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Abstract Ratios of glycerol dialkyl glycerol tetraethers (GDGT), which are membrane lipids of bacteria and archaea, are at the base of several paleoenvironmental proxies. They are frequently applied to soils as well as lake‐ and marine sediments to generate records of past temperature and soil pH. To derive meaningful environmental information from these reconstructions, high analytical reproducibility is required. Based on submitted results by 39 laboratories from across the world, which employ a diverse range of analytical and quantification methods, we explored the reproducibility of brGDGT‐based proxies (MBT′5ME, IR, and #ringstetra) measured on four soil samples and four soil lipid extracts. Correct identification and integration of 5‐ and 6‐methyl brGDGTs is a prerequisite for the robust calculation of proxy values, but this can be challenging as indicated by the large inter‐interlaboratory variation. The exclusion of statistical outliers improves the reproducibility, where the remaining uncertainty translates into a temperature offset from median proxy values of 0.3–0.9°C and a pH offset of 0.05–0.3. There is no apparent systematic impact of the extraction method and sample preparation steps on the brGDGT ratios. Although reported GDGT concentrations are generally consistent within laboratories, they vary greatly between laboratories. This large variability in brGDGT quantification may relate to variations in ionization efficiency or specific mass spectrometer settings possibly impacting the response of brGDGTs masses relative to that of the internal standard used. While ratio values of GDGT are generally comparable, quantities can currently not be compared between laboratories.

ABSTRACT Mammalian AIM-2-like receptor (ALR) proteins bind nucleic acids and initiate production of type I interferons or inflammasome assembly, thereby contributing to host innate immunity. In mice, the Alr locus is highly polymorphic at the sequence and copy number level, and we show here that it is one of the most dynamic regions of the genome. One rapidly evolving gene within this region, Ifi207, was introduced to the Mus genome by gene conversion or an unequal recombination event a few million years ago. Ifi207 has a large, distinctive repeat region that differs in sequence and length among Mus species and even closely related inbred Mus musculus strains. We show that IFI207 controls murine leukemia virus (MLV) infection in vivo and that it plays a role in the STING-mediated response to cGAMP, dsDNA, DMXXA, and MLV. IFI207 binds to STING, and inclusion of its repeat region appears to stabilize STING protein. The Alr locus and Ifi207 provide a clear example of the evolutionary innovation of gene function, possibly as a result of host–pathogen co-evolution.IMPORTANCEThe Red Queen hypothesis predicts that the arms race between pathogens and the host may accelerate evolution of both sides, and therefore causes higher diversity in virulence factors and immune-related proteins, respectively . The Alr gene family in mice has undergone rapid evolution in the last few million years and includes the creation of two novel members, MndaL and Ifi207. Ifi207, in particular, became highly divergent, with significant genetic changes between highly related inbred mice. IFI207 protein acts in the STING pathway and contributes to anti-retroviral resistance via a novel mechanism. The data show that under the pressure of host–pathogen coevolution in a dynamic locus, gene conversion and recombination between gene family members creates new genes with novel and essential functions that play diverse roles in biological processes.

IntroductionConventional culture conditions, such as in T-flasks, require that oxygen diffuse through the medium to reach the islets; in turn, islet surface area density is limited by oxygen availability. To culture a typical clinical islet preparation may require more than 20 T-175 flasks at the standard surface area density of 200 IE/cm2. To circumvent this logistical constraint, we tested islets cultured on top of silicon gas-permeable (GP) membranes which place islets in close proximity to ambient oxygen.MethodsOxygenation of individual islets under three culture conditions, standard low-density, non-GP high density, and GP high density, were first modeled with finite element simulations. Porcine islets from 30 preparations were cultured for 2 days in devices with GP membrane bottoms or in paired cultures under conventional conditions. Islets were seeded at high density (HD, ∼4000 IE/cm2, as measured by DNA) in both GP and non-GP devices.ResultsIn simulations, individual islets under standard culture conditions and high density cultures on GP membranes were both well oxygenated whereas non-GP high density cultured islets were anoxic. Similarly, compared to the non-GP paired controls, islet viability and recovery were significantly increased in HD GP cultures. The diabetes reversal rate in nude diabetic mice was similar for HD GP devices and standard cultures but was minimal with non-GP HD cultures.DiscussionCulturing islets in GP devices allows for a 20-fold increase of islet surface area density, greatly simplifying the culture process while maintaining islet viability and metabolism.

AimTo determine the efficacy and safety of pharmacogenomics (PGx)-guided antidepressant prescribing in patients with depression through an umbrella review and updated meta-analysis.MethodsA comprehensive systematic search was conducted on PsycINFO, PubMed, Embase and the Cochrane databases. The pooled effect sizes of randomized controlled trials (RCTs) were expressed as mean differences for continuous data and risk ratios for noncontinuous data.ResultsPatients who received PGx-guided medications were 41% to 78% more likely to achieve remission and 20% to 49% more likely to respond to antidepressants than patients receiving treatment-as-usual (TAU).ConclusionPGx-guided antidepressant prescribing improves the treatment of depression. However, the significance and magnitude of the benefit varies widely between studies and different PGx testing panels.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD42022321324.

ObjectiveAging-related changes and caregiver burden may increase the risk for sleep disturbances among older caregivers, yet few studies have examined the prevalence of insomnia and daytime sleepiness in this group. We examined the relationship of caregiver status with insomnia and daytime sleepiness among persons of advanced age (>75 years of age).DesignCross-sectional.SettingCommunity.ParticipantsYale Precipitating Events Project participants (n=383, mean age 84.4 years, 67% female, 12% African American, 25% caregivers).MeasurementsCaregivers were persons who reported caring for another person in the past week or caring for/helping a friend or relative >4 times in the past month. We examined the correlates of caregiver status, including demographic (age, sex, race/ethnicity, education, marital status), psychosocial (living alone, Medicaid eligibility, depressive symptoms, social support, hours volunteered), and physical (obesity, chronic conditions, medication use, self-rated health status, physical activity, functional disability, cognitive impairment) factors. We used the Insomnia Severity Index (ISI) to establish insomnia severity (ISI score 0–28) or clinically significant insomnia symptoms (ISI ≥8). We used the Epworth Sleepiness Scale to establish daytime sleepiness (ESS score 0–24) or hypersomnia (ESS ≥10). In nonparametric multivariable regression analyses, we examined the relationship of caregiver status with insomnia or daytime sleepiness.ResultsCompared to non-caregivers, caregivers were younger, more educated, less likely to be Medicaid eligible and had lower rates of depression, obesity, poor self-rated health, low physical activity, functional disability, and cognitive impairment. Mean ISI and ESS scores were in the normal range and similar among non-caregivers and caregivers (ISI scores of 6.9±5.6 and 6.9±5.4, and ESS scores of 6.4±4.7 and 6.1±4.3, in non-caregivers and caregivers, respectively). Multivariable-adjusted models demonstrated no significant differences in ISI and ESS scores between non-caregivers and caregivers (regression coefficients for ISI and ESS scores of −0.01 [95% CI = −1.58, 1.21] and −0.10 [−1.05, 1.21], respectively).ConclusionWhen compared to older non-caregivers, older caregivers had more advantageous demographic, psychosocial, and physical profiles and had similar levels of insomnia and daytime sleepiness on standardized questionnaires. Future research is needed to elucidate contextual factors (e.g., caregiving intensity and care partner disease) that may increase the risk of sleep disturbances among caregivers of advanced age.

Abstract This work evaluates glacial dust as a source of sediment, and associated iron (Fe), to the Fe‐limited Gulf of Alaska (GoA). A reanalysis of GoA sediment data, using rare earth elements and thorium as provenance tracers, suggests a flux to the ocean surface of Copper River (AK) glacial dust, and associated Fe, that is comparable to the flux of dust from Asia, at least 1,000 km from the narrow mountain valley glacial dust source area. This work suggests dust from Asia may not be the largest source of Fe to the GoA. Dust models fail to accurately simulate this glacial dust transport because their coarse resolution underestimates wind speeds, and the dust flux. This work suggests that glacial dust fluxes may have been important in the geologic past (e.g., the last glacial maximum) from locations where there was more extensive coverage by glaciers than at present.

