Low Threshold Research Articles

Abstract 5934: Functional biomarkers for bladder cancer

Abstract Introduction and Objective: Urine tests could offer a less invasive method for identifying bladder cancer, including in patients with hematuria and history of bladder cancer. We previously discovered a first-in-class human Chondroitinase (Chase) that degrades chondroitin sulfate. This Chase is a splice variant of HYAL4 (V1) and promotes a malignant phenotype and chemoresistance in BC cells. The Chase test quantifies enzyme activity by measuring the degradation of chondroitin sulfate using an ELISA-like assay. We evaluated the efficacy of the Chase urine test in identifying bladder cancer. Methods: Test and validation cohorts came from three centers. The validation cohorts were prospective cohorts and assays were conducted in a blinded fashion. The cohorts included patients with microscopic and gross hematuria, benign genitourinary (BGU) conditions, history (HX) of BC or other genitourinary cancers (prostate and renal cell carcinoma). BGU cases included patients with BPH, cystitis, urinary tract infection, renal insufficiency, hematuria, urethral stricture, urolithiasis, and UPJ obstruction. V1 levels were measured by q-PCR and Chase activity by the Chase urine test. Results: Chase levels were significantly elevated in both low- and high-grade tumors, correlating strongly with BC across three cohorts (P<0.0001; OR: 4.4; 95% CI: 3.3-5.9). The Chase test demonstrated high sensitivity in detecting BC, regardless of grade. Similarly, HYAL-4 (V1) transcript levels were elevated in urine exfoliated cells (P<0.0001; OR: 1.5; CI: 1.3-1.7), with 83% sensitivity and specificity, increasing to 86% sensitivity at a lower threshold (79% specificity). In comparison, FDA-approved BTA and NMP22 tests showed <60% efficacy. In cohort 2, Chase achieved 84% accuracy in cases with atypical cytology, while cytology alone had 67% sensitivity and 96.6% specificity. Urinary Chase and HYAL-4 mRNA levels were 4-5 times higher in patients with BC during surveillance than in those without recurrence (P<0.0001). Conclusion: In test and validation cohorts Chase and V1 tests showed high sensitivity to detect BC and to monitor its recurrence. The Chase urine test is a less invasive alternative that could potentially reduce the need for cystoscopies for hematuria work-up and BC surveillance. Support: 1R01CA227277-05A1; 1R01CA283699-01 Citation Format: Tianyu Yang, Karina Aguilar, Joshua van der Eerden, Vinata Lokeshwar. Functional biomarkers for bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5934.

Abstract 4630: A novel approach to define ctDNA molecular response to immunotherapy

Abstract Molecular biomarkers that quantify changes in circulating tumor DNA (ctDNA) can predict clinical outcomes. However, there is no consensus on classification of molecular responders (MRs) and molecular non-responders (nMRs), who may benefit from early treatment intervention. We explored the classification of MRs vs. nMRs in a real-world pan-cancer cohort of patients treated with immune checkpoint inhibitor (ICI) therapy in two ways. (1) As previously described, a ≥ 50% decrease in ctDNA tumor fraction (TF) between baseline and on-treatment time points (MR50), and, (2) hypothesizing that consistently low TF may represent a favorable subgroup with prolonged outcomes despite small increases in TF, MRlow, we evaluated a “low TF” threshold, above the TF detection rate, classifying patients as MRlow if TF remains below the TF threshold at both timepoints, regardless of magnitude change. The cohort consisted of advanced cancer patients from the Tempus de-identified clinicogenomic database who received a liquid biopsy at pre-treatment baseline and within 21-180 days after starting ICI therapy. TF was quantified via an ensemble algorithm, xM for treatment response monitoring, that incorporates pathogenic variant allele frequencies, copy number information, and germline information. Evaluable patients had TF ≥ limit of blank in at least one blood sample. Real-world overall survival (rwOS) was defined as the time from on-treatment testing to death or last known clinical record in event-free patients. Cox proportional hazards models were used to estimate the hazard ratio (HR) for MR status (MR vs. nMR) and tests for significance were conducted using 1-sided Wald tests at a 5% significance level. The evaluable cohort consisted of 71 advanced pan-cancer patients with >10 cancer types; most commonly NSCLC (38.0%, n=27) and small cell lung cancer (19.7%, n=14). Twenty-five patients (35.2%) were treated with ICI monotherapy and 46 (64.8%) were treated with ICI-chemotherapy combination. Using a definition of MR of a 50% decrease in TF alone, 44 patients were MRs and 27 patients were nMRs, with MRs having significantly longer rwOS than nMRs (HR=0.44, P=0.012). We next evaluated various low TF thresholds and found that a 1% low TF threshold further improved the association between MR and rwOS (HR = 0.32, P = 0.0008). 53 patients were classified as MRs [18 MRlow + 35 MR50] and 18 patients were classified as nMRs. Of the MRlow patients, 6 had increasing TF. Median rwOS for nMRs was seven months and not reached at 18 months for both MRlow and MR50.This study suggests that patients with consistently low TF below 1% while on ICI therapy (MRlow), regardless of TF changes, represent a unique, biologically differentiated, prognostic group. Our study suggests that MRlow patients have prolonged rw-survival, similar to molecular responders based on a 50% decrease in TF (MR50). Prospective validation for this threshold is planned. Citation Format: John Guittar, Sandra Hui, Terri Driessen, Wei Zhu, Christine Lo, Akash Mitra, Michelle Stein, Halla Nimeiri, Rotem Ben-Shachar, Wade T. Iams. A novel approach to define ctDNA molecular response to immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4630.

