vSPACE: Exploring virtual spatial representation of articular chondrocytes at the Single-Cell level.

SUMMARY: VSPACE is a web-based application presenting a spatial representation of scRNAseq data obtained from human articular cartilage by emulating the concept of spatial transcriptomics technology, but virtually. This virtual 2D plot presentation of human articular cartage cells generates several zonal distribution patterns, for one or multiple genes at a time, revealing patterns that scientists can appreciate as imputed spatial distribution patterns along the zonal axis. AVAILABILITY AND IMPLEMENTATION: VSPACE is implemented in Python Dash as a web-based toolbox designed for data visualization of zonal gene expression patterns in articular cartilage chondrocytes. This tool is freely accessible at: Https://vspace.cse.uconn.edu/The source code and extra materials for this service can be downloaded from: Https://github.com/zhacheny/vSPACE. CONTACT: Dong-Guk Shin*: dong.shin@uconn.edu. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Biodegradable nanofiber-based piezoelectric transducer.

Piezoelectric materials, a type of "smart" material that generates electricity while deforming and vice versa, have been used extensively for many important implantable medical devices such as sensors, transducers, and actuators. However, commonly utilized piezoelectric materials are either toxic or nondegradable. Thus, implanted devices employing these materials raise a significant concern in terms of safety issues and often require an invasive removal surgery, which can damage directly interfaced tissues/organs. Here, we present a strategy for materials processing, device assembly, and electronic integration to 1) create biodegradable and biocompatible piezoelectric PLLA [poly(l-lactic acid)] nanofibers with a highly controllable, efficient, and stable piezoelectric performance, and 2) demonstrate device applications of this nanomaterial, including a highly sensitive biodegradable pressure sensor for monitoring vital physiological pressures and a biodegradable ultrasonic transducer for blood-brain barrier opening that can be used to facilitate the delivery of drugs into the brain. These significant applications, which have not been achieved so far by conventional piezoelectric materials and bulk piezoelectric PLLA, demonstrate the PLLA nanofibers as a powerful material platform that offers a profound impact on various medical fields including drug delivery, tissue engineering, and implanted medical devices.

Predicting the targets of IRF8 and NFATc1 during osteoclast differentiation using the machine learning method framework cTAP.

BACKGROUND: Interferon regulatory factor-8 (IRF8) and nuclear factor-activated T cells c1 (NFATc1) are two transcription factors that have an important role in osteoclast differentiation. Thanks to ChIP-seq technology, scientists can now estimate potential genome-wide target genes of IRF8 and NFATc1. However, finding target genes that are consistently up-regulated or down-regulated across different studies is hard because it requires analysis of a large number of high-throughput expression studies from a comparable context. METHOD: We have developed a machine learning based method, called, Cohort-based TF target prediction system (cTAP) to overcome this problem. This method assumes that the pathway involving the transcription factors of interest is featured with multiple "functional groups" of marker genes pertaining to the concerned biological process. It uses two notions, Gene-Present Sufficiently (GP) and Gene-Absent Insufficiently (GA), in addition to log2 fold changes of differentially expressed genes for the prediction. Target prediction is made by applying multiple machine-learning models, which learn the patterns of GP and GA from log2 fold changes and four types of Z scores from the normalized cohort's gene expression data. The learned patterns are then associated with the putative transcription factor targets to identify genes that consistently exhibit Up/Down gene regulation patterns within the cohort. We applied this method to 11 publicly available GEO data sets related to osteoclastgenesis. RESULT: Our experiment identified a small number of Up/Down IRF8 and NFATc1 target genes as relevant to osteoclast differentiation. The machine learning models using GP and GA produced NFATc1 and IRF8 target genes different than simply using a log2 fold change alone. Our literature survey revealed that all predicted target genes have known roles in bone remodeling, specifically related to the immune system and osteoclast formation and functions, suggesting confidence and validity in our method. CONCLUSION: cTAP was motivated by recognizing that biologists tend to use Z score values present in data sets for the analysis. However, using cTAP effectively presupposes assembling a sizable cohort of gene expression data sets within a comparable context. As public gene expression data repositories grow, the need to use cohort-based analysis method like cTAP will become increasingly important.

