Cut-off Range Research Articles

The Weight of Nutrition on Post-Resection Oncologic Morbidity and Mortality: A Systematic Review and Meta-Analysis of Nutritional Indices

Abstract Context Nutritional status is a critical factor in the selection of patients for solid tumor resection. A variety of indices have been developed to quantify nutritional status, and they have differing degrees of predictive power for various postoperative outcomes. Objective This study aimed to comprehensively evaluate the predictive ability of commonly used nutritional indices in relation to postoperative complications (POCs), recurrence-free survival (RFS), and OS. Data Sources We performed a systematic review of 14 established nutritional indices from January 2015 to July 2022: Data Extraction The primary end point was OS, while the secondary end points were POCs and RFS. A subsequent meta-analysis was performed to further assess the predictive ability of these indices for OS based on general index type, primary tumor site, and the patient’s index status. Data Analysis In this evaluation, 38 articles reporting data on 23 970 patients were analyzed, focusing on 14 nutritional indices. The indices were categorized into phenotypic, metabolic, immunologic, and combined types. Patients within the cut-off range of any index were predicted to have lower OS (hazard ratio [HR] 2.14, 95% CI 1.84–2.49, P < .01). Lower gastrointestinal (GI) and “other” sites were less predictive than upper GI primary tumors (HR 1.63, HR 1.82, and HR 2.54, respectively; all with P < .01). Phenotypic indices were less predictive than combined indices (HR 1.73 vs HR 2.47, P < .01). Within the combined category, there was no significant difference in the predictive ability of Prognostic Nutritional Index (PNI) vs Geriatric Nutritional Risk Index (GNRI) vs Controlling Nutritional Index (CONUT) (HR 2.63 vs HR 2.42 vs HR 2.07, P = .07). Conclusion The predictive efficacy of a nutritional index was found to be highly dependent on the index type, the primary tumor site, and the outcome of interest. In the context of upper GI resections, nutritional status appeared to be more of a significant predictor of OS, compared with cases involving lower GI and hepatic malignancies. Indices that integrate phenotypic, metabolic, and immunologic patient factors potentially offer greater clinical utility in forecasting OS.

Diagnostic accuracy of the Fibrosis-4 index for advanced liver fibrosis in nonalcoholic fatty liver disease with type 2 diabetes: A systematic review and meta-analysis.

The Fibrosis-4 index (FIB-4) is a noninvasive test widely used to rule out advanced liver fibrosis (AF) in patients with nonalcoholic fatty liver disease (NAFLD). However, its diagnostic accuracy in NAFLD patients with type 2 diabetes mellitus (T2DM) is controversial due to the high prevalence of AF in this population. Research focusing on the diagnostic accuracy of FIB-4 for liver fibrosis as validated by liver histology in NAFLD patients with T2DM was included, and 12 studies (n=5,624) were finally included in the meta-analysis. Sensitivity, specificity, hierarchical summary receiver operating characteristic (HSROC), positive predictive values (PPVs), and negative predictive values (NPVs) at low cutoffs (1.3-1.67) and high cutoffs (2.67-3.25) for ruling in and out AF were calculated. At low cutoffs, the meta-analysis revealed a sensitivity of 0.74, specificity of 0.62, and HSROC of 0.75. At high cutoffs, the analysis showed a sensitivity of 0.33, specificity of 0.92, and HSROC of 0.85, suggesting FIB-4 as useful for identifying or excluding AF. In subgroup analyses, high mean age and F3 prevalence were associated with lower sensitivity. The calculated NPV and PPV were 0.82 and 0.49 at low cutoffs, whereas the NPV was 0.28 and the PPV was 0.70 at high cutoffs. There were insufficient estimated NPVs <0.90 at a hypothesized prevalence of AF >30% at an FIB-4 cutoff range of 1.3-1.67. Collectively, FIB-4 has moderate diagnostic accuracy for identifying or excluding AF in NAFLD patients with T2DM, but more evidence must be accumulated due to the limited number of currently reported studies and their heterogeneity.

Development of charged membranes for the ultrafiltration of siRNA

RNA interference (RNAi) is an exciting new therapeutic approach, using small interfering RNA (siRNA) to silence specific genes for treating various diseases. Ultrafiltration has been widely used for the concentration and purification of monoclonal antibodies and other biotherapeutics; however, its application in the downstream processing of double-stranded oligonucleotides remains underexplored. This study investigates the use of ultrafiltration in the final formulation for concentrating a siRNA drug substance. Initial experiments were conducted with Ultracel™ composite regenerated cellulose membranes over a range of molecular weight cutoffs (MWCO) at different siRNA feed concentrations. Results demonstrated significant effects of both fouling and concentration polarization, with the maximum achievable concentration falling well below the target required for subcutaneous injection. Novel surface-modified ultrafiltration membranes were made by reaction of the cellulose with bromopropanesulfonic acid. These negatively charged membranes showed improved siRNA retention, reduced fouling, and a large increase in the maximum achievable siRNA concentration (from 52 to >180 mg/mL). These findings offer critical insights into novel approaches for developing high performance ultrafiltration processes for siRNA concentration.

