Climate warming shifts riverine macroinvertebrate communities to be more sensitive to chemical pollutants.

Freshwaters are highly threatened ecosystems that are vulnerable to chemical pollution and climate change. Freshwater taxa vary in their sensitivity to chemicals and changes in species composition can potentially affect the sensitivity of assemblages to chemical exposure. Here we explore the potential consequences of future climate change on the composition and sensitivity of freshwater macroinvertebrate assemblages to chemical stressors using the UK as a case study. Macroinvertebrate assemblages under end of century (2080-2100) and baseline (1980-2000) climate conditions were predicted for 608 UK sites for four climate scenarios corresponding to mean temperature changes of 1.28 to 3.78°C. Freshwater macroinvertebrate toxicity data were collated for 19 chemicals and the hierarchical species sensitivity distribution model was used to predict the sensitivity of untested taxa using relatedness within a Bayesian approach. All four future climate scenarios shifted assemblage compositions, increasing the prevalence of Mollusca, Crustacea and Oligochaeta species, and the insect taxa of Odonata, Chironomidae, and Baetidae species. Contrastingly, decreases were projected for Plecoptera, Ephemeroptera (except for Baetidae) and Coleoptera species. Shifts in taxonomic composition were associated with changes in the percentage of species at risk from chemical exposure. For the 3.78°C climate scenario, 76% of all assemblages became more sensitive to chemicals and for 18 of the 19 chemicals, the percentage of species at risk increased. Climate warming-induced increases in sensitivity were greatest for assemblages exposed to metals and were dependent on baseline assemblage composition, which varied spatially. Climate warming is predicted to result in changes in the use, environmental exposure and toxicity of chemicals. Here we show that, even in the absence of these climate-chemical interactions, shifts in species composition due to climate warming will increase chemical risk and that the impact of chemical pollution on freshwater macroinvertebrate biodiversity may double or quadruple by the end of the 21st century.

Complement-mediated thrombotic microangiopathy on a background of Alport syndrome: A case report.

Here we present a case of complement-mediated thrombotic microangiopathy (TMA) in a patient who has a background of Stage 5 chronic kidney disease secondary to Alport syndrome. We explain our approach to the diagnosis of TMA, especially the reliance on non-renal manifestations of TMA and the role of kidney biopsy given there was a background of advanced kidney impairment at baseline.

Estimating the causal effects of income on health: how researchers' definitions of "income" matter.

BACKGROUND: There is a well-established cross-sectional association between income and health, but estimates of the causal effects of income vary substantially. Different definitions of income may lead to substantially different empirical results, yet research is often framed as investigating "the effect of income" as if it were a single, easily definable construct. METHODS/RESULTS: The aim of this paper is to introduce a taxonomy for definitional and conceptual issues in studying individual- or household-level income for health research. We focus on (1) the definition of the income measure (earned and unearned; net, gross, and disposable; real and nominal; individual and household; relative and absolute income) and (2) the definition of the causal contrast (amount, functional form assumptions/transformations, direction, duration of change, and timing of exposure and follow-up). We illustrate the application of the taxonomy to four examples from the published literature. CONCLUSIONS: Quantified estimates of causal effects of income on health and wellbeing have crucial relevance for policymakers to anticipate the consequences of policies targeting the social determinants of health. However, much prior evidence has been limited by lack of clarity in distinguishing between different causal questions. The present framework can help researchers explicitly and precisely articulate income-related exposures and causal questions.

Improving social justice in observational studies: protocol for the development of a global and Indigenous STROBE-equity reporting guideline.

