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Abstract Background Loss of muscle strength and endurance with aging or in various conditions negatively affects quality of life. Resistance exercise training (RET) is the most powerful means to improve muscle mass and strength, but it does not generally lead to improvements in endurance capacity. Free essential amino acids (EAAs) act as precursors and stimuli for synthesis of both mitochondrial and myofibrillar proteins that could potentially confer endurance and strength gains. Thus, we hypothesized that daily consumption of a dietary supplement of nine free EAAs with RET improves endurance in addition to the strength gains by RET. Methods Male C57BL6J mice (9 weeks old) were assigned to control (CON), EAA, RET (ladder climbing, 3 times a week), or combined treatment of EAA and RET (EAA + RET) groups. Physical functions focusing on strength or endurance were assessed before and after the interventions. Several analyses were performed to gain better insight into the mechanisms by which muscle function was improved. We determined cumulative rates of myofibrillar and mitochondrial protein synthesis using 2H2O labelling and mass spectrometry; assessed ex vivo contractile properties and in vitro mitochondrial function, evaluated neuromuscular junction (NMJ) stability, and assessed implicated molecular singling pathways. Furthermore, whole‐body and muscle insulin sensitivity along with glucose metabolism, were evaluated using a hyperinsulinaemic–euglycaemic clamp. Results EAA + RET increased muscle mass (10%, P

Abstract Introduction Due to variable psoriasis symptoms, disease progression, and individual responses to therapy, patients may start, stop, or switch biologic therapies. Real-world data on the associated disease burden of patients with psoriasis who do and do not switch biologics are incomplete. Methods This study compared disease burden among patients from the CorEvitas Psoriasis Registry (July 2017–December 2021) who switched biologics and those who did not within 4–12 months following initiation. Disease-related patient-reported outcomes (PROs) were recorded, including skin pain, itching, activity impairment, and effects on health-related quality of life (HRQoL). Disease severity was measured by body surface area (BSA) and Psoriasis Area and Severity Index (PASI). Unadjusted and adjusted regression models were used to compare study outcome measures between the two groups. Results This study included 2145 patients, with 159 classified as switchers and 1986 as non-switchers. The most common reason for switching therapy was failure to maintain initial response (51.7%; n = 78). Moderate-to-severe disease (BSA ≥ 3) was found among 83.0% (n = 132) of switchers versus 26.1% (n = 516) of non-switchers. PASI > 5 was reported among 49.7% (n = 79) of switchers versus 8.6% (n = 171) of non-switchers. Differences in skin pain, itching, and effects on HRQoL between switchers and non-switchers were larger in magnitude for bio-experienced patients. Conclusions Patients who switched biologic therapy experienced a greater disease burden of psoriasis across PROs than non-switchers. Patient-centered factors may be important drivers of biologic switching. Our findings suggest the association between switching and disease burden may be stronger among patients with prior biologic therapy experience.

Abstract The rovibrational spectrum of the water molecule is the crown jewel of high-resolution molecular spectroscopy. While its significance in numerous scientific and engineering applications and the challenges behind its interpretation have been well known, the extensive experimental analysis performed for this molecule, from the microwave to the ultraviolet, is admirable. To determine empirical energy levels for $${{\bf{H}}}_{{\bf{2}}}^{\,{\bf{16}}}{\bf{O}}$$ H 2 16 O , this study utilizes an improved version of the MARVEL (Measured Active Rotational-Vibrational Energy Levels) scheme, which now takes into account multiplet constraints and first-principles energy-level splittings. This analysis delivers 19027 empirical energy values, with individual uncertainties and confidence intervals, utilizing 309 290 transition wavenumbers collected from 189 (mostly experimental) data sources. Relying on these empirical, as well as some computed, energies and first-principles intensities, an extensive composite line list, named CW2024, has been assembled. The CW2024 dataset is compared to lines in the canonical HITRAN 2020 spectroscopic database, providing guidance for future experimental investigations.

Abstract Previous studies arguing for parental care in dinosaurs have been primarily based on fossil accumulations of adults and hatchlings, perinatal and post-hatchlings in nests and nest areas, and evidence of brooding, the majority of which date to the Late Cretaceous. Similarly, the general body proportions of preserved embryonic skeletons of the much older Early Jurassic Massospondylus have been used to suggest that hatchlings were unable to forage for themselves. Here, we approach the question of parental care in dinosaurs by using a combined morphological, chemical, and biomechanical approach to compare early embryonic and hatchling bones of the Early Jurassic sauropodomorph Lufengosaurus with those of extant avian taxa with known levels of parental care. We compare femora, the main weight-bearing limb bone, at various embryonic and post-embryonic stages in a precocious and an altricial extant avian dinosaur with those of embryonic and hatchling Lufengosaurus, and find that the rate and degree of bone development in Lufengosaurus is closer to that of the highly altricial Columba (pigeon) than the precocious Gallus (chicken), providing strong support for the hypothesis that Lufengosaurus was fully altricial. We suggest that the limb bones of Lufengosaurus hatchlings were not strong enough to forage for themselves and would likely need parental feeding.

Abstract Climate warming disproportionately impacts countries in the Global South by increasing extreme heat exposure. However, geographic disparities in adaptation capacity are unclear. Here, we assess global inequality in green spaces, which urban residents critically rely on to mitigate outdoor heat stress. We use remote sensing data to quantify daytime cooling by urban greenery in the warm seasons across the ~500 largest cities globally. We show a striking contrast, with Global South cities having ~70% of the cooling capacity of cities in the Global North (2.5 ± 1.0 °C vs. 3.6 ± 1.7 °C). A similar gap occurs for the cooling adaptation benefits received by an average resident in these cities (2.2 ± 0.9 °C vs. 3.4 ± 1.7 °C). This cooling adaptation inequality is due to discrepancies in green space quantity and quality between cities in the Global North and South, shaped by socioeconomic and natural factors. Our analyses further suggest a vast potential for enhancing cooling adaptation while reducing global inequality.

Abstract Background Atopic dermatitis (AD) is associated with patient burden, but few studies describe the anatomic distribution of the disease or the impact of number of lesion locations. Objectives To describe lesion locations and assess the relationship between the number of lesion locations (disease extent) and disease burden in patients with AD. Methods This cross‐sectional study included adults with dermatologist‐ or dermatology practitioner‐diagnosed AD enroled in the CorEvitas AD Registry (2020–2021) who initiated systemic therapy within 12 months prior to or at enrolment or had moderate‐to‐severe AD (vIGA‐AD® ≥3 and EASI ≥12) at enrolment. Thirteen areas of lesion involvement were assessed using a body map, and numbers of lesion locations were categorised as: 0, 1, 2–3, 4–6 and ≥7. Demographics, disease characteristics, PROs by number of lesion locations were descriptively compared using effect sizes (ES). The ES thresholds for small, medium, and large differences, respectively, were 0.10, 0.30, and 0.50 for phi (categorical outcomes) and 0.10, 0.25 and 0.40 for Cohen's f (continuous outcomes). Results Among 1211 patients, lesion involvement was most frequent on the arms (69.5%) and lower limbs (61.7%). A total of 10.6%, 9.3%, 20.1%, 26.3% and 33.8% of patients had 0, 1, 2–3, 4–6 and ≥7 lesion locations, respectively. Current use of systemic (≥81.2%) and topical ( ≥74.7%) therapies was common, irrespective of lesion location. Disease severity increased with number of lesion locations: mean total BSA (ES = 1.17), EASI (ES = 1.11), and SCORAD (ES = 1.21). vIGA‐AD ≥3 was observed in 28.3%, 45.3%, 78.0%, and 93.9% of patients with 1, 2–3, 4–6 and ≥7 locations, respectively (ES = 0.63). Greater number of lesion locations was associated with worse PROs: mean POEM (ES = 0.57), sleep loss (ES = 0.41), peak pruritus (ES = 0.50), DLQI (ES = 0.40), and ADCT (ES = 0.53). Uncontrolled AD (ADCT ≥7) was observed in 48.2%, 52.9%, 70.4%, 81.6% of patients with 1, 2–3, 4–6 and ≥7 locations, respectively (ES = 0.42). Conclusions AD lesions were reported for each body area assessed. Greater number of lesion locations was associated with increased disease severity, poor disease control, and decreased quality of life. Patients experienced substantial disease burden regardless of number of lesion locations involved.

