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Abstract Disclosure: S. Lee: None. L. Needleman: None. J. Park: None. R. Schugar: None. J.P. Annes: None. Pathogenic mutations in the succinate dehydrogenase complex, particularly in the SDHB gene, predispose individuals to hereditary pheochromocytoma and paraganglioma (hPPGL). However, more than 80% of missense SDHB variants are classified as variants of uncertain significance (VUS) in ClinVar. Consequently, numerous families harboring an SDHB VUS are at elevated oncologic risk, but do not benefit from early detection protocols. As SDHB pathogenicity is caused by impaired SDH enzymatic activity, functional evaluation may help resolve VUS classification. Hence, we developed a functional biochemical assay using CRISPR/Cas9-engineered SDHB-knockout HEK293 cells to assess succinate/fumarate ratios by LC-MS/MS as a proxy for SDH enzymatic activity. Loss of SDHB led to a marked elevation in the succinate/fumarate ratio, which was restored by transfection of wild-type SDHB. Expression of 35 classified variants (9 benign, 26 pathogenic) clustered into low and high succinate/fumarate ratio groups, validating the assay’s ability to resolve SDHB variant functionality. To improve interpretability, we converted succinate/fumarate ratios into SDH % activity, which was used for the logistic regression modeling of known variants. Using the trained model, P(path) and OddsPath values were calculated to assign ACMG/AMP functional evidence strength (BS3/PS3). Compared to the computational predictor REVEL, our assay provided superior discrimination between benign and pathogenic variants. This model was applied to 33 VUSs, including 16 Stanford patient alleles and three causative of Leigh syndrome. Twenty-three VUSs demonstrated wild-type-like activity (BS3), while 10 exhibited marked SDH dysfunction and were assigned PS3strong. Following ACMG/AMP guidelines, mock clinical interpretation that included our functional assay recategorized 78% of SDHB VUSs (16 likely benign and 10 likely pathogenic). Notably, all SDHB VUSs affecting highly conserved cysteine residues responsible for Fe-S cluster coordination showed complete enzymatic loss, confirming the critical function of these domains. Interestingly, recessive mitochondrial disease-associated SDHB variants (Leighs) were not reliably distinguished from wild-type-like variants, indicating these variants are not causative for hPPGL. Finally, pathogenic variants with relatively lower succinate/fumarate ratios than PPGL-predominant variants were associated with increased occurrence of head and neck paragangliomas (HNPGL; r2=0.45; p=0.0001). Logistic modeling identified a metabolic threshold predictive of tumor location; hence, SDH dysfunction severity influences location-specific tumor risk. Together, these data establish a robust, quantitative platform for SDHB variant classification with immediate clinical implications for risk assessment and tumor surveillance. Presentation: Saturday, July 12, 2025

Context and ObjectiveIn vitro labelling of leukocytes with 99mTc-HMPAO is a haematological test performed and optimised in specialised radiopharmacies in some university hospitals. It is used to differentiate between infection on implanted devices and inflammation in cases of pain. However, it requires high-quality biological samples. Several factors, including those related to the patient and healthcare professionals, affect the outcome. This study aims to establish a link between sample quality and image quality to improve our practices and patient care.Materials and MethodsWe first established criteria to assess blood sample quality, such as the duration of collection, the type of equipment used, the puncture site, sedimentation time, hemolysis, and cell viability tests, alongside an associated score (≤2: excellent, 3≤ score ≤5: average, ≥6: poor). We then defined image quality criteria in the early phase, based on spleen/liver (S/L) activity ratios measured during imaging (a ratio <130% indicating good image quality, 130%–150% moderate quality, and >150% poor quality). Lastly, we statistically compared S/L ratios between two groups: good vs. average/poor samples.ResultsOut of 23 samples, 18 were rated ‘excellent,’ two ‘average,’ and three ‘poor.’ Among the ‘excellent’ samples, 17 had S/L ratios <130%, corresponding to good image quality, while one had a ratio >150%. Among the five ‘average/poor’ samples, one had an S/L ratio <130%, one between 130%–150%, and three >150%. A significant difference (P<0.05) was found between the good and average/poor sample groups.Conclusion/DiscussionOur results suggest that sample quality affects image quality. However, certain biases, such as the small sample size and the low proportion of ‘average/poor’ samples (5/23), should be considered. The choice of quality criteria and scoring system may need refinement. Additionally, the patient’s cell condition at the time of testing and the proximity of the suspected infection to organs like the liver and spleen may influence the results. A larger, long-term study could help develop optimal sampling recommendations.