Responsiveness of the Oswestry Disability Index and Zurich Claudication Questionnaire in patients with lumbar spinal stenosis: evaluation of surgically treated patients from the NORDSTEN study

PurposeTo evaluate the responsiveness of the original low back pain specific Oswestry Disability Index (ODI) and the spinal stenosis specific Zürich Claudication Questionnaire (ZCQ), and to investigate cut-off values for clinical “success” for ODI and ZCQ in surgically treated patients with lumbar spinal stenosis (LSS).MethodsWe included 601 LSS patients (218 with, 383 without degenerative spondylolisthesis) from the NORDSTEN trials. Outcome measures included ODI and ZCQ (symptom severity and physical function scales) with three alternative response parameters: scores at follow-up, absolute and relative changes from baseline to two-year follow-up. Effect size and standardised response mean evaluated internal responsiveness. External responsiveness was assessed by the Spearman rank correlation between patient-reported global perceived effect scale (GPE) and ODI and ZCQ, and receiver operating characteristics (ROC). We evaluated which cut-off values could maximise the percentage of correctly classified patients according to the GPE-anchor “completely recovered” / “much improved” for each parameter.ResultsInternal and external responsiveness were high for all three indices with effect sizes, standardized response means, ROC and corresponding area under the curve > 0.8. Correlations with GPE responses were moderate (> 0.50) for absolute change and strong (> 0.67) for relative change and follow-up scores. The 30% ODI relative change cut-off correctly classified 81% of patients to “success”, within a range of accurate cut-offs according to the GPE-anchor.ConclusionODI and ZCQ demonstrate comparable responsiveness in evaluating outcomes for surgically treated LSS patients. The 30% ODI threshold was consistent with treatment “success” in NORDSTEN trials.Trial registrationClinicalTrials.gov; NCT02007083 10/12/2013, NCT02051374 31/01/2014 and NCT03562936 20/06/2018.

Standardizing and Improving Primary Care-Based Electronic Developmental Screening for Young Children in Federally Qualified Health Center Clinics

ObjectivesMany barriers to implementation of developmental screening in primary care exist, especially for children from under-resourced communities. Developmental screening is vital to early detection of developmental delay and autism spectrum disorder, and early intervention (EI) referral. This study sought to examine whether implementation of a standardized clinical workflow using electronic screening tools improved both rates of developmental screening, and the number of children identified at risk for developmental delay, in a federally qualified health center (FQHC).MethodsA retrospective study was conducted at an academic-affiliated FQHC. Electronic versions of the Ages and Stages Questionnaire 3 (ASQ-3) and Modified Checklist in Autism for Toddlers Revised (M-CHAT-R) were implemented at well-child visits. New clinical workflow training on developmental screening and EI referral was provided. Chi-square and Fisher’s Exact analyses were conducted.ResultsASQ-3 screening rates increased from 62.7 to 73.6% pre- to post-intervention. Post-intervention, there was a significant decrease in paper screens (p < .001), and a significant increase in the percentage of children with ASQ-3 results in the below cutoff range from 14.7 to 18.2% (p < .002). M-CHAT-R screening rates increased from 56.4 to 59.4% pre- to post-intervention. Post-intervention, there was a significant increase in electronic screens (p < .001).Conclusions for PracticeImplementation of electronic screening tools improved universal developmental screening in a FQHC. To decrease barriers in under-resourced communities, the use of electronic tools may decrease the rate of screening error seen with paper screening and have the potential to better identify children at risk for developmental delay.

Self-Assembly of Chiral Porous Metal-Organic Polyhedra from Trianglsalen Macrocycles.

Metal-organic polyhedra (MOPs) can exhibit tunable porosity and functionality, suggesting potential for applications such as molecular separations. MOPs are typically constructed by the bottom-up multicomponent self-assembly of organic ligands and metal ions, and the final functionality can be hard to program. Here, we used trianglsalen macrocycles as preorganized building blocks to assemble octahedral-shaped MOPs. The resultant MOPs inherit most of the preorganized properties of the macrocyclic ligands, including their well-defined cavities and chirality. As a result, the porosity in the MOPs could be tuned by modifying the structure of the macrocycle building blocks. Using this strategy, we could systematically enlarge the size of the MOPs from 26.3 to 32.1 Å by increasing the macrocycle size. The family of MOPs shows experimental surface areas of up to 820 m2/g, and they are stable in water. One of these MOPs can efficiently separate the rare gases Xe from Kr because the prefabricated macrocyclic windows of MOPs can be modified to sit at the Xe/Kr size cutoff range.