The basic reproduction number, R0, is a well-known quantifier of epidemic spread. However, a class of existing methods for estimating R0 from incidence data early in the epidemic can lead to an over-estimation of this quantity. In particular, when fitting deterministic models to estimate the rate of spread, we do not account for the stochastic nature of epidemics and that, given the same system, some outbreaks may lead to epidemics and some may not. Typically, an observed epidemic that we wish to control is a major outbreak. This amounts to implicit selection for major outbreaks which leads to the over-estimation problem. We formally characterised the split between major and minor outbreaks by using Otsu's method which provides us with a working definition. We show that by conditioning a ‘deterministic’ model on major outbreaks, we can more reliably estimate the basic reproduction number from an observed epidemic trajectory.

Abstract Radiopharmaceutical therapy using $$\upalpha$$ α -emitting $$^{225}$$ 225 Ac is an emerging treatment for patients with advanced metastatic cancers. Measurement of the spatial dose distribution in organs and tumors is needed to inform treatment dose prescription and reduce off-target toxicity, at not only organ but also sub-organ scales. Digital autoradiography with $$\upalpha$$ α -sensitive detection devices can measure radioactivity distributions at 20–40 $$\upmu {\hbox {m}}$$ μ m resolution, but anatomical characterization is typically limited to 2D. We collected digital autoradiographs across whole tissues to generate 3D dose volumes and used them to evaluate the simultaneous tumor control and regional kidney dosimetry of a novel therapeutic radiopharmaceutical for prostate cancer, [225Ac]Ac-Macropa-PEG4-YS5, in mice. 22Rv1 xenograft-bearing mice treated with 18.5 kBq of [225Ac]Ac-Macropa-PEG4-YS5 were sacrificed at 24 h and 168 h post-injection for quantitative $$\upalpha$$ α -particle digital autoradiography and hematoxylin and eosin staining. Gamma-ray spectroscopy of biodistribution data was used to determine temporal dynamics and $$^{213}$$ 213 Bi redistribution. Tumor control probability and sub-kidney dosimetry were assessed. Heterogeneous $$^{225}$$ 225 Ac spatial distribution was observed in both tumors and kidneys. Tumor control was maintained despite heterogeneity if cold spots coincided with necrotic regions. $$^{225}$$ 225 Ac dose-rate was highest in the cortex and renal vasculature. Extrapolation of tumor control suggested that kidney absorbed dose could be reduced by 41% while maintaining 90% TCP. The 3D dosimetry methods described allow for whole tumor and organ dose measurements following $$^{225}$$ 225 Ac radiopharmaceutical therapy, which correlate to tumor control and toxicity outcomes.

Abstract Accurate weight predictions are essential for weight management program patients. The freely available National Institutes of Health Body Weight Planner (NIH-BWP) returns expected weights over time but overestimates weight when patients consume a low-calorie diet. This study sought to increase the accuracy of NIH-BWP predicted weights for people on low-calorie diets. People enrolled in a weight management program were included if they received meal replacements with defined caloric content for the 3 months of the weight loss phase of the program. The Ottawa Weight Loss Prediction Model (OWL-PM) modelled the relative difference between observed and NIH-BWP predicted weights using longitudinal analysis methods based on patient factors. OWL-PM was externally validated. 1761 people were included (mean age 46 years, 73.3% women) with a mean (SD) baseline weight in pounds and body mass index of 271.9 (55.6) and 43.9 (7.4), respectively. At the end of the program’s weight loss phase, people lost a median (IQR) of 17.1% (14.8–19.5) of their baseline weight. Observed weight relative to NIH-BWP predicted weights had a median value of − 4.9% but ranged from − 32.1% to + 28.5%. After adjustment, weight overestimation by NIH-BWP was most pronounced in male patients, people without diabetes and with increased observation time. OWL-PM returned expected weights at 3 months that were significantly more accurate than those from NIH-BWP alone (mean difference observed vs. expected [95% CI] 6.7lbs [6.4–7.0] vs. 12.6lbs [12.1–13.0]). In the external validation cohort (n = 106), OWL-PM was significantly more accurate than NIH-BWP (mean squared error 24.3 vs. 40.0, p = 0.0018). OWL-PM incorporated patient-level covariates to significantly increase weight prediction accuracy of NIH-BWP in patients consuming a low-calorie diet.

Abstract Adenoid cystic carcinoma (ACC) is a rare, usually slow-growing yet aggressive head and neck malignancy. Despite its clinical significance, our understanding of the cellular evolution and microenvironment in ACC remains limited. We investigated the intratumoral microbiomes of 50 ACC tumor tissues and 33 adjacent normal tissues using 16S rRNA gene sequencing. This allowed us to characterize the bacterial communities within the ACC and explore potential associations between the bacterial community structure, patient clinical characteristics, and tumor molecular features obtained through RNA sequencing. The bacterial composition in the ACC was significantly different from that in adjacent normal salivary tissue, and the ACC exhibited diverse levels of species richness. We identified two main microbial subtypes within the ACC: oral-like and gut-like. Oral-like microbiomes, characterized by increased diversity and abundance of Neisseria, Leptotrichia, Actinomyces, Streptococcus, Rothia, and Veillonella (commonly found in healthy oral cavities), were associated with a less aggressive ACC-II molecular subtype and improved patient outcomes. Notably, we identified the same oral genera in oral cancer and head and neck squamous cell carcinomas. In both cancers, they were part of shared oral communities associated with a more diverse microbiome, less aggressive tumor phenotype, and better survival that reveal the genera as potential pancancer biomarkers for favorable microbiomes in ACC and other head and neck cancers. Conversely, gut-like intratumoral microbiomes, which feature low diversity and colonization by gut mucus layer-degrading species, such as Bacteroides, Akkermansia, Blautia, Bifidobacterium, and Enterococcus, were associated with poorer outcomes. Elevated levels of Bacteroides thetaiotaomicron were independently associated with significantly worse survival and positively correlated with tumor cell biosynthesis of glycan-based cell membrane components.

