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Abstract In the United States, 2.0 million new cancer cases and around 600,000 cancer deaths are estimated to occur in 2024. Early detection gives cancer patients the best chance for treatment success. Currently, cancer screening in the general population is recommended for a limited set of cancers; as a result, most cancer types are not regularly screened. Thus, in recent years, we have seen a wave of novel, non‐invasive, single‐ and multi‐cancer detection tests (SCD and MCD), promising detection of cancer signals prior to the onset of symptoms and/or clinical diagnosis. To accelerate the development, access, and adoption of these tests, the Blood Profiling Atlas in Cancer (BLOODPAC) Consortium, a collaborative infrastructure for developing standards and best practices, established the Early Detection & Screening (ED&S) Working Group. The early detection space is in need of consensus around definitions for SCD and MCD tests that harmonize terminology across diverse stakeholders, thereby reducing communication barriers and ultimately advancing the discipline. To this end, the ED&S Working Group compiled a lexicon of terms, chosen based on perceived importance, frequency of use, lack of clarity, and unique challenges in the context of SCD and MCD tests. This lexicon was submitted to the FDA for their feedback, which was incorporated. In this work, we present the first installment of the lexicon, consisting of 14 primary terms, that will be part of an online dictionary and provide a foundation for future projects of BLOODPAC's ED&S Working Group.

Background High blood pressure (BP) increases recurrent stroke risk. Methods and Results We assessed hypertension prevalence, treatment, control, medication adherence, and predictors of uncontrolled BP 90 days after ischemic or hemorrhagic stroke among 561 Mexican American and non‐Hispanic White (NHW) survivors of stroke from the BASIC (Brain Attack Surveillance in Corpus Christi) cohort from 2011 to 2014. Uncontrolled BP was defined as average BP ≥140/90 mm Hg at 90 days poststroke. Hypertension was uncontrolled BP or antihypertensive medication prescribed or hypertension history. Treatment was antihypertensive use. Adherence was missing zero antihypertensive doses per week. We investigated predictors of uncontrolled BP using logistic regression adjusting for patient factors. Median (interquartile range) age was 68 (59–78) years, 64% were Mexican American, and 90% of strokes were ischemic. Overall, 94.3% of survivors of stroke had hypertension (95.6% Mexican American versus 92.0% non‐Hispanic White; P=0.09). Of these, 87.9% were treated (87.3% Mexican American versus 89.1% non‐Hispanic White; P=0.54). Among the total population, 38.3% (95% CI, 34.4%–42.4%) had uncontrolled BP. Among those with uncontrolled BP prescribed an antihypertensive, 84.5% reported treatment adherence (95% CI, 78.8%–89.3%). Uncontrolled BP 90 days poststroke was less likely in patients with stroke who had a primary care physician (adjusted odds ratio [aOR], 0.45 [95% CI, 0.24–0.83]; P=0.01), greater stroke severity (aOR per‐1‐point‐higher National Institutes of Health Stroke Scale score, 0.96 [95% CI, 0.93–0.99]; P=0.02), or more depressive symptoms (aOR per‐1‐point‐higher Personal Health Questionnaire Depression Scale‐8 score, 0.95 [95% CI, 0.92–0.99] among those with a history of hypertension at baseline; P=0.009). Conclusions Greater than one third of survivors of stroke have uncontrolled BP at 90 days poststroke in this population‐based study. Interventions are needed to improve BP control after stroke.

Abstract Atomically precise nanoclusters hold promise for supramolecular assembly and (opto)electronic‐ as well as magnetic materials. Herein, this work reports that treating palladium(0) precursors with a triphosphirane affords strongly colored Pd8(PDip)6 that is fully characterized by mass spectrometry, heteronuclear and Cross‐Polarization Magic‐Angle Spinning (CP‐MAS) NMR‐, infrared (IR), UV–vis, and X‐ray photoelectron (XP) spectroscopies, single‐crystal X‐Ray diffraction (sc‐XRD), mass spectrometry, and cyclovoltammetry (CV). This coordinatively unsaturated 104‐electron Pd(0) cluster features a cubic Pd8‐core, µ4‐capping phosphinidene ligands, and is air‐stable. Quantum chemical calculations provide insight to the cluster's electronic structure and suggest 5s/4d orbital mixing as well as minor Pd─P covalency. Trapping experiments reveal that cluster growth proceeds via insertion of Pd(0) into the triphosphirane. The unsaturated cluster senses ethylene and binds isocyanides, which triggers the rearrangement to a tetrahedral structure with a reduced frontier orbital energy gap. These experiments demonstrate facile cluster manipulation and highlight non‐destructive cluster rearrangement as is required for supramolecular assembly.