Lithium insertion/extraction mechanism in Mg2Sn anode for lithium-ion batteries

Due to its high capacity and excellent voltage properties, the Mg2Sn intermetallic phase is considered a promising anode material for next-generation lithium-ion batteries. However, the rapid capacity loss with cycling presently limits the application of Mg2Sn-based anodes. In this work, the Mg2Sn intermetallic phase was synthesized via a conventional casting method, and mechanisms of lithium ions intercalation into Mg2Sn alloy anodes were systematically studied. Density functional theory (DFT) calculations and electrochemical analyses identified two pathways involving four electrochemical reactions for Li+ intercalation/extraction in the Mg2Sn phase. The first pathway involves the insertion reaction of lithium ions into the octahedral sites of the Mg2Sn face center cubic (FCC) matrix, whilst the second involves the substitution of Mg by Li ions (releasing Mg metal). Furthermore, ex-situ EIS analysis and DFT calculations verified that adjusting the cut-off voltage range could control the reaction pathways. Excessively high or low cut-off voltages adversely impact the stability of the Mg2Sn anode. At cut-off voltages between 0.1 and 1 V, Mg2Sn anodes show very good capacity retention (78 % after 50 cycles), benefiting from the minimized formation of metallic Mg and Sn phases.

Recent safety and efficacy findings from a phase 1b/2 open-label combination study of ASP-1929 photoimmunotherapy with anti-PD-1 therapy in EGFR-expressing advanced head and neck squamous cell carcinoma (HNSCC).

6083 Background: In the challenging landscape of advanced HNSCC, patients (pts) have overall low survival and high locoregional (LR) recurrence rates. While LR progression is a key contributor to morbidity and mortality, LR control remains low despite aggressive therapy including surgery, radiation, chemotherapy, and immunotherapy. ASP-1929 photoimmunotherapy (PIT) combines EGFR-targeting cetuximab, with a light-activatable dye, IRDye 700DX, and a laser light for localized drug activation. This novel approach has demonstrated rapid and selective tumor necrosis in preclinical studies, and a manageable safety profile in HNSCC early clinical trials. Phase I/II and preclinical data indicate a potential synergy in anti-tumor activity of PIT when combined with anti-PD-1 therapy. Here we present updated interim evaluation findings based on a recent data cut from this study initially presented at the 2023 American Head and Neck Society meeting. Methods: A phase 1b/2 open-label study of pts with recurrent locally advanced (rLA) and/or metastatic (m) HNSCC evaluating the safety and efficacy of ASP-1929 PIT in combination with anti-PD-1 (pembrolizumab) therapy (NCT04305795). Pts with measurable disease by modified RECIST 1.1, at least 1 lesion accessible to light illumination, combined positive score (CPS) ≥1, and who were not candidate for LR therapy could be eligible for the study. Treatment included ASP-1929 PIT (infusion day 8, target tumors illuminated 24±4 hours later) plus anti-PD-1 (days 1&amp;22) during a 6-week cycle for up to 24 months. Primary objectives: safety/tolerability; objective response rate (ORR). Secondary objectives: overall survival (OS); progression-free survival (PFS); duration of response (DOR). Planned sample size: 26 HNSCC pts. Results: Of the 19 r/m HNSCC pts enrolled, 18 pts received both study therapies (PIT-evaluable). Data cut-off was August 31, 2023 (previously reported data cut-off: October 4, 2022). Efficacy results updated for the 18 PIT-evaluable pts: ORR of 33.3% (95% CI 13.3-59.0), including 4 CRs (22.2%) and 2 PRs (11.1%). Median OS not reached; 24-month OS rate estimate was 52.4% (95%CI 25.9-73.4). No change in median PFS, 2.9 months (95%CI 1.4-14.6). Median DOR was not reached at data cut-off (range 2.8+ to 18.0+ months). Safety data remained consistent with the data previously presented. Most common serious adverse reactions were dysphagia (10.5%) and tongue edema (10.5%). There were two grade 4 events: laryngeal edema (PIT-related) and tumor hemorrhage due to advanced disease, and no fatal events. Conclusions: ASP-1929 PIT in combination with anti-PD-1 therapy was generally well tolerated. Initial data demonstrate promising overall survival and response rates with this combination therapy in pts with rLA and/or m HNSCC lacking LR treatment options. Clinical trial information: NCT04305795 .

