Association with HLA-DRß1 position 37 distinguishes juvenile dermatomyositis from adult-onset myositis.

Juvenile dermatomyositis (JDM) is a rare, severe autoimmune disease and the most common idiopathic inflammatory myopathy of children. JDM and adult-onset dermatomyositis (DM) have similar clinical, biological and serological features, although these features differ in prevalence between childhood-onset and adult-onset disease, suggesting that age of disease onset may influence pathogenesis. Therefore, a JDM-focused genetic analysis was performed using the largest collection of JDM samples to date. Caucasian JDM samples (n = 952) obtained via international collaboration were genotyped using the Illumina HumanCoreExome chip. Additional non-assayed human leukocyte antigen (HLA) loci and genome-wide single-nucleotide polymorphisms (SNPs) were imputed. HLA-DRB1*03:01 was confirmed as the classical HLA allele most strongly associated with JDM [odds ratio (OR) 1.66; 95% confidence interval (CI) 1.46, 1.89; P = 1.4 × 10-14], with an independent association at HLA-C*02:02 (OR = 1.74; 95% CI 1.42, 2.13, P = 7.13 × 10-8). Analyses of amino acid positions within HLA-DRB1 indicated that the strongest association was at position 37 (omnibus P = 3.3 × 10-19), with suggestive evidence this association was independent of position 74 (omnibus P = 5.1 × 10-5), the position most strongly associated with adult-onset DM. Conditional analyses also suggested that the association at position 37 of HLA-DRB1 was independent of some alleles of the Caucasian HLA 8.1 ancestral haplotype (AH8.1) such as HLA-DQB1*02:01 (OR = 1.62; 95% CI 1.36, 1.93; P = 8.70 × 10-8), but not HLA-DRB1*03:01 (OR = 1.49; 95% CR 1.24, 1.80; P = 2.24 × 10-5). No associations outside the HLA region were identified. Our findings confirm previous associations with AH8.1 and HLA-DRB1*03:01, HLA-C*02:02 and identify a novel association with amino acid position 37 within HLA-DRB1, which may distinguish JDM from adult DM.

Cardiovascular risk communication strategies in primary prevention. A systematic review with narrative synthesis.

AIM: To evaluate the effectiveness of cardiovascular risk communication strategies to improve understanding and promote risk factor modification. DESIGN: Systematic review with narrative synthesis. DATA SOURCES: A comprehensive database search for quantitative and qualitative studies was conducted in five databases, Cumulative Index to Nursing and Allied health Literature (CINAHL), Medical Literature Analysis and Retrieval System Online (MEDLINE), EMBASE, Applied Social Sciences Index and Abstracts (ASSIA) and Web of Science. The searches were conducted between 1980 and July 2019. REVIEW METHODS: The systematic review was conducted in accordance with Cochrane review methods. Data were extracted and a narrative synthesis of quantitative and qualitative results was undertaken. RESULTS: The abstracts of 16,613 articles were assessed and 210 underwent in-depth review, with 31 fulfilling the inclusion criteria. We observed significant heterogeneity across study designs and outcomes. Nine communication strategies were identified including numerical formats, graphical formats, qualitative information, infographics, avatars, game interactions, timeframes, genetic risk scores and cardiovascular imaging. Strategies that used cardiovascular imaging had the biggest impact on health behaviour change and risk factor modification. Improvements were seen in diet, exercise, smoking, risk scores, cholesterol and intentions to take preventive medication. CONCLUSION: A wide range of cardiovascular risk communication strategies has been evaluated, with those that employ personalized and visual evidence of current cardiovascular health status more likely to promote action to reduce risk. IMPACT: Future risk communication strategies should incorporate methods to provide individuals with evidence of their current cardiovascular health status.

High-Sensitivity Troponin and the Application of Risk Stratification Thresholds in Patients With Suspected Acute Coronary Syndrome.

