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Haemophagocytic lymphohistiocytosis (HLH) is an aggressive and life-threatening disease of disproportionate immune activation. We present a case of a 25-year-old woman who is postnatal day 26 status post lower segment caesarean section who came with fever, breathlessness and abdominal pain in shock in the background of a malarial infection 3 days ago, which was initially evaluated on the lines of fever with multiple organ dysfunction syndrome. On further evaluation turned out to fulfil the criteria for secondary HLH seemingly triggered by an infectious cause or an autoimmune phenomenon. On further assessment, she was found to be positive for antiphospholipid antibodies which forced other possible diagnoses such as catastrophic antiphospholipid antibody syndrome into contention.

Autoxidation of tartaric acid in air-saturated aqueous solutions in the presence of Fe(II) at low pH, 2.5, shows autocatalytic behavior with distinct initiation, propagation, and termination phases. With increasing pH, the initiation phase speeds up, while the propagation phase shortens and reduces to none. We show that the propagation phase is a chain reaction that occurs via activation of oxygen in the initiation stage with the production of hydrogen peroxide. The subsequent Fenton oxidation that regenerates hydrogen peroxide with a positive feedback is typical of a self-sustained chain reaction. The conditions for such a chain reaction are shown to be similar to those of a dynamical system with critical behavior; namely, the system becomes unstable when the kinetic matrix of pseudo-first-order reaction becomes negatively defined with a negative eigenvalue giving the rate of exponential (chain) growth of the reactive species.

Background Poor diet quality significantly contributes to hypertension disparities affecting Black adults. While the Dietary Approaches to Stop Hypertension (DASH) eating pattern lowers blood pressure (BP), access to DASH-patterned groceries is a major barrier for residents of urban food deserts. Methods The Groceries for Black Residents of Boston to Stop Hypertension among Adults without Treated Hypertension (GoFresh) study is one of five projects in the RESTORE Network, an AHA-funded initiative focused on hypertension prevention. GoFresh is testing whether online, dietitian-assisted, home-delivered, DASH-patterned groceries lowers BP among Black adults with elevated BP. This individual-level, parallel-arm trial will enroll up to 176 Black adults with SBP (systolic blood pressure) between 120 and Results The primary outcome is the difference in SBP after 3 months. Secondary outcomes include a change in 24-hour ambulatory BP, body mass index, 24-hour urine sodium and potassium, hemoglobin A1C, lipids, fruit and vegetable intake, and saturated fat intake. Qualitative interviews with 45 participants 6 months after baseline assessments will determine barriers and facilitators to long-term maintenance of DASH-patterned grocery shopping. Discussion Findings from this study will inform ongoing work on scalable interventions to prevent hypertension among Black adults with implications for public and healthcare-based food supplementation programs. Trial registration NCT05121337. Registered on 16 November 2021, at ClinicalTrials.gov: https://clinicaltrials.gov/ct2/show/NCT05121337

In all species, ribosomes synthesize proteins by faithfully decoding messenger RNA (mRNA) nucleotide sequences using aminoacyl-tRNA substrates. Current knowledge of the decoding mechanism derives principally from studies on bacterial systems1. Although key features are conserved across evolution2, eukaryotes achieve higher-fidelity mRNA decoding than bacteria3. In human, changes in decoding fidelity are linked to ageing and disease and represent a potential point of therapeutic intervention in both viral and cancer treatment4–6. Here we combine single-molecule imaging and cryogenic electron microscopy methods to examine the molecular basis of human ribosome fidelity to reveal that the decoding mechanism is both kinetically and structurally distinct from that of bacteria. Although decoding is globally analogous in both species, the reaction coordinate of aminoacyl-tRNA movement is altered on the human ribosome and the process is an order of magnitude slower. These distinctions arise from eukaryote-specific structural elements in the human ribosome and in the elongation factor eukaryotic elongation factor 1A (eEF1A) that together coordinate faithful tRNA incorporation at each mRNA codon. The distinct nature and timing of conformational changes within the ribosome and eEF1A rationalize how increased decoding fidelity is achieved and potentially regulated in eukaryotic species.

BACKGROUND: The association between obesity (body mass index (BMI) ≥ 30 kg/m(2)) and pattern of medication use during pregnancy in the United States is not well-studied. Higher prepregnancy BMI may be associated with increases or decreases in medication use across pregnancy as symptoms (e.g. reflux) or comorbidities (e.g. gestational diabetes) requiring treatment that may be associated with higher BMI could also change with advancing gestation. OBJECTIVES: To determine whether prenatal medication use, by the number and types of medications, varies by pre-pregnancy obesity status. METHODS: In a secondary data analysis of a racially/ethnically diverse prospective cohort of pregnant women with low risk for fetal abnormalities enrolled in the first trimester of pregnancy and followed to delivery (singleton, 12 United States clinical sites), free text medication data were obtained at enrollment and up to five follow-up visits and abstracted from medical records at delivery. RESULTS: In 436 women with obesity and 1750 women without obesity (pre-pregnancy BMI, 19–29.9 kg/m(2)), more than 70% of pregnant women (77% of women with and 73% of women without obesity) reported taking at least one medication during pregnancy, respectively (adjusted risk ratio (aRR)=1.10, 95% confidence interval (CI)=1.01, 1.20), with 81% reporting two and 69% reporting three or more. A total of 17 classes of medications were identified. Among medication classes consumed by at least 5% of all women, the only class that differed between women with and without obesity was hormones and synthetic substitutes (including steroids, progesterone, diabetes, and thyroid medications) in which women with obesity took more medications (11 vs. 5%, aRR = 1.9, 95% CI = 1.38, 2.61) compared to women without obesity. Within this class, a higher percentage of women with obesity took diabetes medications (2.3 vs. 0.7%) and progesterone (3.4 vs. 1.3%) than their non-obese counterparts. Similar percentages of women with and without obesity reported consuming medications in the remaining medication classes including central nervous system agents (50 and 46%), gastrointestinal drugs (43 and 40%), anti-infective agents (23 and 21%), antihistamines (20 and 17%), autonomic drugs (10 and 9%), and respiratory tract agents (7 and 6%), respectively (p > 0.05 for all adjusted comparisons). There were no differences in medication use by obesity status across gestation. Since the study exclusion criteria limited the non-obese group to women without thyroid disease, in a sensitivity analysis we excluded all women who reported thyroid medication intake and still a higher proportion of women with obesity took the hormones and synthetic substitutes class compared to women without obesity. CONCLUSION: Our findings suggest that pre-pregnancy obesity in otherwise healthy women is associated with a higher use of only selected medications (such as diabetes medications and progesterone) during pregnancy, while the intake of other more common medication types such as analgesics, antibiotics, and antacids does not vary by pre-pregnancy obesity status. As medication safety information for prenatal consumption is insufficient for many medications, these findings highlight the need for a more in-depth examination of factors associated with prenatal medication use.

