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Two cyclic peroxides, plakortides V (1) and W (2) were purified from the organic extract of the sponge Plakinastrella sp. Their planar structures were established based on extensive NMR and MS analysis and the absolute configurations of the three stereogenic centers of the 1,2-dioxane moiety were determined to be 3R,4S,6S by comparative analysis of the 1H NMR spectral data of the R- or S-MTPA Mosher esters. Compounds 1 and 2 exhibited potent cytotoxic activity against LOX IMVI (melanoma), UO-31 (renal), and HL-60 (TB) (leukemia) cell lines in the NCI-60 cytotoxicity assay.

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The amyloid beta (Aß) 42/40 ratio has been widely studied as a biomarker in Alzheimer's disease (AD); however, other Aß peptides could also represent relevant biomarkers. We measured levels of Aß38/40/42 in plasma samples from cognitively-unimpaired older adults and determined the relationships between Aß levels and amyloid positron-emission-tomography (PET) and performance on a learning and memory task. We found that all Aß peptides individually and the Aß42/40 ratio, but not the Aß42/38 ratio, were significantly correlated with brain amyloid (Aß-PET). Multiple linear modeling, adjusting for age, sex, education, APOE4 and Aß-PET showed significant associations between the Aß42/38 ratio and memory. Further, associations between the Aß42/38 ratio and learning scores were stronger in males and in Aß-PET-negative individuals. In contrast, no significant associations were detected between the Aß42/40 ratio and any learning measure. These studies implicate the Aß42/38 ratio as a biomarker to assess early memory deficits and underscore the utility of the Aß38 fragment as an important biomarker in the AD field.

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Despite an established link between personality traits and relationship outcomes, few studies have examined whether personality impacts outcomes of couple interventions. Given the growing popularity of online relationship services, we examined whether Five-Factor Model personality traits moderated change in relationship satisfaction, relationship confidence, and depressive symptoms of couples completing the web-based OurRelationship program. Three-hundred couples were randomly assigned to the program or to a waitlist control group and were repeatedly assessed using self-report measures of relationship satisfaction, relationship confidence, and depressive symptoms. Overall, results suggested that Five-Factor Model personality traits are mostly unrelated to changes in individual and interpersonal well-being. However, across conditions, higher levels of neuroticism predicted a smaller decrease in depressive symptoms (Aim 1). In addition, the effects of the intervention (versus control) on change in relationship satisfaction and depressive symptoms were moderated by neuroticism, such that high levels of neuroticism predicted stronger intervention effects on relationship satisfaction and depressive symptoms (Aim 2). Lastly, the effects of conscientiousness and neuroticism on changes in depressive symptoms were partially mediated by baseline levels of depressive symptoms. These findings suggest that the OurRelationship program may already contain elements that address behaviors associated with high or low personality trait levels and that higher levels of neuroticism may actually augment intervention effects on relationship satisfaction and depressive symptoms. Given the inconsistency of our findings across the various outcomes as well as personality, further research is needed to determine the role of personality in web-based couple interventions.

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BACKGROUND: Trauma remains the leading cause of pediatric mortality in the United States. Although use of massive transfusion protocols (MTPs) in this population is widespread, optimal pediatric resuscitation is not well established. We sought to assess contemporary pediatric MTP practice in the United States. STUDY DESIGN AND METHODS: A web-based survey was designed by the Association for the Advancement of Blood & Biotherapies (AABB) Pediatric Transfusion Medicine Subsection and distributed to select American College of Surgeons (ACS) Level I Verified pediatric trauma centers. The survey assessed current MTP policy, implementation, and recent changes in practice. RESULTS: Response rate was 55% (22/40). Almost half of the respondents were from the South. The median RBC:plasma ratio was 1 (interquartile range 1-1.5). Protocolized fibrinogen supplementation was common while integration of antifibrinolytic therapy into MTPs was infrequent. Viscoelastic testing (VET) was available at most sites, 71% (15/21, one site did not respond), and was generally utilized on an ad-hoc basis. Roughly, a third of sites had changed their MTP in the past 3 years due to blood supply issues, and about a third reported having group O Whole Blood on-site. CONCLUSION: MTP practice is similar throughout the United States. Though fibrinogen supplementation is common-other emerging interventions such as antifibrinolytic therapy or utilization of routine viscoelastic testing-are not widespread. Pediatric transfusion medicine experts must continue to follow practice change, as contemporary large trials begin to characterize new supportive modalities to optimize resuscitation in pediatric trauma patients.

