45 research outputs found

    Neighborhood sampling: how many streets must an auditor walk?

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    This study tested the representativeness of four street segment sampling protocols using the Pedestrian Environment Data Scan (PEDS) in eleven neighborhoods surrounding public housing developments in Houston, TX. The following four street segment sampling protocols were used (1) all segments, both residential and arterial, contained within the 400 meter radius buffer from the center point of the housing development (the core) were compared with all segments contained between the 400 meter radius buffer and the 800 meter radius buffer (the ring); all residential segments in the core were compared with (2) 75% (3) 50% and (4) 25% samples of randomly selected residential street segments in the core. Analyses were conducted on five key variables: sidewalk presence; ratings of attractiveness and safety for walking; connectivity; and number of traffic lanes. Some differences were found when comparing all street segments, both residential and arterial, in the core to the ring. Findings suggested that sampling 25% of residential street segments within the 400 m radius of a residence sufficiently represents the pedestrian built environment. Conclusions support more cost effective environmental data collection for physical activity research

    Small Molecules That Inhibit Tnf Signalling by Stabilising an Asymmetric Form of the Trimer

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    Tumour necrosis factor (TNF) is a cytokine belonging to a family of trimeric proteins; it has been shown to be a key mediator in autoimmune diseases such as rheumatoid arthritis and Crohn\u27s disease. While TNF is the target of several successful biologic drugs, attempts to design small molecule therapies directed to this cytokine have not led to approved products. Here we report the discovery of potent small molecule inhibitors of TNF that stabilise an asymmetrical form of the soluble TNF trimer, compromising signalling and inhibiting the functions of TNF in vitro and in vivo. This discovery paves the way for a class of small molecule drugs capable of modulating TNF function by stabilising a naturally sampled, receptor-incompetent conformation of TNF. Furthermore, this approach may prove to be a more general mechanism for inhibiting protein-protein interactions

    Autoimmune Neuromuscular Disorders in Childhood

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    Autoimmune neuromuscular disorders in childhood include Guillain-Barré syndrome and its variants, chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), juvenile myasthenia gravis (JMG), and juvenile dermatomyositis (JDM), along with other disorders rarely seen in childhood. In general, these diseases have not been studied as extensively as they have been in adults. Thus, treatment protocols for these diseases in pediatrics are often based on adult practice, but despite the similarities in disease processes, the most widely used treatments have different effects in children. For example, some of the side effects of chronic steroid use, including linear growth deceleration, bone demineralization, and chronic weight issues, are more consequential in children than in adults. Although steroids remain a cornerstone of therapy in JDM and are useful in many cases of CIDP and JMG, other immunomodulatory therapies with similar efficacy may be used more frequently in some children to avoid these long-term sequelae. Steroids are less expensive than most other therapies, but chronic steroid therapy in childhood may lead to significant and costly medical complications. Another example is plasma exchange. This treatment modality presents challenges in pediatrics, as younger children require central venous access for this therapy. However, in older children and adolescents, plasma exchange is often feasible via peripheral venous access, making this treatment more accessible than might be expected in this age group. Intravenous immunoglobulin also is beneficial in several of these disorders, but its high cost may present barriers to its use in the future. Newer steroid-sparing immunomodulatory agents, such as azathioprine, tacrolimus, mycophenolate mofetil, and rituximab, have not been studied extensively in children. They show promising results from case reports and retrospective cohort studies, but there is a need for comparative studies looking at their relative efficacy, tolerability, and long-term adverse effects (including secondary malignancy) in children

    Erratum to: Methods for evaluating medical tests and biomarkers

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    [This corrects the article DOI: 10.1186/s41512-016-0001-y.]

    Cerebellar Volume and Disease Staging in Parkinson's Disease: An ENIGMA-PD Study.

