Cardiovascular Magnetic Resonance Radiomics to Identify Components of the Extracellular Matrix in Dilated Cardiomyopathy.

BACKGROUND: Current cardiovascular magnetic resonance sequences cannot discriminate between different myocardial extracellular space (ECSs), including collagen, noncollagen, and inflammation. We sought to investigate whether cardiovascular magnetic resonance radiomics analysis can distinguish between noncollagen and inflammation from collagen in dilated cardiomyopathy. METHODS: We identified data from 132 patients with dilated cardiomyopathy scheduled for an invasive septal biopsy who underwent cardiovascular magnetic resonance at 3 T. Cardiovascular magnetic resonance imaging protocol included native and postcontrast T1 mapping and late gadolinium enhancement (LGE). Radiomic features were computed from the midseptal myocardium, near the biopsy region, on native T1, extracellular volume (ECV) map, and LGE images. Principal component analysis was used to reduce the number of radiomic features to 5 principal radiomics. Moreover, a correlation analysis was conducted to identify radiomic features exhibiting a strong correlation (r>0.9) with the 5 principal radiomics. Biopsy samples were used to quantify ECS, myocardial fibrosis, and inflammation. RESULTS: Four histopathological phenotypes were identified: low collagen (n=20), noncollagenous ECS expansion (n=49), mild to moderate collagenous ECS expansion (n=42), and severe collagenous ECS expansion (n=21). Noncollagenous expansion was associated with the highest risk of myocardial inflammation (65%). Although native T1 and ECV provided high diagnostic performance in differentiating severe fibrosis (C statistic, 0.90 and 0.90, respectively), their performance in differentiating between noncollagen and mild to moderate collagenous expansion decreased (C statistic: 0.59 and 0.55, respectively). Integration of ECV principal radiomics provided better discrimination and reclassification between noncollagen and mild to moderate collagen (C statistic, 0.79; net reclassification index, 0.83 [95% CI, 0.45-1.22]; P<0.001). There was a similar trend in the addition of native T1 principal radiomics (C statistic, 0.75; net reclassification index, 0.93 [95% CI, 0.56-1.29]; P<0.001) and LGE principal radiomics (C statistic, 0.74; net reclassification index, 0.59 [95% CI, 0.19-0.98]; P=0.004). Five radiomic features per sequence were identified with correlation analysis. They showed a similar improvement in performance for differentiating between noncollagen and mild to moderate collagen (native T1, ECV, LGE C statistic, 0.75, 0.77, and 0.71, respectively). These improvements remained significant when confined to a single radiomic feature (native T1, ECV, LGE C statistic, 0.71, 0.70, and 0.64, respectively). CONCLUSIONS: Radiomic features extracted from native T1, ECV, and LGE provide incremental information that improves our capability to discriminate noncollagenous expansion from mild to moderate collagen and could be useful for detecting subtle chronic inflammation in patients with dilated cardiomyopathy.

Endoplasmic reticulum localized TMEM33 domain-containing protein is crucial for all life cycle stages of the malaria parasite.

Endoplasmic reticulum (ER) plays a pivotal role in the regulation of stress responses in multiple eukaryotic cells. However, little is known about the effector mechanisms that regulate stress responses in ER of the malaria parasite. Herein, we aimed to identify the importance of a transmembrane protein 33 (TMEM33)-domain-containing protein in life cycle of the rodent malaria parasite Plasmodium berghei. TMEM33 is an ER membrane-resident protein that is involved in regulating stress responses in various eukaryotic cells. A C-terminal tagged TMEM33 was localized in the ER throughout the blood and mosquito stages of development. Targeted deletion of TMEM33 confirmed its importance for asexual blood stages and ookinete development, in addition to its essential role for sporozoite infectivity in the mammalian host. Pilot scale analysis shows that the loss of TMEM33 results in the initiation of ER stress response and induction of autophagy. Our findings conclude an important role of TMEM33 in the development of all life cycle stages of the malaria parasite, which indicates its potential as an antimalarial target.

Linagliptin, a DPP-4 inhibitor, activates AMPK/FOXO3a and suppresses NFκB to mitigate the debilitating effects of diethylnitrosamine exposure in rat liver: Novel mechanistic insights.