The importance of mechanical loading and its relationship to orthobiologic therapies in the treatment of post-traumatic osteoarthritis (PTOA) is beginning to receive attention. This review explores the current efficacy of orthobiologic interventions, notably platelet-rich plasma (PRP), bone marrow aspirate (BMA), and mesenchymal stem/stromal cells (MSCs), in combating PTOA drawing from a comprehensive review of both preclinical animal models and human clinical studies. This review suggests why mechanical joint loading, such as running, might improve outcomes in PTOA management in conjunction with orthiobiologic administration. Accumulating evidence underscores the influence of mechanical loading on chondrocyte behavior and its pivotal role in PTOA pathogenesis. Dynamic loading has been identified as a key factor for optimal articular cartilage (AC) health and function, offering the potential to slow down or even reverse PTOA progression. We hypothesize that integrating the activation of mechanotransduction pathways with orthobiologic treatment strategies may hold a key to mitigating or even preventing PTOA development. Specific loading patterns incorporating exercise and physical activity for optimal joint health remain to be defined, particularly in the clinical setting following joint trauma.

Abstract The inflammatory response is a key factor affecting tissue regeneration. Inspired by the immunomodulatory role of spermidine, an injectable double network hydrogel functionalized with spermidine (DN‐SPD) is developed, where the first and second networks are formed by dynamic imine bonds and non‐dynamic photo‐crosslinked bonds respectively. The single network hydrogel before photo‐crosslinking exhibits excellent injectability and thus can be printed and photo‐crosslinked in situ to form double network hydrogels. DN‐SPD hydrogel has demonstrated desirable mechanical properties and tissue adhesion. More importantly, an “operando” comparison of hydrogels loaded with spermidine or diethylenetriamine (DETA), a sham molecule resembling spermidine, has shown similar physical properties, but quite different biological functions. Specifically, the outcomes of 3 sets of in vivo animal experiments demonstrate that DN‐SPD hydrogel can not only reduce inflammation caused by implanted exogenous biomaterials and reactive oxygen species but also promote the polarization of macrophages toward regenerative M2 phenotype, in comparison with DN‐DETA hydrogel. Moreover, the immunoregulation by spermidine can also translate into faster and more natural healing of both acute wounds and diabetic wounds. Hence, the local administration of spermidine affords a simple but elegant approach to attenuate foreign body reactions induced by exogenous biomaterials to treat chronic refractory wounds.

Abstract The balance of processes affecting electron density drives the dynamics of upper‐atmospheric electrical events, such as sprites. We examine the detachment of electrons from negatively charged atomic oxygen (O−) via collisions with neutral molecular nitrogen (N2) leading to the formation of nitrous oxide (N2O). Past research posited that this process, even without significant vibrational excitation of N2, strongly impacts the dynamics of sprites. We introduce updated rate coefficients derived from recent experimental measurements which suggest a negligible influence of this reaction on sprite dynamics. Given that previous rates were incompatible with the observed decay of the light emissions from sprite glows, our findings support that glows actually result from electron depletion in sprite columns.

Traditionally, airborne concentrations of aeroallergens are sampled in a single location by an active sampler, which requires electricity and regular maintenance. However, aeroallergen concentrations may vary widely over urban and rural environments, requiring a method that is cost-effective and scalable so that many measurements can be made across an air shed. We developed such a method that uses passive sampling and light microscopy for analysis. Inexpensive and easy to operate, passive samplers rely on the gravitational settling of particles onto microscope slides. This determines airborne pollen concentration through: 1) sample collection using a modified Durham sampler, 2) preparation of samples for microscopy and strategic sample imaging, and 3) simplified particle measurements and calculation of pollen concentration following deposition velocity models proposed by Scheppegrell [1] and Wagner and Leith [2]. This method was verified with two sampling campaigns during the ragweed season of 2020 and the tree pollen season of 2021. The concentrations determined with the passive and Burkard sampling methods were found to be well-correlated (r > 0.99, r = 0.87) and precise (%CV = 20 %, 21 %). The validation of passive samplers will enable measurements of aeroallergens over wider spatial scales and help determine where aeroallergen exposure risks are greatest. • An inexpensive and low-cost method was developed to determine airborne pollen counts. • The method was evaluated for its accuracy and reproducibility. • The method can be applied to examine the concentrations and spatial variability of airborne pollen.

Summary: Recent studies have implicated a crucial role of Hippo signaling in cell fate determination by biomechanical signals. Here we show that mechanical loading triggers the activation of a Hippo-PKCζ-NFκB pathway in chondrocytes, resulting in the expression of NFκB target genes associated with inflammation and matrix degradation. Mechanistically, mechanical loading activates an atypical PKC, PKCζ, which phosphorylates NFκB p65 at Serine 536, stimulating its transcriptional activation. This mechanosensitive activation of PKCζ and NFκB p65 is impeded in cells with gene deletion or chemical inhibition of Hippo core kinases LATS1/2, signifying an essential role of Hippo signaling in this mechanotransduction. A PKC inhibitor AEB-071 or PKCζ knockdown prevents p65 Serine 536 phosphorylation. Our study uncovers that the interplay of the Hippo signaling, PKCζ, and NFκB in response to mechanical loading serves as a therapeutic target for knee osteoarthritis and other conditions resulting from mechanical overloading or Hippo signaling deficiencies.

Summary: Background: Timing drug administration to endogenous circadian rhythms may enhance treatment efficacy. In the Chronotype sub-study of the Treatment in Morning versus Evening (TIME) clinical trial we examined whether timing of usual antihypertensive medications according to patient chronotype (a behavioural marker of personal circadian rhythm) may influence clinical cardiovascular outcomes. Methods: This was a cohort sub-study of TIME, a prospective, randomised, open-label, blinded-endpoint, UK clinical trial of morning versus evening dosing of usual antihypertensive medications and cardiovascular outcomes. On August 3rd, 2020, all active TIME participants were invited to complete a validated chronotype questionnaire. Chronotype was quantitatively assessed as the mid sleep time on free days corrected for sleep debt on workdays (MSFsc). We analysed associations between chronotype and antihypertensive dosing time and explored their combined effect on cardiovascular outcomes (a composite endpoint of hospitalisation for non-fatal myocardial infarction (MI) or non-fatal stroke, and single components) using proportional hazard time-to-event models adjusted for baseline covariates. These were used to specifically test for interactions between dosing time and chronotype. Findings: Between August 3, 2020, and March 31, 2021, 5358 TIME participants completed the online questionnaire. 2778 were previously randomised to morning dosing and 2580 to evening dosing of their usual antihypertensives. Chronotype was symmetrically distributed around a median MSFsc of 3:07 am. The composite endpoint increased for later MSFsc (later chronotype) dosed in the morning but not in those dosed in the evening (hazard ratios 1.46 [95% CI 1.14–1.86] and 0.96 [95% CI 0.70–1.30] per hour of MSFsc, respectively; interaction p = 0.036). Later chronotype was associated with increased risk of hospitalisation for non-fatal MI in the morning dosing group, and reduced risk in the evening dosing group (hazard ratios 1.62 [95% CI 1.18–2.22] and 0.66 [95% CI 0.44–1.00] per hour of MSFsc, respectively; interaction p

Low sensitivity (LS) to alcohol is a risk factor for alcohol use disorder (AUD). Compared to peers with high sensitivity (HS), LS individuals drink more, report more problems, and exhibit potentiated alcohol cue reactivity (ACR). Heightened ACR suggests LS confers AUD risk via incentive sensitization, which is thought to take place in the mesocorticolimbic system. This study examined neural ACR in LS and HS individuals. Young adults (N = 32, Mage=20.3) were recruited based on the Alcohol Sensitivity Questionnaire (HS: n = 16; LS: n = 16; 9 females/group). Participants completed an event-related fMRI ACR task. Group LS had higher ACR in left ventrolateral prefrontal cortex than group HS. In group LS, ACR in left caudomedial orbitofrontal cortex or left putamen was low at low alcohol use levels and high at heavier or more problematic alcohol use levels, whereas the opposite was true in group HS. Alcohol use level also was associated with the level of ACR in left substantia nigra among males in group LS. Taken together, results suggest elevated mesocorticolimbic ACR among LS individuals, especially those using alcohol at hazardous levels. Future studies with larger samples are warranted to determine the neurobiological loci underlying LS-based amplified ACR and AUD risk.