Abstract In response to the COVID-19 pandemic, the American Board of Anesthesiology transitioned from in-person to virtual administration of its APPLIED Examination, assessing more than 3000 candidates for certification purposes remotely in 2021. Four hundred examiners were involved in delivering and scoring Standardized Oral Examinations (SOEs) and Objective Structured Clinical Examinations (OSCEs). More than 80% of candidates started their exams on time and stayed connected throughout the exam without any problems. Only 74 (2.5%) SOE and 45 (1.5%) OSCE candidates required rescheduling due to technical difficulties. Of those who experienced “significant issues”, concerns with OSCE technical stations (interpretation of monitors and interpretation of echocardiograms) were reported most frequently (6% of candidates). In contrast, 23% of examiners “sometimes” lost connectivity during their multiple exam sessions, on a continuum from minor inconvenience to inability to continue. 84% of SOE candidates and 89% of OSCE candidates described “smooth” interactions with examiners and standardized patients/standardized clinicians, respectively. However, only 71% of SOE candidates and 75% of OSCE candidates considered themselves to be able to demonstrate their knowledge and skills without obstacles. When compared with their in-person experiences, approximately 40% of SOE examiners considered virtual evaluation to be more difficult than in-person evaluation and believed the remote format negatively affected their development as an examiner. The virtual format was considered to be less secure by 56% and 40% of SOE and OSCE examiners, respectively. The retirement of exam materials used virtually due to concern for compromise had implications for subsequent exam development. The return to in-person exams in 2022 was prompted by multiple factors, especially concerns regarding standardization and security. The technology is not yet perfect, especially for testing in-person communication skills and displaying dynamic exam materials. Nevertheless, the American Board of Anesthesiology’s experience demonstrated the feasibility of conducting large-scale, high-stakes oral and performance exams in a virtual format and highlighted the adaptability and dedication of candidates, examiners, and administering board staff.

The Barremian-aged Wessex Formation of the Isle of Wight, UK, offers a globally significant glimpse into the sauropod dinosaur faunas of the early Cretaceous. These deposits have yielded specimens of several neosauropod lineages, such as rebbachisaurids, titanosauriforms (including some of the earliest titanosaur remains), and possible flagellicaudatans. Here, we report an undescribed sauropod partial hindlimb from the Wessex Formation (NHMUK PV R16500) and analyse its phylogenetic affinities. This hindlimb preserves the left tibia, astragalus and pes, lacking only a few phalanges. NHMUK PV R16500 can be diagnosed based on two autapomorphies: an unusually high distal end to midshaft transverse width ratio in metatarsals III and IV, and the presence of small bump-like projections located in the centre of the proximal articular surfaces of the unguals of pedal digits I and II. The phylogenetic affinities of NHMUK PV R16500 are uncertain: although our analyses recover it as an early-branching somphospondylan, a single character change moves it to close to Flagellicaudata when extended implied weighting is applied. The possibility of flagellicaudatan affinities for NHMUK PV R16500 implies a potential ghost lineage that survived the Jurassic/Cretaceous boundary; however, we present evidence that the somphospondylan position is more probable and should be preferred.

Aesthetic experience is an altered state of consciousness characterized by a detached absorption in an aesthetic object; it is a pleasant—sometimes ecstatic—liberation from the self and its agenda. I briefly review perceptual-cognitive and affective approaches used by psychologists to understand the phenomenon and suggest the need for a volitional perspective. To illustrate the nature and scope of aesthetic experience, I discuss nine varieties, elicited by different qualities in objects and evoking distinctive responses in perceivers. Over centuries, aesthetic devices have been developed that induce the aesthetic state by manipulating such psychological mechanisms as attention, appraisal, and empathy. I propose explanations for how several important devices operate, and why they are particularly effective in individuals high in the personality trait of Openness to Experience.

This study investigated the influence of economic stressors on the relationship between healthcare adherence attitudes and intentions. The data were collected through two time points, three months apart, from 442 US workers recruited through Amazon’s Mechanical Turk. Multiple regression analysis was used to test the model with perceived income inadequacy and job insecurity as moderators of the adherence attitudes-intentions relationship. The model controlled for adherence intentions at Time 1 (T1), medical illness history, and medical illness recency. The results confirmed the healthcare adherence attitudes-intentions relationship, and supported the hypothesis that economic stressors were negatively correlated with healthcare adherence attitudes and intentions. Job insecurity moderated this relationship and perceived income inadequacy was negatively associated with healthcare intentions across time. The findings highlight the importance of considering economic stress as a social determinant in interventions aimed at improving adherence. Research is needed to understand the mechanisms underlying the relationship between economic stress and healthcare adherence.

Linear erosion channel (LEC) devastates arable land and significantly contributes to soil loss in agricultural watersheds. In the presence of a less- or non-erodible layer, channel widening governs the erosion process once the channel bed incises to this layer, accompanied by failure block generation and transport. Current knowledge on channel widening, however, is limited due to the lack of robust and efficient methods to capture the rapid sidewall expansion process. Laboratory experiments were designed to simulate the channel widening process with an initial channel width of 10 cm. Two packed soil beds with a non-erodible layer and two slope gradients (5 % and 11 %) were subjected to the inflow rate of 0.67 L/s. Images were captured by mounted digital cameras and automatically transformed into orthophotos. Channel edges and failure blocks were automatically detected by deep learning algorithm in a newly developed Channel-DeepLab network model based upon DeepLabv3+ platform. The procedure includes learning samples labelling, data augmentation, model construction, training, and validation. Sediment discharge and changes in channel width, geometry of channel edges, and failure blocks were measured. The results indicate that initial period is critical for erosion prediction and remediation due to its small sidewall failure interval, high channel expansion rate and sediment discharge. Channel surface area has great potential on accumulated sediment discharge prediction. The slope section that witnessed the fastest channel widening rate migrated downwards when slope gradient increased from 5 % to 11 %. The total number and area of the failure blocks increased with time, while the collapse frequency of the sidewalls decreased. Upstream reach experienced the highest sidewall collapse frequency and rate of disaggregation and transport, while the downstream reach experienced the highest total number of failure blocks. A time lag was found between sidewall collapse and sediment discharge, which increased as time progressed, attributing to decreased runoff erosivity as the flow velocity decreased. Results of this study will provide methodological support for channel sidewall and streambank retreat monitoring, realizing the automatic detection of channel edges and efficient output of rapid sidewall expansion process with high temporal and spatial precision. Future work can be focused on broadening the applicability of the Channel-DeepLab network model and quantifying the delayed response process between sidewall failure and sediment discharge.

Black pericarp sorghum has notable value due to the biosynthesis of 3-deoxyanthocyanidins (3-DOAs), a rare class of bioactive polyphenols valued as antioxidant food additives and as bioactive compounds with cytotoxicity to human cancer cells. A metabolic and transcriptomic study was conducted to ascertain the cellular events leading to the activation of 3-DOA biosynthesis in black sorghum pericarp. Prolonged exposure of pericarp during grain maturation to high-fluence ultraviolet (UV) light resulted in elevated levels of reactive oxygen species (ROS) and the activation of 3-DOA biosynthesis in pericarp tissues. In conjunction with 3-DOA biosynthesis was the transcriptional activation of specific family members of early and late flavonoid biosynthesis pathway genes as well as the downstream activation of defense-related pathways. Promoter analysis of genes highly correlated with 3-DOA biosynthesis in black pericarp were enriched in MYB and HHO5/ARR-B motifs. Light microscopy studies of black pericarp tissues suggest that 3-DOAs are predominantly localized in the epicarp and are associated with the cell wall. A working model of UV-induced 3-DOA biosynthesis in black pericarp is proposed that shares features of plant immunity associated with pathogen attack or mechanical wounding. The present model depicts ROS accumulation, the transcriptional activation of receptor kinases and transcription factors (TFs) including NAC, WRKY, bHLH, AP2, and C2H2 Zinc finger domain. This study identified key biosynthetic and regulatory genes of 3-DOA accumulation in black pericarp and provided a deeper understanding of the gene networks and cellular events controlling this tissue-and genotype-specific trait.