BACKGROUND: Guidelines acknowledge the emerging role of high-sensitivity cardiac troponin (hs-cTnl) for risk stratification and the early rule-out of myocardial infarction, but multiple thresholds have been described. We evaluate the safety and effectiveness of risk stratification thresholds in patients with suspected acute coronary syndrome. METHODS: Consecutive patients with suspected acute coronary syndrome (n=48 282) were enrolled in a multicenter trial across 10 hospitals in Scotland. In a prespecified secondary and observational analysis, we compared the performance of the limit of detection (<2 ng/L) and an optimized risk stratification threshold (<5 ng/L) using the Abbott high-sensitivity troponin I assay. Patients with myocardial injury at presentation, with ≤2 hours of symptoms or with ST-segment elevation myocardial infarction were excluded. The negative predictive value was determined in all patients and in subgroups for a primary outcome of myocardial infarction or cardiac death within 30 days. The secondary outcome was myocardial infarction or cardiac death at 12 months, with risk modeled using logistic regression adjusted for age and sex. RESULTS: In total, 32 837 consecutive patients (61±17 years, 47% female) were included, of whom 23 260 (71%) and 12,716 (39%) had hs-cTnl concentrations of <5 ng/L and <2 ng/L at presentation. The negative predictive value for the primary outcome was 99.8% (95% CI, 99.7%-99.8%) and 99.9% (95% CI, 99.8%-99.9%) in those with hs-cTnl concentrations of <5 ng/L and <2 ng/L, respectively. At both thresholds, the negative predictive value was consistent in men and women and across all age groups, although the proportion of patients identified as low risk fell with increasing age. Compared with patients with hs-cTnl concentrations of ≥5 ng/L but <99th centile, the risk of myocardial infarction or cardiac death at 12 months was 77% lower in those <5 ng/L (5.3% vs 0.7%; adjusted odds ratio, 0.23 [95% CI, 0.19-0.28]) and 80% lower in those <2 ng/L (5.3% vs 0.3%; adjusted odds ratio, 0.20 [95% CI, 0.14-0.29]). CONCLUSIONS: Use of risk stratification thresholds for hs-cTnl identify patients with suspected acute coronary syndrome and at least 2 hours of symptoms as low risk at presentation irrespective of age and sex. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01852123.

Exploring Patient Experience of Chest Pain Before and After Implementation of an Early Rule-Out Pathway for Myocardial Infarction: A Qualitative Study.

STUDY OBJECTIVE: High-sensitivity cardiac troponin assays enable myocardial infarction to be excluded in the emergency department (ED). As part of a prospective clinical trial, we explore how introducing an early rule-out pathway may affect patient experience of chest pain. METHODS: In a qualitative study, participants presenting to the ED with suspected acute coronary syndrome, and for whom the diagnosis of myocardial infarction was excluded, were interviewed before (n=23) or after (n=26) implementation of an early rule-out pathway. Preimplementation, diagnosis of myocardial infarction was excluded on serial troponin testing requiring admission to the hospital. Postimplementation, diagnosis could be excluded in the ED, enabling direct patient discharge. Semistructured interviews exploring the patients' illness experience were conducted approximately 1 week postdischarge, transcribed verbatim, and analyzed thematically. Themes emerging pre- and postimplementation are described. RESULTS: Common themes emerged across both pathways: participants commonly sought health care advice before presenting to the ED; a discordance may exist between the objective interpretation of troponin results by clinicians and the patients' experience of illness; and pretest information, trust in the clinician, and active listening may enhance reassurance gained from negative test results. Other themes related to the care pathway were that routine care procedures appeared to be a source of frustration for participants requiring hospital admission, and patients assessed with the early rule-out pathway appeared less likely to appraise their future health status. CONCLUSION: The early rule-out of myocardial infarction may be enhanced by recognition of patient out-of-hospital experience and improved communication surrounding reassurance and future cardiovascular health goals.

High-Sensitivity Cardiac Troponin I and Clinical Risk Scores in Patients With Suspected Acute Coronary Syndrome.

