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Ben Ryan,1 Charlotte Auty,2 Matthew Maden,3 Amy Leggett,4 Alisha Staley,3 Enam Haque3 1Department of Medicine, Lancashire Teaching Hospitals NHS Foundation Trust, Preston, Lancashire, UK; 2Surgical Division, Queen’s Medical Centre, Nottingham University Hospitals NHS Trust, Nottingham, Nottinghamshire, UK; 3University of Manchester Medical School, The University of Manchester, Manchester, Greater Manchester, UK; 4Department of Undergraduate Education, East Lancashire Hospitals NHS Trust, Blackburn, Lancashire, UKCorrespondence: Ben RyanDepartment of Medicine, Lancashire Teaching Hospitals NHS Foundation Trust, Preston, Lancashire, United KingdomTel +441772 716565Email benryan@doctors.org.ukPurpose: Individuals from lower socio-economic backgrounds are under-represented in the medical profession: confidence is a barrier to them successfully applying to medical school. This study examined the impact of two student-led conferences for Year 12 pupils, at which they had the opportunity to present their work. It looked at the ability of the conferences to improve participant confidence, and the feasibility of its replication by other student-led groups.Methods: The first, Conference A, had more time and finances invested into it than the second, Conference B. The latter relied solely on university society funding, but utilised WP criteria for selection of participants. Participants identified their confidence in six areas on a ten-point scale, immediately before and after the intervention.Results: A paired t-test showed a significant improvement (p < 0.01) in all areas of confidence for both conferences. Cohen’s d showed Conference A had larger effect sizes in five out of six areas than Conference B.Conclusion: This intervention has demonstrated a significant positive impact on participant confidence: a key factor to improve their chance of successful admission to medical school. Supporting participants with their presentations prior to the conference was found to further enhance their confidence. The authors feel that this work could be replicated successfully by other student groups.Keywords: widening access, social mobility, medical school admissions, confidence

In this investigation, the optimization of mechanical properties with thermal post-processing treatments was analyzed across a wide range of variants. A major aspect of additive manufacturing is the correlation between heat treatments and the effects on the mechanical properties and microstructure of the printed materials. Therefore, the present paper describes a comprehensive overview of post-process heat treatments for Laser Powder Bed Fusion fabricated AlSi10Mg alloy consisting of stress relief anneals at 190 ̊C and 285 ̊C for 2 h, hot isostatic pressing at 515 ̊C for 3 h, hot isostatic pressing + T6 treatment for 6 h, and final aging of each of these conditions at 177 ̊C for up to 1000 h. This has resulted in 40 experimental variants: 20 in the vertical and 20 in the horizontal tensile direction. After tensile testing, the resulting mechanical properties (ultimate tensile strength, yield strength, and elongation) and stress–strain curves are analyzed for comparison between all variants. Ultra-fine cellular, micro dendritic structures (0.6–1.2 μm) along with melt-band structures dominated the asbuilt and stress relief anneal conditions. In contrast, hot isostatic pressing and hot isostatic pressing + T6 conditions were dominated by ~10 μm, equiaxed, recrystallized grain structures and pseudo-eutectic silicon particles with varying sizes and size distributions. Microhardness and fractography results also corresponded to their specific heat treatment and microstructure. The comparison and correlation of the heat treatments are presented to help advance the selection of design strategies for high performance applications.

Pathogenic mutations in the BRCA2 tumor suppressor gene predispose to breast, ovarian, pancreatic, prostate, and other cancers. BRCA2 maintains genome stability through homology-directed repair (HDR) of DNA double-strand breaks (DSBs) and replication fork protection. Nonsense or frameshift mutations leading to truncation of the BRCA2 protein are typically considered pathogenic; however, missense mutations resulting in single amino acid substitutions can be challenging to functionally interpret. The majority of missense mutations in BRCA2 have been classified as Variants of Uncertain Significance (VUS) with unknown functional consequences. In this study, we identified three BRCA2 VUS located within the BRC repeat region to determine their impact on canonical HDR and fork protection functions. We provide evidence that S1221P and T1980I, which map to conserved residues in the BRC2 and BRC7 repeats, compromise the cellular response to chemotherapeutics and ionizing radiation, and display deficits in fork protection. We further demonstrate biochemically that S1221P and T1980I disrupt RAD51 binding and diminish the ability of BRCA2 to stabilize RAD51-ssDNA complexes. The third variant, T1346I, located within the spacer region between BRC2 and BRC3 repeats, is fully functional. We conclude that T1346I is a benign allele, whereas S1221P and T1980I are hypomorphic disrupting the ability of BRCA2 to fully engage and stabilize RAD51 nucleoprotein filaments. Our results underscore the importance of correctly classifying BRCA2 VUS as pathogenic variants can impact both future cancer risk and guide therapy selection during cancer treatment.

4d transition metal oxides have emerged as promising materials for numerous applications including high mobility electronics. SrNbO3 is one such candidate material, serving as a good donor material in interfacial oxide systems and exhibiting high electron mobility in ultrathin films. However, its synthesis is challenging due to the metastable nature of the d1 Nb4+ cation and the limitations in the delivery of refractory Nb. To date, films have been grown primarily by pulsed laser deposition (PLD), but development of a means to grow and stabilize the material via molecular beam epitaxy (MBE) would enable studies of interfacial phenomena and multilayer structures that may be challenging by PLD. To that end, SrNbO3 thin films were grown using hybrid MBE for the first time using a tris(diethylamido)(tert-butylimido) niobium precursor for Nb and an elemental Sr source on GdScO3 substrates. Varying thicknesses of insulating SrHfO3 capping layers were deposited using a hafnium tert-butoxide precursor for Hf on top of SrNbO3 films to preserve the metastable surface. Grown films were transferred in vacuo for x-ray photoelectron spectroscopy to quantify elemental composition, density of states at the Fermi energy, and Nb oxidation state. Ex situ studies by x-ray absorption near edge spectroscopy and scanning transmission electron microscopy illustrate that the SrHfO3 capping plays an important role in preserving the crystalline quality of the material and the Nb 4d1 metastable charge state under atmospheric conditions.

During the past century, bivalve populations across the globe have collapsed, resulting in negative ecosystem consequences due to their outsized impact on shallow estuaries. In response, there has been strong interest in the restoration of marine bivalve populations. Here, we present a decade-long restoration effort that sought to rebuild a collapsed (99.5% reduction in harvest) and recruitment-limited population of hard clams (Mercenaria mercenaria) in Shinnecock Bay, NY, USA, using spawner sanctuaries: no-harvest zones where adults were planted at high densities (~27 m-2). Between 2012 to 2019, more than 3.2 million clams were planted in 64 discrete sanctuary plots (~1,850 m2 each) located in zones with maximal larval retention and sediment and seawater characteristics that would maximize the conditioning and spawning of adults. Hydrodynamic models, quantification of hard clam larvae, and spatial recruitment patterns demonstrated larvae spawned within sanctuaries were transported to regions where clam densities significantly increased 18-fold over seven years (2015-2021; p

Abstract The protozoan parasite Perkinsus marinus, which causes dermo disease in Crassostrea virginica, is one of the most ecologically important and economically destructive marine pathogens. The rapid and persistent intensification of dermo in the USA in the 1980s has long been enigmatic. Attributed originally to the effects of multi-year drought, climatic factors fail to fully explain the geographic extent of dermo’s intensification or the persistence of its intensified activity. Here we show that emergence of a unique, hypervirulent P. marinus phenotype was associated with the increase in prevalence and intensity of this disease and associated mortality. Retrospective histopathology of 8355 archival oysters from 1960 to 2018 spanning Chesapeake Bay, South Carolina, and New Jersey revealed that a new parasite phenotype emerged between 1983 and 1990, concurrent with major historical dermo disease outbreaks. Phenotypic changes included a shortening of the parasite’s life cycle and a tropism shift from deeper connective tissues to digestive epithelia. The changes are likely adaptive with regard to the reduced oyster abundance and longevity faced by P. marinus after rapid establishment of exotic pathogen Haplosporidium nelsoni in 1959. Our findings, we hypothesize, illustrate a novel ecosystem response to a marine parasite invasion: an increase in virulence in a native parasite.

