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Supplementary Figure Legends 1-2 from Combination of Sulindac and Antimicrobial Eradication of Helicobacter pylori Prevents Progression of Gastric Cancer in Hypergastrinemic INS-GAS Mice

Supplementary Figure 2 from Combination of Sulindac and Antimicrobial Eradication of Helicobacter pylori Prevents Progression of Gastric Cancer in Hypergastrinemic INS-GAS Mice

Chronic infectious diseases, such as Helicobacter pylori infection, can promote cancer in a large part through induction of chronic inflammation. Oncogenic K-ras mutation in epithelial cells activates inflammatory pathways, which could compensate for a lack of infectious stimulus. Gastric histopathology and putative progenitor markers [doublecortin and calcium/calmodulin-dependent protein kinase-like 1 (Dcamkl1) and keratin 19 (K19)] in K19-K-ras-V12 (K19-kras) transgenic mice were assessed at 3, 6, 12, and 18 months of age, in comparison with Helicobacter felis–infected wild-type littermates. Inflammation was evaluated by reverse transcription–PCR of proinflammatory cytokines, and K19-kras mice were transplanted with green fluorescent protein (GFP)–labeled bone marrow. Both H. felis infection and K-ras mutation induced upregulation of proinflammatory cytokines, expansion of Dcamkl1+ cells, and progression to oxyntic atrophy, metaplasia, hyperplasia, and high-grade dysplasia. K19-kras transgenic mice uniquely displayed mucous metaplasia as early as 3 months and progressed to high-grade dysplasia and invasive intramucosal carcinoma by 20 months. In bone marrow–transplanted K19-kras mice that progressed to dysplasia, a large proportion of stromal cells were GFP+ and bone marrow–derived, but only rare GFP+ epithelial cells were observed. GFP+ bone marrow–derived cells included leukocytes and CD45− stromal cells that expressed vimentin or α smooth muscle actin and were often found surrounding clusters of Dcamkl1+ cells at the base of gastric glands. In conclusion, the expression of mutant K-ras in K19+ gastric epithelial cells can induce chronic inflammation and promote the development of dysplasia. Cancer Res; 70(21); 8435–45. ©2010 AACR.

Hepatocellular carcinoma (HCC) is a male-predominant cancer associated with chronic hepatitis. Like human viral hepatitis, murine Helicobacter hepaticus infection produces inflammation and HCC with a masculine bias. We used this model to identify potential mechanisms of male HCC predisposition. Male weanling A/JCr mice (n = 67) were gavaged with H. hepaticus or vehicle. At 1 year, mice were distributed into four groups: surgical castration, chemical castration, castration followed by dihydrotestosterone supplementation, or sexually intact controls. Responses to infection were compared with IFN-γ challenge alone. At 21 months, there was no significant difference in hepatitis between groups. Neither castration nor androgen receptor agonism altered tumor incidence. Infected mice with severe, but not mild, disease exhibited a mosaic of alterations to sexually dimorphic genes and microsomal long-chain fatty acids. By microarray, tumorigenic hepatitis was strongly associated with liver-gender disruption, defined as the loss of a gender-identifying hepatic molecular signature. IFN-γ alone produced similar changes, demonstrating a role for proinflammatory cytokines in this process. In conclusion, hepatocarcinogenesis in male mice with chronic hepatitis is maturationally imprinted and androgen-independent. Proinflammatory cytokines may promote HCC in a male-predominant fashion due to high sensitivity of the masculinized liver to loss of sex-specific transcriptional balance. Liver-gender disruption has pleiotropic implications for hepatic enzyme activity, lipid processing, nuclear receptor activation, apoptosis, and proliferation. We propose a multistep model linking chronic hepatitis to liver cancer through cytokine-mediated derangement of gender-specific cellular metabolism. This model introduces a novel mechanism of inflammation-associated carcinogenesis consistent with male-predominant HCC risk. [Cancer Res 2007;67(24):11536–46]

