Citations

Abstract Purpose: The Pancreatic Cancer Detection Consortium (PCDC) performed a blinded Early Detection Research Network–defined phase II biomarker bakeoff study of blood-based biomarker panels. The aims were to evaluate panel performance, to compare the panels’ performance with that of cancer antigen 19-9 (CA19-9) alone, and to evaluate the performance of new combinations of the individual biomarkers. Experimental Design: Ten biomarkers representing eight biomarker panels and CA19-9 were evaluated using plasma, serum, and germline DNA from 140 stage I to IV pancreatic ductal adenocarcinoma (PDAC) cases and 140 controls from three tertiary care institutions, with controls frequency matched to cases on age and sex. LASSO regression was employed to explore new biomarker combinations. The primary metric was area under the receiver operating characteristic curve (AUC). Results: The study population was 51% female, with median age 67.3 (minimum: 45, maximum: 90) years. Biomarker panel AUCs ranged from 89.9 to 96.3; the AUC for serum CA19-9 alone was 91.7 [95% confidence interval (CI), 87.8–95.6]. Two panels had significantly higher AUCs than serum CA19-9 alone, the CA19-9/FUT2/3 panel (AUC = 96.3, P = 0.002), and the tissue factor pathway inhibitor/tenascin C (TFPI/TNC-FNIII-C) panel (AUC = 95, P = 0.01). Exploratory models to recombine biomarkers retained all but two biomarkers [optimism-corrected AUC = 96.4 (94–98.9)]. Conclusions: The CA19-9/FUT2/3 panel was the best performing panel in this biomarker bakeoff. Its evaluation in larger studies is warranted. Biomarker bakeoffs are an effective strategy for comparing the performance of promising biomarkers for pancreatic cancer early detection, and the PCDC is well poised to conduct such studies. Recommendations for performing such studies are provided.

ABSTRACT Background The optimal timing for basal insulin initiation in diabetic ketoacidosis (DKA) remains unclear. British guidelines endorse early basal insulin (EBI), while the American Diabetes Association emphasises overlap duration with intravenous insulin, without mention of timing. This meta‐analysis evaluates whether EBI administration of basal insulin improves clinical outcomes in adults with DKA. Methods A systematic review and meta‐analysis were performed according to the PRISMA guidelines. Databases searched included MEDLINE, Embase, Scopus, Web of Science and the Cochrane Central Register of Controlled Trials through December 11, 2024. Inclusion criteria included articles in the English‐language randomised controlled trials (RCTs) or observational studies evaluating EBI in adult DKA patients. Non‐human studies, conference abstracts, and case reports were excluded. The primary outcome for this study was hospital length of stay (LOS). Additional outcomes included intensive care unit (ICU) LOS, time to DKA resolution, hypoglycemia, and rebound hyperglycemia between EBI and usual care. Risk of bias was assessed using the Cochrane and Newcastle‐Ottawa tools. Grading of Recommendations Assessment, Development, and Evaluation was performed to evaluate the quality of evidence. Results From 1214 identified studies, eight (4 RCTs, 4 observational) met inclusion criteria for a total of 247 patients in the EBI group and 552 patients in the control group. No significant difference in hospital LOS was found (mean difference −11.17 h; 95% CI: −29.91 to 7.56). ICU LOS, time to DKA resolution, incidence of hypoglycemia, and rebound hyperglycemia also did not demonstrate any significant differences between groups. Significant heterogeneity existed across studies for most outcomes. All studies had a high risk of bias, and the quality of evidence was very low. Conclusion EBI did not result in significant differences in hospital LOS, ICU LOS, or time to DKA resolution; however, there were no increased adverse events with EBI. Current studies of early EBI have significant limitations. Future research should focus on developing high‐quality RCTs.

Background Medication nonadherence has been associated with poor outcomes in transplant recipients yet identifying these behaviors pre-transplant remains challenging. The simplified medication adherence questionnaire (SMAQ) is a brief, reliable instrument to assess medication adherence. The aim of this study was to perform SMAQ testing on thoracic organ candidates and examine correlations between these scores and individual patient factors predicting medication nonadherence. Methods Consenting waitlisted lung, heart, and heart-lung transplant candidates from six thoracic transplant centers were mailed a survey that included demographic information and the Simplified Medication Adherence Questionnaire (SMAQ). Univariate logistic regression analysis was performed to assess association between pre-transplant medication adherence and demographic characteristics, psychosocial factors, and mortality. Results Among 298 participants, 60.7% were medication nonadherent. Nonadherence was associated with some college education (OR: 1.73; CI: 1.06, 2.81), lower positive affect (OR: 0.95; CI: 0.92, 0.99), and higher uncertainty (OR: 1.02; CI: 1.01, 1.04). Higher positivity ratio predicted adherence. Conclusion Identifiable patient-specific characteristics associated with medication nonadherence can be screened for during thoracic transplant evaluation. Interventions aimed at improving these factors during the pre-transplant period may improve clinical post-transplant outcomes, however, larger studies are needed to validate these findings.

