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Within the 9th European Framework programme, since 2021 EUROfusion is operating five tokamaks under the auspices of a single Task Force called ‘Tokamak Exploitation’. The goal is to benefit from the complementary capabilities of each machine in a coordinated way and help in developing a scientific output scalable to future largre machines. The programme of this Task Force ensures that ASDEX Upgrade, MAST-U, TCV, WEST and JET (since 2022) work together to achieve the objectives of Missions 1 and 2 of the EUROfusion Roadmap: i) demonstrate plasma scenarios that increase the success margin of ITER and satisfy the requirements of DEMO and, ii) demonstrate an integrated approach that can handle the large power leaving ITER and DEMO plasmas. The Tokamak Exploitation task force has therefore organized experiments on these two missions with the goal to strengthen the physics and operational basis for the ITER baseline scenario and for exploiting the recent plasma exhaust enhancements in all four devices (PEX: Plasma EXhaust) for exploring the solution for handling heat and particle exhaust in ITER and develop the conceptual solutions for DEMO. The ITER Baseline scenario has been developed in a similar way in ASDEX Upgrade, TCV and JET. Key risks for ITER such as disruptions and run-aways have been also investigated in TCV, ASDEX Upgrade and JET. Experiments have explored successfully different divertor configurations (standard, super-X, snowflakes) in MAST-U and TCV and studied tungsten melting in WEST and ASDEX Upgrade. The input from the smaller devices to JET has also been proven successful to set-up novel control schemes on disruption avoidance and detachment.

In 2021 JET exploited its unique capabilities to operate with T and D–T fuel with an ITER-like Be/W wall (JET-ILW). This second major JET D–T campaign (DTE2), after DTE1 in 1997, represented the culmination of a series of JET enhancements—new fusion diagnostics, new T injection capabilities, refurbishment of the T plant, increased auxiliary heating, in-vessel calibration of 14 MeV neutron yield monitors—as well as significant advances in plasma theory and modelling in the fusion community. DTE2 was complemented by a sequence of isotope physics campaigns encompassing operation in pure tritium at high T-NBI power. Carefully conducted for safe operation with tritium, the new T and D–T experiments used 1 kg of T (vs 100 g in DTE1), yielding the most fusion reactor relevant D–T plasmas to date and expanding our understanding of isotopes and D–T mixture physics. Furthermore, since the JET T and DTE2 campaigns occurred almost 25 years after the last major D–T tokamak experiment, it was also a strategic goal of the European fusion programme to refresh operational experience of a nuclear tokamak to prepare staff for ITER operation. The key physics results of the JET T and DTE2 experiments, carried out within the EUROfusion JET1 work package, are reported in this paper. Progress in the technological exploitation of JET D–T operations, development and validation of nuclear codes, neutronic tools and techniques for ITER operations carried out by EUROfusion (started within the Horizon 2020 Framework Programme and continuing under the Horizon Europe FP) are reported in (Litaudon et al Nucl. Fusion accepted), while JET experience on T and D–T operations is presented in (King et al Nucl. Fusion submitted).

MAST-U is equipped with on-axis and off-axis neutral beam injectors (NBI), and these external sources of super-Alfvénic deuterium fast-ions provide opportunities for studying a wide range of phenomena relevant to the physics of alpha-particles in burning plasmas. The MeV range D-D fusion product ions are also produced but are not confined. Simulations with the ASCOT code show that up to 20% of fast ions produced by NBI can be lost due to charge exchange (CX) with edge neutrals. Dedicated experiments employing low field side (LFS) gas fuelling show a significant drop in the measured neutron fluxes resulting from beam-plasma reactions, providing additional evidence of CX-induced fast-ion losses, similar to the ASCOT findings. Clear evidence of fast-ion redistribution and loss due to sawteeth (ST), fishbones (FB), long-lived modes (LLM), Toroidal Alfvén Eigenmodes (TAE), Edge Localised Modes (ELM) and neoclassical tearing modes (NTM) has been found in measurements with a Neutron Camera (NCU), a scintillator-based Fast-Ion Loss Detector (FILD), a Solid-State Neutral Particle Analyser (SSNPA) and a Fast-Ion Deuterium- α (FIDA) spectrometer. Unprecedented FILD measurements in the range of 1–2 MHz indicate that fast-ion losses can be also induced by the beam ion cyclotron resonance interaction with compressional or global Alfvén eigenmodes (CAEs or GAEs). These results show the wide variety of scenarios and the unique conditions in which fast ions can be studied in MAST-U, under conditions that are relevant for future devices like STEP or ITER.

The fusion reaction between deuterium and tritium, D ( T,n ) ^4 He is the main source of energy in future thermonuclear reactors. Alpha-particles ( ^4 He -ions) born with an average energy of 3.5 MeV transferring energy to the thermal plasma during their slowing down, should provide the self-sustained D–T plasma burn. The adequate confinement of α -particles is essential to provide efficient heating of the bulk plasma and steady burning of a reactor plasma. That is why the fusion-born α -particle studies have been a priority task in the second D–T experiments (DTE2) on the Joint European Torus (JET) to understand the main mechanisms of their slowing down, redistribution and losses and to develop optimal plasma scenarios. JET with Be -wall and W -divertor, enhanced auxiliary heating systems and improved energetic-particle diagnostic capabilities, producing significant population of α -particles, provided the possibility for comprehensive studying of the α -particle behaviour. Selected results of the confined and lost α -particle measurements, evidence of α -particle self-heating and assessments of the fusion performance are presented in this paper giving an opportunity for further modelling and extrapolation to the International Thermonuclear Experimental Reactor and burning plasma reactors.

Recent results from MAST Upgrade are presented, emphasising understanding the capabilities of this new device and deepening understanding of key physics issues for the operation of ITER and the design of future fusion power plants. The impact of MHD instabilities on fast ion confinement have been studied, including the first observation of fast ion losses correlated with Compressional and Global Alfvén Eigenmodes. High-performance plasma scenarios have been developed by tailoring the early plasma current ramp phase to avoid internal reconnection events, resulting in a more monotonic q profile with low central shear. The impact of m / n = 3/2, 2/1 and 1/1 modes on thermal plasma confinement and rotation profiles has been quantified, and scenarios optimised to avoid them have transiently reached values of normalised beta approaching 4.2. In pedestal and ELM physics, a maximum pedestal top temperature of ∼350 eV has been achieved, exceeding the value achieved on MAST at similar heating power. Mitigation of type-I ELMs with n = 1 RMPs has been observed. Studies of plasma exhaust have concentrated on comparing conventional and Super-X divertor configurations, while X-point target, X-divertor and snowflake configurations have been developed and studied in parallel. In L-mode discharges, the separatrix density required to detach the outer divertors is approximately a factor 2 lower in the Super-X than the conventional configuration, in agreement with simulations. Detailed analysis of spectroscopy data from studies of the Super-X configuration reveal the importance of including plasma-molecule interactions and D _2 Fulcher band emission to properly quantify the rates of ionisation, plasma-molecule interactions and volumetric recombination processes governing divertor detachment. In H-mode with conventional and Super-X configurations, the outer divertors are attached in the former and detached in the latter with no impact on core or pedestal confinement.