Loyalty Programs (LPs) aim to increase profit by rewarding, with various benefits, customers who patronize the retailer. This study investigated the benefits LPs provide in the South African Fast-moving consumer goods (FMCG) marketplace and how these influence relationship quality and loyalty between retailer and customer. How the perceived benefits of LPs contribute to relationship quality (satisfaction, trust and commitment), and how they lead to loyalty are examined. To illustrate these relationships, a model showing three independent (perceived benefits, namely altruistic, consumeristic, and egoistic) and three dependent variables (relationship quality, namely trust, satisfaction, and commitment), plus customer loyalty, was developed. A quantitative survey was administered electronically over 11 days to a randomly selected sample of 5000 consumers per day from a commercial database, resulting in 1944 responses. After the deletion of incomplete or inappropriate responses, 479 usable replies remained. Since this sample was self-selected, it should be considered a convenience sample. Structural equation modelling (SEM) with confirmatory factor analysis (CFA) was applied to test the hypotheses and develop the model. SEM indicated that respondents consider egoistic and consumeristic benefits as the same. Furthermore, trust and satisfaction manifest as a single construct. Both consumeristic and altruistic benefits had a significant positive relationship with this unified construct of trust/satisfaction, and the relationship between altruistic benefits and commitment was also positive and significant. Finally, although neither altruistic nor consumeristic benefits appeared to contribute directly to loyalty, a positive relationship existed between the new construct of trust/satisfaction and those of commitment and loyalty. The pathway to loyalty is indirect, and to reach this sought-after goal, relationship quality constructs must first be achieved.

Pliosaurid plesiosaurians are iconic marine reptiles that regulated marine trophic chains from the Middle Jurassic to the early Late Cretaceous. However, their evolution during the Cretaceous remains poorly documented. Recent discoveries from the Hauterivian–Aptian interval suggest that the radiation of brachaucheniine pliosaurids produced a wide disparity of forms following the Pliosaurus-dominated assemblages of the Late Jurassic. Among the most bizarre of these early brachaucheniines is Luskhan itilensis, from the Hauterivian of Russia. We describe the osteology of this tusked, longirostrine pliosaurid and discuss its possible behaviour by drawing comparisons with other marine amniotes possessing forward-pointing teeth. We take this opportunity to make extensive anatomical comparisons among Cretaceous pliosaurids, including previously overlooked cranial features. Bayesian inference of phylogenetic relationships of plesiosaurians reveals that the internal branches in Late Jurassic–Late Cretaceous pliosaurids have generally low rates of morphological evolution, indicating that the recently described Early Cretaceous pliosaurids have effectively bisected the long branch leading to the ‘classical’ brachaucheniines of the middle Cretaceous (Brachauchenius, Kronosaurus and Megacephalosaurus). Pliosaurids exhibit low evolutionary rates and a dwindling disparity before their extinction, mirroring the events seen, roughly at the same time, for ichthyosaurians.

Background Early detection of mobility decline is critical to prevent subsequent reductions in quality of life, disability, and mortality. However, traditional approaches to mobility assessment are limited in their ability to capture daily fluctuations that align with sporadic health events. We aim to describe findings from a pilot study of our Real-time Online Assessment and Mobility Monitor (ROAMM) smartwatch application, which uniquely captures multiple streams of data in real time in ecological settings. Methods Data come from a sample of 31 participants (Mage = 74.7, 51.6% female) who used ROAMM for approximately 2 weeks. We describe the usability and feasibility of ROAMM, summarize prompt data using descriptive metrics, and compare prompt data with traditional survey-based questionnaires or other established measures. Results Participants were satisfied with ROAMM’s function (87.1%) and ranked the usability as “above average.” Most were highly engaged (average adjusted compliance = 70.7%) and the majority reported being “likely” to enroll in a 2-year study (77.4%). Some smartwatch features were correlated with their respective traditional measurements (eg, certain GPS-derived life-space mobility features (r = 0.50–0.51, p < .05) and ecologically measured pain (r = 0.72, p = .01), but others were not (eg, ecologically measured fatigue). Conclusions ROAMM was usable, acceptable, and effective at measuring mobility and risk factors for mobility decline in our pilot sample. Additional work with a larger and more diverse sample is necessary to confirm associations between smartwatch-measured features and traditional measures. By monitoring multiple data streams simultaneously in ecological settings, this technology could uniquely contribute to the evolution of mobility measurement and risk factors for mobility loss.

Background Pain is a dynamic phenomenon dependent on the balance of endogenous excitatory and inhibitory systems, which can be characterized by quantitative sensory testing. Many previous studies of pain modulatory capacity of patients with fibromyalgia syndrome (FM) have reported decreased pain inhibition or increased pain facilitation. This is the first study to assess pain modulation, including conditioned pain modulation (CPM) and temporal pain summation, in the same healthy control (HC) and FM participants. Methods Only sensitivity-adjusted stimuli were utilized for testing of conditioned pain modulation (CPM) and temporal pain summation in 23 FM patients and 28 HC. All subjects received sensitivity-adjusted ramp-hold (sRH) during testing of pain facilitation (temporal summation) and pain inhibition (CPM). CPM efficacy was evaluated with test stimuli applied either concurrently or after application of the conditioning stimulus. Finally, the effects of CPM on pressure pain thresholds were tested. Results FM subjects required significantly less intense test and conditioning stimuli than HC participants to achieve standardized pain ratings of 50 ± 10 numerical rating scale (NRS) ( p = 0.03). Using such stimuli, FM subjects’ temporal pain summation and CPM efficacy was not significantly different from HC (all p > 0.05), suggesting similar pain facilitation and inhibition. Furthermore, the CPM efficacy of FM and HC participants was similar regardless of whether the test stimuli were applied during or after the conditioning stimulus ( p > 0.05). Conclusion Similar to previous studies, FM participants demonstrated hyperalgesia to heat, cold, and mechanical stimuli. However, using only sensitivity-adjusted stimuli during CPM and temporal summation testing, FM patients demonstrated similarly effective pain inhibition and facilitation than HC, suggesting that their pain modulation is not abnormal.

The placenta is a temporary endocrine organ that facilitates gas, nutrient, and waste exchange between maternal and fetal compartments, partially shielding the fetus from potentially hazardous environmental toxicants. However, rather than being "opaque", the placenta is translucent or even transparent to some potential fetal developmental hazards, including toxic trace elements (TEs), perfluoroalkyl and polyfluoroalkyl substances (PFAS), and environmental phenols (EPs) to which women with pregnancy are frequently exposed. These agents are both passively and actively transferred to the fetal compartment, where endocrine disruption, oxidative stress, and epigenetic changes may occur. These pathologies may directly impact the fetus or deposit and accumulate in the placenta to indirectly impact fetal development. Thus, it is critical for clinicians to understand the potential placental toxicity and transfer of widely distributed environmental agents ubiquitous during pregnancy. With such knowledge, targeted interventions and clinical recommendations can be developed to limit those risks.

A large part of the Northeast Atlantic cod caught with trawls is landed frozen, processed, and sold thawed. Many trawlers have adapted a fishing practice termed ‘buffer towing’, causing probability for poor exsanguination and fillet redness. Here, the effect of buffer towing upon color and hemoglobin concentration in cod loin section is studied, and the development of TVB-N during chilled storage of thawed cod. No significant differences were proven for redness or hemoglobin concentration in loin from cod exposed to regular haul-back or buffer towing. Neither were significant differences found in TVB-N levels during chilled storage at 0 and 4°C.