BACKGROUND: High-sensitivity cardiac troponin assays can help to identify patients who are at low risk of myocardial infarction in the emergency department. We aimed to determine whether the addition of clinical risk scores would improve the safety of early rule-out pathways for myocardial infarction. METHODS: In 1935 patients with suspected acute coronary syndrome, we evaluated the safety and efficacy of 2 rule-out pathways alone or in conjunction with low-risk TIMI (Thrombolysis In Myocardial Infarction) (0 or 1), GRACE (Global Registry of Acute Coronary Events) (≤108), EDACS (Emergency Department Assessment of Chest Pain Score) (<16), or HEART (History, ECG, Age, Risk factors, Troponin) (≤3) scores. The European Society of Cardiology 3-hour pathway uses a single diagnostic threshold (99th percentile), whereas the High-STEACS (High-Sensitivity Troponin in the Evaluation of Patients With Acute Coronary Syndrome) pathway applies different thresholds to rule out (<5 ng/L) and rule in (>99th percentile) myocardial infarction. RESULTS: Myocardial infarction or cardiac death during the index presentation or at 30 days occurred in 14.3% of patients (276/1935). The European Society of Cardiology pathway ruled out 70%, with 27 missed events giving a negative predictive value of 97.9% (95% CI, 97.1-98.6). The addition of a HEART score ≤3 reduced the proportion ruled out by the European Society of Cardiology pathway to 25% but improved the negative predictive value to 99.7% (95% CI, 99.0-100; P<0.001). The High-STEACS pathway ruled out 65%, with 3 missed events for a negative predictive value of 99.7% (95% CI, 99.4-99.9). No risk score improved the negative predictive value of the High-STEACS pathways, but all reduced the proportion ruled out (24% to 47%; P<0.001 for all). CONCLUSIONS: Clinical risk scores significantly improved the safety of the European Society of Cardiology 3-hour pathway, which relies on a single cardiac troponin threshold at the 99th percentile to rule in and rule out myocardial infarction. Where lower thresholds are used to rule out myocardial infarction, as applied in the High-STEACS pathway, risk scores halve the proportion of patients ruled out without improving safety. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01852123.

Influence of resampling techniques on Bayesian network performance in predicting increased algal activity.

Early warning of increased algal activity is important to mitigate potential impacts on aquatic life and human health. While many methods have been developed to predict increased algal activity, an ongoing issue is that severe algal blooms often occur with low frequency in water bodies. This results in imbalanced data sets available for model specification, leading to poor predictions of the frequency of increased algal activity. One approach to address this is to resample data sets of increased algal activity to increase the prevalence of higher than normal algal activity in calibration data and ultimately improve model predictions. This study aims to investigate the use of resampling techniques to address the imbalanced dataset and determine if such methods can improve the prediction of increased algal activity. Three techniques were investigated, Kmeans under-sampling (US_Kmeans), synthetic minority over-sampling technique (SMOTE), and 'SMOTE and cluster-based under-sampling technique' (SCUT). The resampling methods were applied to a Bayesian network (BN) model of Lake Burragorang in New South Wales, Australia. The model was developed to predict chlorophyll-a (chl-a) using a range of water quality parameters as predictors. The original data and each of the balanced datasets were used for BN structures and parameter learning. The results showed that the best graphical structure was obtained by adding synthetic data from SMOTE with the highest true positive rate (TPR) and area under the curve (AUC). When compared using a fixed graphical structure for the BN, all resampling techniques increased the ability of the BN to detect events with higher probability of increased algal activity. The resampling model results can also be used to better understand the most important influences on high chl-a concentrations and suggest future data collection and model development priorities.

A critical review of Natural Flood Management application and spatial prioritisation approaches in tropical island catchments.

Tropical island communities face substantial hydrometrological threats, including flood inundation. Flood risk is increasing, driven by climate change but also other factors including urbanisation, land-cover and land-use (LCLU) change, making flood management challenging to address in practice. Protecting, restoring, and emulating the natural functions of catchments to reduce flood risk, also known as Natural Flood Management (NFM), is a promising method for improving flood management. Global NFM research is in its infancy and NFM research in tropical island states has tended to focus on individual catchment projects. Therefore, overall trends, challenges, and opportunities for NFM in tropical island catchments are poorly understood and, until now, have not been reviewed across these geographies. A particular gap in NFM understanding in tropical island catchments is how NFM options can be best implemented within any particular catchment - specifically where NFM should be located, how modelling can support these decisions and the influence of different catchment characteristics on these decisions. This literature review aims to explore what, where and how NFM has been used in catchments in tropical island states, with a specific focus on catchment characteristics and spatial modelling. This paper draws on research and interconnections between multiple environmental science spheres, by reviewing both academic and grey literature to better understand how NFM has been applied in tropical island states, with a primary focus on Pacific Island Countries and Territories (PICTs). The research highlights that some islands have greater potential for exploiting NFM due to their physical catchment characteristics and data availability. NFM spatial modelling approaches need to be further developed and adapted to specific tropical island community requirements to improve inland flood resilience at the pace needed and to ensure resources are directed optimally.

