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Abstract The multi-disciplinary team approach is an effective model for patient care. Allied health professionals (AHPs) are an important part of such teams, bringing specific knowledge and skills related to the target patient population. The AHPs most often involved in allergy care are nurses and dietitians. Nurses are often involved in the care of patients with all types of allergy and also with asthma, whilst allergy-specialist dietitians provide vital nutritional and dietary support for the diagnosis and management of food allergy. There are many other AHPs who have a role to play in allergy care, including physiotherapists, psychologists, pharmacists and speech therapists, and their involvement is likely to develop as allergy care becomes more rooted in the community. With the development of multi-professional teams comes the requirement for disease-specific knowledge and skill sets, with all allergy team members required to have baseline knowledge and competency of the condition being managed. Whilst some competencies for AHPs practising in other disease states have been published, none are available for allergic disease against which AHPs can be benchmarked. The European Academy of Allergy & Clinical Immunology (EAACI) recognised this need, and supported the establishment of a Task Force to develop allergy-focussed competencies for AHPs. The varied skills, expertise and professional background of the Task Force members enabled the creation of a set of allergy competencies relevant to all AHPs working in allergy. It is recognised that the training and allergy expertise of AHPs, and their role within the allergy setting, will vary considerably depending on the country. However, it is important for patient care, that all AHP involved in allergy services have access to training, of a sufficiently high enough level to be aspirational and enable the continued growth and development of a wide range of allergy services, given the increasing need. The EAACI competencies will provide an important benchmark for allergy knowledge and skills against which education and training can be designed and health care professionals can subsequently be measured. However, more importantly, the EAACI AHP allergy competencies will enable the development and reach of specialist allergy services, with allergy-specialist AHPs undertaking key roles, especially in the community care setting.

This STEM research project asks middle school or high school students to work towards creating ecologically friendly packaging. Packaging that can be composted instead of thrown away and collected in landfills and oceans like plastics. This inquiry uses nanocellulose and focuses on water permeability. The fibers of nanocellulose can be dried to make a rather strong and thin film, but due to the spaces between the fibers the film is too water permeable and therefore makes poor packaging materials on its own. Students will create nanocellulose composite films with other biodegradable materials, in an attempt to fill the inter-fiber microscopic spaces and create a new film that can be easily tested for water permeability. Students set up a straightforward science experiment with films, water, and mason jars. They will collect and graph data to determine if their nanocellulose composite films reduce water permeability compared to plain nanocellulose and how close they are to the present standard, plastic. This research is an amalgam of disciplinary core ideas like properties and states of matter, as well as a combination of science and engineering practices. It ignites students' curiosity, provides an organic path to science fair extensions, while also helping to cultivate future scientists, engineers, and environmental activists.

The human embryonic stem cell line RCe007-A (RC-3) was derived from a blastocyst voluntarily donated as unsuitable and surplus to fertility requirements following ethics committee approved informed consent under licence from the UK Human Fertilisation and Embryology Authority. The cell line shows normal pluripotency marker expression and differentiation to the three germ layers in vitro. It has a normal 46XX female karyotype and HLA and blood group typing data is available.

The human embryonic stem cell line RCe008-A (RC-4) was derived from a blastocyst voluntarily donated as unsuitable and surplus to fertility requirements following ethics committee approved informed consent under licence from the UK Human Fertilisation and Embryology Authority. The cell line shows normal pluripotency marker expression and differentiation to ectoderm and mesoderm in vitro. It has a mixed 46XX/45X female karyotype and microsatellite PCR identity and blood group typing data is available.

The human embryonic stem cell line RCe009-A (RC-5) was derived from a frozen and thawed Day 2 embryo voluntarily donated as unsuitable and surplus to requirement for fertility treatment following informed consent under licence from the UK Human Fertilisation and Embryology Authority. RCe009-A carries the common DF508 mutation on the cystic fibrosis trans-membrane regulator gene associated with the disease cystic fibrosis. The cell line shows normal pluripotency marker expression and differentiation to the three germ layers in vitro. It has a normal 46XX female karyotype and microsatellite PCR identity, HLA and blood group typing data are available.

The human embryonic stem cell line RCe006-A (RC-2) was derived from a frozen and thawed blastocyst voluntarily donated as surplus to fertility requirements following ethics committee approved informed consent under licence from the UK Human Fertilisation and Embryology Authority. The cell line exhibits expression of expected pluripotency markers and in vitro differentiation potential to three germinal lineage representative cell populations. It has a male trisomy 12 karyotype (47XY, +12). Microsatellite DNA marker identity and HLA and blood group typing data are available.

The human embryonic stem cell line RCe010-A (RC-6) was derived from a frozen and thawed blastocyst voluntarily donated as unsuitable and surplus to fertility requirements following ethics committee approved informed consent under licence from the UK Human Fertilisation and Embryology Authority. The cell line shows normal pluripotency marker expression and differentiation to the three germ layers in vitro. It has a normal 46XY male karyotype and microsatellite PCR identity, HLA and blood group typing data are available.

Abstract Background Obstructive sleep apnea (OSA) affects 10–26% of adults in the United States with known sex differences in prevalence and severity. OSA is characterized by elevated inflammation, oxidative stress (OS), and cognitive dysfunction. However, there is a paucity of data regarding the role of sex in the OSA phenotype. Prior findings suggest women exhibit different OSA phenotypes than men, which could result in under-reported OSA prevalence in women. To examine the relationship between OSA and sex, we used chronic intermittent hypoxia (CIH) to model OSA in rats. We hypothesized that CIH would produce sex-dependent phenotypes of inflammation, OS, and cognitive dysfunction, and these sex differences would be dependent on mitochondrial oxidative stress (mtOS). Methods Adult male and female Sprague Dawley rats were exposed to CIH or normoxia for 14 days to examine the impact of sex on CIH-associated circulating inflammation (IL-1β, IL-6, IL-10, TNF-α), circulating steroid hormones, circulating OS, and behavior (recollective and spatial memory; gross and fine motor function; anxiety-like behaviors; and compulsive behaviors). Rats were implanted with osmotic minipumps containing either a mitochondria-targeting antioxidant (MitoTEMPOL) or saline vehicle 1 week prior to CIH initiation to examine how inhibiting mtOS would affect the CIH phenotype. Results Sex-specific differences in CIH-induced inflammation, OS, motor function, and compulsive behavior were observed. In female rats, CIH increased inflammation (plasma IL-6 and IL-6/IL-10 ratio) and impaired fine motor function. Conversely, CIH elevated circulating OS and compulsivity in males. These sex-dependent effects of CIH were blocked by inhibiting mtOS. Interestingly, CIH impaired recollective memory in both sexes but these effects were not mediated by mtOS. No effects of CIH were observed on spatial memory, gross motor function, or anxiety-like behavior, regardless of sex. Conclusions Our results indicate that the impact of CIH is dependent on sex, such as an inflammatory response and OS response in females and males, respectively, that are mediated by mtOS. Interestingly, there was no effect of sex or mtOS in CIH-induced impairment of recollective memory. These results indicate that mtOS is involved in the sex differences observed in CIH, but a different mechanism underlies CIH-induced memory impairments.

