Discovery of a new class of cell-penetrating peptides by novel phage display platform.

The primary hurdles for small interference RNA (siRNA) in clinical use are targeted and cytosolic delivery. To overcome both challenges, we have established a novel platform based on phage display, called NNJA. In this approach, a lysosomal cathepsin substrate is engineered within the flexible loops of PIII, that is displaying a unique random sequence at its N-terminus. NNJA library selection targeting cell-expressed targets should yield specific peptides localized in the cytoplasm. That is because phage internalization and subsequent localization to lysosome, upon peptide binding to the cell expressed target, will result in cleavage of PIII, rendering phage non-infective. Such phage will be eliminated from the selected pool and only peptide-phage that escapes lysosomes will advance to the next round. Proof of concept studies with the NNJA library demonstrated cytosolic localization of selected peptide-phage and peptide-siRNA, confirmed through confocal microscopy. More importantly, conjugation of siHPRT to monomeric or multimeric NNJA peptides resulted in significant reduction in HPRT mRNA in various cell types without significant cytotoxicity. Sequence similarity and clustering analysis from NGS dataset provide insights into sequence composition facilitating cell penetration. NNJA platform offers a highly efficient peptide discovery engine for targeted delivery of oligonucleotides to cytosol.

Midsubstance Vastus Lateralis Tear in the Young Athlete: Case Report and a Review of the Literature.

ABSTRACT: Vastus lateralis tendon tear is an infrequent cause of lateral knee pain. Previously reported cases have described acute injury in middle-aged men after eccentric quadriceps contraction. This case report discusses 2 adolescent patients with longitudinal midsubstance tears diagnosed with MRI and dynamic ultrasound and treated successfully with operative intervention.

Failure Rates After Anterior Cruciate Ligament Repair With Suture Tape Augmentation in an Active-Duty Military Population.

Background: Anterior cruciate ligament (ACL) repair had previously been considered the standard of care for a ruptured ACL; however, ACL reconstruction has became the standard of care because of poor midterm outcomes after ACL repair. Recently, studies have suggested that the treatment paradigm should shift back to ACL repair. Purpose/Hypothesis: The purpose of this study was to evaluate the outcomes of ACL repair augmented with suture tape in a high-demand military population. We hypothesized that for proximal ACL avulsions, ACL repair with suture tape augmentation would lead to acceptable failure rates, satisfactory knee stability, excellent functional outcomes, and high rates of return to preinjury activity levels. Study Design: Case series; Level of evidence, 2. Methods: Patients who were treated with ACL repair by a single surgeon between March 2017 and June 2019 and who had a minimum of 2 years of follow-up were included. Intraoperatively, all patients first underwent an arthroscopic examination. If an ACL avulsion of the proximal insertion with adequate remaining tissue was visualized, then ACL repair was performed. The primary outcome assessed was ACL repair failure, defined as reruptures or clinical instability requiring revision to ACL reconstruction. Analysis of the risk factors for ACL repair failure was conducted, with age at surgery, sex, body mass index, level of competition, and tobacco use evaluated. Results: Included were 46 patients (32 male and 14 female; mean age, 28.3 ± 8.4 years) who underwent ACL repair with suture tape augmentation. There were 12 cases of failure (26.1%; 8 male and 4 female). The mean time from injury to surgery in the failure group was 164.1 ± 59.4 days compared to 107.3 ± 98.0 days in the nonfailure group (P = .02). According to multivariate regression analysis, patients aged ≤17 and ≥35 years, elite/competitive/operational patients, and current smokers had a higher chance of ACL repair failure. The mean time to pass a military physical fitness test was 5.0 months. There were no complications other than ACL repair failure. Conclusion: Primary arthroscopic ACL repair with suture tape augmentation resulted in unacceptably high failure rates at a minimum of 2 years of follow-up in a highly active military population. Age ≤17 and ≥35 years, elite level of competition, time from injury to surgery, and active tobacco use were independent risk factors for ACL repair failure.

