Apparent Association Research Articles

Clinical Pharmacology of Asciminib: A Review.

Asciminib is a first-in-class allosteric inhibitor of the kinase activity of BCR::ABL1, specifically targeting the ABL myristoyl pocket (STAMP). This review focuses on the pharmacokinetic (PK) and pharmacodynamic data of asciminib, which is approved at a total daily dose of 80 mg for the treatment of adult patients with chronic myeloid leukemia in chronic phase who are either resistant or intolerant to ≥ 2 tyrosine kinase inhibitors or those harboring the T315I mutation (at a dose of 200 mg twice daily). Asciminib is predicted to be almost completely absorbed from the gut, with an absolute bioavailability (F) of approximately 73%. It should be administered in a fasted state, as food (particularly high-fat meals) reduces exposure. Asciminib displays a slightly greater than dose-proportional increase in exposure, with no time-dependent changes in PK observed following repeated dosing. This drug shows low clearance (6.31 L/h), with a moderate volume of distribution (111 L) and high human plasma protein binding (97.3%). The apparent terminal elimination half-life (t1/2) across studies was estimated to be between 7 and 15h. The PK of asciminib is not substantially affected by body weight, age, gender, race, or renal or hepatic impairment. Asciminib is primarily metabolized via CYP3A4-mediated oxidation (36.0%) and UGT2B7- and UGT2B17-mediated glucuronidation (13.3% and 7.8%, respectively); biliary secretion via breast cancer resistance protein contributes to about 31.1% to total systemic clearance, which is mainly through hepatic metabolism and biliary secretion through the fecal pathway, with renal excretion playing a minor role. The potential for PK drug interaction for asciminib both as a victim and a perpetrator has been summarized here based on clinical and predicted drug-drug interaction studies. Robust exposure-response models characterized asciminib exposure-efficacy and exposure-safety relationships. In patients without the T315I mutation, the exposure-efficacy analysis of the time course of BCR::ABL1IS percentages highlighted the existence of a slightly positive, albeit not clinically significant, relationship. Higher exposure was required for efficacy in patients harboring the T315I mutation compared with those who did not. The exposure-safety relationship analysis showed no apparent association between exposure and adverse events of interest over the broad range of exposure or dose levels investigated. Asciminib has also been shown to have no clinically relevant effect on cardiac repolarization. Here, we review the clinical pharmacology data available to date for asciminib that supported its clinical development program and regulatory applications.

“Friendships fizzled out”: Trajectories and risk factors of youth loneliness following COVID-19

Abstract Background Social distancing and isolation during the COVID-19 pandemic left a mark on the social, emotional and cognitive development of youth. We aimed to identify the course of Dutch youth loneliness and its predictors since the Omicron lockdown in December 2021. Methods Data were obtained from a repeated cross-sectional panel study between March 2022 and September 2023, in which loneliness was assessed using the 6-item De Jong Gierveld Loneliness Scale. Youth (12-25 years) participating in at least three timepoints were included. A latent class growth analysis (LCGA) was performed to identify trajectories of loneliness. Themes identified in qualitative data (open-ended questions halfway 2022) were recoded into binary quantitative variables to be included in regression analyses. Two-step multivariable multinomial logistic regression was used to determine risk factors per trajectory class. Goodness of fit was assessed using the likelihood-ratio test. Results Identified trajectories were: 1) very lonely (n = 140), 2) moderate lonely (n = 373), 3) recovering (n = 511), and 4) not lonely (n = 384; reference). Compared to the other trajectories, youngsters following a moderate or very lonely trajectory had more often little to no trust in the future and more often experienced non-specific symptoms and stress due to various causes. Including perceptions showed that youth in these trajectories experienced a greater impact of the pandemic on their social relationships. The inclusion of perception also improved the model’s goodness of fit (p < 0.001). Conclusions Up to 18 months after the COVID-19 pandemic, youngsters that reported loneliness continue to endure its consequences on their social lives. Despite the apparent association between the Omicron lockdown and continuing loneliness, claims about causality should be made with caution. However, findings implicate the importance of political and social recognition of the pandemic’s ongoing impact on vulnerable youth. Key messages • Lonely youth experienced a greater impact of the COVID-19 pandemic on their social lives. • Political and social recognition of the pandemic’s ongoing impact on vulnerable youth is wanted.