Abstract Background The rugby league tackle has been identified as the game event with the greatest propensity for a clinically diagnosed concussion. This study aims to replicate the work conducted in professional rugby league and rugby union by examining Head Injury Assessment (HIA) events to determine the associated tackle characteristics that increase concussion risk in sub-elite rugby league players. This comparison between competition levels is important due to the less developed physiological and tackle proficiency characteristics of sub-elite rugby league players and the fewer resources available for an on-field diagnosis, compared to the elite level of the sport. Results Tackles resulting in Head Injury Assessments (HIAs, n = 131) and 2,088 tackles that did not result in a head injury were identified and coded from one season of the 2019 Queensland Cup. The body position of both ball carrier and tackler, tackle height, and body contact areas were evaluated. The propensity for tacklers to undergo a head injury assessment was 1.49 HIAs per 1,000 tackles, equating to a 2.5-fold higher risk than that of the ball carrier (0.59 HIAs per 1,000 tackles). The risk for an HIA was 2.75-fold greater when the tackler was upright (2.89 HIAs per 1,000 tackles) compared to a bent-at-the-waist tackler (1.05 HIAs per 1,000 tackles). The greatest risk for the tackler and ball carrier sustaining an HIA occurred when the tackle height was high, with head-to-head contact having the greatest propensity for an HIA (44.37 HIAs per 1,000 tackles). HIA risk was also greater for both players when the ball carrier did not employ an evasion strategy (3.73 HIAs per 1,000 tackles). Conclusions The study replicates results from research in elite rugby league and rugby union. A combination of higher head contact/proximity and upright body position significantly increase an HIA risk. Tackler head position and ball carrier evasion behaviours also affect risk, suggesting that injury prevention strategies designed to reduce tackle height and improve tackle technique by focusing on head position, body position, and in a novel finding, ball carrier evasion, may reduce head injury risk in sub-elite rugby league players.

There are no validated diagnostic criteria for traumatic encephalopathy syndrome (TES). During the early and middle 20th century, TES was described as a clinical condition that was experienced by some high-exposure boxers?and it was believed to reflect chronic traumatic brain injury. Consensus criteria for the diagnosis of TES were published in 2021. We applied the consensus criteria for TES retrospectively to cases of chronic brain damage in boxers described in articles published in the 20th century that were obtained from narrative and systematic reviews. The sample included 157 boxers identified in 21 articles published between 1929 and 1999. Two authors reviewed each case description and coded the criteria for TES. For the core clinical features, cognitive impairment was noted in 63.1%, and in 28.7% of cases the person's cognitive functioning appeared to be broadly normal. Neurobehavioral dysregulation was present in 25.5%. One third (34.4%) were identified as progressive, 30.6% were not progressive, and the course could not be clearly determined in 35.0%. In total, 29.9% met the TES consensus criteria, 28.0% did not, and 42.0% had insufficient information to make a diagnostic determination. TES, in the 20th century, was described as a neurological condition, not a psychiatric disorder?and this supports the decision of the 2021 consensus group to remove primary and secondary psychiatric diagnoses from being a core diagnostic feature. Future research is needed to determine whether, or the extent to which, cognitive impairment or neurobehavioral dysregulation described as characterizing TES are associated with chronic traumatic encephalopathy neuropathological change.

BackgroundSex differences in oxidative stress-associated cognitive decline are influenced by sex hormone levels. Notably, oxidative stress-associated neuronal cell death can be exacerbated through testosterone signaling via membrane androgen receptor AR45, which is complexed with G protein Gαq within plasma membrane-associated lipid rafts. The objective of this study was to elucidate the impact of sex on the expression of AR45 and Gαq in brain regions associated with cognitive function, specifically hippocampus subregions and entorhinal cortex. Additionally, we investigated whether chronic intermittent hypoxia (CIH), an oxidative stressor with sex-specific effects, would modulate AR45 and Gαq expression in these brain regions.MethodsAdult male and female Sprague-Dawley rats were exposed to CIH or normoxia (room air) during their sleep phase for 14 days. We quantified AR45 and Gαq protein expression in various cognition-associated brain regions [dorsal hippocampal CA1, CA3, dentate gyrus (DG), and entorhinal cortex (ETC)] via western blotting. For comparisons, AR45 and Gαq protein expression were also assessed in brain regions outside the hippocampal-ETC circuit [thalamus (TH) and striatum (STR)].ResultsThe highest AR45 levels were expressed in the hippocampal CA1 and DG while the lowest expression was observed in the extrahippocampal STR. The highest Gαq levels were expressed in the hippocampal-associated ETC while the lowest expression was observed in the extrahippocampal TH. Females expressed higher levels of AR45 in the hippocampal DG compared to males, while no sex differences in Gαq expression were observed regardless of brain region assessed. Moreover, there was no effect of CIH on AR45 or Gαq expression in any of the brain regions examined. AR45 expression was positively correlated with Gαq expression in the CA1, DG, ETC, TH, and STR in a sex-dependent manner.ConclusionOur findings reveal enrichment of AR45 and Gαq protein expression within the hippocampal-ETC circuit, which is vulnerable to oxidative stress and neurodegeneration during cognitive decline. Nonetheless, CIH does not modulate the expression of AR45 or Gαq. Importantly, there are sex differences in AR45 expression and its association with Gαq expression in various brain regions, which may underlie sex-specific differences in cognitive and motor function-associated declines with aging.

The world's understanding of the climate and ecological crises rests on science. However, scientists' conventional methods of engagement, such as producing ever more data and findings, writing papers and giving advice to governments, have not been sufficiently effective at persuading politicians to act on the climate and ecological emergency. To date, governments’ decisions (such as continuing with vast subsidies for fossil fuels) clearly show that powerful vested interests have been much more influential than the amassed scientific knowledge and advice. We argue that in the face of this inaction, scientists can have the maximum amount of influence by lending their support to social movements pressing for action, joining as active participants and considering civil disobedience. Scientists seeking to halt continued environmental destruction also need to work through our institutions. Too many scientific organizations, from national academies of science to learned societies and universities, have not taken practical action on climate; for example, many still partner with fossil fuel and other compromised interests. We therefore also outline a vision for how scientists can reform our scientific institutions to become powerful agents for change.