Burning reactor plasmas will be self-heated by fusion born alpha particles from deuterium-tritium reactions. Consequently, a thorough understanding of the confinement and transport of DT-born alpha particles is necessary to maintain the plasma self-heating. Measurements of fast ion losses provide a direct means to monitor alpha particle confinement. JET’s 2021–2022 second experimental DT-campaign offers burning plasma scenarios with advanced fast ion loss diagnostics for the first time in nearly 25 years. Coherent and non-coherent alpha losses were observed due to a variety of low frequency MHD activity. This manuscript will present the loss mechanisms, spatial and pitch dependencies, scalings with plasma parameters, correlations with wall impurities, and magnitude of DT-alpha born losses.

A toroidal Alfvén eigenmode (TAE) has been observed to be driven by alpha particles in a JET deuterium-tritium internal transport barrier plasma. The observation occurred 50 ms after the removal of neutral beam heating (NBI). The mode is observed on magnetics, soft-xray, interferometry and reflectometry measurements. We present detailed stability calculations using a similar tool set validated during deuterium only discharges. These calculations strongly support the conclusion that the observed mode is a TAE, and that this mode was destabilized by alpha particles. Non-ideal effects from the bulk plasma are interpreted as responsible for suppressing the majority of TAEs which were also driven by alpha particles, but the modes that match the observations are predicted to be particularly weak for these non-ideal effects. This mode located far from the core on the outboard midplane is found to be driven by both trapped and passing particles despite alpha particles originating in the core.

The Joint European Torus recently carried out an experimental campaign using a plasma consisting of both deuterium (D) and tritium (T). We observed a high-frequency mode using a reflectometer and an interferometer in a D-T plasma heated with low power neutral beam injection, $P_\mathrm{NBI} = 11.6\,\textrm{MW}$ . This mode was observed at a frequency $f = 156\,\textrm{kHz}$ and was located at major radii $3.1 \leqslant R\,(\textrm{m}) \leqslant 3.3$ . The observed mode was identified as a toroidal Alfvén eigenmode (TAE) using the linear MHD code, MISHKA. Beam ions and fusion-born alpha particles were modelled using the full orbit particle tracking code LOCUST, which produces smooth distribution functions suitable for stability calculations without analytical fits or the use of moments. We calculated the stability of the 21 candidate modes using the HALO code. These calculations revealed that beam ions can drive TAEs with toroidal mode numbers $n\geqslant 8$ with linear growth rates $\gamma_b /\omega \sim 1\%$ , while TAEs with n

Dedicated experiments were performed in JET DTE2 plasmas for obtaining an α -particle bump-on-tail (BOT) distribution aiming at exciting Alfvén eigenmodes (AEs). Neutral beam injection-only heating with modulated power was used so that fusion-born α -particles were the only ions present in the MeV energy range in these DT plasmas. The beam power modulation on a time scale shorter than the α -particle slowing down time was chosen for modulating the α -particle source and thus sustaining a BOT in the α -particle distribution. High-frequency modes in the toroidicity-induced Alfven eigenmode (TAE) frequency range and multiple short-lived modes in a wider frequency range have been detected in these DT discharges with interferometry, soft x-ray cameras, and reflectometry. The modes observed were localised close to the magnetic axis, and were not seen in the Mirnov coils. Analysis with the TRANSP and Fokker-Planck FIDIT codes confirms that α -particle distributions with BOT in energy were achieved during some time intervals in these discharges though no clear correlation was found between the times of the high-frequency mode excitation and the BOT time intervals. The combined magneto-hydrodynamic (MHD) and kinetic modelling studies show that the high-frequency mode in the TAE frequency range is best fitted with a TAE of toroidal mode number n = 9. This mode is driven mostly by the on-axis beam ions while the smaller drive due to the pressure gradient of α -particles allows overcoming the marginal stability and exciting the mode (Oliver et al 2023 Nucl. Fusion submitted). The observed multiple short-lived modes in a wider frequency range are identified as the on-axis kinetic AEs predicted in Rosenbluth and Rutherford (1975 Phys. Rev. Lett. 34 1428).

In the paper we present an overview of interpretive modelling of a database of JET-ILW 2021 D-T discharges using the TRANSP code. The main aim is to assess our capability of computationally reproducing the fusion performance of various D-T plasma scenarios using different external heating and D-T mixtures, and to understand the performance driving mechanisms. We find that interpretive simulations confirm a general power-law relationship between increasing external heating power and fusion output, which is supported by absolutely calibrated neutron yield measurements. A comparison of measured and computed D-T neutron rates shows that the calculations’ discrepancy depends on the absolute neutron yield. The calculations are found to agree well with measurements for higher performing discharges with external heating power above ∼20 $\mathrm{MW}$ , while low-neutron shots display an average discrepancy of around +40% compared to measured neutron yields. A similar trend is found for the ratio between thermal and beam-target fusion, where larger discrepancies are seen in shots with dominant beam-driven performance. We compare the observations to studies of JET-ILW D discharges, to find that on average the fusion performance is well modelled over a range of heating power, although an increased unsystematic deviation for lower-performing shots is observed. The ratio between thermal and beam-induced D-T fusion is found to be increasing weakly with growing external heating power, with a maximum value of $\gtrsim$ 1 achieved in a baseline scenario experiment. An evaluation of the fusion power computational uncertainty shows a strong dependence on the plasma scenario type and fusion drive characteristics, varying between ±25% and 35%. D-T fusion alpha simulations show that the ratio between volume-integrated electron and ion heating from alphas is $\lesssim$ 10 for the majority of analysed discharges. Alphas are computed to contribute between ∼15% and 40% to the total electron heating in the core of highest performing D-T discharges. An alternative workflow to TRANSP was employed to model JET D-T plasmas with the highest fusion yield and dominant non-thermal fusion component because of the use of fundamental radio-frequency heating of a large minority in the scenario, which is calculated to have provided ∼10% to the total fusion power.

Blunt traumatic transection of the innominate artery is rare. We describe a case of a 36-year-old male who presented to our Emergency & Trauma Center after being struck by a motor vehicle at high speed. Computerised Tomography (CT) scanning after the patient was stabilised facilitated the prompt diagnosis of the injury. The patient underwent open repair by midline sternotomy, with debranching of the innominate artery, using hypothermic circulatory arrest as a neuroprotective measure. The patient was successfully extubated on post-operative day 3, without neurological deficit. We provide our experience as an option for treating any patient that presents with such an injury.

Abstract Descending connections from brainstem nuclei are known to exert powerful control of spinal nociception and pain behaviours in adult mammals. Here we present evidence that descending serotonergic fibres not only inhibit nociceptive activity, but also facilitate non-noxious tactile activity in the healthy adult rat spinal dorsal horn via activation of spinal 5-HT3 receptors (5-HT3Rs). We further show that this differential serotonergic control in the adult emerges from a non-modality selective system in young rats. Serotonergic fibres exert background 5-HT3R mediated facilitation of both tactile and nociceptive spinal activity in the first three postnatal weeks. Thus, differential descending serotonergic control of spinal touch and pain processing emerges in late postnatal life to allow flexible and context-dependent brain control of somatosensation.