Surgical treatment of shoulder instability in active-duty service members with subcritical glenoid bone loss: Bankart vs. Latarjet.

INTRODUCTION: Subcritical bone loss has been identified as a risk factor for potentially inferior outcomes following typical arthroscopic soft tissue repair. One alternative that has been presented as an option for patients with bone loss is the Latarjet, an ipsilateral coracoid transfer to the anteroinferior glenoid. The purpose of this study is to compare the outcomes between the arthroscopic Bankart repair and the open Latarjet for the treatment of anterior shoulder instability in patients with subcritical bone loss. We hypothesize that the open Latarjet will provide higher patient-reported outcome measure scores and lower rates of dislocation. METHODS: A retrospective cohort comparison of patients with anterior glenohumeral instability procedures was performed. Inclusion criteria included symptomatic anterior shoulder instability, subcritical glenoid bone loss (13.5%-24%), surgical treatment with arthroscopic Bankart repair or open Latarjet, and minimum follow-up of 2 years. Outcomes included recurrent instability (defined as postoperative dislocation or subjective subluxation), permanent physical restrictions, Western Ontario Shoulder Index (WOSI), and Single Assessment Numeric Evaluation (SANE) scores. RESULTS: Forty-seven patients were included, 25 of whom underwent an arthroscopic Bankart repair and 23 patients an open Latarjet. The average bone loss was 17.8% and 19.3%, respectively. Overall, 8 patients experienced recurrent instability, 6 in the arthroscopic Bankart group and 2 in the open Latarjet group (P = .162). The average postoperative SANE score for arthroscopic Bankart group was 48% and for the open Latarjet group, 84% (P < .001). The average postoperative WOSI score for the arthroscopic Bankart group was 53.6% and for the open Latarjet group, 67.9% (P = .069). There were significantly more patients placed on permanent physical restrictions in the arthroscopic Bankart repair group (16) compared with open Latarjet (3) (P < .001). CONCLUSION: In patients with subcritical glenoid bone loss (defined as 13.5%-24%), patients treated with an open Latarjet have insignificantly higher SANE and WOSI scores and lower permanent physical restrictions than patients treated with an arthroscopic Bankart repair. We found no statistically significant difference in recurrent instability rates between the open Latarjet and arthroscopic Bankart repair (P = .162).

Proinflammatory reaction to a bisphosphonate infusion in a patient with a reverse shoulder replacement and literature review.

Bisphosphonates are the first-line pharmacological treatment for osteoporosis due to their efficacy and low rate of self-limited adverse effects. Challenges in adherence to oral treatment has spurred the development of third-generation bisphosphonates that only require single annual infusion due to high potency and binding efficacy. The authors report the case of a woman in her 70s who presented with postoperative shoulder pain after zoledronic acid infusion. Diagnostic work-up revealed stable prosthesis with no signs of fracture, loosening or infection. Administration of oral steroids resulted in resolution of pain and return to baseline function. Acute postoperative joint pain attributed to bisphosphonate infusion has not been previously described in the literature. This case report and literature review suggests consideration of adverse inflammatory reaction due to bisphosphonate infusion in the setting of a patient presenting with joint replacement and acute exacerbation of pain without clear aetiology.

Quantitative Measurement of Cytosolic and Nuclear Penetration of Oligonucleotide Therapeutics.

A major obstacle in the development of effective oligonucleotide therapeutics is a lack of understanding about their cytosolic and nuclear penetration. To address this problem, we have applied the chloroalkane penetration assay (CAPA) to oligonucleotide therapeutics. CAPA was used to quantitate cytosolic delivery of antisense oligonucleotides (ASOs) and siRNAs and to explore the effects of a wide variety of commonly used chemical modifications and their patterning. We evaluated potential artifacts by exploring the effects of serum, comparing activity data and CAPA data, and assessing the impact of the chloroalkane tag and its linker chemistry. We also used viral transduction to expand CAPA to the nuclear compartment in epithelial and neuronal cell lines. Using this enhanced method, we measured a 48-h time course of nuclear penetration for a panel of chemically diverse modified RNAs. Moving forward, CAPA will be a useful tool for deconvoluting the complex processes of endosomal uptake, escape into the cytosol, and subcellular trafficking of oligonucleotide therapeutics in therapeutically relevant cell types.