Accumulating evidence suggests that dysregulation of FOXO3a plays a significant role in the progression of various malignancies, including hepatocellular carcinoma (HCC). FOXO3a inactivation, driven by oncogenic stimuli, can lead to abnormal cell growth, suppression of apoptosis, and resistance to anticancer drugs. Therefore, FOXO3a emerges as a potential molecular target for the development of innovative treatments in the era of oncology. Linagliptin (LNGTN), a DPP-4 inhibitor known for its safe profile, has exhibited noteworthy anti-inflammatory and anti-oxidative properties in previous in vivo studies. Several potential molecular mechanisms have been proposed to explain these effects. However, the capacity of LNGTN to activate FOXO3a through AMPK activation has not been investigated. In our investigation, we examined the potential repurposing of LNGTN as a hepatoprotective agent against diethylnitrosamine (DENA) intoxication. Additionally, we assessed LNGTN's impact on apoptosis and autophagy. Following a 10-week administration of DENA, the liver underwent damage marked by inflammation and early neoplastic alterations. Our study presents the first experimental evidence demonstrating that LNGTN can reinstate the aberrantly regulated FOXO3a activity by elevating the nuclear fraction of FOXO3a in comparison to the cytosolic fraction, subsequent to AMPK activation. Moreover, noteworthy inactivation of NFκB induced by LNGTN was observed. These effects culminated in the initiation of apoptosis, the activation of autophagy, and the manifestation of anti-inflammatory, antiproliferative, and antiangiogenic outcomes. These effects were concomitant with improved liver function and microstructure. In conclusion, our findings open new avenues for the development of novel therapeutic strategies targeting the AMPK/FOXO3a signaling pathway in the management of chronic liver damage.

Identifying genomic regions associated with C4 photosynthetic activity and leaf anatomy in Alloteropsis semialata.

C4 photosynthesis is a complex trait requiring multiple developmental and metabolic alterations. Despite this complexity, it has independently evolved over 60 times. However, our understanding of the transition to C4 is complicated by the fact that variation in photosynthetic type is usually segregated between species that diverged a long time ago. Here, we perform a genome-wide association study (GWAS) using the grass Alloteropsis semialata, the only known species to have C3, intermediate, and C4 accessions that recently diverged. We aimed to identify genomic regions associated with the strength of the C4 cycle (measured using δ13C), and the development of C4 leaf anatomy. Genomic regions correlated with δ13C include regulators of C4 decarboxylation enzymes (RIPK), nonphotochemical quenching (SOQ1), and the development of Kranz anatomy (SCARECROW-LIKE). Regions associated with the development of C4 leaf anatomy in the intermediate individuals contain additional leaf anatomy regulators, including those responsible for vein patterning (GSL8) and meristem determinacy (GIF1). The parallel recruitment of paralogous leaf anatomy regulators between A. semialata and other C4 lineages implies the co-option of these genes is context-dependent, which likely has implications for the engineering of the C4 trait into C3 species.

Service evaluation suggests variation in clinical care provision in adults with congenital adrenal hyperplasia in the UK and Ireland.

BACKGROUND: Congenital adrenal hyperplasia (CAH) encompasses a rare group of autosomal recessive disorders, characterised by enzymatic defects in steroidogenesis. Heterogeneity in management practices has been observed internationally. The International Congenital Adrenal Hyperplasia registry (I-CAH, https://sdmregistries.org/) was established to enable insights into CAH management and outcomes, yet its global adoption by endocrine centres remains unclear. DESIGN: We sought (1) to assess current practices amongst clinicians managing patients with CAH in the United Kingdom and Ireland, with a focus on choice of glucocorticoid, monitoring practices and screening for associated co-morbidities, and (2) to assess use of the I-CAH registry. MEASUREMENTS: We designed and distributed an anonymised online survey disseminated to members of the Society for Endocrinology and Irish Endocrine Society to capture management practices in the care of patients with CAH. RESULTS: Marked variability was found in CAH management, with differences between general endocrinology and subspecialist settings, particularly in glucocorticoid use, biochemical monitoring and comorbidity screening, with significant disparities in reproductive health monitoring, notably in testicular adrenal rest tumours (TARTs) screening (p = .002), sperm banking (p = .0004) and partner testing for CAH (p < .0001). Adoption of the I-CAH registry was universally low. CONCLUSIONS: Differences in current management of CAH continue to exist. It appears crucial to objectify if different approaches result in different long-term outcomes. New studies such as CaHASE2, incorporating standardised minimum datasets including replacement therapies and monitoring strategies as well as longitudinal data collection, are now needed to define best-practice and standardise care.

Oral epithelial dysplasia with lymphocytic immune response: clinicopathological characterisation of 44 cases.

