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Abstract Background The BETTER (Building on Existing Tools to Improve Chronic Disease Prevention and Screening in Primary Care) intervention was designed to integrate the approach to chronic disease prevention and screening in primary care and demonstrated effective in a previous randomized trial. Methods We tested the effectiveness of the BETTER HEALTH intervention, a public health adaptation of BETTER, at improving participation in chronic disease prevention and screening actions for residents of low-income neighbourhoods in a cluster randomized trial, with ten low-income neighbourhoods in Durham Region Ontario randomized to immediate intervention vs. wait-list. The unit of analysis was the individual, and eligible participants were adults age 40–64 years residing in the neighbourhoods. Public health nurses trained as “prevention practitioners” held one prevention-focused visit with each participant. They provided participants with a tailored prevention prescription and supported them to set health-related goals. The primary outcome was a composite index: the number of evidence-based actions achieved at six months as a proportion of those for which participants were eligible at baseline. Results Of 126 participants (60 in immediate arm; 66 in wait-list arm), 125 were included in analyses (1 participant withdrew consent). In both arms, participants were eligible for a mean of 8.6 actions at baseline. At follow-up, participants in the immediate intervention arm met 64.5% of actions for which they were eligible versus 42.1% in the wait-list arm (rate ratio 1.53 [95% confidence interval 1.22–1.84]). Conclusion Public health nurses using the BETTER HEALTH intervention led to a higher proportion of identified evidence-based prevention and screening actions achieved at six months for people living with socioeconomic disadvantage. Trial registration NCT03052959 , registered February 10, 2017.

SUMMARY: The objective of this study was to evaluate the effect of embryonic thermal manipulation and dietary fat source during the finisher period on carcass characteristics and breast muscle myopathies following acute heat stress. Thermal manipulation (TM) of incubation temperatures has been shown to improve bird resistance to heat stress and enhance breast muscle growth. Fat supplementation is frequently used during heat stress and fat source may alter carcass composition, as fat sources rich in unsaturated fatty acids have been shown to reduce fat pad weight. Ross 708 eggs were incubated at 37.5°C except during TM when temperature was increased to 39.5°C for 12 h daily from embryo day 7 to 16. A total of 1,080 chicks were reared under standard conditions until acute heat stress at 43 d. Dietary treatments were applied during the finisher period beginning at 28 d, with diets including 4.5% of soya oil, poultry fat, or olive oil. At 49 d, 240 male birds were processed to assess carcass and portion weights, as well as breast quality. Carcass and portion weights were decreased by TM, however percent yield was similar to the controls. A decrease in breast muscle myopathies was noted but may have been due to the lower BW of the TM birds. Interactions between the treatments suggest that TM may alter lipid metabolism. Differences in dietary fat source did not affect carcass characteristics. The reduction in breast muscle myopathies may be negated by the negative impact of TM on carcass weights.

Foodborne infection is a result of exposure to complex, dynamic food systems. The efficiency of foodborne infection is driven by ongoing shifts in genetic machinery. Next-generation sequencing technologies can provide high-fidelity data about the genetics of a pathogen. However, food safety surveillance systems do not currently provide similar high-fidelity epidemiological metadata to associate with genetic data. As a consequence, it is rarely possible to transform genetic data into actionable knowledge that can be used to genuinely inform risk assessment or prevent outbreaks. Big data approaches are touted as a revolution in decision support, and pose a potentially attractive method for closing the gap between the fidelity of genetic and epidemiological metadata for food safety surveillance. We therefore developed a simple food chain model to investigate the potential benefits of combining ‘big’ data sources, including both genetic and high-fidelity epidemiological metadata. Our results suggest that, as for any surveillance system, the collected data must be relevant and characterize the important dynamics of a system if we are to properly understand risk: this suggests the need to carefully consider data curation, rather than the more ambitious claims of big data proponents that unstructured and unrelated data sources can be combined to generate consistent insight. Of interest is that the biggest influencers of foodborne infection risk were contamination load and processing temperature, not genotype. This suggests that understanding food chain dynamics would probably more effectively generate insight into foodborne risk than prescribing the hazard in ever more detail in terms of genotype.

Abstract Particle physics today faces the challenge of explaining the mystery of dark matter, the origin of matter over anti-matter in the Universe, the origin of the neutrino masses, the apparent fine-tuning of the electro-weak scale, and many other aspects of fundamental physics. Perhaps the most striking frontier to emerge in the search for answers involves new physics at mass scales comparable to familiar matter, below the GeV-scale, or even radically below, down to sub-eV scales, and with very feeble interaction strength. New theoretical ideas to address dark matter and other fundamental questions predict such feebly interacting particles (FIPs) at these scales, and indeed, existing data provide numerous hints for such possibility. A vibrant experimental program to discover such physics is under way, guided by a systematic theoretical approach firmly grounded on the underlying principles of the Standard Model. This document represents the report of the FIPs 2022 workshop, held at CERN between the 17 and 21 October 2022 and aims to give an overview of these efforts, their motivations, and the decadal goals that animate the community involved in the search for FIPs.

Sea surface temperature (SST) is a key factor in understanding the greater climate of the Earth, and it is also an important variable when making weather predictions. Methods of machine learning have become ever more present and important in data-driven science and engineering, including in important areas for Earth science. Here, we propose an efficient framework that allows us to make global SST forecasts using a coupled reservoir computer method that we have specialized to this domain, allowing for template regions that accommodate irregular coastlines. Reservoir computing is an especially good method for forecasting spatiotemporally complex dynamical systems, as it is a machine learning method that, despite many randomly selected weights, is highly accurate and easy to train. Our approach provides the benefit of a simple and computationally efficient model that is able to predict SSTs across the entire Earth's oceans. The results are demonstrated to generally follow the actual dynamics of the system over a forecasting period of several weeks.

Aquatic resistance training has been proven to be beneficial to many people, in particular those struggling with degenerative joint diseases or recovering from other musculoskeletal issues as the reaction forces acting on the joints become lower, but without compromising the cardiovascular and neuromuscular benefit of the movement. Little has been written on the load produced by or measurements of the devices used in aquatic resistance training. Therefore, uncertainties exist regarding details of how much load can be applied onto the foot when performing the movements and how to quantify progression. In this study, an instrumented robotic arm was designed, built, and used to measure the load acting on the three different types of fins during a simulated flexion/extension movement of a knee. The angular velocities of the knee ranged from 25°/s to 150°/s, which represent the physiological range of in vivo movements. The results demonstrated that the load followed a second-order polynomial with the angular velocities. The load is therefore a function of the angular velocity, the surface area of the fins, and the location of the fins away from the joint center rotation. We modeled the progression of speeds at maximal voluntary movements based on previous studies. The maximum loads measured between 11 kg and 13 kg in extension and 6 kg and 9 kg in flexion at 150°/s rotational velocity.