Prediction of Neonatal Respiratory Distress Biomarker Concentration by Application of Machine Learning to Mid-Infrared Spectra.

The authors of this study developed the use of attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) combined with machine learning as a point-of-care (POC) diagnostic platform, considering neonatal respiratory distress syndrome (nRDS), for which no POC currently exists, as an example. nRDS can be diagnosed by a ratio of less than 2.2 of two nRDS biomarkers, lecithin and sphingomyelin (L/S ratio), and in this study, ATR-FTIR spectra were recorded from L/S ratios of between 1.0 and 3.4, which were generated using purified reagents. The calibration of principal component (PCR) and partial least squares (PLSR) regression models was performed using 155 raw baselined and second derivative spectra prior to predicting the concentration of a further 104 spectra. A three-factor PLSR model of second derivative spectra best predicted L/S ratios across the full range (R2: 0.967; MSE: 0.014). The L/S ratios from 1.0 to 3.4 were predicted with a prediction interval of +0.29, -0.37 when using a second derivative spectra PLSR model and had a mean prediction interval of +0.26, -0.34 around the L/S 2.2 region. These results support the validity of combining ATR-FTIR with machine learning to develop a point-of-care device for detecting and quantifying any biomarker with an interpretable mid-infrared spectrum.

Type V superior labral anterior-posterior tears results in lower rates of return to play.

PURPOSE: The purpose of this study was to evaluate the rate of return to play (RTP) in patients who underwent Type V superior labrum anterior-posterior (SLAP) repair compared to patients who underwent isolated Bankart repair in the setting of traumatic anterior shoulder instability. METHODS: A retrospective review of patients who underwent arthroscopic Bankart repair and SLAP repair by a single surgeon between 2012 and 2017 was performed. Additionally, these were pair-matched in a 1:2 ratio for age, sex, sport and level of pre-operative play, with those undergoing isolated arthroscopic Bankart repair alone as a control group. RTP, level of RTP and the timing of RTP were assessed. RESULTS: The study included a total of 96 patients, with 32 in the study group and 64 in the control group, and a mean follow-up of 59 months. Overall, there was no significant difference in the overall rate of return to play (26/32 (81.3%) vs 56/64 (87.5%), n.s), but there was a significantly higher rate of RTP at the same/higher level in the control group (14/32 (43.6%) vs 43/64 (67.2%), p = 0.0463). There was no significant difference in timing of RTP between the groups (n.s). There was no significant difference in recurrent instability (6/32 (18.8%) vs 5/64 (7.8%), n.s) but there was a significant difference in revision rates (5/32 (15.6%) vs. 2/64 (3.1%), p = 0.0392) between the Type V SLAP repair group and the control group. CONCLUSION: Following arthroscopic repair, patients with Type V SLAP tears had a similar overall rate of RTP when compared directly to a control group of patients who underwent arthroscopic Bankart repair alone. However, those who underwent Type V SLAP repair reported significantly lower rates of RTP at the same or higher level compared to the control group. LEVEL OF EVIDENCE: III.

Parenchymal and stromal tissue regeneration of tooth organ by pivotal signals reinstated in decellularized matrix.

Cells are transplanted to regenerate an organs' parenchyma, but how transplanted parenchymal cells induce stromal regeneration is elusive. Despite the common use of a decellularized matrix, little is known as to the pivotal signals that must be restored for tissue or organ regeneration. We report that Alx3, a developmentally important gene, orchestrated adult parenchymal and stromal regeneration by directly transactivating Wnt3a and vascular endothelial growth factor. In contrast to the modest parenchyma formed by native adult progenitors, Alx3-restored cells in decellularized scaffolds not only produced vascularized stroma that involved vascular endothelial growth factor signalling, but also parenchymal dentin via the Wnt/ß-catenin pathway. In an orthotopic large-animal model following parenchyma and stroma ablation, Wnt3a-recruited endogenous cells regenerated neurovascular stroma and differentiated into parenchymal odontoblast-like cells that extended the processes into newly formed dentin with a structure-mechanical equivalency to native dentin. Thus, the Alx3-Wnt3a axis enables postnatal progenitors with a modest innate regenerative capacity to regenerate adult tissues. Depleted signals in the decellularized matrix may be reinstated by a developmentally pivotal gene or corresponding protein.