A global heat flux model based on a fractional derivative of plasma pressure is proposed for the heat transport in fusion plasmas. The degree of the fractional derivative of the heat flux, α, is defined through the power balance analysis of the steady state. The model was used to obtain the experimental values of α for a large database of the Joint European Torus (JET) carbon-wall as well as ITER like-wall plasmas. The fractional degrees of the electron heat flux are found to be α

Abstract Background Intraoperative hemorrhage in cardiac surgery increases risk of morbidity and mortality. Low pre-operative and perioperative levels of fibrinogen, a key clotting factor, are associated with severity of hemorrhage and increased transfusion of blood components. The ability to supplement fibrinogen during hemorrhagic resuscitation is delayed 45–60 min because cryoprecipitated antihemophilic factor (cryo AHF) is stored frozen, due to a short post-thaw shelf life. Pathogen Reduced Cryoprecipitated Fibrinogen Complex (INTERCEPT Fibrinogen Complex, IFC) can be kept thawed, at room temperature, for up to 5 days, making it possible to be immediately available for hemorrhaging patients. This trial will investigate if earlier correction of acquired hypofibrinogenemia with IFC in hemorrhaging cardiac surgery patients reduces the total number of perioperatively transfused allogeneic blood products (red blood cells, plasma, and platelets) as compared to cryo AHF. Methods This is a single center, prospective, cluster randomized trial with an adaptive design. Acquired hypofibrinogenemia will be assessed by rotational thromboelastometry (ROTEM) and the threshold for cryo AHF/IFC transfusion defined as FIBTEM A10 ≤ 10 mm in bleeding patients. IFC/cryo AHF will be randomized by 1-month blocks. Cardiac surgery patients will be enrolled in the study if they have an eligible procedure and at least one dose of a cryo AHF/IFC product (approximately 2 g fibrinogen) is transfused. Data from the electronic health record, including the blood bank and lab information systems, will be prospectively collected from the health system’s data warehouse. Discussion This trial aims to provide evidence of the clinical efficacy of utilizing readily available thawed IFC during acute bleeding in the cardiac surgery setting compared to traditional cryo AHF. Trial registration ClinicalTrials.gov NCT05711524. Feb 3, 2023.

Abstract Differentially methylated CpG sites (dmCpGs) that distinguish prostate tumour from adjacent benign tissue could aid in the diagnosis and prognosis of prostate cancer. Previously, the identification of such dmCpGs has only been undertaken in radical prostatectomy (RP) samples and not primary diagnostic tumour samples (needle biopsy or transurethral resection of the prostate). We interrogated an Australian dataset comprising 125 tumour and 43 adjacent histologically benign diagnostic tissue samples, including 41 paired samples, using the Infinium Human Methylation450 BeadChip. Regression analyses of paired tumour and adjacent benign samples identified 2,386 significant dmCpGs (Bonferroni p

Abstract Genome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV. Our cis-eQTL/mQTL and colocalization analyses using colorectal tissue-specific transcriptome and methylome data separately from 1299 and 321 individuals, along with functional genomic investigation, uncovered 136 putative CRC susceptibility genes, including 56 genes not previously reported. Analyses of single-cell RNA-seq data from colorectal tissues revealed 17 putative CRC susceptibility genes with distinct expression patterns in specific cell types. Analyses of whole exome sequencing data provided additional support for several target genes identified in this study as CRC susceptibility genes. Enrichment analyses of the 136 genes uncover pathways not previously linked to CRC risk. Our study substantially expanded association signals for CRC and provided additional insight into the biological mechanisms underlying CRC development.

Abstract Coastal saltmarshes keep pace with sea-level rise through in-situ production of organic material and incorporation of allochthonous inorganic sediment. Here we report rates of vertical accretion of 16 new sediment cores collected proximal to platform edges within saltmarshes located behind four barrier islands along the southeast United States coast. All but two of these exceed the contemporaneous rate of relative sea-level rise, often by a factor of 1.5 or more. Comparison with 80 additional measurements compiled across the Georgia Bight reveals that marshes situated closer to inlets and large bays generally accrete faster than those adjacent to small creeks or within platform interiors. These results demonstrate a spatial dichotomy in the resilience of backbarrier saltmarshes: marsh interiors are near a tipping point, but allochthonous mineral sediment fluxes allow enhanced local resilience along well-exposed and platform-edge marshes. Together, this suggests that backbarrier marshes are trending towards rapid, doughnut-like fragmentation.

ABSTRACTBiparatopic antibodies (bpAbs) bind distinct, non-overlapping epitopes on an antigen. This unique binding mode enables new mechanisms of action beyond monospecific and bispecific antibodies (bsAbs) that can make bpAbs effective therapeutics for various indications, including oncology and infectious diseases. Biparatopic binding can lead to superior affinity and specificity, promote antagonism, lock target conformation, and result in higher-order target clustering. Such antibody-target complexes can elicit strong agonism, increase immune effector function, or result in rapid target downregulation and lysosomal trafficking. These are not only attractive properties for therapeutic antibodies but are increasingly being explored for other modalities such as antibody-drug conjugates, T-cell engagers and chimeric antigen receptors. Recent advances in bpAb engineering have enabled the construction of ever more sophisticated formats that are starting to show promise in the clinic.

Background: Childhood abuse (physical, emotional, and sexual) is associated with aberrant connectivity of the amygdala, a key threat-processing region. Heightened amygdala activity also predicts adult anxiety and posttraumatic stress disorder (PTSD) symptoms, as do experiences of childhood abuse. The current study explored whether amygdala resting-state functional connectivity may explain the relationship between childhood abuse and anxiety and PTSD symptoms following trauma exposure in adults. Methods: Two weeks posttrauma, adult trauma survivors (n = 152, mean age [SD] = 32.61 [10.35] years; women = 57.2%) completed the Childhood Trauma Questionnaire and underwent resting-state functional magnetic resonance imaging. PTSD and anxiety symptoms were assessed 6 months posttrauma. Seed-to-voxel analyses evaluated the association between childhood abuse and amygdala resting-state functional connectivity. A mediation model evaluated the potential mediating role of amygdala connectivity in the relationship between childhood abuse and posttrauma anxiety and PTSD. Results: Childhood abuse was associated with increased amygdala connectivity with the precuneus while covarying for age, gender, childhood neglect, and baseline PTSD symptoms. Amygdala-precuneus resting-state functional connectivity was a significant mediator of the effect of childhood abuse on anxiety symptoms 6 months posttrauma (B = 0.065; 95% CI, 0.013–0.130; SE = 0.030), but not PTSD. A secondary mediation analysis investigating depression as an outcome was not significant. Conclusions: Amygdala-precuneus connectivity may be an underlying neural mechanism by which childhood abuse increases risk for anxiety following adult trauma. Specifically, this heightened connectivity may reflect attentional vigilance for threat or a tendency toward negative self-referential thoughts. Findings suggest that childhood abuse may contribute to longstanding upregulation of attentional vigilance circuits, which makes one vulnerable to anxiety-related symptoms in adulthood.

