A Milky Way-like barred spiral galaxy at a redshift of 3.

The majority of massive disk galaxies in the local Universe show a stellar barred structure in their central regions, including our Milky Way1,2. Bars are supposed to develop in dynamically cold stellar disks at low redshift, as the strong gas turbulence typical of disk galaxies at high redshift suppresses or delays bar formation3,4. Moreover, simulations predict bars to be almost absent beyond z = 1.5 in the progenitors of Milky Way-like galaxies5,6. Here we report observations of ceers-2112, a barred spiral galaxy at redshift zphot ≈ 3, which was already mature when the Universe was only 2 Gyr old. The stellar mass (M★ = 3.9 × 109 M⊙) and barred morphology mean that ceers-2112 can be considered a progenitor of the Milky Way7-9, in terms of both structure and mass-assembly history in the first 2 Gyr of the Universe, and was the closest in mass in the first 4 Gyr. We infer that baryons in galaxies could have already dominated over dark matter at z ≈ 3, that high-redshift bars could form in approximately 400 Myr and that dynamically cold stellar disks could have been in place by redshift z = 4-5 (more than 12 Gyrs ago)10,11.

Chromosome catastrophes involve replication mechanisms generating complex genomic rearrangements.

Complex genomic rearrangements (CGRs) consisting of two or more breakpoint junctions have been observed in genomic disorders. Recently, a chromosome catastrophe phenomenon termed chromothripsis, in which numerous genomic rearrangements are apparently acquired in one single catastrophic event, was described in multiple cancers. Here, we show that constitutionally acquired CGRs share similarities with cancer chromothripsis. In the 17 CGR cases investigated, we observed localization and multiple copy number changes including deletions, duplications, and/or triplications, as well as extensive translocations and inversions. Genomic rearrangements involved varied in size and complexities; in one case, array comparative genomic hybridization revealed 18 copy number changes. Breakpoint sequencing identified characteristic features, including small templated insertions at breakpoints and microhomology at breakpoint junctions, which have been attributed to replicative processes. The resemblance between CGR and chromothripsis suggests similar mechanistic underpinnings. Such chromosome catastrophic events appear to reflect basic DNA metabolism operative throughout an organism's life cycle.

Impaired balance between coronary blood flow and myocardial metabolism in postpartum swine.

Understanding of the mechanisms contributing to the increased maternal susceptibility for major adverse cardiovascular events in the postpartum period remains poor. Accordingly, this study tested the hypothesis that the balance between coronary blood flow and myocardial metabolism is compromised during the puerperium period (35-45 days post-delivery) in swine. Systemic and coronary hemodynamic responses were assessed in anesthetized, open-chest control (nonpregnant) and puerperium/postpartum swine at baseline and in response to intravenous infusion of dobutamine (1-30 µg/kg/min). Blood pressure and heart rate were lower in postpartum swine at baseline and in response to dobutamine (P < 0.05). Coronary blood flow and myocardial oxygen delivery were significantly diminished at baseline in postpartum swine (P < 0.001), which corresponded with ∼35% reduction in myocardial oxygen consumption (MVO2) (P < 0.001). Postpartum swine displayed enhanced retrograde coronary flow, larger cardiomyocyte area (P < 0.01) and marked capillary rarefaction (P < 0.01). The relationship between coronary blood flow and heart rate (P < 0.05) or MVO2 (P < 0.001) was significantly diminished in postpartum swine as dobutamine increased MVO2 up to ∼135% in both groups. This reduction in myocardial perfusion was associated with decreases in myocardial lactate uptake (P < 0.001), increases in coronary venous PCO2 (P < 0.01) and decreased coronary venous pH (P < 0.01). These findings suggest an impaired balance between coronary blood flow and myocardial metabolism could contribute to the increased incidence of maternal myocardial ischemia and premature death in the postpartum period.

Unraveling the Gordian knot of coronary pressure-flow autoregulation.