Surgical treatment of anterior shoulder instability with glenoid bone loss with the Latarjet procedure in active-duty military service members.

INTRODUCTION: The arthroscopic Bankart repair in the setting of glenoid bone loss has high rates of failure. In patients with anterior glenoid bone loss, the Latarjet provides glenohumeral stability through restoration of the glenoid bone, the conjoint tendon acting as a sling on the subscapularis, and anterior capsulolabral repair. Active-duty military personnel are at high risk for glenohumeral instability and have been equated to the contact athlete; most are young, male, and engage in contact sports. The purpose of this study is to assess the return to full-duty rates in active-duty military personnel following the Latarjet for anterior glenohumeral instability with glenoid bone loss. METHODS: A retrospective review of all glenohumeral instability procedures were reviewed at a tertiary training hospital from June 2014 to June 2019. The patient population consisted of active-duty military personnel with glenoid bone loss and anterior glenohumeral instability, who were treated with a Latarjet. The primary outcome was return to full-duty status. RESULTS: There were 50 patients identified for the study. Four patients were lost to follow-up, leaving 46 of 50 patients (92.0%) eligible for this study. The average age at the time of the index procedure was 23.1 years. The average percentage bone loss was 18.4%. Forty-one patients (89.1%) were able to return to full-duty status. Four patients (8.7%) sustained a recurrent dislocation following the Latarjet; all 4 dislocations occurred during a combat deployment. Four patients (8.7%) reported episodes of subluxation without dislocation. Forty-one patients (89.1%) reported that their shoulders felt stable, and we found an average return to full duty at 5.3 months CONCLUSION: In our active-duty military cohort, we found an 8.7% rate of recurrent instability after a Latarjet procedure, and 41 patients (89.1%) were able to return to full-duty status. In conclusion, the Latarjet procedure in the active-duty military population with anterior glenoid bone loss resulted in a high rate of return to duty, excellent functional outcomes, low rate of recurrent instability, and a low overall complication rate.

Bilateral multipartite patellae avulsions associated with a unilateral quadriceps tendon rupture.

Multipartite (or bipartite) patella is a developmental anomaly that occurs in 2%-6% of individuals. In 50%, the variant is bilateral. Multipartite patella is usually an asymptomatic condition. Quadriceps tendon rupture is also a rare entity occurring mostly in men aged >40 years and usually results from an acute eccentric quadriceps contracture. The authors present a case of a patient with bilateral multipartite patellae that sustained bilateral multipartite avulsions as well as an associated unilateral quadriceps tendon rupture. This constellation of injuries has never been reported in the literature. The patient was treated with excision of the multipartite patella fragments and quadriceps tendon repair on the side with the extensor mechanism disruption. He was treated non-operatively for the contralateral lower extremity multipartite patella avulsion. This report, along with a thorough review of the literature, serves to demonstrate the clinical and radiographic characteristics of this unusual injury.

The eIF2 kinase GCN2 directs keratinocyte collective cell migration during wound healing via coordination of reactive oxygen species and amino acids.

Healing of cutaneous wounds requires the collective migration of epithelial keratinocytes to seal the wound bed from the environment. However, the signaling events that coordinate this collective migration are unclear. In this report, we address the role of phosphorylation of eukaryotic initiation factor 2 (eIF2) and attendant gene expression during wound healing. Wounding of human keratinocyte monolayers in vitro led to the rapid activation of the eIF2 kinase GCN2. We determined that deletion or pharmacological inhibition of GCN2 significantly delayed collective cell migration and wound closure. Global transcriptomic, biochemical, and cellular analyses indicated that GCN2 is necessary for maintenance of intracellular free amino acids, particularly cysteine, as well as coordination of RAC1-GTP-driven reactive oxygen species (ROS) generation, lamellipodia formation, and focal adhesion dynamics following keratinocyte wounding. In vivo experiments using mice deficient for GCN2 validated the role of the eIF2 kinase during wound healing in intact skin. These results indicate that GCN2 is critical for appropriate induction of collective cell migration and plays a critical role in coordinating the re-epithelialization of cutaneous wounds.