Ageing-associated cognitive decline affects more than half of those in long-term residential aged care. Emerging evidence suggests that gut microbiome-host interactions influence the effects of modifiable risk factors. We investigated the relationship between gut microbiome characteristics and severity of cognitive impairment (CI) in 159 residents of long-term aged care. Severe CI was associated with a significantly increased abundance of proinflammatory bacterial species, includingMethanobrevibacter smithiiandAlistipes finegoldii, and decreased relative abundance of beneficial bacterial clades. Severe CI was associated with increased microbial capacity for methanogenesis, and reduced capacity for synthesis of short-chain fatty acids, neurotransmitters glutamate and gamma-aminobutyric acid, and amino acids required for neuro-protective lysosomal activity. These relationships were independent of age, sex, antibiotic exposure, and diet. Our findings implicate multiple gut microbiome-brain pathways in ageing-associated cognitive decline, including inflammation, neurotransmission, and autophagy, and highlight the potential to predict and prevent cognitive decline through microbiome-targeted strategies.

BackgroundTauopathies are a group of neurodegenerative diseases driven by abnormal aggregates of tau, a microtubule associated protein encoded by theMAPTgene.MAPTexpression is absent in neural progenitor cells (NPCs) and increases during differentiation. This temporally dynamic expression pattern suggests thatMAPTexpression is controlled by transcription factors and cis-regulatory elements specific to differentiated cell types. Given the relevance ofMAPTexpression to neurodegeneration pathogenesis, identification of such elements is relevant to understanding genetic risk factors.MethodsWe performed HiC, chromatin conformation capture (Capture-C), single-nucleus multiomics (RNA-seq+ATAC-seq), bulk ATAC-seq, and ChIP-seq for H3K27Ac and CTCF in NPCs and neurons differentiated from human iPSC cultures. We nominated candidate cis-regulatory elements (cCREs) forMAPTin human NPCs, differentiated neurons, and pure cultures of inhibitory and excitatory neurons. We then assayed these cCREs using luciferase assays and CRISPR interference (CRISPRi) experiments to measure their effects onMAPTexpression. Finally, we integrated cCRE annotations into an analysis of genetic variation in AD cases and controls.ResultsUsing orthogonal genomics approaches, we nominated 94 cCREs forMAPT, including the identification of cCREs specifically active in differentiated neurons. Eleven regions enhanced reporter gene transcription in luciferase assays. Using CRISPRi, 5 of the 94 regions tested were identified as necessary forMAPTexpression as measured by RT-qPCR and RNA-seq. Rare and predicted damaging genetic variation in both nominated and confirmed CREs was depleted in AD cases relative to controls (OR = 0.40, p = 0.004), consistent with the hypothesis that variants that disruptMAPTenhancer activity, and thereby reduceMAPTexpression, may be protective against neurodegenerative disease.ConclusionsWe identified both proximal and distal regulatory elements forMAPTand confirmed the regulatory function for several regions, including three regions centromeric toMAPTbeyond the well-described H1/H2 haplotype inversion breakpoint. This study provides compelling evidence for pursuing detailed knowledge of CREs for genes of interest to permit better understanding of disease risk.

Social psychological theories provide useful tools for identifying interpretive processes that affect individual mental health outcomes. In this paper, we use the affect control theory of self (ACT-Self) to examine the relationship between depressive symptoms and global feelings about the self—self-sentiments—that are evoked by the constellation of identities, traits, moods, characteristics, and roles we hold and have held. We examine this relationship in two separate longitudinal studies conducted with undergraduates ( N = 147) and doctoral students ( N = 178) at a university in the Southeastern U.S., which employ different measures of depressive symptoms (the Center for Epidemiological Studies Depression Scale and Depression, Anxiety, and Stress Scale Short Form, respectively). We present key findings about links between depressive symptoms and evaluation (goodness), potency (powerfulness), and activity (liveliness). First, evaluation negatively predicts depressive symptoms at follow-up in both samples; activity predicts symptoms among undergraduates, and potency predicts symptoms among doctoral students. Second, respondents in both samples with self-sentiments closer to cultural sentiments for “depressed” report more depressive symptoms at follow-up. Third, evaluation gains over time predict less Wave 2 depressive symptoms in both samples; potency gains also predict symptoms among doctoral students. Finally, Wave 1 depressive symptoms—and increases in depression over time—predict lower levels of evaluation and potency in both samples.