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BACKGROUND: Hemolytic disease of the fetus and newborn (HDFN) is caused by maternal alloantibody-mediated destruction of fetal/neonatal red blood cells (RBCs). While the pathophysiology has been well-characterized, the clinical and laboratory monitoring practices are inconsistent. METHODS: We surveyed 103 US institutions to characterize laboratory testing practices for individuals with fetuses at risk of HDFN. Questions included antibody testing and titration methodologies, the use of critical titers, paternal and cell-free fetal DNA testing, and result reporting and documentation practices. RESULTS: The response rate was 44% (45/103). Most respondents (96%, 43/45) assess maternal antibody titers, primarily using conventional tube-based methods only (79%, 34/43). Among respondents, 51% (23/45) rescreen all individuals for antibodies in the third trimester, and 60% (27/45) perform paternal RBC antigen testing. A minority (27%, 12/45) utilize cell-free fetal DNA (cffDNA) testing to predict fetal antigen status. Maternal antibody titers are performed even when the fetus is not considered to be at risk of HDFN based on cffDNA or paternal RBC antigen testing at 23% (10/43) of sites that assess titers. DISCUSSION: There is heterogeneity across US institutions regarding the testing, monitoring, and reporting practices for pregnant individuals with fetuses at risk of HDFN, including the use of antibody titers in screening and monitoring programs, the use of paternal RBC antigen testing and cffDNA, and documentation of fetal antigen results. Standardization of laboratory testing protocols and closer collaboration between the blood bank and transfusion medicine service and the obstetric/maternal-fetal medicine service are needed.

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Protein biomarkers are associated with mortality in cardiovascular disease, but their effect on predicting respiratory and all-cause mortality is not clear. We tested whether a protein risk score (protRS) can improve prediction of all-cause mortality over clinical risk factors in smokers. We utilized smoking-enriched (COPDGene, LSC, SPIROMICS) and general population-based (MESA) cohorts with SomaScan proteomic and mortality data. We split COPDGene into training and testing sets (50:50) and developed a protRS based on respiratory mortality effect size and parsimony. We tested multivariable associations of the protRS with all-cause, respiratory, and cardiovascular mortality, and performed meta-analysis, area-under-the-curve (AUC), and network analyses. We included 2232 participants. In COPDGene, a penalized regression-based protRS was most highly associated with respiratory mortality (OR 9.2) and parsimonious (15 proteins). This protRS was associated with all-cause mortality (random effects HR 1.79 [95% CI 1.31-2.43]). Adding the protRS to clinical covariates improved all-cause mortality prediction in COPDGene (AUC 0.87 vs 0.82) and SPIROMICS (0.74 vs 0.6), but not in LSC and MESA. Protein-protein interaction network analyses implicate cytokine signaling, innate immune responses, and extracellular matrix turnover. A blood-based protein risk score predicts all-cause and respiratory mortality, identifies potential drivers of mortality, and demonstrates heterogeneity in effects amongst cohorts.

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BACKGROUND: Many clinical pathways for the diagnosis of disease are based on diagnostic tests that are performed in sequence. The performance of the full diagnostic sequence is dictated by the diagnostic performance of each test in the sequence as well as the conditional dependence between them, given true disease status. Resulting estimates of performance, such as the sensitivity and specificity of the test sequence, are key parameters in health-economic evaluations. We conducted a methodological review of statistical methods for assessing the performance of diagnostic tests performed in sequence, with the aim of guiding data analysts towards classes of methods that may be suitable given the design and objectives of the testing sequence. METHODS: We searched PubMed, Scopus and Web of Science for relevant papers describing methodology for analysing sequences of diagnostic tests. Papers were classified by the characteristics of the method used, and these were used to group methods into themes. We illustrate some of the methods using data from a cohort study of repeat faecal immunochemical testing for colorectal cancer in symptomatic patients, to highlight the importance of allowing for conditional dependence in test sequences and adjustment for an imperfect reference standard. RESULTS: Five overall themes were identified, detailing methods for combining multiple tests in sequence, estimating conditional dependence, analysing sequences of diagnostic tests used for risk assessment, analysing test sequences in conjunction with an imperfect or incomplete reference standard, and meta-analysis of test sequences. CONCLUSIONS: This methodological review can be used to help researchers identify suitable analytic methods for studies that use diagnostic tests performed in sequence.