The Thwaites Eastern Ice Shelf (TEIS) buttresses the eastern grounded portion of Thwaites Glacier through contact with a pinning point at its seaward limit. Loss of this ice shelf will promote further acceleration of Thwaites Glacier. Understanding the dynamic controls and structural integrity of the TEIS is therefore important to estimating Thwaites' future sea-level contribution. We present a ∼ 20-year record of change on the TEIS that reveals the dynamic controls governing the ice shelf's past behaviour and ongoing evolution. We derived ice velocities from MODIS and Sentinel-1 image data using feature tracking and speckle tracking, respectively, and we combined these records with ITS_LIVE and GOLIVE velocity products from Landsat-7 and Landsat-8. In addition, we estimated surface lowering and basal melt rates using the Reference Elevation Model of Antarctica (REMA) DEM in comparison to ICESat and ICESat-2 altimetry. Early in the record, TEIS flow dynamics were strongly controlled by the neighbouring Thwaites Western Ice Tongue (TWIT). Flow patterns on the TEIS changed following the disintegration of the TWIT around 2008, with a new divergence in ice flow developing around the pinning point at its seaward limit. Simultaneously, the TEIS developed new rifting that extends from the shear zone upstream of the ice rise and increased strain concentration within this shear zone. As these horizontal changes occurred, sustained thinning driven by basal melt reduced ice thickness, particularly near the grounding line and in the shear zone area upstream of the pinning point. This evidence of weakening at a rapid pace suggests that the TEIS is likely to fully destabilize in the next few decades, leading to further acceleration of Thwaites Glacier.

Abstract In this work we present a comprehensive study of the domain structure of a nickel oxide single crystal grown by floating zone melting and suggest a correlation between point defects and the observed domain structure. The properties and structure of domains dictate the dynamics of resistive switching, water splitting and gas sensing, to name but a few. Investigating the correlation between point defects and domain structure can provide a deeper understanding of their formation and structure, which potentially allows one to tailor domain structure and the dynamics of the aforementioned applications. A range of inhomogeneities are observed by diffraction and microscopy techniques. X-ray and low-energy electron diffraction reveal domains on the submicron- and nanometer-scales, respectively. In turn, these domains are visualised by atomic force and scanning tunneling microscopy (STM), respectively. A comprehensive transmission electron microscopy (TEM) study reveals inhomogeneities ranging from domains of varying size, misorientation of domains, variation of the lattice constant and bending of lattice planes. X-ray photoelectron spectroscopy and electron energy-loss spectroscopy indicate the crystal is Ni deficient. Density functional theory calculations—considering the spatial and electronic disturbance induced by the favourable nickel vacancy—reveal a nanoscale distortion comparable to STM and TEM observations. The different inhomogeneities are understood in terms of the structural relaxation induced by ordering of nickel vacancies, which is predicted to be favourable.

Abstract Background Birt-Hogg-Dubé syndrome (BHD) is a rare autosomal dominant disorder caused by mutations in the FLCN gene coding for folliculin. Its clinical expression includes cutaneous fibrofolliculomas, renal tumors, multiple pulmonary cysts, and recurrent spontaneous pneumothoraces. Data on lung function in BHD are scarce and it is not known whether lung function declines over time. We retrospectively assessed lung function at baseline and during follow-up in 96 patients with BHD. Results Ninety-five percent of BHD patients had multiple pulmonary cysts on computed tomography and 59% had experienced at least one pneumothorax. Mean values of forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), FEV1/FVC ratio, and total lung capacity were normal at baseline. Mean (standard deviation) residual volume (RV) was moderately increased to 116 (36) %pred at baseline, and RV was elevated > 120%pred in 41% of cases. Mean (standard deviation) carbon monoxide transfer factor (DLco) was moderately decreased to 85 (18) %pred at baseline, and DLco was decreased

Abstract Background Despite access to quality care at the end-of-life (EOL) being considered a human right, it is not equitable, with many facing significant barriers. Most research examines access to EOL care for homogenous ‘normative’ populations, and as a result, the experiences of those with differing social positioning remain unheard. For example, populations experiencing structural vulnerability, who are situated along the lower rungs of social hierarchies of power (e.g., poor, homeless) will have unique EOL care needs and face unique barriers when accessing care. However, little research examines these barriers for people experiencing life-limiting illnesses and structural vulnerabilities. The purpose of this study was to identify barriers to accessing care among structurally vulnerable people at EOL. Methods Ethnography informed by the critical theoretical perspectives of equity and social justice was employed. This research drew on 30 months of ethnographic data collection (i.e., observations, interviews) with structurally vulnerable people, their support persons, and service providers. Three hundred hours of observation were conducted in homes, shelters, transitional housing units, community-based service centres, on the street, and at health care appointments. The constant comparative method was used with data collection and analysis occurring concurrently. Results Five significant barriers to accessing care at EOL were identified, namely: (1) The survival imperative; (2) The normalization of dying; (3) The problem of identification; (4) Professional risk and safety management; and (5) The cracks of a ‘silo-ed’ care system. Together, findings unveil inequities in accessing care at EOL and emphasize how those who do not fit the ‘normative’ palliative-patient population type, for whom palliative care programs and policies are currently built, face significant access barriers. Conclusions Findings contribute a nuanced understanding of the needs of and barriers experienced by those who are both structurally vulnerable and facing a life-limiting illness. Such insights make visible gaps in service provision and provide information for service providers, and policy decision-makers alike, on ways to enhance the equitable provision of EOL care for all populations.