The effects of augmenting clozapine with oxytocin in schizophrenia: An initial case series.

BACKGROUND: Debilitating symptoms of schizophrenia often persist after sustained treatment with atypical antipsychotics. To date, clozapine has been the most effective of the atypical antipsychotics; however, negative symptoms may persist, indicating a critical need to develop augmenting treatment approaches. METHODS: A retrospective chart review evaluated outcomes for 5 young adult inpatients with treatment-resistant schizophrenia who were prescribed off-label oxytocin (OT; 10 IU/sublingual, 1 time per day, to 20 IU/sublingual, 3 times per day) after their therapeutic response to clozapine plateaued (dose range: 200 to 600 mg). The augmented treatment was well tolerated and continued for at least 1 year after discharge from the hospital, with continued outpatient follow-up by the treating psychiatrist. Evaluation included the Positive and Negative Syndrome Scale and clinical review based on both self and parent/guardian reports. RESULTS: The augmentation of clozapine with sublingual OT in young adults with treatment-resistant schizophrenia appeared to reduce negative symptoms, maintain lowered positive symptoms, and increase occupational and social functioning (eg, return to work or school), as noted by family members. CONCLUSIONS: Future controlled, prospective studies should investigate the possibility that OT can significantly reduce negative symptoms of chronic psychotic illnesses that are inadequately responsive to clozapine or other antipsychotic medications alone.

High prevalence of asymptomatic internal hernias after laparoscopic anterior resection in a retrospective analysis of postoperative computed tomography.

PURPOSE: Internal hernia (IH) after laparoscopic left-sided colorectal resection (small bowel herniating underneath the neo-descending colon) can be a potentially devastating complication, resulting in acute small bowel obstruction or ischemia. IH has been described as a rare occurrence in a few retrospective case series; however, patients undergoing laparoscopic resection seem to be more prone to this complication. We assessed the prevalence of IH in a large cohort of patients who had undergone laparoscopic left-sided colorectal resection for colon or rectal cancer (CRC). METHODS: A database of consecutive patients at a single institution from 2012 to 2017 was reviewed. Postoperative abdominal computed tomography (CT) scans performed for routine cancer follow-up between 3 and 36 months after surgery were assessed retrospectively. RESULTS: During the study period, 276 patients had undergone anterior resection for CRC, with 206 (75%) having been performed laparoscopically. A total of 198 eligible patients were identified, and a follow-up CT scan was available in 105 (53%) of these patients (median time to CT 10 months, range 3-34). Only one of the 198 (0.5%) patients presented with an acute small bowel obstruction secondary to an IH during follow-up. However, the prevalence of asymptomatic IH was noted to be much higher in the postoperative CT scans occurring in 22 of 105 (21%) patients. CONCLUSION: Asymptomatic IH after laparoscopic left-sided colorectal resection is common. Given the potential risk of acute small bowel obstruction and ischemia, routine closure of the mesenteric defect should be considered.

Outcomes following arthroscopic Bankart repair in female patients.

PURPOSE: The purpose of this study is to evaluate clinical outcomes and recurrence among women who have undergone an arthroscopic Bankart repair for recurrent anterior shoulder instability. METHODS: A retrospective review of patients with anterior shoulder instability that have undergone an arthroscopic Bankart repair between 2012-2017 was performed. Patients were followed up to assess their visual analog scale (VAS) score, Rowe score, Shoulder Instability-Return to Sport after Injury (SIRSI), and the Subjective Shoulder Value (SSV) and their satisfaction level. Whether they were able to return to sport, the timing of return, and the level to which they returned were reported. RESULTS: Our study included 31 female patients (34 shoulders), with a mean follow-up of 51.9 months. Overall, 82.4% (28/34 shoulders) were satisfied/very satisfied with their surgery. The mean scores were as follows: Rowe, 79.2; SIRSI, 53.9; SSV, 81.9; and VAS, 1.9. Of the 29 patients (32 shoulders) who played sport prior to surgery, 24 returned to play and 17 returned to the same or higher level. One patient suffered a recurrent dislocation and 2 patients suffered recurrent subluxation. No patients underwent a revision procedure. CONCLUSION: Female patients with anterior shoulder instability treated with arthroscopic Bankart repair have low recurrence rates, with good patient-reported outcomes and high satisfaction rates. Of those participating in sport prior to surgery, there was a high rate of return to play. The overall rate of complications was low, with a low rate of revision surgery.