Speed-dating and simulation data explain the discrepancy between stated and revealed mate preferences

There is little evidence in speed-dating studies that stated preferences – what people say they prefer in a partner – are associated with revealed preferences – what people actually find attractive in a partner. In Study 1, a high-powered speed-dating study ( n = 1145) revealed that four out of nine traits provided evidence of a correspondence between stated and revealed preferences. In Study 2, simulations based on the constraints of Study 1’s speed-dating design showed that when attractiveness depends on multiple independent traits, the stated preference for an individual trait can only be, on average, minimally related to the revealed preference for that trait. In Study 3, we investigated methods that simultaneously combine multiple traits when testing the association between stated and revealed preferences (e.g. Euclidean distance, pattern metric). All four omnibus methods indicated an apparent association between stated and revealed preferences in our speed-dating data. However, additional analyses and permutation tests suggest that these significant associations reflect statistical artefacts rather than true correspondences. We conclude that detecting any association between stated and revealed preferences will be difficult under realistic assumptions about the number of traits involved in partner evaluation. In this light, we discuss previous findings and provide suggestions for future studies in this vein.

Toxicity in patients receiving radiotherapy for ultracentral stage I non-small cell lung cancer: A secondary analysis of the LUSTRE randomized trial

Background and PurposeStereotactic body radiotherapy (SBRT) carries potentially higher risks for ultracentral (UC) NSCLC with limited prospective data to guide decision making. We conducted a secondary analysis from a randomized trial of SBRT and conventionally hypofractionated radiation (CRT) to assess these risks. Materials and MethodsPatients (n = 233) with medically inoperable stage I NSCLC were recruited from 2014 to 2020. Patients with UC targets directly overlapping the proximal bronchial tree (PBT) were identified. The primary objective was the occurrence of related grade 3–5 toxicity > 3 months following radiation. Secondary endpoints included local control, survival, and evaluation of PBT dose and its association with late toxicity. ResultsThirty UC tumors were identified (23 − SBRT 60 Gy/8 fractions, 7 − CRT 60 Gy/15 fractions). Median age was 72 years, and median tumor size was 2.8 cm. Most patients (67 %) had histologically confirmed NSCLC. At a median follow-up of 2.9 years, 3 and 1 patients developed grade 3 and 5 toxicity respectively (all SBRT). 3-year local control was 85 %. Mean PBT dose (converted to 2 Gy dose equivalents) was higher in patients with grade ≥ 3 toxicity, particularly for 4 cc (105.5 vs 51.8 Gy, p = 0.0004), 5 cc (84 vs 46.1 Gy, p = 0.003), and volumetric doses (V65 – V100Gy). The patient with grade 5 toxicity had the highest 5 cc dose (117 Gy), V90Gy (8.2 cc), and V100Gy (7 cc). ConclusionsSBRT for UC NSCLC provides good local control but carries a high rate of late grade 3–5 toxicity. An apparent association between toxicity and PBT volumetric dose was observed, which should be considered if SBRT is offered.

Dynamics and Thermodynamics Study of the Adsorption of Lysozyme to 2D SnSe Nanoflake Surfaces with Associated Unfolding

AbstractIn this work, we explore the interaction as well as corona formation and interfacial phenomena of lysozyme (LYZ) and 2D SnSe nanoflake. The optical results indicate formation of ground state complex with an apparent association constant of 1.5 × 103 (mol)−1. The dynamics of the in situ interaction exhibited surface reorganization (t2 = 73.5 min) and unfolding, which were more prominent than binding (t1 = 3 min) for tryptophan residues of LYZ. The formations of soft and hard corona of the LYZ structure were clearly observed from HRTEM. The emission quenching exhibited tertiary deformation of the LYZ structure with positive cooperative binding (n > 1) and dynamics of quenching followed the sigmoidal Boltzmann nature of the energy transfer process. The ultrafast lifetime of the bioconjugate varied from 1.9–1.35 ns with a maximum 63% energy transfer efficiency within 300 min of the corona evolution. The decrement of α helix (58.87%–21.78%) and increment of β sheet (5.27%–23.98%) were observed after interaction, with the conversion of large amount of α helix into β sheet. The ITC results showed that the injection heat results followed two‐site binding model, and the exothermic binding was dominate over the interaction. The second phase binding is driven by larger positive entropy, where the first binding site has a stronger association.

Association between high-density lipoprotein-related inflammation index and periodontitis: insights from NHANES 2009-2014.