BACKGROUND: Addressing persistent and pervasive health inequities is a global moral imperative, which has been highlighted and magnified by the societal and health impacts of the COVID-19 pandemic. Observational studies can aid our understanding of the impact of health and structural oppression based on the intersection of gender, race, ethnicity, age and other factors, as they frequently collect this data. However, the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guideline, does not provide guidance related to reporting of health equity. The goal of this project is to develop a STROBE-Equity reporting guideline extension. METHODS: We assembled a diverse team across multiple domains, including gender, age, ethnicity, Indigenous background, disciplines, geographies, lived experience of health inequity and decision-making organizations. Using an inclusive, integrated knowledge translation approach, we will implement a five-phase plan which will include: (1) assessing the reporting of health equity in published observational studies, (2) seeking wide international feedback on items to improve reporting of health equity, (3) establishing consensus amongst knowledge users and researchers, (4) evaluating in partnership with Indigenous contributors the relevance to Indigenous peoples who have globally experienced the oppressive legacy of colonization, and (5) widely disseminating and seeking endorsement from relevant knowledge users. We will seek input from external collaborators using social media, mailing lists and other communication channels. DISCUSSION: Achieving global imperatives such as the Sustainable Development Goals (e.g., SDG 10 Reduced inequalities, SDG 3 Good health and wellbeing) requires advancing health equity in research. The implementation of the STROBE-Equity guidelines will enable a better awareness and understanding of health inequities through better reporting. We will broadly disseminate the reporting guideline with tools to enable adoption and use by journal editors, authors, and funding agencies, using diverse strategies tailored to specific audiences.

Implementation of a national smoke-free prison policy: an economic evaluation within the Tobacco in Prisons (TIPs) study.

OBJECTIVE: To determine the cost-effectiveness of a smoke-free prison policy in Scotland, through assessments of the trade-offs between costs (healthcare and non-healthcare-related expenditure) and outcomes (health and non-health-related non-monetary consequences) of implementing the policy. DESIGN: A health economic evaluation consisting of three analyses (cost-consequence, cost-effectiveness and cost-utility), from the perspectives of the healthcare payer, prison service, people in custody and operational staff, assessed the trade-offs between costs and outcomes. Costs associated with the implementation of the policy, healthcare resource use and personal spend on nicotine products were considered, alongside health and non-health outcomes. The cost-effectiveness of the policy was evaluated over 12-month and lifetime horizons (short term and long term). SETTING: Scotland's national prison estate. PARTICIPANTS: People in custody and operational prison staff. INTERVENTION: Implementation of a comprehensive (indoor and outdoor) smoke-free policy. MAIN OUTCOME MEASURES: Concentration of secondhand smoke, health-related quality of life (health utilities and quality-adjusted life-years (QALY)) and various non-health outcomes (eg, incidents of assaults and fires). RESULTS: The short-term analyses suggest cost savings for people in custody and staff, improvements in concentration of secondhand smoke, with no consistent direction of change across other outcomes. The long-term analysis demonstrated that implementing smoke-free policy was cost-effective over a lifetime for people in custody and staff, with approximate cost savings of £28 000 and £450, respectively, and improvement in health-related quality of life of 0.971 QALYs and 0.262, respectively. CONCLUSION: Implementing a smoke-free prison policy is cost-effective over the short term and long term for people in custody and staff.

Exploring the health and sociodemographic characteristics of people seeking advice with claiming universal credit: a cross-sectional analysis of UK citizens advice data, 2017-2021.

BACKGROUND: The UK Department for Work and Pensions (DWP) administers Universal Credit (UC) - the main UK benefit for people in- and out-of-work. UC is being rolled out nationally from 2013 to 2024. Citizens Advice (CA) is an independent charity that provides advice and support to people making a claim for UC. The aim of this study is to understand who is seeking advice from CA when making a UC claim and how the types of people seeking advice are changing as the rollout of UC continues. METHODS: Co-developed with Citizens Advice Newcastle and Citizens Advice Northumberland we performed longitudinal analysis of national data from Citizens Advice for England and Wales on the health (mental health and limiting long term conditions) and socio-demographic of 1,003,411 observations for people seeking advice with claiming UC over four financial years (2017/18 to 2020/21). We summarised population characteristics and estimated the differences between the four financial years using population-weighted t-tests. Findings were discussed with three people with lived experience of seeking advice to claim UC to help frame our interpretation and policy recommendations. RESULTS: When comparing 2017/18 to 2018/19, there was a significantly higher proportion of people with limiting long term conditions seeking advice with claiming UC than those without (+ 2.40%, 95%CI: 1.31-3.50%). However, as the rollout continued between 2018/29 and 2019/20 (-6.75%, 95%CI: -9.62%--3.88%) and between 2019/20 and 2020/21 (-2.09%, 95%CI: -2.54%--1.64%), there were significantly higher proportions of those without a limiting long term condition seeking advice than with. When comparing 2018/19 to 2019/20 and 2019/20 to 2020/21, there was a significant increase in the proportion of self-employed compared to unemployed people seeking advice with claiming UC (5.64%, 95%CI: 3.79-7.49%) and (2.26%, 95%CI: 1.29-3.23%) respectively. CONCLUSION: As the rollout for UC continues, it is important to understand how changes in eligibility for UC may impact on those who need help with applying for UC. Ensuring that the advice process and application process is responsive to a range of people with different needs can help to reduce the likelihood that the process of claiming UC will exacerbate health inequalities.