ABSTRACT Dispersal, environmental filtering, and biotic interactions define the species inventory of local communities. Along successional gradients, these assembly processes are predicted to sequentially vary in their relative importance with dispersal as the dominating process early in succession, followed by environmental filtering and biotic interactions at later stages. While observational data from field studies supported this prediction, controlled experiments confirming a sequence of successional processes are still lacking. We designed miniature ecosystems to explicitly test these assumptions under controlled laboratory conditions. Our “Ecosystems on a Plate” (EsoaP) are 3D-printed customized microplates with 24 connected wells allowing us to track dispersal, niche filtering, and biotic interactions among bacteria and plants in time and space. Within EsoaPs, we created heterogeneous habitat landscapes by well-specific nutrient levels or by providing plant seedlings as mutualistic partners in a checkerboard pattern. Bacteria of a single strain were released in one well and subsequently distributed themselves within the plates. We measured the spatial distribution of bacterial abundances at two time points as a function of abiotic or biotic heterogeneity. Bacterial abundance distribution confirmed a shift from initial dispersal-dominated processes to later niche filtering and biotic interactions as more important processes. Our approach follows the principles of open science as the affordable availability of 3D printers as well as shared STL files makes EsoaPs disseminatable and accessible to all levels of society, facilitating future experimental research.IMPORTANCEHypotheses regarding the underlying processes of ecological successions have primarily emerged from and have been tested in observational studies, lacking substantial support through controlled experiments. The design of such experiments should focus on testing contemporary ecological theories at the intersection of community assembly and successional research. To achieve this, we developed and employed 3D-printed “Ecosystems on a Plate” (EsoaP) within controlled laboratory settings. EsoaPs surmount several limitations of nanoscale instruments that had hindered their application in ecologically meaningful research. By sharing 3D printing designs, experimental protocols, and data openly, we facilitate reproducibility of our experiments by researchers across diverse ecological disciplines. Moreover, our approach facilitates cost-effective replication of experiments, democratizing access to tools for ecological research, and thus holds the potential to serve as a model for future studies and educational purposes.

Given the increasing frequency of simultaneous pancreas-kidney transplants performed in recipients with Type II diabetes and CKD, we sought to evaluate possible differences in the rates of allograft rejection, infection, and surgical complications in 298 Type I (T1D) versus 47 Type II (T2D) diabetic recipients of simultaneous pancreas-kidney transplants between 2006-2017. There were no significant differences in patient or graft survival. The risk of biopsy-proven rejection of both grafts was not significantly different between T2D and T1D recipients (HRpancreas = 1.04, p = 0.93; HRkidney = 0.96; p = 0.93). Rejection-free survival in both grafts were also not different between the two diabetes types (ppancreas = 0.57; pkidney = 0.41). T2D had a significantly lower incidence of de novo DSA at 1 year (21% vs. 39%, p = 0.02). There was no difference in T2D vs. T1D recipients regarding readmissions (HR = 0.77, p = 0.25), infections (HR = 0.77, p = 0.18), major surgical complications (HR = 0.89, p = 0.79) and thrombosis (HR = 0.92, p = 0.90). In conclusion, rejection, infections, and surgical complications after simultaneous pancreas-kidney transplant are not statistically significantly different in T2D compared to T1D recipients.

Modern poriferans are classified into four classes—Calcarea, Demospongiae, Hexactinellida and Homoscleromorpha—the recognition of which in fossil specimens almost exclusively relies on spicule morphology and arrangement. Early fossil representatives of the phylum Porifera are morphologically diverse, and many of them problematically display characteristics that are incompatible with the classification scheme developed for modern taxa. Critically, hexactine spicules—a diagnostic feature of hexactinellids among modern taxa—are found in various Cambrian and Ordovician taxa that cannot be accommodated within the hexactinellid body plan. Here we describe a new poriferan from the Drumian Marjum Formation of Utah, Polygoniella turrelli gen. et sp. nov., which exhibits a unique combination of complex anatomical features for a Cambrian form, including a syconoid-like organization, a thick body wall, and a multi-layered hexactin-based skeleton. The hexactinellid-like body wall architecture of this new species supports a Cambrian origin of the hexactinellid body plan and provides valuable insights into character evolution in early glass sponges.

Summary: Injury is common in the life of organisms. Because the extent of damage cannot be predicted, injured organisms must determine how much tissue needs to be restored. Although it is known that amputation position affects the regeneration speed of appendages, mechanisms conveying positional information remain unclear. We investigated tissue dynamics in regenerating caudal fins of the African killifish (Nothobranchius furzeri) and found position-specific, differential spatial distribution modulation, persistence, and magnitude of proliferation. Single-cell RNA sequencing revealed a transient regeneration-activated cell state (TRACS) in the basal epidermis that is amplified to match a given amputation position and expresses components and modifiers of the extracellular matrix (ECM). Notably, CRISPR-Cas9-mediated deletion of the ECM modifier sequestosome 1 (sqstm1) increased the regenerative capacity of distal injuries, suggesting that regeneration growth rate can be uncoupled from amputation position. We propose that basal epidermis TRACS transduce positional information to the regenerating blastema by remodeling the ECM.

Summary: Tumor acidosis is one of the hallmarks indicating the initiation and progression of various cancers. Here, we present a protocol for preparing a hyperpolarized (HP) 13C-bicarbonate tissue pH MRI imaging contrast agent to detect aggressive tumors. We describe the steps for the formulation and polarization of a precursor molecule 13C-glycerol carbonate (13C-GLC), the post-dissolution reaction, and converting HP 13C-GLC to an injectable HP 13C-bicarbonate solution. We then detail procedures for MRI data acquisition to generate tumor pH maps for assessing tumor aggressiveness.For complete details on the use and execution of this protocol, please refer to Mu et al.1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Objective Evaluate patient‐reported outcomes after 6 months of on‐label guselkumab use in patients with rheumatologist‐diagnosed active psoriatic arthritis (PsA) enrolled in the CorEvitas PsA/Spondyloarthritis Registry. Methods This analysis includes registry participants who initiated and persisted with on‐label guselkumab (after US Food and Drug Administration approval for PsA; 100 mg at weeks 0, 4, and every 8 weeks) at their 6‐month follow‐up visit (On‐Label Persisters). Among patients not meeting response criteria at baseline, responses at 6 months were determined for patient‐reported outcomes, including patient‐reported pain (0–100 mm visual analog scale), patient global assessment of arthritis + psoriasis (PtGA; 0–100 visual analog scale), and Health Assessment Questionnaire‐Disability Index (HAQ‐DI; 0‐3). Unadjusted, nominal P values were calculated via single‐proportion, one‐sided test (H0 = 0%; α = 0.05). Results Of 90 On‐Label Persisters, most had treatment‐resistant PsA (92.2% and 73.3% previously received ≥1 and ≥2 biologic/targeted synthetic disease‐modifying antirheumatic drugs, respectively), with mean (SD) baseline patient‐reported pain, PtGA, and HAQ‐DI scores of 57.0 (24.6), 50.3 (24.4), and 0.9 (0.6), respectively. Among those with patient‐reported pain and PtGA scores of at least 15 at baseline, 40.2% (33/82) and 46.8% (36/77), respectively, achieved at least 15‐mm reductions at 6 months; among those with HAQ‐DI scores of at least 0.35 and more than 0.5 at baseline, respectively, 30.4% (21/69) achieved improvements of at least 0.35 and 10.3% (6/58) achieved scores of 0.5 or lower at 6 months (all nominal P

Objective To describe and identify associated factors for patient–clinician discordance of disease assessment at biologic or Janus kinase inhibitor (JAKi) initiation and over 12 months following initiation in patients with rheumatoid arthritis (RA) from a US RA registry. Methods Analyses included CorEvitas RA Registry patients who initiated their first biologic or JAKi on or after February 1, 2015, and had 6‐ and 12‐month follow‐up visits. Positive discordance was defined as patient global assessment (visual analog scale [VAS‐100]) minus physician's global assessment (VAS‐100) equal to 30 points or more. Persistent discordance was defined as positive discordance at all three visits. Mixed‐effects logistic regression was used to determine risk factors for positive discordance at initiation and for persistent discordance. Results Among 2227 first‐time biologic/JAKi‐initiating patients, 613 had both follow‐up visits available and were included in initiation visit analyses, and of these, 163 had positive discordance at initiation and were included in persistent discordance analyses. About 30% of all patients had positive discordance at any visit, and one third of these (10% total) were persistent at all three visits. Multivariable analyses revealed that worse scores on the Clinical Disease Activity Index, greater patient‐reported pain and fatigue, and greater functional impairment were associated with positive discordance at the time of therapy initiation. Being disabled versus working full‐time and being female were associated with higher odds and having Medicare versus no insurance was associated with lower odds of having persistent positive discordance. Conclusion Results suggest positive discordance is common among real‐world patients with RA initiating their first biologic or JAKi. The identified risk factors associated with patient–clinician discordance will help clinicians foster a more patient‐centric discussion in treatment decisions.