Dickkopf-3 in aberrant endothelial secretome triggers renal fibroblast activation and endothelial-mesenchymal transition.

Background: Our laboratory has previously demonstrated that Sirt1endo-/- mice show endothelial dysfunction and exaggerated renal fibrosis, whereas mice with silenced endothelial transforming growth factor beta (TGF-ß) signaling are resistant to fibrogenic signals. Considering the fact that the only difference between these mutant mice is confined to the vascular endothelium, this indicates that secreted substances contribute to these contrasting responses. Methods: We performed an unbiased proteomic analysis of the secretome of renal microvascular endothelial cells (RMVECs) isolated from these two mutants. We cultured renal fibroblasts and RMVECs and used microfluidic devices for coculturing. Results: Dickkopf-3 (DKK3), a putative ligand of the Wnt/ß-catenin pathway, was present exclusively in the fibrogenic secretome. In cultured fibroblasts, DKK3 potently induced myofibroblast activation. In addition, DKK3 antagonized effects of DKK1, a known inhibitor of the Wnt pathway, in conversion of fibroblasts to myofibroblasts. In RMVECs, DKK3 induced endothelial-mesenchymal transition and impaired their angiogenic competence. The inhibition of endothelial outgrowth, enhanced myofibroblast formation and endothelial-mesenchymal transition were confirmed in coculture. In reporter DKK3-eGFP × Col3.6-GFPcyan mice, DKK3 was marginally expressed under basal conditions. Adriamycin-induced nephropathy resulted in upregulation of DKK3 expression in tubular and, to a lesser degree, endothelial compartments. Sulindac sulfide was found to exhibit superior Wnt pathway-suppressive action and decreased DKK3 signals and the extent of renal fibrosis. Conclusions: In conclusion, this unbiased proteomic screen of the profibrogenic endothelial secretome revealed DKK3 acting as an agonist of the Wnt pathway, enhancing formation of myofibroblasts and endothelial-mesenchymal transition and impairing angiogenesis. A potent inhibitor of the Wnt pathway, sulindac sulfide, suppressed nephropathy-induced DKK3 expression and renal fibrosis.

Anabolic actions of Notch on mature bone.

Notch controls skeletogenesis, but its role in the remodeling of adult bone remains conflicting. In mature mice, the skeleton can become osteopenic or osteosclerotic depending on the time point at which Notch is activated or inactivated. Using adult EGFP reporter mice, we find that Notch expression is localized to osteocytes embedded within bone matrix. Conditional activation of Notch signaling in osteocytes triggers profound bone formation, mainly due to increased mineralization, which rescues both age-associated and ovariectomy-induced bone loss and promotes bone healing following osteotomy. In parallel, mice rendered haploinsufficient in γ-secretase presenilin-1 (Psen1), which inhibits downstream Notch activation, display almost-absent terminal osteoblast differentiation. Consistent with this finding, pharmacologic or genetic disruption of Notch or its ligand Jagged1 inhibits mineralization. We suggest that stimulation of Notch signaling in osteocytes initiates a profound, therapeutically relevant, anabolic response.

Real World, Real People: Can We Assess Walking on a Treadmill to Establish Step Count Recommendations in Adolescents?

