Validating an instrument for measuring community cultural wealth with biology majors at a Hispanic-serving institution.

Boosting underrepresented student persistence in STEM majors has been of interest for several years. Prior research has explored various factors that may influence student success and persistence in STEM majors. Specifically, some of these studies have employed Yosso's community cultural wealth framework to explore how a student's cultural wealth may link to certain outcomes. Most of these studies have taken a qualitative approach when exploring cultural wealth and less adopt a quantitative approach. Using biology students in an introductory biology class during the fall (n = 303) and spring semesters (n = 215) at a large Hispanic-serving institution in the southeastern United States, this study seeks to contribute to the literature by validating a previously constructed instrument with a new population. An exploratory factor analysis (EFA) was conducted using principal axis factoring and an oblique rotation. EFA results revealed 10 dimensions of cultural wealth. Additionally, confirmatory factor analysis confirmed that the model produced properly measures the constructs as intended. Overall, the final 56-item instrument used in this study was validated and can be used for measuring cultural wealth in similar populations.

A sequential binding mechanism for 5' splice site recognition and modulation for the human U1 snRNP.

Splice site recognition is essential for defining the transcriptome. Drugs like risdiplam and branaplam change how human U1 snRNP recognizes particular 5' splice sites (5'SS) and promote U1 snRNP binding and splicing at these locations. Despite the therapeutic potential of 5'SS modulators, the complexity of their interactions and snRNP substrates have precluded defining a mechanism for 5'SS modulation. We have determined a sequential binding mechanism for modulation of -1A bulged 5'SS by branaplam using a combination of ensemble kinetic measurements and colocalization single molecule spectroscopy (CoSMoS). Our mechanism establishes that U1-C protein binds reversibly to U1 snRNP, and branaplam binds to the U1 snRNP/U1-C complex only after it has engaged with a -1A bulged 5'SS. Obligate orders of binding and unbinding explain how reversible branaplam interactions cause formation of long-lived U1 snRNP/5'SS complexes. Branaplam targets a ribonucleoprotein, not only an RNA duplex, and its action depends on fundamental properties of 5'SS recognition.

Soluble Mesothelin-Related Peptide as a Prognosticator in Pleural Mesothelioma Patients Receiving Checkpoint Immunotherapy.

OBJECTIVE: Immune checkpoint therapy (ICT) has significantly impacted malignant pleural mesothelioma (MPM) treatment. Despite some promising results from combination therapies, nearly half of MPM patients do not benefit, underscoring the urgent need for reliable predictive biomarkers. This study assesses the prognostic value of serum soluble mesothelin-related peptide (SMRP) and PD-L1 levels in MPM patients receiving ICT. METHODS: We conducted a retrospective analysis of 125 MPM patients treated with ICT by measuring pre-ICT serum levels of SMRP and PD-L1. We also examined the correlation of these serum levels with tumor mRNA expressions of MSLN and PD-L1. Both univariable and multivariable Cox regression analyses were used to determine independent prognosticators for overall survival (OS). A prospective ICT clinical trial and our historical cohort were included for validation. RESULTS: Seventy-seven patients (62%) were treated with either anti-PD-(L)1 monotherapy, and the remaining 38% were given combination ICT. Higher pre-ICT SMRP levels were observed in epithelioid versus non-epithelioid MPM. Serum PD-L1 levels did not show significant differences between the groups. Univariable analysis identified durable clinical benefit, development of immune-related adverse events, and SMRP levels as significantly associated with OS. Multivariable analysis confirmed SMRP as an independent prognostic factor, with lower levels (≤1.35 nmol/L) correlating with improved OS. The association of high SMRP with worse prognosis was validated in the prospective ICT clinical trial cohort and not in our historical cohort treated without ICT. CONCLUSIONS: SMRP is a promising serum biomarker for predicting survival in MPM patients treated with ICT and warrants prospective investigation.