Harmful algal blooms (HABs) in coastal British Columbia (BC), Canada, negatively impact the salmon aquaculture industry. One disease of interest to salmon aquaculture is Net Pen Liver Disease (NPLD), which induces severe liver damage and is believed to be caused by the exposure to microcystins (MCs). To address the lack of information about algal toxins in BC marine environments and the risk they pose, this study investigated the presence of MCs and other toxins at aquaculture sites. Sampling was carried out using discrete water samples and Solid Phase Adsorption Toxin Tracking (SPATT) samplers from 2017–2019. All 283 SPATT samples and all 81 water samples tested positive for MCs. Testing for okadaic acid (OA) and domoic acid (DA) occurred in 66 and 43 samples, respectively, and all samples were positive for the toxin tested. Testing for dinophysistoxin-1 (DTX-1) (20 samples), pectenotoxin-2 (PTX-2) (20 samples), and yessotoxin (YTX) (17 samples) revealed that all samples were positive for the tested toxins. This study revealed the presence of multiple co-occurring toxins in BC’s coastal waters and the levels detected in this study were below the regulatory limits for health and recreational use. This study expands our limited knowledge of algal toxins in coastal BC and shows that further studies are needed to understand the risks they pose to marine fisheries and ecosystems.

Abstract During plastic deformation of crystalline solids, intricate networks of dislocation lines form and evolve. To capture dislocation density evolution, prominent theories of crystal plasticity assume that 1) multiplication is driven by slip in active slip systems and 2) pair-wise slip system interactions dominate network evolution. In this work, we analyze a massive database of over 100 discrete dislocation dynamics simulations (with cross-slip suppressed), and our findings bring both of these assumptions into question. We demonstrate that dislocation multiplication is commonly observed on slip systems with no applied stress and no plastic strain rate, a phenomenon we refer to as slip-free multiplication. We show that while the formation of glissile junctions provides one mechanism for slip-free multiplication, additional mechanisms which account for the influence of coplanar interactions are needed to fully explain the observations. Unlike glissile junction formation which results from a binary reaction between a pair of slip systems, these new multiplication mechanisms require higher order reactions that lead to complex network configurations. While these complex configurations have not been given much attention previously, they account for about 50% of the line intersections in our database.

Abstract Background Generating and analysing single-cell data has become a widespread approach to examine tissue heterogeneity, and numerous algorithms exist for clustering these datasets to identify putative cell types with shared transcriptomic signatures. However, many of these clustering workflows rely on user-tuned parameter values, tailored to each dataset, to identify a set of biologically relevant clusters. Whereas users often develop their own intuition as to the optimal range of parameters for clustering on each data set, the lack of systematic approaches to identify this range can be daunting to new users of any given workflow. In addition, an optimal parameter set does not guarantee that all clusters are equally well-resolved, given the heterogeneity in transcriptomic signatures in most biological systems. Results Here, we illustrate a subsampling-based approach (chooseR) that simultaneously guides parameter selection and characterizes cluster robustness. Through bootstrapped iterative clustering across a range of parameters, chooseR was used to select parameter values for two distinct clustering workflows (Seurat and scVI). In each case, chooseR identified parameters that produced biologically relevant clusters from both well-characterized (human PBMC) and complex (mouse spinal cord) datasets. Moreover, it provided a simple “robustness score” for each of these clusters, facilitating the assessment of cluster quality. Conclusion chooseR is a simple, conceptually understandable tool that can be used flexibly across clustering algorithms, workflows, and datasets to guide clustering parameter selection and characterize cluster robustness.

The purpose of this work was to develop an open-source deep learning-based algorithm for motion capture marker labelling that can be trained on measured or simulated marker trajectories. In the proposed algorithm, a deep neural network including recurrent layers is trained on measured or simulated marker trajectories. Labels are assigned to markers using the Hungarian algorithm and a predefined generic marker set is used to identify and correct mislabeled markers. The algorithm was first trained and tested on measured motion capture data. Then, the algorithm was trained on simulated trajectories and tested on data that included movements not contained in the simulated data set. The ability to improve accuracy using transfer learning to update the neural network weights based on labelled motion capture data was assessed. The effect of occluded and extraneous markers on labelling accuracy was also examined. Labelling accuracy was 99.6% when trained on measured data and 92.8% when trained on simulated trajectories, but could be improved to up to 98.8% through transfer learning. Missing or extraneous markers reduced labelling accuracy, but results were comparable to commercial software. The proposed labelling algorithm can be used to accurately label motion capture data in the presence of missing and extraneous markers and accuracy can be improved as data are collected, labelled, and added to the training set. The algorithm and user interface can reduce the time and manual effort required to label optical motion capture data, particularly for those with limited access to commercial software.

Abstract For several decades, the World Health Organization has collected, maintained, and distributed invaluable country-specific disease surveillance data that allow experts to develop new analytical tools for disease tracking and forecasting. To capture the extent of available data within these sources, we proposed a completeness metric based on the effective time series length. Using FluNet records for 29 Pan-American countries from 2005 to 2019, we explored whether completeness was associated with health expenditure indicators adjusting for surveillance system heterogeneity. We observed steady improvements in completeness by 4.2–6.3% annually, especially after the A(H1N1)-2009 pandemic, when 24 countries reached > 95% completeness. Doubling in decadal health expenditure per capita was associated with ~ 7% increase in overall completeness. The proposed metric could navigate experts in assessing open access data quality and quantity for conducting credible statistical analyses, estimating disease trends, and developing outbreak forecasting systems.

Advances in nucleic acid sequencing technology have enabled expansion of our ability to profile microbial diversity. These large datasets of taxonomic and functional diversity are key to better understanding microbial ecology. Machine learning has proven to be a useful approach for analyzing microbial community data and making predictions about outcomes including human and environmental health. Machine learning applied to microbial community profiles has been used to predict disease states in human health, environmental quality and presence of contamination in the environment, and as trace evidence in forensics. Machine learning has appeal as a powerful tool that can provide deep insights into microbial communities and identify patterns in microbial community data. However, often machine learning models can be used as black boxes to predict a specific outcome, with little understanding of how the models arrived at predictions. Complex machine learning algorithms often may value higher accuracy and performance at the sacrifice of interpretability. In order to leverage machine learning into more translational research related to the microbiome and strengthen our ability to extract meaningful biological information, it is important for models to be interpretable. Here we review current trends in machine learning applications in microbial ecology as well as some of the important challenges and opportunities for more broad application of machine learning to understanding microbial communities.

Summary: DNA fiber combing is a versatile technique that provides insight into replication fork dynamics at single-molecule resolution. DNA fibers are bound to silanized coverslips and combed, which straightens and aligns the fibers along a single axis. Here, we present a DNA fiber combing protocol that does not use commercial kits; we detail the steps to prepare all materials, reagents, and silanized coverslips. We describe the use of DLD-1 cells, but the protocol is amenable to other cell types.