Abstract PO3-12-07: Utility of Volumetric Measurement for Clinical Diagnosis of Breast Cancer-Related Lymphedema

Abstract Background: Early detection of Breast cancer-related lymphedema (BCRL) is crucial since it can significantly reduce the negative impact on a patient’s quality of life after breast cancer treatment. Several objective screening methods have been used in prior studies but have not proven accurate due to a lack of standardization. Bioimpedance spectroscopy (BIS), which assesses tissue resistance to an electric current and converts it into a score to measure interstitial fluid content, has proven to be an accurate tool in diagnosing lymphedema. SOZO® is a BIS device that generates quantitative results in real time and provides a Lymphedema Index (L-Dex) score by measuring the patient's extracellular fluid volume. However, there is a paucity of literature highlighting its clinical applicability. Thus, we aimed to evaluate the clinical utility of SOZO® in diagnosing BCRL in patients undergoing breast cancer surgery. Materials &amp; Methods: A retrospective chart review was carried out of patients who underwent axillary surgery from January 2019 to December 2022. Demographic information such as age, body mass index (BMI), gender, ethnicity, disease pathology, cancer stage, type of axillary surgery, neoadjuvant and adjuvant treatment received was recorded. Patients undergoing sentinel lymph node biopsy (SLNB) and/or axillary lymph node dissection (ALND) were assessed for their preoperative L-Dex score, and they were followed up postoperatively with repeated measurements of their L-Dex score to diagnose lymphedema for a year at 3 months intervals. Clinical lymphedema was defined as those having an absolute L-Dex score of more than +10 and an increase in L-Dex score by 6.5 from the baseline. SOZO® scores measured at each follow-up were compared to their preoperative baseline scores. Results: A total of 200 patients’ data was evaluated whose mean age and BMI were 57.5+10.9 years and 29.6+5.6 kg/m2, respectively. Eighty-five percent of the patients belonged to ethnic minority groups. Furthermore, 84.5% (n=169) of the patients had SLNB, and 15.5% (n=31) had ALND. All the patients included in the study had their preoperative and postoperative quarterly L-Dex scores recorded. Pre- and post-operative L-Dex scores had a mean of -0.20+6.6 and 0.61+6.8, respectively. A total of 20 (10%) patients developed lymphedema without symptoms detected by SOZO®, with 19 (9.5%) resolving at their respective 3-month follow-up and 1 (0.5%) patient with persistent lymphedema at the end of the 24-month follow-up. All 20 patients were treated with a compression sleeve. Of the 20 patients with lymphedema, 4 patients underwent ALND, whereas 16 patients had SLNB. When compared to their preoperative baseline scores, all patients' SOZO® measurements had an absolute score of more than 10 and an increase of 6.5 from their baseline score. Additionally, 21 other patients had an increase in score of 6.5 from their baseline measurements but did not meet the cut-off range of an absolute score of +10. Therefore, we excluded them from the diagnosis of BCRL, and none of these patients later developed any signs of BCRL, such as swelling, pain, or discomfort. Conclusion: SOZO® procedure can accurately detect BCRL. In our study, 1 patient developed clinical lymphedema after undergoing SLNB and was diagnosed using SOZO®. Additionally, 19 patients who were initially diagnosed with lymphedema were later categorized as transient due to the resolution of lymphedema on follow-up. Early identification of transient lymphedema using SOZO® resulted in the prevention of a potentially life-long debilitation in our patients. Moreover, our findings underscore that an increase in SOZO® score from the baseline by &amp;gt; 6.5 with an absolute score of more than +10 should be the threshold to clinically diagnose lymphedema. Future studies with larger sample sizes and longer follow-up duration are necessary to understand better the utility of SOZO® in diagnosing BCRL. Table 1: Baseline characteristics and follow-up data of the patients included in the study. Citation Format: Fardeen Bhimani, Sheldon Feldman, Yu Chen, Anjuli Gupta, Jessica Pastoriza, Areej Shihabi, Maureen McEvoy. Utility of Volumetric Measurement for Clinical Diagnosis of Breast Cancer-Related Lymphedema [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-12-07.

Novel Tools for Single Comparative and Unified Evaluation of Qualitative and Quantitative Bioassays: SS/PV-ROC and SS-J/PV-PSI Index-ROC Curves with Integrated Concentration Distributions, and SS-J/PV-PSI Index Cut-Off Diagrams.