Water Sensitive Urban Design (WSUD) Spatial Prioritisation through Global Sensitivity Analysis for Effective Urban Pluvial Flood Mitigation.

Water Sensitive Urban Design (WSUD) has attracted growing attention as a sustainable approach for mitigating pluvial flooding (also known as flash flooding), which is expected to increase in frequency and intensity under the impacts of climate change and urbanisation. However, spatial planning of WSUD is not an easy task, not only due to the complex urban environment, but also the fact that not all locations in the catchment are equally effective for flood mitigation. In this study, we developed a new WSUD spatial prioritisation framework that applies global sensitivity analysis (GSA) to identify priority subcatchments where WSUD implementation will be most effective for flood mitigation. For the first time, the complex impact of WSUD locations on catchment flood volume can be assessed, and the GSA in hydrological modelling is adopted for applications in WSUD spatial planning. The framework uses a spatial WSUD planning model, the Urban Biophysical Environments and Technologies Simulator (UrbanBEATS), to generate a grid-based spatial representation of catchment, and an urban drainage model, the U.S. EPA Storm Water Management Model (SWMM), to simulate catchment flooding. The effective imperviousness of all subcatchments was varied simultaneously in the GSA to mimic the effect of WSUD implementation and future developments. Priority subcatchments were identified based on their influence on catchment flooding computed through the GSA. The method was tested for an urbanised catchment in Sydney, Australia. We found that high priority subcatchments were clustering in the upstream and midstream of the main drainage network, with a few distributed close to the catchment outlets. Rainfall frequency, subcatchment characteristics, and pipe network configuration were found to be important factors determining the influence of changes in different subcatchments on catchment flooding. The effectiveness of the framework in identifying influential subcatchments was validated by comparing the effect of removing 6% of the Sydney catchment's effective impervious area under four WSUD spatial distribution scenarios. Our results showed that WSUD implementation in high priority subcatchments consistently achieved the largest flood volume reduction (3.5-31.3% for 1% AEP to 50% AEP storms), followed by medium priority subcatchments (3.1-21.3%) and catchment-wide implementation (2.9-22.1%) under most design storms. Overall, we have demonstrated that the proposed method can be useful for maximising WSUD flood mitigation potential through identifying and targeting the most effective locations.

Transboundary river basins: Scenarios of hydropower development and operation under extreme climate conditions.

Transboundary river basins across developing countries, such as the Lower Mekong River Basin (LMB), are challenging to manage given frequent divergences on development and conservation priorities. Driven by needs to sustain economic performance and reduce poverty, the LMB countries are embarking on significant land use changes in the form of more hydropower dams, to satisfy growing energy demands. This pathway could lead to irreversible changes to the ecosystem of the Mekong River, if not properly managed. Given the uncertain environmental externalities and trade-offs associated with further hydropower development and operation in the LMB, this research develops four plausible scenarios of future hydropower operation, and assesses their likely impact on streamflow and instream total suspended solids and nitrate loads of the Mekong River. The findings suggest that further hydropower operations on either tributary or mainstream could result in annual and wet season flow reduction between 11 and 25% while increase dry season flows by 1 to 15%, when compared to a business-as-usual scenario. Conversely, hydropower operation on both tributary and mainstream could result in dry season flow reduction between 10 and 15%. Both instream TSS and nitrate loads are forecasted to reduce under all three scenarios by as much as 78 and 20%, respectively, compared to the business-as-usual one. These effects are predicted to magnify under extreme climate conditions with dry season flow, TSS, and nitrate levels reduced by as much as 44, 81 and 35%, respectively, during a projected extreme dry climate condition, but less severe under improved operational alternatives. With further hydropower development in the LMB being highly unavoidable, these findings can inform effective transboundary management pathways for balancing electricity generation and protection of riverine ecology, water and food security, and people livelihoods.

Chondroitin sulfate proteoglycans prevent immune cell phenotypic conversion and inflammation resolution via TLR4 in rodent models of spinal cord injury.