Periodontitis, a persistent inflammatory condition, significantly impairs individuals' overall quality of life. Lymphocyte-to-high-density lipoprotein cholesterol ratio (LHR), monocyte-to-high-density lipoprotein cholesterol ratio (MHR), neutrophil-to-high-density lipoprotein cholesterol ratio (NHR), and platelet-to-high-density lipoprotein cholesterol ratio (PHR) are new convenient and economical biomarkers. However, whether the above high-density lipoprotein-related inflammatory biomarkers are associated with periodontitis has rarely been investigated. Therefore, the research endeavor focused on uncovering potential relationships. The research encompassed a diverse and extensive sample, comprising 9,470 participants, selected from the National Health and Nutrition Examination Survey spanning the years 2009 to 2014. The association between high-density lipoprotein-related inflammatory biomarkers and periodontitis was explored utilizing a multivariable logistic regression model with weighted analysis. Additionally, the study employed smoothed curve fitting to explore potential nonlinear relationships. Further stratified analyses and interaction tests were performed. This study indicated no apparent association between MHR and PHR with periodontitis, whereas LHR and NHR demonstrated a statistically significant positive relationship with the prevalence of periodontitis. In the fully adjusted model, participants belonging to the highest tertile of both LHR and NHR showed a notably higher likelihood of having periodontitis compared to those in the lowest tertile (LHR: OR = 1.22, 95% CI: 1.06, 1.39; NHR: OR = 1.27, 95% CI: 1.09, 1.49). Furthermore, smooth curve fitting was employed to investigate the potential nonlinear relationship between LHR, NHR, and periodontitis. The results indicated that there was a significant increase in the occurrence of periodontitis when Log2 (LHR) exceeded 1.01 and Log2(NHR) surpassed 2.16 (Log2(LHR): OR = 1.42; 95% CI: 1.19, 1.69; Log2(NHR): OR = 1.40; 95% CI: 1.15, 1.71). The subgroup analysis revealed that the associations between periodontitis and either LHR or NHR, separately, were more pronounced among individuals under the age of 50 and those without hypertension. This cross-sectional study revealed a positive relationship between LHR、NHR and periodontitis, particularly when these indicators exceeded their thresholds. LHR and NHR may serve as potential inflammatory markers for identifying periodontitis, thereby facilitating early warning for both patients and dentists, and enabling early intervention in the oral environment. Besides, extensive prospective cohort investigations are essential to confirm and solidify this observation.

Family-homelessness and child absence from school: How data linkage research has identified and quantified the association in Wales, UK

BackgroundHome and school experiences are linked. Though evidence exists quantifying the association between family-homelessness and school absences, it largely originates from the United States. Understanding the nature of this association in Wales, UK, is important given differing social, economic, and homelessness policy contexts when compared to the United States. ApproachAnalysis included pupils attending state funded schools in a single local authority in Wales, during the academic years 2012/13 to 2015/16. Pupils were flagged as experiencing family-homelessness in an academic year if their family were supported by the housing service operating in the local authority area. Outcomes of interest were number of total, authorised, and unauthorised half-day-sessions absent per academic year. Pupils were observed over multiple academic years (N = 105,355 pupil-years), enabling both cross-sectional and longitudinal (panel) analyses. ResultsOn average, pupils in families accessing the housing service missed a total of 10 half-day-sessions more per academic year than pupils whose families were not accessing the service. Unauthorised half-day-sessions absent were double for pupils in families who had approached the housing service. After controlling for personal and area characteristics, rates of all absences were higher among pupils whose families accessed the service. ConclusionThis study represents the first published linkage of homelessness and education data in the UK. Given the apparent association between absenteeism and accessing housing support, changes to policy, practice, and law should be explored to facilitate co-operation between schools and housing services in Wales, and to protect children and their families from further disadvantage.

Skin tone discrimination and birth control avoidance among women in Harris County, Texas: a cross-sectional study