Background: This investigation is both a study of potential non-invasive diagnostic approaches for the bladder cancer biomarker UBC® Rapid test and a study including novel comparative methods for bioassay evaluation and comparison that uses bladder cancer as a useful example. The objective of the paper is not to investigate specific data. It is used only for demonstration, partially to compare ROC methodologies and also to show how both sensitivity/specificity and predictive values can be used in clinical diagnostics and decision making. This study includes ROC curves with integrated cut-off distribution curves for a comparison of sensitivity/specificity (SS) and positive/negative predictive values (PPV/NPV or PV), as well as SS-J index/PV-PSI index-ROC curves and SS-J/PV-PSI index cut-off diagrams (J = Youden, PSI = Predictive Summary Index) for the unified direct comparison of SS-J/PV results achieved via quantitative and/or qualitative bioassays and an identification of optimal separate or unified index cut-off points. Patients and Methods: According to the routine diagnostics, there were 91 patients with confirmed bladder cancer and 1152 patients with no evidence of bladder cancer, leading to a prevalence value of 0.073. This study performed a quantitative investigation of used-up test cassettes from the visual UBC® Rapid qualitative point-of-care assay, which had already been applied in routine diagnostics. Using a photometric reader, quantitative data could also be obtained from the test line of the used cassettes. Interrelations between SS and PV values were evaluated using cumulative distribution analysis (CAD), SS/PV-ROC curves, SS-J/PV-PSI index-ROC curves, and the SS-J/PV-PSI index cut-off diagram. The maximum unified SS-J/PV-PSI index value and its corresponding cut-off value were determined and calculated with the SS-J/PV-PSI index cut-off diagram. Results: The use of SS/PV-ROC curves with integrated cut-off concentration distribution curves provides improved diagnostic information compared to "traditional" ROC curves. The threshold distributions integrated as curves into SS/PV-ROC curves and SS-J/PV-PSI index-ROC curves run in opposite directions. In contrast to the SS-ROC curves, the PV-ROC and the novel PV-PSI index-ROC curves had neither an area under the curve (AUC) nor a range from 0% to 100%. The cut-off level of the qualitative assay was 7.5 µg/L, with a sensitivity of 65.9% and a specificity of 63.3%, and the PPV was 12.4% and the NPV was 95.9%, at a threshold value of 12.5 µg/L. Based on these set concentrations, the reader-based evaluation revealed a graphically estimated 5% increase in sensitivity and a 13% increase in specificity, as compared to the visual qualitative POC test. In the case of predictive values, there was a gain of 8% for PPV and 10% for NPV. The index values and cut-offs were as follows: visual SS-J index, 0.328 and 35 µg/L; visual PV-PSI index, 0.083 and 5.4 µg/L; maximal reader Youden index, 0.0558 and 250 µg/L; and maximal PV-PSI index, 0.459 and 250 µg/L, respectively. The maximum unified SS-J/PV-PSI index value was 0.32, and the cut-off was 43 µg/L. The reciprocal SS-J index correctly detected one out of three patients, while the reciprocal PV-PSI index gave one out of twelve patients a correct diagnosis. Conclusions: ROC curves including cut-off distribution curves supplement the information lost in "traditionally plotted" ROC curves. The novel sets of ROC and index-ROC curves and the new SS/PV index cut-off diagrams enable the simultaneous comparison of sensitivity/specificity and predictive value profiles of diagnostic tools and the identification of optimal cut-off values at maximal index values, even in a unifying SS/PV approach. Because the curves within an SS-J/PV-PSI index cut-off diagram are distributed over the complete cut-off range of a quantitative assay, this field is open for special clinical considerations, with the need to vary the mentioned clinical diagnostic parameters. Complete or partial areas over the x-axis (AOX) can be calculated for summarized quantitative or qualitative effectivity evaluations with respect to single and/or unified SS-J and PV-PSI indices and with respect to single, several, or several unified assays. The SS-J/PV-PSI index-AOX approach is a new tool providing additional joint clinical information, and the reciprocal SS-J indices can predict the number of patients with a correct diagnosis and the number of persons who need to be examined in order to correctly predict a diagnosis of the disease. These methods could be used in applications like medical or plant epidemiology, machine learning algorithms, and neural networks.

Diagnosing and staging epithelial ovarian cancer by serum glycoproteomic profiling.

There is a need for diagnostic tests for screening, triaging and staging of epithelial ovarian cancer (EOC). Glycoproteomics of blood samples has shown promise for biomarker discovery. We applied glycoproteomics to serum of people with EOC or benign pelvic masses and healthy controls. A total of 653 analytes were quantified and assessed in multivariable models, which were tested in an independent cohort. Additionally, we analyzed glycosylation patterns in serum markers and in tissues. We identified a biomarker panel that distinguished benign lesions from EOC with sensitivity and specificity of 83.5% and 90.1% in the training set, and of 86.7 and 86.7% in the test set, respectively. ROC analysis demonstrated strong performance across a range of cutoffs. Fucosylated multi-antennary glycopeptide markers were higher in late-stage than in early-stage EOC. A comparable pattern was found in late-stage EOC tissues. Blood glycopeptide biomarkers have the potential to distinguish benign from malignant pelvic masses, and early- from late-stage EOC. Glycosylation of circulating and tumor tissue proteins may be related. This study supports the hypothesis that blood glycoproteomic profiling can be used for EOC diagnosis and staging and it warrants further clinical evaluation.