To evaluate the most common femoral shaft fracture morphology associated with an ipsilateral femoral neck fracture in high-energy blunt trauma using magnetic resonance imaging (MRI).Retrospective review.Level 1 trauma center.219 consecutive patients sustaining 228 femoral shaft fractures from high-energy blunt trauma.Fracture patterns were analyzed using the OTA/AO classification system. In addition, location of the fracture was measured as the distance from the distal aspect of the lesser trochanter to the center of the femoral shaft fracture.An OTA/AO 31 type fracture was seen in 16.5% (20/121) of patients presenting with OTA/AO 32-A type fractures, 12% (6/50) of patients with OTA/AO 32-B type fractures, and 26.3% (15/57) of patients with OTA/AO 32-C type fractures. The fractures that occurred in the middle or distal third of the femur shaft constituted 95.1% (39/41).In this cohort, patients with middle and distal third OTA/AO 32-C type fractures had the highest association with an ipsilateral OTA/AO 31 type fracture. OTA/AO 32-A2 and 32-A3 type fractures had the highest association with femoral neck fractures seen only on MRI. The data presented suggest continued usage of the rapid sequence pelvic MRI for all patients with high-energy femoral shaft fractures in whom a femoral neck fracture was not seen on an x-ray or a computed tomography scan.Diagnostic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Summary Background Infection control is critical to safe hospital care. However, how bacteria within nosocomial environments relate to space utilisation and occupancy remains poorly understood. Our aim was to characterise the hospital microbiome in the context of the closure of a tertiary hospital and the opening of a new facility. Methods Environmental swabs were collected from common and inpatient areas in the old and new hospitals during a 12-month transition period. Microbiota characteristics were determined by 16S rRNA gene sequencing and quantitative (q)PCR. Targeted assays were used to detect Methicillin-resistant Staphylococcus aureus (MRSA) and vanB-positive Vancomycin-Resistant Enterococci (VRE). Results The transition to full occupancy in the new facility was associated with an increase in bacterial load (inpatient areas, 3 months p = 0.001; common areas, 6 months p = 0.039) and a change in microbiota composition (baseline-12 months, PERMANOVA p = 0.002). These changes were characterised by an increase in human microbiota-associated taxa, including Acinetobacter and Veillonella. Closure of the existing facility was associated with a decrease in bacterial load (p = 0.040). Detection of MRSA did not differ significantly between sites. Conclusions Occupancy is a major determinant of bacterial dispersion within hospital environments. Steady-state bacterial levels and microbiota composition provide a basis for assessment of infection control measures.

Objective The goal of this study was to develop an approach that can be used where baseline risk estimates that are directly applicable to prioritized patient-important outcomes are not available from published studies. Study design The McMaster University GRADE Centre and the ASH guideline panel for the prevention of VTE in surgical patients developed a modeling approach based on explicit assumptions about the distribution of symptoms, anatomical location, and severity of VTE events. Results We applied the approach to derive modeled estimates of baseline risk. These estimates were used to calculated absolute measures of anticipated effects that informed the discussion of the evidence and the formulation of 30 guideline recommendations. Conclusion Our approach can assist guideline developers facing a lack of information about baseline risk estimates that directly apply to outcomes of interest. The use of modeled estimates increases transparency in the process and makes the baseline risk used by guideline experts explicit during their decision-making.

Social research highlights the stability of cultural beliefs, broadly arguing that population-level changes are uncommon and mostly explained by cohort replacement rather than individual-level change. We find evidence suggesting that cultural change may also occur rapidly in response to an economically and socially transformative period. Using data collected just before and after the outbreak of Covid-19 in the U.S., we explore whether cultural beliefs about essential and non-essential occupations are dynamic in the face of an exogenous social and economic shock. Using a sample of respondents whose characteristics match the U.S. Census on sex, age, and race/ethnicity, we fielded surveys measuring cultural beliefs about 85 essential and non-essential occupations using the evaluation, potency, and activity (EPA) dimensions from the Affect Control Theory paradigm. We expected that EPA ratings of essential work identities would increase due to positive media coverage of essential occupations as indispensable and often selfless roles in the pandemic, while EPA ratings of non-essential identities would decline. Our findings show patterns that are both clear and inconsistent with our predictions. For both essential and non-essential occupations, almost all statistically significant changes in mean evaluation and potency were negative; activity showed relatively little change. Changes in evaluation scores were more negative for non-essential occupations than essential occupations. Results suggest that pervasive and persistent exogenous events are worth investigating as potential sources of episodic cultural belief change.