The coronary circulation has the inherent ability to maintain myocardial perfusion constant over a wide range of perfusion pressures. The phenomenon of pressure-flow autoregulation is crucial in response to flow-limiting atherosclerotic lesions which diminish coronary driving pressure and increase risk of myocardial ischemia and infarction. Despite well over half a century of devoted research, understanding of the mechanisms responsible for autoregulation remains one of the most fundamental and contested questions in the field today. The purpose of this review is to highlight current knowledge regarding the complex interrelationship between the pathways and mechanisms proposed to dictate the degree of coronary pressure-flow autoregulation. Our group recently likened the intertwined nature of the essential determinants of coronary flow control to the symbolically unsolvable "Gordian knot". To further efforts to unravel the autoregulatory "knot", we consider recent challenges to the local metabolic and myogenic hypotheses and the complicated dynamic structural and functional heterogeneity unique to the heart and coronary circulation. Additional consideration is given to interrogation of putative mediators, role of K+ and Ca2+ channels, and recent insights from computational modeling studies. Improved understanding of how specific vasoactive mediators, pathways, and underlying disease states influence coronary pressure-flow relations stands to significantly reduce morbidity and mortality for what remains the leading cause of death worldwide.

Activation of androgen receptor-expressing neurons in the posterior medial amygdala is associated with stress resistance in dominant male hamsters.

Social stress is a negative emotional experience that can increase fear and anxiety. Dominance status can alter the way individuals react to and cope with stressful events. The underlying neurobiology of how social dominance produces stress resistance remains elusive, although experience-dependent changes in androgen receptor (AR) expression is thought to play an essential role. Using a Syrian hamster (Mesocricetus auratus) model, we investigated whether dominant individuals activate more AR-expressing neurons in the posterior dorsal and posterior ventral regions of the medial amygdala (MePD, MePV), and display less social anxiety-like behavior following social defeat stress compared to subordinate counterparts. We allowed male hamsters to form and maintain a dyadic dominance relationship for 12 days, exposed them to social defeat stress, and then tested their approach-avoidance behavior using a social avoidance test. During social defeat stress, dominant subjects showed a longer latency to submit and greater c-Fos expression in AR+ cells in the MePD/MePV compared to subordinates. We found that social defeat exposure reduced the amount of time animals spent interacting with a novel conspecific 24 h later, although there was no effect of dominance status. The amount of social vigilance shown by dominants during social avoidance testing was positively correlated with c-Fos expression in AR+ cells in the MePV. These findings indicate that dominant hamsters show greater neural activity in AR+ cells in the MePV during social defeat compared to their subordinate counterparts, and this pattern of neural activity correlates with their proactive coping response. Consistent with the central role of androgens in experience-dependent changes in aggression, activation of AR+ cells in the MePD/MePV contributes to experience-dependent changes in stress-related behavior.

Oxygen-sensing pathways below autoregulatory threshold act to sustain myocardial oxygen delivery during reductions in perfusion pressure.

The coronary circulation has an innate ability to maintain constant blood flow over a wide range of perfusion pressures. However, the mechanisms responsible for coronary autoregulation remain a fundamental and highly contested question. This study interrogated the local metabolic hypothesis of autoregulation by testing the hypothesis that hypoxemia-induced exaggeration of the metabolic error signal improves the autoregulatory response. Experiments were performed on open-chest anesthetized swine during stepwise changes in coronary perfusion pressure (CPP) from 140 to 40 mmHg under normoxic (n = 15) and hypoxemic (n = 8) conditions, in the absence and presence of dobutamine-induced increases in myocardial oxygen consumption (MVO2) (n = 5-7). Hypoxemia (PaO2 < 40 mmHg) decreased coronary venous PO2 (CvPO2) ~ 30% (P < 0.001) and increased coronary blood flow ~ 100% (P < 0.001), sufficient to maintain myocardial oxygen delivery (P = 0.14) over a wide range of CPPs. Autoregulatory responsiveness during hypoxemia-induced reductions in CvPO2 were associated with increases of autoregulatory gain (Gc; P = 0.033) but not slope (P = 0.585) over a CPP range of 120 to 60 mmHg. Preservation of autoregulatory Gc (P = 0.069) and slope (P = 0.264) was observed during dobutamine administration ± hypoxemia. Reductions in coronary resistance in response to decreases in CPP predominantly occurred below CvPO2 values of ~ 25 mmHg, irrespective of underlying vasomotor reserve. These findings support the presence of an autoregulatory threshold under which oxygen-sensing pathway(s) act to preserve sufficient myocardial oxygen delivery as CPP is reduced during increases in MVO2 and/or reductions in arterial oxygen content.

Awareness of social care needs in people with epilepsy and intellectual disability.