Abstract. Objectives:. To determine venous thromboembolism (VTE) testing patterns in an orthopaedic trauma population and to evaluate for differences in VTE surveillance by prophylaxis regimen through a secondary analysis of the ADAPT trial. Design:. Prospective randomized trial. Setting:. Level I trauma center. Patients:. Three hundred twenty-nine adult (18 years and older) trauma patients presenting with an operative extremity fracture proximal to the metatarsals/carpals or any pelvic or acetabular fracture requiring VTE prophylaxis. Intervention:. VTE imaging studies recorded within 90 days post injury. Main Outcome Measurements:. Percentage of patients tested for VTE were compared between treatment groups using Fisher's exact test. Subsequently, multivariable regression was used to determine patient factors significantly associated with risk of receiving a VTE imaging study. Results:. Sixty-seven patients (20.4%) had VTE tests ordered during the study period. Twenty (29.9%) of these 67 patients with ordered VTE imaging tests had a positive finding. No difference in proportion of patients tested for VTE by prophylaxis regimen (18.8% on aspirin vs. 22.0% on LMWH, P = 0.50) was observed. Factors associated with increased likelihood of VTE testing included White race (adjusted odds ratio [aOR]: 2.61, 95% CI: 1.26–5.42), increased Injury Severity Score (aOR for every 1-point increase: 1.10, 95% CI: 1.05–1.15), and lower socioeconomic status based on the Area Deprivation Index (aOR for every 10-point increase: 1.14, 95% CI: 1.00–1.30). Conclusions:. VTE surveillance did not significantly differ by prophylaxis regimen. Patient demographic factors including race, injury severity, and socioeconomic status were associated with differences in VTE surveillance. Level of Evidence:. Level I, Therapeutic.

Summary: Background: Marginal zone lymphomas (MZL), comprised of three unique but related subtypes, lack a unifying prognostic score applicable to all the patients in need for systemic chemotherapy and/or immunotherapy. Methods: Patients from the prospective NF10 study (NCT02904577) with newly diagnosed MZL and receiving frontline systemic therapy at diagnosis or after observation were used to train a prognostic model. The primary endpoint was progression-free survival (PFS) from start of treatment. The model was externally validated in a pooled analysis of two independent cohorts from the University of Iowa and Mayo Clinic Molecular Epidemiology Resource and the University of Miami. Findings: We identified 501 eligible patients. After multivariable modeling, lactate dehydrogenase (LDH) above upper normal limit, hemoglobin

Exposure to ultraviolet (UV) radiation from the sun has both harms and benefits for human health. The best-known benefit of sun exposure is the generation of vitamin D within the skin and the best-known harm is malignant skin cancer. Australia and New Zealand have very high ambient UV radiation, resulting in high rates of skin cancer incidence and mortality, yet there is an appreciable prevalence of vitamin D deficiency (defined as blood 25-hydroxyvitamin D (25(OH)D) < 50 nmol/L) in both populations. The purpose of this study was to create a microsimulation model to replicate population 25(OH)D concentrations of people living in Australia and New Zealand, thus enabling the effect of different population-wide interventions to be estimated. We used large population datasets containing data on sun behaviours and socio-demographic variables, and environmental data on UV radiation, ozone, and solar zenith angle. Latitude, weather and time of day were accounted for. We simulated the conversion of daily UV radiation to a standard vitamin D dose (SDD) (100 J/m2 vitamin D-weighted UV) and monthly accumulation of SDD to 25(OH)D concentration. The model was calibrated to match the seasonal prevalence of vitamin D deficiency. This report describes the Sun Exposure (SUNEX) microsimulation model, its development, data inputs and calibration against population prevalence of vitamin D deficiency.

Abstract AKS-452, a subunit vaccine comprising an Fc fusion of the ancestral wild-type (WT) SARS-CoV-2 virus spike protein receptor binding domain (SP/RBD), was evaluated without adjuvant in a single cohort, non-randomized, open-labelled phase II study (NCT05124483) at a single site in The Netherlands for safety and immunogenicity. A single 90 µg subcutaneous booster dose of AKS-452 was administered to 71 adults previously primed with a registered mRNA- or adenovirus-based vaccine and evaluated for 273 days. All AEs were mild and no SAEs were attributable to AKS-452. While all subjects showed pre-existing SP/RBD binding and ACE2-inhibitory IgG titers, 60–68% responded to AKS-452 via ≥2-fold increase from days 28 to 90 and progressively decreased back to baseline by day 180 (days 28 and 90 mean fold-increases, 14.7 ± 6.3 and 8.0 ± 2.2). Similar response kinetics against RBD mutant proteins (including omicrons) were observed but with slightly reduced titers relative to WT. There was an expected strong inverse correlation between day-0 titers and the fold-increase in titers at day 28. AKS-452 enhanced neutralization potency against live virus, consistent with IgG titers. Nucleocapsid protein (Np) titers suggested infection occurred in 66% (46 of 70) of subjects, in which only 20 reported mild symptomatic COVID-19. These favorable safety and immunogenicity profiles support booster evaluation in a planned phase III universal booster study of this room-temperature stable vaccine that can be rapidly and inexpensively manufactured to serve vaccination at a global scale without the need of a complex distribution or cold chain.

Abstract Primary human trophoblast stem cells (TSCs) and TSCs derived from human pluripotent stem cells (hPSCs) can potentially model placental processes in vitro. Yet, the pluripotent states and factors involved in the differentiation of hPSCs to TSCs remain poorly understood. In this study, we demonstrate that the primed pluripotent state can generate TSCs by activating pathways such as Epidermal Growth Factor (EGF) and Wingless-related integration site (WNT), and by suppressing tumor growth factor beta (TGFβ), histone deacetylases (HDAC), and Rho-associated protein kinase (ROCK) signaling pathways, all without the addition of exogenous Bone morphogenetic protein 4 (BMP4)—a condition we refer to as the TS condition. We characterized this process using temporal single-cell RNA sequencing to compare TS conditions with differentiation protocols involving BMP4 activation alone or BMP4 activation in conjunction with WNT inhibition. The TS condition consistently produced a stable, proliferative cell type that closely mimics first-trimester placental cytotrophoblasts, marked by the activation of endogenous retroviral genes and the absence of amnion expression. This was observed across multiple cell lines, including various primed induced pluripotent stem cell (iPSC) and embryonic stem cell (ESC) lines. Primed-derived TSCs can proliferate for over 30 passages and further specify into multinucleated syncytiotrophoblasts and extravillous trophoblast cells. Our research establishes that the differentiation of primed hPSCs to TSC under TS conditions triggers the induction of TMSB4X, BMP5/7, GATA3, and TFAP2A without progressing through a naive state. These findings propose that the primed hPSC state is part of a continuum of potency with the capacity to differentiate into TSCs through multiple routes.

Abstract The fatal motor neuron (MN) disease Amyotrophic Lateral Sclerosis (ALS) is characterized by progressive MN degeneration. Phrenic MNs (phMNs) controlling the activity of the diaphragm are prone to degeneration in ALS, leading to death by respiratory failure. Understanding of the mechanisms of phMN degeneration in ALS is limited, mainly because human experimental models to study phMNs are lacking. Here we describe a method enabling the derivation of phrenic-like MNs from human iPSCs (hiPSC-phMNs) within 30 days. This protocol uses an optimized combination of small molecules followed by cell-sorting based on a cell-surface protein enriched in hiPSC-phMNs, and is highly reproducible using several hiPSC lines. We show further that hiPSC-phMNs harbouring ALS-associated amplification of the C9orf72 gene progressively lose their electrophysiological activity and undergo increased death compared to isogenic controls. These studies establish a previously unavailable protocol to generate human phMNs offering a disease-relevant system to study mechanisms of respiratory MN dysfunction.