Abstract Much of the world’s population lives close to coastlines and this proximity is becoming increasingly impactful because of sea-level rise (SLR). Barrier islands and backbarrier saltmarshes, which comprise >10% of these coasts, are particularly susceptible. To better understand this risk, we model backbarrier morphologic and hydrodynamic evolution over a 200-year period of SLR, incorporating an erodible bed and a range of grain sizes. Here, we show that reduction in intertidal area creates negative feedback, shifting transport of coarse sediment (silt and sand) through the inlet from net export to net import. Imposing a modest marsh vertical accretion rate decreases the period of silt and sand import to 40 years (years 90 to 130) before being exported again. Clay is continuously exported thereby decreasing inorganic deposition on marshes and threatening their sustainability. Simulated marsh loss increases tidal prism and the volume of sand contained in ebb deltas, depleting coastal sand resources.

Abstract We investigated whether prostate cancer patients treated with external beam radiation therapy (EBRT) have a higher cumulative incidence of secondary cancer compared with patients treated with radical prostatectomy (RP). We used state-wide linked data from South Australia to follow men with prostate cancer diagnosed from 2002 to 2019. The cumulative incidence of overall and site-specific secondary cancers between 5 and 15 years after treatment was estimated. Fine-Gray competing risk analyses were performed with additional sensitivity analyses to test different scenarios. A total of 7625 patients were included (54% underwent RP and 46% EBRT). Characteristics of the two groups differed significantly, with the EBRT group being older (71 vs. 64 years), having higher comorbidity burden and being more likely to die during follow-up than the RP group. Fifteen-year cumulative incidence for all secondary cancers was 27.4% and 22.3% in EBRT and RP groups, respectively. In the adjusted models, patients in the EBRT group had a significantly higher risk of genitourinary (adjusted subhazard ratio (aSHR), 2.29; 95%CI 1.16–4.51) and lung (aSHR, 1.93; 95%CI 1.05–3.56) cancers compared with patients in the RP group. However, there was no statistically significant difference between the two groups for risk of any secondary cancer, gastro-intestinal, skin or haematologic cancers. No statistically significant differences in overall risk of secondary cancer were observed in any of the sensitivity analyses and patterns for risk at specific cancer sites were relatively consistent across different age restriction and latency/time-lag scenarios. In conclusion, the increased risk of genitourinary and lung cancers among men undergoing EBRT may relate partly to treatment effects and partly to unmeasured residual confounding.

Since 2017, there has been a considerable increase in the recorded sea salt aerosol (SSA) levels across the United States, particularly the economically critical Baltimore–Washington Corridor (BWC). This unexpected escalation, as reported in the Environmental Protection Agency’s (EPA) annual air quality report, has generated worries about the potential effects on air quality, public health, and regional climate dynamics. However, this technical note demonstrates that the apparent rise in SSA levels is mostly due to a change in the EPA’s Chemical Speciation Network’s (CSN) approach to measuring these aerosols. In 2017, the CSN switched from utilizing chlorine to chloride as a tracer for SSAs. Speciation data for this region show that chloride concentrations are often an order of magnitude greater than chlorine concentrations, explaining the significant increase in SSA levels following the methodological modification. The absence of a similar spike in SSA levels at the nearby IMPROVE site, which has been consistent with its methodology, provides more evidence to corroborate this conclusion. These findings demonstrate the importance of methodological consistency and openness in environmental monitoring networks. Clear documentation of such changes is critical to avoiding data misunderstanding, which might lead to the development of incorrect public health and environmental policies. We advocate for continued collaboration among researchers to establish standardized measuring procedures and data analysis tools to accommodate and clarify methodological changes, resulting in accurate environmental evaluations and informed decision-making.

Abstract Background Knee replacements are increasingly performed in older adults but uncertainty remains regarding their benefits in the context of age-related decline in physical function and other comorbidities. This study aimed to examine (1) the effect of knee replacement on functional outcomes in the context of age-related decline in physical function and (2) the factors associated with minimal important improvement in physical function after knee replacement in community-dwelling older adults aged ≥ 70 years. Methods This cohort study was performed within the ASPREE trial, with 889 participants undergoing knee replacement during the trial and 858 age- and sex-matched controls without knee or hip replacement identified from 16,703 Australian participants aged ≥ 70 years. Health-related quality of life was assessed annually using the SF-12, including its physical and mental component summary (PCS and MCS). Gait speed was measured biennially. Multiple linear regression and analysis of covariance were used to adjust for potential confounders. Results Participants with knee replacement had significantly lower pre- and post-replacement PCS scores and gait speed compared with age- and sex-matched controls. Participants with knee replacement had significant improvement in PCS score following knee replacement (mean change 3.6, 95% CI 2.9–4.3) while PCS score remaining unchanged in age- and sex-matched controls (-0.02, 95% CI -0.6 to 0.6) during follow-up period. The greatest improvements were observed for bodily pain and physical function. Following knee replacement, 53% of participants experienced minimal important improvement in PCS score (increased by ≥ 2.7), while 24% experienced worsened PCS score (reduced by > 2.7). Participants experiencing improved PCS score postoperatively had significantly lower PCS and higher MCS scores pre-surgery. Conclusions Although community-based older adults experienced a significant improvement in PCS scores after knee replacement, their postoperative physical functional status remained significantly lower than age- and sex-matched controls. The degree of preoperative physical function impairment was a strong predictor of functional improvement, suggesting that this could be an important consideration when identifying older people most likely to benefit from knee replacement surgery.

Abstract Background Intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections are the standard of care for diabetic macular edema (DME), a common complication of diabetes. This study aimed to identify factors influencing DME intravitreal anti-VEGF treatment outcomes in real-world practice. Methods This was a multi-center retrospective observational study using medical chart review of participants receiving anti-VEGF injections for DME (N = 248). Demographic and clinical variables were assessed for association with best corrected visual acuity (BCVA) and central macular thickness (CMT) outcomes using regression models. Results There was a significant improvement in BCVA (p

Studies focusing on virga are rare, even though it is a commonly occurring phenomenon. In this study, we investigated aerosol backscatter profiles from a ceilometer located on The University of Texas at El Paso (UTEP) campus from 2015–2021 to identify virga events. Ceilometer data effectively captured virga events from regular precipitation based on the backscattering intensities. To characterize the virga phenomena, a systematic method was developed using ceilometer profiles, soundings, surface rain gauges, and radar data from the nearest National Weather Service (NWS) site. A total of 50 virga events were identified during the study period. These events appeared only during a specific time of the year, revealing a seasonal occurrence pattern. We identified and classified these virga events and investigated their impact on the surface measurements recorded by the on-campus Continuous Ambient Air Monitoring Station (CAMS). Virga events were classified as columnar and non-columnar events based on their aerosol profiles. We observed that during some of the columnar virga events, surface particulate matter (PM) levels displayed a sudden upward trend indicating aerosol loading in the surface layer after precipitation evaporation. In total, 20 of the virga events showed a columnar structure out of the 50 identified in this study. More detailed analysis of selected events shows that virga affects regional air quality. A significant result of this study is that analysis of sudden changes in local air quality needs to consider the possible effects of virga on the surface layer.