We introduce this two-part special issue that celebrates David Heise and his pathbreaking theories: affect control theory (ACT), affect control theory of the self (ACTS), and affect control theory of institutions (ACTI). These interlocking, multi-level, mathematically based theories explain a range of social processes, including impression formation, social interaction, trait and mood attributions, emotional experiences, emotion management, and identity adoption, and they do so in multiple languages and cultures. The 15 articles in this two-part issue test, apply, and develop the theories in new and innovative ways. After briefly summarizing each theory and Bayesian affect control theory (BayesACT), we highlight the key findings from each of the articles that follow.

The MGnify platform (https://www.ebi.ac.uk/metagenomics) facilitates the assembly, analysis and archiving of microbiome-derived nucleic acid sequences. The platform provides access to taxonomic assignments and functional annotations for nearly half a million analyses covering metabarcoding, metatranscriptomic, and metagenomic datasets, which are derived from a wide range of different environments. Over the past 3 years, MGnify has not only grown in terms of the number of datasets contained but also increased the breadth of analyses provided, such as the analysis of long-read sequences. The MGnify protein database now exceeds 2.4 billion non-redundant sequences predicted from metagenomic assemblies. This collection is now organised into a relational database making it possible to understand the genomic context of the protein through navigation back to the source assembly and sample metadata, marking a major improvement. To extend beyond the functional annotations already provided in MGnify, we have applied deep learning-based annotation methods. The technology underlying MGnify's Application Programming Interface (API) and website has been upgraded, and we have enabled the ability to perform downstream analysis of the MGnify data through the introduction of a coupled Jupyter Lab environment.

Introduction Diversity in the healthcare workforce is associated with improved performance and patient-reported outcomes. Gender disparity in Trauma and Orthopaedics (T&O) is well recognised. The aim of this study was to compare factors that influence career choice in T&O between male and female final-year students. Furthermore, the trend of representation of women in T&O over the last decade was also compared with other surgical specialities. Methods An online survey of final-year students who attended nationally advertised T&O courses over a 2-year period was conducted. Data from NHS digital was obtained to assess gender diversity in T&O compared with other surgical specialities. Results A total of 414 students from 13 UK medical schools completed the questionnaire. Compared with male students (34.2%), a significantly higher proportion of women (65.8%) decided against a career in T&O, pConclusion T&O remains an unpopular career choice among women. To enhance recruitment of women in T&O, future strategies should be directed toward medical students. Universities, orthopaedic departments and societies must work collaboratively to embed culture change, improve the delivery of the undergraduate curriculum, and facilitate students’ exposure to operating theatres and female role models.

SummaryCell type-specific transcriptional differences between brain tissues from donors with Alzheimer’s disease (AD) and unaffected controls have been well-documented, but few studies have rigorously interrogated the regulatory mechanisms responsible for these alterations. We performed single nucleus multiomics (snRNA-seq+snATAC-seq) on 105,332 nuclei isolated from cortical tissues from 7 AD and 8 unaffected donors to identify candidate cis-regulatory elements (CREs) involved in AD-associated transcriptional changes. We detected 319,861 significant correlations, or links, between gene expression and cell type-specific transposase accessible regions enriched for active CREs. Among these, 40,831 were unique to AD tissues. Validation experiments confirmed the activity of many regions, including several candidate regulators of APP expression. We identified ZEB1 and MAFB as candidate transcription factors playing important roles in AD-specific gene regulation in neurons and microglia, respectively. Microglial links were globally enriched for heritability of AD risk and previously identified active regulatory regions.