Abstract Objectives The aim of this study is to evaluate the impact of radiologist and urologist variability on detection of prostate cancer (PCa) and clinically significant prostate cancer (csPCa) with magnetic resonance imaging (MRI)‐transrectal ultrasound (TRUS) fusion prostate biopsies. Patients and methods The Prospective Loyola University MRI (PLUM) Prostate Biopsy Cohort (January 2015 to December 2020) was used to identify men receiving their first MRI and MRI/TRUS fusion biopsy for suspected PCa. Clinical, MRI and biopsy data were stratified by radiologist and urologist to evaluate variation in Prostate Imaging‐Reporting and Data System (PI‐RADS) grading, lesion number and cancer detection. Multivariable logistic regression (MVR) models and area under the curve (AUC) comparisons assessed the relative impact of individual radiologists and urologists. Results A total of 865 patients (469 biopsy‐naïve) were included across 5 urologists and 10 radiologists. Radiologists varied with grading 15.4% to 44.8% of patients with MRI lesions as PI‐RADS 3. PCa detection varied significantly by radiologist, from 34.5% to 66.7% (p = 0.003) for PCa and 17.2% to 50% (p = 0.001) for csPCa. Urologists' PCa diagnosis rates varied between 29.2% and 55.8% (p = 0.013) and between 24.6% and 39.8% (p = 0.36) for csPCa. After adjustment for case‐mix on MVR, a fourfold to fivefold difference in PCa detection was observed between the highest‐performing and lowest‐performing radiologist (OR 0.22, 95%CI 0.10–0.47, p

This paper introduces a lightweight bilateral underactuated upper limb exoskeleton (UULE) designed to assist chronic stroke patients with distal joint (Elbow-Wrist) impairments during bimanual activities of daily living (ADL). The UULE aims to assist patients in shoulder flexion/extension, elbow flexion/extension, forearm pronation/supination, and wrist flexion/extension. Notable features include (i) a cable-driven mechanism maintaining a lightweight structure (1.783 kg); (ii) passive joints conforming to less-impaired proximal joints, reducing restrictions on their movements; (iii) a compact design with passive ball joints enabling bilateral configuration for scapula protraction/retraction; and (iv) implementation of the master-slave joint assistance training strategy in an underactuated exoskeleton, achieving symmetric robot joint motion in bimanual ADL. Experiments with ten healthy subjects demonstrated the UULE’s effectiveness by revealing significant reductions in muscle activity in a symmetric bimanual ADL task. These advancements address critical limitations of current exoskeletons, showcasing the UULE as a promising contribution to lightweight and effective robotic rehabilitation strategies for chronic stroke patients.

Abstract While microplastics have been recently detected in human blood and the placenta, their impact on human health is not well understood. Using a mouse model of environmental exposure during pregnancy, our group has previously reported that exposure to polystyrene micro- and nanoplastics throughout gestation results in fetal growth restriction. While polystyrene is environmentally relevant, polyethylene is the most widely produced plastic and amongst the most commonly detected microplastic in drinking water and human blood. In this study, we investigated the effect of maternal exposure to polyethylene micro- and nanoplastics on fetal growth and placental function. Healthy, pregnant CD-1 dams were divided into three groups: 106 ng/L of 740–4990 nm polyethylene with surfactant in drinking water (n = 12), surfactant alone in drinking water (n = 12) or regular filtered drinking water (n = 11). At embryonic day 17.5, high-frequency ultrasound was used to investigate the placental and fetal hemodynamic responses following exposure. While maternal exposure to polyethylene did not impact fetal growth, there was a significant effect on placental function with a 43% increase in umbilical artery blood flow in the polyethylene group compared to controls (p

Abstract Crowdsourcing has been used in computational pathology to generate cell and cell nuclei annotations for machine learning. Herein, we broaden its scope to the previously unsolved challenging task of glioma cell detection. This requires multiplexed immunofluorescence microscopy due to diffuse invasiveness and exceptional similarity between glioma cells and reactive astrocytes. In four pilot experiments, we iteratively developed a task design enabling high-quality annotations by crowdworkers on Amazon Mechanical Turk. We applied majority or weighted vote and validated them against ground truth in the final setting. On the base of a YOLO convolutional neural network architecture, we used these consensus labels for training with different image representations regarding colors, intensities, and immmunohistochemical marker combinations. A crowd of 712 workers defined aggregated point annotations in 235 images with an average $$F_1$$ F 1 score of 0.627 for majority vote. The networks resulted in acceptable $$F_1$$ F 1 scores up to 0.69 for YOLOv8 on average and indicated first evidence for transferability to images lacking tumor markers, especially in IDH-wildtype glioblastoma. Our work confirms feasibility of crowdsourcing to generate labels suitable for training of machine learning tools in the challenging and clinically relevant use case of glioma microenvironment.

Abstract Background Although age is the biggest known risk factor for dementia, there remains uncertainty about other factors over the life course that contribute to a person’s risk for cognitive decline later in life. Furthermore, the pathological processes leading to dementia are not fully understood. The main goals of Insight 46—a multi-phase longitudinal observational study—are to collect detailed cognitive, neurological, physical, cardiovascular, and sensory data; to combine those data with genetic and life-course information collected from the MRC National Survey of Health and Development (NSHD; 1946 British birth cohort); and thereby contribute to a better understanding of healthy ageing and dementia. Methods/Design Phase 1 of Insight 46 (2015–2018) involved the recruitment of 502 members of the NSHD (median age = 70.7 years; 49% female) and has been described in detail by Lane and Parker et al. 2017. The present paper describes phase 2 (2018–2021) and phase 3 (2021–ongoing). Of the 502 phase 1 study members who were invited to a phase 2 research visit, 413 were willing to return for a clinic visit in London and 29 participated in a remote research assessment due to COVID-19 restrictions. Phase 3 aims to recruit 250 study members who previously participated in both phases 1 and 2 of Insight 46 (providing a third data time point) and 500 additional members of the NSHD who have not previously participated in Insight 46. Discussion The NSHD is the oldest and longest continuously running British birth cohort. Members of the NSHD are now at a critical point in their lives for us to investigate successful ageing and key age-related brain morbidities. Data collected from Insight 46 have the potential to greatly contribute to and impact the field of healthy ageing and dementia by combining unique life course data with longitudinal multiparametric clinical, imaging, and biomarker measurements. Further protocol enhancements are planned, including in-home sleep measurements and the engagement of participants through remote online cognitive testing. Data collected are and will continue to be made available to the scientific community.

This paper addresses the challenges in existing upper limb robotic rehabilitation training for asymmetric bimanual activities of daily living (ADL), crucial for stroke patients’ ADL-related functional recovery. Our proposed exoskeleton control framework introduces independent joint control and visual guidance in virtual reality (VR) to facilitate asymmetric bimanual ADL training. Unlike conventional task-space control methods, our approach implements independent joint control into underactuated exoskeletons, offering individualized assistance tailored to patients’ joint impairment conditions. The framework utilizes human-demonstrated ADL motions for joint trajectory planning, potentially teaching compensatory techniques with unique joint coordination patterns through therapist demonstrations. To address interjoint coordination challenges in underactuated exoskeletons, VR visual guidance aids patients in self-coordinating unassisted and assisted joints. The proposed framework was evaluated by human experiments with 15 healthy subjects. It demonstrated the effectiveness of the proposed visual guidance, exhibiting a motion period similar to human-demonstrated motion and statistically significant reductions in angle errors at the shoulder (sF/E-A) and wrist (wF/E-A). The robot assistance provided by the control framework was further validated through statistically significant reductions in electromyography (EMG) and angle errors at robot-assisted joints. This proof-of-concept on healthy subjects suggests the potential of our control framework to assist stroke patients in asymmetric bimanual ADL training.