Understanding inequalities in mental health by family structure during COVID-19 lockdowns: evidence from the UK Household Longitudinal Study.

PURPOSE: The COVID-19 pandemic increased psychiatric distress and impacts differed by family structure. We aimed to identify mechanisms contributing to these inequalities. METHODS: Survey data were from the UK Household Longitudinal Study. Psychiatric distress (GHQ-12) was measured in April 2020 (first UK lockdown; n = 10,516), and January 2021 (lockdown re-introduced following eased restrictions; n = 6,893). Pre-lockdown family structure comprised partner status and presence of children (< 16 years). Mediating mechanisms included: active employment, financial strain, childcare/home-schooling, caring, and loneliness. Monte Carlo g-computation simulations were used to adjust for confounding and estimate total effects and decompositions into: controlled direct effects (effects if the mediator was absent), and portions eliminated (PE; representing differential exposure and vulnerability to the mediator). RESULTS: In January 2021, after adjustment, we estimated increased risk of distress among couples with children compared to couples with no children (RR: 1.48; 95% CI 1.15-1.82), largely because of childcare/home-schooling (PE RR: 1.32; 95% CI 1.00-1.64). Single respondents without children also had increased risk of distress compared to couples with no children (RR: 1.55; 95% CI 1.27-1.83), and the largest PE was for loneliness (RR: 1.16; 95% CI 1.05-1.27), though financial strain contributed (RR: 1.05; 95% CI 0.99-1.12). Single parents demonstrated the highest levels of distress, but confounder adjustment suggested uncertain effects with wide confidence intervals. Findings were similar in April 2020 and when stratified by sex. CONCLUSION: Access to childcare/schooling, financial security and social connection are important mechanisms that need addressing to avoid widening mental health inequalities during public health crises.

The effect of school summer holidays on inequalities in children and young people's mental health and cognitive ability in the UK using data from the millennium cohort study.

BACKGROUND: Summer learning loss has been the subject of longstanding concern among researchers, the public and policy makers. The aim of the current research was to investigate inequality changes in children's mental health and cognitive ability across the summer holidays. METHODS: We conducted linear and logistic regression analysis of mental health (borderline-abnormal total difficulty and prosocial scores on the strengths and difficulties questionnaire (SDQ)) and verbal cognitive ability (reading, verbal reasoning or vocabulary) at ages 7, 11 and 14, comparing UK Millennium Cohort Study members who were interviewed before and after the school summer holidays. Inequalities were assessed by including interaction terms in the outcome models between a discrete binary variable with values representing time periods and maternal academic qualifications. Coefficients of the interaction terms were interpreted as changes from the pre- to post-holiday period in the extent of inequality in the outcome between participants whose mothers had high or low educational qualifications. Separate models were fitted for each age group and outcome. We used inverse probability weights to allow for differences in the characteristics of cohort members assessed before and after the summer holidays. RESULTS: Mental health (borderline/abnormal SDQ total and prosocial scores) at ages 7 and 14 worsened and verbal cognitive ability scores at age 7 were lower among those surveyed after the summer holidays. Mental health inequalities were larger after the holidays at age 7 ([OR = 1.4; 95%CI (0.6, 3.2) and 14: [OR = 1.5; 95%CI (0.7, 3.2)], but changed little at age 11 (OR = 0.9; 95%CI (0.4, 2.6)]. There were differences in pro-social behaviours among those surveyed before/after the school holidays at age 14 [OR = 1.2; 95%CI (0.5, 3.5)] but not at age 7 or 11. There was little change in inequalities in verbal cognitive ability scores over the school holidays [Age 7: b = 1.3; 95%CI (- 3.3, 6.0); Age 11: b = - 0.7; 95%CI (- 4.3, 2.8); Age 14: b = - 0.3; 95%CI (- 1.0, 0.4)]. CONCLUSION: We found inequalities in mental health and cognitive ability according to maternal education, and some evidence or worsening mental health and mental health inequalities across school summer holidays. We found little evidence of widening inequalities in verbal cognitive ability. Widespread school closures during the COVID-19 restrictions have prompted concerns that prolonged closures may widen health and educational inequalities. Management of school closures should focus on preventing or mitigating inequalities that may arise from differences in the support for mental health and learning provided during closures by schools serving more or less disadvantaged children.