Abstract Salt marshes are threatened by rising sea levels and human activities, and a major mechanism of marsh loss is edge retreat or erosion. To understand and predict loss in these valuable ecosystems, studies have related erosion to marsh hydrodynamics and wave characteristics such as wave power. Across global studies, erosion is reported to be largely linearly related to wave power, with this relationship having implications for the resilience of marshes to extreme events such as storms. However, there is significant variability in this relationship across marshes because of marsh heterogeneity and the uniqueness of each physical setting. Here, we investigate the results of individual studies throughout the world that report a linear relationship and add a new dataset from the Great Marsh in Massachusetts (USA). We find that most marsh wave power and erosion data are not normally distributed and when these datasets are properly plotted to account for their distributions, the resulting relationships vary from previously published curves. Our Great Marsh data suggest that events from specific wind directions can have an outsized impact on edge erosion due to their larger fetch and wind speeds. We also find that factors other than wave attack such as edge erosion along tidal channels, can have a measurable impact on retreat rates. We show the importance of maintaining statistical assumptions when performing regressions, as well as emphasize the site-specificity of these relationships. Without calibration of a marsh erosion-wave power relationship using robust regressions for each individual marsh, such a relationship is not fully constrained, resulting in unreliable predictions of future marsh resilience and response to climate change.

ABSTRACT Genome-scale analyses have revealed many transcription factor binding sites within, rather than upstream of, genes, raising questions as to the function of these binding sites. Here, we use complementary approaches to map the regulon of the Escherichia coli transcription factor PhoB, a response regulator that controls transcription of genes involved in phosphate homeostasis. Strikingly, the majority of PhoB binding sites are located within genes, but these intragenic sites are not associated with detectable transcription regulation and are not evolutionarily conserved. Many intragenic PhoB sites are located in regions bound by H-NS, likely due to shared sequence preferences of PhoB and H-NS. However, these PhoB binding sites are not associated with transcription regulation even in the absence of H-NS. We propose that for many transcription factors, including PhoB, binding sites not associated with promoter sequences are transcriptionally inert and hence are tolerated as genomic “noise.” IMPORTANCE Recent studies have revealed large numbers of transcription factor binding sites within the genes of bacteria. The function, if any, of the vast majority of these binding sites has not been investigated. Here, we map the binding of the transcription factor PhoB across the Escherichia coli genome, revealing that the majority of PhoB binding sites are within genes. We show that PhoB binding sites within genes are not associated with regulation of the overlapping genes. Indeed, our data suggest that bacteria tolerate the presence of large numbers of nonregulatory, intragenic binding sites for transcription factors and that these binding sites are not under selective pressure.

Background Prolonged activation of angiotensin II is the main mediator that contributes to the development of heart diseases, so converting angiotensin II into angiotensin 1‐7 has emerged as a new strategy to attenuate detrimental effects of angiotensin II. Prolylcarboxypeptidase is a lysosomal pro‐X carboxypeptidase that is able to cleave angiotensin II at a preferential acidic pH optimum. However, insufficient attention has been given to the cardioprotective functions of prolylcarboxylpeptidase. Methods and Results We established a CRISPR/CRISPR‐associated protein 9–mediated global prolylcarboxylpeptidase‐knockout and adeno‐associated virus serotype 9–mediated cardiac prolylcarboxylpeptidase overexpression mouse models, which were challenged with the angiotensin II infusion (2 mg/kg per day) for 4 weeks, aiming to investigate the cardioprotective effect of prolylcarboxylpeptidase against hypertensive cardiac hypertrophy. Prolylcarboxylpeptidase expression was upregulated after 2 weeks of angiotensin II infusion and then became downregulated afterward in wild‐type mouse myocardium, suggesting its compensatory function against angiotensin II stress. Moreover, angiotensin II–treated prolylcarboxylpeptidase‐knockout mice showed aggravated cardiac remodeling and dampened cardiac contractility independent of hypertension. We also found that prolylcarboxylpeptidase localizes in cardiomyocyte lysosomes, and loss of prolylcarboxylpeptidase led to excessive angiotensin II levels in myocardial tissue. Further screening demonstrated that hypertrophic prolylcarboxylpeptidase‐knockout hearts showed upregulated extracellular signal‐regulated kinases 1/2 and downregulated protein kinase B activities. Importantly, adeno‐associated virus serotype 9–mediated restoration of prolylcarboxylpeptidase expression in prolylcarboxylpeptidase‐knockout hearts alleviated angiotensin II–induced hypertrophy, fibrosis, and cell death. Interestingly, the combination of adeno‐associated virus serotype 9–mediated prolylcarboxylpeptidase overexpression and an antihypertensive drug, losartan, likely conferred more effective protection than a single treatment protocol to mitigate angiotensin II–induced cardiac dysfunction. Conclusions Our data demonstrate that prolylcarboxylpeptidase protects the heart from angiotensin II–induced hypertrophic remodeling by controlling myocardial angiotensin II levels.

This research study focuses on the coupling between particulate matter and the planetary boundary layer. Particulate matter affects human health and it is a complex mixture of suspended substances. Various sources of particulate matter include volcanic eruptions, soil lofted by strong winds, wildfires, and particles formed from chemical reactions of gas-phase emissions. Strong winds are one source of dust pollution when they loft soil particles. Particulate matter and the planetary boundary layer are closely linked. The planetary boundary layer plays a critical role in meteorology and particulate matter concentrations due to its involvement in energy, latent heat, and mass transfer with the free troposphere. Currently, there has been no research on the impact of dust events on the planetary boundary layer in our region, El Paso, Texas, which is located on one of the biggest sources of dust in the Western Hemisphere, the Chihuahuan Desert. In this study, we used PM10 concentrations to detect dust events during the 2016–2022 period in the El Paso region. During the study period, we observed 74 dust events. The dust events were categorized as synoptic or convective cases. Synoptic cases are associated with cold fronts, while convective cases are associated with local convective systems such as thunderstorms. We observed that synoptic cases occurred most frequently during springtime, while convective cases were more frequent during summer monsoon months. Synoptic cases tend to occur earlier in the afternoon with lower temperatures, while convective cases tend to occur in the late evening with higher temperatures. We also found that the planetary boundary layer height collapsed after the maximum hourly PM10 concentration and then the boundary layer returned to its original height.