Inflammation plays a central role in the pathophysiology of chronic obstructive pulmonary disease (COPD). Exposure to cigarette smoke induces the recruitment of inflammatory cells in the airways and stimulates innate and adaptive immune mechanisms. Airway inflammation is involved in increased bronchial wall thickness, increased bronchial smooth muscle tone, mucus hypersecretion and loss of parenchymal elastic structures. Oxidative stress impairs tissue integrity, accelerates lung ageing and reduces the efficacy of corticosteroids by decreasing levels of histone deacetylase-2. Protease–antiprotease imbalance impairs tissues and is involved in inflammatory processes. Inflammation is also present in the pulmonary artery wall and at the systemic level in COPD patients, and may be involved in COPD-associated comorbidities. Proximal airways inflammation contributes to symptoms of chronic bronchitis while distal and parenchymal inflammation relates to airflow obstruction, emphysema and hyperinflation. Basal levels of airways and systemic inflammation are increased in frequent exacerbators. Inhaled corticosteroids are much less effective in COPD than in asthma, which relates to the intrinsically poor reversibility of COPD-related airflow obstruction and to molecular mechanisms of resistance relating to oxidative stress. Ongoing research aims at developing new drugs targeting more intimately COPD-specific mechanisms of inflammation, hypersecretion and tissue destruction and repair. Among new anti-inflammatory agents, phosphodiesterase-4 inhibitors have been the first to emerge.

This study, performed in 1982–2007, deals with the processes in the acrotelm and the subsequent addition (accretion) of material to the catotelm of an ombrotrophic bog in southern Sweden. It is based on analyses of C and N in biomass, necromass and mire water combined with age determinations by 210Pb. The C input to the acrotelm was 102 g m-2 a-1 of which 69% was released through decay and the rest either retained as peat or exported as dissolved organic matter (DOM). The mean C accretion to the catotelm was 20–25% lower in 1900–1980 than in 1800–1900 due to the rising bog surface, continuously increasing acrotelm thickness and total decay loss. Annual runoff, determined indirectly from [Na+] in precipitation and drainage water, varied more (range 200–770 mm) than the concentration of dissolved organic C (DOC; range 25–55 mg L¬-1) and mainly determined DOC export. During 1993–2007, with high precipitation (mean 880 mm a-1) and mild winters, the mean DOC export and C accretion to the catotelm were equal at 16 g m-2 a-1. During 1953–1960, with lower precipitation (~700 mm a¬-1) and “normal” winters, the DOC export and C accretion were probably about 9 and 23 g m-2, respectively. The release of C to the atmosphere downstream from the bog was correspondingly lower. As a C sink, the bog at present may be half as efficient as it was 50–200 years ago. The DOC exported was accompanied by 25–50% of the N input in litter.

Psychedelic therapies are an emerging class of treatments in psychiatry with great potential, however relatively little is known about their interactions with other commonly used psychiatric medications. As psychedelic therapies become more widespread and move closer to the clinic, they likely will need to be integrated into existing treatment models which may include one or more traditional pharmacological therapies, meaning an awareness of potential drug-drug interactions will become vital. This commentary outlines some of the issues surrounding the study of drug-drug interactions of this type, provides a summary of some of the relevant key results to date, and charts a way forward which relies crucially on multimodal neuroimaging investigations. Studies in humans which combine Positron Emission Tomography (PET) and functional Magnetic Resonance Imaging (fMRI), plus ancillary measures, are likely to provide the most comprehensive assessment of drug-drug interactions involving psychedelics and the relevant effects at multiple levels of the drug response (molecular, functional, and clinical).

Abstract Distressing low sexual desire, termed Hypoactive Sexual Desire Disorder (HSDD), affects approximately 10% of women and 8% of men. In women, the ‘top-down’ theory of HSDD describes hyperactivity in higher-level cognitive brain regions, suppressing lower-level emotional/sexual brain areas. However, it is unknown how this neurofunctional disturbance compares to HSDD in men. To investigate this, we employed task-based functional MRI in 32 women and 32 men with HSDD to measure sexual-brain processing during sexual versus non-sexual videos, as well as psychometric questionnaires to assess sexual desire/arousal. We demonstrate that women had greater activation in higher-level and lower-level brain regions, compared to men. Indeed, women who had greater hypothalamic activation in response to sexual videos, reported higher psychometric scores in the evaluative (r = 0.55, P = 0.001), motivational (r = 0.56, P = 0.003), and physiological (r = 0.57, P = 0.0006) domains of sexual desire and arousal after watching the sexual videos in the scanner. By contrast, no similar correlations were observed in men. Taken together, this is the first direct comparison of the neural correlates of distressing low sexual desire between women and men. The data supports the ‘top-down’ theory of HSDD in women, whereas in men HSDD appears to be associated with different neurofunctional processes.

Abstract Background Mitochondrial function plays a key role in regulating neurotransmission and may contribute to general intelligence. Mitochondrial complex I (MC-I) is the largest enzyme of the respiratory chain. Recently, it has become possible to measure MC-I distribution in vivo, using a novel positron emission tomography tracer [18F]BCPP-EF, thus, we set out to investigate the association between MC-I distribution and measures of cognitive function in the living healthy brain. Results Analyses were performed in a voxel-wise manner and identified significant associations between [18F]BCPP-EF DVRCS−1 in the precentral gyrus and parietal lobes and WAIS-IV predicted IQ, WAIS-IV arithmetic and WAIS-IV symbol-digit substitution scores (voxel-wise Pearson’s correlation coefficients transformed to Z-scores, thresholded at Z = 2.3 family-wise cluster correction at p

Summary: Background: Paediatric hepatocellular carcinomas (HCC) traditionally arise in the context of a normal structural and functional liver and carry a dismal prognosis. While chemotherapy is the frontline standard, there is emerging interest in the study of immunotherapies for paediatric patients with relapsed/refractory disease. There is limited data to support whether immunotherapies will be of utility in this patient population. Methods: Six paediatric patients (median age:16 years, range: 12–17 at the time of treatment) with advanced hepatocellular neosplams, either conventional hepatocellular or fibrolamellar carcinoma, were treated with immunotherapy. Patients were consented to institutional genomic profiling and biobanking protocols. Baseline samples and serial tissue samples, when available, were evaluated for somatic mutation rate, actionable gene mutations, and pan-immune bulk RNA expression profiling. Results were correlated with clinical course. Findings: Three patients responded to checkpoint inhibition: one achieved a complete, durable response and the other two, prolonged stable disease. Three additional patients progressed. Diagnostic tissue from the complete responder demonstrated a higher relative mutational burden and robust immune infiltrate. Pre-treatment samples from the three responders demonstrated decreased expression of genes associated with T-cell dysfunction. Interpretation: A subset of patients with primary paediatric hepatocellular tumours will respond to immunotherapy. Immunotherapies are currently under prospective study for relapsed/refractory liver tumours in paediatric patients. Results from this report support the prospective collection of serial serum and tissue samples which may further identify genomic and immunophenotypic patterns predictive of response. Funding: This work was supported by Philanthropic funds (Pan Mass Challenge, Team Angus and Team Perspective).