Chondroitin sulfate proteoglycans (CSPGs) act as potent inhibitors of axonal growth and neuroplasticity after spinal cord injury (SCI). Here we reveal that CSPGs also play a critical role in preventing inflammation resolution by blocking the conversion of pro-inflammatory immune cells to a pro-repair phenotype in rodent models of SCI. We demonstrate that enzymatic digestion of CSPG glycosaminoglycans enhances immune cell clearance and reduces pro-inflammatory protein and gene expression profiles at key resolution time points. Analysis of phenotypically distinct immune cell clusters revealed CSPG-mediated modulation of macrophage and microglial subtypes which, together with T lymphocyte infiltration and composition changes, suggests a role for CSPGs in modulating both innate and adaptive immune responses after SCI. Mechanistically, CSPG activation of a pro-inflammatory phenotype in pro-repair immune cells was found to be TLR4-dependent, identifying TLR4 signalling as a key driver of CSPG-mediated immune modulation. These findings establish CSPGs as critical mediators of inflammation resolution failure after SCI in rodents, which leads to prolonged inflammatory pathology and irreversible tissue destruction.

Favorable antibody responses to human coronaviruses in children and adolescents with autoimmune rheumatic diseases.

BACKGROUND: Differences in humoral immunity to coronaviruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), between children and adults remain unexplained, and the effect of underlying immune dysfunction or suppression is unknown. Here, we sought to examine the antibody immune competence of children and adolescents with prevalent inflammatory rheumatic diseases, juvenile idiopathic arthritis (JIA), juvenile dermatomyositis (JDM), and juvenile systemic lupus erythematosus (JSLE) against the seasonal human coronavirus (HCoV)-OC43 that frequently infects this age group. METHODS: Sera were collected from JIA (n = 118), JDM (n = 49), and JSLE (n = 30) patients and from healthy control (n = 54) children and adolescents prior to the coronavirus disease 19 (COVID-19) pandemic. We used sensitive flow-cytometry-based assays to determine titers of antibodies that reacted with the spike and nucleoprotein of HCoV-OC43 and cross-reacted with the spike and nucleoprotein of SARS-CoV-2, and we compared them with respective titers in sera from patients with multisystem inflammatory syndrome in children and adolescents (MIS-C). FINDINGS: Despite immune dysfunction and immunosuppressive treatment, JIA, JDM, and JSLE patients maintained comparable or stronger humoral responses than healthier peers, which was dominated by immunoglobulin G (IgG) antibodies to HCoV-OC43 spike, and harbored IgG antibodies that cross-reacted with SARS-CoV-2 spike. In contrast, responses to HCoV-OC43 and SARS-CoV-2 nucleoproteins exhibited delayed age-dependent class-switching and were not elevated in JIA, JDM, and JSLE patients, which argues against increased exposure. CONCLUSIONS: Consequently, autoimmune rheumatic diseases and their treatment were associated with a favorable ratio of spike to nucleoprotein antibodies. FUNDING: This work was supported by a Centre of Excellence Centre for Adolescent Rheumatology Versus Arthritis grant, 21593, UKRI funding reference MR/R013926/1, the Great Ormond Street Children's Charity, Cure JM Foundation, Myositis UK, Lupus UK, and the NIHR Biomedical Research Centres at GOSH and UCLH. This work was supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK, the UK Medical Research Council, and the Wellcome Trust.

Gene therapy restores dopamine transporter expression and ameliorates pathology in iPSC and mouse models of infantile parkinsonism.

Most inherited neurodegenerative disorders are incurable, and often only palliative treatment is available. Precision medicine has great potential to address this unmet clinical need. We explored this paradigm in dopamine transporter deficiency syndrome (DTDS), caused by biallelic loss-of-function mutations in SLC6A3, encoding the dopamine transporter (DAT). Patients present with early infantile hyperkinesia, severe progressive childhood parkinsonism, and raised cerebrospinal fluid dopamine metabolites. The absence of effective treatments and relentless disease course frequently leads to death in childhood. Using patient-derived induced pluripotent stem cells (iPSCs), we generated a midbrain dopaminergic (mDA) neuron model of DTDS that exhibited marked impairment of DAT activity, apoptotic neurodegeneration associated with TNFα-mediated inflammation, and dopamine toxicity. Partial restoration of DAT activity by the pharmacochaperone pifithrin-µ was mutation-specific. In contrast, lentiviral gene transfer of wild-type human SLC6A3 complementary DNA restored DAT activity and prevented neurodegeneration in all patient-derived mDA lines. To progress toward clinical translation, we used the knockout mouse model of DTDS that recapitulates human disease, exhibiting parkinsonism features, including tremor, bradykinesia, and premature death. Neonatal intracerebroventricular injection of human SLC6A3 using an adeno-associated virus (AAV) vector provided neuronal expression of human DAT, which ameliorated motor phenotype, life span, and neuronal survival in the substantia nigra and striatum, although off-target neurotoxic effects were seen at higher dosage. These were avoided with stereotactic delivery of AAV2.SLC6A3 gene therapy targeted to the midbrain of adult knockout mice, which rescued both motor phenotype and neurodegeneration, suggesting that targeted AAV gene therapy might be effective for patients with DTDS.