In this data paper, we describe environmental DNA (eDNA) cytochrome c oxidase (COI) amplicon sequence data from New York City’s Bronx River Estuary. As urban systems continue to expand, describing and monitoring their biodiversity is increasingly important for sustainability. Once polluted and overexploited, New York City’s Bronx River Estuary is undergoing revitalization and restoration. To investigate and characterize the area’s diversity, we collected and sequenced river sediment and surface water samples from Hunts Point Riverside and Soundview Parks (ntotal = 48; nsediment = 25; nwater = 23). COI analysis using universal primers mlCOIintF and jgHCO2198 detected 27,328 Amplicon Sequence Variants (ASVs) from 7,653,541 sequences, and rarefaction curves reached asymptotes indicating sufficient sampling depth. Of these, eukaryotes represented 9,841ASVs from 3,562,254 sequences. At the study sites over the sampling period, community composition varied by substrate (river sediment versus surface water) and with water temperature, but not pH. The three most common phyla were Bacillariophyta (diatoms), Annelida (segmented worms), and Ochrophyta (e.g. brown and golden algae). Of the eukaryotic ASVs, we identified 614 (6.2%) to species level, including several dinoflagellates linked to Harmful Algal Blooms such as Heterocapsa spp., as well as the invasive amphipod Grandidierella japonica. The analysis detected common bivalves including blue (Mytilus edulis) and ribbed (Geukensia demissa) mussels, as well as soft-shell clams (Mya arenaria), in addition to Eastern oysters (Crassostrea virginica) that are being reintroduced to the area. Fish species undergoing restoration such as river herring (Alosa pseudoharengus, A. aestivalis) failed to be identified, although relatively common fish including Atlantic silversides (Menidia menidia), menhaden (Brevoortia tyrannus), striped bass (Morone saxatilis), and mummichogs (Fundulus heteroclitus) were found. The data highlight the utility of eDNA metabarcoding for analyzing urban estuarine biodiversity and provide a baseline for future work in the area.

Background: Early definitive fixation of clavicular fractures is rising in popularity when compared with conservative management. Despite this, the relative risk of subsequent hardware removal or revision surgery is relatively undocumented in the literature. The aim of this study was to review all clavicle fractures treated operatively in a single tertiary referral trauma unit and determine the true incidence of hardware removal and revision rates among this cohort. Methods: A retrospective electronic review was performed in a single tertiary trauma unit for all open reduction internal fixation of clavicle fractures over 10 years (2010-2019 inclusive). All patients were cross referenced for hardware removal during the same period. Patients identified as having undergone ORIF clavicle were reviewed via the National Integrated Medical Imaging System to identify the fracture pattern, fixation method, radiographic nonunion, or radiographic malunion. Age, gender, time from injury to fixation, and time from insertion to removal of hardware where relevant were also collected. Results: Over the 10-year period from 2010 to 2019, 352 patients underwent ORIF of clavicular fractures. After application of inclusion and exclusion criteria, 346 patients (76% male and 24% female) were analyzed with a mean age of 34.46 years old (95% confidence interval [33.02-35.91]). In total, 54 (15.6%) patients underwent removal of hardware. When fracture type and fixation method were accounted for, only 11% of plate fixations for mid-shaft fractures (n = 29) were removed, whereas 76% of clavicular hook plates for distal fractures (n = 25) underwent removal (P

Abstract Global fisheries kill millions of seabirds annually through bycatch, but little is known about population‐level impacts, particularly in species that form metapopulations. U.S. North Pacific groundfish fisheries catch thousands of Northern Fulmars (Fulmarus glacialis rodgersii) each year, making fulmars the most frequently caught seabird in federally managed U.S. fisheries. Here, we used genetic stock identification to assign 1,536 fulmars sampled as bycatch to one of four Alaska breeding colonies and quantified the similarity of bycatch locations at sea among colonies. We found disproportionately high bycatch from the Pribilof Islands (6% of metapopulation, 23% of bycatch), and disproportionately low bycatch from Chagulak Island (34% of metapopulation, 14% of bycatch). Overlap between fisheries and colony‐specific foraging areas diverge more during the summer breeding season, leading to greater differences in bycatch susceptibility. Contemporary and historical gene flow likely contributes to low genetic differentiation among colonies (FST = 0.003–0.01), yet these values may not represent present connectivity. Our findings illustrate how genetic stock identification can link at‐sea threats to colonies and inform management to reduce bycatch from impacted colonies.

Abstract Men living in regional and remote areas experience disparities in prostate cancer (PrCa) diagnosis, clinical characteristics and treatment modalities. We sought to determine whether such disparities exist in PrCa patients from Tasmania; a regional state of Australia with the second-highest rate of diagnosis and where over a third of residents live in outer regional and remote areas. Our study included clinicopathological data from 1526 patients enrolled in the Prostate Cancer Outcomes Registry-Tasmania. Regression analyses were undertaken to determine whether demographic, clinical and treatment variables differed between inner regional and outer regional/remote patients. Men from outer regional/remote areas were significantly more likely to reside in lower socio-economic areas, be diagnosed at a later age and with more clinically aggressive features. However, in contrast to previous studies, there were no overall differences in diagnostic or treatment method, although men from outer regional/remote areas took longer to commence active treatment and travelled further to do so. This study is the first to investigate PrCa disparities in a wholly regional Australian state and highlights the need to develop systematic interventions at the patient and healthcare level to improve outcomes in outer regional and remote populations in Australia and across the globe.

Abstract Objectives To assess whether insulin therapy impacts the effectiveness of anti-vascular endothelial growth factor (anti-VEGF) injection for the treatment of diabetic macular edema (DME) in type 2 diabetes mellitus. Methods This was a retrospective multi-center analysis. The best-corrected visual acuity (BCVA) at 12 months, BCVA change, central macular thickness (CMT), CMT change, and cumulative injection number were compared between the insulin and the oral hypoglycemic agent (OHA) groups. Results The mean final BCVA and CMT improved in both the insulin (N = 137; p 0.05) and baseline HbA1c (p > 0.05). Conclusion Insulin therapy does not alter treatment outcomes for anti-VEGF therapy in DME.

Objective: To investigate the optimal combination of somatosensory- and transcranial motor-evoked potential (SSEP/tcMEP) modalities and monitored extremities during clip reconstruction of aneurysms of the anterior cerebral artery (ACA) and its branches. Methods: A retrospective review of 104 cases of surgical clipping of ruptured and unruptured aneurysms was performed. SSEP/tcMEP changes and postoperative motor deficits (PMDs) were assessed from upper and lower extremities (UE/LE) to determine the diagnostic accuracy of each modality separately and in combination. Results: PMDs were reported in 9 of 104 patients; 7 LE and 8 UE (3.6% of 415 extremities). Evoked potential (EP) monitoring failed to predict a PMD in 8 extremities (1.9%). Seven of 8 false negatives had subarachnoid hemorrhage. Sensitivity and specificity in LE were 50% and 97% for tcMEP, 71% and 98% for SSEP, and 83% and 98% for dual-monitoring of both tcMEP/SSEP. Sensitivity and specificity in UE were 38% and 99% for tcMEP, and 50% and 97% for tcMEP/SSEP, respectively. Conclusions: Combined tcMEP/SSEP is more accurate than single-modality monitoring for LE but is relatively insensitive for UE PMDs. Significance: During ACA aneurysm clipping, multiple factors may confound the ability of EP monitoring to predict PMDs, especially brachiofacial hemiparesis caused by perforator insufficiency.