AIMS: Oral epithelial dysplasia (OED) often exhibits a lymphocytic/lichenoid immune response (LIR), imparting histological resemblance to lichenoid mucositis and rendering diagnosis challenging. The clinical appearances of OED and lichenoid inflammatory processes are generally divergent, presenting as well-demarcated hyperkeratotic plaques and diffuse white and/or red mucosal change with variably prominent Wickham striae, respectively. To date, clinicopathological characterisation of OED with LIR, including clinical/gross appearance, has not been depicted. METHODS AND RESULTS: Cases of solitary OED with LIR for which a clinical photograph was available were identified in the authors' institutional files. Clinical and histological features were documented. In 44 identified cases, dysplasia was mild (19 of 44, 43.2%), moderate (19 of 44, 43.2%) and severe (six of 44, 13.6%). Clinically/grossly, all 44 cases (100.0%), presented as well-demarcated hyperkeratotic plaques lacking diffuse white-and-red mucosal change or Wickham striae. Histologically, OED with LIR exhibited numerous 'lichenoid' features beyond the lymphocytic band in the superficial lamina propria, including: leucocyte transmigration (38 of 44, 86.4%), spongiosis (37 of 44, 84.1%), Civatte/colloid bodies (36 of 44, 81.8%), basal cell degeneration (29 of 45, 65.9%), sawtooth rete ridges (11 of 44, 25.0%) and subepithelial clefting (7 of 44, 15.9%). CONCLUSIONS: Virtually any lichenoid histological feature may be seen in OED with LIR, representing a significant diagnostic pitfall. The typical clinical appearance of OED with LIR is of a well-demarcated hyperkeratotic plaque, characteristic of keratinising dysplasia and devoid of lichenoid features. This suggests that pathologist access to clinical photographs during diagnostic interpretation of biopsied white lesions, which represents opportunity to perform gross examination of the disease process, may reduce interobserver variability and improve diagnostic accuracy in this challenging differential diagnosis.

Soil recalcitrant but not labile organic nitrogen mineralization contributes to microbial nitrogen immobilization and plant nitrogen uptake.

Soil organic nitrogen (N) mineralization not only supports ecosystem productivity but also weakens carbon and N accumulation in soils. Recalcitrant (mainly mineral-associated organic matter) and labile (mainly particulate organic matter) organic materials differ dramatically in nature. Yet, the patterns and drivers of recalcitrant (MNrec) and labile (MNlab) organic N mineralization rates and their consequences on ecosystem N retention are still unclear. By collecting MNrec (299 observations) and MNlab (299 observations) from 57 15N tracing studies, we found that soil pH and total N were the master factors controlling MNrec and MNlab, respectively. This was consistent with the significantly higher rates of MNrec in alkaline soils and of MNlab in natural ecosystems. Interestingly, our analysis revealed that MNrec directly stimulated microbial N immobilization and plant N uptake, while MNlab stimulated the soil gross autotrophic nitrification which discouraged ammonium immobilization and accelerated nitrate production. We also noted that MNrec was more efficient at lower precipitation and higher temperatures due to increased soil pH. In contrast, MNlab was more efficient at higher precipitation and lower temperatures due to increased soil total N. Overall, we suggest that increasing MNrec may lead to a conservative N cycle, improving the ecosystem services and functions, while increasing MNlab may stimulate the potential risk of soil N loss.

Tracking the therapeutic efficacy of a ketone mono ester and ß-hydroxybutyrate for ulcerative colitis in rats: New perspectives.

Ulcerative colitis (UC) is an inflammatory condition that affects the colon's lining and increases the risk of colon cancer. Despite ongoing research, there is no identified cure for UC. The recognition of NLRP3 inflammasome activation in the pathogenesis of UC has gained widespread acceptance. Notably, the ketone body ß-hydroxybutyrate inhibits NLRP3 demonstrating its anti-inflammatory properties. Additionally, BD-AcAc 2 is ketone mono ester that increases ß-hydroxybutyrate blood levels. It has the potential to address the constraints associated with exogenous ß-hydroxybutyrate as a therapeutic agent, including issues related to stability and short duration of action. However, the effects of ß-hydroxybutyrate and BD-AcAc 2 on colitis have not been fully investigated. This study found that while both exogenous ß-hydroxybutyrate and BD-AcAc 2 produced the same levels of plasma ß-hydroxybutyrate, BD-AcAc 2 demonstrated superior effectiveness in mitigating dextran sodium sulfate-induced UC in rats. The mechanism of action involves modulating the NF-κB signaling, inhibiting the NLRP3 inflammasome, regulating antioxidant capacity, controlling tight junction protein expression and a potential to inhibit apoptosis and pyroptosis. Certainly, BD-AcAc 2's anti-inflammatory effects require more than just increasing plasma ß-hydroxybutyrate levels and other factors contribute to its efficacy. Local ketone concentrations in the gastrointestinal tract, as well as the combined effect of specific ketone bodies, are likely to have contributed to the stronger protective effect observed with ketone mono ester ingestion in our experiment. As a result, further investigations are necessary to fully understand the mechanisms of BD-AcAc 2 and optimize its use.

The Role of the European Reference Network for Rare Bone Diseases (ERN BOND) and European Registries for Rare Bone and Mineral Conditions (EuRR-Bone) in the Governance of the Management of Rare Bone and Mineral Diseases.