IntroductionStructural racism plays a major role in reproductive health inequities. Colorism, discrimination based on skin color, may profoundly impact reproductive health access and service delivery. However, quantitative research in this area is limited.MethodsWe administered an online survey of women (n = 1,299) aged 18–44 from Harris County, Texas to assess the relationship between skin color discrimination and reproductive health service avoidance. The survey included questions on demographics, self-reported skin tone, and dichotomous measures of previous discrimination experiences and avoidance of care because of perceived discrimination. Binary logistic regression was used to examine whether race/ethnicity, skin tone, and previous discrimination experiences were related to avoidance of contraceptive care because of perceived discrimination.ResultsApproximately one-third (31.5%) of the sample classified themselves as non-Hispanic Whites (31.5%), 22.4% as Black, 27.4% as Hispanic and born within the US, and 7.6% as Hispanic born outside of the US. Approximately one-third of women classified themselves in the lightest skin tones, whereas almost one in five women classified themselves in the darkest skin tone palates. Darker skin tones had increasingly greater odds of reporting that they avoided seeking birth control out of a concern for discrimination compared to the lightest skin tone. After adjusting for race/ethnicity and sociodemographic variables (model 3), darker skin tones remained significantly associated with avoiding birth control.DiscussionThis study demonstrates the role that skin color discrimination plays in negative reproductive health experiences. While this is not surprising given that those with racist ideologies developed the concept of these racial and ethnic categories, the apparent association with darker skin colors and avoidance of seeking birth control provides evidence that structural and individual racism continues to have far-reaching and insidious consequences.ConclusionContraception is recognized for reducing maternal mortality, improving child health, increasing female empowerment, and decreasing poverty. However, not all women equally enjoy the benefits of access to contraception. Addressing colorism within reproductive healthcare has become critically important as the nation becomes increasingly diverse. Focusing on skin tone-based discrimination and its roots in anti-blackness expands our understanding beyond a Black–White binary traditionally applied when addressing racism in healthcare delivery.

Rare germline genetic variation in PAX8 transcription factor binding sites and susceptibility to epithelial ovarian cancer.

Common genetic variation throughout the genome together with rare coding variants identified to date explain about a half of the inherited genetic component of epithelial ovarian cancer risk. It is likely that rare variation in the non-coding genome will explain some of the unexplained heritability, but identifying such variants is challenging. The primary problem is lack of statistical power to identifying individual risk variants by association as power is a function of sample size, effect size and allele frequency. Power can be increased by using burden tests which test for association of carriers of any variant in a specified genomic region. This has the effect of increasing the putative effect allele frequency. PAX8 is a transcription factor that plays a critical role in tumour progression, migration and invasion. Furthermore, regulatory elements proximal to target genes of PAX8 are enriched for common ovarian cancer risk variants. We hypothesised that rare variation in PAX8 binding sites are also associated with ovarian cancer risk, but unlikely to be associated with risk of breast, colorectal or endometrial cancer. We have used publicly available, whole-genome sequencing data from the UK 100,000 Genomes Project to evaluate the burden of rare variation in PAX8 binding sites across the genome. Data were available for 522 ovarian cancers, 2,984 breast cancers, 2,696 colorectal cancers, 836 endometrial cancers and 2253 non-cancer controls. Active binding sites were defined using data from multiple PAX8 and H3K27 ChIPseq experiments. We found no association between the burden of rare variation in PAX8 binding sites (defined in several ways) and risk of ovarian, breast or endometrial cancer. An apparent association with colorectal cancer was likely to be a technical artefact as a similar association was also detected for rare variation in random regions of the genome. Despite the null result this study provides a proof-of -principle for using burden testing to identify rare, non-coding germline genetic variation associated with disease. Larger sample sizes available from large-scale sequencing projects together with improved understanding of the function of the non-coding genome will increase the potential of similar studies in the future.

Evaluating the impact of a trial of labor after cesarean section on labor duration: a retrospective cohort study

BackgroundCesarean section (C-section) rates are increasing globally, and repeated C-sections are associated with increased maternal morbidity. Trial of labor after C-section (TOLAC) is an approach to reduce the recurrence of C-sections. However, limited research exists on the impact of cesarean scars on labor duration in TOLAC, considering the termination of labor through C-section and selection bias. This study aimed to investigate the impact of cesarean scars on labor duration in TOLAC participants, accounting for potential confounding factors and biases.MethodsThis retrospective cohort study included 2,964 women who attempted vaginal birth at a single center in Japan from 2012 to 2021. The study categorized participants into TOLAC (n = 187) and non-TOLAC (n = 2,777) groups. Propensity scores were calculated based on 14 factors that could influence labor duration, and inverse probability of treatment weighting (IPTW) was applied. Cox proportional hazards regression analysis estimated hazard ratios (HRs) for labor duration, with and without IPTW adjustment. Sensitivity analyses used propensity score matching, bootstrapping, and interval censoring to address potential biases, including recall bias in the reported onset of labor.ResultsThe unadjusted HR for labor duration in the TOLAC group compared to the non-TOLAC group was 0.83 (95% CI: 0.70–0.98, P = 0.027), indicating a longer labor duration in the TOLAC group. After adjusting for confounding factors using IPTW, the HR was 0.98 (95% CI: 0.74–1.30, P = 0.91), suggesting no significant difference in labor duration between the groups. Sensitivity analyses using propensity score matching, bootstrapping, and interval censoring yielded consistent results. These findings suggested that the apparent association between TOLAC and longer labor duration was because of confounding factors rather than TOLAC itself.ConclusionsAfter adjusting for confounding factors and addressing potential biases, cesarean scars had a limited impact on labor duration in TOLAC participants. Maternal and fetal characteristics may have a more substantial influence on labor duration.