Abstract Background We aimed to explore the three-way interaction among age, gender, and kidney function on the risk of all-cause mortality and cardiovascular mortality among patients with type 2 diabetes (T2D). Methods In a retrospective cohort study, patients aged > 40 years with T2D with serum creatinine and urine albumin measured from 2013 to 2019 were included from a multi-institutional diabetes registry. The exposure was estimated glomerular filtration rate (eGFR), outcomes were all-cause mortality (primary outcome) and cardiovascular disease (CVD) mortality (secondary outcome). We applied multivariable cox proportional hazards regression analysis to compute the association between eGFR and mortality. Results A total of 36,556 patients were followed for up to 6 years during which 2492 (6.82%) died from all causes, and 690 (1.9%) died from CVD. We observed a significant three-way interaction (p = 0.021) among age (younger,

Abstract American football has become the focus of numerous studies highlighting a growing concern that cumulative exposure to repetitive, sports-related head acceleration events (HAEs) may have negative consequences for brain health, even in the absence of a diagnosed concussion. In this longitudinal study, brain functional connectivity was analyzed in a cohort of high school American football athletes over a single play season and compared against participants in non-collision high school sports. Football athletes underwent four resting-state functional magnetic resonance imaging sessions: once before (pre-season), twice during (in-season), and once 34–80 days after the contact activities play season ended (post-season). For each imaging session, functional connectomes (FCs) were computed for each athlete and compared across sessions using a metric reflecting the (self) similarity between two FCs. HAEs were monitored during all practices and games throughout the season using head-mounted sensors. Relative to the pre-season scan session, football athletes exhibited decreased FC self-similarity at the later in-season session, with apparent recovery of self-similarity by the time of the post-season session. In addition, both within and post-season self-similarity was correlated with cumulative exposure to head acceleration events. These results suggest that repetitive exposure to HAEs produces alterations in functional brain connectivity and highlight the necessity of collision-free recovery periods for football athletes.

Abstract Background Dexamethasone is routinely administered to horses but its effect on the antibody response to a commercial EIV/EHV vaccine is unclear. Hypothesis Horses receiving dexamethasone will have lower postvaccination antibody levels against EIV and EHV‐1 than vaccinated controls. Animals Fifty‐five healthy adult research horses. Methods Randomized cohort study. Control (no vaccine, group 1), vaccination only (EIV/EHV‐1/EHV‐4, Prestige 2, Merck Animal Health, group 2), vaccination and concurrent single intravenous dose of dexamethasone (approximately .05 mg/kg, group 3), vaccination and 3 intravenous doses of dexamethasone at 24 hours intervals (group 4). Serum SAA levels were measured on day 1 and day 3. Antibody levels against EIV (hemagglutination inhibition assay, Kentucky 2014 antigen) and EHV‐1 (multiplex ELISA targeting total IgG and IgG 4/7) were measured on day 1 and day 30. Results Significantly increased mean antibody titers after vaccination were only noted against EIV and only after the vaccination alone (n = 14, prevaccine mean [prvm] 166.9, SD 259.6, 95% CI 16.95‐316.8; postvaccine mean [povm] 249.1, SD 257.2, 95% confidence interval [CI] 100.6‐397.6, P = .02) and the single dose dexamethasone (n = 14, prvm 93.14, SD 72.2, CI 51.45‐134.8; povm 185.1, SD 118, CI 116.7‐253.6, P = .01), but not after multiple doses of dexamethasone (n = 14, prvm 194.3, SD 258.3, CI 45.16‐343.4; povm 240.0, SD 235.7, CI 103.9‐376.1, P > .05). Conclusion The effect of dexamethasone on the postvaccine antibody response varies depending on the dosing frequency and the antigen‐specific antibody type.

Abstract Background Post-hospitalization remote patient monitoring (RPM) has potential to improve health outcomes for high-risk patients with chronic medical conditions. The purpose of this study is to determine the extent to which RPM for patients with congestive heart failure (CHF) and chronic obstructive pulmonary disease (COPD) is associated with reductions in post-hospitalization mortality, hospital readmission, and ED visits within an Accountable Care Organization (ACO). Methods Nonrandomized prospective study of patients in an ACO offered enrollment in RPM upon hospital discharge between February 2021 and December 2021. RPM comprised of vital sign monitoring equipment (blood pressure monitor, scale, pulse oximeter), tablet device with symptom tracking software and educational material, and nurse-provided oversight and triage. Expected enrollment was for at least 30-days of monitoring, and outcomes were followed for 6 months following enrollment. The co-primary outcomes were (a) the composite of death, hospital admission, or emergency care visit within 180 days of eligibility, and (b) time to occurrence of this composite. Secondary outcomes were each component individually, the composite of death or hospital admission, and outpatient office visits. Adjusted analyses involved doubly robust estimation to address confounding by indication. Results Of 361 patients offered remote monitoring (251 with CHF and 110 with COPD), 140 elected to enroll (106 with CHF and 34 with COPD). The median duration of RPM-enrollment was 54 days (IQR 34–85). Neither the 6-month frequency of the co-primary composite outcome (59% vs 66%, FDR p-value = 0.47) nor the time to this composite (median 29 vs 38 days, FDR p-value = 0.60) differed between the groups, but 6-month mortality was lower in the RPM group (6.4% vs 17%, FDR p-value = 0.02). After adjustment for confounders, RPM enrollment was associated with nonsignificantly decreased odds for the composite outcome (adjusted OR [aOR] 0.68, 99% CI 0.25–1.34, FDR p-value 0.30) and lower 6-month mortality (aOR 0.41, 99% CI 0.00–0.86, FDR p-value 0.20). Conclusions RPM enrollment may be associated with improved health outcomes, including 6-month mortality, for selected patient populations.

Abstract Five essential oils (EOs) were previously characterized in vitro and identified as candidate EOs for the development of an intranasal EO spray to mitigate bovine respiratory disease (BRD) pathogens. In the present study, these EOs were evaluated for their potential to (i) reduce BRD pathogens, (ii) modulate nasopharyngeal microbiota, and (iii) influence animal performance, feeding behavior and immune response when a single dose administered intranasally to feedlot cattle. Forty beef steer calves (7–8 months old, Initial body weight = 284 ± 5 kg [SE]) received either an intranasal EO spray (ajowan, thyme, fennel, cinnamon leaf, and citronella) or PBS (Control; n = 20/group) on day 0. Deep nasopharyngeal swabs were collected on days (d) -1, 1, 2, 7, 14, 28, and 42 and processed for 16S rRNA gene sequencing, qPCR, and culturing. Significant effects of EO on community structure (d1), microbial richness and diversity, relative abundance of some dominant phyla (d1, d2, and d14), and the overall interaction network structure of the nasopharyngeal microbiota were detected. The relative abundance of Mannheimia was lower in the EO calves (4.34%) than in Control calves (10.4%) on d2, and M. haemolytica prevalence on d7 as compared to control calves. Feed intake, average daily gain, feeding behavior, and blood cell counts were not affected by EO treatment. Overall, a single intranasal dose of EO spray resulted in moderate modulation of nasopharyngeal microbiota and short-term inhibition of Mannheimia while not influencing animal performance, feeding behavior or immune response. Our study, for the first time, shows the potential use of intranasal EO to mitigate BRD in feedlot cattle.

Abstract We measure the trajectories of macroscopic magnetic particles pulled against gravity between twisted alternating magnetic square patterns in a superposed homogeneous magnetic field normal to both patterns. The two patterns are built from a set of magentic cubes having a distribution of magnetization. The magnetic potential between the patterns is a sum of three contributions: two being periodic on two lattices with different magnitude and orientation, and the third random contribution arising from the distribution of magnetization of the cubes. As one varies the twist angle between the two patterns each time the twist angle coincides with a magic twist angle one of the two periodic lattices becomes a sublattice of the other lattice. Simulations of particles moving through patterns with a precise cube magnetization produce pronounced mobility peaks near magic twist angles that are associated with flat channels. Weak random fluctuations of the cube magnetization in the experiment and the simulations cause enhanced random disorder of the potential and reduce the mobility by scattering particles into the interior of the twisted Wigner Seitz cells. The mobility undergoes an Anderson transition from magic to generic behavior as the magnetization disorder increases beyond half of a percent of the cube magnetization.