Abstract The dominant benthic primary producers in coral reef ecosystems are complex holobionts with diverse microbiomes and metabolomes. In this study, we characterize the tissue metabolomes and microbiomes of corals, macroalgae, and crustose coralline algae via an intensive, replicated synoptic survey of a single coral reef system (Waimea Bay, Oʻahu, Hawaii) and use these results to define associations between microbial taxa and metabolites specific to different hosts. Our results quantify and constrain the degree of host specificity of tissue metabolomes and microbiomes at both phylum and genus level. Both microbiome and metabolomes were distinct between calcifiers (corals and CCA) and erect macroalgae. Moreover, our multi-omics investigations highlight common lipid-based immune response pathways across host organisms. In addition, we observed strong covariation among several specific microbial taxa and metabolite classes, suggesting new metabolic roles of symbiosis to further explore.

Abstract Background Pediatric interventional oncology (PIO) is a growing field intended to provide additional or alternative treatment options for pediatric patients with benign or malignant tumors. Large series of patients treated uniformly and subjected to rigorous endpoints for efficacy are not available. Methods We designed a collaborative initiative to capture data from pediatric patients with benign and malignant tumors who underwent a therapeutic interventional radiology procedure. Modified Response Evaluation Criteria in Solid Tumors (mRECIST) was utilized as a measure of radiologic response and data were collected regarding improvement in pain and functional endpoints. Cumulative incidence of progressive disease was calculated using both the treated site and the patient as the analytic unit. Findings Forty patients, 16 with malignant tumors and 24 with benign tumors, underwent a total of 88 procedures. Cryo‐ and radiofrequency ablation were the most frequently utilized techniques for both cohorts of patients. A complete or partial response, or prolonged disease stability, were achieved in approximately 40% of patients with malignant tumors and 60% of patients with benign tumors. No patients had progressive disease as their best response. Resolution of pain and improved mobility with return‐to‐baseline activity were demonstrated across patients from both cohorts. Only minor complications were experienced. Interpretation Interventional radiology‐guided interventions can serve as an alternative or complementary approach to the treatment of benign and malignant tumors in pediatric patients. Prospective, multi‐institutional trials are required to adequately study utility, treatment endpoints, and durability of response.

Marine heatwaves and regional coral bleaching events have become more frequent and severe across the world’s oceans over the last several decades due to global climate change. Observational studies have documented spatiotemporal variation in the responses of reef-building corals to thermal stress within and among taxa across geographic scales. Although many tools exist for predicting, detecting, and quantifying coral bleaching, it remains difficult to compare bleaching severity (e.g., percent cover of bleached surface areas) among studies and across species or regions. For this review, we compiled over 2,100 in situ coral bleaching observations representing 87 reef-building coral genera and 250 species of common morphological groups from a total of 74 peer-reviewed scientific articles, encompassing three broad geographic regions (Atlantic, Indian, and Pacific Oceans). While bleaching severity was found to vary by region, genus, and morphology, we found that both genera and morphologies responded differently to thermal stress across regions. These patterns were complicated by (i) inconsistent methods and response metrics across studies; (ii) differing ecological scales of observations (i.e., individual colony-level vs. population or community-level); and (iii) temporal variability in surveys with respect to the onset of thermal stress and the chronology of bleaching episodes. To improve cross-study comparisons, we recommend that future surveys prioritize measuring bleaching in the same individual coral colonies over time and incorporate the severity and timing of warming into their analyses. By reevaluating and standardizing the ways in which coral bleaching is quantified, researchers will be able to track responses to marine heatwaves with increased rigor, precision, and accuracy.

Deforestation and subsequent land-use conversion has altered ecosystems and led to negative effects on biodiversity. To ameliorate these effects, nitrogen-fixing (N2-fixing) trees are frequently used in the reforestation of degraded landscapes, especially in the tropics; however, their influence on ecosystem properties such as nitrogen (N) availability and carbon (C) stocks are understudied. Here, we use a 30-y old reforestation site of outplanted native N2-fixing trees (Acacia koa) dominated by exotic grass understory, and a neighboring remnant forest dominated by A. koa canopy trees and native understory, to assess whether restoration is leading to similar N and C biogeochemical landscapes and soil and plant properties as a target remnant forest ecosystem. We measured nutrient contents and isotope values (δ15N, δ13C) in soils, A. koa, and non-N2-fixing understory plants (Rubus spp.) and generated δ15N and δ13C isoscapes of the two forests to test for (1) different levels of biological nitrogen fixation (BNF) and its contribution to non-N2-fixing understory plants, and (2) the influence of historic land conversion and more recent afforestation on plant and soil δ13C. In the plantation, A. koa densities were higher and foliar δ15N values for A. koa and Rubus spp. were lower than in the remnant forest. Foliar and soil isoscapes also showed a more homogeneous distribution of low δ15N values in the plantation and greater influence of A. koa on neighboring plants and soil, suggesting greater BNF. Foliar δ13C also indicated higher water use efficiency (WUEi) in the plantation, indicative of differences in plant-water relations or soil water status between the two forest types. Plantation soil δ13C was higher than the remnant forest, consistent with greater contributions of exotic C4-pasture grasses to soil C pools, possibly due to facilitation of non-native grasses by the dense A. koa canopy. These findings are consequential for forest restoration, as they contribute to the mounting evidence that outplanting N2-fixing trees produces different biogeochemical landscapes than those observed in reference ecosystems, thereby influencing plant-soil interactions which can influence restoration outcomes.