Abstract 6528: The role of health behaviors in microbial dysbiosis and lung cancer inequities

Abstract Lung cancer remains the leading cause of cancer-related morbidity and mortality worldwide. African Americans (AA) are disproportionally affected by the disease, and mortality is higher in AA compared to European Americans (EA). The mortality rate among AA is higher than EA even when diagnosed at an early stage, implying biological differences associated with health behaviors such as smoking and its impact on microbial dysbiosis. A higher mortality rate in AA diagnosed at an early stage compared to EA highlights the biological differences in AA are primarily due to health behaviors such as smoking and its impact on microbial dysbiosis, making AA predisposed to higher risk and mortality. Microbial dysbiosis in lung cancer was analyzed using GEO and All of Us data repositories. Our analysis provides compelling evidence of the interplay between microbial dysbiosis, health behaviors, and racial disparities in lung cancer outcomes. Our study shows that smoking exacerbates microbial imbalances, particularly with the prevalence of Streptococcus and its differential impact on AA and EA. Dysbiosis correlates strongly with lung cancer pathogenesis, particularly the abundance of Streptococcus, Haemophilus, Neisseria, and Pseudomonas. AA participants show higher susceptibility to Streptococcus invasion, with detectable levels in the blood at just 7 cigars daily compared to 23 cigars in EAs. Urine samples of AAs smoking only 17 cigars per day are positive for streptococcus, while for EAs the bacteria is detected only when they smoke 20 cigars daily. These findings underscore a biological predisposition that amplifies cancer risk for AAs at lower smoking intensities. The lower thresholds for Streptococcus detection among AA populations suggest a heightened biological vulnerability, emphasizing the need for tailored public health interventions and early screening programs in these communities. These results underscore the importance of integrating microbial profiling in personalized medicine approaches and addressing underlying health inequities to improve lung cancer outcomes across diverse populations. Citation Format: Murugesh Eswaran, Briana A. Brock, Hina Mir, Gabriela Oprea-Ilies, Eric Flenaugh, James W. Lillard, Brian M. Rivers, Rajesh Singh, Shailesh Singh. The role of health behaviors in microbial dysbiosis and lung cancer inequities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6528.