Abstract Background Cardiac repair and remodeling following myocardial infarction (MI) is a multifactorial process involving pro-reparative inflammation, angiogenesis and fibrosis. Noninvasive imaging using a radiotracer targeting these processes could be used to elucidate cardiac wound healing mechanisms. The alpha7 nicotinic acetylcholine receptor (ɑ7nAChR) stimulates pro-reparative macrophage activity and angiogenesis, making it a potential imaging biomarker in this context. We investigated this by assessing in vitro cellular expression of ɑ7nAChR, and by using a tritiated version of the PET radiotracer [18F]NS14490 in tissue autoradiography studies. Results ɑ7nAChR expression in human monocyte-derived macrophages and vascular cells showed the highest relative expression was within macrophages, but only endothelial cells exhibited a proliferation and hypoxia-driven increase in expression. Using a mouse model of inflammatory angiogenesis following sponge implantation, specific binding of [3H]NS14490 increased from 3.6 ± 0.2 µCi/g at day 3 post-implantation to 4.9 ± 0.2 µCi/g at day 7 (n = 4, P

Abstract The ventromedial prefrontal cortex (vmPFC; rodent infralimbic cortex (IL)), is posited to be an important locus of fear extinction-facilitating effects of the dopamine (DA) bio-precursor, L-DOPA, but this hypothesis remains to be formally tested. Here, in a model of impaired fear extinction (the 129S1/SvImJ inbred mouse strain; S1), we monitored extracellular DA dynamics via in vivo microdialysis in IL during fear extinction and following L-DOPA administration. Systemic L-DOPA caused sustained elevation of extracellular DA levels in IL and increased neuronal activation in a subpopulation of IL neurons. Systemic L-DOPA enabled extinction learning and promoted extinction retention at one but not ten days after training. Conversely, direct microinfusion of DA into IL produced long-term fear extinction (an effect that was insensitive to ɑ-/ß-adrenoreceptor antagonism). However, intra-IL delivery of a D1-like or D2 receptor agonist did not facilitate extinction. Using ex vivo multi-electrode array IL neuronal recordings, along with ex vivo quantification of immediate early genes and DA receptor signalling markers in mPFC, we found evidence of reduced DA-evoked mPFC network responses in S1 as compared with extinction-competent C57BL/6J mice that were partially driven by D1 receptor activation. Together, our data demonstrate that locally increasing DA in IL is sufficient to produce lasting rescue of impaired extinction. The finding that systemic L-DOPA increased IL DA levels, but had only transient effects on extinction, suggests L-DOPA failed to reach a threshold level of IL DA or produced opposing behavioural effects in other brain regions. Collectively, our findings provide further insight into the neural basis of the extinction-promoting effects of DA and L-DOPA in a clinically relevant animal model, with possible implications for therapeutically targeting the DA system in anxiety and trauma-related disorders.

Abstract Structured patient data play a key role in all types of clinical research. They are often collected in study databases for research purposes. In order to describe characteristics of a next-generation study database and assess the feasibility of its implementation a proof-of-concept study in a German university hospital was performed. Key characteristics identified include FAIR access to electronic case report forms (eCRF), regulatory compliant Electronic Data Capture (EDC), an EDC with electronic health record (EHR) integration, scalable EDC for medical documentation, patient generated data, and clinical decision support. In a local case study, we then successfully implemented a next-generation study database for 19 EDC systems (n = 2217 patients) that linked to i.s.h.med (Oracle Cerner) with the local EDC system called OpenEDC. Desiderata of next-generation study databases for patient data were identified from ongoing local clinical study projects in 11 clinical departments at Heidelberg University Hospital, Germany, a major tertiary referral hospital. We compiled and analyzed feature and functionality requests submitted to the OpenEDC team between May 2021 and July 2023. Next-generation study databases are technically and clinically feasible. Further research is needed to evaluate if our approach is feasible in a multi-center setting as well.

Official protection of an exploited species sometimes precedes any quantitative understanding of its use, including any dependence of local residents on it for food and livelihood. Conservation initiatives could suffer without this information. The Goliath frog Conraua goliath is iconic globally because of its large size, and is categorized as Endangered on the IUCN Red List. The main threat to this species in Cameroon is overexploitation, but any associated socio-economic aspects of this have not been quantified. We provide insights into local perceptions of the Goliath frog and its consumption through structured interviews with 223 people living alongside this species. The Goliath frog is well known and hunted both for home consumption and the wild meat trade. We trailed seven collaborative Cameroonian Goliath frog hunters over two seasons to determine offtake. A total of 192 Goliath frogs were collected by these hunters, peaking in March. The hunters used nets, shotguns and spears. Their catch was eaten at home or sold fresh within the community or to travellers for XAF 1,500–5,000 (USD 3–10) each. We also studied the Goliath frog trade by examining the databases of the Cameroonian Ministry of Forestry and Wildlife, and CITES. CITES and hunters reported large exports of Goliath frogs but no trade was documented by the Ministry of Forestry and Wildlife. To support conservation planning, this study provides preliminary quantitative information on the extent of the threat of hunting to this Endangered frog.

Abstract Background We developed models for tumor segmentation to automate the assessment of total tumor volume (TTV) in patients with colorectal liver metastases (CRLM). Methods In this prospective cohort study, pre- and post-systemic treatment computed tomography (CT) scans of 259 patients with initially unresectable CRLM of the CAIRO5 trial (NCT02162563) were included. In total, 595 CT scans comprising 8,959 CRLM were divided into training (73%), validation (6.5%), and test sets (21%). Deep learning models were trained with ground truth segmentations of the liver and CRLM. TTV was calculated based on the CRLM segmentations. An external validation cohort was included, comprising 72 preoperative CT scans of patients with 112 resectable CRLM. Image segmentation evaluation metrics and intraclass correlation coefficient (ICC) were calculated. Results In the test set (122 CT scans), the autosegmentation models showed a global Dice similarity coefficient (DSC) of 0.96 (liver) and 0.86 (CRLM). The corresponding median per-case DSC was 0.96 (interquartile range [IQR] 0.95–0.96) and 0.80 (IQR 0.67–0.87). For tumor segmentation, the intersection-over-union, precision, and recall were 0.75, 0.89, and 0.84, respectively. An excellent agreement was observed between the reference and automatically computed TTV for the test set (ICC 0.98) and external validation cohort (ICC 0.98). In the external validation, the global DSC was 0.82 and the median per-case DSC was 0.60 (IQR 0.29–0.76) for tumor segmentation. Conclusions Deep learning autosegmentation models were able to segment the liver and CRLM automatically and accurately in patients with initially unresectable CRLM, enabling automatic TTV assessment in such patients. Relevance statement Automatic segmentation enables the assessment of total tumor volume in patients with colorectal liver metastases, with a high potential of decreasing radiologist’s workload and increasing accuracy and consistency. Key points • Tumor response evaluation is time-consuming, manually performed, and ignores total tumor volume. • Automatic models can accurately segment tumors in patients with colorectal liver metastases. • Total tumor volume can be accurately calculated based on automatic segmentations. Graphical Abstract

Abstract Machine learning (ML) has increasingly been used to assist and expand current practices in neuropathology. However, generating large imaging datasets with quality labels is challenging in fields which demand high levels of expertise. Further complicating matters is the often seen disagreement between experts in neuropathology-related tasks, both at the case level and at a more granular level. Neurofibrillary tangles (NFTs) are a hallmark pathological feature of Alzheimer disease, and are associated with disease progression which warrants further investigation and granular quantification at a scale not currently accessible in routine human assessment. In this work, we first provide a baseline of annotator/rater agreement for the tasks of Braak NFT staging between experts and NFT detection using both experts and novices in neuropathology. We use a whole-slide-image (WSI) cohort of neuropathology cases from Emory University Hospital immunohistochemically stained for Tau. We develop a workflow for gathering annotations of the early stage formation of NFTs (Pre-NFTs) and mature intracellular (iNFTs) and show ML models can be trained to learn annotator nuances for the task of NFT detection in WSIs. We utilize a model-assisted-labeling approach and demonstrate ML models can be used to aid in labeling large datasets efficiently. We also show these models can be used to extract case-level features, which predict Braak NFT stages comparable to expert human raters, and do so at scale. This study provides a generalizable workflow for various pathology and related fields, and also provides a technique for accomplishing a high-level neuropathology task with limited human annotations.