An experiment under microcosm was conducted to assess the allelochemical potential of Mikania micrantha on the growth andgermination of Lactuca sativa through a pot culture experiment. Soil samples were collected from two different sites i.e., M. micranthainvaded soil (for the experimental pot) and healthy forest soil (for control pot). Various seed germination and growth parametershave been analyzed to evaluate the inhibitory and stimulatory effects of the allelochemicals released from M. micrantha. The resultsrevealed that the germination and growth parameters of the crop were inhibited and suppressed by M. micrantha. Out of the fifteenseeds planted in both pots, thirteen seeds were able to germinate in the experimental pot, while fourteen were in the control pot. Theseedling height (8.85 cm), shoot length (8.75 cm), seedling biomass (0.408 g), vigor index (0.52), root length (0.091 cm), germinationpotential (0.73), germination percentage (86.66%), germination index, (3.66) and germination rate index (317.17) were lower in theexperimental pot and higher in the control pot. Therefore, M. micrantha showed an inhibitory effect on the growth and germination ofL. sativa and induced negative allelopathic effects.

Alisa J Johnson,1,2,&ast; Taylor Buchanan,3,&ast; Chavier Laffitte Nodarse,1,2 Pedro A Valdes Hernandez,1,2 Zhiguang Huo,4 James H Cole,5,6 Thomas W Buford,3 Roger B Fillingim,1,2,7 Yenisel Cruz-Almeida1,2,7 1Pain Research & Intervention Center of Excellence, University of Florida, Gainesville, FL, USA; 2Department of Community Dentistry & Behavioral Science, College of Dentistry, University of Florida, Gainesville, FL, USA; 3Department of Medicine, University of Alabama, Birmingham, AL, USA; 4Department of Biostatistics, College of Public Health & Health Professions College of Medicine, University of Florida, Gainesville, FL, USA; 5Centre for Medical Image Computing, Department of Computer Science, University College London, London, UK; 6Dementia Research Centre, Institute of Neurology, University College London, London, UK; 7Department of Neuroscience, College of Medicine, University of Florida, Gainesville, FL, USA&ast;These authors contributed equally to this workCorrespondence: Yenisel Cruz-Almeida, University of Florida, PO Box 103628, 1329 SW 16th Street, Ste 5180, Gainesville, FL, 32608, USA, Tel +1 352-294-8584, Fax +1 352-273-5985, Email cryeni@ufl.eduPurpose: Knee OA-related pain varies in impact across individuals and may relate to central nervous system alterations like accelerated brain aging processes. We previously reported that older adults with chronic musculoskeletal pain had a significantly greater brain-predicted age, compared to pain-free controls, indicating an “older” appearing brain. Yet this association is not well understood. This cross-sectional study examines brain-predicted age differences associated with chronic knee osteoarthritis pain, in a larger, more demographically diverse sample with consideration for pain’s impact.Patients and Methods: Participants (mean age = 57.8 ± 8.0 years) with/without knee OA-related pain were classified according to pain’s impact on daily function (ie, impact): low-impact (n=111), and high-impact (n=60) pain, and pain-free controls (n=31). Participants completed demographic, pain, and psychosocial assessments, and T1-weighted magnetic resonance imaging. Brain-predicted age difference (brain-PAD) was compared across groups using analysis of covariance. Partial correlations examined associations of brain-PAD with pain and psychosocial variables.Results: Individuals with high-impact chronic knee pain had significantly “older” brains for their age compared to individuals with low-impact knee pain (p < 0.05). Brain-PAD was also significantly associated with clinical pain, negative affect, passive coping, and pain catastrophizing (p’s< 0.05).Conclusion: Our findings suggest that high impact chronic knee pain is associated with an older appearing brain on MRI. Future studies are needed to determine the impact of pain-related interference and pain management on somatosensory processing and brain aging biomarkers for high-risk populations and effective intervention strategies.Keywords: knee osteoarthritis, high impact chronic pain, brain aging, experimental pain, psychosocial

Characterizing how variation in the tempo and mode of evolution has structured the phenotypic diversity of extant species is a central goal of macroevolution1,2,3. However, studies are typically limited to a handful of traits4,5,6, providing incomplete information. We analyse morphological diversification in living birds, an ecologically diverse group7, documenting structural scales from ‘pan-skeletal’ proportions down to the localized three-dimensional shape changes of individual bones. We find substantial variation in evolutionary modes among avian subgroups and among skeletal parts, indicating widespread mosaicism and possible differences in the structure of the macroevolutionary landscape across Earth’s main environments. Water-linked groups, especially Aequorlitornithes (waterbirds), have repeatedly explored a large portion of their total morphospace, emphasizing variation in body proportions and in the shape of bones close to the body core, which are functionally related to the mechanics of locomotion8. By contrast, landbirds (Inopinaves) evolved distinct, group-specific body forms early in the aftermath of the K-Pg and subsequently emphasized local shape variation, especially in the head and distal limb bones, which interact more directly with the environment. Passerines, which comprise more than half of all bird species, show a conservative evolutionary dynamic that resulted in low disparity across all skeletal parts. Evidence for early establishment of the morphospace of living birds is clear for some skeletal parts, including beaks and the combined skeletal morphology. However, we find little evidence for early partitioning of that morphospace, contrary to more specific predictions of ‘niche-filling’ models1,9. Nevertheless, early divergence among broad environmental types may have caused an early divergence of evolutionary modes, suggesting an important role for environmental divergence in structuring the radiation of crown-group birds.

Jeholornis is a representative of the earliest-diverging bird lineages, providing important evidence of anatomical transitions involved in bird origins. Although ~100 specimens have been reported, its cranial morphology remains poorly documented owing to poor two-dimensional preservation, limiting our understanding of the morphology and ecology of the key avian lineage Jeholornithiformes, in addition to cranial evolution during the origin and early evolution of birds. Here, we provide a detailed description of the cranial osteology of Jeholornis prima, based primarily on high-quality, three-dimensional data of a recently reported specimen. New anatomical information confirms the overall plesiomorphic morphology of the skull, with the exception of the more specialized rostrum. Data from a large sample size of specimens reveal the dental formula of J. prima to be 0–2–3 (premaxillary–maxillary–dentary tooth counts), contrary to previous suggestions that the presence of maxillary teeth is diagnostic of a separate species, Jeholornis palmapenis. We also present evidence of sensory adaptation, including relatively large olfactory bulbs in comparison to other known stem birds, suggesting that olfaction was an important aspect of Jeholornis ecology. The digitally reconstructed scleral ring suggests a strongly diurnal habit, supporting the hypothesis that early-diverging birds were predominantly active during the day.