Abstract Purpose Periprosthetic joint infection (PJI) following total knee arthroplasty (TKA) presents significant challenges, especially in elderly and comorbid patients, often necessitating revision surgeries. We report on a series of patients with confirmed PJI of the knee and concomitant soft‐tissue/extensor apparatus defects, treated by using pedicled myocutaneous medial or lateral sural artery perforator (MSAP/LSAP) gastrocnemius flaps. Methods Our retrospective study at the Center for Musculoskeletal Infections, included patients with knee PJI undergoing pedicled myocutaneous MSAP/LSAP gastrocnemius flap reconstruction for combined soft tissue and extensor apparatus defects. The tendinous back of the gastrocnemius muscle was used and, if required, the Achilles tendon for extensor apparatus reconstruction, with the skin island addressing the cutaneous defect. Perioperative complications and postoperative outcomes after 1 year were evaluated, including functional and clinical assessments with the American Knee Society Score (AKSS). Results Eight patients (mean age 73 years; five female) were included, predominantly with Staphylococcus aureus infections. Six patients involved isolated MSAP flaps, two were extended with the Achilles tendon. The median time for wound healing was 9 days. Short‐term follow‐up showed successful reconstruction in seven patients, with minor wound dehiscence in one patient. One patient required flap revision for a perigenicular haemato‐seroma and two patients were diagnosed with new haematogenous PJI infection. Significant improvement in AKSS scores after surgery was observed (functional AKSS: median 33–85; clinical AKSS: median 64–91, p = 0.001). Conclusion Pedicled myocutaneous MSAP/LSAP gastrocnemius flaps offer a safe, reliable and versatile option for reconstructing combined soft tissue and extensor apparatus defects in PJI after TKA. This approach yields excellent functional outcomes with minimal peri‐ and postoperative complications, which is particularly beneficial in elderly and comorbid patients and feasible in settings without microsurgical availability. Level of evidence Level IV.

Background Stroke survivors believe neighborhood resources such as community centers are beneficial; however, little is known about the influence of these resources on stroke outcomes. We evaluated whether residing in neighborhoods with greater resource density is associated with favorable post‐stroke outcomes. Methods and Results We included Mexican American and non‐Hispanic White stroke survivors from the Brain Attack Surveillance in Corpus Christi project (2009–2019). The exposure was density of neighborhood resources (eg, community centers, restaurants, stores) within a residential census tract at stroke onset. Outcomes included time to death and recurrence, and at 3 months following stroke: disability (activities of daily living/instrumental activities of daily living), cognition (Modified Mini‐Mental State Exam), depression (Patient Health Questionnaire‐8), and quality of life (abbreviated Stroke‐Specific Quality of Life scale). We fit multivariable Cox regression and mixed linear models. We considered interactions with stroke severity, ethnicity, and sex. Among 1786 stroke survivors, median age was 64 years (interquartile range, 56–73), 55% men, and 62% Mexican American. Resource density was not associated with death, recurrence, or depression. Greater resource density (75th versus 25th percentile) was associated with more favorable cognition (Modified Mini‐Mental State Exam mean difference=0.838, 95% CI=0.092, 1.584) and among moderate–severe stroke survivors, with more favorable functioning (activities of daily living/instrumental activities of daily living=−0.156 [95% CI, −0.284 to 0.027]) and quality of life (abbreviated Stroke‐Specific Quality of Life scale=0.194 [95% CI, 0.029–0.359]). Conclusions We observed associations between greater resource density and cognition overall and with functioning and quality of life among moderate–severe stroke survivors. Further research is needed to confirm these findings and determine if neighborhood resources may be a tool for recovery.