Abstract Background There is a lack of contemporary data describing global variations in vascular access for hemodialysis (HD). We used the third iteration of the International Society of Nephrology Global Kidney Health Atlas (ISN-GKHA) to highlight differences in funding and availability of hemodialysis accesses used for initiating HD across world regions. Methods Survey questions were directed at understanding the funding modules for obtaining vascular access and types of accesses used to initiate dialysis. An electronic survey was sent to national and regional key stakeholders affiliated with the ISN between June and September 2022. Countries that participated in the survey were categorized based on World Bank Income Classification (low-, lower-middle, upper-middle, and high-income) and by their regional affiliation with the ISN. Results Data on types of vascular access were available from 160 countries. Respondents from 35 countries (22% of surveyed countries) reported that > 50% of patients started HD with an arteriovenous fistula or graft (AVF or AVG). These rates were higher in Western Europe (n = 14; 64%), North & East Asia (n = 4; 67%), and among high-income countries (n = 24; 38%). The rates of > 50% of patients starting HD with a tunneled dialysis catheter were highest in North America & Caribbean region (n = 7; 58%) and lowest in South Asia and Newly Independent States and Russia (n = 0 in both regions). Respondents from 50% (n = 9) of low-income countries reported that > 75% of patients started HD using a temporary catheter, with the highest rates in Africa (n = 30; 75%) and Latin America (n = 14; 67%). Funding for the creation of vascular access was often through public funding and free at the point of delivery in high-income countries (n = 42; 67% for AVF/AVG, n = 44; 70% for central venous catheters). In low-income countries, private and out of pocket funding was reported as being more common (n = 8; 40% for AVF/AVG, n = 5; 25% for central venous catheters). Conclusions High income countries exhibit variation in the use of AVF/AVG and tunneled catheters. In low-income countries, there is a higher use of temporary dialysis catheters and private funding models for access creation.

Abstract Osteoarthritis (OA) is increasing in prevalence and has a severe impact on patients’ lives. However, our understanding of biomarkers driving OA risk remains limited. We developed a model predicting the five-year risk of OA diagnosis, integrating retrospective clinical, lifestyle and biomarker data from the UK Biobank (19,120 patients with OA, ROC-AUC: 0.72, 95%CI (0.71–0.73)). Higher age, BMI and prescription of non-steroidal anti-inflammatory drugs contributed most to increased OA risk prediction ahead of diagnosis. We identified 14 subgroups of OA risk profiles. These subgroups were validated in an independent set of patients evaluating the 11-year OA risk, with 88% of patients being uniquely assigned to one of the 14 subgroups. Individual OA risk profiles were characterised by personalised biomarkers. Omics integration demonstrated the predictive importance of key OA genes and pathways (e.g., GDF5 and TGF-β signalling) and OA-specific biomarkers (e.g., CRTAC1 and COL9A1). In summary, this work identifies opportunities for personalised OA prevention and insights into its underlying pathogenesis.

The pollination process is one of the most important contributors to a successful date production since the yield and quality of the fruit depends on its correct successful. Liquid pollination in the date palm production is a recently used technique that seeks to obtain acceptable fruit set percentages (FSP) with lower pollen consumption. In this study, during the 2021 and 2022 growing seasons, the effect of pollination with pollen grains in liquid suspension on the FSP in the date palm cultivar ‘Mejhoul’ was evaluated in the Mexicali Valley, Mexico. The applications were in various proportions of pollen in liquid suspension (1, 2, 3 and 4 g/L), with approximately 40 mL on each inflorescence. The results revealed that the best treatment was 4 g/L with an average FSP of 67.89 and 68.69% for the years 2021 and 2022 respectively, while the control treatment obtained 54.94 and 57.75%, for the same years. Likewise, this method did not affect the physical and chemical properties and yields. Finally, this study suggests that in addition to consuming a smaller amount of pollen, this method has better pollination efficiency.

The gut microbiota drives progression to liver fibrosis, the main determinant of mortality in metabolic dysfunction-associated steatohepatitis (MASH). In this study, we aimed to identify bacterial species associated with protection against liver fibrosis in a high-risk population, and test their potential to protect against liver fibrosis in vivo. Based on stool shotgun metagenomic sequencing of 340 subjects from a population cohort disproportionally affected by MASH, we identified bacterial species from the Bacteroidales and Clostridiales orders associated with reduced risk of liver fibrosis. A bacterial consortium was subsequently tested in a mouse model of MASH, which demonstrated protective effects against liver fibrosis. Six of the eight inoculated bacteria were detected in mouse stool and liver. Intrahepatic presence of bacteria was further confirmed by bacterial culture of mouse liver tissue. Changes in liver histological parameters, gut functional profiles, and amino acid profiles were additionally assessed. Comparison between fibrosis-associated human metagenome and bacteria-induced metagenome changes in mice identified microbial functions likely to mediate the protective effect against liver fibrosis. Amino acid profiling confirmed an increase in cysteine synthase activity, associated with reduced fibrosis. Other microbiota-induced changes in amino acids associated with reduced fibrosis included increased gut asparaginase activity and decreased hepatic tryptophan-to-kynurenine conversion. This human-to-mouse study identified bacterial species and their effects on amino acid metabolism as innovative strategies to protect against liver fibrosis in MASH.

FAIR Principles are a set of high-level guidelines for sharing digital resources. The growing global adoption of the FAIR Principles by policymakers, funders, and organizations compels data professionals, projects, and repositories to demonstrate the level of FAIR-compliance (referred to as FAIRness) of their digital data, metadata, and infrastructures. Because the FAIR Principles offer general objectives rather than specific implementation instructions, discrepancies exist due to different interpretations, domain-specific requirements, and intended applications. These discrepancies hinder direct comparisons and integration of assessment outcomes. To address this issue, we propose a novel framework, including a consolidated FAIR vocabulary. This framework establishes quality measures upfront in FAIRness assessment workflows to surpass the intricacies arising from the aforementioned dependencies. The established quality measures encapsulate the distinctive core concepts inherent in individual FAIR principles and can serve as common, fundamental pillars of holistic FAIRness assessment workflows. Building upon this fundamental set of the quality measures, we introduce a FAIRness quality maturity matrix (FAIR-QMM) as a structured, tiered, and progressive approach for evaluating and reporting the degree of FAIR-compliance. The FAIR-QMM can be used as a FAIRness assessment tool independently and/or as a translator between other FAIRness assessment tools or models.