Simulation of streamflow and instream loads of total suspended solids and nitrate in a large transboundary river basin using Source model and geospatial analysis.

The management of LULC changes in transboundary river basins continues to challenge water resources managers due to the differences in development and conservation priorities of the countries sharing the basin. While various watershed models (WMs) exist to support decision making, basin-wide sustainable application of the instituted WM depends on the management priorities, resources, data availability, and knowledge gaps at national and sub-basin levels. Building on the results of our prior comparative analysis of WMs for a large transboundary river basin, we applied the 'Source' model to the Lower Mekong Basin (LMB). The constructed LMB-Source model was evaluated based on its streamflow and instream total suspended solids (TSS) and nitrate loads simulative performances. A combination of predictive performance metrics (PPMs) and sophisticated hydrologic signatures were used to calibrate model parameters and diagnose the model performance. Calibration results indicated strong similarity between the simulated and observed time series data and were further confirmed by the validation results. The successful model calibration generated parameters that represent hydrologic response characteristics (HRCs) and overland TSS and nitrate generation and removal dynamics (GRDs) previously not available for the LMB. The HRCs and GRDs can be regionalised with physical attributes of the LMB in future studies which can be used to support the management of ungauged sub-basins. This study confirms Source's capability as a decision support tool for the management of transboundary river basins, and provides basin-specific values of HRCs and GRDs that can be used for a better evaluation of the potential effects of LULC changes.

Preexisting and de novo humoral immunity to SARS-CoV-2 in humans.

Zoonotic introduction of novel coronaviruses may encounter preexisting immunity in humans. Using diverse assays for antibodies recognizing SARS-CoV-2 proteins, we detected preexisting humoral immunity. SARS-CoV-2 spike glycoprotein (S)-reactive antibodies were detectable using a flow cytometry-based method in SARS-CoV-2-uninfected individuals and were particularly prevalent in children and adolescents. They were predominantly of the immunoglobulin G (IgG) class and targeted the S2 subunit. By contrast, SARS-CoV-2 infection induced higher titers of SARS-CoV-2 S-reactive IgG antibodies targeting both the S1 and S2 subunits, and concomitant IgM and IgA antibodies, lasting throughout the observation period. SARS-CoV-2-uninfected donor sera exhibited specific neutralizing activity against SARS-CoV-2 and SARS-CoV-2 S pseudotypes. Distinguishing preexisting and de novo immunity will be critical for our understanding of susceptibility to and the natural course of SARS-CoV-2 infection.

Low-frequency changes in finger volume in patients after surgery, related to respiration and venous pressure.

BACKGROUND AND OBJECTIVE: In patients after surgery, we observed large-amplitude low-frequency changes in digital plethysmograph measurements when DC coupling of the signal was used. We set out to assess factors that might contribute to these events and in particular to test the possibility that low-frequency signals could be used to assess respiratory disturbances. METHODS: We recorded values in 23 patients who had undergone gynaecological surgery. We measured nasal flow, abdominal pressure (by urinary catheter), venous pressure in the hand, and DC-coupled optical transmission plethysmography. Signals were replayed and analysed to assess the incidence of specific patterns of events. RESULTS: Most patients received morphine for postoperative analgesia. Respiratory irregularity and expiratory muscle action were very frequent. Increases in abdominal pressure during expiration caused increases in venous pressure and pulsation. In 12 out of 23 patients, a characteristic response consistent with vasoconstriction was noted after increases in breath size, and, in seven patients, very-low-frequency (0.2-0.7 Hz) oscillations of finger volume were present that appeared unrelated to respiratory events. Patients who did not receive morphine had very different plethysmograph patterns, with significantly smaller pulse amplitude. CONCLUSION: Low-frequency changes in finger volume can be simply obtained and provide considerable information about peripheral circulatory dynamics. Diverse patterns can be recognized, but the range of responses suggests that current techniques cannot be used alone to assess cardiorespiratory status. However, a combination of plethysmography with respiratory measurements shows characteristic events.