BACKGROUND: Nearly a quarter of people with intellectual disability (ID) have epilepsy with large numbers experiencing drug-resistant epilepsy, and premature mortality. To mitigate epilepsy risks the environment and social care needs, particularly in professional care settings, need to be met. PURPOSE: To compare professional care groups as regards their subjective confidence and perceived responsibility when managing the need of people with ID and epilepsy. METHOD: A multi-agency expert panel developed a questionnaire with embedded case vignettes with quantitative and qualitative elements to understand training and confidence in the health and social determinants of people with ID and epilepsy. The cross-sectional survey was disseminated amongst health and social care professionals working with people with ID in the UK using an exponential non-discriminative snow-balling methodology. Group comparisons were undertaken using suitable statistical tests including Fisher's exact, Kruskal-Wallis, and Mann-Whitney. Bonferroni correction was applied to significant (p < 0.05) results. Content analysis was conducted and relevant categories and themes were identified. RESULTS: Social and health professionals (n = 54) rated their confidence to manage the needs of people with ID and epilepsy equally. Health professionals showed better awareness (p < 0.001) of the findings/recommendations of the latest evidence on premature deaths and identifying and managing epilepsy-related risks, including the relevance of nocturnal monitoring. The content analysis highlighted the need for clearer roles, improved care pathways, better epilepsy-specific knowledge, increased resources, and better multi-disciplinary work. CONCLUSIONS: A gap exists between health and social care professionals in awareness of epilepsy needs for people with ID, requiring essential training and national pathways.

Lameness recovery rates following treatment of dairy cattle with claw horn lameness in the Waikato region of New Zealand.

AIMS: To describe the time in days for lame dairy cows to recover after diagnosis and treatment of claw horn lameness, and to investigate whether cure rates differed between farms. METHODS: Five dairy farms in the Waikato region were conveniently enrolled into a descriptive epidemiological study. Three of these farms had dairy cattle enrolled over two consecutive seasons, while two farms enrolled for one year. Lame cattle diagnosed by the farmers were enrolled into the study if they had a lameness score (LS ≥ 2 on a 0-3 scale) and claw horn lesions. All enrolled animals were treated by a single veterinarian following a consistent methodology, and subsequently assessed for LS at a median frequency of 4 days from enrolment until they were sound (LS = 0). The times (days) taken for animals to become sound and non-lame (LS < 2) were reported for all animals, and Kaplan-Meier survival curves used to present the results. A Cox-proportional hazard model was used to assess if the hazard of soundness was associated with farm, age, breed, lesion, number of limbs involved, and LS at enrolment. RESULTS: A total of 241 lame cattle with claw horn lesions were enrolled across the five farms. White line disease was the predominant pain-causing lesion in 225 (93%) animals, and blocks were applied to 205 (85%) of enrolled animals. The overall median days from enrolment to becoming sound was 18 (95% CI = 14-21) days, and 7 (95% CI = 7-8) days to become non-lame. A difference in the hazards of lameness cure between farms was identified (p = 0.007), with median days to lameness cure between farms ranging from 11 to 21 days. No associations were identified between age, breed, limb, or LS at enrolment on the lameness cure rates. CONCLUSIONS: Treatment of claw horn lameness following industry-standard guidelines in dairy cattle on five New Zealand dairy farms resulted in rapid cure, although cure rates differed between farms. CLINICAL RELEVANCE: Following industry best-practice lameness treatment guidelines, including frequent use of blocks, can result in rapid lameness cure rates in New Zealand dairy cows. This study also suggests that management of lame cattle on pasture can positively benefit their welfare and recovery times. The reported cure rates provide veterinarians with benchmarks on the length of time after which a lame animal should be re-examined, and in the investigation of poor treatment response rates at the herd level.

Radiation dose to staff from medical X-ray scatter in the orthopaedic theatre.

PURPOSE: Given the growing demand for intraoperative imaging, there is increased concern for radiation dose for orthopaedic surgical staff. This study sought to determine the distribution of scatter radiation from fluoroscopic imaging in the orthopaedic surgical environment, with particular emphasis on the positions of personnel and the type of orthopaedic surgery performed. METHODS: A radiation survey detector was deployed at various angles and distances around an anthropomorphic phantom. The scatter dose rate in microsieverts per hour (µSv/h) was recorded using consistent exposure parameters for five common surgical procedures. A C-arm unit produced radiation for the hip arthroscopy, hip replacement and knee simulations, whilst a mini C-arm unit produced fluoroscopy for the foot and hand simulations. RESULTS: Readings were tabulated, and coloured heatmaps were generated from scatter measurements for each of the five procedures. Positions corresponding to the typical location of the surgical staff (surgeon, surgical assistant, anaesthetist, instrument (scrub) nurse, circulation (scout) nurse and anaesthetic nurse) were superimposed on heatmaps. The surgeon's proximity to the radiation source meant this position experienced the greatest amount of radiation in all five surgical procedures. Mini C-arm doses were considered low in all procedures for positions, with and without lead protection. CONCLUSION: This investigation demonstrated the distribution of scattered radiation dose experienced at different positions within the orthopaedic surgical theatre. It reinforces the importance of staff increasing their distance from the primary beam where possible, reducing exposure time and increasing shielding with lead protection.