Background: Rugby league is a popular collision sport among Australian adolescent and young adult men. Concussion is one of the more common injuries in rugby league. Few studies have examined concussion in youth rugby league. To examine medically diagnosed concussions from a single season within two elite-level pathway rugby league competitions by evaluating game play risk factors and conducting a video review of potential concussion signs. Methods: All players involved in the Queensland Rugby League's (QRL) under 18 years and under 20 years age group competitions during the 2019 season were included in this study. Data included all head injury assessments (HIAs) identified in real-time through the QRL injury surveillance system for these two QRL age group competitions. The purpose of this study was to (i) report the rates of HIAs and medically diagnosed concussions; (ii) examine video signs of potential concussion; (iii) review game play risk factors related to HIAs and concussions; and (iv) determine the number of days until a concussed player returned to match play and the number of subsequent games missed by concussed players. Results: There were 86 HIAs and 30 medically diagnosed concussions from the two competitions. The concussion incidence was 2.93 per 1000 player match hours in the under 18-year age group and 5.75 per 1000 player match hours in the under 20-year age group. Slow to stand was the most commonly observed video sign (78.6%; 22/28 concussions). Most concussed players (91%, 21/23) missed at least one subsequent game (M ​= ​1.4, SD ​= ​1.7, range ​= ​0–7 games), with the average days to return-to-play being 15.7 (SD ​= ​7.0, range ​= ​7–41 days). Conclusions: In elite-level pathway rugby league, the incidences of HIAs and medically diagnosed concussions were higher in the under 20 age group than the under 18 age group. Both age groups had lower incidences of HIAs and concussions than professional adult rugby league players. Return-to-play following concussion was similar across the two age groups and differed considerably compared to the elite level, with a longer time before return to play for the younger elite level development pathway players.

For over 100 years there has been an academic pursuit of understanding and applying the principals of sport psychology to improve athletic performance. How is it that certain athletes do their best when it means the most while others “choke”? Meeting and exceeding the challenges that are presented can completely change the trajectory of any athlete's career. What is it that separates the good from the great and the great from the superstars? Is it motivation, preparation, determination, discipline, commitment, natural talent, physical strength, or work ethic? Maybe it is a combination of all of these characteristics. Without the right mentality everything can fall apart. In Alcoholics Anonymous, it is said, “you don't have a drinking problem – you have a thinking problem.” The evidence is quite clear that the mental game can have a substantial impact, both for the better and for the worse, on performance. In this perspectives and viewpoints, we share our own insights from our experience for athletes to obtain the ultra-mentality and maximise their athletic performance. We have attempted to take simple words to briefly explain complicated concepts.

Abstract Loss-of-function of DDX3X is a leading cause of neurodevelopmental disorders (NDD) in females. DDX3X is also a somatically mutated cancer driver gene proposed to have tumour promoting and suppressing effects. We perform saturation genome editing of DDX3X, testing in vitro the functional impact of 12,776 nucleotide variants. We identify 3432 functionally abnormal variants, in three distinct classes. We train a machine learning classifier to identify functionally abnormal variants of NDD-relevance. This classifier has at least 97% sensitivity and 99% specificity to detect variants pathogenic for NDD, substantially out-performing in silico predictors, and resolving up to 93% of variants of uncertain significance. Moreover, functionally-abnormal variants can account for almost all of the excess nonsynonymous DDX3X somatic mutations seen in DDX3X-driven cancers. Systematic maps of variant effects generated in experimentally tractable cell types have the potential to transform clinical interpretation of both germline and somatic disease-associated variation.

Abstract Background Gestational sleep apnea is a hypoxic sleep disorder that affects 8–26% of pregnancies and increases the risk for central nervous system dysfunction in offspring. Specifically, there are sex differences in the sensitivity of the fetal hippocampus to hypoxic insults, and hippocampal impairments are associated with social dysfunction, repetitive behaviors, anxiety, and cognitive impairment. Yet, it is unclear whether gestational sleep apnea impacts these hippocampal-associated functions and if sex and age modify these effects. To examine the relationship between gestational sleep apnea and hippocampal-associated behaviors, we used chronic intermittent hypoxia (CIH) to model late gestational sleep apnea in pregnant rats. We hypothesized that late gestational CIH would produce sex- and age-specific social, anxiety-like, repetitive, and cognitive impairments in offspring. Methods Timed pregnant Long-Evans rats were exposed to CIH or room air normoxia from GD 15–19. Behavioral testing of offspring occurred during either puberty or young adulthood. To examine gestational hypoxia-induced behavioral phenotypes, we quantified hippocampal-associated behaviors (social function, repetitive behaviors, anxiety-like behaviors, and spatial memory and learning), hippocampal neuronal activity (glutamatergic NMDA receptors, dopamine transporter, monoamine oxidase-A, early growth response protein 1, and doublecortin), and circulating hormones in offspring. Results Late gestational CIH induced sex- and age-specific differences in social, repetitive, and memory functions in offspring. In female pubertal offspring, CIH impaired social function, increased repetitive behaviors, and elevated circulating corticosterone levels but did not impact memory. In contrast, CIH transiently induced spatial memory dysfunction in pubertal male offspring but did not impact social or repetitive functions. Long-term effects of gestational CIH on social behaviors were only observed in female offspring, wherein CIH induced social disengagement and suppression of circulating corticosterone levels in young adulthood. No effects of gestational CIH were observed in anxiety-like behaviors, hippocampal neuronal activity, or circulating testosterone and estradiol levels, regardless of sex or age of offspring. Conclusions Our results indicate that hypoxia-associated pregnancy complications during late gestation can increase the risk for behavioral and physiological outcomes in offspring, such as social dysfunction, repetitive behaviors, and cognitive impairment, that are dependent on sex and age.

Abstract Background Iliosacral screw placement is ubiquitous and now part of the surgeon’s pelvic trauma armamentarium. More recent evidence supports sacroiliac arthrodesis for treating sacroiliac joint (SIJ) dysfunction in select patients. Regardless of the surgical indication, there are currently no studies examining lag screw compression biomechanics across the SIJ. The objective of this biomechanical investigation was to quantify iliosacral implant compressive loads and to examine the insertion torque and compressive load profile over time. Methods Eight human cadaveric pelvic specimens underwent SIJ fixation at S1 and S2 using 11.5 and 10.0 mm iFuse-TORQ Lag implants, respectively, and standard 7.3 mm trauma lag screws. Load decay analysis was performed, and insertion and removal torques were measured. Results For both implants at S1 and S2 levels, the load relaxed 50% in approximately 67 min. Compressive load decay was approximately 70% on average occurring approximately 15 h post-insertion. Average insertion torque for the 11.5 mm TORQ implant at S1 was significantly greater than the trauma lag screw. Similarly, at S2, insertion torque of the 10.0 mm TORQ implant was greater than the trauma lag screw. At S1, removal torque for the 11.5 mm TORQ implant was higher than the trauma lag screw; there was no significant difference in the removal torque at S2. Conclusions In this study, we found that a novel posterior pelvic implant with a larger diameter, roughened surface, and dual pitch threads achieved improved insertion and removal torques compared to a standard screw. Load relaxation characteristics were similar between all implants.