TERT promoter mutations and survival outcomes in adult-type granulosa cell tumors.

OBJECTIVES: T0 evaluate survival outcomes among patients with adult-type granulosa cell tumors who have telomerase reverse transcriptase (TERT) promoter mutations. METHODS: This is a retrospective cohort study using the MD Anderson Rare Gynecologic Malignancy Registry. Patients with adult granulosa cell tumors who underwent molecular testing for TERT promoter and FOXL2 c.C402G mutations were included. We used descriptive statistics to compare demographic and clinical variables and estimated progression-free and overall survival with Kaplan-Meier curves. Cox proportional hazards regression and log-rank tests were employed for comparisons, with multivariable analyses adjusting for various factors. RESULTS: Among 70 patients, 28 (40%) had TERT+ tumors. The median age at diagnosis was 40 years (range 12-71) for TERT- patients and 46 years (range 25-76) for TERT+ patients. At diagnosis, 22 (63%) of 35 TERT- patients were stage I, 10 (29%) stage II, and 3 (9%) stage III, while in the TERT+ group, 17/23 (74%) were stage I, 3 (13%) stage II, and 3 (13%) stage II. Univariable analysis showed no difference in time from diagnosis to first recurrence (p=0.19) and from first recurrence to second recurrence (p=0.24) based on tumor TERT status. The median time from first to second recurrence in the TERT- group was 27.3 months (95% CI 14.1 to 40.0) and in the TERT+ group was 14.8 months (95% CI 8.1 to 21.0). There was no observed difference in overall survival between the groups (HR=0.53; 95% CI 0.19 to 1.45; p=0.21). Multivariable analysis adjusting for age at diagnosis, TERT promoter mutation status, systemic chemotherapy, and stage demonstrated a significant difference in progression-free survival based on TERT mutation status (HR=2.89; 95% CI 1.32 to 6.36). CONCLUSIONS: After adjustment for covariates, patients with adult granulosa cell tumors and TERT+ tumors had shorter progression-free survival after first recurrence. TERT promoter mutations may identify a subset of patients with recurrent adult granulosa cell tumors and less favorable outcomes.

The association of the chemotherapy response score and homologous recombination deficiency in patients undergoing interval tumor reductive surgery following neoadjuvant chemotherapy.

OBJECTIVES: In patients undergoing interval tumor reductive surgery, a good response to neoadjuvant chemotherapy may limit available tumor for homologous recombination deficiency testing. The objective of this study was to assess whether the chemotherapy response score predicts homologous recombination status. METHODS: We identified patients with advanced epithelial ovarian cancer (diagnosed January 2019 to 20 June 2023) who received neoadjuvant chemotherapy, underwent interval surgery, and for whom a chemotherapy response score was reported (1=no or minimal tumor response, 2=appreciable tumor response, 3=complete or near complete response with no residual tumor). Comparisons were made using ANOVAs or Kruskal-Wallis test for continuous variables and χ2 or Fisher's exact test for categorical variables. RESULTS: The cohort consisted of 234 patients with advanced ovarian cancer who underwent interval surgery following neoadjuvant chemotherapy. Of those who underwent germline genetic testing, 22% (51/232) had a pathogenic BRCA1 or BRCA2 mutation and of those with tumors sent for testing, 65% were found to have homologous recombination deficiency (66/146). With increasing chemotherapy response scores, a higher likelihood of a complete gross resection was observed (50% (chemotherapy response score, CRS 1) vs 77% (CRS 2) vs 88% (CRS 3), p<0.001). On multivariable analysis, CRS 2 (adjusted odds ratio=3.28, 95% CI 1.12 to 9.60, p=0.03) and CRS 3 (5.83, 1.79 to 18.93, p=0.003) were independently associated with homologous recombination deficiency compared with CRS 1. CONCLUSION: A positive response to chemotherapy at the time of interval tumor reductive surgery defined by the chemotherapy response score was associated with homologous recombination status and the likelihood of achieving a complete gross resection.