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BACKGROUND AND OBJECTIVES: Not all gastric neuroendocrine tumors (GNETs) may be classified into one of the three described clinicopathologic subtypes. The purpose of this study was to better characterize GNET subtypes and associated outcomes. METHODS: Patients treated for GNET at our institution (1995-2021) were identified. Pathologic specimens of tumors that could not be classified as type 1, 2, or 3 were further reviewed. GNETs were categorized as proton pump inhibitor (PPI)-associated based on changes in the background gastric mucosa consistent with PPI use. Distant metastasis at presentation (DM) and disease-specific survival (DSS) were evaluated. RESULTS: Among 246 patients, there were 164 (67%) type 1, 5 (2%) type 2, 52 (21%) type 3, and 18 (7%) PPI-associated GNETs. Seven (3%) tumors remained unclassified. DM was more frequent with type 3 GNETs (38%) than type 1 (1%), type 2 (20%), or PPI-associated tumors (11%, p < 0.001). Ten-year DSS rates were 100% for type 1, 53% (95% confidence interval [CI], 38%-75%) for type 3, and 80% (95% CI, 58%-100%) for PPI-associated tumors (p < 0.001). GNET subtype, race, and DM were independently associated with DSS. CONCLUSIONS: PPI-associated tumors may represent a distinct GNET subtype with intermediate outcomes. Other factors should also be considered in overall prognosis.

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Cancer-related cognitive impairment (CRCI) is a broad term encompassing subtle cognitive problems to more severe impairment. CRCI severity is influenced by host, disease, and treatment factors and affects patients prior to, during, and following cancer treatment. The National Cancer Institute (NCI) Symptom Management and Health-Related Quality of Life Steering Committee (SxQoL SC) convened a Clinical Trial Planning Meeting (CTPM) to review the state of the science on CRCI and to develop both Phase II/III intervention trials aimed at improving cognitive function in cancer survivors with non-central nervous system (CNS) disease and longitudinal studies to understand the trajectory of cognitive impairment and contributing factors. Participants included experts in the field of CRCI, members of the SxQOL SC, patient advocates, representatives from all seven NCI Community Oncology Research Program (NCORP) Research Bases, and the NCI. Presentations focused on the following topics: measurement, lessons learned from pediatric and geriatric oncology, biomarker and mechanism endpoints, longitudinal study designs, and pharmacologic and behavioral intervention trials. Panel discussions provided guidance on priority cognitive assessments, considerations for remote assessments, inclusion of relevant biomarkers, and strategies for ensuring broad inclusion criteria. Three CTPM working groups (longitudinal studies and pharmacologic and behavioral intervention trials) convened for one year to discuss and report on top priorities and to design studies. The CTPM experts concluded sufficient data exist to advance Phase II/Phase III trials utilizing selected pharmacologic and behavioral interventions for the treatment of CRCI in the non-CNS setting with recommendations included herein.

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The anteromedial temporal region and the lateral wall of the sphenoid can be the site of an array of pathology including trigeminal schwannoma, encephalocele, cholesterol granuloma of the petrous apex, malignancy, infection, and sellar pathology extending to the lateral cavernous sinus. Approaches to this region are technically challenging and the existing approach requires sacrifice of all of the turbinates including the nasolacrimal duct, which can cause postoperative complications. We describe a novel anatomical landmark between the periorbita and the periosteum of the pterygopalatine fossa (which is located at the inferolateral periorbital periosteal line [ILPPL]). The posterior one-third of the incision line lies between the foramen rotundum and the superior orbital fissure, which is proximal to the maxillary strut. A 1.5-cm incision can divide the orbital and pterygoid contents and lead us to the posterior inferolateral orbital region, anteromedial temporal region, lateral wall of the sphenoid sinus, and lateral wall of the cavernous sinus. A combined multiangled approach to the ILPPL will enable us to preserve all of the turbinates and the septum, and the nasolacrimal duct, allowing for the preservation of the physiological function and pedicled flaps, such as the middle turbinate, inferior turbinate, and septal membrane flap. The ILPPL is a simple, effective, and novel landmark for the minimally invasive approach to the anteromedial temporal fossa.