Rare diseases (RDs) bear a significant challenge to individuals, healthcare systems, and societies. The European reference network on Rare BONe diseases (ERN BOND) is committed to improving multidisciplinary, patient-centred care for individuals with rare bone and mineral diseases (RBMDs). Its affiliated project, the European registries for rare bone and mineral conditions (EuRR-Bone) collects data using two different platforms, an electronic surveillance system (e-REC) that captures the occurrence of RBMDs and the Core Registry, a platform with the infrastructure for collecting Core data fields and longitudinal generic and condition-specific information. With emerging registries and the overlap with other ERNs, it is key to maintain the capability of the platforms to adapt to the needs of the network and the community whilst adhering to quality and FAIR (findable, accessible, interoperable, and reusable) principles. This binomial ensures long-term sustainability and potential advances in the care pathway of RBMDs whilst promoting good practice standards within Europe and beyond.

Scanner-Independent MyoMapNet for Accelerated Cardiac MRI T1 Mapping Across Vendors and Field Strengths.

BACKGROUND: In cardiac T1 mapping, a series of T1 -weighted (T1 w) images are collected and numerically fitted to a two or three-parameter model of the signal recovery to estimate voxel-wise T1 values. To reduce the scan time, one can collect fewer T1 w images, albeit at the cost of precision or/and accuracy. Recently, the feasibility of using a neural network instead of conventional two- or three-parameter fit modeling has been demonstrated. However, prior studies used data from a single vendor and field strength; therefore, the generalizability of the models has not been established. PURPOSE: To develop and evaluate an accelerated cardiac T1 mapping approach based on MyoMapNet, a convolution neural network T1 estimator that can be used across different vendors and field strengths by incorporating the relevant scanner information as additional inputs to the model. STUDY TYPE: Retrospective, multicenter. POPULATION: A total of 1423 patients with known or suspected cardiac disease (808 male, 57 ± 16 years), from three centers, two vendors (Siemens, Philips), and two field strengths (1.5 T, 3 T). The data were randomly split into 60% training, 20% validation, and 20% testing. FIELD STRENGTH/SEQUENCE: A 1.5 T and 3 T, Modified Look-Locker inversion recovery (MOLLI) for native and postcontrast T1 . ASSESSMENT: Scanner-independent MyoMapNet (SI-MyoMapNet) was developed by altering the deep learning (DL) architecture of MyoMapNet to incorporate scanner vendor and field strength as inputs. Epicardial and endocardial contours and blood pool (by manually drawing a large region of interest in the blood pool) of the left ventricle were manually delineated by three readers, with 2, 8, and 9 years of experience, and SI-MyoMapNet myocardial and blood pool T1 values (calculated from four T1 w images) were compared with conventional MOLLI T1 values (calculated from 8 to 11 T1 w images). STATISTICAL TESTS: Equivalency test with 95% confidence interval (CI), linear regression slope, Pearson correlation coefficient (r), Bland-Altman analysis. RESULTS: The proposed SI-MyoMapNet successfully created T1 maps. Native and postcontrast T1 values measured from SI-MyoMapNet were strongly correlated with MOLLI, despite using only four T1 w images, at both field-strengths and vendors (all r > 0.86). For native T1 , SI-MyoMapNet and MOLLI were in good agreement for myocardial and blood T1 values in institution 1 (myocardium: 5 msec, 95% CI [3, 8]; blood: -10 msec, 95%CI [-16, -4]), in institution 2 (myocardium: 6 msec, 95% CI [0, 11]; blood: 0 msec, [-18, 17]), and in institution 3 (myocardium: 7 msec, 95% CI [-8, 22]; blood: 8 msec, [-14, 30]). Similar results were observed for postcontrast T1 . DATA CONCLUSION: Inclusion of field strength and vendor as additional inputs to the DL architecture allows generalizability of MyoMapNet across different vendors or field strength. EVIDENCE LEVEL: 2. TECHNICAL EFFICACY: Stage 2.

Unraveling the miRNA Puzzle in Atherosclerosis: Revolutionizing Diagnosis, Prognosis, and Therapeutic Approaches.

PURPOSE OF REVIEW: To eradicate atherosclerotic diseases, novel biomarkers, and future therapy targets must reveal the burden of early atherosclerosis (AS), which occurs before life-threatening unstable plaques form. The chemical and biological features of microRNAs (miRNAs) make them interesting biomarkers for numerous diseases. We summarized the latest research on miRNA regulatory mechanisms in AS progression studies, which may help us use miRNAs as biomarkers and treatments for difficult-to-treat diseases. RECENT FINDINGS: Recent research has demonstrated that miRNAs have a regulatory function in the observed changes in gene and protein expression during atherogenesis, the process that leads to atherosclerosis. Several miRNAs play a role in the development of atherosclerosis, and these miRNAs could potentially serve as non-invasive biomarkers for atherosclerosis in various regions of the body. These miRNAs have the potential to serve as biomarkers and targets for early treatment of atherosclerosis. The start and development of AS require different miRNAs. It reviews new research on miRNAs affecting endothelium, vascular smooth muscle, vascular inflammation, lipid retention, and cholesterol metabolism in AS. A miRNA gene expression profile circulates with AS everywhere. AS therapies include lipid metabolism, inflammation reduction, and oxidative stress inhibition. Clinical use of miRNAs requires tremendous progress. We think tiny miRNAs can enable personalized treatment.