Comparative analysis of hormonal therapy in low-grade endometrial stromal sarcoma: A retrospective study.

OBJECTIVE: To evaluate the disease course of patients with low grade endometrial stromal sarcoma (LG-ESS) and compare oncologic outcomes associated with hormonal therapy in primary and recurrent disease. METHODS: This is a retrospective study of patients with LG-ESS who underwent active treatment between January 2000 and July 2023. Recurrence-free survival (RFS) and overall survival (OS) were estimated using the Kaplan-Meier product-limit estimator and modeled via Cox proportional hazards regression. RESULTS: A total of 221 patients were included; 58 % of patients (91/157) were stage I, 12 % (19/157) stage II, 13 % (20/157) stage III, and 17 % (27/157) stage IV. Surgery was the primary treatment for 98 % (213/218). Only 79 patients received hormonal adjuvant therapy, 58 % (46/79) Megace, 24 % (19/79) Letrozole, and 18 % (14/79) received other hormonal therapy. There was no significant difference in RFS (p = 0.159) and OS (p = 0.167) between patients receiving Megace versus Letrozole as adjuvant therapy. At first recurrence, patients given Megace had a similar RFS to those on Letrozole (p = 0.302), but a better OS (27 vs 10 months, p = 0.018).  Negative status of estrogen, smooth muscle actin, and desmin were associated with lower RFS (p = 0.039, p = 0.002, and p = 0.015, respectively) and OS (p = 0.008, p = 0.012, and p = 0.013, respectively). Lymphovascular invasion was associated with lower RFS (p = 0.033), and negative status of progesterone was associated with lower OS (p = 0.003). CONCLUSION: There was no difference in oncologic outcomes between Megace and Letrozole in patients who received adjuvant therapy for LG-ESS. Megace may have potential survival advantage in recurrent disease. Further study is warranted to determine the most effective agents and their sequence in the treatment of LG-ESS.

A Bayesian analysis of heart rate variability changes over acute episodes of bipolar disorder.

Bipolar disorder (BD) involves autonomic nervous system dysfunction, detectable through heart rate variability (HRV). HRV is a promising biomarker, but its dynamics during acute mania or depression episodes are poorly understood. Using a Bayesian approach, we developed a probabilistic model of HRV changes in BD, measured by the natural logarithm of the Root Mean Square of Successive RR interval Differences (lnRMSSD). Patients were assessed three to four times from episode onset to euthymia. Unlike previous studies, which used only two assessments, our model allowed for more accurate tracking of changes. Results showed strong evidence for a positive lnRMSSD change during symptom resolution (95.175% probability of positive direction), though the sample size limited the precision of this effect (95% Highest Density Interval [-0.0366, 0.4706], with a Region of Practical Equivalence: [-0.05; 0.05]). Episode polarity did not significantly influence lnRMSSD changes.

Polygenic risk scores stratify breast cancer risk among women with benign breast disease.

PURPOSE: Most breast biopsies are diagnosed as benign breast disease (BBD), with 1.5- to fourfold increased breast cancer (BC) risk. Apart from pathologic diagnoses of atypical hyperplasia, few factors aid in BC risk assessment of these patients. We assessed whether a 313-SNP polygenic risk score (PRS) stratifies risk of BBD patients. PATIENTS AND METHODS: We pooled data from five Breast Cancer Association Consortium case-control studies (mean age = 59.9 years), including 6,706 cases and 8,488 controls. Using logistic regression, we estimated BC risk associations by self-reported BBD history and strata of PRS, with median PRS category among women without BBD as the referent. We assessed interactions and mediation of BBD and PRS with BC risk. RESULTS: BBD history was associated with increased BC risk (OR = 1.48, 95% CI: 1.37-1.60; p < .001). PRS increased BC risk, irrespective of BBD history (p-interaction = 0.48), with minimal evidence of mediation of either factor by the other. Women with BBD and PRS in the highest tertile had over 2-fold increased odds of BC (OR = 2.73, 95% CI: 2.41-3.09) and those with BBD and PRS in the lowest tertile experienced reduced BC risk (OR = 0.79, 95% CI: 0.70-0.91), compared to the reference group. Women with BBD and PRS in the highest decile had a 3.7- fold increase (95% CI: 3.00-4.61) compared to those with median PRS without BBD. CONCLUSION: BC risks are elevated among women with BBD and increase progressively with PRS, suggesting that optimal combinations of these factors may improve risk stratification.

