in patients with spinocerebellar ataxia type 3 (SCA3) and how they change with time. A retrospective review was conducted on SCA3 patients. Clinical variables such as disease duration, number of CAG repeats, and the Scale for the Assessment and Rating of Ataxia (SARA) score were correlated with SD-OCT measurements, including retinal nerve fiber layer (RNFL) thickness, ganglion cell complex (GCC) thickness, macular volume (MV), and central macular thickness (CMT). Seventeen SCA3 patients with an average follow-up of 44.9months were recruited. Clinical features with significant baseline correlations with SD-OCT measurements included disease duration (CMT r = - 0.590; GCC r = - 0.585), SARA score (CMT r = - 0.560; RNFL r = - 0.390), and number of CAG repeats (MV r = - 0.552; RNFL r = - 0.503; GCC r = - 0.493). The annual rate of change of the SARA score during follow-up was associated with that of both the MV (r = - 0.494; p = 0.005) and GCC thickness (r = - 0.454; p = 0.012). High disability (stages 2 and 3) was independently inversely associated with the annual change in MV (ß coefficient - 17.09; p = 0.025). This study provides evidence of an association between clinical features and objective anatomical measurements obtained by SD-OCT in SCA3 patients. MV and GCC thickness could serve as potential biomarkers of disease severity, as their rates of decrease seem to be related to a worsening in the SARA score. These findings highlight the potential of SD-OCT as a noninvasive tool for assessing disease severity and progression in SCA3 patients.

Clinical Results of a Randomized Placebo Controlled Trial of Inhaled Mometasone to Promote Reduction in Vaso-Occlusive Events (IMPROVE-II)

Introduction: A subset of patients living with sickle cell disease (SCD) who do not meet diagnostic criteria for asthma exhibit episodic cough or wheeze (ECW), and this is associated with higher rates of vaso-occlusive pain crisis and acute chest syndrome. ECW may be caused by pulmonary inflammation from SCD. In the former IMPROVE trial, 54 patients with SCD and ECW were randomized to receive 16 weeks of placebo or mometasone furoate, an inhaled corticosteroid used to treat pulmonary inflammation. Treatment with mometasone was associated with significant reductions in daily pain, markers of hemolysis, and soluble vascular cell adhesion molecule (sVCAM) (a biomarker of disease severity in SCD) compared to placebo. The IMPROVE-II trial evaluated whether treatment with mometasone over a longer period could improve clinical and biological endpoints in non-asthmatic patients with SCD and ECW. We report here the clinical outcomes from the IMPROVE-II trial. Methods: We conducted a randomized, placebo-controlled, single-center interventional trial. Patients with SCD without asthma were randomized to receive either mometasone furoate 220 mcg or placebo inhaled powder for 48 weeks followed by a 4-week wash out. Key inclusion criteria included age > 18 years with SCD genotype HbSS/HbSβ0 at stable baseline who endorsed ECW. Patients were excluded if they had >15 emergency department (ED) visits for vaso-occlusive pain crisis in the past 12 months or if other treatments for SCD (i.e. hydroxyurea, L-glutamine) were being titrated. The primary outcome was the change in soluble vascular cell adhesion molecule (sVCAM) level with treatment. Clinical outcomes included ED visits and hospitalizations for any reason, and health care visits for acute chest syndrome, pneumonia, stroke, or transient ischemic attack, as well as daily pain (self-report 1-10 scale), and 6 Minute Walk. Adaptive covariate randomization was used to balance covariates including hydroxyurea use (yes/no), age, and previous rate of ED use. Results: A total of 80 patients were randomized and 77 received study treatment; 40 were assigned to mometasone and 37 to placebo (Figure 1). There were no significant differences between treatment groups in patient demographics (Table 1). Treatment with mometasone was associated with higher rates of acute care visits for vaso-occlusive crisis (4 (2/19) vs 1 (1/3) /patient year (50%(25%/75%), p<0.001), hospitalization for acute chest syndrome (mean 0.2 vs 0.1/patient year, p=0.05) and ED utilization (2 (1/5) vs 2 (1/4) /patient year (50%(25%/75%), p0.01). Laboratory outcomes including sVCAM are not yet resulted. Adverse events that were reported by more than 5% of patients are listed in Table 1; there was no difference between rates of adverse (<5%) events between mometasone and placebo. There were no deaths during the study. Conclusions: In individuals with SCD and ECW who do not have asthma, long-term treatment with inhaled corticosteroids did not improve clinical outcomes and may be harmful as they were associated with higher rates of acute care visits for pain crisis, ED visits, and acute chest syndrome. Further analyses of biological endpoints and clinical laboratory data are needed to fully elucidate the effects of inhaled corticosteroids in SCD.

Effect of chemotherapy on urinary volatile biomarkers for lung cancer by HS-SPME-GC-MS and chemometrics.

Volatile organic compounds (VOCs) have been studied as possible biomarkers in several diseases, including lung cancer. Early detection of cancer can improve long-term survival rates and the quality of life, so the study of VOCs in exhaled breath and urine has been increasing in recent years. This study aimed to assess the urinary VOCs that are modified after chemotherapy to identify those with the potential to be lung cancer biomarkers that can be monitored during treatment. Three urine samples from 10 men with stage IV lung adenocarcinoma were collected, as well as urine samples from 14 men with other types of cancer (control group). All samples were analyzed by headspace-solid phase microextraction gas chromatography coupled with mass spectrometry. A total of 21 urinary VOCs were found with different levels after the administration of chemotherapy, with 2-pentanone being one of those that significantly decreased. Furthermore, 2-pentanone and 3-hydroxy-2,4,4-trimethylpentyl-2-methylpropanoate showed statistically significant differences with the control group. Chemotherapy administered to patients with advanced lung adenocarcinoma modified the volatile profile of urine. 2-Pentanone, a final product of the increased rate of fatty acid oxidation and protein hypermetabolism, significantly decreased after chemotherapy. Therefore, monitoring its urinary excretion could be very useful since its decrease over time could indicate an adequate response to chemotherapy and arrest of cancer development. Another VOC that could be a potential lung cancer biomarker is 3 hydroxy-2,4,4-trimethylpentyl-2-methylpropanoate, whose origin may be due to inhibition of the propanoic acid metabolic pathway or increased aldehyde dehydrogenase activity.