Chronic high-rate pacing induces heart failure with preserved ejection fraction-like phenotype in Ossabaw swine.

The lack of pre-clinical large animal models of heart failure with preserved ejection fraction (HFpEF) remains a growing, yet unmet obstacle to improving understanding of this complex condition. We examined whether chronic cardiometabolic stress in Ossabaw swine, which possess a genetic propensity for obesity and cardiovascular complications, produces an HFpEF-like phenotype. Swine were fed standard chow (lean; n = 13) or an excess calorie, high-fat, high-fructose diet (obese; n = 16) for ~ 18 weeks with lean (n = 5) and obese (n = 8) swine subjected to right ventricular pacing (180 beats/min for ~ 4 weeks) to induce heart failure (HF). Baseline blood pressure, heart rate, LV end-diastolic volume, and ejection fraction were similar between groups. High-rate pacing increased LV end-diastolic pressure from ~ 11 ± 1 mmHg in lean and obese swine to ~ 26 ± 2 mmHg in lean HF and obese HF swine. Regression analyses revealed an upward shift in LV diastolic pressure vs. diastolic volume in paced swine that was associated with an ~ twofold increase in myocardial fibrosis and an ~ 50% reduction in myocardial capillary density. Hemodynamic responses to graded hemorrhage revealed an ~ 40% decrease in the chronotropic response to reductions in blood pressure in lean HF and obese HF swine without appreciable changes in myocardial oxygen delivery or transmural perfusion. These findings support that high-rate ventricular pacing of lean and obese Ossabaw swine initiates underlying cardiac remodeling accompanied by elevated LV filling pressures with normal ejection fraction. This distinct pre-clinical tool provides a unique platform for further mechanistic and therapeutic studies of this highly complex syndrome.

Delineating sociodemographic, medical and quality of life factors associated with psychological distress in individuals with endometriosis.

STUDY QUESTION: What is the relationship between specific quality of life domains and depression, anxiety and stress in the endometriosis population? SUMMARY ANSWER: Psychosocial domains of quality of life, such as a perception of social support and self-image, are more strongly associated with depression, anxiety and stress than pain and medical factors. WHAT IS KNOWN ALREADY: Prior research indicates a high prevalence of anxiety and depression in individuals with endometriosis. Pain is thought to be critical in the development of psychological distress, however prior research has investigated this association without consideration of psychosocial quality of life domains such as social functioning, perceived social support and self-image. STUDY DESIGN, SIZE, DURATION: This study is a cross-sectional analysis of baseline data collected in a longitudinal study exploring psychological distress in endometriosis (n = 584). PARTICIPANTS/MATERIALS, SETTING, METHODS: Individuals living with endometriosis participated in this study and were recruited via online platforms of community organizations and support groups. Demographic and medical information concerning endometriosis treatment and diagnosis was self-reported. Psychological distress and quality of life was measured using the Depression, Anxiety and Stress Scale (DASS-21), Endometriosis Health Profile-30 (EHP-30) and the Short Form Survey (SF-36v2). A series of linear regression analyses explored the relationship between specific quality of life domains and the primary outcomes of depression, anxiety and stress. MAIN RESULTS AND THE ROLE OF CHANCE: Approximately half of the participants in this sample reported moderate to severe anxiety, depression and stress. Quality of life domains, particularly perceived social support, social functioning and self-image, were more strongly associated with psychological distress than medical or demographic factors. Pain was associated with anxiety, but not depression or stress. A greater number of endometriosis symptoms was only associated with depression. LIMITATIONS, REASONS FOR CAUTION: These data are cross-sectional and, therefore, causality cannot be inferred from this analysis. Information about endometriosis diagnosis and treatment was self-reported, and not verified against medical records. WIDER IMPLICATIONS OF THE FINDINGS: This study indicates that psychosocial factors may be more salient factors underlying depression, anxiety and stress in the endometriosis population than pain and medical factors. There is a need for interventions that target psychological distress in this population with a focus on the broader impact of endometriosis beyond pain and physical symptomatology. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by the Research Training Program (RTP) Scholarship awarded to C.S.M. by Macquarie University. The remaining authors have nothing to declare. TRIAL REGISTRATION NUMBER: ACTRN12619001508167.