Abstract Background Cholangiocarcinoma (CCA) is a fatal cancer of the bile duct with a poor prognosis owing to limited therapeutic options. The incidence of intrahepatic CCA (iCCA) is increasing worldwide, and its molecular basis is emerging. Environmental factors may contribute to regional differences in the mutation spectrum of European patients with iCCA, which are underrepresented in systematic genomic and transcriptomic studies of the disease. Methods We describe an integrated whole‐exome sequencing and transcriptomic study of 37 iCCAs patients in Germany. Results We observed as most frequently mutated genes ARID1A (14%), IDH1, BAP1, TP53, KRAS, and ATM in 8% of patients. We identified FGFR2::BICC1 fusions in two tumours, and FGFR2::KCTD1 and TMEM106B::ROS1 as novel fusions with potential therapeutic implications in iCCA and confirmed oncogenic properties of TMEM106B::ROS1 in vitro. Using a data integration framework, we identified PBX1 as a novel central regulatory gene in iCCA. We performed extended screening by targeted sequencing of an additional 40 CCAs. In the joint analysis, IDH1 (13%), BAP1 (10%), TP53 (9%), KRAS (7%), ARID1A (7%), NF1 (5%), and ATM (5%) were the most frequently mutated genes, and we found PBX1 to show copy gain in 20% of the tumours. According to other studies, amplifications of PBX1 tend to occur in European iCCAs in contrast to liver fluke‐associated Asian iCCAs. Conclusions By analyzing an additional European cohort of iCCA patients, we found that PBX1 protein expression was a marker of poor prognosis. Overall, our findings provide insight into key molecular alterations in iCCA, reveal new targetable fusion genes, and suggest that PBX1 is a novel modulator of this disease.

Abstract Background The need for new therapies to improve survival and outcomes in pediatric oncology along with the lack of approval and accessible clinical trials has led to “out‐of‐trial” use of innovative therapies. We conducted a retrospective analysis of requests for innovative anticancer therapy in Canadian pediatric oncology tertiary centers for patients less than 30 years old between 2013 and 2020. Methods Innovative therapies were defined as cancer‐directed drugs used (a) off‐label, (b) unlicensed drugs being used outside the context of a clinical trial, or (c) approved drugs with limited evidence in pediatrics. We excluded cytotoxic chemotherapy, cellular products, and cytokines. Results We retrieved data on 352 innovative therapy drug requests. Underlying diagnosis was primary CNS tumor 31%; extracranial solid tumor 37%, leukemia/lymphoma 22%, LCH 2%, and plexiform neurofibroma 6%. RAS/MAP kinase pathway inhibitors were the most frequently requested innovative therapies in 28% of all requests followed by multi‐targeted tyrosine kinase inhibitors (17%), inhibitors of the PIK3CA‐mTOR‐AKT pathway (8%), immune checkpoints inhibitors (8%), and antibody drug conjugates (8%). In 112 out of 352 requests, innovative therapies were used in combination with another anticancer agent. 48% of requests were motivated by the presence of an actionable molecular target. Compassionate access accounted for 52% of all requests while public insurance was used in 27%. Mechanisms of funding varied between provinces. Conclusion This real‐world data collection illustrates an increasing use of “out‐of‐trial” innovative therapies in pediatric oncology. This new field of practice warrants further studies to understand the impact on patient trajectory and equity in access to innovative therapies.