Background and purpose: Effective communication of radiologic findings is crucial in the acute evaluation of stroke. Conventional methods (CM) of communication can present challenges leading to delays in reporting, ultimately impacting patient outcomes. The goal of this retrospective study was to assess the utility of a HIPAA-compliant messaging system (MS) for expediting communication of CT findings by radiologists to members of the stroke team. Materials and methods: Multimodal stroke protocol CT examinations performed at a high-volume stroke center between January and December 2019 were identified as part of this IRB-approved retrospective study. Read-back times were determined based on templated documentation within individual radiologic reports. The time interval between identification of findings and notification was calculated for each report, and usage of CM versus MS was documented. In addition, an online voluntary survey was disseminated to staff to assess user satisfaction with the MS. Results and conclusions: In total, 442 CTs were included, and 126 (29%) documented use of the MS. The MS was associated with significant reductions in median read-back times, both for all reported findings (1.5 versus 16 minutes, p

The BRCA2 germline missense variant, R3052W, resides in the DNA binding domain and has been previously classified as a pathogenic allele. In this study, we sought to determine how R3052W alters the cellular functions of BRCA2 in the DNA damage response. The BRCA2 R3052W mutated protein exacerbates genome instability, is unable to rescue homology-directed repair, and fails to complement cell survival following exposure to PARP inhibitors and crosslinking drugs. Surprisingly, despite anticipated defects in DNA binding or RAD51-mediated DNA strand exchange, the BRCA2 R3052W protein mislocalizes to the cytoplasm precluding its ability to perform any DNA repair functions. Rather than acting as a simple loss-of-function mutation, R3052W behaves as a dominant negative allele, likely by sequestering RAD51 in the cytoplasm.

Endogenous and exogenously administered S-nitrosothiols modulate the activities of central and peripheral systems that control breathing. We have unpublished data showing that the deleterious effects of morphine on arterial blood-gas chemistry (i.e., pH, pCO2, pO2, and sO2) and Alveolar-arterial gradient (i.e., index of gas exchange) were markedly diminished in anesthetized Sprague Dawley rats that received a continuous intravenous infusion of the endogenous S-nitrosothiol, S-nitroso-L-cysteine. The present study extends these findings by showing that unanesthetized adult male Sprague Dawley rats receiving an intravenous infusion of S-nitroso-L-cysteine (100 or 200 nmol/kg/min) markedly diminished the ability of intravenous injections of the potent synthetic opioid, fentanyl (10, 25, and 50 μg/kg), to depress the frequency of breathing, tidal volume, and minute ventilation. Our study also found that the ability of intravenously injected fentanyl (10, 25, and 50 μg/kg) to disturb eupneic breathing, which was measured as a marked increase of the non-eupneic breathing index, was substantially reduced in unanesthetized rats receiving intravenous infusions of S-nitroso-L-cysteine (100 or 200 nmol/kg/min). In contrast, the deleterious effects of fentanyl (10, 25, and 50 μg/kg) on frequency of breathing, tidal volume, minute ventilation and non-eupneic breathing index were fully expressed in rats receiving continuous infusions (200 nmol/kg/min) of the parent amino acid, L-cysteine, or the D-isomer, namely, S-nitroso-D-cysteine. In addition, the antinociceptive actions of the above doses of fentanyl as monitored by the tail-flick latency assay, were enhanced by S-nitroso-L-cysteine, but not L-cysteine or S-nitroso-D-cysteine. Taken together, these findings add to existing knowledge that S-nitroso-L-cysteine stereoselectively modulates the detrimental effects of opioids on breathing, and opens the door for mechanistic studies designed to establish whether the pharmacological actions of S-nitroso-L-cysteine involve signaling processes that include 1) the activation of plasma membrane ion channels and receptors, 2) selective intracellular entry of S-nitroso-L-cysteine, and/or 3) S-nitrosylation events. Whether alterations in the bioavailability and bioactivity of endogenous S-nitroso-L-cysteine is a key factor in determining the potency/efficacy of fentanyl on breathing is an intriguing question.

NASA has recently completed several long-duration missions to the International Space Station and is solidifying plans to return to the Moon, with an eye toward Mars and beyond. As NASA pushes the boundaries of human space exploration, the hazards of spaceflight, including space radiation, levy an increasing burden on astronaut health and performance. The cardiovascular system may be especially vulnerable due to the combined impacts of space radiation exposure, lack of gravity, and other spaceflight hazards. On Earth, the risk for cardiovascular disease (CVD) following moderate to high radiation doses is well-established from clinical, environmental, and occupational exposures (largely from gamma- and x-rays). Less is known about CVD risks associated with high-energy charged ions found in space and increasingly used in radiotherapy applications on Earth, making this a critical area of investigation for occupational radiation protection. Assessing CVD risk is complicated by its multifactorial nature, where an individual's risk is strongly influenced by factors such as family history, blood pressure, and lipid profiles. These known risk factors provide the basis for development of a variety of clinical risk prediction models (CPMs) that inform the likelihood of medical outcomes over a defined period. These tools improve clinical decision-making, personalize care, and support primary prevention of CVD. They may also be useful for individualizing risk estimates for CVD following radiation exposure both in the clinic and in space. In this review, we summarize unique aspects of radiation risk assessment for astronauts, and we evaluate the most widely used CVD CPMs for their use in NASA radiation risk assessment applications. We describe a comprehensive dual-use risk assessment framework that supports both clinical care and operational management of space radiation health risks using quantitative metrics. This approach is a first step in using personalized medicine for radiation risk assessment to support safe and productive spaceflight and long-term quality of life for NASA astronauts.

With an increase in subject knowledge expertise required to solve specific biological questions, experts from different fields need to collaborate to address increasingly complex issues. To successfully collaborate, everyone involved in the collaboration must take steps to “meet in the middle.” We thus present a guide on truly cross-disciplinary work using bioimage analysis as a showcase, where it is required that the expertise of biologists, microscopists, data analysts, clinicians, engineers, and physicists meet. We discuss considerations and best practices from the perspective of both users and technology developers, while offering suggestions for working together productively and how this can be supported by institutes and funders. Although this guide uses bioimage analysis as an example, the guiding principles of these perspectives are widely applicable to other cross-disciplinary work.

Abstract Rodents can influence the succession and assembly of plant communities by preying on and dispersing seeds. Using a seed tray experiment with three common seeds, American beech (Fagus grandifolia), red maple (Acer rubrum), and eastern hemlock (Tsuga canadensis), we assessed factors that influence seed selection and foraging time of three rodents: deer mice (Peromyscus maniculatus), white‐footed mice (Peromyscus leucopus), and southern red‐backed voles (Myodes gapperi). All three rodents preferred beech seeds, likely due to its large size and high lipid content. However, when beech availability was low, secondary seed selection differed by rodent species with P. maniculatus equally selecting hemlock and red maple, P. leucopus preferring hemlock, and M. gapperi preferring red maple. Red maple seeds contained high levels of phenolic compounds, which hinder digestion, and the elongated cecum of M. gapperi may allow for better processing of these compounds relative to Peromyscus. Beech seeds were nearly always removed from trays intact, suggesting rodents could be important dispersers compared to the small‐seeded species, which were generally processed on trays. The influence of environmental factors on seed selection was only notable when beech seed availability was low. Beech seed availability was also the primary factor influencing foraging time on trays, with individuals increasing foraging time as beech availability decreased. Consistent with predator avoidance behaviors, denser shrub cover increased foraging time for P. maniculatus, whereas moon luminosity decreased foraging for all three species. Our findings underscore that seed quality drives seed selection but that preferences are context dependent, varying with seed availability and digestive capacity.