Urinary complement proteins and risk of end-stage renal disease: quantitative urinary proteomics in patients with type 2 diabetes and biopsy-proven diabetic nephropathy.

PURPOSE: To investigate the association between urinary complement proteins and renal outcome in biopsy-proven diabetic nephropathy (DN). METHODS: Untargeted proteomic and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional analyses and targeted proteomic analysis using parallel reaction-monitoring (PRM)-mass spectrometry was performed to determine the abundance of urinary complement proteins in healthy controls, type 2 diabetes mellitus (T2DM) patients, and patients with T2DM and biopsy-proven DN. The abundance of each urinary complement protein was individually included in Cox proportional hazards models for predicting progression to end-stage renal disease (ESRD). RESULTS: Untargeted proteomic and functional analysis using the KEGG showed that differentially expressed urinary proteins were primarily associated with the complement and coagulation cascades. Subsequent urinary complement proteins quantification using PRM showed that urinary abundances of C3, C9, and complement factor H (CFAH) correlated negatively with annual estimated glomerular filtration rate (eGFR) decline, while urinary abundances of C5, decay-accelerating factor (DAF), and CD59 correlated positively with annual rate of eGFR decline. Furthermore, higher urinary abundance of CFAH and lower urinary abundance of DAF were independently associated with greater risk of progression to ESRD. Urinary abundance of CFAH and DAF had a larger area under the curve (AUC) than that of eGFR, proteinuria, or any pathological parameter. Moreover, the model that included CFAH or DAF had a larger AUC than that with only clinical or pathological parameters. CONCLUSION: Urinary abundance of complement proteins was significantly associated with ESRD in patients with T2DM and biopsy-proven DN, indicating that therapeutically targeting the complement pathway may alleviate progression of DN.

An exploration of the impact of SARS-CoV-2 (COVID-19) restrictions on marginalised groups in the UK.

BACKGROUND: To contain the spread of COVID-19 within the UK over the past year, there have been a series of local and national lockdowns. These restrictions are likely to have impacted upon the health and well-being of marginalised groups who rely on now closed social and community support services to stay healthy. An understanding of the experiences of marginalised people is important; therefore, this study aimed to explore the impact of the COVID-19 restrictions on the health and well-being of marginalised groups in the UK. METHODS: In summer 2020, a rapid telephone survey was conducted by trained, trusted volunteers with 76 participants who were from marginalised groups. As part of this survey, 64 participants consented to describe their experience of lockdown. These case studies were thematically analysed to identify patterns of meaning. RESULTS: Findings indicate that lockdown led to the deterioration of health of participants, impacted adversely on their socio-economic positions and affected access to food and essential supplies. In addition, government public health messaging was considered confusing and inadequate. CONCLUSIONS: This study highlights the need for pathways into services which support marginalised groups to remain accessible during periods of restrictions and essential supplies and food to be mapped and protected for marginalised individuals within our local communities.

Cohabitation COVID-19 transmission rates in a United States suburban community: A retrospective study of familial infections.

OBJECTIVES: SARS-CoV-2 is a highly contagious virus that causes coronavirus disease 2019 (COVID-19) and can affect people of any age with potential for serious symptoms. Since the start of the COVID-19 pandemic, global infection rates have been on the rise with world leaders looking to slow and stop viral transmission. This study is looking at suburban cohabitation/familial infection to compare to similar studies from other countries. STUDY DESIGN: A retrospective review of medical records was collected using the Connecticut Electronic Disease Surveillance System. METHODS: A total of 406 cases who tested positive for SARS-COV-2 from February to June 2020 were reviewed from three towns located in Connecticut, USA. Cohabitation infection rates were identified using the home addresses of those with confirmed SARS-CoV-2 test results, with the first documented case being the index case, and additional home members being the secondary cases. RESULTS: Secondary transmission of SARS-CoV-2 developed in 126 of 406 household contacts (31%). Linear regression indicated positive relationship between cohabitation and age. CONCLUSIONS: The cohabitation infection attack rate of SARS-CoV-2 is significantly higher than previously reported. Age of household contacts and spousal relationship to the index case are risk factors for transmission of SARS-CoV-2 within a household.