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Age is a major risk factor for cancer, but how aging impacts tumor control remains unclear. Here, we establish that aging of the immune system, regardless of the age of the stroma and tumor, drives lung cancer progression. Hematopoietic aging enhances emergency myelopoiesis, resulting in the local accumulation of myeloid progenitor-like cells in lung tumors. These cells are a major source of IL-1⍺ that drives the enhanced myeloid response. The age-associated decline of DNMT3A enhances IL-1⍺ production, and disrupting IL-1R1 signaling early during tumor development normalized myelopoiesis and slowed the growth of lung, colonic, and pancreatic tumors. In human tumors, we identified an enrichment for IL-1⍺-expressing monocyte-derived macrophages linked to age, poorer survival, and recurrence, unraveling how aging promotes cancer and offering actionable therapeutic strategies.

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Combination monoclonal broadly neutralizing antibodies (bnAbs) are currently being developed for preventing HIV-1 acquisition. Recent work has focused on predicting in vitro neutralization potency of both individual bnAbs and combination regimens against HIV-1 pseudoviruses using Env sequence features. To predict in vitro combination regimen neutralization potency against a given HIV-1 pseudovirus, previous approaches have applied mathematical models to combine individual-bnAb neutralization and have predicted this combined neutralization value; we call this the combine-then-predict (CP) approach. However, prediction performance for some individual bnAbs has exceeded that for the combination, leading to another possibility: combining the individual-bnAb predicted values and using these to predict combination regimen neutralization; we call this the predict-then-combine (PC) approach. We explore both approaches in both simulated data and data from the Los Alamos National Laboratory's Compile, Neutralize, and Tally NAb Panels repository. The CP approach is superior to the PC approach when the neutralization outcome of interest is binary (e.g., neutralization susceptibility, defined as inhibitory 80% concentration < 1 µg/mL). For continuous outcomes, the CP approach performs nearly as well as the PC approach when the individual-bnAb prediction algorithms have strong performance, and is superior to the PC approach when the individual-bnAb prediction algorithms have poor performance. This knowledge may be used when building prediction models for novel antibody combinations in the absence of in vitro neutralization data for the antibody combination; this, in turn, will aid in the evaluation and down-selection of these antibody combinations into prevention efficacy trials.

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Background: Patients with cancer use the internet to inform medical decision making. Objective: To examine the content of ChatGPT responses to a hypothetical patient question about decision making in advanced cancer. Design: We developed a medical advice-seeking vignette in English about a patient with metastatic melanoma. When inputting this vignette, we varied five characteristics (patient age, race, ethnicity, insurance status, and preexisting recommendation of hospice/the opinion of an adult daughter regarding the recommendation). ChatGPT responses (N = 96) were coded for mentions of: hospice care, palliative care, financial implications of treatment, second opinions, clinical trials, discussing the decision with loved ones, and discussing the decision with care providers. We conducted additional analyses to understand how ChatGPT described hospice and referenced the adult daughter. Data were analyzed using descriptive statistics and chi-square analysis. Results: Responses more frequently mentioned clinical trials for vignettes describing 45-year-old patients compared with 65- and 85-year-old patients. When vignettes mentioned a preexisting recommendation for hospice, responses more frequently mentioned seeking a second opinion and hospice care. ChatGPT's descriptions of hospice focused primarily on its ability to provide comfort and support. When vignettes referenced the daughter's opinion on the hospice recommendation, approximately one third of responses also referenced this, stating the importance of talking to her about treatment preferences and values. Conclusion: ChatGPT responses to questions about advanced cancer decision making can be heterogeneous based on demographic and clinical characteristics. Findings underscore the possible impact of this heterogeneity on treatment decision making in patients with cancer.

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Abstract: Interlayer excitons (IXs), composed of electron and hole states localized in different layers, excel in bilayers composed of atomically thin van der Waals materials such as semiconducting transition-metal dichalcogenides (TMDs) due to drastically enlarged exciton binding energies, exciting spin-valley properties, elongated lifetimes, and large permanent dipoles. The latter allows modification by electric fields and the study of thermalized bosonic quasiparticles, from the single particle level to interacting degenerate dense ensembles. Additionally, the freedom to combine bilayers of different van der Waals materials without lattice or relative twist-angle constraints leads to layer-hybridized and Moiré excitons, which can be widely engineered. This article covers fundamental aspects of IXs, including correlation phenomena as well as the consequence of Moiré superlattices with a strong focus on TMD homo- and heterobilayers.