Abstract The fundamental interactions between an edge dislocation and a random solid solution are studied by analyzing dislocation line roughness profiles obtained from molecular dynamics simulations of Fe0.70Ni0.11Cr0.19 over a range of stresses and temperatures. These roughness profiles reveal the hallmark features of a depinning transition. Namely, below a temperature-dependent critical stress, the dislocation line exhibits roughness in two different length scale regimes which are divided by a so-called correlation length. This correlation length increases with applied stress and at the critical stress (depinning transition or yield stress) formally goes to infinity. Above the critical stress, the line roughness profile converges to that of a random noise field. Motivated by these results, a physical model is developed based on the notion of coherent line bowing over all length scales below the correlation length. Above the correlation length, the solute field prohibits such coherent line bow outs. Using this model, we identify potential gaps in existing theories of solid solution strengthening and show that recent observations of length-dependent dislocation mobilities can be rationalized.

Objective Airway obstruction after postoperative extubation is a dreaded but uncommon complication in patients undergoing circumferential cervical spine surgery (CCSS). The cuff leak test (CLT) has been utilized to assess air leak around the endotracheal tube which may reflect airway swelling. In this prospective observational study, we analyze the temporal evolution of CLT and perioperative factors that may influence it. Methods Twenty patients undergoing single-stage CCSS were managed according to our extubation protocol. Patients were maintained intubated overnight following surgery. They were extubated if a CLT > 200 mL and both intensive care unit (ICU) and Neurosurgery teams agreed that it was safe. Patients extubated in the first postoperative day (8 of 20) comprised the early group, and the remaining patients (12 of 20) the delayed group. Patient and operative data were analyzed as a single group and comparing both groups. Results The main indication for surgery was cervical deformity. Median number of levels fused was 5 anteriorly (range, 1–6) and 6 (range, 1–13) posteriorly. Patients were kept intubated for an average of 73.6 hours (range, 26–222 hours) and stayed in the ICU for 119.1 hours (range, 36–360 hours). There were 4 failed extubations and 3 patients (15%) required a tracheostomy. Patient profiles between both groups were very similar across most patient variables but differed significantly regarding infraglottic luminal area (p < 0.05). Patients with larger preoperative cuff leak values tended to have a shorter intubation period (p=0.053). Conclusion This study objectively demonstrates the difficulties in airway management following CCSS and provides useful insight for preoperative planning and counseling. Local anatomic factors influence airway outcome more than operative factors. The study format does not allow for testing of interventions but we suggest that patients with favorable anatomy (larger infraglottic luminal area) may benefit from a less strict airway management protocol.

A wide range of post process hot isostatic pressing (HIP) studies of electron beam additively manufactured Ti-6Al-4V in this research program have shown that cooling rates of 103 °C/min from temperatures above and below the beta transus produced acicular alpha-prime martensite characteristic elongations < 10%. Optimum yield strength (0.9 GPa), UTS (1.0 GPa), and elongation (∼14%) were achieved for slow cooling (at 102 °C/min) from 850 °C HIP which produced a dense, Widmanstatten alpha structure within the retained, as-fabricated columnar grains by alpha-prime decomposition. These results suggest that manipulation of AM process parameters to produce a small-grain, equiaxed microstructure, HIPed below the beta transus and slow cooled, will have a wide range of superior, isotropic mechanical properties corresponding to a Widmanstatten alpha microstructure within the equiaxed grains.

Abstract Background To test the hypothesis that intraventricular ADC values can be used to determine the presence of neoplastic leptomeningeal disease (LMD). Materials and methods ADC values were measured at multiple sites in the ventricular system in 32 patients with cytologically-proven LMD and 40 control subjects. Multiple linear regression analysis was used to determine the mean difference of ADCs between the LMD and control groups after adjusting for ventricle size and tumor type. Receiver operating characteristics (ROC) analysis was performed and optimal ADC value cut-off point for predicting the presence of LMD. ADC was compared to T1 enhancement and FLAIR signal hyperintensity for determining the presence of LMD. Results After adjusting for ventricular volume and tumor type, the mid body of lateral ventricles showed no significant difference in ventricular volume and a significant difference in ADC values between the control and LMD groups (p > 0.05). In the mid-body of the right lateral ventricle the AUC was 0.69 (95% CI 0.57–0.81) with an optimal ADC cut off point of 3.22 × 10− 9 m2/s (sensitivity, specificity; 0.72, 0.68). In the mid-body of left lateral ventricle the AUC was 0.7 (95% CI 0.58–0.82) with an optimal cut-off point of 3.23 × 10− 9 m2/s (0.81, 0.62). Using an average value of HU measurements in the lateral ventricles the AUC was 0.73 (95% CI 0.61–0.84) with an optimal cut off point was 3.11 × 10− 9 m2/s (0.78, 0.65). Compared to the T1 post-contrast series, ADC was predictive of the presence of LMD in the mid-body of the left lateral ventricle (p = 0.036). Conclusion Complex interactions affect ADC measurements in patients with LMD. ADC values in the lateral ventricles may provide non-invasive clues to the presence of LMD.

The DNA cytosine deaminases APOBEC3A and APOBEC3B have emerged from cancer genomics studies as drivers of mutation in cancers and tumor heterogeneity. Here the authors present a computational approach to identify the RNA mutations specifically driven by APOBEC3A, and developed an RNA mutation-based assay to quantify ongoing APOBEC3A activity in tumor cells.

Purpose: Lacerations to the ulnar and median nerve in the volar forearm have demonstrated considerable long-term clinical and socioeconomic impacts on patients. The purpose of this study was to evaluate the outcomes of complex volar forearm lacerations involving one or more major peripheral nerves in an economically disadvantaged patient population. Methods: In this study, a retrospective analysis of 61 patients who sustained lacerations to the median nerve, ulnar nerve, or both with volar wrist lacerations was performed. Each patient’s preinjury and postinjury occupation, dominant extremity, and demographic variables were evaluated. Sensation recovery, motor recovery, Disabilities of the Arm, Shoulder, and Hand scores, visual analog scale scores, cold intolerance, and return to work were evaluated at 3, 6, and 12 months after the injury. Results: Patients with isolated median nerve injuries demonstrated improved motor recovery compared with patients with isolated ulnar nerve injuries. Patients with combined nerve injuries had worse sensation recovery and motor recovery, and lower rates of return to work than either group of patients with isolated nerve injuries. Manual laborers had worse motor recovery and lower rates of return to work than did patients who were office workers. Conclusions: Patients with combined median and ulnar nerve injuries have worse functional recovery and lower rates of return to work than do patients with isolated median or isolated ulnar nerve injuries at 1 year. Manual laborers demonstrated worse functional recovery and lower rates of return to work compared with office workers at 1 year. Type of study/level of evidence: Therapeutic III. Key words: Nerve laceration, Nerve repair, Return to work, Spaghetti wrist, Volar laceration

"AIM: To report the outcomes of patients undergoing anterior segment optical coherence tomography-guided transepithelial phototherapeutic keratectomy (ASOCT T-PTK) for central corneal scarring after pterygium excision. METHODS: The charts of 11 eyes of 10 patients that underwent ASOCT T-PTK following excision of visual axis-involving pterygia were retrospectively reviewed from a single private practice institution. The visual outcomes and corneal topographic findings were evaluated 4±1mo after pterygium excision and 6±2mo after transepithelial phototherapeutic keratectomy (T-PTK). RESULTS: All 11 eyes tolerated both the pterygium excision and T-PTK procedure well without any significant intraoperative or postoperative complications. Uncorrected distance visual acuity (UDVA) and manifest refraction corrected distance visual acuity (CDVA) improved after pterygium excision (P=0.03 and P=0.05, respectively). The UDVA and CDVA improved further after T-PTK (P=0.004 and P=0.002, respectively). The topographic surface asymmetry index, topographic surface regularity index, and topographic projected visual acuity significantly improved after T-PTK (P=0.0092, P=0.0022, and P=0.0002, respectively). None of the subjects lost any lines of CDVA, developed recurrence of pterygia or required keratoplasty during the postoperative period. CONCLUSION: ASOCT T-PTK can provide excellent visual and anatomic outcomes in patients with central corneal scarring after excision of visual axis-involving pterygia."