Co-administration of midazolam and psilocybin: differential effects on subjective quality versus memory of the psychedelic experience.

Aspects of the acute experience induced by the serotonergic psychedelic psilocybin predict symptomatic relief in multiple psychiatric disorders and improved well-being in healthy participants, but whether these therapeutic effects are immediate or are based on memories of the experience is unclear. To examine this, we co-administered psilocybin (25 mg) with the amnestic benzodiazepine midazolam in 8 healthy participants and assayed the subjective quality of, and memory for, the dosing-day experience. We identified a midazolam dose that allowed a conscious psychedelic experience to occur while partially impairing memory for the experience. Furthermore, midazolam dose and memory impairment tended to associate inversely with salience, insight, and well-being induced by psilocybin. These data suggest a role for memory in therapeutically relevant behavioral effects occasioned by psilocybin. Because midazolam blocks memory by blocking cortical neural plasticity, it may also be useful for evaluating the contribution of the pro-neuroplastic properties of psychedelics to their therapeutic activity.

Study of the effect of bleaching agents on the crystalline index of cellulose-based materials derived from corn husk by CP/MAS 13C NMR and FT-IR spectroscopies.

This work proposes an evaluation of the Crystalline Index (CrI) in function of the bleaching process employed during cellulose extraction from corn husk, for further characterization using CP/MAS 13C NMR, XRD, and FT-IR. In that sense, CrI values were calculated by FT-IR and the bands associated with the crystalline and amorphous regions were observed at 1424 cm-1 and 896 cm-1, respectively. Similarly, the signals due to ordered (89.1 ppm) and disordered (84.2 ppm) cellulose chains were detected by solid-state 13C NMR, while the Segal equation was only used for comparison purposes. Additionally, PCA studies showed consistent results attributed to the crystalline region in cellulose domains analyzed by both, FT-IR and solid-state 13C NMR. The results revealed the coexistence of cellulose I/cellulose II and its effect on CrI, as well as the incomplete mercerization process, in some cases non-cellulosic residues can cause an overestimation of CrI. Additionally, the thermal stability and the glass transition temperature were determined by TGA/DTA and DSC analyses. Finally, a partially fibrillated-network morphology with a diameter of 20.47 ± 2.77 µm was observed in cellulose bleached with peracetic acid, whereas organosolv method provides flexible and clean microfibrils with diameter sizes between 10 and 9 µm.

A systematic review of the outcomes of partial ulnar collateral ligament tears of the elbow in athletes treated non-operatively with platelet-rich plasma injection.

Background: This study aimed to analyze the effects of platelet-rich plasma (PRP) for partial ulnar collateral ligament (UCL) tears in athletes and predicted positive outcomes. Methods: The researchers systematically reviewed the PubMed, Cochrane CENTRAL, MEDLINE, Scopus, and Google Scholar databases to identify studies with clinical outcomes of PRP for partial UCL tears. They excluded studies that did not stratify data by tear type or included surgical management. Results: Five studies with 156 patients were included. The timing, amount, platelet concentration, type, and number of PRP injections were highly variable among the studies. However, 75% (n = 97/127) of athletes returned to sport (RTS) at a weighted average of 82.1 days (37-84) after PRP injection. One study showed significant improvements in patient-reported outcomes. Two studies showed positive outcomes in the modified Conway scale, complete reconstitution of the UCL in 87% of patients on MRI, and significant improvement in the humeral-ulnar joint space after PRP injection via ultrasound. The Coleman methodology score (CMS) averaged 48/100, indicating an overall poor quality of evidence. Conclusion: This review demonstrates favorable RTS, clinical, and radiographic outcomes in patients receiving PRP for partial UCL tears, but the literature remains heterogeneous and of low quality. Level of Evidence: III.