Establishing Reference Values for a New Computerized Cognitive Function Test Program for Children.

To establish reference values for the computerized cognitive test and evaluate cognitive function improvements across different age groups, we introduce the computerized Cognitive Function Test program (eCFT), specifically designed for children. We aimed to establish eCFT reference values and assess cognitive function improvements across different age groups. We included children aged 3-6 years with confirmed normal cognition based on the Korean Developmental Screening Test for Infants and Children and Kaufman Assessment Battery for Children-II. The eCFT consists of 8 subtests for visual perception, attention, memory, and executive function. A total of 66 participants (36 males and 30 females) with an average age of 4.4 years participated. The age 6 group consistently outperformed both age group 3 and 4 in terms of correct responses. With regard to the completed stage, the "selective auditory stimulus" test findings were 2.0 and 3.9 for the age 3 and age 6 groups, respectively (p<0.05). The "trail-making" test findings were 1.7, 2.1, 2.6, and 2.8, respectively (between ages 3 and 6, p<0.01; between ages 4 and 6, p<0.05); moreover, the age 5 group surpassed the age 3 group (2.6 and 1.7, respectively, p<0.05). The eCFT is an easily accessible tool to evaluate cognitive function in young children. We introduce reference values with a cutoff range for preschool-aged children, enabling early intervention for those with cognitive impairment. Given its accessibility and relatively short evaluation time, the eCFT has potential for clinical use.

Interactions of HRLCMS-QTOF Detected Plant Metabolites of &lt;i&gt;Abrus precatorius&lt;/i&gt; L. Seeds with EGFR and the Effect of Classically Detoxification Process

Abrus precatorius L. is one of the most important medicinal plants with toxic principles which has been reported for many cases of poisoning throughout the globe. Shodhana is an important technique in Ayurveda which includes a set of procedures to detoxify the toxic herbal raw drugs. Hence three varieties of unprocessed and shodhana processed Abrus precatorius L. seeds were chosen and the hydro alcoholic extracts were prepared by maceration. These extracts were subjected to HRLCMS-QTOF analysis and the receptor-specific action of all the major components selected with the cutoff range of more than 0.2x106 counts was analyzed with GLIDE (Schrodinger 2021-1, maestro v13.6) software. Totally 570 molecules were identified in HRLCMS, and 299 molecules were docked against EGFR downloaded from the RCSB database with the crystal structure of 5XDK. The HRLCMS has revealed the presence of many unknown compounds in extracts and the major compounds identified were Indoleacrylic acid, PABA, Galangin 3- [galactosyl-(1-&gt;4), Chrysoeriol 7-O-neohesperidoside, gallic acid, calendoflaside, etc. In docking studies, the glide scores of the ligands were compared with the standard ligand 8JK and it was found that the compounds present in the extracts have shown good binding scores in comparison with the standard ligand. It is concluded that the shodhana processed seed extracts show a wide range of phytochemical variation and a notable in silico docking score and hence the raw drug after shodhana can be considered promising for research and development of cancer management therapies.

Maximally local two-nucleon interactions at N3LO in Δ -less chiral effective field theory

We present new maximally local two-nucleon interactions derived in Δ-less chiral effective field theory up to next-to-next-to-next-to-leading order (N3LO), which include all contact and pion-exchange contributions to the nuclear Hamiltonian up to this order. Our interactions are fit to nucleon-nucleon phase shifts using a Bayesian statistical approach, and explore a wide cutoff range from 0.6–0.9 fm (≈660–440MeV). These interactions can be straightforwardly employed in quantum Monte Carlo methods, such as the auxiliary field diffusion Monte Carlo method. Together with local three-nucleon forces, calculations with these new interactions will provide improved benchmarks for the structure of atomic nuclei and serve as crucial input to analyses of astrophysical phenomena of neutron stars, such as binary neutron-star mergers. Published by the American Physical Society 2024

Tissue-specific thresholds of mutation burden associated with anti-PD-1/L1 therapy benefit and prognosis in microsatellite-stable cancers.

Immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 or its ligand (PD-1/L1) have expanded the treatment landscape against cancers but are effective in only a subset of patients. Tumor mutation burden (TMB) is postulated to be a generic determinant of ICI-dependent tumor rejection. Here we describe the association between TMB and survival outcomes among microsatellite-stable cancers in a real-world clinicogenomic cohort consisting of 70,698 patients distributed across 27 histologies. TMB was associated with survival benefit or detriment depending on tissue and treatment context, with eight cancer types demonstrating a specific association between TMB and improved outcomes upon treatment with anti-PD-1/L1 therapies. Survival benefits were noted over a broad range of TMB cutoffs across cancer types, and a dose-dependent relationship between TMB and outcomes was observed in a subset of cancers. These results have implications for the use of cancer-agnostic and universal TMB cutoffs to guide the use of anti-PD-1/L1 therapies, and they underline the importance of tissue context in the development of ICI biomarkers.