Abstract Approximately one‐third of Merkel cell carcinoma (MCC) patients eventually develop distant metastatic disease. Little is known about whether the location of the primary lesion is predictive of initial distant metastatic site, or if survival likelihood differs depending on the metastatic site. Such data could inform imaging/surveillance practices and improve prognostic accuracy. Multivariate and competing‐risk analyses were performed on a cohort of 215 MCC patients with distant metastases, 31% of whom had two or more initial sites of distant metastasis. At time of initial distant metastasis in the 215 patients, metastatic sites (n = 305) included non‐regional lymph nodes (present in 41% of patients), skin/body wall (25%), liver (23%), bone (21%), pancreas (8%), lung (7%), and brain (5%). Among the 194 patients who presented with MCC limited to local or regional sites (stage I‐III) but who ultimately developed distant metastases, distant progression occurred in 49% by 1 year and in 80% by 2 years following initial diagnosis. Primary MCC locations differed in how likely they were to metastasize to specific organs/sites (P

Obstructive sleep apnea (OSA) is characterized by repetitive partial/complete collapse of the pharynx during sleep, which results in apnea/hypopnea leading to arterial oxygen desaturations and arousals. Repetitive apnea/hypopnea-arousal episodes cause hypoxia/reoxygenation cycles, which increase free radical generation and oxidative stress that cause motor/sensory nerve impairments and muscle damage. We hypothesize that antioxidants may protect and/or reverse from oxidative stress-induced damage in OSA patients. To understand the acute protective effects of antioxidants on respiratory muscles, we studied the systemic effects of a membrane permeable superoxide dismutase mimetic, Tempol, on genioglossus (EMGGG) and diaphragmatic (EMGDIA) electro-myographic activities, hypoglossal motoneuron (HMN) nerve activity and cardiorespiratory parameters (mean arterial blood pressure, heart rate) in adult isoflurane-anesthetized obese Zucker rats (OZR) and age-matched lean Zucker rats (LZR). Tempol dose-dependently (1–100 mg/kg) increased EMGGG without changing EMGDIA in OZR and LZR. Tempol increased respiratory rate and tidal volume in OZR and LZR. Tempol (1–25 mg/kg) dose-dependently increased HMN nerve activity in healthy Sprague Dawley rats. Tempol (100 mg/kg) increased EMGGG output by 189% in OZR and 163% in LZR. With respect to mechanisms of effect, Tempol (100 mg/kg) did not augment EMGGG after bilateral HMN transection in Sprague Dawley rats. Although future studies are warranted, available data suggest that in addition to its antioxidant and antihypertensive properties, Tempol can selectively augment EMGGG through modulating HMN and this effect may prevent collapsibility and/or improve stability of the upper airway pharyngeal dilator muscles during episodes of partial and/or complete collapse of the upper airway in OSA human subjects.

Mapping the characteristics of Africa’s smallholder-dominated croplands, including the sizes and numbers of fields, can provide critical insights into food security and a range of other socioeconomic and environmental concerns. However, accurately mapping these systems is difficult because there is 1) a spatial and temporal mismatch between satellite sensors and smallholder fields, and 2) a lack of high-quality labels needed to train and assess machine learning classifiers. We developed an approach designed to address these two problems, and used it to map Ghana’s croplands. To overcome the spatio-temporal mismatch, we converted daily, high resolution imagery into two cloud-free composites (the primary growing season and subsequent dry season) covering the 2018 agricultural year, providing a seasonal contrast that helps to improve classification accuracy. To address the problem of label availability, we created a platform that rigorously assesses and minimizes label error, and used it to iteratively train a Random Forests classifier with active learning, which identifies the most informative training sample based on prediction uncertainty. Minimizing label errors improved model F1 scores by up to 25%. Active learning increased F1 scores by an average of 9.1% between first and last training iterations, and 2.3% more than models trained with randomly selected labels. We used the resulting 3.7 m map of cropland probabilities within a segmentation algorithm to delineate crop field boundaries. Using an independent map reference sample (n = 1,207), we found that the cropland probability and field boundary maps had respective overall accuracies of 88 and 86.7%, user’s accuracies for the cropland class of 61.2 and 78.9%, and producer’s accuracies of 67.3 and 58.2%. An unbiased area estimate calculated from the map reference sample indicates that cropland covers 17.1% (15.4–18.9%) of Ghana. Using the most accurate validation labels to correct for biases in the segmented field boundaries map, we estimated that the average size and total number of field in Ghana are 1.73 ha and 1,662,281, respectively. Our results demonstrate an adaptable and transferable approach for developing annual, country-scale maps of crop field boundaries, with several features that effectively mitigate the errors inherent in remote sensing of smallholder-dominated agriculture.

It has been estimated that the deltoid ligament complex is injured in 5-15% of acute inversion ankle injuries. This injury can result in clinically significant pain and instability. Accurate diagnosis is a combination of positive clinical findings and advanced imaging. However, arthroscopy can be a valuable tool in the diagnosis of deltoid ligament (medial ankle) instability. The authors describe the medial drive-through sign, an arthroscopic finding indicative of clinically significant deltoid ligament instability in which the ability to pass a 4mm shaver between the medial malleolus and talus is indicative of a positive medial drive through sign. The authors further introduce an anchor assisted surgical repair technique for direct repair of the deltoid ligament complex that is currently being studied for later reporting and publication.

Animals seem to rely on antipredator behavior to avoid vehicle collisions. There is an extensive body of antipredator behavior theory that have been used to predict the distance/time animals should escape from predators. These models have also been used to guide empirical research on escape behavior from vehicles. However, little is known as to whether antipredator behavior models are appropriate to apply to an approaching high-speed vehicle scenario. We addressed this gap by (a) providing an overview of the main hypotheses and predictions of different antipredator behavior models via a literature review, (b) exploring whether these models can generate quantitative predictions on escape distance when parameterized with empirical data from the literature, and (c) evaluating their sensitivity to vehicle approach speed using a simulation approach wherein we assessed model performance based on changes in effect size with variations in the slope of the flight initiation distance (FID) vs. approach speed relationship. The slope of the FID vs. approach speed relationship was then related back to three different behavioral rules animals may rely on to avoid approaching threats: the spatial, temporal, or delayed margin of safety. We used literature on birds for goals (b) and (c). Our review considered the following eight models: the economic escape model, Blumstein's economic escape model, the optimal escape model, the perceptual limit hypothesis, the visual cue model, the flush early and avoid the rush (FEAR) hypothesis, the looming stimulus hypothesis, and the Bayesian model of escape behavior. We were able to generate quantitative predictions about escape distance with the last five models. However, we were only able to assess sensitivity to vehicle approach speed for the last three models. The FEAR hypothesis is most sensitive to high-speed vehicles when the species follows the spatial (FID remains constant as speed increases) and the temporal margin of safety (FID increases with an increase in speed) rules of escape. The looming stimulus effect hypothesis reached small to intermediate levels of sensitivity to high-speed vehicles when a species follows the delayed margin of safety (FID decreases with an increase in speed). The Bayesian optimal escape model reached intermediate levels of sensitivity to approach speed across all escape rules (spatial, temporal, delayed margins of safety) but only for larger (> 1 kg) species, but was not sensitive to speed for smaller species. Overall, no single antipredator behavior model could characterize all different types of escape responses relative to vehicle approach speed but some models showed some levels of sensitivity for certain rules of escape behavior. We derive some applied applications of our findings by suggesting the estimation of critical vehicle approach speeds for managing populations that are especially susceptible to road mortality. Overall, we recommend that new escape behavior models specifically tailored to high-speeds vehicles should be developed to better predict quantitatively the responses of animals to an increase in the frequency of cars, airplanes, drones, etc. they will face in the next decade.