Abstract Background Cocaine is an illegal recreational drug used worldwide, yet little is known about whether cocaine inhalation (smoking/snorting) increases the risk of head and neck cancer (HNC). Methods The analyses were conducted by pooling data from three case–control studies with 1639 cases and 2506 controls from the International Head and Neck Cancer Epidemiology Consortium. Epidemiologic data, including cocaine use histories, were obtained in face‐to‐face interviews. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated using hierarchical logistic regression models. Results Controlling for cumulative tobacco and alcohol use, we observed a weak positive association between cocaine use and HNC (ORever vs. never = 1.35, 95% CI: 0.96, 1.90). In stratified analysis, while we did not detect associations among never tobacco or alcohol users due to the limited sample size, the association with cocaine use was observed among tobacco users and alcohol drinkers. ORs for ever and high cumulative use (>18 times) versus never use were 1.40 (95% CI: 0.98, 2.00) and 1.66 (95% CI: 1.03, 2.69) among tobacco users, and 1.34 (95% CI: 0.93, 1.92) and 1.59 (95% CI: 1.00, 2.51) among alcohol drinkers, respectively. Conclusion In this pooled analysis, we observed a weak positive association between cocaine inhalation and HNC risk. Our findings provide preliminary evidence of the potential carcinogenic effect of cocaine on HNC. Because of study limitations, including limited number of cocaine users, confounding, and heterogeneity across studies, future investigations will require larger studies with more detailed information on cocaine use history.

Abstract Omega‐6 fatty acids are the primary polyunsaturated fatty acids in most Western diets, while their role in diabetes remains controversial. Exposure of omega‐6 fatty acids to an oxidative environment results in the generation of a highly reactive carbonyl species known as trans, trans‐2,4‐decadienal (tt‐DDE). The timely and efficient detoxification of this metabolite, which has actions comparable to other reactive carbonyl species, such as 4‐hydroxynonenal, acrolein, acetaldehyde, and methylglyoxal, is essential for disease prevention. However, the detoxification mechanism for tt‐DDE remains elusive. In this study, the enzyme Aldh9a1b is identified as having a key role in the detoxification of tt‐DDE. Loss of Aldh9a1b increased tt‐DDE levels and resulted in an abnormal retinal vasculature and glucose intolerance in aldh9a1b−/− zebrafish. Transcriptomic and metabolomic analyses revealed that tt‐DDE and aldh9a1b deficiency in larval and adult zebrafish induced insulin resistance and impaired glucose homeostasis. Moreover, alterations in hyaloid vasculature is induced by aldh9a1b knockout or by tt‐DDE treatment can be rescued by the insulin receptor sensitizers metformin and rosiglitazone. Collectively, these results demonstrated that tt‐DDE is the substrate of Aldh9a1b which causes microvascular damage and impaired glucose metabolism through insulin resistance.

Introduction Vein of Galen Malformations (VOGM) are congenital brain arteriovenous malformations which often present during the neonatal or infantile periods. While endovascular embolization is the recommended management for this pathology, a subset of VOGM patients present with pathologic angiogenesis which complicates endovascular therapy. Previous studies have shown that these patients require a greater number of embolizations to achieve cure, but it is unclear whether this radiographic finding is associated with differences in clinical presentation. Methods A single‐center retrospective review identified all patients with a Vein of Galen Malformation from January 2004 to May 2023. Patients were stratified into three groups based on the development and timing of angiogenesis during their treatment course: pre‐intervention angiogenesis, post‐intervention angiogenesis, and no angiogenesis. Clinical presentations, relevant imaging, radiographic data, and procedural details were reviewed. Results 178 patients with VOGM were identified. 38 patients were in the pre‐intervention angiogenesis group, 51 patients were in the post‐intervention angiogenesis group, and 89 patients were in the no angiogenesis group. Pre‐intervention angiogenesis patients were significantly older on presentation for initial angiogram than post‐intervention angiogenesis or no angiogenesis patients (p

Abstract The year when total column ozone (TCO) returns to 1980 levels is commonly used to quantify recovery from disturbance caused by ozone‐depleting substances. This date is reasonable but somewhat arbitrary. Here we borrow an indicator from climate change research, the signal‐to‐noise (S/N) metric to investigate how TCO might return to statistically similar levels to those of the pre‐ozone hole era (1960–1970). We calculate S/N for ozone projections from the Chemistry‐Climate Model Initiative. In most regions, a return to 1980 levels doesn't represent TCO recovery to pre‐disturbance conditions because it does not account for internal variability or reflect when statistically significant TCO losses occurred. Future projections show that, in most regions, TCO “de‐emerges” (i.e., S/N becomes less than one standard deviation from the pre‐disturbance mean) before it returns to its 1980 value. We conclude that S/N is an appropriate, perhaps complementary metric for determining when TCO returns to a pre‐disturbance state.