High-risk human papillomavirus infection and cervical cytopathology: relationship with cervical nitric oxide levels.

BACKGROUND: Nitric oxide (NO) may contribute to the persistence of high-risk human papillomavirus (hrHPV) infection, which has been linked to the development of premalignant lesions and cervical cancer. Our study aimed to examine the relationship between cervical NO metabolite (NOx) levels, hrHPV infection, and cytopathological findings. Additionally, we assessed cervical NOx levels as a biomarker for predicting hrHPV infection and epithelial atypia. METHODS: The study involved 74 women who attended the Gynecology and Obstetrics outpatient clinics at Cairo University Hospitals between November 2021 and August 2022. Cervical samples were subjected to Pap testing, assessment of NOx levels by the Griess method, and detection of hrHPV DNA by real-time polymerase chain reaction. RESULTS: High-risk HPV was detected in 37.8% of women. EA was found in 17.1% of cases, with a higher percentage among hrHPV-positive than negative cases (35.7% vs. 4.3%, p = 0.001). The most prevalent hrHPV genotype was HPV 16 (89.3%). The cervical NOx level in hrHPV-positive cases was significantly higher (37.4 µmol/mL, IQR: 34.5-45.8) compared to negative cases (2.3 µmol/mL, IQR: 1.2-9.8) (p = < 0.001). Patients with high-grade atypia showed significantly higher NOx levels (38.0 µmol/mL, IQR: 24.6-94.7) in comparison to NILM and low-grade atypia cases (5.0 µmol/mL, IQR: 1.6-33.3 and 34.5 µmol/mL, IQR: 11.7-61.7, respectively) (p = 0.006). Although the NOx levels among hrHPV-positive cases with low-grade atypia (40.4 µmol/mL, IQR: 33.3‒61.8) were higher than those with NILM (36.2 µmol/mL, IQR: 35.7‒44.0) and high-grade atypia (38.0 µmol/mL, IQR: 24.6‒94.7), the difference was not significant (p = 0.771). ROC curve analysis indicated that the cervical NOx cut-off values of > 23.61 µmol/mL and > 11.35 µmol/mL exhibited good diagnostic accuracy for the prediction of hrHPV infection and EA, respectively. CONCLUSIONS: The high prevalence of hrHPV infection, particularly HPV 16, in our hospital warrants targeted treatment and comprehensive screening. Elevated cervical NOx levels are associated with hrHPV infection and high-grade atypia, suggesting their potential use as biomarkers for predicting the presence of hrHPV and abnormal cytological changes.

Early-life bisphenol A exposure causes neuronal pyroptosis in juvenile and adult male rats through the NF-κB/IL-1ß/NLRP3/caspase-1 signaling pathway: exploration of age and dose as effective covariates using an in vivo and in silico modeling approach.

Bisphenol A (BPA), a common endocrine-disrupting chemical, is found in a wide range of home plastics. Early-life BPA exposure has been linked to neurodevelopmental disorders; however, the link between neuroinflammation, pyroptosis, and the development of psychiatric disorders is rarely studied. The current study attempted to investigate the toxic effect of BPA on inflammatory and microglial activation markers, as well as behavioral responses, in the brains of male rats in a dose- and age-dependent manner. Early BPA exposure began on postnatal day (PND) 18 at dosages of 50 and 125 mg/kg/day. We started with a battery of behavioral activities, including open field, elevated plus- and Y-maze tests, performed on young PND 60 rats and adult PND 95 rats. BPA causes anxiogenic-related behaviors, as well as cognitive and memory deficits. The in vivo and in silico analyses revealed for the first time that BPA is a substantial activator of nuclear factor kappa B (NF-κB), interleukin (IL)-1ß, -2, -12, cyclooxygenase-2, and the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, with higher beclin-1 and LC3B levels in BPA rats' PFC and hippocampus. Furthermore, BPA increased the co-localization of caspase-1 immunoreactive neurons, as well as unique neurodegenerative histopathological hallmarks. In conclusion, our results support the hypothesis that neuroinflammation and microglial activation are involved with changes in the brain after postnatal BPA exposure and that these alterations may be linked to the development of psychiatric conditions later in life. Collectively, our findings indicate that BPA triggers anxiety-like behaviors and pyroptotic death of nerve cells via the NF-κB/IL-1ß/NLRP3/Caspase-1 pathway.