Results of neuroimaging datasets aggregated from multiple sites may be biased by site-specific profiles in participants’ demographic and clinical characteristics, as well as MRI acquisition protocols and scanning platforms. We compared the impact of four different harmonization methods on results obtained from analyses of cortical thickness data: (1) linear mixed-effects model (LME) that models site-specific random intercepts (LMEINT), (2) LME that models both site-specific random intercepts and age-related random slopes (LMEINT+SLP), (3) ComBat, and (4) ComBat with a generalized additive model (ComBat-GAM). Our test case for comparing harmonization methods was cortical thickness data aggregated from 29 sites, which included 1,340 cases with posttraumatic stress disorder (PTSD) (6.2–81.8 years old) and 2,057 trauma-exposed controls without PTSD (6.3–85.2 years old). We found that, compared to the other data harmonization methods, data processed with ComBat-GAM was more sensitive to the detection of significant case-control differences (Χ2(3) = 63.704, p < 0.001) as well as case-control differences in age-related cortical thinning (Χ2(3) = 12.082, p = 0.007). Both ComBat and ComBat-GAM outperformed LME methods in detecting sex differences (Χ2(3) = 9.114, p = 0.028) in regional cortical thickness. ComBat-GAM also led to stronger estimates of age-related declines in cortical thickness (corrected p-values < 0.001), stronger estimates of case-related cortical thickness reduction (corrected p-values < 0.001), weaker estimates of age-related declines in cortical thickness in cases than controls (corrected p-values < 0.001), stronger estimates of cortical thickness reduction in females than males (corrected p-values < 0.001), and stronger estimates of cortical thickness reduction in females relative to males in cases than controls (corrected p-values < 0.001). Our results support the use of ComBat-GAM to minimize confounds and increase statistical power when harmonizing data with non-linear effects, and the use of either ComBat or ComBat-GAM for harmonizing data with linear effects.

Characterising and monitoring biological diversity to foster sustainable ecosystems is highly recommended as urban centres rapidly expand. However, much of New York City’s biodiversity remains undescribed, including in the historically degraded, but recovering Bronx River Estuary. In a pilot study to identify organisms and characterise biodiversity patterns there, 18S rRNA gene amplicons (V1–V3 region), obtained from river sediments and surface waters of Hunts Point Riverside and Soundview Parks, were sequenced. Across 48 environmental samples collected over three seasons in 2015 and 2016, following quality control and contaminant removal, 2,763 Amplicon Sequence Variants (ASVs) were identified from 1,918,463 sequences. Rarefaction analysis showed sufficient sampling depth, and community composition varied over time and by substrate at the study sites over the sampling period. Protists, plants, fungi and animals, including organisms of management concern, such as Eastern oysters (Crassostrea virginica), wildlife pathogens and groups related to Harmful Algal Blooms, were detected. The most common taxa identified in river sediments were annelid worms, nematodes and diatoms. In the water column, the most commonly observed organisms were diatoms, algae of the phylum Cryptophyceae, ciliates and dinoflagellates. The presented dataset demonstrates the reach of 18S rRNA metabarcoding for characterising biodiversity in an urban estuary.

Background: Portal placement is an important factor in performing a successful shoulder arthroscopy. Recent cadaveric studies have found variance in the anatomy of the glenohumeral joint. Our aim was to determine if computerized tomography (CT) images could be used to map the trajectory of the posterior portal objectively and then measure the distance between this trajectory and palpable landmarks to apply this knowledge to clinical practice. Methods: Two-dimensional multiplanar reformatted CT images were generated using OsiriX (Pixmeo, Switzerland) from CT images performed in a tertiary hospital over a 1-month period. The center of the glenoid was identified and a trajectory through it radiologically mapped. Horizontal and lateral measurements were taken from this trajectory to both the posterolateral edge of the acromion and tip of the coracoid. Results: Following application of inclusion and exclusion criteria, 226 shoulders were analyzed. Fifty scans were selected at random and re-reviewed by the primary examiner to assess intra-rater reliability which showed strong correlation and no significant differences between first and second measurements (P < .01, r > 0.6). The mean distance from acromion to portal trajectory was 1.39 cm inferiorly (95% confidence interval [CI] 1.31-1.48, standard deviation [SD] 0.65 cm) and 1.44 cm medially (95% CI 1.35-1.53, SD 0.71 cm). The mean distance from the coracoid to the trajectory was 1.71 cm inferiorly (95% CI 1.64-1.78, SD 0.55 cm) and 1.26 cm medially (95% CI 1-2-1.31, SD 0.45 cm). Paired t-test analysis between right and left shoulders within the same subject, where these data were available (n = 81), showed no significant difference (P > .05) between sides. Subset analysis was also performed between males and females, but only showed a significant difference between the vertical distance from the coracoid process to the center of the glenohumeral joint. This distance was shorter in females compared to males (1.56 cm in females compared to 1.84 cm in males, P < .001). Conclusions: Knowledge of shoulder anatomy is vital to the placement of arthroscopic portals, yet research on this topic has been based primarily on surface anatomy, small sample sized cadaveric studies or expert opinion alone. Our study shows that posterior portal placement in shoulder arthroscopy can be measured objectively using CT scanning.

It is currently unclear if cell-free DNA samples from metastatic cancers are as informative as tissue ones for cancer profiling. Here the authors show that cell-free DNA samples from rapid autopsies capture clonal and subclonal alterations of metastatic tumours and reveal more driver alterations than single tissue samples.

Objective Determine the pharmacokinetics (PK) and exposure–response of hydroxychloroquine (HCQ) and desethylhydroxychloroquine (DHCQ) in paediatric SLE (pSLE).Methods We conducted an exploratory phase 2, direct-to-family trial. Children enrolled in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry with a diagnosis of pSLE were eligible if they were receiving HCQ as standard of care for ≥3 months. Biological samples were collected at up to four visits over a 6-month period. At each visit, plasma was obtained to measure the concentrations of HCQ and DHCQ, as well as cytokines. HCQ and DHCQ plasma PK data were analysed using a population PK modelling approach.Results Twenty-five subjects provided a total of 88 plasma concentrations for PK analysis. There was a poor linear fit between HCQ concentrations and total body weight (R2=0.03). There was a decline in both interferon (IFN)-alpha and IFN-gamma with higher concentrations of HCQ and DHCQ. Volume of distribution for HCQ in plasma was higher in children compared with published values in adults (73 000 L vs 44 000 L), but clearance values in children were similar to adults.Conclusions We report the first population PK model for HCQ and DHCQ in children using data from a novel direct-to-family clinical trial. We observed high interindividual variability in HCQ PK and found that weight-based dosing for HCQ is poorly correlated with drug concentrations, suggesting the need to use therapeutic drug monitoring to individualise dosing. Furthermore, our results suggest that the current weight-based dosing paradigm for HCQ may result in suboptimal drug exposures, particularly for children with obesity. Accordingly, additional studies of HCQ are needed in pSLE to determine the optimal drug concentration and dosing to reduce disease activity and improve outcomes.Trial registration number NCT04358302.