Purpose: Risk factors for congenital upper limb differences (CoULDs) are often studied at the general population level. The CoULD registry provides a unique opportunity to study prenatal risk factors within a large patient sample. Methods: All patients enrolled between June 2014 and March 2020 in the prospective CoULD registry, a national multicenter database of patients diagnosed with a CoULD, were included in the analysis. We analyzed self-reported, prenatal risk factors, including maternal smoking, alcohol use, recreational drug use, prescription drug use, gestational diabetes mellitus (GDM), and gestational hypertension. The outcome measures included comorbid medical conditions, proximal involvement of limb difference, bilateral involvement, and additional orthopedic conditions. Multivariable logistic regression was used to analyze the effect of the risk factors, controlling for sex and the presence of a named syndrome. Results: In total, 2,410 patients were analyzed, of whom 72% (1,734) did not have a self-reported risk factor. Among the 29% (676) who did have at least 1 risk factor, prenatal maternal prescription drug use was the most frequent (376/2,410; 16%). Maternal prescription drug use was associated with increased odds of patient medical comorbidities (odds ratio [OR] = 1.43, P = .02). Gestational diabetes mellitus was associated with increased odds of comorbid medical conditions (OR = 1.58, P = .04), additional orthopedic conditions (OR = 1.51, P = .04), and proximal involvement (OR = 1.52, P = .04). Overall, reporting 1 or more risk factors increased the odds of patient comorbid medical conditions (OR = 1.42, P < .001) and additional orthopedic conditions (OR = 1.25, P = .03). Conclusions: Most caregivers (72%) did not report a risk factor during enrollment. However, reporting a risk factor was associated with patient medical and orthopedic comorbidities. Of note, GDM alone significantly increased the odds of both these outcome measures along with proximal limb differences. These findings highlight the ill-defined etiology of CoULDs but suggest that prenatal risk factors, especially GDM, are associated with a higher degree of morbidity. Type of study/level of evidence: Prognostic III.

Background. Androgen deprivation therapy (ADT) for prostate cancer is implicated as a possible cause of cognitive impairment (CI). CI in dementia and Alzheimer’s disease is associated with neuroinflammation. In this study, we investigated a potential role of neuroinflammation in ADT-related CI. Methods. Patients with prostate cancer on ADT for ≥3 months were categorized as having ADT-emergent CI or normal cognition (NC) based on self-report at interview. Neuroinflammation was evaluated using positron emission tomography (PET) with the translocator protein (TSPO) radioligand [11C]-PBR28. [11C]-PBR28 uptake in various brain regions was quantified as standardized uptake value (SUVR, normalized to cerebellum) and related to blood oxygen level-dependent functional magnetic resonance imaging (BOLD-fMRI) choice-reaction time task (CRT) activation maps. Results. Eleven patients underwent PET: four with reported CI (rCI), six with reported NC (rNC), and one status unrecorded. PET did not reveal any between-group differences in SUVR regionally or globally. There was no difference between groups on brain activation to the CRT. Regardless of the reported cognitive status, there was strong correlation between PET-TSPO signal and CRT activation in the hippocampus, amygdala, and medial cortex. Conclusions. We found no difference in neuroinflammation measured by PET-TSPO between patients with rCI and rNC. However, we speculate that the strong correlation between TSPO uptake and BOLD-fMRI activation in brain regions involved in memory and known to have high androgen-receptor expression mediating plasticity (hippocampus and amygdala) might reflect inflammatory effects of ADT with compensatory upregulated/increased synaptic functions. Further studies of this imaging readout are warranted to investigate ADT-related CI.

Background: Reward processing deficits are a core feature of schizophrenia and are thought to underlie negative symptoms. Pre-clinical evidence suggests that opioid neurotransmission is linked to reward processing. However, the contribution of Mu Opioid Receptor (MOR) signalling to the reward processing abnormalities in schizophrenia is unknown. Here, we examined the association between MOR availability and the neural processes underlying reward anticipation in patients with schizophrenia using multimodal neuroimaging. Method: 37 subjects (18 with Schizophrenia with moderate severity negative symptoms and 19 age and sex-matched healthy controls) underwent a functional MRI scan while performing the Monetary Incentive Delay (MID) task to measure the neural response to reward anticipation. Participants also had a [11C]-carfentanil PET scan to measure MOR availability. Results: Reward anticipation was associated with increased neural activation in a widespread network of brain regions including the striatum. Patients with schizophrenia had both significantly lower MOR availability in the striatum as well as striatal hypoactivation during reward anticipation. However, there was no association between MOR availability and striatal neural activity during reward anticipation in either patient or controls (Pearson's Correlation, controls df = 17, r = 0.321, p = 0.18, patients df = 16, r = 0.295, p = 0.24). There was no association between anticipation-related neural activation and negative symptoms (r = –0.120, p = 0.14) or anhedonia severity (social r = –0.365, p = 0.14 physical r = –0.120, p = 0.63). Conclusions: Our data suggest reduced MOR availability in schizophrenia might not underlie striatal hypoactivation during reward anticipation in patients with established illness. Therefore, other mechanisms, such as dopamine dysfunction, warrant further investigation as treatment targets for this aspect of the disorder.

BACKGROUND Hypoactive sexual desire disorder (HSDD) is characterized by a persistent deficiency of sexual fantasies and desire for sexual activity, causing marked distress and interpersonal difficulty. It is the most prevalent female sexual health problem globally, affecting approximately 10% of women, but has limited treatment options. Melanocortin 4 receptor (MC4R) agonists have emerged as a promising therapy for women with HSDD, through unknown mechanisms. Studying the pathways involved is crucial for our understanding of normal and abnormal sexual behavior.METHODS Using psychometric, functional neuroimaging, and hormonal analyses, we conducted a randomized, double-blinded, placebo-controlled, crossover clinical study to assess the effects of MC4R agonism compared with placebo on sexual brain processing in 31 premenopausal heterosexual women with HSDD.RESULTS MC4R agonism significantly increased sexual desire for up to 24 hours after administration compared with placebo. During functional neuroimaging, MC4R agonism enhanced cerebellar and supplementary motor area activity and deactivated the secondary somatosensory cortex, specifically in response to visual erotic stimuli, compared with placebo. In addition, MC4R agonism enhanced functional connectivity between the amygdala and the insula during visual erotic stimuli compared with placebo.CONCLUSION These data suggest that MC4R agonism enhanced sexual brain processing by reducing self-consciousness, increasing sexual imagery, and sensitizing women with HSDD to erotic stimuli. These findings provide mechanistic insight into the action of MC4R agonism in sexual behavior and are relevant to the ongoing development of HSDD therapies and MC4R agonist development more widely.TRIAL REGISTRATION ClinicalTrials.gov NCT04179734.FUNDING This is an investigator-sponsored study funded by AMAG Pharmaceuticals Inc., the Medical Research Council (MRC) (MR/T006242/1), and the National Institute for Health Research (NIHR) (CS-2018-18-ST2-002 and RP-2014-05-001).