Development Characteristics of Natural Fractures in Metamorphic Basement Reservoirs and Their Impacts on Reservoir Performance: A Case Study from the Bozhong Depression, Bohai Sea Area, Eastern China

Archaean metamorphic basement reservoirs, characterized by the development of natural fractures, constitute the primary target for oil and gas exploration in the Bozhong Depression, Bohai Bay Basin, Eastern China. Based on analyses of geophysical image logs, cores, scanning electron microscopy (SEM), and laboratory measurements, tectonic fractures are identified as the dominant type of natural fracture. Their development is primarily controlled by lithology, weathering intensity, and faulting. Fractures preferentially develop in metamorphic rocks with low plastic mineral content and are positively correlated with weathering intensity. Fracture orientations are predominantly parallel or subparallel to fault strikes, while localized stress perturbations induced by faulting significantly increase fracture density. Open fractures, constituting more than 60% of the total reservoir porosity, serve as both primary storage spaces and dominant fluid flow conduits, fundamentally governing reservoir quality. Consequently, spatial heterogeneity in fracture distribution drives distinct vertical zonation within the reservoir. The lithological units are ranked by fracture development potential (in descending order): leptynite, migmatitic granite, gneiss, cataclasite, diorite-porphyrite, and diabase. Diabase represents the lower threshold for effective reservoir formation, whereas overlying lithologies may function as reservoirs under favorable conditions. The large-scale compressional orogeny during the Indosinian period marked the primary phase of tectonic fracture formation. Subsequent uplift and inversion during the Yanshanian period further modified and overlaid the Indosinian structures. These structures are characterized by strong strike-slip strain, resulting in a series of conjugate shear fractures. During the Himalayan period, preexisting fractures were primarily reactivated, significantly influencing fracture effectiveness. The development model of the fracture network system in the metamorphic basement reservoirs of the study area is determined by a coupling mechanism of dominant lithology and multiphase fracturing. The spatial network reservoir system, under the control of multistage structure and weathering, is key to the formation of large-scale effective reservoirs in the metamorphic basement.

Diagnostic delays in infective discitis – an unresolved problem

Study DesignA retrospective study.ObjectivesNeurological deficits occur in 1/3 of spinal infection cases. Non-specific symptoms can lead to delays in diagnosis. This study reviews outcomes and the timeliness of diagnosis in patients with spinal infection who sustained subsequent spinal cord impairment.SettingAll 40 patients admitted to The Princess Royal Spinal Injuries Centre, Sheffield, UK, between 2016–2018 for rehabilitation for spinal cord impairment secondary to spinal infection.ResultsThe average age was 58.6 years (31–85; SD 13.1) with 24 (60%) being male. 36 (90%) had native infections and 3 (7.5%) were acquired post-operatively (1 (2.5%) unknown). 7 patients had been intravenous drug users (17.5%). 50% (20) had previously sought medical attention for the same symptoms. There were long intervals to suspected diagnosis and to MRI (range 0–30 days). 15 (37.5%) patients deteriorated neurologically following admission to hospital; 8 were taking antibiotics at the time of deterioration. None of the patients had normal C-reactive protein levels at presentation. 7 (17.5%) sustained complete spinal cord impairment. 27 (67.5%) were discharged as wheelchair users.ConclusionsWhilst the majority of patients responded to rehabilitation interventions, they were left with residual life changing disabilities. Among those requiring rehabilitation, delays in diagnosis appear to frequently occur pre-hospital. This could be attributed to a low index of suspicion in the community. Some deteriorated neurologically despite antibiotics. Close neurological monitoring of those suspected or confirmed to have a diagnosis of spinal infection is appropriate. There should be a low threshold for the use of inflammatory markers when investigating back pain.

Higher hyperpolarization activated current (Ih) in a subpopulation of interneurons in stratum oriens of area CA1 in the hippocampus of Fragile X mice.

Fragile X syndrome is the most common inherited form of intellectual disability and the leading monogenetic cause of autism. Studies in mouse models of autism spectrum disorders, including the Fmr1 knockout (FX) mouse, suggest that abnormal inhibition in hippocampal circuits contributes to behavioral phenotypes. In FX mice, changes in multiple voltage-gated ion channels occur in excitatory pyramidal neurons of the hippocampus. Whether there are also changes in the intrinsic properties of hippocampal inhibitory interneurons, however, remains largely unknown. We made whole-cell current clamp recordings from both fast-spiking (FS) and low threshold spiking (LTS) interneurons in the stratum oriens region of the hippocampus. We found that LTS, but not FS, interneurons in FX mice had lower input resistance and action potential firing compared to wild type. When we subdivided LTS interneurons into low-threshold high Ih (LTH) and putative oreins-lacunosum moleculare (OLM) cells (Hewitt et al., 2021), we found that it was the LTH subgroup that had significantly lower input resistance in FX mice. The difference in input resistance between wild type and FX LTH interneurons was absent in the presence of the h-channel blocker ZD7288, suggesting a greater contribution of Ih in FX LTH interneurons. Voltage clamp recordings found that indeed, Ih was significantly higher in FX LTH interneurons compared to wild type. Our results suggest that altered inhibition in the hippocampus of FX mice may be due in part to changes in the intrinsic excitability of LTH inhibitory interneurons.