The Moraxella catarrhalis AdhC-FghA system is important for formaldehyde detoxification and protection against pulmonary clearance.

Multidrug-resistant clinical isolates of Moraxella catarrhalis have emerged, increasing the demand for the identification of new treatment and prevention strategies. A thorough understanding of how M. catarrhalis can establish an infection and respond to different stressors encountered in the host is crucial for new drug-target identification. Formaldehyde is a highly cytotoxic compound that can be produced endogenously as a by-product of metabolism and exogenously from environmental sources. Pathways responsible for formaldehyde detoxification are thus essential and are found in all domains of life. The current work investigated the role of the system consisting of the S-hydroxymethyl alcohol dehydrogenase (AdhC), a Zn-dependent class III alcohol dehydrogenase, and the S-formyl glutathione hydrolase (FghA) in the formaldehyde detoxification process in M. catarrhalis. Bioinformatics showed that the components of the system are conserved across the species and are highly similar to those of Streptococcus pneumoniae, which share the same biological niche. Isogenic mutants were constructed to study the function of the system in M. catarrhalis. A single fghA knockout mutant did not confer sensitivity to formaldehyde, while the adhC-fghA double mutant is formaldehyde-sensitive. In addition, both mutants were significantly cleared in a murine pulmonary model of infection as compared to the wild type, demonstrating the system's importance for this pathogen's virulence. The respective phenotypes were reversed upon the genetic complementation of the mutants. To date, this is the first study investigating the role of the AdhC-FghA system in formaldehyde detoxification and pathogenesis of M. catarrhalis.

Serum endocan, asymmetric dimethylarginine and lipid profile in children with familial Mediterranean fever.

BACKGROUND: Familial Mediterranean fever (FMF) is a chronic inflammatory disease, and it is thought that subclinical inflammation persists even when there are no attacks, eventually causing endothelial dysfunction (ED) and atherosclerosis. Limited data are available about serum endocan, asymmetric dimethylarginine (ADMA) and lipid profile in children with FMF, so we aimed to evaluate these markers in children with FMF during the attack-free period. METHODS: A total of 50 patients diagnosed with FMF and 50 age and sex-matched healthy children were recruited. Serum endocan, ADMA and lipid profiles were measured. Also, atherogenic indices (Castelli's risk indices I and II [CRI I and II], atherogenic index of plasma [AIP] and atherogenic coefficient [AC]) were calculated. RESULTS: Serum endocan, ADMA levels, low-density lipoprotein cholesterol, triglycerides, CRI II and AIP of the FMF patients were significantly higher than controls (p < 0.001). Unlike serum endocan, serum ADMA showed a positive significant correlation with total cholesterol, non-high density lipoprotein cholesterol, CRI I, AIP and AC (p < 0.001, p < 0.001, p = 0.004, p = 0.028, p = 0.004 respectively). CONCLUSION: Serum ADMA and lipid profile might be used as potential markers for endothelial dysfunction and increased cardiovascular risk in FMF patients. IMPACT: Theoretically, serum ADMA may affect lipid profiles and serum endocan represents an intriguing biomarker related to inflammation. Coexistence of dyslipidemia represents an additional risk factor that contributes to the onset of early atherosclerosis. A few studies investigated the role of changes in lipid profile and lipid ratios in accelerated atherosclerosis pathogenesis in FMF patients. The relationship between colchicine and lipid profile is contradictory. Although colchicine can cause dyslipidemia, it also has anti-atherosclerosis effects. Elevated ADMA level and atherogenic indices in FMF children reflect their potential role in the early detection of cardiovascular affection in FMF patients.

HbA1c or fructosamine on evaluating glucose intolerance in children with beta- thalassemia.