The present research work's purpose is to examine the vital factors that affect the solvency of the Indian construction sector. The two different parameters of solvency, namely debt to total assets (DTA) and cash flow to total liabilities (CFTL), are used in the present study. These two solvency indicators have been categorized using zero and one numerical values. One indicates financially sound companies, and zero indicates weak companies with poor solvency ratios. The different financial ratios, namely, profitability, liquidity, leverages, and turnovers, are used as predictors or explanatory variables of insolvency of Indian construction companies. The study employs multivariate discriminant analysis (MDA) and binary logistic regression to predict the factors accountable for the insolvency of the Indian construction sector. The empirical findings of MDA and logistic regression show significant discrimination in the solvency position of construction companies according to their different financial performance parameters, namely, profitability, liquidity, leverage, and management efficiency. Since there are two categories of companies as per their solvency position. So one discriminant function is created and found significant at 5% levels for two different solvency parameters. In the case of the first measure of solvency (DTA), turnover liquidity leverage ratios are the critical indicators for predicting the solvency of the Indian construction industry. Findings of MDA indicate that in the case of the second parameter of solvency (CFTL), profitability and management efficiency significantly discriminate between solvent and solvent companies. The logistic regression findings show that In the case of the first measure (DTA), leverage, liquidity, and management efficiency significantly distinct two sets of construction companies. In the case of the second measure of solvency (CFTL), profitability, management efficiency significantly discriminate solvency of two sets of companies. Overall the findings of MDA and logistic regression are consistent with each other. The outcomes of the study will be helpful to policymakers' different stakeholders. Society will also be benefitted by knowing the critical factors responsible for companies that are likely to become insolvent. Accordingly, the policymakers may issue financial assistance, subsidies, and advice to concerned companies.

We present a new methodology of computing incremental contribution for performance ratios for portfolio like Sharpe, Treynor, Calmar or Sterling ratios. Using Euler’s homogeneous function theorem, we are able to decompose these performance ratios as a linear combination of individual modified performance ratios. This allows understanding the drivers of these performance ratios as well as deriving a condition for a new asset to provide incremental performance for the portfolio. We provide various numerical examples of this performance ratio decomposition. Mathematics Subject Classification: C12; G11

Background The utility of neutrophil‐to‐lymphocyte ratio (NLR), platelet to‐lymphocyte ratio (PLR) and monocyte‐to‐lymphocyte ratio (MLR) as prognostic indicators has not been investigated in canine parvovirosis (CPV). Hypothesis To evaluate whether these hematological ratios obtained at hospital admission in CPV are associated with outcome or duration of hospitalization. Animals. Four hundred one client‐owned dogs presented with CPV. Methods‐Retrospective multicenter cohort study. Medical records were reviewed to identify dogs with CPV. Data regarding signalment, complete blood count at admission, duration of hospitalization and outcome were collected. Results Of the 401 dogs included in the study, 336 (83.8%) survived to discharge. The median (25th and 75th percentiles) PLR in nonsurvivors (336.56 [159.84‐635.77]) was significantly higher than in survivors (217.65 [117.67‐389.65]) (P = .003). The area under the receiver‐operating characteristic curve for nonsurvival was 0.615 (95% CI [0.593‐0.691], P = .003). A cut off of 700 showed a 21.5% sensitivity and 90% specificity for nonsurvival. No association was observed between hospitalization duration and either hematological ratios or total WBC counts. The median (25th and 75th percentiles) lymphocyte count was below reference interval in all dogs and was significantly lower in the dogs which died (0.82 × 109/L [0.5‐1.87]) than in survivors (1.27 × 109/L [0.73‐2.22]) (P = .005). The median (25th and 75th percentiles) monocyte count however was lower in survivors (0.38 × 109/L [0.29‐1.59]), than in nonsurvivors (0.73 × 109/L [0.1‐2]) (P = .002). Conclusions Evaluation of PLR at hospital admission might be a useful marker of disease severity and could have prognostic value in dogs with CPV.

Background The CD4/CD8 ratio has been associated with the risk of AIDS and non-AIDS events. We describe trends in immunological parameters in people who underwent a switch to monotherapy or dual therapy, compared to a control group remaining on triple antiretroviral therapy (ART). Methods We included patients in Icona who started a three-drug combination ART regimen from an ART-naïve status and achieved a viral load ≤ 50 copies/mL; they were subsequently switched to another triple or to a mono or double regimen. Standard linear regression at fixed points in time (12-24 months after the switch) and linear mixed model analysis with random intercepts and slopes were used to compare CD4 and CD8 counts and their ratio over time according to regimen types (triple vs. dual and vs. mono). Results A total of 1241 patients were included; 1073 switched to triple regimens, 104 to dual (72 with 1 nucleoside reverse transcriptase inhibitor (NRTI), 32 NRTI-sparing), and 64 to monotherapy. At 12 months after the switch, for the multivariable linear regression the mean change in the log 10 CD4/CD8 ratio for patients on dual therapy was −0.03 (95% confidence interval (CI) –0.05, –0.0002), and the mean change in CD8 count was +99 (95% CI +12.1, +186.3), taking those on triple therapy as reference. In contrast, there was no evidence for a difference in CD4 count change. When using all counts, there was evidence for a significant difference in the slope of the ratio and CD8 count between people who were switched to triple (points/year change ratio = +0.056, CD8 = −25.7) and those to dual regimen (ratio = −0.029, CD8 = +110.4). Conclusions We found an increase in CD8 lymphocytes in people who were switched to dual regimens compared to those who were switched to triple. Patients on monotherapy did not show significant differences. The long-term implications of this difference should be ascertained.