Mobile phone use affects the dynamics of gait by impairing visual control of the surrounding environment and introducing additional cognitive demands. Although it has been shown that using a mobile phone alters whole-body dynamic stability, no clear information exists on its impacts on motor variability during gait. This study aimed at assessing the impacts of various types of mobile phone use on motor variability during gait; quantified using the short- and long-term Lyapunov Exponent (λS and λL) of lower limb joint angles and muscle activation patterns, as well as the centre of mass position. Fourteen females and Fifteen males (27.72 ± 4.61 years, body mass: 70.24 ± 14.13 Kg, height: 173.31 ± 10.97 cm) walked on a treadmill under six conditions: normal walking, normal walking in low-light, walking while looking at the phone, walking while looking at the phone in low-light, walking and talking on the phone, and walking and listening to music. Variability of the hip (p λS = .015, λL = .043) and pelvis (p λS = .039, λL = .017) joint sagittal angles significantly increased when the participants walked and looked at the phone, either in normal or in low-light conditions. No significant difference was observed in the variability of the centre of mass position and muscle activation patterns. When individuals walk and look at the phone screen, the hip and knee joints are constantly trying to adopt a new angle to regulate and maintain gait stability, which might put an additional strain on the neuromuscular system. To this end, it is recommended not to look at the mobile phone screen while walking, particularly in public places with higher risks of falls.

This case highlights the importance of pursuing nonpharmacologic analgesic modalities in orthopedic surgery to combat the current opioid epidemic. Presented is a patient who underwent an arthroscopic rotator cuff repair and biceps tenodesis operation and through the use of neurostimulation (in the form of auricular electrostimulation), fully recovered from surgery without the usage of any opioid or nonsteroidal anti-inflammatory medications. The patient was fitted with a novel auricular electrostimulation device (DyAnsys Primary Relief) in the immediate postoperative period that provided constant neurostimulation for 10 days, this neurostimulator was the only analgesic modality used in this case, and the patient reported minimal postoperative pain. The utility of this case centers around the lack of postoperative opioid use, presenting the idea that postsurgical orthopedic pain can be managed in a nonpharmacologic capacity, combatting the fields’ ongoing opioid epidemic.

Pediatric health and mental health professionals with expertise in the physical and emotional needs of immigrant children seeking humanitarian protection are trained to understand and address the sometimes deeply traumatic nature of their experience. This expertise plays an important role in collaborating with immigration attorneys to provide compassionate, trauma-informed representation that centers on children’s best interests. In medicine, we say that “children are not small adults,” such that meeting a child’s needs requires consideration of their developmental stage and the unique impacts of child trauma exposure. This also holds true for legal professionals dedicated to protecting the rights of children in migration. This article aims to (1) review the principles of trauma-informed care in the context of child development, (2) understand the traumatic nature of the migration paradigm for children from Mexico and Central America seeking safety and protection, and (3) suggest ways that healthcare, mental health and legal professionals can inform one another’s efforts to optimize the wellbeing of children and improve legal outcomes. The application of this knowledge in practice can advance legal goals, reduce risk for child re-traumatization during interviews, and reinforce child strengths while also reducing vicarious trauma and burnout for legal professionals.

Experimental examples of as-built microstructures and associated microindentation hardnesses (HV) for a wide range of metal additive manufacturing (AM) processes for Inconel 625 alloy are presented in this research paper. These processes included cold spray, laser powder bed fusion, wire arc additive manufacturing, electron beam directed energy deposition, laser hot wire, binder jetting, laser power directed energy deposition, electron beam melting, and laser wire directed energy deposition. Microstructures ranged from impact bonded, flattened 625 alloy grains containing microdendrites and dislocations, having a microindentation hardness of HV 590 for cold spray, to large, equiaxed grains for binder jet-printed components having a microindentation hardness of HV 180. Electron and laser beam melt-related processes, including wire and powder feeds, produced varying sizes of columnar grains with parallel and cellular arrays of microdendrites, having microindentation hardnesses ranging from HV 304 to HV 228. Delta phase precipitate needles were also produced in laser-powered directed energy deposition microstructures along with columns of gamma double-prime precipitates for electron beam melting. The results demonstrate a range of AM processes applications and strategies to produce as-built and surface-modified Inconel 625 alloy products and components. These results demonstrate differences in the microstructure from the various AM processes and considerations for use in end use applications.

Changes in photosynthetic and respiration rates in coastal marine habitats cause considerable variability in ecosystem metabolism on timescales ranging from diel to tidal to seasonal. Here, temporal and spatial dynamics of dissolved oxygen (DO), carbonate chemistry, and net ecosystem metabolism (NEM) were quantified from spring through fall in multiple, distinct, temperate estuarine habitats: seagrass meadows, salt marshes, an open water estuary, and a shallow water habitat dominated by benthic macroalgae. DO and pHT (total scale) measurements were made via high frequency sensor arrays coupled with discrete measurements of dissolved inorganic carbon (DIC) and high-resolution spatial mapping was used to document intra-habitat spatial variability. All habitats displayed clear diurnal patterns of pHT and DO that were stronger than tidal signals, with minimums and maximums observed during early morning and afternoon, respectively. Diel ranges in pHT and DO varied by site. In seagrass meadows and the open estuarine site, pHT ranged 7.8–8.4 and 7.5–8.2, respectively, while DO exceeded hypoxic thresholds and aragonite was typically saturated (ΩAr > 1). Conversely, pHT in a shallow macroalgal and salt marsh dominated habitats exhibited strong diel oscillations in pHT (6.9–8.4) with diel acidic (pHT < 7) and hypoxic (DO < 3 mg L–1) conditions often observed during summer along with extended periods of aragonite undersaturation (ΩAr < 1). The partial pressure of carbon dioxide (pCO2) exceeded 3000 and 2000 μatm in the salt marsh and macroalgal bed, respectively, while pCO2 never exceeded 1000 μatm in the seagrass and open estuarine site. Mesoscale (50–100 m) spatial variability was observed across sites with the lowest pHT and DO found within regions of more restricted flow. NEM across habitats ranged from net autotrophic (macroalgae and seagrass) to metabolically balanced (open water) and net heterotrophic (salt marsh). Each habitat exhibited distinct buffering capacities, varying seasonally, and modulated by adjacent biological activity and variations in total alkalinity (TA) and DIC. As future predicted declines in pH and DO are likely to shrink the spatial extent of estuarine refuges from acidification and hypoxia, efforts are required to expand seagrass meadows and the aquaculture of macroalgae to maximize their ecosystem benefits and maintain these estuarine refuges.