Objectives Chronic pain results in significant impairment in older adults, yet some individuals maintain adaptive functioning. Limited research has considered the role of positive resources in promoting resilience among older adults. Likewise, these factors have largely been examined independently. We aimed to identify resilience domains based on biopsychosocial factors and explore whether resilience phenotypes vary across sleep disturbance, fatigue, and cognitive function. Methods Sixty adults (ages ≥60 years) with chronic low back pain completed measures of psychological, health, and social functioning. On the basis of previously published analyses, principal-components analysis was conducted to create composite domains for these measures, followed by cluster analysis to identify phenotypes. Results Four profiles emerged: Cluster 1, with high levels of psychosocial and health-related functioning; Cluster 2, with high health-related functioning and low psychosocial functioning; Cluster 3, with high psychosocial functioning and poorer health; and Cluster 4, with low levels of functioning across all domains. Significant differences across cluster membership emerged for sleep disturbance (ηp2 = 0.29), fatigue (ηp2 = 0.29), and cognitive abilities (ηp2 = 0.47). Individuals with the highest levels of resilience demonstrated more optimal outcomes in sleep and fatigue (P values ≤0.001) than did individuals with a less resilient phenotype. Furthermore, the High-Resilience group (Cluster 1) and the High Psychosocial / Low Health group (Cluster 3) had lower cognitive impairment than did the High Health / Low Psychosocial group (Cluster 2) and the Low-Resilience group (Cluster 4) (P values ≤0.009). Conclusions A higher array of protective resources could buffer against the negative sequelae associated with chronic low back pain. These exploratory findings support the multidimensional nature of resilience and suggest that targeting resilience from a multisystem perspective might help to optimize interventions for older adults with chronic pain.

Somatic symptom disturbance is among the strongest predictors of painful temporomandibular disorder (TMD). Related psychological constructs, such as anxiety and depression, respond therapeutically to omega-3 polyunsaturated fatty acids (PUFAs) in clinical trials. This cross-sectional study investigated associations between the omega-6/omega-3 PUFA ratio and somatic symptom disturbance and depressive symptoms in a community-based sample of 501 adults and determined whether these associations differed between adults with and without TMD or irritable bowel syndrome (IBS). Liquid chromatography tandem mass spectrometry quantified PUFAs in circulating erythrocytes. Somatic symptoms and depression were quantified using Symptom Checklist-90-Revised subscales. Presence or absence of TMD and IBS, respectively, were determined by clinical examination and Rome III screening questions. The standardized beta coefficient for the omega-6/omega-3 long-chain PUFA ratio was 0.26 (95% confidence limits (CL): 0.08, 0.43) in a multivariable linear regression model in which somatic symptom disturbance was the dependent variable. When modelling depressive symptoms as the dependent variable, the standardized beta coefficient was 0.17 (95% CL:0.01, 0.34). Both associations were stronger among TMD cases and IBS cases than among non-cases. Future randomized control trials that lower the omega-6/omega-3 PUFA ratio could consider somatic or depressive symptoms as a therapeutic target for TMD or IBS pain. PERSPECTIVE: In people with TMD or IBS, a high n-6/n-3 PUFA ratio was positively associated with somatic symptom disturbance and depressive symptoms. Both measures of psychological distress were elevated in people with painful TMD and IBS. Future randomized clinical trials will determine whether lowering the n-6/n-3 ratio is therapeutic for pain.

ImportanceCetuximab-based and carboplatin-based chemoradiotherapy (CRT) are often used for patients with locally advanced head and neck cancer who are ineligible for cisplatin. There are no prospective head-to-head data comparing cetuximab-based and carboplatin-based regimens for radiosensitization.ObjectiveTo compare survival with cetuximab-based and carboplatin-based CRT in locally advanced head and neck squamous cell carcinoma (HNSCC).Design, Setting, and ParticipantsThis cohort study included US veterans who received a diagnosis of HNSCC between January 2006 and December 2020 and were treated with systemic therapy and radiation. Data cutoff was March 1, 2022 and data analysis was conducted from April-May 2022.ExposuresCisplatin, cetuximab, or carboplatin-based systemic therapy as captured in VA medication data and cancer registry.Main Outcomes and MeasuresOverall survival by systemic therapy was estimated using Kaplan-Meier methods. We used propensity score and inverse probability weighting to achieve covariate balance between cetuximab-treated and carboplatin-treated patients and used Cox regression to estimate cause-specific hazard ratios of death associated with carboplatin vs cetuximab. We also performed subgroup analyses of patients with oropharynx vs nonoropharynx primary sites.ResultsA total of 8290 patients (median [IQR] age, 63 [58-68] years; 8201 men [98.9%]; 1225 [15.8%] Black or African American and 6424 [82.6%] White individuals) with nonmetastatic HNSCC were treated with CRT with cisplatin (5566 [67%]), carboplatin (1231 [15%]), or cetuximab (1493 [18%]). Compared with cisplatin-treated patients, patients treated with carboplatin and cetuximab were older with worse performance status scores and higher comorbidity burden. Median (IQR) overall survival was 74.4 (22.3-162.2) months in patients treated with cisplatin radiotherapy (RT), 43.4 (15.3-123.8) months in patients treated with carboplatin RT, and 31.1 (12.4-87.8) months in patients treated with cetuximab RT. After propensity score and inverse probability weighting, carboplatin was associated with improved overall survival compared with cetuximab (cause-specific hazard ratio, 0.85; 95% CI, 0.78-0.93; P = .001). This difference was prominent in the oropharynx subgroup.Conclusions and RelevanceIn this cohort study of a US veteran population with HNSCC undergoing treatment with CRT, almost a third of patients were ineligible to receive treatment with cisplatin and received cetuximab-based or carboplatin-based radiosensitization. After propensity score matching, carboplatin-based systemic therapy was associated with 15% improvement in overall survival compared with cetuximab, suggesting that carboplatin may be the preferred radiosensitizer, particularly in oropharynx cancers.

Chronic musculoskeletal pain is a health burden that may accelerate the aging process. Accelerated brain aging and epigenetic aging have separately been observed in those with chronic pain. However, it is unknown whether these biological markers of aging are associated with each other in those with chronic pain. We aimed to explore the association of epigenetic aging and brain aging in middle-to-older age individuals with varying degrees of knee pain. Participants (57.91 ± 8.04 y) with low impact knee pain (n = 95), high impact knee pain (n = 53), and pain-free controls (n = 26) completed self-reported pain, a blood draw, and an MRI scan. We used an epigenetic clock previously associated with knee pain (DNAmGrimAge), the subsequent difference of predicted epigenetic and brain age from chronological age (DNAmGrimAge-Difference and Brain-PAD, respectively). There was a significant main effect for pain impact group (

Opioid prescribing for postoperative pain management is challenging because of inter-patient variability in opioid response and concern about opioid addiction. Tramadol, hydrocodone, and codeine depend on the cytochrome P450 2D6 (CYP2D6) enzyme for formation of highly potent metabolites. Individuals with reduced or absent CYP2D6 activity (i.e., intermediate metabolizers [IMs] or poor metabolizers [PMs], respectively) have lower concentrations of potent opioid metabolites and potentially inadequate pain control. The primary objective of this prospective, multicenter, randomized pragmatic trial is to determine the effect of postoperative CYP2D6-guided opioid prescribing on pain control and opioid usage. Up to 2020 participants, age ≥8 years, scheduled to undergo a surgical procedure will be enrolled and randomized to immediate pharmacogenetic testing with clinical decision support (CDS) for CYP2D6 phenotype-guided postoperative pain management (intervention arm) or delayed testing without CDS (control arm). CDS is provided through medical record alerts and/or a pharmacist consult note. For IMs and PM in the intervention arm, CDS includes recommendations to avoid hydrocodone, tramadol, and codeine. Patient-reported pain-related outcomes are collected 10 days and 1, 3, and 6 months after surgery. The primary outcome, a composite of pain intensity and opioid usage at 10 days postsurgery, will be compared in the subgroup of IMs and PMs in the intervention (n = 152) versus the control (n = 152) arm. Secondary end points include prescription pain medication misuse scores and opioid persistence at 6 months. This trial will provide data on the clinical utility of CYP2D6 phenotype-guided opioid selection for improving postoperative pain control and reducing opioid-related risks.