Scaling cervical cancer screening in Mozambique: analysis of loop electrosurgical excision procedure (LEEP) specimens.

OBJECTIVES: As cervical cancer screening programs are implemented and expanded, an increasing number of women require loop electrosurgical excision procedure (LEEP) for treatment of pre-invasive cervical disease. Our objective was to describe the pathological results of LEEP specimens performed as part of the MULHER study and identify factors associated with positive LEEP margins. METHODS: The MULHER study enrolled 9014 women who underwent HPV testing followed by visual assessment for treatment (VAT) using visual inspection with acetic acid (VIA) and thermal ablation for those with positive results. Participants with lesions ineligible for ablation underwent LEEP. Pathology reports were reviewed for specimen size/volume, number of fragments, pathological diagnosis and margin status. Multivariable regression analysis was performed to identify variables associated with positive LEEP margins. RESULTS: 169 participants underwent LEEP. The median age was 38 years (range 30-49). 65.1% were women living with HIV. Pathological diagnosis was available for 154 patients and included cancer (n=6, 3.9%); cervical intraepithelial neoplasia (CIN) 2/3 (n=75, 48.7%); CIN 1 (n=67, 43.5%); and normal/benign findings (n=6,3.9%). 31.8% of LEEP specimens were removed in more than one fragment. The mean specimen volume was 2.9 cm3 (range 0.2-15.0). LEEP margin status was available for 130 patients. Positive margins (ectocervical/endocervical only, or both) were noted in 76 (58.5%) patients and associated with HIV+status (p=0.0499) and a diagnosis of CIN 2 or worse (p=0.0197). There were no associations between margin status and age, number of fragments or specimen volume. CONCLUSION: Our results showed a high number of LEEP specimens with positive margins. Additional evaluation is needed to better understand the characteristics of precancerous cervical lesions in this high-risk population. As cervical cancer screening programs are scaled in Mozambique and other lower-resource countries, there is a need to train providers to perform high-quality LEEP and for accurate and timely pathological interpretation.

Binding of Inhibitors to Nuclear Localization Signal Peptide from Venezuelan Equine Encephalitis Virus Capsid Protein Explored with All-Atom Replica Exchange Molecular Dynamics.

Several small molecule inhibitors have been designed to block binding of the Venezuelan equine encephalitis virus (VEEV) nuclear localization signal (NLS) sequence to the importin-α nuclear transport protein. To probe the inhibition mechanism on a molecular level, we used all-atom explicit water replica exchange molecular dynamics to study the binding of two inhibitors, I1 and I2, to the coreNLS peptide, representing the core fragment of the VEEV NLS sequence. Our objective was to evaluate the possibility of masking wherein binding of these inhibitors to the coreNLS occurs prior to its binding to importin-α. We found that the free energy of I1 and I2 binding to the coreNLS is less favorable than that to importin-α. This outcome argues against preemptive inhibitor binding to the coreNLS prior to importin-α. Instead, both inhibitors are expected to compete with the coreNLS peptide for binding to importin-α. The two factors responsible for the low affinities of the inhibitors to the coreNLS peptide are (i) the low cooperativity of binding to the peptide and (ii) the strong hydrophobic effect associated with binding to importin-α. Our results further show that upon binding to the coreNLS peptide, the inhibitors form multiple diverse binding poses. The coreNLS peptide coincubated with I1 and I2 adopts several conformational states, including open and collapsed, which underscores the fluidity of the coreNLS conformational ensemble as a target for inhibitors. Taken together with our prior investigations, this study sheds light on the molecular mechanism by which I1 and I2 ligands inhibit binding of the VEEV capsid protein to importin-α.