Determinants of Human Asymmetry: Does Asymmetrical Retinal Vasculature Predict Asymmetry Elsewhere in the Body?

The aim of this study was to explore retinal vasculature asymmetry (ReVA) patterns in subjects from the islands of Vis and Korcula and the city of Split, Croatia. Asymmetry estimates were based on topographic image analysis of non-mydriatic retinal fundus photographs and compared with nine ophthalmic measurements, three Doppler-based pressure indices and eight frequencies of audiometry. ReVA was also correlated to the genomic runs of homozygosity (ROHs) and used in a Cox regression survival model, where we adjusted for the effects of sex, age and comorbidity. In 1873 subjects, ReVA estimates were significantly correlated with most ophthalmic asymmetry measures, less strongly with the ankle-brachial pressure index and only modestly with higher-amplitude audiometry asymmetries (lowest p = 0.020). ReVA was significantly correlated with the number of ROHs (r = 0.229, p < 0.001) but less strongly with the ROH length (r = 0.101, p < 0.001). The overlap of asymmetries was low, with only 107 subjects (5.7% of the total sample) who had two or more instances in which they were among the top 10%. Multiple asymmetries did not affect survival (HR = 0.74, 95% confidence intervals 0.45-1.22). Retinal vasculature asymmetry is a poor predictor of asymmetry elsewhere in the body. Despite its existence and apparent association with comorbidities, the observed extent of retinal vasculature asymmetry did not affect the lifespan in this population.

Height, body mass index, physical activity, and risk of colorectal cancer in relation to expression of insulin receptor: The Japan Public Health Center-based Prospective Study.

To ascertain the involvement of insulin receptors (IRs) in colorectal carcinogenesis, we investigated the association of height, body mass index (BMI), and physical activity with colorectal cancer (CRC) and two subtypes of CRC according to the expression level of IR. We utilized data from a large-scale, population-based prospective cohort study of 18,158 middle-aged and elderly subjects in Akita and Okinawa, Japan. In the statistical analysis, we used the Cox proportional hazards model and estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for the risk of CRC and its subtypes as defined by immunohistochemistry of IRβ, a transmembrane subunit of IR. In the IRβ-defined subtypes, height showed no apparent association with the risk of IRβ-positive CRC. In contrast, a multivariable HR of IRβ-positive CRC was 1.77 (95% CI = 1.04-3.03) with a BMI of ≥30.0 kg/m2 (i.e., obesity), compared to a BMI of <25.0 kg/m2. Further, an increase in physical activity was significantly associated with decreased risk of IRβ-positive CRC (multivariable HR per 5 METs-hour/day = 0.93, 95% CI = 0.88-0.99). Meanwhile, we found no significant association between any exposure and IRβ-negative CRC. Likewise, heterogeneity between the two subtypes of CRC was not statistically significant. These findings imply that obesity and physical activity exert promoting and suppressing effects on the development of CRC expressing IRs, respectively.

Surveillance for Distant Metastasis in Breast Cancer Patients Who Underwent Contemporary Management: A Report from the Korean Breast Cancer Society Survivor Research Group

BackgroundCurrent guidelines recommend against the use of routine imaging tests to detect distant metastasis in asymptomatic breast cancer patients. However, recent advancements in effective therapeutics and diagnostic accuracy have raised the need to reassess the clinical efficacy of intensive metastasis surveillance. We report the results of a multicenter retrospective study to investigate the association between intensive imaging studies and survival outcomes.Patients and MethodsWe retrospectively reviewed the data of 4130 patients who underwent surgery from 11 hospitals in Korea between January 2010 and December 2011. Patients were divided into two groups on the basis of the intensity of metastasis imaging studies during their disease-free period. The types and intervals of the imaging studies were based on each physician’s decisions.ResultsHigh-intensive screening showed a shorter distant metastasis-free survival [p < 0.001, hazard ratio (HR) 1.62; 95% confidence interval (CI) 1.29–2.04], especially for patients in whom bone or lung was the first site of metastasis. With a median follow-up period of 110.0 months, the 5-year breast cancer-specific survival (BCSS) rate was 96.5%. The high-intensity screening group showed significantly poorer BCSS compared with the low-intensity screening group (p < 0.001, HR 3.13; 95% CI 2.32–4.21). However, both multivariable analysis and propensity score matching analysis showed no significant association between the screening intensity and BCSS.ConclusionsFrequent imaging studies to detect distant metastasis were associated with earlier detection of distant metastasis, especially for lung and bone metastasis. However, intensive surveillance showed no apparent association with BCSS despite the use of currently available treatments.