ImportanceMature trauma systems are critical in building and maintaining national, state, and local resilience against all-hazard disasters. Currently, pediatric state trauma system plans are not standardized and thus are without concrete measures of potential effectiveness.ObjectiveTo develop objective measures of pediatric trauma system capability at the state level, hypothesizing significant variation in capabilities between states, and to provide a contemporary report on the status of national pediatric trauma system planning and development.Design, Setting, and ParticipantsA national survey was deployed in 2018 to perform a gap analysis of state pediatric trauma system capabilities. Four officials from each state were asked to complete the survey regarding extensive pediatric-related or specific trauma system parameters. Using these parameters, a panel of 14 individuals representing national stakeholder sectors in pediatric trauma care convened to identify the essential components of the ideal pediatric trauma system using Delphi methodology. Data analysis was conducted from March 16, 2019, to February 23, 2020.Main Outcomes and MeasuresBased on results from the national survey and consensus panel parameters, each state was given a composite score. The score was validated using US Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research (CDC WONDER) fatal injury database.ResultsThe national survey had less than 10% missing data. The consensus panel reached agreement on 6 major domains of pediatric trauma systems (disaster, legislation/funding, access to care, injury prevention/recognition, quality improvement, pediatric readiness) and was used to develop the Pediatric Trauma System Assessment Score (PTSAS) based on 100 points. There was substantial variation across states, with state scores ranging from 48.5 to 100. Based on US CDC WONDER data, for every 1-point increase in PTSAS, there was a 0.12 per 100 000 decrease in mortality (95% CI, −0.22 to −0.02; P = .03).Conclusions and RelevanceResults of this cross-sectional study suggest that a more robust pediatric trauma system has a significant association with pediatric injury mortality. This study assessed the national landscape of capability and preparedness to provide pediatric trauma care at the state level. These parameters can tailor the maturation of children’s interests within a state trauma system and assist with future state, regional, and national planning.

COVID-19 has demonstrated the devastating consequences of the rapid spread of an airborne virus in residential aged care. We report the use of CO2-based ventilation assessment to empirically identify potential ‘super-spreader’ zones within an aged care facility, and determine the efficacy of rapidly implemented, inexpensive, risk reduction measures.

Objective National movements have raised awareness of the adverse mental health effects of police brutality. This study examines the relationship between perceived police brutality and unmet need for mental health care. Data sources We used the 2018 Survey of the Health of Urban Residents (N = 4338), a quota sample survey of adults in urban areas in the contiguous United States. Study design Multivariate regressions were used to understand the association between police brutality and unmet need for mental health care. Unmet need was regressed on police brutality (the independent variable), controlling for sociodemographic and health status characteristics of respondents and access to care. We then stratified the sample by experiences of police brutality (no negative encounters with the police, encounters that were perceived as necessary, and encounters that were considered unnecessary) and described how medical mistrust and perceived respect within health care settings were associated with odds of unmet need for each subsample. Data collection Data were collected online. Principal findings Negative police encounters perceived as necessary were associated with greater odds of unmet need compared to no negative police encounters (odds ratio [OR] = 1.98, confidence interval [CI] = 1.30-2.65). Odds of unmet need were also higher among persons with negative and unnecessary police encounters (OR = 1.28, CI = 1.05-1.56). Greater respect was associated with lower odds of unmet need among persons who reported negative unnecessary encounters with the police (OR = 0.88, CI = 0.72-0.97). Medical mistrust was associated with greater odds of unmet need among those with negative unnecessary police encounters (OR = 1.52, CI = 1.12-1.93). Conclusions Persons who are exposed to police brutality are also likely to be those who experience unmet need for mental health care. Ensuring that they feel respected within medical settings and establishing conditions that build trust in medical institutions are important for eliminating unmet need for mental health care.

We sought to determine the secondary overtriage rate of pediatric trauma patients admitted to pediatric trauma centers. We hypothesized that pediatric secondary overtriage (POT) would constitute a large percentage of admissions to PTC.The Pennsylvania Trauma Outcome Study database was retrospectively queried from 2003 to 2017 for pediatric (age ≤ 18 y) trauma patients transferred to accredited pediatric trauma centers in Pennsylvania (n = 6). Patients were stratified based on discharge within (early) and beyond (late) 24 h following admission. POT was defined as patients transferred to a PTC with an early discharge. Multilevel mixed-effects logistic regression model controlling for demographic and injury severity covariates were utilized to determine the adjusted impact of injury patterns on early discharge.A total of 37,653 patients met inclusion criteria. For transfers, POT compromised 18,752 (49.8%) patients. Compared to POT, non-POT were more severely injured (ISS: 10 versus 6;P0.001) and spent less time in the ED (Min: 181 versus 207;P0.001). In adjusted analysis, concussion, closed skull vault fractures, supracondylar humerus fractures, and consults to neurosurgery were associated with increased odds of POT. Overall, femur fracture, child abuse evaluation, and consults to plastic surgery, orthopedics, and ophthalmology were all associated with a decreased risk of being POT.POT comprises 49.8% of PTC transfer admissions in Pennsylvania's trauma system. Improving community resources for management of pediatric concussion and mild TBI could result in decreased rates of POT to PTCs. Developing better inter-facility transfer guidelines and increased education of adult TC and nontrauma center hospitals is needed to decrease POT.Epidemiologic study, level III.