Using microspherical scaffolds as building blocks to repair bone defects of specific size and shape has been proposed as a tissue engineering strategy. Here, phosphate glass (PG) microcarriers doped with 5 mol % TiO 2 and either 0 mol % CoO (CoO 0%) or 2 mol % CoO (CoO 2%) were investigated for their ability to support osteogenic and vascular responses of human mesenchymal stem cells (hMSCs). Together with standard culture techniques, cell-material interactions were studied using a novel perfusion microfluidic bioreactor that enabled cell culture on microspheres, along with automated processing and screening of culture variables. While titanium doping was found to support hMSCs expansion and differentiation, as well as endothelial cell-derived vessel formation, additional doping with cobalt did not improve the functionality of the microspheres. Furthermore, the microfluidic bioreactor enabled screening of culture parameters for cell culture on microspheres that could be potentially translated to a scaled-up system for tissue-engineered bone manufacturing.

The trace element selenium (Se) contributes to redox signaling, antioxidant defense, and immune responses in critically ill neonatal and adult patients. Se is required for the synthesis and function of selenoenzymes including thioredoxin (Trx) reductase-1 (TXNRD1) and glutathione peroxidases (GPx). We have previously identified TXNRD1, primarily expressed by airway epithelia, as a promising therapeutic target to prevent lung injury, likely via nuclear factor E2-related factor 2 (Nrf2)-dependent mechanisms. The present studies utilized the TXNRD1 inhibitor auranofin (AFN) to test the hypothesis that Se positively influences Nrf2 activation and selenoenzyme responses in lung epithelial cells. Murine transformed Club cells (mtCCs) were supplemented with 0, 10, 25, or 100 nM Na2SeO3 to create a range of Se conditions and were cultured in the presence or absence of 0.5 μM AFN. TXNRD1 and GPX2 protein expression and enzymatic activity were significantly greater upon Se supplementation (p

Working memory performance is thought to depend on both striatal dopamine 2/3 receptors (D2/3Rs) and task-induced functional organisation in key cortical brain networks. Here, we combine functional magnetic resonance imaging and D2/3R positron emission tomography in 51 healthy volunteers, to investigate the relationship between working memory performance, task-induced default mode network (DMN) functional connectivity changes, and striatal D2/3R availability. Increasing working memory load was associated with reduced DMN functional connectivity, which was itself associated with poorer task performance. Crucially, the magnitude of the DMN connectivity reduction correlated with striatal D2/3R availability, particularly in the caudate, and this relationship mediated the relationship between striatal D2/3R availability and task performance. These results inform our understanding of natural variation in working memory performance, and have implications for understanding age-related cognitive decline and cognitive impairments in neuropsychiatric disorders where dopamine signalling is altered.

Tissue engineering is a promising approach for bone regeneration; yet challenges remain that limit successful translation to patients. It is necessary to understand how real-world manufacturing processes will affect the constituent cells and biomaterials that are needed to create engineered bone. Bioactive phosphate glasses processed into microspheres are an attractive platform for expanding bone-forming cells and also for driving their osteogenic differentiation and maturation. The aim of this study was to assess whether Ti-doped phosphate glass microspheres could support osteoblastic cell responses in dynamic cell culture environments. Dynamic culture conditions were achieved using microwell studies under orbital agitation. Dimensionless parameters such as the Froude number were used to inform the choice of agitation speeds, and the impact on cell proliferation and microunit formation was quantified. We found that phosphate glass microspheres doped with titanium dioxide at both 5 and 7 mol% provided a suitable biomaterial platform for effective culture of MG63 osteoblastic cells and was not cytotoxic. Dynamic culture conditions supported expansion of MG63 cells and both 150 and 300 rpm orbital shake resulted in higher cell yield than static cultures at the end of the culture (day 13). The Froude number analysis provided insight into how the microunit size could be manipulated to enable an appropriate agitation speed to be used, while ensuring buoyancy of the microunits. These small-scale experiments and analyses provide understanding of the impact of fluid flow on cell expansion that will have increasing importance when scaling up to process technologies that can deliver clinical quantities of cell-microsphere units. Such knowledge will enable future engineering of living bone-like material using processing systems such as bioreactors that use mixing and agitation for nutrient transfer, therefore introducing cells to dynamic culture conditions.

Background: Alveolar macrophages (AMs) are resident inflammatory cells in the lung that serve as early sentinels of infection or injury. We have identified thioredoxin reductase 1 inhibition by gold compounds increases activation of nuclear factor erythroid 2-related factor 2 (NRF2)-dependent pathways to attenuate inflammatory responses. The present studies utilized murine alveolar macrophages (MH-S) to test the hypothesis that the gold compound, auranofin (AFN), decreases interleukin (IL)-1β expression through NRF2-mediated interactions with nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway genes and/or increases in glutathione synthesis. Methods: MH-S cells were treated with AFN and lipopolysaccharide (LPS) and analyzed at 6 and 24 h. The Il1b promoter was analyzed by chromatin immunoprecipitation for direct interaction with NRF2. Results: Expression of IL-1β, p-IκBα, p-p65 NF-kB, and NOD-, LRR-, and pyrin domain-containing protein 3 were elevated by LPS exposure, but only IL-1β expression was suppressed by AFN treatment. Both AFN and LPS treatments increased cellular glutathione levels, but attenuation of glutathione synthesis by buthionine sulfoximine (BSO) did not alter expression of Il-1β. Analysis revealed direct NRF2 binding to the Il1b promoter which was enhanced by AFN and inhibited the transcriptional activity of DNA polymerase II. Conclusions: Our data demonstrate that AFN-induced NRF2 activation directly suppresses IL-1β synthesis independent of NFκB and glutathione-mediated antioxidant mechanisms. NRF2 binding to the promoter region of IL1β directly inhibits transcription of the IL1β gene. Collectively, our research suggests that gold compounds elicit NRF2-dependent pulmonary protection by suppressing macrophage-mediated inflammation.