Abstract 1213: Tissue-specific thresholds and microenvironment correlates of tumor mutation burden associated with immunotherapy benefit and prognosis in microsatellite stable cancers

Abstract Background: Immune checkpoint inhibitors (ICIs) targeting anti-PD-1/L1 have expanded the treatment landscape against cancers, but are only effective in a subset of patients across all cancer types. Tumor mutation burden (TMB) is postulated to be a generic determinant of ICI dependent-tumor rejection. Here, we clarify the association between TMB and survival outcomes among microsatellite-stable cancers in a real-world clinicogenomic cohort including 70,698 patients distributed across 27 histologies. Methods: Patients were segregated into mutually exclusive anti-PD-1/L1 (N=14,736, immune checkpoint inhibitor, ICI) and non-ICI cohorts (N=55,962) if they had received pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab, or cemiplimab, and non-ICI therapies, respectively, during the course of treatment for individual cancer types. Patients treated with chemo-immunotherapy combination regimens were included in the ICI cohorts, but anti-CTLA-4 agents were excluded from both cohorts. For both ICI and non-ICI cohorts, patients were reiteratively categorized as TMB-high or -low using increasing TMB thresholds up to the 90th percentile TMB for individual cancer types. Outcomes were then assessed using Cox regression analyses of overall survival (OS). Results: Across 27 histologies, 12 cancer types had at least one TMB cutoff associated with survival benefit upon ICIs (melanoma, NSCLC, SCLC, bladder, cervical, colorectal, gastric, ovarian, head and neck, vulvar cancers, as well as carcinoma of unknown primary, and sarcoma), and these associations were generally conserved across sex and age groups, although not necessarily significant in all cases. In two cancer types (cholangiocarcinoma and neuroendocrine tumors), TMB cutoffs were associated with worse OS with ICIs. The lowest TMB cutoff in which a survival benefit could be detected with ICIs ranged from 2 mut/Mb in melanoma to 9 mut/Mb in colorectal cancer. TMB thresholds with the greatest predictive value (defined as the lowest survival hazard ratio) were frequently near the highest TMB examined for individual cancer types, suggesting that TMB may scale with ICI benefit. Conclusion: TMB was associated with survival benefit or detriment depending on tissue and treatment context. Detectable survival benefits were noted over a broad range of TMB cutoffs across cancer types, and a dose-dependent relationship between TMB and outcomes was observed in a subset of cancers. These results may have implications for cancer-agnostic and universal TMB cutoffs to guide the use of anti-PD-1/L1 therapies, and underline the importance of tissue context in the clinical development of ICI biomarkers. Citation Format: Maishara Muquith, Magdalena Espinoza, Andrew Elliott, Joanne Xiu, Andreas Seeber, Wafik El-Deiry, Emmanuel S. Antonarakis, Stephanie Graff, Michael J. Hall, Hossein Borghaei, Dave S. Hoon, Stephen V. Liu, Patrick C. Ma, Rana R. McKay, Trisha Wise-Draper, John Marshall, George W. Sledge, David Spetzler, Hao Zhu, David Hsieh. Tissue-specific thresholds and microenvironment correlates of tumor mutation burden associated with immunotherapy benefit and prognosis in microsatellite stable cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1213.

Potential of dynamic ocean management strategies for western Pacific leatherback sea turtle bycatch mitigation in New Zealand

Western Pacific leatherback sea turtles (Dermochelys coriacea) are a priority bycatch mitigation concern due to the projected extinction of the population before the end of the 21st century. The species regularly occurs as bycatch in gillnet and surface longline fisheries. Here, we explore the potential for dynamic ocean management in an emerging hotspot of leatherback sea turtle bycatch in the New Zealand pelagic longline fishery. We compared spatial areas of different sizes built from single oceanographic covariates as well as built from a composite risk surface developed through ensemble random forests. We found that, individually, the Okubo–Weiss parameter, sea surface temperature (SST) anomaly, SST, moon phase, and distance to the SST front were important oceanographic covariates for leatherback sea turtle bycatch. However, the spatial areas built from the composite risk surface were the most effective at discriminating sets with and without bycatch across a range of risk cutoffs. When we also considered implementation metrics of spatial area and coherence as part of performance, the area derived from the composite risk surface with a risk of interaction per set greater than 52% performed best. This spatial area was ephemeral, occurring 1 or 2 weeks each year, and localized, occurring along the north coast of East Cape in the North Island of New Zealand. The apparent presence of discrete spatial areas with elevated risk may be useful to inform future management in the area. Considering implementation metrics in defining utility was useful for identifying tradeoffs between the total size and the underlying covariates delineating a spatial area. As such, we recommend these types of metrics to be included when designing spatial bycatch mitigation strategies elsewhere.