Background:. There is significant variation in methods used for diagnosis and treatment of neurogenic thoracic outlet syndrome (NTOS). The lack of definitions and criteria for diagnosis as well as controversy in treatment options hampers standardized reporting of outcomes. In the orthopedic and plastic hand surgery literature, there are not standardized guidelines to direct evidence-based practice for hand surgeons relating to NTOS. Hence, expert consensus may provide guidance for clinical practice. Methods:. An international workgroup of 21 expert hand surgeons with cumulative experience of 5519 NTOS procedures was assembled. The Delphi method was used to arrive at consensus recommendations to guide diagnosis, treatment, surgery, and postoperative management of patients with NTOS. Results:. The workgroup achieved majority (greater than 75%) consensus with 17 statements. A modified version of the Society for Vascular Surgery clinical diagnostic criteria is recommended for diagnosis of NTOS. The elevated arm stress test and Tinel sign are recommended as provocative maneuvers. A cervical spine or chest radiograph should be routinely obtained preoperatively. Conservative management should be first line for NTOS, except in patients with significant muscle atrophy or weakness. An anterior supraclavicular approach is recommended for exposure of the supraclavicular brachial plexus, with the necessity for an additional infraclavicular approach or adjunctive surgeries indicated for specific patients. Conclusions:. Standardized consensus guidelines help guide management of NTOS by specialized hand surgeons, with an aim toward standardizing criteria for diagnosis and treatment of patients as well as measures and tools used for research and reporting of outcomes.

Loss-on-ignition (LOI) has been widely used to estimate soil organic carbon (OC) content for coastal wetland soils, owing to recent interest in ‘blue carbon’ systems. Comparatively less attention has been paid to soil nutrient retention, specifically total nitrogen (TN), despite being a historically limited resource that influences C cycling and aquatic ecosystem health. A single conversion equation is available to estimate soil TN content from LOI, derived from salt marshes. This study investigated the utility of creating TN conversion equations from LOI data for application in mangrove soils to improve global understanding of their role in TN interception and sequestration. A dataset of 1275 mangrove soil samples from 17 regions in the western hemisphere was used to create one general equation, two equations pertaining to sedimentary settings, and equations for each of seven coastal environmental settings (CES) that differed in mineral sediment provision, geomorphology, and hydrology. Soil mean LOI and TN ranged from respective lows of 9.5% and 0.18% in terrigenous estuaries to respective highs of 51.4% and 1.25% in carbonate estuaries. The ability of LOI to predict TN in mangrove soils was strong, with an R2 for the general equation of 0.88, and several regional equations exceeding 0.90. Total N represented between 1.1 and 3.7% of LOI. Differences in equations were minimal between mangrove soils and a previous equation for salt marsh soils, and between carbonate and terrigenous sedimentary settings. Significant differences were observed among CES. Deltas had the lowest TN:LOI (0.014), followed by terrigenous estuaries and open coasts (0.017 and 0.019, respectively). Terrigenous lagoons, carbonate estuaries, and carbonate open coasts had the highest TN:LOI (0.024 for all three). The study provides a decision tree to select an appropriate approach for estimating TN content of mangrove soils, offering an important tool for improving the understanding of the role of coastal wetlands in global TN sequestration.

Chronic pain syndromes affect over one-third of the US adult population and often lead to significant disability and a reduced quality of life. Despite their high prevalence, causal links between chronic pain syndromes and anatomic abnormalities are often not apparent. Most current chronic pain treatments provide modest, if any, relief. Thus, there is a pressing need to understand the causal mechanisms implicated in chronic pain as a means to develop more targeted interventions for improvement in clinical outcomes and reduction in morbidity and financial burden. In the present manuscript, we summarize the current literature on treatment for chronic pain, and hypothesize that non-specific chronic back pain (without a clear organic etiology, such as tumors, infections or fractures) is of psychophysiologic origin. Based on this hypothesis, we developed Psychophysiologic Symptom Relief Therapy (PSRT), a novel pain reduction intervention for understanding and treating chronic pain. In this manuscript, we provide the rationale for PSRT, which we have tested in a pilot trial with a subsequent larger randomized trial underway. In the proposed trial, we will evaluate whether non-specific chronic back pain can be treated by addressing the underlying stressors and psychological underpinnings without specific physical interventions.

Abstract Historically, the precipitation trend over the past few decades in the Contiguous United States (CONUS) exhibits a “Dry‐West Wet‐East” pattern; this is manifested by recent droughts/floods in the western/eastern US. However, it remains elusive what atmospheric phenomenon has potentially driven such a remarkable, and impactful precipitation pattern. Here we found that a coupled climate mode—the Pacific Meridional Mode (PMM) exerted strong impacts on the precipitation pattern over the CONUS during the summer season. We discovered a significant association between the PMM index and precipitation across the majority of the CONUS; this was manifested as a zonal dipole pattern—negative correlations in the western U.S. along with positive correlations in the eastern and central U.S. Overall, the physical mechanisms based on observations were supported by using Atmospheric Model Intercomparison Project simulations available from the Coupled Model Intercomparison Project Phase 6.

Operational forecasts rely on accurate and timely observations and it is important that the ocean forecasting community demonstrates the impact of those observations to the observing community and its funders while providing feedback on requirements for the design of the ocean observing system. One way in which impact of new observations can be assessed is through Observing System Simulation Experiments (OSSEs). Various satellite missions are being proposed to measure Total Surface Current Velocities (TSCV). This study uses OSSEs to assess the potential impact of assimilating TSCV observations. OSSEs have been performed using two global ocean forecasting systems; the Met Office’s (MetO) Forecasting Ocean Assimilation Model and the Mercator Ocean International (MOI) system. Developments to the individual systems, the design of the experiments and results have been described in two companion papers. This paper provides an intercomparison of the OSSEs results from the two systems. We show that global near surface velocity analysis root-mean-squared-errors (RMSE) are reduced by 20-30% and 10-15% in the MetO and MOI systems respectively, we also demonstrate that the percentage of particles forecast to be within 50 km of the true particle locations after drifting for 6 days has increased by 9%/7%. Furthermore, we show that the global subsurface velocities are improved down to 1500m in the MetO system and down to 400m in the MOI system. There are some regions where TSCV assimilation degrades the results, notably the middle of the gyres in the MetO system and at depth in the MOI system. Further tuning of the background and observation error covariances are required to improve performance in these regions. We also provide some recommendations on TSCV observation requirements for future satellite missions. We recommend that at least 80% of the ocean surface is observed in less than 4 to 5 days with a horizontal resolution of 20 to 50 km. Observations should be provided within one day of measurement time to allow real time assimilation and should have an accuracy of 10 cm/s in the along and across track direction and uncertainty estimates should be provided with each measurement.

Facultative parthenogenesis (FP) has historically been regarded as rare in vertebrates, but in recent years incidences have been reported in a growing list of fish, reptile, and bird species. Despite the increasing interest in the phenomenon, the underlying mechanism and evolutionary implications have remained unclear. A common finding across many incidences of FP is either a high degree of homozygosity at microsatellite loci or low levels of heterozygosity detected in next-generation sequencing data. This has led to the proposal that second polar body fusion following the meiotic divisions restores diploidy and thereby mimics fertilization. Here, we show that FP occurring in the gonochoristic Aspidoscelis species A. marmoratus and A. arizonae results in genome-wide homozygosity, an observation inconsistent with polar body fusion as the underlying mechanism of restoration. Instead, a high-quality reference genome for A. marmoratus and analysis of whole-genome sequencing from multiple FP and control animals reveals that a post-meiotic mechanism gives rise to homozygous animals from haploid, unfertilized oocytes. Contrary to the widely held belief that females need to be isolated from males to undergo FP, females housed with conspecific and heterospecific males produced unfertilized eggs that underwent spontaneous development. In addition, offspring arising from both fertilized eggs and parthenogenetic development were observed to arise from a single clutch. Strikingly, our data support a mechanism for facultative parthenogenesis that removes all heterozygosity in a single generation. Complete homozygosity exposes the genetic load and explains the high rate of congenital malformations and embryonic mortality associated with FP in many species. Conversely, for animals that develop normally, FP could potentially exert strong purifying selection as all lethal recessive alleles are purged in a single generation.