ABSTRACT: The antimicrobial efficacy of caprylic acid (CA), a medium-chain fatty acid, against multidrug-resistant Salmonella Heidelberg (MDR SH) on chicken drumsticks in a soft-scalding temperature-time setup was investigated. Based on the standardization experiments in nutrient media and on chicken breast fillet portions, intact chicken drumsticks were spot inoculated with MDR SH and immersed in water with or without antimicrobial treatments at 54°C for 2 min. The treatments included 0.5% CA, 1% CA, 0.05% peracetic acid (PAA), 0.5% CA + 0.05% PAA, and 1.0% CA + 0.05% PAA. Additionally, the efficacy of the potential scald treatments against MDR SH survival on drumsticks for a storage period of 48 h at 4°C was determined. Furthermore, the effect of these treatments on the surface color of the drumsticks was also evaluated. Appropriate controls were included for statistical comparisons. The antimicrobial treatments resulted in a significant reduction of MDR SH on drumsticks. For the lower inoculum (∼2.5 log10 CFU/g) experiments, 0.5% CA, 1% CA, 0.05% PAA, 0.5% CA + 0.05% PAA, and 1.0% CA + 0.05% PAA resulted in 0.7-, 1.0-, 2.5-, 1.4-, and 1.5- log10 CFU/g reduction of MDR SH on drumsticks, respectively (P < 0.05). The same treatments resulted in 0.9-, 1.3-, 2.5-, 2.2-, and 2.6- log10 CFU/g reduction of MDR SH when the drumsticks were contaminated with a higher inoculum (∼4.5 log10 CFU/g) level (P < 0.05). Moreover, the antimicrobial treatments inactivated MDR SH in the treatment water to undetectable levels, whereas 2.0- to 4.0- log10 CFU/mL MDR SH survived in the positive controls (P < 0.05). Also, the treatments were effective in inhibiting MDR SH on the drumsticks compared to the respective controls during a storage period of 48 h at 4°C; however, the magnitude of reduction remained the same as observed during the treatment (P < 0.05). Additionally, none of the treatments affected the color of the drumsticks (P > 0.05). Results indicate that CA could be an effective natural processing aid against MDR SH on chicken products.

Introduction The annual mortality and national expense of the opioid crisis continue to rise in the USA (130 deaths/day, $50 billion/year). Opioid use disorder usually starts with the prescription of opioids for a medical condition. Its risk is associated with greater pain intensity and coping strategies characterised by pain catastrophising. Non-pharmacological analgesics in the hospital setting are critical to abate the opioid epidemic. One promising intervention is virtual reality (VR) therapy. It has performed well as a distraction tool and pain modifier during medical procedures; however, little is known about VR in the acute pain setting following traumatic injury. Furthermore, no studies have investigated VR in the setting of traumatic brain injury (TBI). This study aims to establish the safety and effect of VR therapy in the inpatient setting for acute traumatic injuries, including TBI.Methods and analysis In this randomised within-subjects clinical study, immersive VR therapy will be compared with two controls in patients with traumatic injury, including TBI. Affective measures including pain catastrophising, trait anxiety and depression will be captured prior to beginning sessions. Before and after each session, we will capture pain intensity and unpleasantness, additional affective measures and physiological measures associated with pain response, such as heart rate and variability, pupillometry and respiratory rate. The primary outcome is the change in pain intensity of the VR session compared with controls.Ethics and dissemination Dissemination of this protocol will allow researchers and funding bodies to stay abreast in their fields through exposure to research not otherwise widely publicised. Study protocols are compliant with federal regulation and University of Maryland Baltimore’s Human Research Protections and Institutional Review Board (protocol number HP-00090603). Study results will be published on completion of enrolment and analysis, and deidentified data can be shared by request to the corresponding author.Trial registration number NCT04356963; Pre-results.

Alpha Thalassemia/Mental Retardation Syndrome X-Linked (ATRX) is mutated frequently in gliomas and represents a potential target for cancer therapies. ATRX is known to function as a histone chaperone that helps incorporate histone variant, H3.3, into the genome. Studies have implicated ATRX in key DNA damage response (DDR) pathways but a distinct role in DNA repair has yet to be fully elucidated. To further investigate the function of ATRX in the DDR, we created isogenic wild-type (WT) and ATRX knockout (KO) model cell lines using CRISPR-based gene targeting. These studies revealed that loss of ATRX confers sensitivity to poly(ADP)-ribose polymerase (PARP) inhibitors, which was linked to an increase in replication stress, as detected by increased activation of the ataxia telangiectasia and Rad3-related (ATR) signaling axis. ATRX mutations frequently co-occur with mutations in isocitrate dehydrogenase-1 and -2 (IDH1/2), and the latter mutations also induce HR defects and PARP inhibitor sensitivity. We found that the magnitude of PARP inhibitor sensitivity was equal in the context of each mutation alone, although no further sensitization was observed in combination, suggesting an epistatic interaction. Finally, we observed enhanced synergistic tumor cell killing in ATRX KO cells with ATR and PARP inhibition, which is commonly seen in HR-defective cells. Taken together, these data reveal that ATRX may be used as a molecular marker for DDR defects and PARP inhibitor sensitivity, independent of IDH1/2 mutations. These data highlight the important role of common glioma-associated mutations in the regulation of DDR, and novel avenues for molecularly guided therapeutic intervention.

The neurovascular unit (NVU) is a complex multi-cellular structure consisting of endothelial cells (ECs), neurons, glia, smooth muscle cells (SMCs), and pericytes. Each component is closely linked to each other, establishing a structural and functional unit, regulating central nervous system (CNS) blood flow and energy metabolism as well as forming the blood-brain barrier (BBB) and inner blood-retina barrier (BRB). As the name suggests, the “neuro” and “vascular” components of the NVU are well recognized and neurovascular coupling is the key function of the NVU. However, the NVU consists of multiple cell types and its functionality goes beyond the resulting neurovascular coupling, with cross-component links of signaling, metabolism, and homeostasis. Within the NVU, glia cells have gained increased attention and it is increasingly clear that they fulfill various multi-level functions in the NVU. Glial dysfunctions were shown to precede neuronal and vascular pathologies suggesting central roles for glia in NVU functionality and pathogenesis of disease. In this review, we take a “glio-centric” view on NVU development and function in the retina and brain, how these change in disease, and how advancing experimental techniques will help us address unanswered questions.

Regulating the balance between self-renewal (proliferation) and differentiation is key to the long-term functioning of all stem cell pools. In the Caenorhabditis elegans germline, the primary signal controlling this balance is the conserved Notch signaling pathway. Gain-of-function mutations in the GLP-1/Notch receptor cause increased stem cell self-renewal, resulting in a tumour of proliferating germline stem cells. Notch gain-of-function mutations activate the receptor, even in the presence of little or no ligand, and have been associated with many human diseases, including cancers. We demonstrate that reduction in CUP-2 and DER-2 function, which are Derlin family proteins that function in endoplasmic reticulum-associated degradation (ERAD), suppresses the C. elegans germline over-proliferation phenotype associated with glp-1(gain-of-function) mutations. We further demonstrate that their reduction does not suppress other mutations that cause over-proliferation, suggesting that over-proliferation suppression due to loss of Derlin activity is specific to glp-1/Notch (gain-of-function) mutations. Reduction of CUP-2 Derlin activity reduces the expression of a read-out of GLP-1/Notch signaling, suggesting that the suppression of over-proliferation in Derlin loss-of-function mutants is due to a reduction in the activity of the mutated GLP-1/Notch(GF) receptor. Over-proliferation suppression in cup-2 mutants is only seen when the Unfolded Protein Response (UPR) is functioning properly, suggesting that the suppression, and reduction in GLP-1/Notch signaling levels, observed in Derlin mutants may be the result of activation of the UPR. Chemically inducing ER stress also suppress glp-1(gf) over-proliferation but not other mutations that cause over-proliferation. Therefore, ER stress and activation of the UPR may help correct for increased GLP-1/Notch signaling levels, and associated over-proliferation, in the C. elegans germline.