Ribosomes in cancer cells accumulate numerous patient-specific structural and functional modifications that facilitate tumor progression by modifying protein translation. We have taken a unique synthetic chemistry approach to generate novel macrolides, Ribosome Modulating Agents (RMAs), that are proposed to act distal to catalytic sites and exploit cancer ribosome heterogeneity. The RMA ZKN-157 shows two levels of selectivity: 1) selective translation inhibition of a subset of proteins enriched for components of the ribosome and protein translation machinery that are upregulated by MYC; and 2) selective inhibition of proliferation of a subset of colorectal cancer (CRC) cell lines. Mechanistically, the selective ribosome targeting in sensitive cells triggered cell cycle arrest and apoptosis. Consequently, in CRC, sensitivity to ZKN-157 in cell lines and patient-derived organoids was restricted to the Consensus Molecular Subtype 2 (CMS2) subtype that is distinguished by high MYC and WNT pathway activity. ZKN-157 showed efficacy as single agent and, the potency and efficacy of ZKN-157 synergized with clinically approved DNA intercalating agents which have previously been shown to inhibit ribogenesis as well. ZKN-157 thus represents a new class of ribosome modulators that display cancer selectivity through specific ribosome inhibition in the CMS2 subtype of CRC potentially targeting MYC-driven addiction to high protein translation.

Supplementary methods

FACS analysis demonstrating ZKN-157 selectively induces cell cycle arrest and apoptosis

Ribosomes in cancer cells accumulate numerous patient-specific structural and functional modifications that facilitate tumor progression by modifying protein translation. We have taken a unique synthetic chemistry approach to generate novel macrolides, Ribosome Modulating Agents (RMAs), that are proposed to act distal to catalytic sites and exploit cancer ribosome heterogeneity. The RMA ZKN-157 shows two levels of selectivity: 1) selective translation inhibition of a subset of proteins enriched for components of the ribosome and protein translation machinery that are upregulated by MYC; and 2) selective inhibition of proliferation of a subset of colorectal cancer (CRC) cell lines. Mechanistically, the selective ribosome targeting in sensitive cells triggered cell cycle arrest and apoptosis. Consequently, in CRC, sensitivity to ZKN-157 in cell lines and patient-derived organoids was restricted to the Consensus Molecular Subtype 2 (CMS2) subtype that is distinguished by high MYC and WNT pathway activity. ZKN-157 showed efficacy as single agent and, the potency and efficacy of ZKN-157 synergized with clinically approved DNA intercalating agents which have previously been shown to inhibit ribogenesis as well. ZKN-157 thus represents a new class of ribosome modulators that display cancer selectivity through specific ribosome inhibition in the CMS2 subtype of CRC potentially targeting MYC-driven addiction to high protein translation.

ZKN-157- chemical characterization

Table showing the top 20 MYC gene targets with the highest positive charge density