Obstructive sleep apnea (OSA) is a sleep disorder characterized by intermittent complete or partial occlusion of the airway. Despite a recognized association between OSA and glaucoma, the nature of the underlying link remains unclear. In this study, we investigated whether mild OSA induces morphological, inflammatory, and metabolic changes in the retina resembling those seen in glaucoma using a rat model of OSA known as chronic intermittent hypoxia (CIH). Rats were randomly assigned to either normoxic or CIH groups. The CIH group was exposed to periodic hypoxia during its sleep phase with oxygen reduction from 21% to 10% and reoxygenation in 6 min cycles over 8 h/day. The eyes were subsequently enucleated, and then the retinas were evaluated for retinal ganglion cell number, oxidative stress, inflammatory markers, metabolic changes, and hypoxic response modulation using immunohistochemistry, multiplex assays, and capillary electrophoresis. Statistically significant differences were observed between normoxic and CIH groups for oxidative stress and inflammation, with CIH resulting in increased HIF-1α protein levels, higher oxidative stress marker 8-OHdG, and increased TNF-α. Pyruvate dehydrogenase kinase-1 protein was significantly reduced with CIH. No significant differences were found in retinal ganglion cell number. Our findings suggest that CIH induces oxidative stress, inflammation, and upregulation of HIF-1α in the retina, akin to early-stage glaucoma.

Background:. Fracture-related infection is one of the most challenging complications in orthopaedic trauma surgery. However, the effect of infection on functional and pain-related outcomes has not been well established. The aims of this study were to evaluate functional recovery for patients with fracture and a deep surgical site infection compared with patients with fracture without infection and to evaluate whether pain severity, social support, and preinjury mental health have a moderating effect on the magnitude and direction of the relationship between deep surgical site infection and functional recovery. Methods:. This is a secondary retrospective cohort study using prospectively collected data from the VANCO trial (Local Antibiotic Therapy to Reduce Infection After Operative Treatment of Fractures at High Risk of Infection) and the OXYGEN (Supplemental Perioperative Oxygen to Reduce Surgical Site Infection After High Energy Fracture Surgery) trial. In this study, 2,116 patients with tibial plateau, pilon, or calcaneal fractures at high risk for infection were included. Patients were divided into cohorts of patients who experienced a deep surgical site infection and those who did not. The primary outcome measure was the functional outcome using the Veterans RAND 12-Item Health Survey (VR-12). Results:. After controlling for covariates, deep surgical site infection was independently associated with functional outcome, with a 3.3-point reduction in the VR-12 Physical Component Score, and pain severity was independently associated with functional outcome, with a 2.5-point reduction in the VR-12 Physical Component Score. Furthermore, the Brief Pain Inventory pain severity demonstrated an important moderating effect on the relationship between infection and functional outcome. In patients with lower pain scores, infection had a large negative impact on functional outcome, whereas, in patients with higher pain scores, infection had no significant impact on functional outcome. Furthermore, the functional outcome in the entire cohort remains at only 61% of baseline. Conclusions:. This study documents the negative impact of postoperative infection on functional recovery after injury, as well as the novel finding of pain severity as an important moderating factor. This study emphasizes not only the importance of developing effective interventions designed to reduce postoperative infection, but also the role that factors that moderate pain severity plays in limiting recovery of physical function. Level of evidence:. Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Summary: Neuron migration is a key phase of neurogenesis, critical for the assembly and function of neuronal circuits. In songbirds, this process continues throughout life, but how these newborn neurons disperse through the adult brain is unclear. We address this question using in vivo two-photon imaging in transgenic zebra finches that express GFP in young neurons and other cell types. In juvenile and adult birds, migratory cells are present at a high density, travel in all directions, and make frequent course changes. Notably, these dynamic migration patterns are well fit by a superdiffusive model. Simulations reveal that these superdiffusive dynamics are sufficient to disperse new neurons throughout the song nucleus HVC. These results suggest that superdiffusive migration may underlie the formation and maintenance of nuclear brain structures in the postnatal brain and indicate that transgenic songbirds are a useful resource for future studies into the mechanisms of adult neurogenesis.

Over the last decade, the strain on the English National Health Service (NHS) has increased. This has been especially felt by acute hospital trusts where the volume of admissions has steadily increased. Patient outcomes, including inpatient mortality, vary between trusts. The extent to which these differences are explained by systems-based factors, and whether they are avoidable, is unclear. Few studies have investigated these relationships. A systems-based methodology recognises the complexity of influences on healthcare outcomes. Rather than clinical interventions alone, the resources supporting a patient's treatment journey have near-equal importance. This paper first identifies suitable metrics of resource and demand within healthcare delivery from routinely collected, publicly available, hospital-level data. Then it proceeds to use univariate and multivariable linear regression to associate such systems-based factors with standardised mortality. Three sequential cross-sectional analyses were performed, spanning the last decade. The results of the univariate regression analyses show clear relationships between five out of the six selected predictor variables and standardised mortality. When these five predicators are included within a multivariable regression analysis, they reliably explain approximately 36% of the variation in standardised mortality between hospital trusts. Three factors are consistently statistically significant: the number of doctors per hospital bed, bed occupancy, and the percentage of patients who are placed in a bed within four hours after a decision to admit them. Of these, the number of doctors per bed had the strongest effect. Linear regression assumption testing and a robustness analysis indicate the observations have internal validity. However, our empirical strategy cannot determine causality and our findings should not be interpreted as established causal relationships. This study provides hypothesis-generating evidence of significant relationships between systems-based factors of healthcare delivery and standardised mortality. These have relevance to clinicians and policymakers alike. While identifying causal relationships between the predictors is left to the future, it establishes an important paradigm for further research.

Purpose: Structural variants such as multiexon deletions and duplications are an important cause of disease but are often overlooked in standard exome/genome sequencing analysis. We aimed to evaluate the detection of copy-number variants (CNVs) from exome sequencing (ES) in comparison with genome-wide low-resolution and exon-resolution chromosomal microarrays (CMAs) and to characterize the properties of de novo CNVs in a large clinical cohort. Methods: We performed CNV detection using ES of 9859 parent-offspring trios in the Deciphering Developmental Disorders (DDD) study and compared them with CNVs detected from exon-resolution array comparative genomic hybridization in 5197 probands from the DDD study. Results: Integrating calls from multiple ES-based CNV algorithms using random forest machine learning generated a higher quality data set than using individual algorithms. Both ES- and array comparative genomic hybridization–based approaches had the same sensitivity of 89% and detected the same number of unique pathogenic CNVs not called by the other approach. Of DDD probands prescreened with low-resolution CMAs, 2.6% had a pathogenic CNV detected by higher-resolution assays. De novo CNVs were strongly enriched in known DD-associated genes and exhibited no bias in parental age or sex. Conclusion: ES-based CNV calling has higher sensitivity than low-resolution CMAs currently in clinical use and comparable sensitivity to exon-resolution CMA. With sufficient investment in bioinformatic analysis, exome-based CNV detection could replace low-resolution CMA for detecting pathogenic CNVs.