Background Neutral‐to‐lymphocyte ratio (NLR), lymphocyte‐to‐monocyte ratio (LMR), and platelet‐to‐lymphocyte ratio (PLR) are associated with coronavirus disease 2019 (COVID‐19) and many diseases, but there are few data about the reference interval (RI) of NLR, LMR, and PLR. Methods The neutrophil count, lymphocyte count, monocyte count, and platelet count of 404,272 Chinese healthy adults (>18 years old) were measured by Sysmex XE‐2100 automatic hematology analyzer, and NLR, LMR, and PLR were calculated. According to CLSI C28‐A3, the nonparametric 95% percentile interval is defined as the reference interval. Results The results of Mann‐Whitney U test showed that NLR (p < .001) in male was significantly higher than that in female; LMR (p < .001) and PLR (p < .001) in male were significantly lower than that in female. Kruskal‐Wallis H test showed that there were significant differences in NLR, LMR, and PLR among different genders and age groups (p < .001). The linear graph showed that the reference upper limit of NLR and PLR increased with age and the reference upper limit of LMR decreases with age in male population. In female population, the reference upper limit of NLR in 50–59 group, LMR in >80 group, and PLR in 70–79 group appeared a trough; the reference upper limit of NLR in >80 group, LMR in 50–59 group, and PLR in 40–49 group appeared peak. Conclusion The establishment of RI for NLR, LMR, and PLR in Chinese healthy adults according to gender and age will promote the standardization of clinical application. Values of upper reference limits for three indicators in different age partitions. A: Values of upper reference limits for NLR in different age partitions. B: Values of upper reference limits for LMR in different age partitions. C: Values of upper reference limits for PLR in different age partitions. The line chart based on age showed that the reference upper limit of NLR, LMR, and PLR increased with age in male population. In female population, the reference upper limit of NLR in 50–59 group, LMR in >80 group, and PLR in 70–79 group showed a trough; the reference upper limit of NLR in >80 group, LMR in 50–59 group, and PLR in 40–49 group showed peak.

Cardiovascular disease, particularly coronary artery disease (CAD), remains a predominant cause of mortality globally. Factors such as atherosclerosis and inflammation play significant roles in the pathogenesis of CAD. The nexus between inflammation and CAD is underscored by the role of immune cells, such as neutrophils, lymphocytes, monocytes, and macrophages. These cells orchestrate the inflammatory process, a core component in the initiation and progression of atherosclerosis. The activation of these pathways and the subsequent lipid, fibrous element, and calcification accumulation can result in vessel narrowing. Hematological parameters derived from routine blood tests offer insights into the underlying inflammatory state. Recent studies have highlighted the potential of inflammatory hematological ratios, such as the neutrophil/lymphocyte ratio, platelet/lymphocyte ratio, monocyte/lymphocyte ratio and lymphocyte/monocyte ratio. These parameters are not only accessible and cost-effective but also mirror the degree of systemic inflammation. Several studies have indicated a correlation between these markers and the severity, prognosis, and presence of CAD. Despite the burgeoning interest in the relationship between inflammatory markers and CAD, there remains a paucity of data exploring these parameters in young patients with acute myocardial infarction. Such data could offer valuable insights into the unique pathophysiology of early-onset CAD and improve risk assessment and predictive strategies.

Ecological stoichiometry is concerned with the ratios of different elements, particularly carbon, nitrogen, and phosphorus. Ratios by their nature do not respond symmetrically to changes in the numerator and denominator and do not follow normal distributions; however, researchers frequently fail to consider these properties in their analyses, which has biased reported results. Calculating means, variance, or linear slopes based on untransformed ratios results in biased results. I demonstrate the consequences of these errors for inferences from stoichiometric analyses using simple examples and several large monitoring data sets. I then review 100 studies in ecological stoichiometry and find that misuse of ratio data is common, with 93% of studies containing at least one error. These errors may be problematic, particularly in large-scale meta-analyses summarizing data over large ranges. Fortunately, most of these mistakes can be easily avoided by first log transforming elemental ratios. I therefore recommend that, to ensure robust and reproducible results, researchers in ecological stoichiometry should adopt a convention of presenting stoichiometric ratio data as the logarithm of molar ratios in the future. The widespread use of untransformed nitrogen to phosphorus ratio as an indicator of nutrient limitation has likely exaggerated the importance of phosphorus limitation, particularly in freshwater systems.