Metabolic control of cellular function is significant in the context of inflammation-induced metabolic dysregulation in immune cells. Generation of reactive oxygen species (ROS) such as hydrogen peroxide and superoxide are one of the critical events that modulate the immune response in neutrophils. When activated, neutrophil NADPH oxidases consume large quantities of oxygen to rapidly generate ROS, a process that is referred to as the oxidative burst. These ROS are required for the efficient removal of phagocytized cellular debris and pathogens. In chronic inflammatory diseases, neutrophils are exposed to increased levels of oxidants and pro-inflammatory cytokines that can further prime oxidative burst responses and generate lipid oxidation products such as 4-hydroxynonenal (4-HNE). In this study we hypothesized that since 4-HNE can target glycolysis then this could modify the oxidative burst. To address this the oxidative burst was determined in freshly isolated healthy subject neutrophils using 13-phorbol myristate acetate (PMA) and the extracellular flux analyzer. Neutrophils pretreated with 4-HNE exhibited a significant decrease in the oxidative burst response and phagocytosis. Mass spectrometric analysis of alkyne-HNE treated neutrophils followed by click chemistry detected modification of a number of cytoskeletal, metabolic, redox and signaling proteins that are critical for the NADPH oxidase mediated oxidative burst. These modifications were confirmed using a candidate immunoblot approach for critical proteins of the active NADPH oxidase enzyme complex (Nox2 gp91phox subunit and Rac1 of the NADPH oxidase) and glyceraldehyde phosphate dehydrogenase, a critical enzyme in the metabolic regulation of oxidative burst. Taken together, these data suggest that 4-HNE-induces a pleiotropic mechanism to inhibit neutrophil function. These mechanisms may contribute to the immune dysregulation associated with chronic pathological conditions where 4-HNE is generated.

Background Functional magnetic resonance imaging (fMRI) is a popular method for examining pharmacological effects on the brain; however, the BOLD response is dependent on intact neurovascular coupling, and potentially modulated by a number of physiological factors. Pharmacological fMRI is therefore vulnerable to confounding effects of pharmacological probes on general physiology or neurovascular coupling. Controlling for such non-specific effects in pharmacological fMRI studies is therefore an important consideration, and there is an additional need for well-validated fMRI task paradigms that could be used to control for such effects, or for general testing purposes. Methods We have developed two variants of a standardized control task that are short (5 minutes duration) simple (for both the subject and experimenter), widely applicable, and yield a number of readouts in a spatially diverse set of brain networks. The tasks consist of four functionally discrete three-second trial types (plus additional null trials) and contain visual, auditory, motor and cognitive (eye-movements, and working memory tasks in the two task variants) stimuli. Performance of the tasks was assessed in a group of 15 subjects scanned on two separate occasions, with test-retest reliability explicitly assessed using intra-class correlation coefficients. Results Both tasks produced robust patterns of brain activation in the expected brain regions, and region of interest-derived reliability coefficients for the tasks were generally high, with four out of eight task conditions rated as ‘excellent’ or ‘good’, and only one out of eight rated as ‘poor’. Median values in the voxel-wise reliability measures were also >0.7 for all task conditions, and therefore classed as ‘excellent’ or ‘good’. The spatial concordance between the most highly activated voxels and those with the highest reliability coefficients was greater for the sensory (auditory, visual) conditions than the other (motor, cognitive) conditions. Discussion Either of the two task variants would be suitable for use as a control task in future pharmacological fMRI studies or for any other investigation where a short, reliable, basic task paradigm is required. Stimulus code is available online for re-use by the scientific community.

Invasive macroalgae pose a serious threat to coral reef biodiversity by monopolizing reef habitats, competing with native species, and directly overgrowing, and smothering reef corals. Several invasive macroalgae (Eucheuma clade E, Kappaphycus clade A and B, Gracilaria salicornia, and Acanthophora spicifera) are established within Kāne‘ohe Bay (O‘ahu, Hawai‘i, USA), and reducing invasive macroalgae cover is a coral reef conservation and management priority. Invasive macroalgae control techniques, however, are limited and few successful large-scale applications exist. Therefore, a two-tiered invasive macroalgae control approach was designed, where first, divers manually remove invasive macroalgae (Eucheuma and Kappaphycus) aided by an underwater vacuum system (“The Super Sucker”). Second, hatchery-raised juvenile sea urchins (Tripneustes gratilla), were outplanted to graze and control invasive macroalgae regrowth. To test the effectiveness of this approach in a natural reef ecosystem, four discrete patch reefs with high invasive macroalgae cover (15–26%) were selected, and macroalgae removal plus urchin biocontrol (treatment reefs, n = 2), or no treatment (control reefs, n = 2), was applied at the patch reef-scale. In applying the invasive macroalgae treatment, the control effort manually removed ∼19,000 kg of invasive macroalgae and ∼99,000 juvenile sea urchins were outplanted across to two patch reefs, totaling ∼24,000 m2 of reef area. Changes in benthic cover were monitored over 2 years (five sampling periods) before-and-after the treatment was applied. Over the study period, removal and biocontrol reduced invasive macroalgae cover by 85% at treatment reefs. Our results show manual removal in combination with hatchery raised urchin biocontrol to be an effective management approach in controlling invasive macroalgae at reef-wide spatial scales and temporal scales of months to years.

Direct reprogramming of cardiac fibroblasts (CFs) to induced cardiomyocytes (iCMs) is a newly emerged promising approach for cardiac regeneration, disease modeling, and drug discovery. However, its potential has been drastically limited due to the low reprogramming efficiency and largely unknown underlying molecular mechanisms. We have previously screened and identified epigenetic factors related to histone modification during iCM reprogramming. Here, we used shRNAs targeting an additional battery of epigenetic factors involved in chromatin remodeling and RNA splicing factors to further identify inhibitors and facilitators of direct cardiac reprogramming. Knockdown of RNA splicing factors Sf3a1 or Sf3b1 significantly reduced the percentage and total number of cardiac marker positive iCMs accompanied with generally repressed gene expression. Removal of another RNA splicing factor Zrsr2 promoted the acquisition of CM molecular features in CFs and mouse embryonic fibroblasts (MEFs) at both protein and mRNA levels. Moreover, a consistent increase of reprogramming efficiency was observed in CFs and MEFs treated with shRNAs targeting Bcor (component of BCOR complex superfamily) or Stag2 (component of cohesin complex). Our work thus reveals several additional epigenetic and splicing factors that are either inhibitory to or required for iCM reprogramming and highlights the importance of epigenetic regulation and RNA splicing process during cell fate conversion.