COVID-19 pandemic: Restrictions and functionality in the knees of physiotherapy students, preliminary study

Background: The COVID-19 pandemic declared by the WHO in 2020 led to restrictive measures that exerted an impact on physical activity, which can affect musculoskeletal health. Objective: The aim of the present study was to analyze the impact of the pandemic on knee pain and functioning among university students influenced by social isolation measures. Methods: An observational, cross-sectional study was conducted at the Evangelical University of Goiás (UniEVANGELICA) with 52 physiotherapy students. Data were collected with the aid of an online questionnaire addressing lifestyle habits, physical activity, knee pain, and functioning using the Lysholm knee score. Data analysis was performed with SPSS 21, using appropriate statistical tests. Results: The chi-square test revealed no significant association between COVID-19 and knee pain, but an apparent relationship was found between physical activity and pain. No significant association was found between COVID-19 and worse walking function, although a tendency was suggested. Discussion: Despite the apparent association between physical activity and pain, the lack of statistical significance indicates the need for more detailed analyses. The present results diverge from those of global studies, underscoring the complexity of the relationship between the pandemic and musculoskeletal health. Limitations of the study include the sample size and self-reporting. Conclusion: This study provides insights into the relationships between COVID-19, knee pain, physical activity, and walking function in university students. Although no significant association was found in some analyzes performed in this study, caution should be exercised when interpreting the results. Further research considering additional variables is recommended to gain a robust understanding of these relationships.

Comparing Influences of Solar Wind, ULF Waves, and Substorms on 20 eV–2 MeV Electron Flux (RBSP) Using ARMAX Models

AbstractElectron fluxes (20 eV–2 MeV, RBSP‐A satellite) show reasonable simple correlation with a variety of parameters (solar wind, IMF, substorms, ultralow frequency (ULF) waves, geomagnetic indices) over L‐shells 2–6. Removing correlation‐inflating common cycles and trends (using autoregressive and moving average terms in an ARMAX analysis) results in a 10 times reduction in apparent association between drivers and electron flux, although many are still statistically significant (p &lt; 0.05). Corrected influences are highest in the 20 eV–1 keV and 1–2 MeV electrons, more modest in the midrange (2–40 keV). Solar wind velocity and pressure (but not number density), IMF magnitude (with lower influence of Bz), SME (a substorm measure), a ULF wave index, and geomagnetic indices Kp and SymH all show statistically significant associations with electron flux in the corrected individual ARMAX analyses. We postulate that only pressure, ULF waves, and substorms are direct drivers of electron flux and compare their influences in a combined analysis. SME is the strongest influence of these three, mainly in the eV and MeV electrons. ULF is most influential on the MeV electrons. Pressure shows a smaller positive influence and some indication of either magnetopause shadowing or simply compression on the eV electrons. While strictly predictive models may improve forecasting ability by including indirect driver and proxy parameters, and while these models may be made more parsimonious by choosing not to explicitly model time series behavior, our present analyses include time series variables in order to draw valid conclusions about the physical influences of exogenous parameters.

EHR documentation of cost discussions and financial interventions for a cohort of patients with advanced cancer: Findings from a retrospective chart review-based study.