Abstract We report the case of a 79-year-old woman with Alzheimer’s disease who participated in a Phase III randomized controlled trial called CLARITY-AD testing the experimental drug lecanemab. She was randomized to the placebo group and subsequently enrolled in an open-label extension which guaranteed she received the active drug. After the third biweekly infusion, she suffered a seizure characterized by speech arrest and a generalized convulsion. Magnetic resonance imaging revealed she had multifocal swelling and a marked increase in the number of cerebral microhemorrhages. She was treated with an antiepileptic regimen and high-dose intravenous corticosteroids but continued to worsen and died after 5 days. Post-mortem MRI confirmed extensive microhemorrhages in the temporal, parietal and occipital lobes. The autopsy confirmed the presence of two copies of APOE4, a gene associated with a higher risk of Alzheimer’s disease, and neuropathological features of moderate severity Alzheimer’s disease and severe cerebral amyloid angiopathy with perivascular lymphocytic infiltrates, reactive macrophages and fibrinoid degeneration of vessel walls. There were deposits of β-amyloid in meningeal vessels and penetrating arterioles with numerous microaneurysms. We conclude that the patient likely died as a result of severe cerebral amyloid-related inflammation.

Abstract Background Red blood cell (RBC) transfusion is a critical supportive therapy in cardiovascular surgery (CVS). Donor selection and testing have reduced the risk of transfusion-transmitted infections; however, risks remain from bacteria, emerging viruses, pathogens for which testing is not performed and from residual donor leukocytes. Amustaline (S-303)/glutathione (GSH) treatment pathogen reduction technology is designed to inactivate a broad spectrum of infectious agents and leukocytes in RBC concentrates. The ReCePI study is a Phase 3 clinical trial designed to evaluate the efficacy and safety of pathogen-reduced RBCs transfused for acute anemia in CVS compared to conventional RBCs, and to assess the clinical significance of treatment-emergent RBC antibodies. Methods ReCePI is a prospective, multicenter, randomized, double-blinded, active-controlled, parallel-design, non-inferiority study. Eligible subjects will be randomized up to 7 days before surgery to receive either leukoreduced Test (pathogen reduced) or Control (conventional) RBCs from surgery up to day 7 post-surgery. The primary efficacy endpoint is the proportion of patients transfused with at least one study transfusion with an acute kidney injury (AKI) diagnosis defined as any increased serum creatinine (sCr) level ≥ 0.3 mg/dL (or 26.5 µmol/L) from pre-surgery baseline within 48 ± 4 h of the end of surgery. The primary safety endpoints are the proportion of patients with any treatment-emergent adverse events (TEAEs) related to study RBC transfusion through 28 days, and the proportion of patients with treatment-emergent antibodies with confirmed specificity to pathogen-reduced RBCs through 75 days after the last study transfusion. With ≥ 292 evaluable, transfused patients (> 146 per arm), the study has 80% power to demonstrate non-inferiority, defined as a Test group AKI incidence increase of no more than 50% of the Control group rate, assuming a Control incidence of 30%. Discussion RBCs are transfused to prevent tissue hypoxia caused by surgery-induced bleeding and anemia. AKI is a sensitive indicator of renal hypoxia and a novel endpoint for assessing RBC efficacy. The ReCePI study is intended to demonstrate the non-inferiority of pathogen-reduced RBCs to conventional RBCs in the support of renal tissue oxygenation due to acute anemia and to characterize the incidence of treatment-related antibodies to RBCs.

Abstract Background The role of ACTA2 mutations in Familial Aortic Disease has been increasingly recognized. We describe a highly penetrant variant (R118Q) in a family with aortic disease. Case report A patient presented to us for elective repair of an ascending aortic aneurysm with a family history of his mother expiring after aortic dissection. Genetic testing revealed he was a heterozygous carrier of the ACTA2 missense mutation R118Q. Subsequently, all living family members were tested for this variant and a full medical history was obtained to compile a family tree for the variant and penetrance of an aortic event (defined as lifetime occurrence of aortic surgery / dissection). In total 9 family members were identified and underwent genetic testing with 7/9 showing presence of the ACTA2 R118Q mutation or an aortic event. All patients over the age of 50 (n = 4) had an aortic event. Those events occurred at ages 54, 55, 60, and 62 (mean event at 57.8 ± 3.9 years). Three family members with the variant under the age of 40 have not had an aortic event and most are undergoing regular aortic surveillance via CT scan. Conclusions Existing studies of known ACTA2 mutations describe a 76% aortic event rate by 85 years old. The R118Q missense mutation is a less common ACTA2 variant, estimated to be found in about 5% of patients with known mutations. Prior studies have predicted the R118Q mutation to have a slightly decreased risk of aortic events compared to other ACTA2 mutations. In this family, however, we demonstrate 100% penetrance of aortic disease above age 50. In today’s era of excellent outcomes in elective aortic surgery, our team aggressively offers elective repair. We advocate for strict aortic surveillance for patients with this variant and would consider elective aortic replacement at 4.5 cm, or at an even smaller diameter in patients with a strong family history of dissection who are identified with this mutation.

1- and 2-Propargyl-tetrazole (1- and 2-PryTz) were synthesized by reaction of propargyl bromide with sodium tetrazolate and used as ligands in energetic coordination compounds (ECCs) and evaluated concerning their thermal and mechanical sensitivities. Furthermore, the two nitrogen-rich compounds 1-((1H-1,2,3-triazol-4-yl)methyl)-1H-tetrazole (TriMT, 3) and 1-((1-(2-(1H-tetrazol-1-yl)ethyl)-1H-1,2,3-triazol-4-yl)methyl)-1H-tetrazole (TriMTET, 4) were prepared. Both were characterized by IR spectroscopy, NMR measurements, and low-temperature X-Ray diffraction analysis. Due to the highly endothermic enthalpy of formation of the propargyl-tetrazole ligands, powerful, yet relatively safe to handle, laser-ignitable ECCs were obtained.

While the oxidative chemistry of transition metals such as iron and copper is a highly developed area of investigation, the study of similar chemistry with nickel is much younger. However, nickel offers rich coordination chemistry with oxygen and other oxidants and is a promising avenue of research for applications such as sustainable hydrocarbon functionalization. Herein, we summarize the progress made recently in nickel coordination chemistry relevant to hydrocarbon functionalization and offer our perspectives on open questions in the field.

Obligate anaerobic beer spoilage bacteria have been a menace to the brewing industry for several decades. Technological advances in the brewing process aimed at suppressing aerobic spoilers gave rise to problems with obligate anaerobes. In previous studies, the metabolic spectrum of Pectinatus and Megasphaera species has been described, but their metabolism in the beer environment remains largely unknown. We used high-performance anion exchange chromatography with pulsed amperometric detection (HPAEC-PAD) and headspace solid-phase microextraction–gas chromatography–mass spectrometry (HS-SPME-GCMS) to further characterize beer spoiled by 30 different strains from six beer-spoiling species of Pectinatus and Megasphaera (P. cerevisiiphilus, P. frisingensis, P. haikarae, M. cerevisiae, M. paucivorans, and M. sueciensis). We detected differences in carbohydrate utilization and the volatile organic compounds (volatilome) produced during beer spoilage by all six species. We were able to show that glycerol, one of the basic components of beer, is the common carbon source used by all strains. It appears that this carbon source allows for anaerobic beer spoilage by Pectinatus and Megasphaera despite the spoilage-preventing intrinsic barriers of beer (iso-α-acids, ethanol, low pH, scarce nutrients); thus, extrinsic countermeasures are key for prevention.