Prediction modeling-part 2: using machine learning strategies to improve transplantation outcomes.

Kidney transplant recipients and transplant physicians face important clinical questions where machine learning methods may help improve the decision-making process. This mini-review explores potential applications of machine learning methods to key stages of a kidney transplant recipient's journey, from initial waitlisting and donor selection, to personalization of immunosuppression and prediction of post-transplantation events. Both unsupervised and supervised machine learning methods are presented, including k-means clustering, principal components analysis, k-nearest neighbors, and random forests. The various challenges of these approaches are also discussed.

Regression Discontinuity Designs in Health: A Systematic Review.

BACKGROUND: Regression discontinuity designs are non-randomized study designs that permit strong causal inference with relatively weak assumptions. Interest in these designs is growing but there is limited knowledge of the extent of their application in health. We aimed to conduct a comprehensive systematic review of the use of regression discontinuity designs in health research. METHODS: We included studies that used regression discontinuity designs to investigate the physical or mental health outcomes of any interventions or exposures in any populations. We searched 32 health, social science, and gray literature databases (1 January 1960 to 1 January 2019). We critically appraised studies using eight criteria adapted from the What Works Clearinghouse Standards for regression discontinuity designs. We conducted a narrative synthesis, analyzing the forcing variables and threshold rules used in each study. RESULTS: The literature search retrieved 7658 records, producing 325 studies that met the inclusion criteria. A broad range of health topics was represented. The forcing variables used to implement the design were age, socioeconomic measures, date or time of exposure or implementation, environmental measures such as air quality, geographic location, and clinical measures that act as a threshold for treatment. Twelve percent of the studies fully met the eight quality appraisal criteria. Fifteen percent of studies reported a prespecified primary outcome or study protocol. CONCLUSIONS: This systematic review demonstrates that regression discontinuity designs have been widely applied in health research and could be used more widely still. Shortcomings in study quality and reporting suggest that the potential benefits of this method have not yet been fully realized.

Conceptualising natural and quasi experiments in public health.

BACKGROUND: Natural or quasi experiments are appealing for public health research because they enable the evaluation of events or interventions that are difficult or impossible to manipulate experimentally, such as many policy and health system reforms. However, there remains ambiguity in the literature about their definition and how they differ from randomized controlled experiments and from other observational designs. We conceptualise natural experiments in the context of public health evaluations and align the study design to the Target Trial Framework. METHODS: A literature search was conducted, and key methodological papers were used to develop this work. Peer-reviewed papers were supplemented by grey literature. RESULTS: Natural experiment studies (NES) combine features of experiments and non-experiments. They differ from planned experiments, such as randomized controlled trials, in that exposure allocation is not controlled by researchers. They differ from other observational designs in that they evaluate the impact of events or process that leads to differences in exposure. As a result they are, in theory, less susceptible to bias than other observational study designs. Importantly, causal inference relies heavily on the assumption that exposure allocation can be considered 'as-if randomized'. The target trial framework provides a systematic basis for evaluating this assumption and the other design elements that underpin the causal claims that can be made from NES. CONCLUSIONS: NES should be considered a type of study design rather than a set of tools for analyses of non-randomized interventions. Alignment of NES to the Target Trial framework will clarify the strength of evidence underpinning claims about the effectiveness of public health interventions.