e23150 Background: Financial Toxicity (FT), the adverse impact of high medical costs on quality of life, notably affects many oncology patients. In a prior initiative to improve quality of life for advanced cancer patients, a palliative care-trained nurse practitioner (PCNP) was embedded in an academic oncology practice. Patients completed the Edmonton Symptom Assessment System (ESAS) and Canadian Problem Checklist (CPC) to gauge physical symptoms, psychosocial issues, and financial concerns. However, the incidence of self-reported financial issues and electronic health record (EHR) documentation of cost discussions and interventions remain unclear for this patient group. Methods: The study included adult oncology patients with advanced cancer seen by the PCNP from January 1, 2020, to January 1, 2022. We assessed incidence of self-reported financial concerns via CPC checklists in this cohort. Ten charts underwent detailed manual review for evidence of cost discussions or referral to finance-related interventions for up to 1 year from the initial consult with the PCNP or until death. During the review, we identified keywords in documentation of cost discussions and finance-related interventions to create a keyword library. We iteratively compared the library to our reference standard manual chart review to ensure 100% sensitivity. We then employed this keyword library to evaluate the remaining charts. Descriptive statistics were employed to assess correlations between self-reported financial concerns, chart documentation of cost discussions or financial interventions, and patient demographics. Results: Out of 109 eligible patients, 71% (77) completed pre-visit questionnaires, with 30% (23) reporting financial issues. Of this group, 43% (10) died during the study period. Average follow-up was 5.0 months among the decedents. Among those reporting financial concerns, 65% (15) had documented cost discussions or financial assistance referrals in the EHR, involving physicians, social workers, and other clinic staff. Most interventions addressed medication costs and referrals to financial assistance as indicated. Patient demographics (age, sex, insurance type) showed no apparent association with chart documentation of cost discussions or financial assistance. Conclusions: We used retrospective chart review to evaluate the extent of documentation of cost discussions and finance-related intervention in a cohort of patients with advanced cancer. In our patient cohort, 30% self-reported financial concerns, a proportion consistent with previously reported incidence of FT among oncology patients. Notably, 35% of the patients with known financial concerns had no other relevant documentation in the EHR. More work is needed to establish best practices for systematic screening for FT and interventions to support patients.

Investigation of the Affinity of Aptamers for Bacteria by Surface Plasmon Resonance Imaging Using Nanosomes.

The cell-SELEX method enables efficient selection of aptamers that bind whole bacterial cells. However, after selection, it is difficult to determine their binding affinities using common screening methods because of the large size of the bacteria. Here we propose a simple surface plasmon resonance imaging method (SPRi) for aptamer characterization using bacterial membrane vesicles, called nanosomes, instead of whole cells. Nanosomes were obtained from membrane fragments after mechanical cell disruption in order to preserve the external surface epitopes of the bacterium used for their production. The study was conducted on Bacillus cereus (B. cereus), a Gram-positive bacterium commonly found in soil, rice, vegetables, and dairy products. Four aptamers and one negative control were initially grafted onto a biochip. The binding of B. cereus cells and nanosomes to immobilized aptamers was then compared. The use of nanosomes instead of cells provided a 30-fold amplification of the SPRi signal, thus allowing the selection of aptamers with higher affinities. Aptamer SP15 was found to be the most sensitive and selective for B. cereus ATCC14579 nanosomes. It was then truncated into three new sequences (SP15M, SP15S1, and SP15S2) to reduce its size while preserving the binding site. Fitting the results of the SPRi signal for B. cereus nanosomes showed a similar trend for SP15 and SP15M, and a slightly higher apparent association rate constant kon for SP15S2, which is the truncation with a high probability of a G-quadruplex structure. These observations were confirmed on nanosomes from B. cereus ATCC14579 grown in milk and from the clinical strain B. cereus J066. The developed method was validated using fluorescence microscopy on whole B. cereus cells and the SP15M aptamer labeled with a rhodamine. This study showed that nanosomes can successfully mimic the bacterial membrane with great potential for facilitating the screening of specific ligands for bacteria.

Mirikizumab Exposure-Response Relationships in Patients with Moderately-to-Severely Active Ulcerative Colitis in Randomized Phase II and III Studies.

Mirikizumab is a humanized anti-interleukin-23p19 monoclonal antibody being developed for ulcerative colitis (UC) and Crohn's disease. We characterized the relationship of mirikizumab systemic exposure with efficacy and safety end points in patients with UC using phase II (NCT02589665) and III (NCT03518086, NCT03524092) trial data. Exposure-response models were developed for clinical remission, clinical response, endoscopic remission, and change in modified Mayo score following induction (50-1,000 mg i.v. every 4 weeks) and maintenance (200 mg s.c. every 4 or 12 weeks) treatment. These models evaluated observed and pharmacokinetic model-predicted mirikizumab exposures as the exposure measure. Key safety event rates were compared across mirikizumab exposure quartiles in the phase III trial. Mirikizumab efficacy in patients with UC showed an apparent positive association with systemic exposure following both induction and maintenance. However, further analysis found this relationship to be overstated by the presence of confounding factors that were not among the tested patient covariates. While prior biologic experience and baseline disease severity showed statistically significant influences on estimated placebo effect, no patient factors affected the mirikizumab effect parameters in any of the phase III exposure-response models. There was no apparent mirikizumab concentration relationship with any adverse event of special interest. When the phase II and III data and confounding are considered together, efficacy was unlikely to be strongly affected by variation in exposures across individual patients at the phase III dose. Together with the previously demonstrated mirikizumab exposure insensitivity to patient factors, these findings indicate that mirikizumab dose adjustment to patient characteristics is not required.