Cost-effectiveness of NALIRIFOX versus Nab-paclitaxel and gemcitabine in previously untreated metastatic pancreatic ductal adenocarcinoma

Background & aimsThe NAPOLI 3 trial demonstrated that compared to the nab-paclitaxel and gemcitabine (GemNab) regimen, the NALIRIFOX (5-fluorouracil, leucovorin, liposomal irinotecan, oxaliplatin) regimen can significantly improve patients' overall survival (OS) and progression-free survival (PFS), and the safety of this regimen is generally controllable. To ensure the appropriateness of the chosen treatment, economic evaluation is essential. Thus, from the perspective of American healthcare systems, we explored the cost-effectiveness comparison between NALIRIFOX or GemNab in treating patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) who had not previously received treatment.MethodsA three-state partitioned survival model was developed, incorporating a lifetime horizon with a 4-week cycle length. The efficacy data were sourced from the NAPOLI 3 study, while treatment costs, health state utilities, and adverse events (AEs) were obtained from public databases and literature. Applying an annual discount rate of 3%, the analysis focused on total cost, quality-adjusted life-years (QALYs), and the incremental cost-effectiveness ratio (ICER) as primary outcomes. Conducted within a US healthcare system perspective over a 13-year lifetime horizon, the analysis set willingness-to-pay (WTP) thresholds of $50,000, $100,000 and $150,000 per QALY. Sensitivity analyses were performed to assess the robustness of the model's findings.ResultsIn our base-case analysis, NALIRIFOX group was estimated to achieve an incremental gain of 0.13 QALYs. Compared to the GemNab group, treatment with NALIRIFOX resulted in higher costs ($150,437 vs $130,683). The ICER for NALIRIFOX therapy was calculated to be $155,602.83/QALYs. Sensitivity analysis revealed the model's robustness across a range of parameters. Through probabilistic sensitivity analysis applying Monte Carlo simulation with 1000 iterations, NALIRIFOX therapy was identified as the cost-effective regimen in 45.7% of all iterations at a WTP threshold of $150,000/QALYs.ConclusionsTreatment with NALIRIFOX strategy was estimated to provide a significant clinical advantage over GemNab. According to the model outcomes, NALIRIFOX therapy is borderline cost-effective for treatment-naive patients with mPDAC, slightly exceeding the highest conventional US willingness-to-pay threshold of 150,000/QALY. However, at lower thresholds, such as 100,000/QALY, NALIRIFOX fails to demonstrate cost-effectiveness in all simulations. In addition, NALIRIFOX therapy emerges as a cost-effective treatment strategy at higher willingness-to-pay thresholds or when the drug price is significantly reduced.