The Heart Failure with Preserved Ejection Fraction Conundrum-Redefining the Problem and Finding Common Ground?

PURPOSE OF REVIEW: Heart failure with preserved ejection fraction (HFpEF) or diastolic heart failure (DHF) makes up more than half of all congestive heart failure presentations (CHF). With an ageing population, the case load and the financial burden is projected to increase, even to epidemic proportions. CHF hospitalizations add too much of the financial and infrastructure strain. Unlike systolic heart failure (SHF), much is still either uncertain or unknown. Specifically, in epidemiology, the disease burden is established; however, risk factors and pathophysiological associations are less clear; diagnostic tools are based on rigid parameters without the ability to accurately monitor treatments effects and disease progression; finally, therapeutics are similar to SHF but without prognostic data for efficacy. RECENT FINDINGS: The last several years have seen guidelines changing to account for greater epidemiological observations. Most of these remain general observation of shortness of breath symptom matched to static echocardiographic parameters. The introduction of exercise diastolic stress test has been welcome and warrants greater focus. HFpEF is likely to see new thinking in the coming decades. This review provides some of perspective on this topic.

Interactive Effects of Naturalistic Drinking Context and Alcohol Sensitivity on Neural Alcohol Cue-Reactivity Responses.

BACKGROUND: Considerable evidence indicates that a low level of subjective response to alcohol's acute effects (i.e., low sensitivity) is associated with enhanced risk for alcohol use disorder (AUD). Recent work suggests that the highest risk response profile consists of blunted sensitivity to alcohol's sedation-like effects, coupled with enhanced sensitivity to alcohol's stimulation-like effects (i.e., differential sensitivity). A largely separate body of work indicates that enhanced reactivity to alcohol-related cues is associated with increased AUD risk. AIMS: The current research examined the extent to which variability in alcohol response phenotypes is associated with enhanced P3 event-related potential (ERP) responses to alcohol-related pictures (ACR-P3), and whether this reactivity varies according to depicted drinking contexts. METHODS: Eighty young adults (aged 18 to 33 years) completed a self-report measure of alcohol sensitivity (the Alcohol Sensitivity Questionnaire) and viewed images depicting drinking in naturalistic contexts, alcohol and nonalcohol beverages in isolation (devoid of naturalistic drinking context), and neutral nonbeverage control images while ERPs were recorded. RESULTS: Results indicated that blunted sensitivity to alcohol's sedative-like effects was differentially associated with enhanced ACR-P3 but reduced P3 reactivity to nonalcohol cues. Variation in sensitivity to alcohol's stimulant-like effects was not associated with differential ACR-P3. Contrary to predictions, these effects were not potentiated by drinking contexts. CONCLUSIONS: The current results replicate and extend previous work linking low alcohol sensitivity with enhanced incentive salience for alcohol-related cues and suggest that cues depicting drinking contexts are less likely to differentiate high-risk from low-risk drinkers.

11 Beta-hydroxysteroid dehydrogenase type 1 regulates synovitis, joint destruction, and systemic bone loss in chronic polyarthritis.

OBJECTIVE: In rheumatoid arthritis, the enzyme 11 beta-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) is highly expressed at sites of inflammation, where it converts inactive glucocorticoids (GC) to their active counterparts. In conditions of GC excess it has been shown to be a critical regulator of muscle wasting and bone loss. Here we examine the contribution of 11ß-HSD1 to the pathology of persistent chronic inflammatory disease. METHODS: To determine the contribution of 11ß-HSD1 to joint inflammation, destruction and systemic bone loss associated with persistent inflammatory arthritis, we generated mice with global and mesenchymal specific 11ß-HSD1 deletions in the TNF-transgenic (TNF-tg) model of chronic polyarthritis. Disease severity was determined by clinical scoring. Histology was assessed in formalin fixed sections and fluorescence-activated cell sorting (FACS) analysis of synovial tissue was performed. Local and systemic bone loss were measured by micro computed tomography (micro-CT). Measures of inflammation and bone metabolism were assessed in serum and in tibia mRNA. RESULTS: Global deletion of 11ß-HSD1 drove an enhanced inflammatory phenotype, characterised by florid synovitis, joint destruction and systemic bone loss. This was associated with increased pannus invasion into subchondral bone, a marked polarisation towards pro-inflammatory M1 macrophages at sites of inflammation and increased osteoclast numbers. Targeted mesenchymal deletion of 11ß-HSD1 failed to recapitulate this phenotype suggesting that 11ß-HSD1 within leukocytes mediate its protective actions in vivo. CONCLUSIONS: We demonstrate a fundamental role for 11ß-HSD1 in the suppression of synovitis, joint destruction, and systemic bone loss. Whilst a role for 11ß-HSD1 inhibitors has been proposed for metabolic complications in inflammatory diseases, our study suggests that this approach would greatly exacerbate disease severity.