Modified UCN2 Peptide Acts as an Insulin Sensitizer in Skeletal Muscle of Obese Mice.

The neuropeptide urocortin 2 (UCN2) and its receptor corticotropin-releasing hormone receptor 2 (CRHR2) are highly expressed in skeletal muscle and play a role in regulating energy balance and glucose metabolism. We investigated a modified UCN2 peptide as a potential therapeutic agent for the treatment of obesity and insulin resistance, with a specific focus on skeletal muscle. High-fat-fed mice (C57BL/6J) were injected daily with a PEGylated UCN2 peptide (compound A) at 0.3 mg/kg subcutaneously for 14 days. Compound A reduced body weight, food intake, whole-body fat mass, and intramuscular triglycerides compared with vehicle-treated controls. Furthermore, whole-body glucose tolerance was improved by compound A treatment, with increased insulin-stimulated Akt phosphorylation at Ser473 and Thr308 in skeletal muscle, concomitant with increased glucose transport into extensor digitorum longus and gastrocnemius muscle. Mechanistically, this is linked to a direct effect on skeletal muscle because ex vivo exposure of soleus muscle from chow-fed lean mice to compound A increased glucose transport and insulin signaling. Moreover, exposure of GLUT4-Myc-labeled L6 myoblasts to compound A increased GLUT4 trafficking. Our results demonstrate that modified UCN2 peptides may be efficacious in the treatment of type 2 diabetes by acting as an insulin sensitizer in skeletal muscle.

Neighborhood Built and Social Environments and Change in Weight Status over the Summer in Low-Income Elementary School Children.

Neighborhoods can provide opportunities for children to maintain a healthy weight or encourage unhealthy weight gain. Which neighborhood characteristics matter most remains poorly understood. We investigated links between neighborhood characteristics and weight change over the summer in children from 12 elementary schools with a high proportion of children from low-income families, in a mid-sized city in the US South. Mixed models and objective measures of height and weight were used. Study participants were 2770 children (average age 8.3, range 5.6⁻12.6 years). Older and female children and those who were already overweight were more likely to gain weight over the summer compared to younger, male, and normal weight children. Overweight children who lived near 2 or more small grocery stores gained less weight than overweight children who lived near 0 (weight change, p = 0.0468; body mass index (BMI) change, p = 0.0209) or 1 store (weight change, p = 0.0136; BMI change, p = 0.0033). Normal weight children living in neighborhoods with more large multifamily buildings gained more weight over the summer, although this association only approached significance. Additional efforts to understand which neighborhood factors have greater significance for overweight compared to normal weight children are warranted.

Psychometric validation of the Coronary Revascularisation Outcome Questionnaire (CROQv2) in the context of the NHS Coronary Revascularisation PROMs Pilot.