Periorbital necrotizing fasciitis: the Manchester experience

BackgroundTo describe the presentation and management of patients with periorbital necrotizing fasciitis (PONF) through an observational retrospective case series. The clinical notes of twelve consecutive patients managed by the Oculoplastic and Orbital Service and Maxillofacial Service of the Manchester University NHS Foundation Trust between 2018 and 2023 were reviewed. Five of these patients were contactable and gave informed consent for inclusion in the study.MethodsRetrospective review of patient characteristics, risk factors, clinical findings, Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC) score, imaging results, microbiology and histology results, patient management and mortality.ResultsThe majority of the patients were male (n = 3) with a median (IQR) age of 63 (51–71) years. The median (IQR) number of risk factors per patient was 1 (0–1.5). All patients had periorbital swelling at presentation. Median (IQR) LRINEC score was 5 (3–8.5). Group A Streptococcus was isolated from at least one sample (wound swab, tissue sampling, blood culture) in 4 cases. Histology was consistent with PONF in the remaining case. All patients received intravenous antibiotics and had between 1 and 4 surgical debridements. The median (IQR) time from the onset of symptoms to antibiotic treatment was 24 (17–42) hours, and the time of suspected diagnosis to debridement was 4 (2.3–6) hours. The median (IQR) final best recorded visual acuity (BRVA) was 2.0 (0.23–3) logMAR. Three patients developed orbital compartment syndrome; 2 of these had a final BRVA of no perception of light (NPL). The median (IQR) time from the initial surgery to the most recent follow-up was 4 (2.5–42) months. There was no mortality.ConclusionsThis study showed no mortality in PONF due to early antibiotic treatment and surgical debridement. A high index of clinical suspicion for PONF using the LRINEC score and other parameters combined with a low threshold for treatment should be maintained, especially in high-risk groups. Urgent referral to specialist surgical teams to ensure prompt diagnosis and treatment is essential to optimise outcomes in the face of this destructive infection.

Synthesis of AgInS2 quantum dots loaded with celastrol for induction of apoptosis and autophagy in hepatocellular carcinoma cells

Hepatocellular carcinoma (HCC) is a predominant form of liver cancer and one of the leading causes of cancer-related death globally. Therefore, there is an urgent need for innovative therapeutic strategies that target the molecular mechanisms underlying HCC progression and metastasis, aiming to improve treatment efficacy and patient survival. The natural product celastrol (Cel) has demonstrated inhibitory effects in various cancer cell lines. However, its clinical application has been hindered by high toxicity and a low safety threshold. Metal-free quantum dots (QDs), AgInS2 (AIS QDs) not only eliminate toxic risks associated with heavy metals but also exhibit high biocompatibility in the biomedical field. By developing AIS QD@Cel, an AIS QDs nano-delivery system for Cel, the cell selectivity and inhibitory effects of Cel on HCC were enhanced. Fourier-transform infrared spectroscopy (FTIR) analysis revealed that AIS QDs can interact with Cel via amide bonds. The encapsulation rate of AIS QDs to Cel reached 27.5%. AIS QD@Cel eliminated toxicity on 293T and enhanced inhibition on HCC cells by over 10 times. Furthermore, the western blotting and flow cytometry experiments showed that AIS QD@Cel promoted apoptosis and autophagy signal pathway. Finally, transcriptome sequencing revealed that AIS QD@Cel effect on HCC by regulating gene expression involved in critical signaling pathways that are implicated in the progression of cancer. This strategy holds the potential to increase safety threshold and clinical applicability of Cel, offering significant clinical value for the treatment of HCC patients.

Improving the washability of conductive textiles by constructing a dually crosslinked polyvinyl alcohol network with silver nanowires.

Conductive textiles, as an important platform for developing wearable electronic devices, often face challenges related to washing to remove dirt while retaining conductivity. It is still a great challenge to manufacture textiles with high conductivity, washability and uniformity in an efficient and economical way. Polyvinyl alcohol (PVA) containing numerous hydroxyl groups allowing easy modification and crosslinking is a promising candidate for conductive textile construction. Herein, a stable composite ink with PVA as the matrix and silver nanowires (AgNWs) as the conductive filler for screen printing on textile surfaces is proposed. The composite conductive network endows the fabric with the highest conductivity up to 2087 S cm-1 and a low percolation threshold of 0.025 mg cm-2 for AgNW mass loading. The printed conductive pattern shows high uniformity even for a line width as small as 500 μm on fabric. The resistance change of conductive textiles washed at 60 °C for 1 h is reduced from 500 000% to 40%, thanks to the cooperation of a physically and chemically dually crosslinked polymer network with a conductive AgNW network. The prepared outperforming conductive textiles and their potential for mass production of patterned fabric electrodes provide a basis for further development of smart fabrics and wearable electronics.