Abstract Clonal hematopoiesis (CH)—age-related expansion of mutated hematopoietic clones—can differ in frequency and cellular fitness by CH type (e.g., mutations in driver genes (CHIP), gains/losses and copy-neutral loss of chromosomal segments (mCAs), and loss of sex chromosomes). Co-occurring CH raises questions as to their origin, selection, and impact. We integrate sequence and genotype array data in up to 482,378 UK Biobank participants to demonstrate shared genetic architecture across CH types. Our analysis suggests a cellular evolutionary trade-off between different types of CH, with LOY occurring at lower rates in individuals carrying mutations in established CHIP genes. We observed co-occurrence of CHIP and mCAs with overlap at TET2, DNMT3A, and JAK2, in which CHIP precedes mCA acquisition. Furthermore, individuals carrying overlapping CH had high risk of future lymphoid and myeloid malignancies. Finally, we leverage shared genetic architecture of CH traits to identify 15 novel loci associated with leukemia risk.

Abstract This report describes a 3D microelectrode array integrated on a thin-film flexible cable for neural recording in small animals. The fabrication process combines traditional silicon thin-film processing techniques and direct laser writing of 3D structures at micron resolution via two-photon lithography. Direct laser-writing of 3D-printed electrodes has been described before, but this report is the first to provide a method for producing high-aspect-ratio structures. One prototype, a 16-channel array with 300 µm pitch, demonstrates successful electrophysiological signal capture from bird and mouse brains. Additional devices include 90 µm pitch arrays, biomimetic mosquito needles that penetrate through the dura of birds, and porous electrodes with enhanced surface area. The rapid 3D printing and wafer-scale methods described here will enable efficient device fabrication and new studies examining the relationship between electrode geometry and electrode performance. Applications include small animal models, nerve interfaces, retinal implants, and other devices requiring compact, high-density 3D electrodes.

Abstract Indium (In) is a neutron absorbing additive that could feasibly be used to mitigate criticality in ceramic wasteforms containing Pu in the immobilised form, for which zirconolite (nominally CaZrTi2O7) is a candidate host phase. Herein, the solid solutions Ca1-xZr1-xIn2xTi2O7 (0.10 ≤ x ≤ 1.00; air synthesis) and Ca1-xUxZrTi2-2xIn2xO7 (x = 0.05, 0.10; air and argon synthesis) were investigated by conventional solid state sintering at a temperature of 1350 °C maintained for 20 h, with a view to characterise In3+ substitution behaviour in the zirconolite phase across the Ca2+, Zr4+ and Ti4+ sites. When targeting Ca1-xZr1-xIn2xTi2O7, single phase zirconolite-2M was formed at In concentrations of 0.10 ≤ x ≤ 0.20; beyond x ≥ 0.20, a number of secondary In-containing phases were stabilised. Zirconolite-2M remained a constituent of the phase assemblage up to a concentration of x = 0.80, albeit at relatively low concentration beyond x ≥ 0.40. It was not possible to synthesise the In2Ti2O7 end member compound using a solid state route. Analysis of the In K-edge XANES spectra in the single phase zirconolite-2M compounds confirmed that the In inventory was speciated as trivalent In3+, consistent with targeted oxidation state. However, fitting of the EXAFS region using the zirconolite-2M structural model was consistent with In3+ cations accommodated within the Ti4+ site, contrary to the targeted substitution scheme. When deploying U as a surrogate for immobilised Pu in the Ca1-xUxZrTi2-2xIn2xO7 solid solution, it was demonstrated that, for both x = 0.05 and 0.10, In3+ was successfully able to stabilise zirconolite-2M when U was distributed predominantly as both U4+ and average U5+, when synthesised under argon and air, respectively, determined by U L3-edge XANES analysis.

BackgroundTo better understand the biomechanical profile of direct head impacts and the game scenarios in which they occur in Rugby Union, there is a need for an on-field validation of a new instrumented mouthguard (IMG) against the reference standard. This study considers the potential of a combined biomechanical (IMG) and video analysis approach to direct head impact recognition, both of which in isolation have limitations. The aim of this study is to assess the relationship between an instrumented mouthguard and video analysis in detection of direct head impacts in rugby union.DesignPilot Study - Observational Cohort designMethodsThe instrumented mouthguard was worn by ten (3 backs, 7 forwards) professional Rugby Union players during the 2020–21 Gallagher Premiership (UK) season. Game-day video was synchronized with timestamped head acceleration events captured from the instrumented mouthguard. Direct Head Impacts were recorded in a 2 × 2 contingency table to determine sensitivity. Impact characteristics were also collected for all verified head impacts to further the understanding of head biomechanics during the game.ResultsThere were 2018 contact events that were reviewed using video analysis. Of those 655 were categorized as direct head impacts which also correlated with a head acceleration event captured by the IMG. Sensitivity analysis showed an overall sensitivity of 93.6% and a positive predictive value (PPV of 92.4%). When false positives were excluded due to ball out of play, mouthguard removal or handling after a scoring situation or stoppage, PPV was improved (98.3%). Most verified head impacts occurred in and around the ruck contest (31.2%) followed by impacts to the primary tackler (28.4%).ConclusionThis pilot validation study demonstrates that this IMG provides a highly accurate measurement device that could be used to complement video verification in the recognition of on-field direct head impacts. The frequency and magnitude of direct head impacts derived from specific game scenarios has been described and allows for greater recognition of high-risk situations. Further studies with larger sample sizes and in different populations of Rugby Union players are required to develop our understanding of head impact and enable strategies for injury mitigation.