BackgroundMany adaptative deep brain stimulation (DBS) paradigms rely upon the ability to sense neural signatures of specific clinical signs or symptoms in order to modulate therapeutic stimulation. In first-generation bidirectional neurostimulators, the ability to sense neural signals during active stimulation was often limited by artifact. Newer devices, with improved design specifications for sensing, have recently been developed and are now clinically available.ObjectiveTo compare the sensing capabilities of the first-generation Medtronic PC + S and second-generation Percept PC neurostimulators within a single patient.MethodsA 42-year-old man with Parkinson’s disease was initially implanted with left STN DBS leads connected to a PC + S implantable pulse generator. Four years later, the PC + S was replaced with the Percept PC. Local field potential (LFP) signals were recorded, both with stimulation OFF and ON, at multiple timepoints with each device and compared. Offline processing of time series data included artifact removal using digital filtering and template subtraction, before subsequent spectral analysis. With Percept PC, embedded processing of spectral power within a narrow frequency band was also utilized.ResultsIn the absence of stimulation, both devices demonstrated a peak in the beta range (approximately 20 Hz), which was stable throughout the 4-year period. Similar to previous reports, recordings with the PC + S during active stimulation demonstrated significant stimulation artifact, limiting the ability to recover meaningful LFP signal. In contrast, the Percept PC, using the same electrodes and stimulation settings, produced time series data during stimulation with spectral analysis revealing a peak in the beta-band. Online analysis by the Percept demonstrated a reduction in beta-band activity with increasing stimulation amplitude.ConclusionThis report highlights recent advances in implantable neurostimulator technology for DBS, demonstrating improvements in sensing capabilities during active stimulation between first- and second-generation devices. The ability to reliably sense during stimulation is an important step toward both the clinical implementation of adaptive algorithms and the further investigation into the neurophysiology underlying movement disorders.

Abstract Background The advent of the immunomodulatory imide drugs (IMiDs) lenalidomide and thalidomide for the treatment of patients with plasma cell myeloma (PCM), has contributed to more than a doubling of the overall survival of these individuals. As a result, PCM patients join survivors of other malignancies such as breast and prostate cancer with a relatively new clinical problem – second primary malignancies (SPMs) – many of which are a result of the treatment of the initial cancer. PCM patients have a statistically significant increased risk for acute myeloid leukemia (AML) and Kaposi sarcoma. IMiD treatment has also been associated with an increased risk of myelodysplastic syndrome (MDS), AML, and squamous cell carcinoma of the skin. However, within these overlapping groups, acute lymphoblastic leukemia (ALL) is much less common. Case presentation Herein, we describe an elderly man with PCM and a 14-year cumulative history of IMiD therapy who developed persistent pancytopenia and was diagnosed with B-cell acute lymphoblastic leukemia (B-ALL). He joins a group of 17 other patients documented in the literature who have followed a similar sequence of events starting with worsening cytopenias while on IMiD maintenance for PCM. These PCM patients were diagnosed with B-ALL after a median time of 36 months after starting IMiD therapy and at a median age of 61.5 years old. Conclusions PCM patients with subsequent B-ALL have a poorer prognosis than their de novo B-ALL counterparts, however, the very low prevalence rate of subsequent B-ALL and high efficacy of IMiD maintenance therapy in PCM should not alter physicians’ current practice. Instead, there should be a low threshold for bone marrow biopsy for unexplained cytopenias.

Abstract Identifying the mechanisms that structure niche breadth and overlap between species is important for determining how species interact and assessing their functional role in an ecosystem. Without manipulative experiments, assessing the role of foraging ecology and interspecific competition in structuring diet is challenging. Systems with regular pulses of resources act as a natural experiment to investigate the factors that influence the dietary niches of consumers. We used natural pulses of mast‐fruiting of American beech (Fagus grandifolia) to test whether optimal foraging or competition structure the dietary niche breadth and overlap between two congener rodent species (Peromyscus leucopus and P. maniculatus), both of which are generalist consumers. We reconstructed diets seasonally over a 2‐year period using stable isotope analysis (δ13C, δ15N) of hair and of potential dietary items and measured niche dynamics using standard ellipse area calculated within a Bayesian framework. Changes in niche breadth were generally consistent with predictions of optimal foraging theory, with both species consuming more beechnuts (a high‐quality food resource) and having a narrower niche breadth during masting seasons compared to nonmasting seasons when dietary niches expanded and more fungi (a low‐quality food source) were consumed. In contrast, changes in dietary niche overlap were consistent with competition theory, with higher diet overlap during masting seasons than during nonmasting seasons. Overall, dietary niche dynamics were closely tied to beech masting, underscoring that food availability influences competition. Diet plasticity and niche partitioning between the two Peromyscus species may reflect differences in foraging strategies, thereby reducing competition when food availability is low. Such dietary shifts may have important implications for changes in ecosystem function, including the dispersal of fungal spores.

Painful diabetic neuropathy (PDN) is a devastating neurological complication of diabetes. Methylglyoxal (MG) is a reactive metabolite whose elevation in the plasma corresponds to PDN in patients and pain-like behavior in rodent models of type 1 and type 2 diabetes. Here, we addressed the MG-related spinal mechanisms of PDN in type 2 diabetes using db/db mice, an established model of type 2 diabetes, and intrathecal injection of MG in conventional C57BL/6J mice. Administration of either a MG scavenger (GERP10) or a vector overexpressing glyoxalase 1, the catabolic enzyme for MG, attenuated heat hypersensitivity in db/db mice. In C57BL/6J mice, intrathecal administration of MG produced signs of both evoked (heat and mechanical hypersensitivity) and affective (conditioned place avoidance) pain. MG-induced Ca2+ mobilization in lamina II dorsal horn neurons of C57BL/6J mice was exacerbated in db/db, suggestive of MG-evoked central sensitization. Pharmacological and/or genetic inhibition of transient receptor potential ankyrin subtype 1 (TRPA1), adenylyl cyclase type 1 (AC1), protein kinase A (PKA), or exchange protein directly activated by cyclic adenosine monophosphate (Epac) blocked MG-evoked hypersensitivity in C57BL/6J mice. Similarly, intrathecal administration of GERP10, or inhibitors of TRPA1 (HC030031), AC1 (NB001), or Epac (HJC-0197) attenuated hypersensitivity in db/db mice. We conclude that MG and sensitization of a spinal TRPA1-AC1-Epac signaling cascade facilitate PDN in db/db mice. Our results warrant clinical investigation of MG scavengers, glyoxalase inducers, and spinally-directed pharmacological inhibitors of a MG-TRPA1-AC1-Epac pathway for the treatment of PDN in type 2 diabetes.

Background: Peripheral neuropathies are often caused by disruption of genes responsible for myelination or axonal transport. In particular, impairment in mitochondrial fission and fusion are known causes of peripheral neuropathies. However, the causal mechanisms for peripheral neuropathy gene mutations are not always known. While loss of function mutations in MYH14 typically cause non-syndromic hearing loss, the recently described R941L mutation in MYH14, encoding the non-muscle myosin protein isoform NMIIC, leads to a complex clinical presentation with an unexplained peripheral neuropathy phenotype. Methods: Confocal microscopy was used to examine mitochondrial dynamics in MYH14 patient fibroblast cells, as well as U2OS and M17 cells overexpressing NMIIC. The consequence of the R941L mutation on myosin activity was modeled in C. elegans. Findings: We describe the third family carrying the R941L mutation in MYH14, and demonstrate that the R941L mutation impairs non-muscle myosin protein function. To better understand the molecular basis of the peripheral neuropathy phenotype associated with the R941L mutation, which has been hindered by the fact that NMIIC is largely uncharacterized, we have established a previously unrecognized biological role for NMIIC in mediating mitochondrial fission in human cells. Notably, the R941L mutation acts in a dominant-negative fashion to inhibit mitochondrial fission, especially in the cell periphery. In addition, we observed alterations to the organization of the mitochondrial genome. Interpretation: As impairments in mitochondrial fission cause peripheral neuropathy, this insight into the function of NMIIC likely explains the peripheral neuropathy phenotype associated with the R941L mutation. Fund: This study was supported by the Alberta Children's Hospital Research Institute, the Canadian Institutes of Health Research and the Care4Rare Canada Consortium. Keywords: Mitochondria, Mitochondrial fission, Peripheral neuropathy, Non-muscle myosin, mtDNA, Caenorhabditis elegans