OBJECTIVES: The Coronary Revascularisation Outcome Questionnaire (CROQ) is a patient-reported outcome measure (PROM) for coronary artery bypass surgery (CABG) and percutaneous coronary intervention (PCI). We tested the psychometric properties of a modified version (CROQv2) when administered in a National Health Service (NHS)/Department of Health (DH) funded pilot of PROMs for coronary revascularisation. DESIGN: Psychometric validation study. SETTING: 11 English hospitals in the UK taking part in the NHS/DH funded pilot of PROMs for coronary revascularisation. PARTICIPANTS: Comprehensive analyses of acceptability, reliability, validity and responsiveness were conducted independently for each of the prerevascularisation (n=2685 and n=3711) and postrevascularisation (n=869 and n=837) versions of the CROQ-CABG and CROQ-PCI, respectively. RESULTS: All versions met prespecified stringent criteria for (1) acceptability of items (missing data) and scales (missing data, floor and ceiling effects, skewness); (2) tests of scaling assumptions; (3) reliability: internal consistency (Cronbach's α, item-total correlations); (4) construct validity based on within-scale analyses (internal consistency, intercorrelations between scales, factor analysis and hypothesis testing); (5) construct validity based on comparisons with external measures (convergent and discriminant validity and hypothesis testing) and (6) responsiveness. Results were also confirmed when tests were repeated on subsamples of CABG (n=639) and PCI (n=615) patients who reported receiving help completing prerevascularisation questionnaires. CONCLUSIONS: The availability of a psychometrically robust procedure-specific tool that could be used as part of a large-scale coronary revascularisation PROMs programme to capture the patients' perspective of coronary revascularisation will enable outcomes important to patients to be routinely collected alongside clinical outcomes. The CROQ is suitable for administration by postal survey or the prerevascularisation versions can be administered in the clinical setting as in the Coronary Revascularisation PROMs Pilot.

Effects of a 12-Month Pedometer-Based Walking Intervention in Women of Low Socioeconomic Status.

This study examined the effects of a 12-month walking intervention in overweight/obese, low socioeconomic women. Forty-six women (48.2 ± 8.0 years) entered the study. Outcomes included weight, waist and hip circumferences, body mass index (BMI), blood pressure, glycosylated hemoglobin, blood lipids, fibrinogen, and high-sensitivity C-reactive protein (hsCRP). Both intention-to-treat analyses in all participants and group analyses in study completers only (3K group = increased steps/day by ≥3,000; No Δ group = did not increase steps/day by ≥3,000) were conducted. Group × time ANOVA was used. In study completers, 3K significantly increased steps/day (6,903 ± 3,328 to 12,323 ± 5,736) compared to No Δ (4,926 ± 3,374 to 5,174 ± 3,095) from baseline to 12 months. There was a significant time effect for weight (P = 0.030), BMI (P = 0.029), and hsCRP (P = 0.044). Low socioeconomic women who adhere to a long-term, pedometer-based walking intervention significantly increased steps/day and may improve body weight, BMI, and hsCRP. This could help reduce health disparities in this population over time.

Severity of road crashes involving pedestrians in Metro Manila, Philippines.

Pedestrians are considered as one of the most vulnerable road users in less developed countries (LDCs). Yet, pedestrian safety remains poorly addressed in both urban and rural transportation plans in most LDCs. Since most pedestrian injury severity studies are conducted in developed countries, this study fills the gap with an inquiry focused on a highly urbanized region of an LDC that faces a rapid increase in car ownership and increasing pedestrian-related traffic injuries, documenting specific pedestrian safety issues and providing guidance for injury prevention measures in such places. Using the Metro Manila Accident Reporting and Analysis System (MMARAS) data from 2008 to 2011, this study combines binomial logistic regression and street level analysis that further explores the statistical results and examines other factors that contribute to collisions and increase the potential for serious injury or death in three cities in Metro Manila: Makati, Manila, and Quezon. The results of the binomial regression analysis show that traffic crashes that involve heavy and multiple vehicles, and an elderly pedestrian (60 years old and above), as well as those that occurred during the evening (7 pm to midnight) and late at night (1 am to 5 am) have significantly higher odds of resulting in a fatal outcome; when the crash involves a female pedestrian and when the road surface is wet the odds of a fatal outcome are lower. Moreover, by closely examining the environment of these roadways, the study finds that most pedestrian fatalities occur on high-speed, high-traffic-volume, multilane roadways, that are surrounded by land uses that generate a particularly problematic mix of heavy vehicular and pedestrian traffic. The street level analysis also finds that fatal pedestrian crashes occur close to different types of transit stations. The results of this study of three cities in Metro Manila, reflect the twofold challenge to pedestrian safety in rapidly urbanizing areas in countries such as the Philippines that are classified as lower-middle-income: they face some of the same pedestrian safety issues as more developed areas, but with a much larger number of pedestrians using the streets, and a built environment that was not planned for the high volume and speed of motor vehicle traffic on today's roadways. Policies and planning that support increased pedestrian safety therefore need to address this dual challenge in the contexts where they are most needed.