Perception of the ethical acceptability of live prey feeding to aquatic species kept in captivity.

Previous research into public perceptions of live prey feeding has been focused on terrestrial animals. The reasons for this likely relate to the difficulty humans have in being compassionate to animals who are phylogenetically distantly related. In order to test these assumptions, the general public (two groups; one who had just visited an aquarium; and one group who had just visited a zoo), aquarium professionals in the UK/US and terrestrial zoo animal professionals (UK) were investigated to see how they would differ in their responses when asked about feeding various live aquatic animals to one another. Likert based surveys were used to obtain data face to face and via online social media. Demographics in previous research identified a lower acceptance of live prey feeding by females, however in aquatic animals this was not reflected. Instead, separations in perception were seen to exist between participants dependent on whether they had just visited a zoo or aquarium, or worked with animals.

CD161 contributes to prenatal immune suppression of IFNγ-producing PLZF+ T cells.

BACKGROUND: While the human fetal immune system defaults to a program of tolerance, there is concurrent need for protective immunity to meet the antigenic challenges encountered after birth. Activation of T cells in utero is associated with the fetal inflammatory response with broad implications for the health of the fetus and of the pregnancy. However, the characteristics of the fetal effector T cells that contribute to this process are largely unknown. METHODS: We analyzed primary human fetal lymphoid and mucosal tissues and performed phenotypic, functional, and transcriptional analysis to identify T cells with pro-inflammatory potential. The frequency and function of fetal-specific effector T cells was assessed in the cord blood of infants with localized and systemic inflammatory pathologies and compared to healthy term controls. RESULTS: We identified a transcriptionally distinct population of CD4+ T cells characterized by expression of the transcription factor Promyelocytic Leukemia Zinc Finger (PLZF). PLZF+ CD4+ T cells were specifically enriched in the fetal intestine, possessed an effector memory phenotype, and rapidly produced pro-inflammatory cytokines. Engagement of the C-type lectin CD161 on these cells inhibited TCR-dependent production of IFNγ in a fetal-specific manner. IFNγ-producing PLZF+ CD4+ T cells were enriched in the cord blood of infants with gastroschisis, a natural model of chronic inflammation originating from the intestine, as well as in preterm birth, suggesting these cells contribute to fetal systemic immune activation. CONCLUSION: Our work reveals a fetal-specific program of protective immunity whose dysregulation is associated with fetal and neonatal inflammatory pathologies.

Presenting Symptoms in Men and Women Diagnosed With Myocardial Infarction Using Sex-Specific Criteria.

Background Sex-specific criteria are recommended for the diagnosis of myocardial infarction, but the impact of these on presenting characteristics is unknown. Methods and Results We evaluated patient-reported symptoms in 1941 patients (39% women) with suspected acute coronary syndrome attending the emergency department in a substudy of a prospective trial. Standardized criteria defined typical and atypical presentations based on pain nature, location, radiation, and additional symptoms. Diagnosis of myocardial infarction was adjudicated using a high-sensitivity cardiac troponin I assay with sex-specific thresholds (>16 ng/L women, >34 ng/L men). Patients identified who were missed by the contemporary assay with a uniform threshold (≥50 ng/L) were reclassified by this approach. Type 1 myocardial infarction was diagnosed in 16% (184/1185) of men and 12% (90/756) of women, with 9 (5%) men and 27 (30%) women reclassified using high-sensitivity cardiac troponin I and sex-specific thresholds. Chest pain was the presenting symptom in 91% (1081/1185) of men and 92% (698/756) of women. Typical symptoms were more common in women than in men with myocardial infarction (77% [69/90] versus 59% [109/184]; P=0.007), and differences were similar in those reclassified (74% [20/27] versus 44% [4/9]; P=0.22). The presence of ≥3 typical features was associated with a positive likelihood ratio for the diagnosis of myocardial infarction in women (positive likelihood ratio, 1.18; 95% CI, 1.03-1.31) but not in men (positive likelihood ratio 1.09; 95% CI, 0.96-1.24). Conclusions Typical symptoms are more common and have greater predictive value in women than in men with myocardial infarction whether or not they are diagnosed using sex-specific criteria. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier NCT01852123.