Social Network Analysis Identifies Key Participants in Conservation Development.

Understanding patterns of participation in private lands conservation, which is often implemented voluntarily by individual citizens and private organizations, could improve its effectiveness at combating biodiversity loss. We used social network analysis (SNA) to examine participation in conservation development (CD), a private land conservation strategy that clusters houses in a small portion of a property while preserving the remaining land as protected open space. Using data from public records for six counties in Colorado, USA, we compared CD participation patterns among counties and identified actors that most often work with others to implement CDs. We found that social network characteristics differed among counties. The network density, or proportion of connections in the network, varied from fewer than 2 to nearly 15%, and was higher in counties with smaller populations and fewer CDs. Centralization, or the degree to which connections are held disproportionately by a few key actors, was not correlated strongly with any county characteristics. Network characteristics were not correlated with the prevalence of wildlife-friendly design features in CDs. The most highly connected actors were biological and geological consultants, surveyors, and engineers. Our work demonstrates a new application of SNA to land-use planning, in which CD network patterns are examined and key actors are identified. For better conservation outcomes of CD, we recommend using network patterns to guide strategies for outreach and information dissemination, and engaging with highly connected actor types to encourage widespread adoption of best practices for CD design and stewardship.

Implementation of Reach Out and Read by Health Departments Increases Rural Access.

BACKGROUND: Reach Out and Read is an evidence based early literacy program used in primary care practices. In 2014, the program expanded to County Health Departments in Oklahoma. OBJECTIVE: To evaluate how implementation of the program in Health Departments affects access for at risk children. METHODS: Oklahoma program sites were classified as either Health Department or practice, geocoded, and mapped to census tract, census block group, and county subdivision maps. Sites were classified as rural or urban, and census data was used to classify sites as high or low poverty prevalence and education level. Sites were compared to determine their accessibility to at risk children as defined by living in rural areas, high poverty, and low educational level. RESULTS: There were 18 Health Department and 67 practice sites. Health Department sites were more likely to be in rural areas: 13 of 18 sites versus 16 of 67 practices (p<0.001). They were less likely to be in areas of high poverty: 10 of 18 versus 61 of 67 practices (p<0.001), and they were not more likely to be in areas of lower education, with 8 of 18 sites in low education areas versus 34 of 67 practices (p=0.8342). CONCLUSIONS: Implementation of Reach Out and Read in Health Departments in Oklahoma increased the number of rural program sites. Health Department locations were less likely to be in areas of poverty and lower education. Use of the program in Health Departments is an effective way to expand the program to serve rural children.

Access to Care for Children under five in Oklahoma: a Geographic Imputation Application.

OBJECTIVE: Geographic access to primary care can be a barrier to receiving appropriate preventative services. Oklahoma has been identified as having relatively few primary care providers per capita to care for its population compared to the US. The goal of this analysis was to identify the areas in Oklahoma with significant concentrations of children under five, no pediatrician within reasonable driving distance, and whether other primary care providers are present. METHODS: The 2016 American Community Survey was used to estimate the total population of children under five years of age for each Census Block Group in Oklahoma. Access was defined as a thirty-minute drive time radius computed around each child's imputed location. The National Provider Identifier database was used to identify and locate pediatricians, family medicine physicians, and mid-level providers in Oklahoma. Areas of high concentrations of children with no pediatrician access were identified and non-pediatrician provider locations were superimposed. RESULTS: Of the estimated 265,818 children under five in Oklahoma, approximately 7% were outside of a thirty-minute drive from a pediatrician. These children are concentrated in northwestern and southeastern Oklahoma, with several smaller additional groupings. There are multiple non-pediatrician primary care providers operating in many of these areas. CONCLUSION: There are areas in the state where a paucity of pediatricians and high concentrations of young children lend themselves to collaborations using technology and education to improve the care of children.