Trait stacking via targeted genome editing.

Modern agriculture demands crops carrying multiple traits. The current paradigm of randomly integrating and sorting independently segregating transgenes creates severe downstream breeding challenges. A versatile, generally applicable solution is hereby provided: the combination of high-efficiency targeted genome editing driven by engineered zinc finger nucleases (ZFNs) with modular 'trait landing pads' (TLPs) that allow 'mix-and-match', on-demand transgene integration and trait stacking in crop plants. We illustrate the utility of nuclease-driven TLP technology by applying it to the stacking of herbicide resistance traits. We first integrated into the maize genome an herbicide resistance gene, pat, flanked with a TLP (ZFN target sites and sequences homologous to incoming DNA) using WHISKERS™-mediated transformation of embryogenic suspension cultures. We established a method for targeted transgene integration based on microparticle bombardment of immature embryos and used it to deliver a second trait precisely into the TLP via cotransformation with a donor DNA containing a second herbicide resistance gene, aad1, flanked by sequences homologous to the integrated TLP along with a corresponding ZFN expression construct. Remarkably, up to 5% of the embryo-derived transgenic events integrated the aad1 transgene precisely at the TLP, that is, directly adjacent to the pat transgene. Importantly and consistent with the juxtaposition achieved via nuclease-driven TLP technology, both herbicide resistance traits cosegregated in subsequent generations, thereby demonstrating linkage of the two independently transformed transgenes. Because ZFN-mediated targeted transgene integration is becoming applicable across an increasing number of crop species, this work exemplifies a simple, facile and rapid approach to trait stacking.

Genome-wide screen for modulation of hepatic apolipoprotein A-I (ApoA-I) secretion.

Control of plasma cholesterol levels is a major therapeutic strategy for management of coronary artery disease (CAD). Although reducing LDL cholesterol (LDL-c) levels decreases morbidity and mortality, this therapeutic intervention only translates into a 25-40% reduction in cardiovascular events. Epidemiological studies have shown that a high LDL-c level is not the only risk factor for CAD; low HDL cholesterol (HDL-c) is an independent risk factor for CAD. Apolipoprotein A-I (ApoA-I) is the major protein component of HDL-c that mediates reverse cholesterol transport from tissues to the liver for excretion. Therefore, increasing ApoA-I levels is an attractive strategy for HDL-c elevation. Using genome-wide siRNA screening, targets that regulate hepatocyte ApoA-I secretion were identified through transfection of 21,789 siRNAs into hepatocytes whereby cell supernatants were assayed for ApoA-I. Approximately 800 genes were identified and triaged using a convergence of information, including genetic associations with HDL-c levels, tissue-specific gene expression, druggability assessments, and pathway analysis. Fifty-nine genes were selected for reconfirmation; 40 genes were confirmed. Here we describe the siRNA screening strategy, assay implementation and validation, data triaging, and example genes of interest. The genes of interest include known and novel genes encoding secreted enzymes, proteases, G-protein-coupled receptors, metabolic enzymes, ion transporters, and proteins of unknown function. Repression of farnesyltransferase (FNTA) by siRNA and the enzyme inhibitor manumycin A caused elevation of ApoA-I secretion from hepatocytes and from transgenic mice expressing hApoA-I and cholesterol ester transfer protein transgenes. In total, this work underscores the power of functional genetic assessment to identify new therapeutic targets.

Neighborhood urban form, social environment, and depression.

We examined whether neighborhood urban form, along with the social environment, was associated with depressive symptoms in a sample of Miami residents. Using a validated measure of depressive symptoms, we found that living in neighborhoods with higher housing density was associated with fewer symptoms. A larger acreage of green spaces was also linked to fewer depressive symptoms but did not reach significance in the full model. Our results suggest that how residents use the environment matters. Living in neighborhoods with a higher density of auto commuters relative to land area, an indicator of chronic noise exposure, was associated with more symptoms.