Gut microbiota composition has been reported to affect pathogen susceptibility but its specific effects, the underlying mechanisms and the potential influence of the diet remain unexplored. In their recent study, Desai and colleagues (Wolter et al, 2024), explore the complex interaction between diet, the gut microbiota and pathogen susceptibility, highlighting a diet-dependent role of the mucin-degrading microbe Akkermansia muciniphila.

Abstract Introduction Data assessing longer-term real-world effectiveness and treatment patterns with upadacitinib (UPA), a Janus kinase inhibitor, in rheumatoid arthritis (RA) are lacking. We assessed improvement in clinical and patient-reported outcomes and treatment patterns for up to 12 months among adult patients with RA initiating UPA. Methods Data were collected from the CorEvitas® RA Registry (08/2019–04/2022). Eligible patients had moderate to severe RA (Clinical Disease Activity Index [CDAI] > 10) and follow-up visits at 6 or 12 months after UPA initiation. Outcomes were mean change from baseline, percentage achieving minimal clinically important differences (MCID) in clinical and patient-reported outcomes, and disease activity at follow-up. We evaluated clinical outcomes and therapy changes among patients with tumor necrosis factor inhibitor (TNFi) experience and among those receiving UPA as first-line therapy, as well as those receiving UPA as monotherapy versus as part of combination therapy. We further evaluated whether outcomes were similar among those that remained on therapy. Results Patients treated with UPA (6-month cohort, N = 469; 12-month cohort, N = 263) had statistically significant improvements (p

Abstract Both targeted therapies and immunotherapies provide benefit in resected Stage III melanoma. We hypothesized that the combination of targeted and immunotherapy given prior to therapeutic lymph node dissection (TLND) would be tolerable and drive robust pathologic responses. In NeoACTIVATE (NCT03554083), a Phase II trial, patients with clinically evident resectable Stage III melanoma received either 12 weeks of neoadjuvant vemurafenib, cobimetinib, and atezolizumab (BRAF-mutated, Cohort A, n = 15), or cobimetinib and atezolizumab (BRAF-wild-type, Cohort B, n = 15) followed by TLND and 24 weeks of adjuvant atezolizumab. Here, we report outcomes from the neoadjuvant portion of the trial. Based on intent to treat analysis, pathologic response (≤50% viable tumor) and major pathologic response (complete or near-complete, ≤10% viable tumor) were observed in 86.7% and 66.7% of BRAF-mutated and 53.3% and 33.3% of BRAF-wild-type patients, respectively (primary outcome); these exceeded pre-specified benchmarks of 50% and 30% for major pathologic response. Grade 3 and higher toxicities, primarily dermatologic, occurred in 63% during neoadjuvant treatment (secondary outcome). No surgical delays nor progression to regional unresectability occurred (secondary outcome). Peripheral blood CD8 + TCM cell expansion associated with favorable pathologic responses (exploratory outcome).

Introduction Proton craniospinal irradiation (pCSI) is a treatment option for leptomeningeal disease (LMD), which permits whole neuroaxis treatment while minimizing toxicity. Despite this, patients inevitably experience progression. Adding systemic therapy to pCSI may improve outcomes. Methods In this single-institution retrospective case series, we present the feasibility of treatment with pCSI (30Gy, 10 fractions) and an immune checkpoint inhibitor (ICI) in two sequential patients with LMD from melanoma. Results The first patient developed LMD related to BRAF V600E-mutant melanoma after prior ICI and BRAF-targeted therapy. After pCSI with concurrent nivolumab, the addition of relatlimab, and BRAF-targeted therapy, he remained alive 7 months after LMD diagnosis despite central nervous system progression. The second patient developed LMD related to BRAF-wildtype melanoma after up-front ICI. He received pCSI with concurrent ipilimumab and nivolumab, then nivolumab maintenance. Though therapy was held for ICI hepatitis, the patient remained progression-free 5 months after LMD diagnosis. Conclusion Adding an ICI to pCSI is feasible for patients with LMD and demonstrates a tolerable toxicity profile. While prospective evaluation is ultimately warranted, pCSI with ICI may confer survival benefits, even after prior ICI.

Abstract Background Mastectomies are commonly performed and strongly associated with chronic postsurgical pain (CPSP), more specifically termed postmastectomy pain syndrome (PMPS), with 25–60% of patients reporting pain 3 months after surgery. PMPS interferes with function, recovery, and compliance with adjuvant therapy. Importantly, it is associated with chronic opioid use, as a recent study showed that 1 in 10 patients continue to use opioids at least 3 months after curative surgery. The majority of PMPS patients are women, and, over the past 10 years, women have outpaced men in the rate of growth in opioid dependence. Standard perioperative multimodal analgesia is only modestly effective in prevention of CPSP. Thus, interventions to reduce CPSP and PMPS are urgently needed. Ketamine is well known to improve pain and reduce opioid use in the acute postoperative period. Additionally, ketamine has been shown to control mood in studies of anxiety and depression. By targeting acute pain and improving mood in the perioperative period, ketamine may be able to prevent the development of CPSP. Methods Ketamine analgesia for long-lasting pain relief after surgery (KALPAS) is a phase 3, multicenter, randomized, placebo-controlled, double-blind trial to study the effectiveness of ketamine in reducing PMPS. The study compares continuous perioperative ketamine infusion vs single-dose ketamine in the postanesthesia care unit vs placebo for reducing PMPS. Participants are followed for 1 year after surgery. The primary outcome is pain at the surgical site at 3 months after the index surgery as assessed with the Brief Pain Inventory-short form pain severity subscale. Discussion This project is part of the NIH Helping to End Addiction Long-term (HEAL) Initiative, a nationwide effort to address the opioid public health crisis. This study can substantially impact perioperative pain management and can contribute significantly to combatting the opioid epidemic. Trial registration ClinicalTrials.gov NCT05037123. Registered on September 8, 2021.

This article provides a comprehensive overview of all currently available datasets of the Long-term Ecosystem Research (LTER) site Oberes Stubachtal. The site is located in the Hohe Tauern mountain range (Eastern Alps, Austria) and includes both protected areas (Hohe Tauern National Park) and unprotected areas (Stubach valley). While the main research focus of the site is on high mountains, glaciology, glacial hydrology, and biodiversity, the eLTER Whole-System Approach (WAILS) was used for data selection. This approach involves a systematic screening of all available data to assess their suitability as eLTER Standard Observations (SOs). This includes the geosphere, atmosphere, hydrosphere, biosphere, and sociosphere. These SOs are fundamental to the development of a comprehensive long-term ecosystem research framework. In total, more than 40 datasets have been collated for the LTER site Oberes Stubachtal and included in the Dynamic Ecological Information Management System—Site and Data Registry (DEIMS-SDR), the eLTER’s data platform. This paper provides a detailed inventory of the datasets and their primary attributes, evaluates them against the WAILS-required observation data, and offers insights into strategies for future initiatives. All datasets are made available through dedicated repositories for FAIR (findable, accessible, interoperable, reusable) use.