ABSTRACT Objective Falls are a leading cause of morbidity and loss of independence in adults. The association between overactive bladder (OAB) and fall risk has not been thoroughly investigated. This study evaluated the association between OAB and fall history in a nationally representative sample of US adults aged 20−69 years. Methods We performed a cross‐sectional analysis of adults aged 20−69 years from the 2021−2023 National Health and Nutrition Examination Survey (NHANES). OAB was classified using a composite symptom severity score that assessed urge urinary incontinence and nocturia. Fall history was assessed by self‐reporting (only in participants aged 20−69 years), where a recent fall was defined as experiencing at least one fall within the past year. Survey multivariable logistic regression was used to estimate adjusted odds ratios (aOR) for the association between fall history and OAB after controlling for sociodemographic and clinical covariates. Results Among 4118 participants, the population‐weighted prevalence of OAB was 19.6% (standard error [SE]: 1.1%), and the prevalence of a recent fall was 28.3% (SE: 1.3%). The prevalence of a recent fall was higher among those with OAB (39.7% [SE: 1.6%] vs. 25.7% [SE: 1.5%]). The prevalence of a recent fall increased progressively with OAB symptom severity (24.3% in those with no symptoms vs. 52.4% in those with severe symptoms). In the fully adjusted model controlling for sociodemographic and clinical covariates, OAB was independently associated with a 42% higher odds of experiencing a recent fall (aOR, 1.42; 95% CI, 1.10 to 1.83; p = 0.01). Conclusion OAB is independently associated with an increased risk of a recent fall in US adults aged 20‐69 years, with a strong positive relationship between OAB severity and fall risk. These findings suggest that screening for OAB may be a useful adjunct to fall risk assessment. Future studies are needed to determine whether OAB management reduces the risk of falls.

Abstract Frailty predicts adverse outcomes in multiple myeloma (MM), yet an objective frailty biomarker is lacking. Circulating senescence-associated secretory phenotype (SASP) factors correlate with frailty and adverse outcomes in chronic diseases, but their relevance in MM is unclear. In this study, we investigated the relationship between 36 plasma SASP factors, frailty, and clinical outcomes in: (1) a historical cohort using stored specimens from 59 patients with newly diagnosed MM, and (2) a prospective cohort of 36 patients initiating new MM treatment. Several SASP factors were significantly associated with frailty after adjusting for age, sex, and body mass index; GDF-15, TNF-RI, IL-6, and IL-8 showed positive correlations with both cumulative-deficit based and physical frailty indices. Additionally, significant age-adjusted associations were observed between SASP factors and treatment outcomes, including overall survival (OS), high-grade toxicity, and healthcare utilization. We developed a 5-factor SASP model that demonstrated superior predictive performance for OS compared to chronological age, R-ISS stage, and clinical frailty, and TNF-RI alone (5-year OS AUC: 0.90). These findings highlight the association between senescence biomarkers and frailty and OS, and support further investigation of SASP factors as objective frailty biomarkers in MM.

ABSTRACT Introduction Non‐muscle invasive bladder cancer (NMIBC) is a chronic disease with a lifelong treatment burden that may cause substantial urinary morbidity. Such quality‐of‐life changes remain understudied. We therefore evaluated the incidence and predictors of treatment for overactive bladder (OAB) among older adults following diagnosis of NMIBC. Materials and Methods We identified adults aged 66–89 years with newly diagnosed NMIBC from 2007 to 2017 in the linked SEER‐Medicare database. We examined the incidence of treatment initiation for OAB following initial transurethral resection of bladder tumor (TURBT) and evaluated associations with baseline characteristics using Cox regression. Results We identified 9,819 patients, of whom 68% had Ta disease, 29% had T1 disease, and 4% had CIS. Within the first 12 months of TURBT, 7% of patients received treatment for OAB, and this increased to 15% of patients at 5 years. In the first year, the most utilized therapies were anticholinergic medications (early 3.72%, late 2.74%) and beta‐3 agonists (early 0.11%, late 0.32%), while procedural OAB therapy utilization was rare (0.2%). On multivariable analysis, female gender (HR 1.26, 95% CI 1.11–1.42), congestive heart failure (HR 1.21, 95% CI 1.03–1.43), and T1 tumor stage (HR 1.27, 95% CI 1.12–1.44 vs. Ta) were independently associated with an increased risk of OAB treatment. Conclusions The incidence of OAB requiring treatment among patients with NMIBC is substantial, with approximately one in six patients receiving treatment by 5 years after diagnosis. Predictive clinicopathologic features for OAB treatment—including, sex, high‐risk tumor features, and repeat TURBT—may be useful for clinical counseling.