The long-term health effects of attending a selective school: a natural experiment.

BACKGROUND: Education is widely associated with better physical and mental health, but isolating its causal effect is difficult because education is linked with many socioeconomic advantages. One way to isolate education's effect is to consider environments where similar students are assigned to different educational experiences based on objective criteria. Here we measure the health effects of assignment to selective schooling based on test score, a widely debated educational policy. METHODS: In 1960s Britain, children were assigned to secondary schools via a test taken at age 11. We used regression discontinuity analysis to measure health differences in 5039 people who were separated into selective and non-selective schools this way. We measured selective schooling's effect on six outcomes: mid-life self-reports of health, mental health, and life limitation due to health, as well as chronic disease burden derived from hospital records in mid-life and later life, and the likelihood of dying prematurely. The analysis plan was accepted as a registered report while we were blind to the health outcome data. RESULTS: Effect estimates for selective schooling were as follows: self-reported health, 0.1 worse on a 4-point scale (95%CI - 0.2 to 0); mental health, 0.2 worse on a 16-point scale (- 0.5 to 0.1); likelihood of life limitation due to health, 5 percentage points higher (- 1 to 10); mid-life chronic disease diagnoses, 3 fewer/100 people (- 9 to + 4); late-life chronic disease diagnoses, 9 more/100 people (- 3 to + 20); and risk of dying before age 60, no difference (- 2 to 3 percentage points). Extensive sensitivity analyses gave estimates consistent with these results. In summary, effects ranged from 0.10-0.15 standard deviations worse for self-reported health, and from 0.02 standard deviations better to 0.07 worse for records-derived health. However, they were too imprecise to allow the conclusion that selective schooling was detrimental. CONCLUSIONS: We found that people who attended selective secondary school had more advantaged economic backgrounds, higher IQs, higher likelihood of getting a university degree, and better health. However, we did not find that selective schooling itself improved health. This lack of a positive influence of selective secondary schooling on health was consistent despite varying a wide range of model assumptions.

Impact of UK Tobacco Control Policies on Inequalities in Youth Smoking Uptake: A Natural Experiment Study.

INTRODUCTION: UK countries implemented smoke-free public places legislation and increased the legal age for tobacco purchase from 16 to 18 years between 2006 and 2008. We evaluated the immediate and long-term impacts of these UK policy changes on youth smoking uptake and inequalities therein. AIMS AND METHODS: We studied 74 960 person-years of longitudinal data from 14 992 youths (aged 11-15 years) in annual UK household surveys between 1994 and 2016. Discrete-time event history analyses examined whether changes in rates of youth smoking transitions (initiation, experimentation, and escalation to daily smoking or quitting) or their inequalities (by parental education) were associated with policy implementation. Parallel analyses examined smoke-free legislation and the change in legal age. We interpret the results as a combined effect of the two pieces of legislation as their implementation dates were too close to identify separate effects. Models were adjusted for sex, age, UK country, historical year, tobacco taxation, and e-cigarette prevalence, with multiple imputation for missing data. RESULTS: For both policies, smoking initiation reduced following implementation (change in legal age odds ratio [OR]: 0.67; 95% confidence interval [CI]: 0.55 to 0.81; smoke-free legislation OR: 0.68; 95% CI: 0.56 to 0.82), while inequalities in initiation narrowed over subsequent years. The legal age change was associated with annual increases in progression from initiation to occasional smoking (OR: 1.26; 95% CI: 1.07 to 1.50) and a reduction in quitting following implementation (OR: 0.57; 95% CI: 0.35 to 0.94). Similar effects were observed for smoke-free legislation but CIs overlapped the null. CONCLUSIONS: Policies such as these may be highly effective in preventing and reducing socioeconomic inequalities in youth smoking initiation. IMPLICATIONS: UK implementation of smoke-free legislation and an increase in the legal age for tobacco purchase from 16 to 18 years were associated with an immediate reduction in smoking initiation and a narrowing of inequalities in initiation over subsequent years. While the policies were associated with reductions in the initiation, progression to occasional smoking increased and quitting decreased following the legislation.