CRANIAL OSTEOLOGY OF JEHOLORNIS Premaxilla The premaxillae are complete in STM 3-8 (Fig. 2A–F). They are edentulous, as reported in previous publications (Zhou & Zhang, 2002, 2003; Lefèvre et al., 2014), and their external surfaces are marked by several nutrient foramina. No pits are present to receive the dentary teeth, which is different from the condition present in Ichthyornis Marsh, 1873 (Field et al., 2018). The tip of the corpus forms a ventral projection, suggesting that the tip of the beak might have been slightly hooked. Caudal to the rostral ‘hook’, the ventral margin of the premaxillary corpus is straight. The relative level of the ventral projection of this rostral ‘hook’ varies among previously reported specimens, being absent in Jeholornis YFGP-yb2 and exaggerated relative to STM 3-8 in Kompsornis AGB- 6997 (Lefèvre et al., 2014; Wang et al., 2020a). This is interpreted here as attributable to variation in preservation, but further studies are needed to exclude the possibility of intraspecific variation confidently. The premaxillary corpora are fused, whereas the frontal processes are separated (Hu et al., 2022). The frontal (nasal) process of the premaxilla is relatively short and therefore does not contact the frontal but instead articulates distally with the dorsal surface of the nasal, as in other non-ornithothoracine stem birds (e.g. Archaeopteryx and Sapeornis; Rauhut, 2014; Kundrát et al., 2018; Hu et al., 2020a) apart from Confuciusornis Hou et al., 1995 (Chiappe et al., 1999; El&zdot;anowski et al., 2018; Wang et al., 2019a). This is evidenced by the extension level of the articular facet present in the frontal process of the premaxilla. The maxillary process of the premaxilla is short and articulates medially with the premaxillary process of the maxilla (Fig. 2A, B). It appears to be step-like, with the dorsal margin extending farther caudally than the ventral margin. The palatal process is crushed mediolaterally but could still be distinguished from the maxillary process in the 3D reconstruction. Maxilla The maxillae in Jeholornis STM 3-8 are well preserved, being almost in articulation with the premaxillae and the lacrimals (Fig. 2A, B, J–L). The premaxillary process bears a lateral depression that receives the dorsal part of the maxillary process of premaxilla. The jugal process is slender, being half of the dorsoventral height of the premaxillary process and more than twice its length. A shallow groove is present along the medial surface of the jugal process, indicating extensive contact area with the palatine, similar to Archaeopteryx (Mayr et al., 2007). The medial surface of the maxilla is rarely visible among Mesozoic bird specimens, precluding further comparisons. Although the palatal process is mostly crushed, it seems that it was sheet-like and well developed, and therefore most probably contacted the vomer, similar to the Late Cretaceous enantiornithine Gobipteryx El&zdot;anowski, 1974 and the ornithuromorph Ichthyornis (Chiappe et al., 2001; Field et al., 2018), the only other Mesozoic birds in which the morphology of the palatal process of the maxilla is known so far. A dorsoventrally elongate oval fenestra is present between the jugal process and the ascending process in Jeholornis, being enclosed caudally by a thin, bony bar. We identify this tentatively as the maxillary fenestra (Witmer, 1997). However, it is unclear whether it is homologous with the maxillary fenestra or promaxillary fenestra of non-avian theropods and Archaeopteryx (Witmer, 1997; Barsbold & Osmólska, 1999; Xu & Wu, 2001; Mayr et al., 2007; Rauhut, 2014; Rauhut et al., 2018) or with the accessory fenestra present in the enantiornithine bird Pengornis Zhou, Clarke & Zhang, 2008 (O’Connor & Chiappe, 2011). Two alveoli are present in the maxilla. Two teeth are preserved in the left maxilla, and another two similar-sized teeth are dislocated beside the right maxilla. The maxillary teeth are straight and subconical, with blunt crowns and an expanded root. Lacrimal Both lacrimals are well preserved in articulation with the maxillae in Jeholornis STM 3-8 (Fig. 2A, B, G–I). The rostrodorsal ramus is remarkably short, approximately one-quarter the length of the long caudodorsal ramus. This differs from most other Early Cretaceous birds and non-avian theropods (e.g. Archaeopteryx and Sinornithosaurus Xu, Wang & Wu, 1999; Xu & Wu, 2001; Rauhut, 2014; Kundrát et al., 2018; Rauhut et al., 2018), in which the rostrodorsal ramus is long and the caudodorsal ramus short. The ventral ramus is caudally recurved in Jeholornis, such that the caudal margin formed by the ventral and caudodorsal processes is concave, forming the rostral/ rostrodorsal margin of the orbit. This is similar to the morphology in more crownward birds (e.g. the Late Cretaceous ornithurine bird Ichthyornis), although the rostrodorsal ramus is even more strongly reduced in Ichthyornis and does not contact the maxilla, unlike in Jeholornis (Field et al., 2018). The lacrimal morphology of Jeholornis also contrasts with the morphology of most other Early Cretaceous birds and non-avian theropods, in which the ventral ramus is almost perpendicular to the ventral margin of the skull or is inclined cranially (Wang et al., 2021). The lacrimal of the confuciusornithiforms appears to be slender and reduced, also presenting a short or totally absent rostrodorsal ramus and slightly caudally recurved ventral ramus (El&zdot;anowski et al., 2018; Wang & Zhou, 2018; Wang et al., 2019a), potentially similar to Jeholornis. However, owing to the potential uncertainty from 2D preservation of currently published skulls of confuciusornithiforms, 3D data are needed to confirm this in future analyses. Disarticulation prevents detailed reconstruction of articulations between the lacrimal, the nasal and the preorbital ossification in Jeholornis STM 3-8. The ventral ramus of the lacrimal is interpreted as contacting the jugal process of the maxilla and, potentially, might have contacted the rostral tip of the jugal, whereas the lacrimal contacts the jugal in other theropods (Xu & Wu, 2001; Rauhut, 2014; Kundrát et al., 2018; Rauhut et al., 2018). The caudal margin of the lacrimal, which forms the cranial margin of the orbit, is remarkably excavated, and the excavation extends across both the ventral and caudodorsal processes. A lacrimal foramen lies within the centre of the excavation, entering medially into the main body of the lacrimal at around its mid-height, at the junction of the ventral ramus and the caudodorsal ramus. The size and central position of this foramen resemble the condition in Ichthyornis (Field et al., 2018), although the lacrimal of Ichthyornis differs in lacking the rostrodorsal ramus and thus the contact with the maxilla. In contrast, this foramen is much smaller and penetrates lateromedially in enantiornithine IVPP V12707, which also lacks any excavation on the lacrimal on the rostral orbit margin of the lacrimal (Wang et al. 2021). This contrasts with the craniocaudal extension of the lacrimal foramen in Jeholornis. Nasal The left nasal is well preserved (Fig. 3A, B). The nasal corpus is mediolaterally broad, similar to Sapeornis (Hu et al., 2019, 2020a) but unlike the more elongated condition present in Archaeopteryx (Mayr et al., 2007; Rauhut, 2014; Kundrát et al., 2018), confuciusornithiforms (El&zdot;anowski et al., 2018; Wang et al., 2019a) and enantiornithines (O’Connor & Chiappe, 2011). Both the premaxillary and the maxillary processes are delicate and sharply tapered rostrally. The premaxillary process is slightly longer than the maxillary process, and the deflections of both processes in the left nasal are taphonomic, resulting from crushing between the right nasal and left lacrimal. The premaxillary process does not extend to the base of the frontal process of the premaxilla, therefore leaving the premaxilla to form most of the rostrodorsal margin of the external naris. This is different from the condition in Archaeopteryx, in which the premaxillary process is substantially longer than the maxillary process and forms part of the dorsal–rostrodorsal margin of the external naris (Rauhut, 2014; Kundrát et al., 2018). The maxillary process of the premaxilla of Jeholornis is also relatively short and does not extend to the base of the ascending process of the maxilla, therefore not contacting the premaxilla. This leaves the maxilla to form the caudoventral margin of the external naris, similar to Archaeopteryx (Rauhut, 2014). Preorbital ossification Specimen STM 3-8 preserves a mysterious pair of sheet-like elements previously referred to as ‘preorbital ossifications’ (Fig. 3C, D; Hu et al., 2022), which might represent prefrontals based on their overall shape and location. This is supported by their location almost parallel to the craniodorsal process of the lacrimal, which rules out identification as the ectethmoid, especially considering that other rostral elements are mostly preserved in situ. If this element is the prefrontal, it differs from the prefrontals of all other pennaraptorans so far, which are strongly reduced or absent, being typically smaller than the nasal (e.g. in Archaeopteryx and Sinornithosaurus; Xu & Wu, 2001; Rauhut et al., 2018). This could suggest that an unfused, expanded prefrontal might be a derived feature of Jeholornis and challenges the hypothesis based on the embryonic observations that the prefrontal fused to form the caudodorsal ramus of the lacrimal in all birds (Smith-Paredes et al., 2018). If correctly identified, this suggests that a broad prefrontal co-exists with a lacrimal with a well-developed caudodorsal process in Jeholornis. However, owing to the lack of available comparisons of any similar ossifications among non-avian dinosaurs and birds, we cannot exclude the possibility that this bone represents some other element that is rarely preserved or developed in Mesozoic birds. For example, the preorbital ossification described here could be a palpebral, although we consider this to be much less likely owing to its preserved location, close to the midline of the skull. Jugal Only the left jugal is preserved in STM 3-8 (Fig. 3G, H). The maxillary process is as slender as the jugal process of the maxilla, similar to the jugal of Archaeopteryx (El&zdot;anowski & Wellnhofer, 1996; Kundrát et al., 2018; Rauhut et al., 2018) but in contrast to the relatively more robust condition in Sapeornis (Hu et al., 2020a). The rostral quarter of the maxillary process is slightly constricted and bears a depression in the distal end of the dorsal margin, defining the articulation with the maxilla. The articulation between the jugal and the maxilla is much shorter than in Sapeornis, in which the maxilla extends caudally almost to the base of the postorbital bar (Hu et al., 2020a). An oval concavity is present centrally on the lateral surface of the maxillary process. A similar depression is also present in Archaeopteryx, although in a more rostral position (Mayr et al., 2007; Rauhut, 2014), but is absent in most other Mesozoic birds (e.g. Sapeornis, Ichthyornis and enantiornithines; Wang & Hu, 2017; Field et al., 2018; Hu et al., 2020a). The quadratojugal process of the jugal of Jeholornis lacks the notch present in Sapeornis and many non-avian theropods, which is also absent in known enantiornithines but possibly present in Ichthyornis (Rauhut, 2003; Xu et al., 2015; Wang & Hu, 2017; Field et al., 2018; Hu et al., 2020b). Because of this, the quadratojugal of Jeholornis articulates with the dorsolateral surface of the quadratojugal process of the jugal, differing from the wedge-like articulation seen in Sapeornis and other Mesozoic theropods (e.g. Linheraptor Xu et al., 2015; Xu et al., 2015; Hu et al., 2020a). The postorbital process of the jugal of Jeholornis is triangular with a broad base and is dorsally oriented. This contrasts with the caudodorsal orientation seen in Archaeopteryx and Sapeornis (Mayr et al., 2007; Rauhut, 2014; Kundrát et al., 2018; Hu et al., 2020a). A shallow impression on the rostrolateral surface of the postorbital process defines the articulation with the postorbital, indicating the presence of a complete postorbital bar in Jeholornis. Quadratojugal The left quadratojugal is complete, but slightly disarticulated from the jugal (Fig. 3E, F). The jugal process is twice as long as the squamosal process and is more slender; both are bluntly tapered. The ventromedial surface of the jugal process contacts the jugal, in contrast to the inserting articulation with the caudal notch of the jugal in Sapeornis and most non-avian theropods (Xu et al., 2015; Hu et al., 2020a). The squamosal process is reduced and does not contact the squamosal dorsally, similar to the condition in other Mesozoic birds, including Archaeopteryx, Sapeornis and various others (e.g. RapaxaƲis pani Morschhauser et al., 2009 and Cruralispennia multidonta Wange et al., 2017; Mayr et al., 2007; O’Connor et al., 2011; Rauhut, 2014; Wang et al., 2017b; Hu et al., 2020a). Postorbital The left postorbital is completely preserved and the right is broken in STM 3-8 (Fig. 3I–K). The postorbital is triradiate and more robust than that of Archaeopteryx (Kundrát et al., 2018; Rauhut et al., 2018; Hu et al., 2020a). The jugal process is long and tapers ventrally, extending most of the skull height ventrally, and therefore forming most of the postorbital bar. In contrast, one specimen of Archaeopteryx preserves a slightly longer jugal process (Rauhut et al., 2018), whereas others preserve a jugal process almost equal in length to the other processes (Kundrát et al., 2018). The elongate jugal process of Jeholornis more closely resembles the condition in some enantiornithines (e.g. Longusunguis Wang et al., 2014 and enantiornithines LP4450 and IVPP V12707). However, it is much more robust than that of some other enantiornithines (Sanz et al., 1997; Hu et al., 2020b; Zhou et al., 2008). The squamosal process of the postorbital of Jeholornis is short, less than half the length of the frontal process, and has a sharply tapered end, whereas this process is longer in Sapeornis and Archaeopteryx (Rauhut et al., 2018; Hu et al., 2020a). The dorsal surface of the squamosal process bears a concave facet for articulation with the squamosal. Squamosal Both squamosals are preserved, although only the right is complete in STM 3-8 (Fig. 3L, M). The squamosal is not fused to the braincase, similar to the condition in non-avian theropods, Archaeopteryx and enantiornithines (e.g. LP4450 and IVPP V12707; El&zdot;anowski & Wellnhofer, 1996; Sanz et al., 1997; Rauhut, 2003; Norman et al., 2004; Xu et al., 2015; Rauhut et al., 2018; Wang et al., 2021). The rarity with which squamosals are preserved in other stem birds complicates interpretation of the morphology seen in Jeholornis. However, the concavity in the medial surface of this bone fits the otic process of the quadrate, and thus could be interpreted as the quadrate cotyle of the squamosal, supporting our identification of this element as a squamosal. The triangular, sharply tapered, rostroventrally directed process is identified as the postorbital process, resembling that in enantiornithine IVPP V12707 (Wang et al., 2021), and contrasts with the forked condition in Archaeopteryx (El&zdot;anowski & Wellnhofer, 1996; Kundrát et al., 2018). The ventrally oriented quadratojugal process is short, with a blunt ventral margin, not contacting the quadratojugal. This suggests that the loss of the quadratojugal–squamosal contact might have evolved independently in Jeholornis and in ornithurines, but remained present in at least some enantiornithines (e.g. IVPP 12707) [although it also could have been regained secondarily as a derived feature (Wang et al., 2021)]. It cannot be determined whether the dorsal portion is complete, hence the shape of the parietal and the paroccipital processes of the squamosal remain uncertain. Quadrate Both quadrates are almost completely preserved (Fig. 4A–C). The shaft of the quadrate extends from the otic process dorsally to the lateral condyle caudoventrally. The orbital process is broad and lateromedially thin, resembling that of Archaeopteryx (Rauhut et al., 2018), Sapeornis (Hu et al., 2020a) and known enantiornithines [e.g. Zhouornis Zhang et al., 2013 (Zhang et al., 2013) and Pterygornis Wang et al., 2014 (Wang et al., 2015)], and differs from the narrow and rostrally projecting condition in Ichthyornis and crown birds, including the Late Cretaceous Asteriornis Field et al., 2020 (El&zdot;anowski & Stidham, 2010; Field et al., 2018, 2020). The otic process is plesiomorphically single headed, as in Sapeornis and enantiornithines (Wang et al., 2015, 2021; Hu et al., 2020a), but differing from the divided otic capitulum and squamosal capitulum in neognaths, including Asteriornis (Field et al., 2020). A dorsoventrally oriented longitudinal ridge is present caudally on the medial surface of the otic process, similar to the condition in Sapeornis and enantiornithines (Zhang et al., 2013; Wang et al., 2015; Hu et al., 2020a), defining the caudal margin of a gentle excavation on the medial surface of the orbital process. The lateral surface is also excavated by a similar dorsoventrally oriented longitudinal ridge, but it cannot be determined whether this is attributable to the lateromedially crushed preservation of the orbital process. No pneumatic foramen is observed, different from the condition in most modern birds and Late Cretaceous ornithurines (e.g. Ichthyornis and Asteriornis; El&zdot;anowski & Stidham, 2010; Field et al., 2018, 2020). However, two potential pneumatic recesses could be identified on the lateral surface of the quadrate in Jeholornis. Both the lateral and medial condyles are of a similar size and project caudally, defining a concave caudal margin for the quadrate. Frontal The frontals are tightly articulated with each other in STM 3-8, but not entirely fused, with the interfrontal suture clearly visible (Fig. 4D, E), similar to the condition observed in other Jeholornis specimens (Lefèvre et al, Published as part of Hu, Han, Wang, Yan, Fabbri, Matteo, O, Jingmai K., Connor, Mcdonald, Paul G., Wroe, Stephen, Yin, Xuwei, Zheng, Xiaoting, Zhou, Zhonghe & Benson, Roger B. J., 2023, Cranial osteology and palaeobiology of the Early Cretaceous bird Jeholornis prima (Aves: Jeholornithiformes), pp. 93-112 in Zoological Journal of the Linnean Society 198 (1) on pages 95-107, DOI: 10.1093/zoolinnean/zlac089, http://zenodo.org/record/7926859, {"references":["Zhou Z, Zhang F. 2002. A long-tailed, seed-eating bird from the Early Cretaceous of China. Nature 418: 405 - 409.","Zhou Z, Zhang F. 2003. 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Hu, Han, Wang, Yan, Fabbri, Matteo, O, Jingmai K., Connor, Mcdonald, Paul G., Wroe, Stephen, Yin, Xuwei, Zheng, Xiaoting, Zhou, Zhonghe, Benson, Roger B. J. (2023): Cranial osteology and palaeobiology of the Early Cretaceous bird Jeholornis prima (Aves: Jeholornithiformes). Zoological Journal of the Linnean Society 198 (1): 93-112, DOI: 10.1093/zoolinnean/zlac089, URL: https://academic.oup.com/zoolinnean/article/198/1/93/6768673