Optimal filters for ERP research II: Recommended settings for seven common ERP components.

In research with event-related potentials (ERPs), aggressive filters can substantially improve the signal-to-noise ratio and maximize statistical power, but they can also produce significant waveform distortion. Although this tradeoff has been well documented, the field lacks recommendations for filter cutoffs that quantitatively address both of these competing considerations. To fill this gap, we quantified the effects of a broad range of low-pass filter and high-pass filter cutoffs for seven common ERP components (P3b, N400, N170, N2pc, mismatch negativity, error-related negativity, and lateralized readiness potential) recorded from a set of neurotypical young adults. We also examined four common scoring methods (mean amplitude, peak amplitude, peak latency, and 50% area latency). For each combination of component and scoring methods, we quantified the effects of filtering on data quality (noise level and signal-to-noise ratio) and waveform distortion. This led to recommendations for optimal low-pass and high-pass filter cutoffs. We repeated the analyses after adding artificial noise to provide recommendations for data sets with moderately greater noise levels. For researchers who are analyzing data with similar ERP components, noise levels, and participant populations, using the recommended filter settings should lead to improved data quality and statistical power without creating problematic waveform distortion.

ROX index as a predictor of failure of high-flow nasal cannula in infants with bronchiolitis

High-flow nasal cannula (HFNC) is a relatively recent therapy that has been used to treat respiratory failure. Until now, the criterion for failure requiring escalation to other forms of ventilatory support has remained unclear. This study evaluated how the ROX index predicts the success or failure of HFNC in infants with bronchiolitis. A prospective, observational, multicenter study was conducted in 2 pediatric ICUs. The data were collected at 7 moments. Patients were categorized into failure and success groups according to HFNC. A total of 102 infants were included, 18(17.6%) of whom failed HFNC therapy. For the ROX index, significant differences were observed between the failure 5.8(95%CI 4.7–7.1) and success 7.7(95%CI 7.2–8.2) groups (p = 0.005) at the 12 h evaluation. According to the analysis of the performance of the ROX index, the AUC at 12 h was 0.716(95%CI 0.591–0.842; p = 0.016). The best cutoff range for the ROX index at 12 h was 6.50–7.18, with a sensitivity of 42% and a specificity of 66% at the cutoff of 6.50, and a sensitivity of 92% and a specificity of 54% at the cutoff of 7.18. We concluded that the ROX index could be effective at predicting the failure of HFNC therapy in infants with bronchiolitis beginning at 12 h after installation.

Development of an Adaptive Artifact Subspace Reconstruction Based on Hebbian/Anti-Hebbian Learning Networks for Enhancing BCI Performance.

Brain-computer interface (BCI) actively translates the brain signals into executable actions by establishing direct communication between the human brain and external devices. Recording brain activity through electroencephalography (EEG) is generally contaminated with both physiological and nonphysiological artifacts, which significantly hinders the BCI performance. Artifact subspace reconstruction (ASR) is a well-known statistical technique that automatically removes artifact components by determining the rejection threshold based on the initial reference EEG segment in multichannel EEG recordings. In real-world applications, the fixed threshold may limit the efficacy of the artifact correction, especially when the quality of the reference data is poor. This study proposes an adaptive online ASR technique by integrating the Hebbian/anti-Hebbian neural networks into the ASR algorithm, namely, principle subspace projection ASR (PSP-ASR) and principal subspace whitening ASR (PSW-ASR) that segmentwise self-organize the artifact subspace by updating the synaptic weights according to the Hebbian and anti-Hebbian learning rules. The effectiveness of the proposed algorithm is compared to the conventional ASR approaches on benchmark EEG dataset and three BCI frameworks, including steady-state visual evoked potential (SSVEP), rapid serial visual presentation (RSVP), and motor imagery (MI) by evaluating the root-mean-square error (RMSE), the signal-to-noise ratio (SNR), the Pearson correlation, and classification accuracy. The results demonstrated that the PSW-ASR algorithm effectively removed the EEG artifacts and retained the activity-specific brain signals compared to the PSP-ASR, standard ASR (Init-ASR), and moving-window ASR (MW-ASR) methods, thereby enhancing the SSVEP, RSVP, and MI BCI performances. Finally, our empirical results from the PSW-ASR algorithm suggested the choice of an aggressive cutoff range of c = 1-10 for activity-specific BCI applications and a moderate range of for the benchmark dataset and general BCI applications.