Testing food web theory in a large lake: The role of body size in habitat coupling in Lake Michigan.

The landscape theory of food web architecture (LTFWA) describes relationships among body size, trophic position, mobility, and energy channels that serve to couple heterogenous habitats, which in turn promotes long-term system stability. However, empirical tests of the LTFWA are rare and support differs among terrestrial, freshwater, and marine systems. Further, it is unclear whether the theory applies in highly altered ecosystems dominated by introduced species such as the Laurentian Great Lakes. Here, we provide an empirical test of the LTFWA by relating body size, trophic position, and the coupling of different energy channels using stable isotope data from species throughout the Lake Michigan food web. We found that body size was positively related to trophic position, but for a given trophic position, organisms predominately supported by pelagic energy had smaller body sizes than organisms predominately supported by nearshore benthic energy. We also found a hump-shaped trophic relationship in the food web where there is a gradual increase in the coupling of pelagic and nearshore energy channels with larger body sizes as well as higher trophic positions. This highlights the important role of body size and connectivity among habitats in structuring food webs. However, important deviations from expectations are suggestive of how species introductions and other anthropogenic impacts can affect food web structure in large lakes. First, native top predators appear to be flexible couplers that may provide food web resilience, whereas introduced top predators may confer less stability when they specialize on a single energy pathway. Second, some smaller bodied prey fish and invertebrates, in addition to mobile predators, coupled energy from pelagic and nearshore energy channels, which suggests that some prey species may also be important integrators of energy pathways in the system. We conclude that patterns predicted by the LTFWA are present in the face of species introductions and other anthropogenic stressors to a degree, but time-series evaluations are needed to fully understand the mechanisms that promote stability.

Cardiac lymphatics undergo distinct remodeling during hypertrophic and non-hypertrophic pregnancy.

Lymphatic vessels of the heart undergo dynamic remodeling in response to physiological and pathological cardiovascular events such as development, adult cardiac maintenance and injury repair. During pregnancy, the cardiovascular system undergoes physiological changes to meet the increased demand of blood supply to the fetus. These extensive physiologic changes make pregnancy and delivery a high-risk period in a woman's life. However, whether and how cardiac lymphatics change during pregnancy is largely undefined. Therefore, we used whole mount immunofluorescent labeling and quantitative morphometric analysis to characterize the changes in cardiac lymphatic vasculature during pregnancy using two genetically distinct inbred mouse strains, C57BL/6J and BALB/cJ. Compared to age-matched, non-pregnant C57BL/6J control mice, the hearts of C57BL/6J dams in late-pregnancy (gestation day 17.5 (G17.5)) undergo physiologic hypertrophy. However, there were no significant changes in the cardiac lymphatic vasculature. In contrast, BALB/cJ mice do not exhibit pregnancy-induced cardiac hypertrophy at G17.5 compared to age-matched, non-pregnant mice. Yet interestingly, the cardiac lymphatic vasculature of pregnant BALB/cJ dams undergoes extensive morphological changes, including decreased lymphatic length, number of endpoints, and vessel branchpoint junctions on the ventral side of the heart. These findings underscore the complexity of genetic and physiologic factors that contribute to the heterotypic remodeling of cardiac lymphatics during late pregnancy.

Artificial intelligence for geoscience: Progress, challenges, and perspectives.