In this review, we explore the intricate relationship between glucose metabolism and mechanotransduction pathways, with a specific focus on the role of the Hippo signaling pathway in chondrocyte pathophysiology. Glucose metabolism is a vital element in maintaining proper chondrocyte function, but it has also been implicated in the pathogenesis of osteoarthritis (OA) via the induction of pro-inflammatory signaling pathways and the establishment of an intracellular environment conducive to OA. Alternatively, mechanotransduction pathways such as the Hippo pathway possess the capacity to respond to mechanical stimuli and have an integral role in maintaining chondrocyte homeostasis. However, these mechanotransduction pathways can be dysregulated and potentially contribute to the progression of OA. We discussed how alterations in glucose levels may modulate the Hippo pathway components via a variety of mechanisms. Characterizing the interaction between glucose metabolism and the Hippo pathway highlights the necessity of balancing both metabolic and mechanical signaling to maintain chondrocyte health and optimal functionality. Furthermore, this review demonstrates the scarcity of the literature on the relationship between glucose metabolism and mechanotransduction and provides a summary of current research dedicated to this specific area of study. Ultimately, increased research into this topic may elucidate novel mechanisms and relationships integrating mechanotransduction and glucose metabolism. Through this review we hope to inspire future research into this topic to develop innovative treatments for addressing the clinical challenges of OA.

The use of inertial measurement units (IMUs) as an alternative to optical marker-based systems has the potential to make gait analysis part of the clinical standard of care. Previously, an IMU-based system leveraging Rauch–Tung–Striebel smoothing to estimate knee angles was assessed using a six-degrees-of-freedom joint simulator. In a clinical setting, however, accurately measuring abduction/adduction and external/internal rotation of the knee joint is particularly challenging, especially in the presence of soft tissue artefacts. In this study, the in vivo IMU-based joint angles of 40 asymptomatic knees were assessed during level walking, under two distinct sensor placement configurations: (1) IMUs fixed to a rigid harness, and (2) IMUs mounted on the skin using elastic hook-and-loop bands (from here on referred to as “skin-mounted IMUs”). Estimates were compared against values obtained from a harness-mounted optical marker-based system. The comparison of these three sets of kinematic signals (IMUs on harness, IMUs on skin, and optical markers on harness) was performed before and after implementation of a REference FRame Alignment MEthod (REFRAME) to account for the effects of differences in coordinate system orientations. Prior to the implementation of REFRAME, in comparison to optical estimates, skin-mounted IMU-based angles displayed mean root-mean-square errors (RMSEs) up to 6.5°, while mean RMSEs for angles based on harness-mounted IMUs peaked at 5.1°. After REFRAME implementation, peak mean RMSEs were reduced to 4.1°, and 1.5°, respectively. The negligible differences between harness-mounted IMUs and the optical system after REFRAME revealed that the IMU-based system was capable of capturing the same underlying motion pattern as the optical reference. In contrast, obvious differences between the skin-mounted IMUs and the optical reference indicated that the use of a harness led to fundamentally different joint motion being measured, even after accounting for reference frame misalignments. Fluctuations in the kinematic signals associated with harness use suggested the rigid device oscillated upon heel strike, likely due to inertial effects from its additional mass. Our study proposes that optical systems can be successfully replaced by more cost-effective IMUs with similar accuracy, but further investigation (especially in vivo and upon heel strike) against moving videofluoroscopy is recommended.

Objectives: The adolescent development period is critical for rugby league athletes, given the physical growth, neuromuscular adaptation, and skill acquisition that occurs. Secondary schools play an important role in the development of adolescent rugby league players; however, players may be selected into rugby league academies and development programs outside of school, as well as participating in additional sports. In turn, the training loads these young athletes accrue and the implications of these loads are currently unknown. Our aim was to quantify the training loads and concomitant changes in physical qualities of schoolboy and adolescent rugby league players during mesocycles within the pre-season and in-season phases. Design: This is a prospective experimental study. Methods: Twenty-one schoolboy rugby league players (16.2 ± 1.3 years) were monitored across separate 4-week mesocycles in the pre-season and in-season. Session frequency, duration, and the session rating of perceived exertion (sRPE) load were reported for all examples of training and match participation in the school rugby league program, as well as club and representative teams for any sport and personal strength and conditioning. Various physical qualities were assessed before and after each 4-week mesocycle. Results: The sRPE load that accumulated across the 4-week mesocycles was higher in the pre-season than the in-season (8260 ± 2021 arbitrary units [AU] vs. 6148 ± 980 AU, p < 0.001), with non-significant differences in accumulated session frequency and duration between phases. Session frequency, duration, and sRPE load differed (p < 0.05) between some weeks in an inconsistent manner during the pre-season and in-season mesocycles. Regarding physical qualities, improvements (p < 0.05) in the 10 m sprint test, Multistage Fitness Test, medicine ball throw, and 1-repetition maximum back squat and bench press performances were evident across the pre-season mesocycle, with declines (p < 0.05) in the 505-Agility Test, L-run Test, and 1-repetition maximum back squat performances across the in-season mesocycle. Conclusions: These novel training load data show schoolboy rugby league players experience considerable demands that may be suitable in developing several physical qualities during the pre-season but detrimental to maintaining such qualities across the in-season.

Understanding the interactions between plants and pollinators within a system can provide information about pollination requirements and the degree to which species contribute to floral reproductive success. Past research has focused largely on interactions within monocultured agricultural systems and only somewhat on wild pollination networks. This study focuses on the culturally significant Three Sisters Garden, which has been grown and tended by many Indigenous peoples for generations in the Great Lakes Region. Here, the plant-pollinator network of the traditional Three Sisters Garden with the inclusion of some additional culturally significant plants was mapped. Important visitors in this system included the common eastern bumble bee, Bombus impatiens Cresson (Hymenoptera: Apidae), and the hoary squash bee, Xenoglossa pruinosa (Say) (Hymenoptera: Apidae), as determined by their abundances and pollinator service index (PSI) values. Understanding the key pollinators in the Three Sisters Garden links biological diversity to cultural diversity through the pollination of culturally significant plants. Further, this information could be of use in supporting Indigenous food sovereignty by providing knowledge about which wild pollinators could be supported to increase fruit and seed set within the Three Sisters Garden. Our findings can also lead to more effective conservation of important wild pollinator species.

Inadequate lateral branch development can lead to decreased apple (Malus ×domestica Borkh.) orchard productivity and profitability in modern high-density orchard systems. Although plant growth regulator applications are used to increase lateral branching on leaders of young apple trees, inconsistent responses have been observed in the southeastern United States. In North Carolina and Washington, three experiments were conducted to identify effective leader management strategies to increase lateral branching. Effects and interactions of leader bagging, 6-benzyladenine (6-BA), and 6-BA + gibberellic acid (GA4+7) on lateral branch development of 1-year-old leaders were evaluated. Across all experiments, leader bagging was an influential factor. When compared with unbagged trees, leader bagging increased lateral branch number (20% to 48%), number of feathers (74% to 125%), average branch length (28% to 34%), and total linear bearing surface (428%) of the treated section of the leader. Blossom cluster density and final fruit set were increased in bagged trees, 65% and 36%, respectively. At the rates and timings tested, 6-BA and 6-BA + GA4+7 were generally ineffective in stimulating lateral branching and interactions among the factors evaluated were not influential. Leader bagging was an effective lateral branch induction strategy, although the mechanism of action is poorly understood. Future research to characterize the bagged environment and/or physiological responses to bagging may aid in the development of future environmentally sustainable technologies to stimulate lateral branching of apple trees.