EMENDED DIAGNOSIS OF J. PRIMA Based on the morphological study of this specimen, we provide the following revised diagnosis for J. prima. A large stem bird with the following combination of features: premaxilla edentulous with short maxillary process; two teeth with blunt crowns in maxilla and three relatively smaller teeth in dentary (new); paired, sheet-like preorbital ossifications present near the nasals (new, autapomorphy); C-shaped lacrimal with short rostrodorsal ramus and lacrimal foramen (new); unreduced postorbital forming a complete postorbital bar with jugal (new); pterygoid rami of vomer much longer than the fused rostral portion, expanded in the middle and lacking the caudodorsal process (new); palatine with broad pterygoid wing and jugal process (new); narrow and restricted mandibular fenestra between prearticular and surangular (new); 27 caudal vertebrae in total, with the transition point occurring after the fifth vertebra; lateral trabecula of sternum absent; caudalmost pair of sternal ribs expanded; first phalanx of the third manual digit twice as long as the second phalanx; ratio of forelimb (humerus plus ulna plus carpometacarpus) to hindlimb (femur plus tibiotarsus plus tarsometatarsus) of ~1.2:1; dorsal margin of the ilium nearly straight and craniodorsal–caudoventrally oriented (modified from Zhou & Zhang, 2002; O’Connor et al., 2012; Zheng et al., 2020)., Published as part of Hu, Han, Wang, Yan, Fabbri, Matteo, O, Jingmai K., Connor, Mcdonald, Paul G., Wroe, Stephen, Yin, Xuwei, Zheng, Xiaoting, Zhou, Zhonghe & Benson, Roger B. J., 2023, Cranial osteology and palaeobiology of the Early Cretaceous bird Jeholornis prima (Aves: Jeholornithiformes), pp. 93-112 in Zoological Journal of the Linnean Society 198 (1) on page 107, DOI: 10.1093/zoolinnean/zlac089, http://zenodo.org/record/7926859, {"references":["Zhou Z, Zhang F. 2002. A long-tailed, seed-eating bird from the Early Cretaceous of China. Nature 418: 405 - 409.","O'Connor JK, Sun C, Xu X, Wang X, Zhou Z. 2012. A new species of Jeholornis with complete caudal integument. Historical Biology 24: 29 - 41.","Zheng X, Sullivan C, O'Connor JK, Wang X, Wang Y, Zhang X, Zhou Z. 2020. Structure and possible ventilatory function of unusual, expanded sternal ribs in the Early Cretaceous bird Jeholornis. Cretaceous Research 116: 104597."]}