Reliability and sensitivity to change of the Family Life Questionnaire in a clinical population.

BACKGROUND: The Family Life Questionnaire (FLQ) is a new measure of family functioning, which acknowledges that the experience of the family unit may vary between different children. This study examined the reliability and sensitivity to change of the FLQ in a clinical population. METHOD: The FLQ was administered to 91 parents attending the first session of the Incredible Years parenting programmes in Devon during 2009, 71 of them completed it on a second occasion a week later and 55 on a third occasion at the end of the programme. Internal consistency, test-retest reliability and sensitivity to change were calculated. RESULTS: Internal consistency and test-retest reliability of the scales varied between moderate and very good, except for the discipline and special allowances items which had poor internal consistency when grouped as a scale. The measures showed promising evidence of sensitivity to change. CONCLUSIONS: The FLQ is a reliable measure of family function that seems sensitive to change. There is some evidence of validity but a lack of suitable comparators limited this part of the study. The study sample was too small to explore the scale structure.

A hierarchy of sociodemographic and environmental correlates of walking and obesity.

OBJECTIVES: Initial studies demonstrate the need for further investigation of how the association of built environment with physical activity and BMI may differ by sociodemographic subgroups. The aim of this study was to use a novel statistical technique to identify possible subgroups. METHODS: Data from the 2002 Strategies for Metro Atlanta's Regional Transportation and Air Quality (SMARTRAQ) study were analyzed to explore relationships between measures of residential density, street connectivity, land use mix, and sociodemographic characteristics of individuals in predicting walking, overweight and obesity status. Chi-squared Automatic Interaction Detector (CHAID) analyses were used to partition the population into subgroups (N=13,065). RESULTS: Subgroups, were more likely to walk if they lived in neighborhoods with greater residential density, greater street connectivity and greater land use mix. A similar relationship was seen in men for the outcomes of obesity and overweight. Male residents of more walkable neighborhoods were less likely to be obese or overweight. In contrast, features of walkability were related to higher rates of obesity and overweight in women and non whites. CONCLUSIONS: These analyses reveal that gender and ethnic subgroups display substantially different weight outcomes across different levels of walkability. In contrast, walking was consistently higher for all groups in the more walkable neighborhoods. This information can contribute to better targeting of interventions, and calls for more detailed investigation of the moderators that affect weight and physical activity across subgroups. This information supports a more efficient use of scarce resources to promote physical activity and healthy body weight.

Neighborhood disorder, perceived safety, and readiness to encourage use of local playgrounds.

BACKGROUND: Knowledge of the association between the neighborhood physical environment and adults' readiness to encourage children's use of local playgrounds, and the extent to which perceived safety acts as a mediator, can inform efforts to increase children's physical activity. METHODS: Data were obtained from seven European cities based on a cross-sectional household survey conducted between 2001 and 2002. The sample included 2123 household informants (from a total of 2782 households) with a median age of 48 years; 65% were women, 66% were married, and 33% had achieved a secondary education. Indicators of local neighborhood physical disorder (litter, graffiti, lack of greenery), traffic volume, and land use were directly observed by trained surveyors. Perceived safety, encouragement of playground use, and physical activity levels were assessed with self-reported measures. Analyses were conducted in 2007. RESULTS: Respondents in neighborhoods showing signs of low or moderate physical disorder compared to high physical disorder had slightly over twice the odds of encouraging children to use local playgrounds (p<0.01). The percentage of the effect of neighborhood physical disorder accounted for by perceived safety was between 15% and 20%. Neighborhood physical disorder was associated only with adults' occasional involvement in sports or exercise and only among women (p<0.05); perceived safety was not significantly associated with physical activity for either men or women. CONCLUSIONS: Neighborhood physical environments and perceived safety influence adults' readiness to encourage children's physical activity and women's occasional involvement in sports or exercise. Health promotion strategies designed to upgrade the environments near where children live and to address parental safety concerns merit further exploration.