A high fruit and vegetable (FV) diet reduces asthma exacerbations in adults; this has not been examined in children to date.To investigate the effect of a 6-month, high FV diet on the time to first asthma exacerbation in children with asthma, in a parallel-group, randomized, controlled trial.Children (aged 3-11 years) with asthma, history of exacerbations and usual low FV intake (≤3 serves/day) were randomized to the intervention (high FV diet) or control group (usual diet) for 6 months. The primary outcome was time to first exacerbation requiring medical intervention. Secondary outcomes included exacerbation rate, lung function, plasma TNF-α, CRP, and IL-6, faecal microbiota and peripheral blood mononuclear cell (PBMC) histone deacetylase (HDAC) activity and G-protein coupled receptor (GPR) 41/43 and HDAC (1-11) expression.67 children were randomized between September 2015 and July 2018. FV intake (difference in change (∆): 3.5 serves/day, 95% CI: [2.6, 4.4] p 0.001) and plasma total carotenoids (∆: 0.44 µg/ml [0.19, 0.70] p = 0.001) increased after 6 months (intervention vs control). Time to first exacerbation (HR: 0.81, 95% CI: [0.38, 1.69], p = 0.569; control vs. intervention) and exacerbation rate (IRR: 0.84, [0.47, 1.49], p = 0.553; control vs. intervention) were similar between groups. In per-protocol analysis, airway reactance z-scores increased in the intervention versus control group (XA high FV diet did not affect asthma exacerbations over the 6-month intervention, though warrants further investigation as a strategy for improving lung function and protecting against systemic inflammation in children with asthma.

Immune checkpoint inhibitors target suppressor receptors, including cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1), and programmed cell death ligand 1 (PD-L1). The activated T cells are not antigen specific; therefore, the blockade of the immune checkpoint may result in the development of autoimmune adverse events. The most common immune-related adverse events (irAEs) are rash, colitis, and endocrinopathies. However, irAEs that affect the hematologic system are rare and can affect red blood cells (e.g., autoimmune hemolytic anemia), white blood cells, and platelets (e.g., immune thrombocytopenia). Usually one cell line is affected; however, in some cases, multiple cell lines can be affected. Other changes in the hematologic system can also be affected (e.g., cryoglobulinemia, cytokine release syndrome). Due to the rarity and lack of recognition of these AEs, the timing, spectrum of events, and clinical presentation are poorly understood. Management of hematologic irAEs usually involves the use of steroids; however, other agents (e.g., IVIG, cyclosporine, rituximab) or procedures (e.g., plasma exchange, transfusions) can also be used.

Introduction The COVID-19 pandemic presented extraordinary challenges to the UK healthcare system. This study aimed to assess the impact of the COVID-19 lockdown on the epidemiology, treatment pathways and 30-day mortality rates of hip fractures. Outcomes of COVID-19 positive patients were compared against those who tested negative. Methods An observational, retrospective, multicentre study was conducted across six hospitals in the South East of England. Data were retrieved from the National Hip Fracture Database and electronic medical records. Data was collected for the strictest UK lockdown period (period B=23 March 2020–11 May 2020), and the corresponding period in 2019 (period A). Results A total of 386 patients were admitted during period A, whereas 381 were admitted during period B. Despite the suspension of the ‘Best Practice Tariff’ during period B, time to surgery, time to orthogeriatric assessment, and 30-day mortality were similar between period A and B. The length of inpatient stay was significantly shorter during period B (11.5 days vs 17.0 days, p36h (46.4% vs 30.8%, p=0.049), and increased length of inpatient stay (15.8 vs 11.7 days, p=0.015). Conclusions The COVID-19 lockdown did not alter the epidemiology of hip fractures. A substantially higher mortality rate was observed among patients with a COVID-19 positive test. These findings should be taken into consideration by the healthcare policymakers while formulating contingency plans for a potential ‘second wave’.