BACKGROUND: Beta-thalassemia major (ß-TM) patients are more likely to experience blood glucose intolerance and to date; the blood markers that could evaluate this are debatable. So, this study aimed to assess the roles of glycated hemoglobin A1c (HbA1c) and fructosamine in evaluating glucose intolerance in children with ß-TM and figuring out role of insulin resistance in these patients. METHODS: One hundred children diagnosed with ß-TM and 100 age and sex-matched controls were enrolled. Fasting plasma glucose (FPG), 2-h post-prandial blood glucose (2-h PG), HbA1c, fructosamine, fasting insulin level (FINS), insulin resistance index (HOMA-IR), and insulin sensitivity index (HOMA-IS) were evaluated. RESULTS: FPG and 2-h PG revealed glucose intolerance in 51 patients (51%), 19 of them had diabetes mellitus. HbA1c, fructosamine, FINS, and HOMA-IR showed a high statistically significant increase in patients compared to controls, (P < 0.001). Results revealed fructosamine was more specific in detecting prediabetes state and more sensitive in identifying diabetes mellitus in our patients when compared to HbA1c. CONCLUSIONS: Despite controversies on HbA1c in children with ß-TM, it is still valuable in glucose intolerance detection. Fructosamine showed more sensitivity and specificity. Furthermore, insulin resistance was prevalent in children with ß-TM highlighting the necessity of regular glycemic state evaluation. IMPACT: Glucose intolerance is a common complication in beta thalassemia patients. Conflicting data was reported about the role of HbA1c and fructosamine in evaluating glucose intolerance in thalassemic patients. Fructosamine does not yet have a threshold that may be used to distinguish between patients who have diabetes mellitus and those who do not. Fructosamine was more specific in detecting blood glucose intolerance compared to HbA1c and was more sensitive for diagnosing diabetes mellitus. Insulin resistance was common in patients with beta-thalassemia and often present before the onset of overt diabetes.

Serum eosinophil-derived neurotoxin: a new promising biomarker for cow's milk allergy diagnosis.

BACKGROUND: Cow's Milk Allergy (CMA) diagnosis is often a challenge due to the non-specific nature of symptoms and lack of a confirmatory diagnostic test. To our knowledge no previous studies investigated serum Eosinophil-Derived Neurotoxin (sEDN) in CMA. So, we aimed to assess the role of sEDN in CMA diagnosis. METHODS: Forty-five infants with CMA were compared to 45 infants with functional gastrointestinal disorders (FGIDs) and 45 healthy controls. For all participants, Cow's Milk-related Symptom Score (CoMiSS) was documented, and sEDN level with hematological parameters were measured before starting elimination diet. RESULTS: Receiver operation characteristic (ROC) curve identified sEDN > 14 ng/mL and CoMiSS > 9 as the optimal cut-off points to discriminate CMA from other groups with sensitivity 86.67%, 97.78% and specificity 60.00%, 78.89% respectively. Additionally, absolute neutrophil count (ANC) showed the highest sensitivity and specificity (80.0% and 78.89%) among hematological parameters. Although CoMiSS and ANC showed a significant positive correlation with sEDN in CMA group, CoMiSS was the only significant predictor for sEDN in multivariate linear regression. CONCLUSIONS: sEDN showed high sensitivity in discriminating infants with and without CMA. Therefore, it is suggested as a potential biomarker for CMA diagnosis. Also, ANC should be closely monitored in these infants. IMPACT: CMA presents with high heterogeneity, which complicates the diagnosis especially non-IgE-mediated and mixed types. So, oral food challenge continues to be the gold standard for its diagnosis. ROC curve identified CoMiSS > 9 as the best cut-off point to identify CMA. However, CoMiSS is a good awareness tool for CMA but not a diagnostic tool. sEDN level was significantly higher in infants with CMA with a good diagnostic performance in differentiating them than those without CMA. So, it is suggested as a potential biomarker for CMA diagnosis. ANC could have a role in CMA diagnosis and differentiating it from FGIDs.

Association of ACE1 I/D polymorphism and susceptibility to COVID-19 in Egyptian children and adolescents.

BACKGROUND: Given the sparse data on the renin-angiotensin system (RAS) and its biological effector molecules ACE1 and ACE2 in pediatric COVID-19 cases, we investigated whether the ACE1 insertion/deletion (I/D) polymorphism could be a genetic marker for susceptibility to COVID-19 in Egyptian children and adolescents. METHODS: This was a case-control study included four hundred sixty patients diagnosed with COVID-19, and 460 well-matched healthy control children and adolescents. The I/D polymorphism (rs1799752) in the ACE1 gene was genotyped by polymerase chain reaction (PCR), meanwhile the ACE serum concentrations were assessed by ELISA. RESULTS: The ACE1 D/D genotype and Deletion allele were significantly more represented in patients with COVID-19 compared to the control group (55% vs. 28%; OR = 2.4; [95% CI: 1.46-3.95]; for the DD genotype; P = 0.002) and (68% vs. 52.5%; OR: 1.93; [95% CI: 1.49-2.5] for the D allele; P = 0.032). The presence of ACE1 D/D genotype was an independent risk factor for severe COVID-19 among studied patients (adjusted OR: 2.6; [95% CI: 1.6-9.7]; P < 0.001. CONCLUSIONS: The ACE1 insertion/deletion polymorphism may confer susceptibility to SARS-CoV-2 infection in Egyptian children and adolescents. IMPACT: Recent studies suggested a crucial role of renin-angiotensin system and its biological effector molecules ACE1 and ACE2 in the pathogenesis and progression of COVID-19. To our knowledge, ours is the first study to investigate the association of ACE1 I/D polymorphism and susceptibility to COVID-19 in Caucasian children and adolescents. The presence of the ACE1 D/D genotype or ACE1 Deletion allele may confer susceptibility to SARS-CoV-2 infection and being associated with higher ACE serum levels; may constitute independent risk factors for severe COVID-19. The ACE1 I/D genotyping help design further clinical trials reconsidering RAS-pathway antagonists to achieve more efficient targeted therapies.