Background In RAS-mutant tumors, combined MEK and autophagy inhibition using chloroquine demonstrated synthetic lethality in preclinical studies. This phase II trial evaluated the safety and activity of the MEK inhibitor binimetinib combined with hydroxychloroquine (HCQ) in patients with advanced KRAS-mutant non-small cell lung cancer (NSCLC). Methods Eligibility criteria included KRAS-mutant NSCLC, progression after first-line therapy, ECOG PS 0-1, and adequate end-organ function. Binimetinib 45 mg was administered orally (p.o.) bid with HCQ 400 mg p.o. bid. The primary endpoint was objective response rate (ORR). A Simon’s 2-stage phase II clinical trial design was used, with an α error of 5% and a power β of 80%, anticipating an ORR of 30% to proceed to the 2-stage expansion. Results Between April 2021 and January 2022, 9 patients were enrolled to stage I: median age 64 years, 44.4% females, 78% smokers. The best response was stable disease in one patient (11.1%). The median progression free survival (PFS) was 1.9 months, and median overall survival (OS) was 5.3 months. Overall, 5 patients (55.6%) developed a grade 3 adverse event (AE). The most common grade 3 toxicity was rash (33%). Pre-specified criteria for stopping the trial early due to lack of efficacy were met. Conclusion The combination of B + HCQ in second- or later-line treatment of patients with advanced KRAS-mutant NSCLC did not show significant antitumor activity. (ClinicalTrials.gov Identifier: NCT04735068).

Supplementary Table from An Empirical Antigen Selection Method Identifies Neoantigens That Either Elicit Broad Antitumor T-cell Responses or Drive Tumor Growth

PDF - 1019K, Figure S1 The CIN70 signature predicts survival in PDAC patients. Figure S2 Murine PDAC KRC cells exhibit chromosome instability and evidence of a weakened SAC. Figure S3 Clonogenic survival of PANC-1 and BxPC3 cells treated with NMS-P715. Figure S4 Growth of human adipose stem cells (ASCs) in the presence of NMS-P715. Figure S5 Murine PDAC KRC cell growth is inhibited by NMS-P715. Figure S6 Inhibition of PDAC cell growth after pre-treatment with NMS-P715. Table S1 Chromosome stability in cell lines. Table S2 PDAC CIN25 genes ranked by Cox score Supplementary methods for gene expression and survival analyses.

Neoantigens are critical targets of antitumor T-cell responses. The ATLAS bioassay was developed to identify neoantigens empirically by expressing each unique patient-specific tumor mutation individually in Escherichia coli, pulsing autologous dendritic cells in an ordered array, and testing the patient's T cells for recognition in an overnight assay. Profiling of T cells from patients with lung cancer revealed both stimulatory and inhibitory responses to individual neoantigens. In the murine B16F10 melanoma model, therapeutic immunization with ATLAS-identified stimulatory neoantigens protected animals, whereas immunization with peptides associated with inhibitory ATLAS responses resulted in accelerated tumor growth and abolished efficacy of an otherwise protective vaccine. A planned interim analysis of a clinical study testing a poly-ICLC adjuvanted personalized vaccine containing ATLAS-identified stimulatory neoantigens showed that it is well tolerated. In an adjuvant setting, immunized patients generated both CD4+ and CD8+ T-cell responses, with immune responses to 99% of the vaccinated peptide antigens.Significance:Predicting neoantigens in silico has progressed, but empirical testing shows that T-cell responses are more nuanced than straightforward MHC antigen recognition. The ATLAS bioassay screens tumor mutations to uncover preexisting, patient-relevant neoantigen T-cell responses and reveals a new class of putatively deleterious responses that could affect cancer immunotherapy design.This article is highlighted in the In This Issue feature, p. 521