The UK climate is projected to become warmer, with more frequent hotter, drier summers. Many governments and international organisations are concerned about how climate change will affect food production and security. Mycorrhizal fungi are an essential part of agricultural systems and yet little is known about how climate change will affect mycorrhizal fungi. We investigated the effect of reduced precipitation on levels of arbuscular mycorrhizal (AM) colonisation in the top 10 cm of soil in the grass Holcus lanatus L. (Yorkshire Fog) in a permanent pasture in South Gloucestershire, UK. Incident rainfall was reduced, by approximately 50%, using clear gutters supported on steel frames. Over three growing seasons we observed little difference in levels of AM colonisation and numbers of intra-root fungal structures between the roots of H. lanatus grown with reduced or full incident rainfall. Time of year when water stress occurred had a stronger effect on levels of colonisation than the absolute amount of precipitation received. In H. lanatus, growing in a permanent pasture, levels of AM colonisation were around 40%–50%, across a range of precipitation, from 18% above to 36% below the long-term average. The results highlight the complex relationships between mycorrhizal fungi, host plant, and abiotic stress.

Evolution and change generated an incredible diversity of organisms on this earth. Yet, some processes are so central to life that change is strongly selected against. Synthesis of the eukaryotic messenger RNA is one example. The assemblies that carry out transcription and processing (capping, polyadenylation, and splicing) are so conserved that most genes have recognizable orthologs in yeast and humans. Naturally, most would conclude transcription and processing are identical in both sexes. However, this is an assumption. Men and women vastly differ in their physiologies. The incidence of pathologies, symptom presentation, disease outcome, and therapeutic response in each sex vary enormously. Despite the harm ignorance causes women, biological research has been historically carried out without regard to sex. The male mouse was the default mammal. A cultured cell's sex was considered irrelevant. Attempts to fill this knowledge gap have revealed molecular dissimilarities. For example, the earliest embryonic male and female transcriptomes differ long before fetal sex hormones appear. We used public data to challenge the assumption of sameness by reviewing reports of sex-biased gene expression and gene targeting. We focused on 120 genes encoding nonregulatory proteins involved in mRNA synthesis. Remarkably, genes with recognizable orthologs in yeast and thus LEAST likely to differ, did differ between the sexes. The rapidly growing public databases can be used to compare the expression of any gene in male and female tissues. Appreciating the principles that drive sex differences will enrich our understanding of RNA biology in all humans-men and women. This article is categorized under: RNA in Disease and DevelopmentRNA in Development RNA Evolution and GenomicsComputational Analyses of RNA.

Introduction Trauma and orthopaedics is renowned for being a challenging yet rewarding career. The value of mentorship in medical and surgical training is known to be beneficial; however, the prevalence and quality of mentorship opportunities in orthopaedics are less well studied. Identifying the strengths and weaknesses of mentoring programmes in orthopaedic training and recognising barriers to effective mentorship are key to unlocking the full potential of future orthopaedic surgeons. Methods A comprehensive search of PubMed, Medline, EMBASE and the Cochrane Library was performed. All studies published in the English language that reported data on mentorship programmes in orthopaedic training were included. Findings A total of 23 studies met the inclusion criteria. These studies demonstrated that formal mentorship programmes in orthopaedics are lacking but are sought after, with a positive influence on satisfaction and future career choice/subspecialty selection identified. Several barriers to mentoring in the field were recognised including the difficulty faced by female trainees, the availability of mentors and time constraints. The opportunity to choose a mentor, a mentor with the same interests, regular meetings and the option of gender congruent mentorship were all identified as crucial requirements for effective mentorship. Conclusion Mentorship opportunities must be more accessible to all orthopaedic trainees alike and should aim to incorporate the attributes identified to provide the highest calibre of training to prospective orthopaedic surgeons.