This paper explores the evolution of geoscientific inquiry, tracing the progression from traditional physics-based models to modern data-driven approaches facilitated by significant advancements in artificial intelligence (AI) and data collection techniques. Traditional models, which are grounded in physical and numerical frameworks, provide robust explanations by explicitly reconstructing underlying physical processes. However, their limitations in comprehensively capturing Earth's complexities and uncertainties pose challenges in optimization and real-world applicability. In contrast, contemporary data-driven models, particularly those utilizing machine learning (ML) and deep learning (DL), leverage extensive geoscience data to glean insights without requiring exhaustive theoretical knowledge. ML techniques have shown promise in addressing Earth science-related questions. Nevertheless, challenges such as data scarcity, computational demands, data privacy concerns, and the "black-box" nature of AI models hinder their seamless integration into geoscience. The integration of physics-based and data-driven methodologies into hybrid models presents an alternative paradigm. These models, which incorporate domain knowledge to guide AI methodologies, demonstrate enhanced efficiency and performance with reduced training data requirements. This review provides a comprehensive overview of geoscientific research paradigms, emphasizing untapped opportunities at the intersection of advanced AI techniques and geoscience. It examines major methodologies, showcases advances in large-scale models, and discusses the challenges and prospects that will shape the future landscape of AI in geoscience. The paper outlines a dynamic field ripe with possibilities, poised to unlock new understandings of Earth's complexities and further advance geoscience exploration.

Association between surgical admissions, cognition, and neurodegeneration in older people: a population-based study from the UK Biobank.

BACKGROUND: Previous studies have shown that major surgical and medical hospital admissions are associated with cognitive decline in older people (aged 40-69 years at recruitment), which is concerning for patients and caregivers. We aimed to validate these findings in a large cohort and investigate associations with neurodegeneration using MRI. METHODS: For this population-based study, we analysed data from the UK Biobank collected from March 13, 2006, to July 16, 2023, linked to the National Health Service Hospital Episode Statistics database, excluding participants with dementia diagnoses. We constructed fully adjusted models that included age, time, sex, Lancet Commission dementia risk factors, stroke, and hospital admissions with a participant random effect. Primary outcomes were hippocampal volume and white matter hyperintensities, both of which are established markers of neurodegeneration, and exploratory analyses investigated the cortical thickness of Desikan-Killiany-Tourville atlas regions. The main cognitive outcomes were reaction time, fluid intelligence, and prospective and numeric memory. Surgeries were calculated cumulatively starting from 8 years before the baseline evaluation. FINDINGS: Of 502 412 participants in the UK Biobank study, 492 802 participants were eligible for inclusion in this study, of whom 46 706 underwent MRI. Small adverse associations with cognition were found per surgery: reaction time increased by 0·273 ms, fluid intelligence score decreased by 0·057 correct responses, prospective memory (scored as correct at first attempt) decreased (odds ratio 0·96 [95% CI 0·95 to 0·97]), and numeric memory maximum correct matches decreased by 0·025 in fully adjusted models. Surgeries were associated with smaller hippocampal volume (ß=-5·76 mm³ [-7·89 to -3·64]) and greater white matter hyperintensities volume (ß=100·02 mm³ [66·17 to 133·87]) in fully adjusted models. Surgeries were also associated with neurodegeneration of the insula and superior temporal cortex. INTERPRETATION: This population-based study corroborates that surgeries are generally safe but cumulatively are associated with cognitive decline and neurodegeneration. Perioperative brain health should be prioritised for older and vulnerable patients, particularly those who have multiple surgical procedures. FUNDING: The Australian and New Zealand College of Anaesthetists (ANZCA) Foundation and the University of Sydney.

Nonthermal Plasma Activation of Adsorbates: The Case of CO on Pt.

Nonthermal plasmas provide a unique approach to electrically driven heterogeneous catalytic processes. Despite much interest from the community, fundamental activation pathways in these processes remain poorly understood. Here, we investigate how exposure to a nonthermal plasma sustained in an argon nonreactive atmosphere affects the desorption of carbon monoxide (CO) from platinum nanoparticles. Temperature-programmed desorption measurements indicate that the plasma reduces the effective binding energy (BE) of CO to Pt surfaces by as much as ∼0.3 eV, with the reduction in the BE scaling linearly with the plasma density. We find that the effective CO BE is most strongly reduced for under-coordinated sites (steps and edges) compared to well-coordinated sites (terraces). Density functional theory calculations suggest that this is due to plasma-induced charging and electric fields at the catalyst surface, which preferentially affect under-coordinated sites. This study provides direct experimental evidence of plasma-induced nonthermal activation of the adsorbate-catalyst couple.