Prediction of non-responders to oral appliance treatment of obstructive sleep apnea: a pilot study

PurposeSeveral clinically available variables have been identified as predictors of non-response to oral appliance (OA) treatment, including endotypical traits such as severe upper airway collapsibility, unstable ventilatory control, and low arousal threshold. This study aimed to identify potential predictors of non-response to OA treatment in patients with OSA non-adherent to treatment with positive airway pressure.MethodsPatients in this study were initially treated with OAs with and without elastic bands in a crossover design. Subsequently, each patient selected their preferred treatment modality for continued therapy based on subjective preferences. The chosen OA treatment. The chosen OA treatment modality was titrated optimally based on reduction of REI. Patients not reaching > 50% reduction of REI from baseline were classified as non-responders. Statistical analyses were conducted using Student’s t-test and Pearson’s chi-squared test to assess differences in baseline variables between responders and non-responders, and logistic regression analyses were performed to investigate variables associated with not responding to OA treatment.ResultsOverall, 63.2% (n = 36) of the patients were responders to OA treatment following titration. Smaller distance from habitual bite position to maximal retruded position (Odds ratio: 0.28, p = 0.016), positional OSA (Odds ratio: 0.94, p = 0.024) and a higher number of the endotypical OSA traits severe collapsibility, high loop gain and low arousal threshold (Odds ratio: 7.41, p = 0.038), were found to predict non-response to OA treatment.ConclusionThese novel findings suggest that severe upper airway collapsibility, high loop gain and low arousal threshold, identified through clinically available variables, appear to be important predictors of non-response to OA treatment, along with short distance from habitual bite position to maximal retruded position and positional OSA.Trial registration numberNCT05987618 (clinicaltrials.gov).

Germanium target sensed by phonon-mediated kinetic inductance detectors

Cryogenic phonon detectors are adopted in experiments searching for dark matter interactions or coherent elastic neutrino-nucleus scattering, thanks to the low energy threshold they can achieve. The phonon-mediated sensing of particle interactions in passive silicon absorbers has been demonstrated with kinetic inductance detectors (KIDs). Targets with neutron number larger than silicon, however, feature a higher cross section to neutrinos, while multi-target absorbers in the dark matter experiments would provide a stronger evidence of a possible signal. In this work, we present the design, fabrication, and operation of KIDs coupled to a germanium absorber, achieving phonon-sensing performance comparable to silicon absorbers. The device introduced in this work is a proof of concept for a scalable neutrino detector and for a multi-target dark matter experiment.

Misinformation and Disinformation on TikTok

With the rise of social media, platforms like TikTok have become key providers of information. However, the low threshold for content generation has contributed to the widespread distribution of misinformation and deception. This study investigates the contrasts between misinformation and disinformation, emphasizing on their impact during the COVID-19 pandemic. Through content analysis, the study explores how misinformation about vaccines spreads on TikTok and how the platform’s algorithm effects its reach. The data reveal that misinformation often emerges from ignorance, while disinformation is purposefully manufactured to affect public opinion. TikTok has introduced fact-checking and reporting methods, however issues remain owing to the platform's viral nature. The study comes to the conclusion that to minimize the consequences of false information and disinformation on social media, a multifarious strategy including platform control, outside monitoring, and better media literacy is required.

Estimating mutation rate and characterising single nucleotide de novo mutations in pigs

BackgroundDirect estimates of mutation rates in humans have changed our understanding of evolutionary timing and de novo mutations (DNM) have been associated with several developmental disorders in humans. Livestock species, including pigs, can contribute to the study of DNM because of their ideal population structure and routine phenotype collection. In principle, there is the potential for livestock populations to quickly accumulate new genetic variants because of short generation intervals and high selection intensity. However, the impact of DNM on the fitness of individuals is not known and with current genomic selection programs they cannot contribute to estimated breeding values. The aims of our project were to detect and validate single nucleotide DNM in two commercial pig breeding lines, estimate the single nucleotide mutation rate, and characterise DNM.ResultsWe sequenced (150 bp paired end reads, 30X coverage) 46 pig trios from two commercial lines. Single nucleotide DNM were detected using a trio-aware method. We defined candidate DNM as single nucleotide variants (SNVs) found in heterozygous state in trio-offspring with both trio-parents homozygous for the reference allele. In this study, we estimate a lower threshold of the DNM rate in pigs of 6.3 × 10–9 per site per gamete. Our findings are consistent with those from other mammals and those published for a small number of livestock species. Most DNM we detected were in introns (47%) and intergenic regions (49%). The mutational spectrum in pigs differs from that in humans and we found several DNM predicted to have an effect on animal’s fitness based on the base pair change and their location in the genome.ConclusionsWith this study, we have generated fundamental knowledge on mutation rate in a non-primate species and identified DNM that could have an impact on the fitness of individuals.