Congenital heart disease (CHD) is a common group of birth defects with a strong genetic contribution to their etiology, but historically the diagnostic yield from exome studies of isolated CHD has been low. Pleiotropy, variable expressivity, and the difficulty of accurately phenotyping newborns contribute to this problem. We hypothesized that performing exome sequencing on selected individuals in families with multiple members affected by left-sided CHD, then filtering variants by population frequency, in silico predictive algorithms, and phenotypic annotations from publicly available databases would increase this yield and generate a list of candidate disease-causing variants that would show a high validation rate. In eight of the nineteen families in our study (42%), we established a well-known gene/phenotype link for a candidate variant or performed confirmation of a candidate variant's effect on protein function, including variants in genes not previously described or firmly established as disease genes in the body of CHD literature: BMP10, CASZ1, ROCK1 and SMYD1. Two plausible variants in different genes were found to segregate in the same family in two instances suggesting oligogenic inheritance. These results highlight the need for functional validation and demonstrate that in the era of next-generation sequencing, multiplex families with isolated CHD can still bring high yield to the discovery of novel disease genes.

Nearly 14 percent of Americans live in a socioeconomically disadvantaged neighborhood. Lower individual socioeconomic position (iSEP) has been linked to increased exposure to trauma and stress, as well as to alterations in brain structure and function; however, the neural effects of neighborhood SEP (nSEP) factors, such as neighborhood disadvantage, are unclear. Using a multi-modal approach with participants who recently experienced a traumatic injury (N = 185), we investigated the impact of neighborhood disadvantage, acute post-traumatic stress symptoms, and iSEP on brain structure and functional connectivity at rest. After controlling for iSEP, demographic variables, and acute PTSD symptoms, nSEP was associated with decreased volume and alterations of resting-state functional connectivity in structures implicated in affective processing, including the insula, ventromedial prefrontal cortex, amygdala, and hippocampus. Even in individuals who have recently experienced a traumatic injury, and after accounting for iSEP, the impact of living in a disadvantaged neighborhood is apparent, particularly in brain regions critical for experiencing and regulating emotion. These results should inform future research investigating how various levels of socioeconomic circumstances may impact recovery after a traumatic injury as well as policies and community-developed interventions aimed at reducing the impact of socioeconomic stressors.

This Special Issue of the open-access journal Atmosphere, “Advances in Air Pollution Meteorology”, presents papers that highlight important research showing the relationships between meteorology, emissions and air pollutants, including ozone and particulate matter [...]

Background: Little is known about what distinguishes those who are resilient after trauma from those at risk for developing posttraumatic stress disorder (PTSD). Previous work indicates white matter integrity may be a useful biomarker in predicting PTSD. Research has shown changes in the integrity of three white matter tracts—the cingulum bundle, corpus callosum (CC), and uncinate fasciculus (UNC)—in the aftermath of trauma relate to PTSD symptoms. However, few have examined the predictive utility of white matter integrity in the acute aftermath of trauma to predict prospective PTSD symptom severity in a mixed traumatic injury sample.Method: Thus, the current study investigated acute brain structural integrity in 148 individuals being treated for traumatic injuries in the Emergency Department of a Level 1 trauma center. Participants underwent diffusion-weighted magnetic resonance imaging 2 weeks post-trauma and completed several self-report measures at 2-weeks (T1) and 6 months (T2), including the Clinician Administered PTSD Scale for DSM-V (CAPS-5), post-injury.Results: Consistent with previous work, T1 lesser anterior cingulum fractional anisotropy (FA) was marginally related to greater T2 total PTSD symptoms. No other white matter tracts were related to PTSD symptoms.Conclusions: Results demonstrate that in a traumatically injured sample with predominantly subclinical PTSD symptoms at T2, acute white matter integrity after trauma is not robustly related to the development of chronic PTSD symptoms. These findings suggest the timing of evaluating white matter integrity and PTSD is important as white matter differences may not be apparent in the acute period after injury.

Fungal endophytes in perennial ryegrass are essential to New Zealand’s pastoral system due to anti-insect effects. However, endophytes also produce compounds which can be detrimental to animals. Furthermore, as these toxins have been detected in the milk and fat of animals grazing common-toxic (containing lolitrem B) or AR37 endophyte-infected herbage they could enter the human food chain. To assess the risk to human health mice were fed for 90 days with three dose rates of lolitrem B and of AR37. Parameters indicative of animal health were measured as well as chemical, hematological and histological analysis of samples collected on day 90. Since endophyte toxin residues have been detected in milk, they could be transferred from mother to offspring via breast milk. To evaluate possible effects on reproduction two complete generations of mice were fed lolitrem B or AR37. At the dose rates given no adverse effects were observed in either study. The 100-fold safety factor to allow the use of animal data in human health assessments was applied and by considering the concentrations of lolitrem B or AR37 metabolites which could be ingested by a consumer it is highly unlikely that they pose any risk to human health.

Objective To compare the visual outcomes of intravitreal antivascular endothelial growth factor (anti-VEGF) injections in neovascular age-related macular degeneration (nAMD), diabetic macular oedema (DMO) and retinal vein occlusion (RVO) in a real-world setting.Methods and analysis Retrospective analysis of data from the Tasmanian Ophthalmic Biobank database. The median change in best-corrected visual acuity (BCVA) between baseline and 12 months post initiating intravitreal anti-VEGF treatment were compared between the three diseases. Final BCVA, central macular thickness (CMT), cumulative number of injections and overall predictors of change in BCVA and CMT were also determined.Results At 12 months, change in BCVA was significantly different between nAMD, DMO and RVO cohorts (p=0.032), with lower median change for DMO (2 letters, range −5 to 20) than for RVO (11 letters, range −20 to 35). Likewise, CMT change was significantly different between the three cohorts (p=0.022), with a smaller reduction in CMT in DMO (−54 µm, range −482 to 50) than RVO patients (−137 µm, range −478 to 43; p=0.033). Total number of injections received (p=0.028) and final BCVA score (p=0.024) were also significantly different between the groups. Baseline BCVA was a negative predictor (p=0.042) and baseline CMT a positive predictor (p

Biological mechanisms associated with response to trauma may impact risk for depression. One such mechanism is endocannabinoid signaling (eCB), a neuromodulatory system comprised of the CB1 subtype of cannabinoid receptors (CB1R), encoded by the CNR1 gene, and two primary endogenous ligands: 2-arachidonoylglycerol (2-AG) and N-arachidonylethanolamine (AEA), hydrolyzed by monoacylglycerol lipase (gene name MGLL) and fatty acid amide hydrolase (gene name FAAH). Preclinical data suggest that eCB/CB1R signaling acts as a stress buffer and its loss or suppression increases depression-like behaviors. We examined circulating concentrations of the eCBs (2-AG and AEA) days and six months after a traumatic injury as a marker of eCB/CB1R signaling and as predictors of Center for Epidemiologic Studies of Depression Scale-Revised [CESD-R] scores as a measure of depression severity six months after injury. We also explored associations of CNR1, FAAH, and MGLL genetic variance with depression severity at six months. Results from hierarchical multiple linear regressions showed that higher 2-AG serum concentrations after trauma predicted greater depression at six months (β = 0.23, p = 0.007); neither AEA after trauma, nor 2-AG and AEA at six months were significant predictors (p's > 0.305). Carriers of minor allele for the putative single nucleotide polymorphism in the CNR1 gene rs806371 (β = 0.19, p = 0.024) experienced greater depression at six months. These data suggest that the eCB signaling system is highly activated following trauma and that eCB/CB1R activity contributes to long-term depression risk.