Making the most of natural experiments: What can studies of the withdrawal of public health interventions offer?

Many interventions that may have large impacts on health and health inequalities, such as social and public health policies and health system reforms, are not amenable to evaluation using randomised controlled trials. The United Kingdom Medical Research Council's guidance on the evaluation of natural experiments draws attention to the need for ingenuity to identify interventions which can be robustly studied as they occur, and without experimental manipulation. Studies of intervention withdrawal may usefully widen the range of interventions that can be evaluated, allowing some interventions and policies, such as those that have developed piecemeal over a long period, to be evaluated for the first time. In particular, sudden removal may allow a more robust assessment of an intervention's long-term impact by minimising 'learning effects'. Interpreting changes that follow withdrawal as evidence of the impact of an intervention assumes that the effect is reversible and this assumption must be carefully justified. Otherwise, withdrawal-based studies suffer similar threats to validity as intervention studies. These threats should be addressed using recognised approaches, including appropriate choice of comparators, detailed understanding of the change processes at work, careful specification of research questions, and the use of falsification tests and other methods for strengthening causal attribution. Evaluating intervention withdrawal provides opportunities to answer important questions about effectiveness of population health interventions, and to study the social determinants of health. Researchers, policymakers and practitioners should be alert to the opportunities provided by the withdrawal of interventions, but also aware of the pitfalls.

The impact of participatory budgeting on health and wellbeing: a scoping review of evaluations.

BACKGROUND: Participatory budgeting (PB), citizens deliberating among themselves and with officials to decide how to allocate funds for public goods, has been increasingly implemented across Europe and worldwide. While PB is recommended as good practice by the World Bank and the United Nations, with potential to improve health and wellbeing, it is unclear what evaluations have been conducted on the impact of PB on health and wellbeing. METHODS: For this scoping review, we searched 21 databases with no restrictions on publication date or language. The search term 'participatory budget' was used as the relevant global label for the intervention of interest. Studies were included if they reported original analysis of health, social, political, or economic and budgetary outcomes of PB. We examined the study design, analysis, outcomes and location of included articles. Findings are reported narratively. RESULTS: From 1458 identified references, 37 studies were included. The majority of evaluations (n = 24) were of PB in South America, seven were in Europe. Most evaluations were case studies (n = 23) conducting ethnography and surveys, focussing on political outcomes such as participation in PB or impacts on political activities. All of the quantitative observational studies analysing population level data, except one in Russia, were conducted in South America. CONCLUSION: Despite increasing interest in PB, evaluations applying robust methods to analyse health and wellbeing outcomes are scarce, particularly beyond Brazil. Therefore, implementation of PB schemes should be accompanied by rigorous qualitative and quantitative evaluation to identify impacts and the processes by which they are realised.

Natural Experiments: An Overview of Methods, Approaches, and Contributions to Public Health Intervention Research.

Population health interventions are essential to reduce health inequalities and tackle other public health priorities, but they are not always amenable to experimental manipulation. Natural experiment (NE) approaches are attracting growing interest as a way of providing evidence in such circumstances. One key challenge in evaluating NEs is selective exposure to the intervention. Studies should be based on a clear theoretical understanding of the processes that determine exposure. Even if the observed effects are large and rapidly follow implementation, confidence in attributing these effects to the intervention can be improved by carefully considering alternative explanations. Causal inference can be strengthened by including additional design features alongside the principal method of effect estimation. NE studies often rely on existing (including routinely collected) data. Investment in such data sources and the infrastructure for linking exposure and outcome data is essential if the potential for such studies to inform decision making is to be realized.

Adipose stromal cells differentiate along a smooth muscle lineage pathway upon endothelial cell contact via induction of activin A.