Alpha-synuclein pathology in isolated rapid eye movement sleep behaviour disorder: a meta-analysis.

Accumulating evidence indicates that patients with isolated rapid eye movement sleep behaviour disorder (iRBD), a prodromal stage of synucleinopathies, show abnormal deposition of misfolded alpha-synuclein (a-Syn) in peripheral tissues. The clinical utility of testing for a-Syn in iRBD is unclear. This meta-analysis focused on the utility of testing for the abnormal a-Syn phosphorylated at Ser129 (p-syn) and a-Syn seeding activity (a-Syn seed amplification assays [aSyn-SAA]). Following an electronic database search, 15 studies were included that provided at a minimum data on test positivity in participants with iRBD. Test positivity from cerebrospinal fluid (CSF) was 80% (95% confidence interval [CI] 68-88%, I2 = 71%) and for skin was 74.8% (95% CI 53.2-88.5%, I2 = 64%) for aSyn-SAA and 78.5% (95% CI 70.4-84.9%, I2 = 14%) for p-syn. The phenoconversion rate ratio of biopsy-positive versus biopsy-negative iRBD was 1.28 (95% CI 0.68-2.41, I2 = 0%). Skin as a source had a specificity of 99% (95% CI 95-100%, I2 = 0%; p = 0.01 compared to CSF). As a test, p-syn, had a specificity of 100% (95% CI 93-100%, I2 = 0%; p < 0.001) compared to aSyn-SAA. The odds ratio of a-Syn test positivity in iRBD versus other RBDs was 112 (95% CI 20-629, I2 = 0%). These results demonstrate clinically significant test positivity in iRBD and favour skin over CSF as the source of a-Syn pathological analysis, and p-syn over aSyn-SAA as the testing method. Overall, these findings indicate that testing for a-Syn could help in differentiating iRBD from RBD secondary to other conditions.

Focused UTUC pathways with a risk-stratified approach to diagnostic ureteroscopy: is it the need of the hour? A retrospective cohort analysis.

INTRODUCTION: Upper urinary tract urothelial cancer is a rare, aggressive variant of urinary tract cancer. There is often delay to diagnosis and management for this entity in view of diagnostic and staging challenges needing additional investigations and risk stratifications for improved outcomes. In this article, we share our experience in developing a dedicated diagnostic and treatment pathway for UTUC and assess its impact on time lines to radical nephroureterectomy (RNU). We also evaluate the impact of diagnostic ureteroscopy (DUR) on UTUC care pathways timelines. MATERIALS AND METHODS: A prospective database was maintained for all patients who underwent a RNU from January 2015 to August 2022 in a high-volume single tertiary care centre in the UK. In 2019, a Focused UTUC pathway (FUP) was implemented at the centre to streamline diagnostic and RNU pathways. A retrospective analysis of the database was conducted to compare time lines and diagnostic trends between the pre-FUP and FUP cohorts. Primary outcome measures were time to RNU from MDT. Secondary outcome measures were: impact of DUR on time to RNU from MDT and negative UTUC rates between DUR and non-DUR cohorts. Differences in continuous variables across categories were assessed using the independent sample t test. Categorical variables between cohorts were analysed using the chi-square (χ2). Statistical significance in this study was set as p < 0.05. RESULTS: A total of 500 patients with complete data were included in the analysis. The pre-FUP and FUP cohorts consisted of 313 patients and 187 patients, respectively. The overall cohort had a mean age (SD) of 70 years (9.3). 66% of the overall cohort were males. The median time to RNU from MDT in the FUP was significantly lower compared to the pre-FUP cohort; 62 days (IQR 59) vs. 48 days (IQR 41.5), p < 0.0001. The median time to RNU from MDT in patients who underwent a diagnostic URS in the FUP cohort was significantly lower compared to the pre-FUP cohort; 78.5 days (IQR 54.8) vs. 68 days (IQR 48), p-NS. The non-UTUC rates in the DUR and non-DUR cohorts were 6/248 (2.4%) and 14/251 (5.6%), respectively (NS). CONCLUSION: In this series, we illustrate the effectiveness of integrating a multidisciplinary approach with specialised personnel, ring-fenced clinics, efficient diagnostic assessment and optimised theatre capacity. By adopting a risk-stratified approach to diagnostic ureteroscopy, we have achieved a significant reduction in time to RNU.