Cardiac troponin is a strong prognostic biomarker for patients admitted with heart failure

Abstract Background Cardiac troponin T (cTnT) and I (cTnI) are strong prognostic biomarkers in several diseases and play a key role in risk stratification of patients admitted with cardiac disease. Though viewed as equals, there are substantial differences in the biology and frequency of elevations among non-cardiac illnesses between cTnT and cTnI. A recent study of all comers with a measurement of cTn showed that the risk of mortality was highest for patients with low grade elevations of cTn, while high concentrations were associated with a paradoxical decrease in the risk. We aimed to investigate whether this pattern exists among patients with heart failure. Purpose To compare the prognostic ability of cTnT and cTnI among patients admitted with heart failure. Methods This nationwide cohort study includes patients admitted with heart failure who had cTn measurements from 2009-2022 using one of five different cTn assays: Roche high-sensitivity cTnT (hs-cTnT), Abbott Alinity high sensitivity cTnI (hs-cTnI), Siemens Vista Hs-cTnI, Siemens Atellica hs-cTnI and Beckman-Coulter hs-cTnI. We selected the peak concentration of cTn on admission and grouped patients into those with measurements of cTnI and those with cTnT. The primary outcome was all-cause mortality. We divided the peak cTn concentrations into groups based on the bands of concentrations of cTn from <1 times the 99th percentile, 1-2, 2-5, 5-100 and >100 times the 99th percentile and compared cumulative mortality using Kaplan-Meier analysis and the risk of mortality for each group using logistic regression for the 30-day mortality. Results A total of 9,344 patients were included in this study with a median age of 75 years (65-83) and 5,613 (60%) were males. Of these, 2,874 (31%) had a history of heart failure and 2,349 (25%) had a history of ischemic heart disease. When grouping for type of cTn used, there were more patients treated using hs-cTnT (n = 7,131 76%) than hs-cTnI (n = 2,213, 24%). The median age of patients treated who had a measurement of cTnI was slightly higher; 77 years (IQR 67-84) vs cTnT 74 years (64-83) p<0.001. Of the 9,344 patients, 1,096 (12%) died within 30 days of admission. Figure 1 shows the absolute risk of 1-year all-cause mortality for each band of cTn concentration for (panel A) hs-cTnI and (panel B) hs-cTnT. This showed an increase in the risk of mortality for patients up to 2-5 times the 99th percentile for cTnI and 5-100 times the 99th percentile for cTnT. Figure 2 shows the risk of 30-day mortality for patients for each concentration of cTn. There was a much higher risk of mortality associated with elevation of cTnT than cTnI for all bands of concentration. Conclusion Though both cTnI and cTnT are strong prognostic markers of mortality among patients admitted with heart failure, cTnT seemed to be the strongest prognostic marker. The risk of mortality increased with concentration of cTnT up to very high concentrations of >5 times the 99th percentile.Figure 1Figure 2

The antithrombin activity recovery after substitution therapy is associated with improved 28-day mortality in patients with sepsis-associated disseminated intravascular coagulation

BackgroundDisseminated intravascular coagulation (DIC) is a common and critical complication in sepsis. Antithrombin activity, which is considered a biomarker for disease severity, was measured in septic DIC treated with antithrombin concentrates in this study.MethodsWe conducted a retrospective analysis of post-marketing survey data that included 1,800 patients with sepsis-associated DIC and antithrombin activity of 70% or less who were treated with antithrombin concentrates. The changes in sequential organ failure assessment (SOFA) score, DIC score, and antithrombin activity were sequentially assessed. Logistic regression analysis and receiver operating characteristic (ROC) curve analysis were performed to evaluate the performance of antithrombin activity to assess 28-day survival. Furthermore, the relationship between post-treatment antithrombin activity and survival was examined by Logistic regression analysis.ResultsSex, baseline SOFA score, baseline antithrombin activities, and the presence of pneumonia and soft tissue infection were significantly associated with 28-day mortality. The area under the curve for mortality was 0.639 for post-treatment antithrombin activity, and higher than those of baseline- and delta antithrombin activities. Logistic regression analysis revealed that higher post-treatment antithrombin activity was associated with better 28-day survival. When post-treatment antithrombin activity was more than 80%, the estimated survival was 88.2%. Whereas, the survival was 74.4% when the antithrombin activity was 80% or less (P < 0.0001). However, the relationship between post-treatment antithrombin activity and 28-day survival was considerably different between patients who recovered from DIC by Day 6 compared to those who did not. Similarly, the estimated 28-day survival, based on antithrombin activity, varied among patients with high and low SOFA scores, and the calculation needs to be adjusted based on the severity of the condition.ConclusionsPost-treatment antithrombin activity measurement was helpful in estimating the 28-day survival in patients with sepsis-associated DIC. However, patient outcomes vary considerably depending on factors that include baseline SOFA score, age, and baseline antithrombin activity. These variables play a substantial role in determining patient prognosis and should be considered when evaluating and interpreting the results.