BACKGROUND Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a primary immunodeficiency disorder caused by heterozygous gain-of-function CXCR4 mutations. Myelokathexis is a kind of neutropenia caused by neutrophil retention in bone marrow and in WHIM syndrome is associated with lymphopenia and monocytopenia. The CXCR4 antagonist plerixafor mobilizes leukocytes to the blood; however, its safety and efficacy in WHIM syndrome are undefined.METHODS In this investigator-initiated, single-center, quadruple-masked phase III crossover trial, we compared the total infection severity score (TISS) as the primary endpoint in an intent-to-treat manner in 19 patients with WHIM who each received 12 months treatment with plerixafor and 12 months treatment with granulocyte CSF (G-CSF, the standard of care for severe congenital neutropenia). The treatment order was randomized for each patient.RESULTS Plerixafor was nonsuperior to G-CSF for TISS (P = 0.54). In exploratory endpoints, plerixafor was noninferior to G-CSF for maintaining neutrophil counts of more than 500 cells/μL (P = 0.023) and was superior to G-CSF for maintaining lymphocyte counts above 1,000 cells/μL (P < 0.0001). Complete regression of a subset of large wart areas occurred on plerixafor in 5 of 7 patients with major wart burdens at baseline. Transient rash occurred on plerixafor, and bone pain was more common on G-CSF. There were no significant differences in drug preference or quality of life or the incidence of drug failure or serious adverse events.CONCLUSION Plerixafor was not superior to G-CSF in patients with WHIM for TISS, the primary endpoint. Together with wart regression and hematologic improvement, the infection severity results support continued study of plerixafor as a potential treatment for WHIM syndrome.TRIAL REGISTRATION Clinicaltrials.gov NCT02231879.FUNDING This study was funded by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases.

Despite thousands of higher education institutions (HEIs) having issued Climate Emergency declarations, most academics continue to operate according to ‘business-as-usual’. However, such passivity increases the risk of climate impacts so severe as to threaten the persistence of organized society, and thus HEIs themselves. This paper explores why a maladaptive cognitive-practice gap persists and asks what steps could be taken by members of HEIs to activate the academy. Drawing on insights from climate psychology and sociology, we argue that a process of ‘socially organized denial’ currently exists within universities, leading academics to experience a state of ‘double reality’ that inhibits feelings of accountability and agency, and this is self-reenforcing through the production of ‘pluralistic ignorance.’ We further argue that these processes serve to uphold the cultural hegemony of ‘business-as-usual’ and that this is worsened by the increasing neo-liberalization of modern universities. Escaping these dynamics will require deliberate efforts to break taboos, through frank conversations about what responding to a climate emergency means for universities’ – and individual academics’ – core values and goals.

Zirconolite is a candidate ceramic wasteform under consideration for the immobilisation of the UK civil PuO2 inventory. In the present work, a baseline dual-substituted zirconolite with the target composition (Ca0.783Gd0.017Ce0.2)(Zr0.883Gd0.017Ce0.1)(Ti1.6Al0.4)O7 was fabricated by hot isostatic pressing (HIPing). In order to optimise the microstructure properties and improve the obtained yield of the zirconolite phase, a range of planetary ball milling parameters were investigated prior to consolidation by HIP. This included milling the batched oxide precursors at 400 rpm for up to 120 min, the pre-milling of CeO2 (PuO2 surrogate) to reduce the particle size and using a CeO2 source with finer particle size (3-edge X-ray absorption spectroscopy was utilised to determine the Ce oxidation state. In this study, the ideal milling parameter for the fabrication of zirconolite waste forms was defined as 60 min at 400 rpm.

The emergence of new virus variants, including the Omicron variant (B.1.1.529) of SARS-CoV-2, can lead to reduced vaccine effectiveness (VE) and the need for new vaccines or vaccine doses if the extent of immune evasion is severe. Neutralizing antibody titers have been shown to be a correlate of protection for SARS-CoV-2 and other pathogens, and could be used to quickly estimate vaccine effectiveness for new variants. However, no model currently exists to provide precise VE estimates for a new variant against severe disease for SARS-CoV-2 using robust datasets from several populations. We developed predictive models for VE against COVID-19 symptomatic disease and hospitalization across a 54-fold range of mean neutralizing antibody titers. For two mRNA vaccines (mRNA-1273, BNT162b2), models fit without Omicron data predicted that infection with the BA.1 Omicron variant increased the risk of hospitalization 2.8–4.4-fold and increased the risk of symptomatic disease 1.7–4.2-fold compared to the Delta variant. Out-of-sample validation showed that model predictions were accurate; all predictions were within 10% of observed VE estimates and fell within the model prediction intervals. Predictive models using neutralizing antibody titers can provide rapid VE estimates, which can inform vaccine booster timing, vaccine design, and vaccine selection for new virus variants.

IntroductionSleep dysfunction is frequently experienced by people with Parkinson’s disease (PD) and negatively influences quality of life. Although subthalamic nucleus (STN) deep brain stimulation (DBS) can improve sleep in PD, sleep microstructural features such as sleep spindles provide additional insights about healthy sleep. For example, sleep spindles are important for better cognitive performance and for sleep consolidation in healthy adults. We hypothesized that conventional STN DBS settings would yield a greater enhancement in spindle density compared to OFF and low frequency DBS.MethodsIn a previous within-subject, cross-sectional study, we evaluated effects of low (60 Hz) and conventional high (≥130 Hz) frequency STN DBS settings on sleep macroarchitectural features in individuals with PD. In this post hoc, exploratory analysis, we conducted polysomnography (PSG)-derived quantitative electroencephalography (qEEG) assessments in a cohort of 15 individuals with PD who had undergone STN DBS treatment a median 13.5 months prior to study participation. Fourteen participants had unilateral DBS and 1 had bilateral DBS. During three nonconsecutive nights of PSG, the participants were assessed under three different DBS conditions: DBS OFF, DBS LOW frequency (60 Hz), and DBS HIGH frequency (≥130 Hz). The primary objective of this study was to investigate the changes in sleep spindle density across the three DBS conditions using repeated-measures analysis of variance. Additionally, we examined various secondary outcomes related to sleep qEEG features. For all participants, PSG-derived EEG data underwent meticulous manual inspection, with the exclusion of any segments affected by movement artifact. Following artifact rejection, sleep qEEG analysis was conducted on frontal and central leads. The measures included slow wave (SW) and spindle density and morphological characteristics, SW-spindle phase-amplitude coupling, and spectral power analysis during non-rapid eye movement (NREM) sleep.ResultsThe analysis revealed that spindle density was significantly higher in the DBS HIGH condition compared to the DBS LOW condition. Surprisingly, we found that SW amplitude during NREM was significantly higher in the DBS LOW condition compared to DBS OFF and DBS HIGH conditions. However, no significant differences were observed in the other sleep qEEG features during sleep at different DBS conditions.ConclusionThis study presents preliminary evidence suggesting that conventional HIGH frequency DBS settings enhance sleep spindle density in PD. Conversely, LOW frequency settings may have beneficial effects on increasing slow wave amplitude during sleep. These findings may inform mechanisms underlying subjective improvements in sleep quality reported in association with DBS. Moreover, this work supports the need for additional research on the influence of surgical interventions on sleep disorders, which are prevalent and debilitating non-motor symptoms in PD.