Background While rural health guidelines have often cautioned against digital interventions due to infrastructure and literacy barriers, this study introduces an SMS-based conversational artificial intelligence (CAI) that overcomes these limitations to promote HPV vaccination. Objective To evaluate an SMS-based CAI using the Centers for Disease Control (CDC)’s presumptive and CASE (Corroborate, About Me, Science and Explain) frameworks to promote HPV vaccination among rural parent-adolescent dyads by: (1) testing its usability; (2) assessing the feasibility of co-design with clinicians and parent-adolescents; (3) identifying adoption barriers and (4) examining communication preferences across behavioural profiles. Methods We developed a CAI simulator using the presumptive approach and the structured CASE method to address 11 common concerns about the HPV vaccine. A multimethod usability study with 13 rural parent-adolescent dyads (n=26) included in-depth interviews and the System Usability Scale. Results The CAI achieved excellent usability (mean SUS 85.2, ~96th percentile). A previously undocumented behavioural profile—vaccine-unaware—was identified, distinct from hesitancy, and best addressed through empathetic, exploratory dialogue. Key adoption barriers included integration with existing preventive care routines and endorsement by trusted local providers. Conclusions Contrary to the assumption that rural residents resist digital tools, participants engaged readily when content was credible, locally endorsed and accessible via SMS. Findings highlight the conditional effectiveness of the CDC’s presumptive style in CAIs—well-suited for vaccine-compliant users but less effective for sceptical or unaware groups, who, we argue, would respond better to conversational, empathetic tones.

Abstract Medulloblastoma (MB) is one of the most prevalent malignant brain tumors in children, with tremendous cognitive and neuroendocrine disability among survivors. Group 3 (G3) MBs have poor overall survival at < 50%, higher frequency of metastasis, and no targeted therapies. Amplification of MYC and activation of TGFβ signaling are frequent in G3MB. Remarkably, some tumors have no reported mutations, suggesting roles for epigenetic mechanisms in driving disease. We have generated novel humanized models for G3MB by transducing neuroepithelial stem cells (NESC) derived from human induced pluripotent stem (iPSC) cells with TGFβ effectors alone and/or in combination with MYC, prioritizing combinations observed in patients. We determined that both MYC and TGFβ effectors drove tumor formation in vivo with the combination driving more aggressive tumors and higher frequency of metastasis. NESC-derived tumors clustered with human G3/G4MB, indicating our models recapitulated human disease. To decipher mechanisms of resistance, we integrated CUT&RUN for MYC genomic localization and histone PTMs with RNA-sequencing and discovered MYC-bound neural developmental genes repressed in MYC and TGFβR1-driven lines. Further interrogation identified JARID1B, a MYC binding partner, as a regulator of many of these repressed neural genes. We postulate that deregulation of MYC and context-specific targeting to the chromatin template culminates in transcriptional alterations that promote aggressive G3MB. To further investigating therapeutic vulnerabilities, we have performed a in vivo whole genome CRISPRi screen to reveal important drivers of malignancy, one of the first of it’s kind in brain tumors. We are functionally validating key candidate sgRNAs that were differentially significant in primary tumors and may also have key roles in driving metastasis. Excitingly, many sgRNAs identified from the screen were chromatin modifiers and may be important co-factors of MYC-mediated regulation on the epigenome. Collectively, our studies provide a critical framework for understanding mechanisms of resistance and the epigenetic landscape of MYC- and TGFβ-driven MB.

Discoidin Domain Receptor 2 (DDR2) is a collagen-activated tyrosine kinase required for bone and tooth development as well as regeneration of calvarial and long bones. Although DDR2 is expressed in alveolar bone, its functions in this site have not been previously examined. The present study used global and conditional knockout approaches and lineage tracing to examine the functions of DDR2 in alveolar bone formation during tooth socket healing. First molars were extracted from the maxillae of wild-type and globally Ddr2 -deficient ( Ddr2 LacZ/LacZ ) mice, and socket healing was measured after 1, 2, or 4 wk. At all times, Ddr2 inactivation significantly reduced socket healing. These changes were associated with decreased cell proliferation 3 d after extraction without any detectable changes in apoptosis. In addition, collagen fibril orientation, measured using Picrosirius Red staining under polarized light, was disrupted in tooth sockets from Ddr2 -deficient mice. For lineage tracing, 4-wk-old Ddr2 mer-cre-mer ; R26R tdTomato and Gli1 CreERT2 ; R26R tdTomato mice were induced with tamoxifen, first molars were extracted, and socket healing was examined after 1, 3, or 7 d. In both cases, tdTomato+ cells migrated into sockets, where they sequentially co-localized with preosteoblast and osteoblast markers. Thus, both DDR2 + and GLI1 + cells contribute to socket healing. The considerable overlap observed between DDR2 + and GLI1+ cells suggested that DDR2 functioned in GLI1 + cells, which are known to have skeletal progenitor properties. Consistent with localization data, conditional knockout ( Gli1 CreERT2 ; Ddr2 fl/fl ) mice exhibited reductions in socket healing 1 wk postextraction, although the inhibition of socket repair was less than that seen in global Ddr2 knockouts. In summary, this work demonstrates a role for DDR2 in alveolar bone repair, a finding that may have therapeutic implications for the treatment of alveolar bone loss associated with periodontal disease and other disorders.