Thermal biology of Hypogeococcus pungens (Hemiptera: Pseudococcidae) explains its variable performance as a classical biological control agent for Harrisia martinii (Cactaceae) in Australia.

The mealybug, Hypogeococcus pungens Granara de Willink (Hemiptera: Pseudococcidae), was released in Australia as a biological control agent for Harrisia martinii (Labour.) Britton (Cactaceae) in 1975. Although the mealybug successfully established in all released locations, its impact has been variable among regions, possibly as a result of climatic differences. Life-history traits (settling time, survival, development time, female reproduction, adult longevity) were compared at 6 constant temperatures (15 to 40 °C) in the laboratory. The mealybug settled on H. martinii at all temperatures tested, but at 15 °C and 40 °C, insects failed to develop and died. Temperature affected female size, fecundity, and integrated performance, all of which were highest at 25 °C. A linear model that fitted temperature to development time indicated a lower developmental threshold of 14.5 °C for both male and female mealybugs. CLIMEX models were developed for the mealybug and its host, H. martinii, and used to investigate the suitability of different regions of Australia, where H. martinii occurs for Hy. pungens. The Hy. pungens CLIMEX model suggests that cold stress limits mealybug growth in southern Queensland and that mealybug performance will vary between regions based on local temperatures. Locations with extreme low winter and extreme high summer temperatures are likely to have the most constrained populations. This may account for the observed differences in the effectiveness of Hy. pungens as a biological control agent at locations within the established range of H. martini in Australia.

Estradiol is Pro-Nociceptive and Associated with a Small-Fiber Neuropathy Among Premenopausal Women with Sickle Cell Disease

Vaso-occlusive crisis (VOC) pain episodes often occur with menses and concurrent hormonal contraceptive use may reduce their frequency. This study tested the hypothesis that among women with sickle cell disease (SCD), sex hormones are associated with pain detection thresholds. Women with SCD aged minimum 18 years with regular menses, and without acute illnesses, pregnancy, oophorectomy, or hormonal contraceptive use within three months prior were included. Pain detection thresholds for heat (HPT) and pressure (PPT), and serum estradiol, progesterone and testosterone were measured at follicular and luteal phases. The Adult Sickle Cell Quality-of-Life Measurement Information System assessed quality-of-life and VOC frequency and severity scores. Generalized linear mixed models were performed, including the day of the cycle standardized by cycle length. Among 125 participants, neither the day nor phase of the menstrual cycle was associated with PPT or HPT. In multivariate analyses, worse VOC scores (β = 1.7) and severe genotype (β = −46.0) were associated with higher and lower trapezius PPT, respectively. Older age was associated with lower forearm HPT (β = −0.1). Among leg measurements, ovulatory cycles (β = −1.1) and hydroxyurea use (β = −1.2) were associated with lower HPT, while worse VOC scores (β = 0.1) were associated with higher HPT. Higher estradiol was associated with lower HPT at the leg (β = −0.02), with an interaction with the cycle day (β = 0.001) predicting lower thresholds earlier in the cycle for the same estradiol level. Estradiol is associated with a time-varying, length-dependent small-fiber neuropathy among SCD women; and may be a potential therapeutic target and biomarker for SCD pain.