RATIONALE: Adipose stromal cells (ASC) are therapeutically potent progenitor cells that possess properties of pericytes. In vivo, ASC in combination with endothelial cells (EC) establish functional multilayer vessels, in which ASC form the outer vessel layer and differentiate into mural cells. OBJECTIVE: To identify factors responsible for ASC differentiation toward the smooth muscle cell phenotype via interaction with EC. METHODS AND RESULTS: An in vitro model of EC cocultivation with ASC was used, in which EC organized into vascular cords, accompanied by ASC migration toward EC and upregulation of α-smooth muscle actin, SM22α, and calponin expression. Conditioned media from EC-ASC, but not from EC cultures, induced smooth muscle cell protein expression in ASC monocultures. EC-ASC cocultivation induced marked accumulation of activin A but not transforming growth factor-ß1 in conditioned media. This was attributed to induction of activin A expression in ASC on contact with EC. Although transforming growth factor-ß and activin A were individually sufficient to initiate expression of smooth muscle cell antigens in ASC, only activin A IgG blocked the effect of EC-ASC conditioned media. Although transforming growth factor-ß was able to induce activin A expression in ASC, in cocultures this induction was transforming growth factor-ß independent. In EC-ASC cocultures, activin A IgG or ALK4/5/7 receptor inhibitors blocked expression of α-smooth muscle actin in ASC in the absence of direct EC-cord contact, but this inhibition was circumvented in ASC by direct EC contact. CONCLUSIONS: EC initiate a smooth muscle cell differentiation program in adjacent ASC and propagate this differentiation in distant ASC by induction of activin A expression.

Closing the tau loop: the missing tau mutation.

Frontotemporal lobar degeneration comprises a group of disorders characterized by behavioural, executive, language impairment and sometimes features of parkinsonism and motor neuron disease. In 1994 we described an Irish-American family with frontotemporal dementia linked to chromosome 17 associated with extensive tau pathology. We named this disinhibition-dementia-parkinsonism-amyotrophy complex. We subsequently identified mutations in the MAPT gene. Eleven MAPT gene splice site stem loop mutations were identified over time except for 5' splice site of exon 10. We recently identified another Irish family with autosomal dominant early amnesia and behavioural change or parkinsonism associated with the 'missing' +15 mutation at the intronic boundary of exon 10. We performed a clinical, neuropsychological and neuroimaging study on the proband and four siblings, including two affected siblings. We sequenced MAPT and performed segregation analysis. We looked for a biological effect of the tau variant by performing real-time polymerase chain reaction analysis of RNA extracted from human embryonic kidney cells transfected with exon trapping constructs. We found a c.915+15A>C exon 10/intron 10 stem loop mutation in all affected subjects but not in the unaffected. The c.915+15A>C variant caused a shift in tau splicing pattern to a predominantly exon 10+ pattern presumably resulting in predominant 4 repeat tau and little 3 repeat tau. This strongly suggests that the c.915+15A>C variant is a mutation and that it causes frontotemporal dementia linked to chromosome 17 in this pedigree by shifting tau transcription and translation to +4 repeat tau. Tau (MAPT) screening should be considered in families where amnesia or atypical parkinsonism coexists with behavioural disturbance early in the disease process. We describe the final missing stem loop tau mutation predicted 15 years ago. Mutations have now been identified at all predicted sites within the 'stem' when the stem-loop model was first proposed and no mutations have been found within the 'loop' region as expected. Therefore we 'close the tau loop' having 'opened the loop' 21 years ago.

Electronic Spectra of the Tetraphenylcyclobutadienecyclopentadienylnickel(II) Cation and Radical.

Properties of the tetraphenylcyclobutadienecyclopentadienylnickel(II) cation 1 and its tetra-o-fluoro derivative 1a have been measured and calculated. The B3LYP/TZP optimized geometry of the free cation 1 agrees with a single-crystal X-ray diffraction structure except that in the crystal one of the phenyl substituents is strongly twisted to permit a close-packing interaction of two of its hydrogens with a nearby BF4(-) anion. The low-energy parts of the solution electronic absorption and magnetic circular dichroism (MCD) spectra of 1 and 1a have been interpreted by comparison with TD-DFT (B3LYP/TZP) results. Reduction or pulse radiolysis lead to a neutral 19-electron radical, whose visible absorption and MCD spectra have been recorded and interpreted as well. The reduction is facilitated by ∼0.1 V upon going from 1 to 1a. Unsuccessful attempts to prepare several other aryl substituted derivatives of 1 by the classical synthetic route are described in the Supporting Information .