The most common complication in older surgical patients is postoperative delirium (POD). POD is associated with preoperative cognitive impairment and longer durations of intraoperative burst suppression (BSup) – electroencephalography (EEG) with repeated periods of suppression (very low-voltage brain activity). However, BSup has modest sensitivity for predicting POD. We hypothesized that a brain state of lowered EEG power immediately precedes BSup, which we have termed “pre-burst suppression” (preBSup). Further, we hypothesized that even patients without BSup experience these preBSup transient reductions in EEG power, and that preBSup (like BSup) would be associated with preoperative cognitive function and delirium risk. Data included 83 32-channel intraoperative EEG recordings of the first hour of surgery from 2 prospective cohort studies of patients ≥age 60 scheduled for ≥2-h non-cardiac, non-neurologic surgery under general anesthesia (maintained with a potent inhaled anesthetic or a propofol infusion). Among patients with BSup, we defined preBSup as the difference in 3–35 Hz power (dB) during the 1-s preceding BSup relative to the average 3–35 Hz power of their intraoperative EEG recording. We then recorded the percentage of time that each patient spent in preBSup, including those without BSup. Next, we characterized the association between percentage of time in preBSup and (1) percentage of time in BSup, (2) preoperative cognitive function, and (3) POD incidence. The percentage of time in preBSup and BSup were correlated (Spearman’s ρ [95% CI]: 0.52 [0.34, 0.66], p < 0.001). The percentage of time in BSup, preBSup, or their combination were each inversely associated with preoperative cognitive function (β [95% CI]: −0.10 [−0.19, −0.01], p = 0.024; −0.04 [−0.06, −0.01], p = 0.009; −0.04 [−0.06, −0.01], p = 0.003, respectively). Consistent with prior literature, BSup was significantly associated with POD (odds ratio [95% CI]: 1.34 [1.01, 1.78], p = 0.043), though this association did not hold for preBSup (odds ratio [95% CI]: 1.04 [0.95, 1.14], p = 0.421). While all patients had ≥1 preBSup instance, only 20.5% of patients had ≥1 BSup instance. These exploratory findings suggest that future studies are warranted to further study the extent to which preBSup, even in the absence of BSup, can identify patients with impaired preoperative cognition and/or POD risk.

IntroductionSome ultra-high exposure boxers from the 20th century suffered from neurological problems characterized by slurred speech, personality changes (e.g., childishness or aggressiveness), and frank gait and coordination problems, with some noted to have progressive Parkinsonian-like signs. Varying degrees of cognitive impairment were also described, with some experiencing moderate to severe dementia. The onset of the neurological problems often began while they were young men and still actively fighting. More recently, traumatic encephalopathy syndrome (TES) has been proposed to be present in athletes who have a history of contact (e.g., soccer) and collision sport participation (e.g., American-style football). The characterization of TES has incorporated a much broader description than the neurological problems described in boxers from the 20th century. Some have considered TES to include depression, suicidality, anxiety, and substance abuse.PurposeWe carefully re-examined the published clinical literature of boxing cases from the 20th century to determine whether there is evidence to support conceptualizing psychiatric problems as being diagnostic clinical features of TES.MethodsWe reviewed clinical descriptions from 155 current and former boxers described in 21 articles published between 1928 and 1999.ResultsMore than one third of cases (34.8%) had a psychiatric, neuropsychiatric, or neurobehavioral problem described in their case histories. However, only 6.5% of the cases were described as primarily psychiatric or neuropsychiatric in nature. The percentages documented as having specific psychiatric problems were as follows: depression = 11.0%, suicidality = 0.6%, anxiety = 3.9%, anger control problems = 20.0%, paranoia/suspiciousness = 11.6%, and personality change = 25.2%.DiscussionWe conclude that depression, suicidality (i.e., suicidal ideation, intent, or planning), and anxiety were not considered to be clinical features of TES during the 20th century. The present review supports the decision of the consensus group to remove mood and anxiety disorders, and suicidality, from the new 2021 consensus core diagnostic criteria for TES. More research is needed to determine if anger dyscontrol is a core feature of TES with a clear clinicopathological association. The present findings, combined with a recently published large clinicopathological association study, suggest that mood and anxiety disorders are not characteristic of TES and they are not associated with chronic traumatic encephalopathy neuropathologic change.

The behaviour of Ce-containing zirconolites in hot isostatically pressed (HIPed) materials is complex, characterised by redox interactions between the metallic HIP canister that result in reduction of Ce4+ to Ce3+. In this work, a glass–ceramic of composition 70 wt.% CaZr0.9Ce0.1Ti2O7 ceramic in 30 wt.% Na2Al2Si6O16 glass was produced by HIP (approx. 170 cm3 canister) to examine the extent of the material–canister interaction. A complex material with six distinct regions was produced, with the extent of Ce reduction varying depending on the distance from the canister. Notably, the innermost bulk regions (those approximately 7 mm from the canister) contained only Ce4+, demonstrating that a production-scale HIPed glass–ceramic would indeed have a bulk region unaffected by the reducing environment induced by a ferrous HIP canister despite the flow of glass at the HIP temperature. Each of the six regions was characterised by XRD (including Rietveld method refinements), SEM/EDX and linear combination fitting of Ce L3-edge XANES spectra. Regions in the lower part of the canister were found to contain a significantly higher fraction of Ce4+ compared to the upper regions. Though zirconolite-2M was the major crystalline phase observed in all regions, the relative abundances of minor phases (including sphene, baddeleyite, rutile and perovskite) were higher in the outermost regions, which comprised a significantly reduced Ce inventory.

ObjectiveThe tackle is the most injurious event in rugby league and carries the greatest risk of concussion. This study aims to replicate previous research conducted in professional men's rugby league by examining the association between selected tackle characteristics and head impact events (HIEs) in women's professional rugby league.MethodsWe reviewed and coded 83 tackles resulting in an HIE and every tackle (6,318 tackles) that did not result in an HIE for three seasons (2018–2020) of the National Rugby League Women's (NRLW) competition. Tackle height, body position of the tackler and ball carrier, as well as the location of head contact with the other player's body were evaluated. Propensity of each situation that caused an HIE was calculated as HIEs per 1,000 tackles.ResultsThe propensity for tacklers to sustain an HIE was 6.60 per 1,000 tackles (95% CI: 4.87–8.92), similar to that of the ball carrier (6.13 per 1,000 tackles, 95% CI: 4.48–8.38). The greatest risk of an HIE to either the tackler or ball carrier occurred when head proximity was above the sternum (21.66 per 1,000 tackles, 95% CI: 16.55–28.35). HIEs were most common following impacts between two heads (287.23 HIEs per 1,000 tackles, 95% CI: 196.98–418.84). The lowest propensity for both tackler (2.65 per 1,000 tackles, 95% CI: 0.85–8.20) and ball carrier HIEs (1.77 per 1,000 tackles, 95% CI: 0.44–7.06) occurred when the head was in proximity to the opponent's shoulder and arm. No body position (upright, bent or unbalanced/off feet) was associated with an increased propensity of HIE to either tackler or ball carrier.ConclusionsIn the NRLW competition, tacklers and ball carriers have a similar risk of sustaining an HIE during a tackle, differing from men's NRL players, where tacklers have a higher risk of HIEs. Further studies involving larger samples need to validate these findings. However, our results indicate that injury prevention initiatives in women's rugby league should focus on how the ball carrier engages in contact during the tackle as well as how the tackler executes the tackle.