Enhanced Sample Selection with Confidence Tracking: Identifying Correctly Labeled Yet Hard-to-Learn Samples in Noisy Data

We propose a novel sample selection method for image classification in the presence of noisy labels. Existing methods typically consider small-loss samples as correctly labeled. However, some correctly labeled samples are inherently difficult for the model to learn and can exhibit high loss similar to mislabeled samples in the early stages of training. Consequently, setting a threshold on per-sample loss to select correct labels results in a trade-off between precision and recall in sample selection: a lower threshold may miss many correctly labeled hard-to-learn samples (low recall), while a higher threshold may include many mislabeled samples (low precision). To address this issue, our goal is to accurately distinguish correctly labeled yet hard-to-learn samples from mislabeled ones, thus alleviating the trade-off dilemma. We achieve this by considering the trends in model prediction confidence rather than relying solely on loss values. Empirical observations show that only for correctly labeled samples, the model's prediction confidence for the annotated labels typically increases faster than for any other classes. Based on this insight, we propose tracking the confidence gaps between the annotated labels and other classes during training and evaluating their trends using the Mann-Kendall Test. A sample is considered potentially correctly labeled if all its confidence gaps tend to increase. Our method functions as a plug-and-play component that can be seamlessly integrated into existing sample selection techniques. Experiments on several standard benchmarks and real-world datasets demonstrate that our method enhances the performance of existing methods for learning with noisy labels.

Pharmacokinetic study of a novel anti-malaria CN005M and its analogue MeCN005M in albino rat model

Malaria remains a threat to human life and a burden to the global economy due to the emergence of drug-resistant malaria parasites. Thus, the development of an effective anti-malarial drug is required. CN005M and MeCN05M were evaluated. Wister rats were grouped into two groups (n=6) and administered 10 mg/kg bw of CN005M or MeCN005M. Plasma was analyzed using HPLC. CN005M volume of distribution (34.96 ± 7.04) was non-significantly (P > 0.05) changed when compared to MeCN005M (27.33 ± 0.08). CN005M and MeCN005M Mean Retention Time resided non-significantly (P > 0.05) for a period of 9.90 and 12.77 h respectively in the body. Cmax value of CN005M (0.42 μg/mL) was significantly higher (P < 0.05) when compared to the equivalent dose of the MeCN005M (0.24 μg/mL). CN005M (0.50 h) significantly (P < 0.05) reached Tmax sixteen (16) fold faster compared to MeC005M (8.00 h). There was a significant (P < 0.05) reduction in drug clearance and increased last measurable plasma concentration in MeCN005M when compared to CN005M. The results indicate MeCN005M has a lower Cmax with an extended Tmax, with a low toxicity threshold and sustained efficacy. MeCN005M may provide the benefits of reducing the required dose and frequency while maintaining therapeutic efficacy.

Enhancing Dementia Classification for Diverse Demographic Groups: Using Vision Transformer-Based Continuous Scoring of Clock Drawing Tests.

Alzheimer's disease and related dementias significantly impact older adults' quality of life. The clock-drawing test (CDT) is a widely used dementia screening tool due to its ease of administration and effectiveness. However, manual CDT-coding in large-scale studies can be time-intensive and prone to coding errors and is typically limited to ordinal responses. In this study, we developed a continuous CDT score using a deep learning neural network (DLNN) and evaluated its ability to classify participants as having dementia or not. Using a nationally representative sample of older adults from the National Health and Aging Trends Study (NHATS), we trained deep learning models on CDT images to generate both ordinal and continuous scores. Using a modified NHATS dementia classification algorithm as a benchmark, we computed the Area Under the Receiver Operating Characteristic Curve for each scoring approach. Thresholds were determined by balancing sensitivity and specificity, and demographic-specific thresholds were compared to a uniform threshold for classification accuracy. Continuous CDT scores provided more granular thresholds than ordinal scores for dementia classification, which vary by demographic characteristics. Lower thresholds were identified for Black individuals, those with lower education, and those ages 90 or older. Compared to ordinal scores, continuous scores also allowed for a more balanced sensitivity and specificity. This study demonstrates the potential of continuous CDT generated by DLNN to enhance dementia classification. By identifying demographic-specific thresholds, it offers a more inclusive and adaptive approach, which could lead to improved guidelines for using CDT in dementia screening.

Phenotype Description and Lower Pathogenicity Threshold in a Large Cohort of SCA27B (P6-5.028)

Phenotype Description and Lower Pathogenicity Threshold in a Large Cohort of SCA27B (P6-5.028)