Massive decline of invasive apple snail populations after blue crab invasion in the Ebro River, Spain

The negative interaction between multiple invasive species, when an invasive predator benefits from a previously introduced and abundant prey, poses unanticipated challenges for the joint management of invaders. To illustrate this question, we describe the surge and collapse of the invasive apple snail Pomacea maculata population before and after the arrival of the invasive blue crab, Callinectes sapidus, in the Ebro River (NE Spain). These two invaders have coincided for the first time beyond their respective native and prior invasive ranges, and thus lack any previous shared eco-evolutionary history facilitating coexistence. We leverage data from a 9-year apple snail removal programme (2014–2022) conducted by authorities to evaluate the effectiveness of the management programme and describe the apple snail temporal dynamics in the Ebro River. Since its arrival in 2013, the apple snail population increased exponentially along the river and adjacent rice-fields despite labour-intensive eradication efforts. Unexpectedly, riverine populations of the apple snail declined by 90% in 2018 relative to the prior year without apparent association with previous management efforts. Simultaneously, the blue crab was first recorded in the Ebro River in 2018, and its distribution rapidly overlapped the whole area invaded by apple snails. We suggest that over-predation by the blue crab is the main cause of the decline observed in the apple snail, and discuss the implications of this new invader-invader interaction for management. This study underscores the unforeseen consequences of subsequent waves of invasion, and the importance of supporting management with a deeper understanding of ecological interactions among invasive predator and prey species.

Animal Shelter Wastewater Sampling for Pathogens With Epidemic Potential

Canine distemper virus (CDV), canine parvovirus (CPV), and Streptococcus zooepidemicus (S. zoo) represent a range of infectious agents that can cause epidemic disease in dogs, particularly those housed in animal shelters. Outbreaks of disease associated with these agents are relatively common in shelters, resulting in isolation, quarantine, euthanasia, and in some cases, shelter closure in efforts to manage the outbreak. In recent years, outbreaks of CDV and S. zoo have been particularly challenging for shelters in Arizona. Wastewater-based epidemiology (WBE) has proven useful in disease monitoring and outbreak prediction in human populations, including congregate locations, and we hypothesized that it may also be useful in surveillance and prediction for agents responsible for either gastrointestinal (GI) or respiratory disease in shelter animals. Our specific aims were to develop and validate a protocol for detecting infectious agents from wastewater samples collected from shelter run sections and to investigate associations with agent burden and counts of animals with clinical signs. Once protocols for sampling and preparation were optimized, environmental wastewater samples were collected weekly between November 2023 and April 2024 at a large open intake municipal animal shelter in Phoenix, Arizona. The samples were collected from seven drains located in seven run sections in three separate buildings, and were evaluated for the presence of the three agent nucleic acids using quantitative, multiplex PCR. The counts of dogs actively showing GI and respiratory symptoms, graded as mild, moderate, and severe, were collected the afternoon of the day of sampling. Biosafety committee approval was granted for the viruses in this study. Shedding of CPV was found to be widespread and variable over time. S. zoo was detected five times on five different weeks in five different run sections. CDV was found once. There were only six dogs reported with GI signs during the study period. Counts of respiratory disease ranged from 42-132 dogs per run section with most cases being mild in severity and reported in the isolation run section. There is no apparent association between counts of either respiratory or GI cases and the three agents detected through wastewater sampling. During the study there was a single incident of a S. zoo PCR positive dog being isolated and later dying at the shelter. S. zoo was detected through wastewater sampling the week prior to the incident, however, in a run section located in a different building than where the PCR positive dog was housed. To the authors’ knowledge, this study is the first of its kind to develop protocols to detect critical pathogens in wastewater samples from an animal shelter. CPV has been the pathogen most frequently detected, which we speculate may be largely due to the shedding typically observed in dogs post-vaccination, given the absence of GI signs. Further investigation is warranted to better characterize the absence of amplifiable CDV nucleic acids and to examine these samples for other common shelter pathogens.