Addition of Metastasis-Directed Therapy to Systemic Therapy for Oligometastatic Pancreatic Ductal Adenocarcinoma (EXTEND): A Multicenter, Randomized Phase II Trial.

PURPOSE: The EXTEND trial tested the hypothesis that adding comprehensive metastasis-directed therapy (MDT) to chemotherapy would improve progression-free survival (PFS) over chemotherapy alone among patients with oligometastatic pancreatic ductal adenocarcinoma (PDAC). METHODS: EXTEND (ClinicalTrials.gov identifier: NCT03599765) is a multicenter, phase II basket trial randomly assigning patients with ≤five metastases 1:1 to MDT plus systemic therapy versus systemic therapy. Disease progression was defined by radiologic criteria (RECIST v1.1), clinical progression, or death. The primary end point was PFS in the per-protocol population, evaluated after all patients achieved at least 6 months of follow-up. Exploratory end points included systemic immune response measures. RESULTS: Between March 19, 2019, and February 13, 2023, 41 patients were randomly assigned and 40 were eligible for the primary analysis of PFS (19 patients in the MDT arm; 21 patients in the control arm). At a median follow-up time of 17 months, the median PFS time was 10.3 months (95% CI, 4.6 to 14.0) in the MDT arm versus 2.5 months (95% CI, 1.7 to 5.1) in the control arm. PFS was significantly improved by the addition of MDT to systemic therapy (P = .030 for stratified log-rank test) with a hazard ratio of 0.43 (95% CI, 0.20 to 0.94). No grade ≥3 or greater adverse events related to MDT were observed. Systemic immune activation events were associated with MDT and correlated with improved PFS. CONCLUSION: This study supports the addition of MDT to systemic therapy for patients with oligometastatic PDAC. Induction of systemic immunity is a possible mechanism of benefit. These results warrant confirmatory trials to refine treatment strategy and provide external validation.

Cyclin A/B RxL Macrocyclic Inhibitors to Treat Cancers with High E2F Activity.

Cancer cell proliferation requires precise control of E2F1 activity; excess activity promotes apoptosis. Here, we developed cell-permeable and bioavailable macrocycles that selectively kill small cell lung cancer (SCLC) cells with inherent high E2F1 activity by blocking RxL-mediated interactions of cyclin A and cyclin B with select substrates. Genome-wide CRISPR/Cas9 knockout and random mutagenesis screens found that cyclin A/B RxL macrocyclic inhibitors (cyclin A/Bi) induced apoptosis paradoxically by cyclin B- and Cdk2-dependent spindle assembly checkpoint activation (SAC). Mechanistically, cyclin A/Bi hyperactivate E2F1 and cyclin B by blocking their RxL-interactions with cyclin A and Myt1, respectively, ultimately leading to SAC activation and mitotic cell death. Base editor screens identified cyclin B variants that confer cyclin A/Bi resistance including several variants that disrupted cyclin B:Cdk interactions. Unexpectedly but consistent with our base editor and knockout screens, cyclin A/Bi induced the formation of neo-morphic Cdk2-cyclin B complexes that promote SAC activation and apoptosis. Finally, orally-bioavailable cyclin A/Bi robustly inhibited tumor growth in chemotherapy-resistant patient-derived xenograft models of SCLC. This work uncovers gain-of-function mechanisms by which cyclin A/Bi induce apoptosis in cancers with high E2F activity, and suggests cyclin A/Bi as a therapeutic strategy for SCLC and other cancers driven by high E2F activity.