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    peer reviewed[en] BACKGROUND: Increasing evidence points to a pathophysiological role for the cerebellum in Parkinson's disease (PD). However, regional cerebellar changes associated with motor and non-motor functioning remain to be elucidated. OBJECTIVE: To quantify cross-sectional regional cerebellar lobule volumes using three dimensional T1-weighted anatomical brain magnetic resonance imaging from the global ENIGMA-PD working group. METHODS: Cerebellar parcellation was performed using a deep learning-based approach from 2487 people with PD and 1212 age and sex-matched controls across 22 sites. Linear mixed effects models compared total and regional cerebellar volume in people with PD at each Hoehn and Yahr (HY) disease stage, to an age- and sex- matched control group. Associations with motor symptom severity and Montreal Cognitive Assessment scores were investigated. RESULTS: Overall, people with PD had a regionally smaller posterior lobe (dmax  = -0.15). HY stage-specific analyses revealed a larger anterior lobule V bilaterally (dmax  = 0.28) in people with PD in HY stage 1 compared to controls. In contrast, smaller bilateral lobule VII volume in the posterior lobe was observed in HY stages 3, 4, and 5 (dmax  = -0.76), which was incrementally lower with higher disease stage. Within PD, cognitively impaired individuals had lower total cerebellar volume compared to cognitively normal individuals (d = -0.17). CONCLUSIONS: We provide evidence of a dissociation between anterior "motor" lobe and posterior "non-motor" lobe cerebellar regions in PD. Whereas less severe stages of the disease are associated with larger motor lobe regions, more severe stages of the disease are marked by smaller non-motor regions

    Evidence synthesis to inform model-based cost-effectiveness evaluations of diagnostic tests: a methodological systematic review of health technology assessments

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    Background: Evaluations of diagnostic tests are challenging because of the indirect nature of their impact on patient outcomes. Model-based health economic evaluations of tests allow different types of evidence from various sources to be incorporated and enable cost-effectiveness estimates to be made beyond the duration of available study data. To parameterize a health-economic model fully, all the ways a test impacts on patient health must be quantified, including but not limited to diagnostic test accuracy. Methods: We assessed all UK NIHR HTA reports published May 2009-July 2015. Reports were included if they evaluated a diagnostic test, included a model-based health economic evaluation and included a systematic review and meta-analysis of test accuracy. From each eligible report we extracted information on the following topics: 1) what evidence aside from test accuracy was searched for and synthesised, 2) which methods were used to synthesise test accuracy evidence and how did the results inform the economic model, 3) how/whether threshold effects were explored, 4) how the potential dependency between multiple tests in a pathway was accounted for, and 5) for evaluations of tests targeted at the primary care setting, how evidence from differing healthcare settings was incorporated. Results: The bivariate or HSROC model was implemented in 20/22 reports that met all inclusion criteria. Test accuracy data for health economic modelling was obtained from meta-analyses completely in four reports, partially in fourteen reports and not at all in four reports. Only 2/7 reports that used a quantitative test gave clear threshold recommendations. All 22 reports explored the effect of uncertainty in accuracy parameters but most of those that used multiple tests did not allow for dependence between test results. 7/22 tests were potentially suitable for primary care but the majority found limited evidence on test accuracy in primary care settings. Conclusions: The uptake of appropriate meta-analysis methods for synthesising evidence on diagnostic test accuracy in UK NIHR HTAs has improved in recent years. Future research should focus on other evidence requirements for cost-effectiveness assessment, threshold effects for quantitative tests and the impact of multiple diagnostic tests

    Erratum to: Methods for evaluating medical tests and biomarkers

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    [This corrects the article DOI: 10.1186/s41512-016-0001-y.]

    Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

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    IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

    The relative influence of urban form on a child's travel mode to school

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    Walking and bicycling to school has decreased in recent years, while private vehicle travel has increased. Policies and programs focusing on urban form improvements such as Safe Routes to School were created to address this mode shift and possible related children's health issues, despite minimal research showing the influence of urban form on children's travel and health. This research examined: (1) the influence of objectively measured urban form on travel mode to school and; (2) the magnitude of influence urban form and non-urban form factors have on children's travel behavior. The results of the analysis support the hypothesis that urban form is important but not the sole factor that influences school travel mode choice. Other factors may be equally important such as perceptions of neighborhood safety and traffic safety, household transportation options, and social/cultural norms. Odds ratios indicate that the magnitude of influence of these latter factors is greater than that of urban form; however, model improvement tests found that urban form contributed significantly to model fit. This research provides evidence that urban form is an influential factor in non-motorized travel behavior and therefore is a possible intervention to target through programs such as Safe Routes to School.
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