The ultrasonic-assisted spray dryer, also known as a nano spray dryer and predominantly used on a lab scale in the pharmaceutical and food industries, enables the production of nanometer-sized particles. In this study, the nano spray dryer was applied to cellulosic materials, such as cellulose nanofibrils (CNFs) and cellulose nanocrystals (CNCs). CNC suspensions were successfully dried, while the CNF suspensions could not be dried, attributable to their longer fibril lengths. The nano spray drying process was performed under different drying conditions, including nebulizer hole sizes, solid concentrations, and gas flow rates. It was confirmed that the individual particle size of nano spray-dried CNCs (nano SDCNCs) decreased as the nebulizer hole sizes and solid contents of the suspensions decreased. The production rate of the nano spray dryer increased with higher solid contents and lower gas flow rates. The resulting nano SDCNCs were added to a polyvinyl alcohol (PVA) matrix as a reinforcing material to evaluate their reinforcement behavior in a plastic matrix using solvent casting. After incorporating the 20 wt.% nano SDCNCs into the PVA matrix, the tensile strength and tensile modulus elasticity of the neat PVA nanocomposite film increased by 22% and 32%, respectively, while preserving the transparency of the films.

Enzyme-treated cellulose nanofibrils (CNFs) were produced via a lab-scale mass colloider using bleached kraft pulp (BKP) to evaluate their processability and power requirements during refining and spray-drying operations. To evaluate the energy efficiency in the CNF refining process, the net energy consumption, degree of polymerization (DP), and viscosity were determined. Less energy was consumed to attain a given fines level by using the endoglucanase enzymes. The DP and viscosity were also decreased using the enzymes. The morphological properties of the enzyme-pretreated spray-dried CNF powders (SDCNFs) were measured. Subsequently, the enzyme-pretreated SDCNFs were added to a PP matrix with MAPP as a coupling agent. The mixture was then compounded through a co-rotating twin-screw extruder to determine whether the enzyme treatment of the CNFs affects the mechanical properties of the composites. Compared to earlier studies on enhancing PMCs with SDCNF powders, this research investigates the use of enzyme-pretreated SDCNF powders. It was confirmed that the strength properties of PP increased by adding SDCNFs, and the strength properties were maintained after adding enzyme-pretreated SDCNFs.

ABSTRACT The open ocean is an extremely competitive environment, partially due to the dearth of nutrients. Trichodesmium erythraeum, a marine diazotrophic cyanobacterium, is a keystone species in the ocean due to its ability to fix nitrogen and leak 30 to 50% into the surrounding environment, providing a valuable source of a necessary macronutrient to other species. While there are other diazotrophic cyanobacteria that play an important role in the marine nitrogen cycle, Trichodesmium is unique in its ability to fix both carbon and nitrogen simultaneously during the day without the use of specialized cells called heterocysts to protect nitrogenase from oxygen. Here, we use the advanced modeling framework called multiscale multiobjective systems analysis (MiMoSA) to investigate how Trichodesmium erythraeum can reduce dimolecular nitrogen to ammonium in the presence of oxygen. Our simulations indicate that nitrogenase inhibition is best modeled as Michealis-Menten competitive inhibition and that cells along the filament maintain microaerobia using high flux through Mehler reactions in order to protect nitrogenase from oxygen. We also examined the effect of location on metabolic flux and found that cells at the end of filaments operate in distinctly different metabolic modes than internal cells despite both operating in a photoautotrophic mode. These results give us important insight into how this species is able to operate photosynthesis and nitrogen fixation simultaneously, giving it a distinct advantage over other diazotrophic cyanobacteria because they can harvest light directly to fuel the energy demand of nitrogen fixation. IMPORTANCE Trichodesmium erythraeum is a marine cyanobacterium responsible for approximately half of all biologically fixed nitrogen, making it an integral part of the global nitrogen cycle. Interestingly, unlike other nitrogen-fixing cyanobacteria, Trichodesmium does not use temporal or spatial separation to protect nitrogenase from oxygen poisoning; instead, it operates photosynthesis and nitrogen fixation reactions simultaneously during the day. Unfortunately, the exact mechanism the cells utilize to operate carbon and nitrogen fixation simultaneously is unknown. Here, we use an advanced metabolic modeling framework to investigate and identify the most likely mechanisms Trichodesmium uses to protect nitrogenase from oxygen. The model predicts that cells operate in a microaerobic mode, using both respiratory and Mehler reactions to dramatically reduce intracellular oxygen concentrations.

Background:. The purpose of this study was to evaluate the impact of an 8-week remote summer program in supporting underrepresented students interested in orthopaedic surgery. Methods:. We received 115 applications, and a total of 17 students participated in the program (14.8%). Nine faculty mentors were matched with 1 or 2 students each. The program delivered a curriculum from June-August 2021 consisting of (1) weekly instructional courses on research-related topics led by a content expert; (2) weekly faculty lectures discussing topics including orthopaedic topics, diversity in medicine, leadership, and work-life balance; and (3) a research experience paired with a faculty mentor and peer mentor. We surveyed students to measure skill progression, satisfaction, and overall program evaluation. Preprogram/postprogram evaluation, midprogram check-in, and student feedback surveys were collected. Results:. Program participants represented a range of race and ethnic backgrounds, research experience levels, and various geographic locations across the United States. The cohort included a high rate of female (42%) and Black (35%) participants. On average, postprogram survey scores indicated that participants believed that the summer program improved their research skills (9.6 of 10), improved their orthopaedic interest (8.9 of 10), and improved mentorship and networking (9.1 of 10). For feedback surveys, 14 respondents of 15 total responses (93%) felt they were adequately matched to their faculty mentor. Twelve (80%) felt they had realistic deliverables for research projects within the 8-week program. Thirteen (87%) indicated they contributed to an abstract or manuscript as a coauthor. Conclusion:. Our findings indicate that students improved their research skills, interest, and confidence to pursue orthopaedic residency and mentorship/networks in the field. The long-term goal is to improve the accessibility and quality of mentorship for underrepresented students in order to foster an equitable pathway into the field of orthopaedic surgery.