Ocean acidification (OA) is predicted to reduce reef coral calcification rates and threaten the long-term growth of coral reefs under climate change. Reduced coral growth at elevated pCO2 may be buffered by sufficiently high irradiances; however, the interactive effects of OA and irradiance on other fundamental aspects of coral physiology, such as the composition and energetics of coral biomass, remain largely unexplored. This study tested the effects of two light treatments (7.5 versus 15.7 mol photons m−2 d−1) at ambient or elevated pCO2 (435 versus 957 µatm) on calcification, photopigment and symbiont densities, biomass reserves (lipids, carbohydrates, proteins), and biomass energy content (kJ) of the reef coral Pocillopora acuta from Kāne‘ohe Bay, Hawai‘i. While pCO2 and light had no effect on either area- or biomass-normalized calcification, tissue lipids gdw−1 and kJ gdw−1 were reduced 15% and 14% at high pCO2, and carbohydrate content increased 15% under high light. The combination of high light and high pCO2 reduced protein biomass (per unit area) by approximately 20%. Thus, under ecologically relevant irradiances, P. acuta in Kāne‘ohe Bay does not exhibit OA-driven reductions in calcification reported for other corals; however, reductions in tissue lipids, energy content and protein biomass suggest OA induced an energetic deficit and compensatory catabolism of tissue biomass. The null effects of OA on calcification at two irradiances support a growing body of work concluding some reef corals may be able to employ compensatory physiological mechanisms that maintain present-day levels of calcification under OA. However, negative effects of OA on P. acuta biomass composition and energy content may impact the long-term performance and scope for growth of this species in a high pCO2 world.

Neuroimaging experiments can generate impressive volumes of data and many images of the results. This is particularly true of multi-modal imaging studies that use more than one imaging technique, or when imaging is combined with other assessments. A challenge for these studies is appropriate visualisation of results in order to drive insights and guide accurate interpretations. Next-generation visualisation technology therefore has much to offer the neuroimaging community. One example is the Imperial College London Data Observatory; a high-resolution (132 megapixel) arrangement of 64 monitors, arranged in a 313 degree arc, with a 6 metre diameter, powered by 32 rendering nodes. This system has the potential for high-resolution, large-scale display of disparate data types in a space designed to promote collaborative discussion by multiple researchers and/or clinicians. Opportunities for the use of the Data Observatory are discussed, with particular reference to applications in Multiple Sclerosis (MS) research and clinical practice. Technical issues and current work designed to optimise the use of the Data Observatory for neuroimaging are also discussed, as well as possible future research that could be enabled by the use of the system in combination with eye-tracking technology.

In 2007, due to growing concerns of declines in nearshore fisheries in Hawai'i, a ban on gillnets was implemented in designated areas around the island of O'ahu in the main Hawaiian Islands. Utilizing a 17 year time-series of juvenile fish abundance beginning prior to the implementation of the gillnet ban, we examined the effects of the ban on the abundance of juveniles of soft-bottom associated fish species. Using a Before-After-Control-Impact (BACI) sampling design, we compared the abundance of targeted fishery species in a bay where gillnet fishing was banned (Kailua, O'ahu), and an adjacent bay where fishing is still permitted (Waimānalo, O'ahu). Our results show that when multiple juvenile fish species were combined, abundance declined over time in both locations, but the pattern varied for each of the four species groups examined. Bonefishes were the only species group with a significant BACI effect, with higher abundance in Kailua in the period after the gillnet ban. This study addressed a need for scientific assessment of a fisheries regulation that is rarely possible due to lack of quality data before enactment of such restrictions. Thus, we developed a baseline status of juveniles of an important fishery species, and found effects of a fishery management regulation in Hawai'i.

Background: Chronic skin wounds are a growing financial burden for healthcare providers, causing discomfort/immobility to patients. Whilst animal chronic wound models have been developed to allow for mechanistic studies and to develop/test potential therapies, such systems are not good representations of the human chronic wound state. As an alternative, human chronic wound fibroblasts (CWFs) have permitted an insight into the dysfunctional cellular mechanisms that are associated with these wounds. However, such cells strains have a limited replicative lifespan and therefore a limited reproducibility/usefulness. Objectives: To develop/characterise immortalised cell lines of CWF and patient-matched normal fibroblasts (NFs). Methods and Results: Immortalisation with human telomerase resulted in both CWF and NF proliferating well beyond their replicative senescence end-point (respective cell strains senesced as normal). Gene expression analysis demonstrated that, whilst proliferation-associated genes were up-regulated in the cell lines (as would be expected), the immortalisation process did not significantly affect the disease-specific genotype. Immortalised CWF (as compared to NF) also retained a distinct impairment in their wound repopulation potential (in line with CWF cell strains). Conclusions: These novel CWF cell lines are a credible animal alternative and could be a valuable research tool for understanding both the aetiology of chronic skin wounds and for therapeutic pre-screening.

Pharmacological Magnetic Resonance Imaging (phMRI) is a variant of conventional MRI that adds pharmacological manipulations in order to study the effects of drugs, or uses pharmacological probes to investigate basic or applied (e.g. clinical) neuroscience questions. Issues that may confound the interpretation of results from various types of phMRI studies are briefly discussed, and a set of methodological strategies that can mitigate these problems are described. These include strategies that can be employed at every stage of investigation, from study design to interpretation of resulting data, and additional techniques suited for use with clinical populations are also featured. Pharmacological MRI is a challenging area of research that has both significant advantages and formidable difficulties, however with due consideration and use of these strategies many of the key obstacles can be overcome.

There are a wide variety of reactive species which can affect cell function, including reactive oxygen, nitrogen, and lipid species. Some are formed endogenously through enzymatic or non-enzymatic pathways, and others are introduced through diet or environmental exposure. Many of these reactive species can interact with biomolecules, and can result in oxidative post-translational modification of proteins. It is well documented that some oxidative modifications cause macromolecular damage and cell death. However, a growing body of evidence suggests that certain classes of reactive species initiate cell signaling by reacting with specific side chains of peptide residues without causing cell death. This process is generally termed ‘redox signaling,’ and its role in physiological and pathological processes is a subject of active investigation. This review will give an overview of oxidative protein modification as a mechanism of redox signaling, including types of reactive species and how they modify proteins, examples of modified proteins, and a discussion about the current concepts in this area.