Patients undergoing immune effector cell therapy (IECT) are at high risk for infections. We assessed seropositivity against pneumococcus, tetanus, and diphtheria in patients before and after IECT and the patients’ response to vaccination. We enrolled patients who underwent IECT from January 2020 to March 2022. Antibody levels for diphtheria, tetanus, and pneumococcus were measured before IECT, at 1 month, and 3–6 months after. Eligible patients were vaccinated after IECT. In non-seroprotected patients, we discontinued testing. Before IECT, most patients had seroprotective antibody levels against tetanus (68/69, 99%) and diphtheria (65/69, 94%), but fewer did against pneumococcus (24/67, 36%). After IECT, all patients had seroprotective antibody levels for tetanus at 1 month (68/68) and 3–6 months (56/56). For diphtheria, 65/65 patients (100%) had seroprotective antibody levels at 1 month, and 48/53 (91%) did at 3–6 months. For pneumococcus, seroprotective antibody levels were identified in 91% (21/23) of patients at 1 month and 79% (15/19) at 3–6 months following IECT. Fifteen patients received a pneumococcal vaccine after IECT, but none achieved seroprotective response. One patient received the tetanus-diphtheria vaccine and had a seroprotective antibody response. Because some patients experience loss of immunity after IECT, studies evaluating vaccination strategies post-IECT are needed.

Aiming at the increasing demand for electric energy in aircraft in the future, a multi-objective optimization aircraft engine constrained model predictive control method based on generation power distribution is proposed. Firstly, based on the aircraft engine component level model and the equilibrium manifold theory, the aircraft engine equilibrium manifold expansion model is established. Secondly, the influence of the power generation is modeled, and the influence of the low- and high-pressure shaft generators on the normal operation of the aircraft engine is studied and compared. The control variables such as fuel flow and total generation power are taken as the constraint conditions to design the constraint model predictive controller. Furthermore, the multi-objective grey wolf optimization algorithm is introduced to intelligently optimize the parameters of the designed controller. At last, the simulation based on the component level model shows that the high-pressure shaft generator has less influence on the state quantity, including engine thrust, than the low-pressure shaft generator. The proposed control method using the multi-objective gray wolf optimization (MOGWO) algorithm has rapid response and no steady-state error.

Accurate prediction of ocean surface currents is important for marine safety, ship routing, tracking of pollutants and in coupled forecasting. Presently, velocity observations are not routinely assimilated in global ocean forecasting systems, largely due to the sparsity of the observation network. Several satellite missions are now being proposed with the capability to measure Total Surface Current Velocities (TSCV). If successful, these would substantially increase the coverage of ocean current observations and could improve accuracy of ocean current forecasts through data assimilation. In this paper, Observing System Simulation Experiments (OSSEs) are used to assess the impact of assimilating TSCV in the Met Office’s global ocean forecasting system. Synthetic observations are generated from a high-resolution model run for all standard observation types (sea surface temperature, profiles of temperature and salinity, sea level anomaly and sea ice concentration) as well as TSCV observations from a Sea surface KInematics Multiscale monitoring (SKIM) like satellite. The assimilation of SKIM like TSCV observations is tested over an 11 month period. Preliminary experiments assimilating idealised single TSCV observations demonstrate that ageostrophic velocity corrections are not well retained in the model. We propose a method for improving ageostrophic currents through TSCV assimilation by initialising Near Inertial Oscillations with a rotated incremental analysis update (IAU) scheme. The OSSEs show that TSCV assimilation has the potential to significantly improve the prediction of velocities, particularly in the Western Boundary Currents, Antarctic Circumpolar Current and in the near surface equatorial currents. For global surface velocity the analysis root-mean-square-errors (RMSEs) are reduced by 23% and there is a 4-day gain in forecast RMSE. There are some degradations to the subsurface in the tropics, generally in regions with complex vertical salinity structures. However, outside of the tropics, improvements are seen to velocities throughout the water column. Globally there are also improvements to temperature and sea surface height when TSCV are assimilated. The TSCV assimilation largely corrects the geostrophic ocean currents, but results using the rotated IAU method show that the energy at inertial frequencies can be improved with this method. Overall, the experiments demonstrate significant potential benefit of assimilating TSCV observations in a global ocean forecasting system.

Abstract INTRODUCTION Alzheimer's disease (AD) is the predominant dementia globally, with heterogeneous presentation and penetrance of clinical symptoms, variable presence of mixed pathologies, potential disease subtypes, and numerous associated endophenotypes. Beyond the difficulty of designing treatments that address the core pathological characteristics of the disease, therapeutic development is challenged by the uncertainty of which endophenotypic areas and specific targets implicated by those endophenotypes to prioritize for further translational research. However, publicly funded consortia driving large‐scale open science efforts have produced multiple omic analyses that address both disease risk relevance and biological process involvement of genes across the genome. METHODS Here we report the development of an informatic pipeline that draws from genetic association studies, predicted variant impact, and linkage with dementia associated phenotypes to create a genetic risk score. This is paired with a multi‐omic risk score utilizing extensive sets of both transcriptomic and proteomic studies to identify system‐level changes in expression associated with AD. These two elements combined constitute our target risk score that ranks AD risk genome‐wide. The ranked genes are organized into endophenotypic space through the development of 19 biological domains associated with AD in the described genetics and genomics studies and accompanying literature. The biological domains are constructed from exhaustive Gene Ontology (GO) term compilations, allowing automated assignment of genes into objectively defined disease‐associated biology. This rank‐and‐organize approach, performed genome‐wide, allows the characterization of aggregations of AD risk across biological domains. RESULTS The top AD‐risk‐associated biological domains are Synapse, Immune Response, Lipid Metabolism, Mitochondrial Metabolism, Structural Stabilization, and Proteostasis, with slightly lower levels of risk enrichment present within the other 13 biological domains. DISCUSSION This provides an objective methodology to localize risk within specific biological endophenotypes and drill down into the most significantly associated sets of GO terms and annotated genes for potential therapeutic targets.

IntroductionDopamine D3 receptor (D3R) ligands have been studied for the possible treatment of neurological and neuropsychiatric disorders. However, selective D3R radioligands for in vitro binding studies have been challenging to identify due to the high structural similarity between the D2R and D3R. In a prior study, we reported a new conformationally-flexible benzamide scaffold having a high affinity for D3R and excellent selectivity vs. D2R. In the current study, we characterized the in vitro binding properties of a new radioiodinated ligand, [125I]HY-3-24.MethodsIn vitro binding studies were conducted in cell lines expressing D3 receptors, rat striatal homogenates, and rat and non-human primate (NHP) brain tissues to measure regional brain distribution of this radioligand.ResultsHY-3-24 showed high potency at D3R (Ki = 0.67 ± 0.11 nM, IC50 = 1.5 ± 0.58 nM) compared to other D2-like dopamine receptor subtypes (D2R Ki = 86.7 ± 11.9 nM and D4R Ki > 1,000). The Kd (0.34 ± 0.22 nM) and Bmax (38.91 ± 2.39 fmol/mg) values of [125I]HY-3-24 were determined. In vitro binding studies in rat striatal homogenates using selective D2R and D3R antagonists confirmed the D3R selectivity of [125I]HY-3-24. Autoradiography results demonstrated that [125I]HY-3-24 specifically binds to D3Rs in the nucleus accumbens, islands of Calleja, and caudate putamen in rat and NHP brain sections.ConclusionThese results suggest that [125I]HY-3-24 appears to be a novel radioligand that exhibits high affinity binding at D3R, with low binding to other D2-like dopamine receptors. It is anticipated that [125I]HY-3-24 can be used as the specific D3R radioligand.

An enzyme that remodels the cell wall of Enterococcus faecium helps these gut bacteria to divide and generate peptide fragments that enhance the immune response against cancer.