BACKGROUND: Currently, it is not known how much walking should be advocated for good health in an adolescent population. Step count recommendations for minimum time in moderate-intensity activity have been translated predominantly from treadmill walking. PURPOSE: To compare the energy cost of walking on a treadmill with overground walking in adolescent girls. METHODS: A total of 26 adolescent girls undertook resting metabolic measurements for individual determination of 1 metabolic equivalent using indirect calorimetry. Energy expenditure was subsequently assessed during treadmill and overground walking at slow, moderate, and fast walking speeds for 4 to 6 minutes. Treadmill step rates were matched overground using a metronome. RESULTS: The energy cost of treadmill walking was found to be significantly greater than and not equivalent to overground walking at 133 steps per minute; (equivalent to the fast walking pace): V˙O2 3.90 (2.78-5.01), P < .001, mean absolute percentage error (MAPE) = 18.18%, and metabolic equivalent 0.77 (0.54-1.00), P < .001, MAPE = 18.16%. The oxygen cost per step (V˙O2 mL·step-1) was significantly greater and not equivalent on the treadmill at 120 and 133 steps per minute: 0.43 (0.12-0.56), P < .05, MAPE = 10.12% versus 1.40 (1.01-1.76), P < .001, MAPE = 17.64%, respectively. CONCLUSION: The results suggest that there is a difference in energy cost per step of walking on a treadmill and overground at the same step rate. This should be considered when utilizing the treadmill in energy expenditure studies. Studies which aim to provide step recommendations should focus on overground walking where most walking activity is adopted.

Innovative Surgical Treatment of Severe Cherubism.

BACKGROUND: Cherubism is an autosomal dominant syndrome characterized by excessive bilateral maxillomandibular bony degeneration and fibrous tissue hyperplasia. Conservative management is the preferred treatment as cherubism has a self-limiting course. Functional or emotional disturbances may, however, demand surgical intervention. We report a patient who underwent surgical intervention. METHOD/DESCRIPTION: He had significant enlargement of lower cheeks and bilateral lower lid scleral show. On computed tomography of the face, the patient had significant fibrous tissue involving bilateral maxilla and mandible. The mandibular tumor was excised. Given normal inferior border, bilateral sagittal split osteotomy was performed to infracture and inset the outer cortex. During the procedure, patient required blood transfusion intraoperatively, so the maxillary portion of the procedure was delayed until 6 months later. For the maxilla, bilateral transconjunctival approach was used to resect parts of the orbital floors that were concave, resulting in 1 × 2 cm defects bilaterally which were reconstructed using resorbable plates. Then the anterior maxillary tumor was excised. RESULTS: The patient and his parents were satisfied with his appearance after surgery. The patient was noted to have improvement in contour and decreased scleral show. He has most recently followed up 15 months after the initial surgery. There were no long-term complications. CONCLUSIONS: Severity of cherubism influences the type of surgical intervention. The present case is innovative because this is the first reported case of recontouring orbital floors with resorbable plates and infracturing of the mandible using sagittal split osteotomies for surgical treatment of cherubism.

Cell origin, volume and arrangement are drivers of articular cartilage formation, morphogenesis and response to injury in mouse limbs.

Limb synovial joints are composed of distinct tissues, but it is unclear which progenitors produce those tissues and how articular cartilage acquires its functional postnatal organization characterized by chondrocyte columns, zone-specific cell volumes and anisotropic matrix. Using novel Gdf5CreERT2 (Gdf5-CE), Prg4-CE and Dkk3-CE mice mated to R26-Confetti or single-color reporters, we found that knee joint progenitors produced small non-migratory progenies and distinct local tissues over prenatal and postnatal time. Stereological imaging and quantification indicated that the columns present in juvenile-adult tibial articular cartilage consisted of non-daughter, partially overlapping lineage cells, likely reflecting cell rearrangement and stacking. Zone-specific increases in cell volume were major drivers of tissue thickening, while cell proliferation or death played minor roles. Second harmonic generation with 2-photon microscopy showed that the collagen matrix went from being isotropic and scattered at young stages to being anisotropic and aligned along the cell stacks in adults. Progenitor tracing at prenatal or juvenile stages showed that joint injury provoked a massive and rapid increase in synovial Prg4+ and CD44+/P75+ cells some of which filling the injury site, while neighboring chondrocytes appeared unresponsive. Our data indicate that local cell populations produce distinct joint tissues and that articular cartilage growth and zonal organization are mainly brought about by cell volume expansion and topographical cell rearrangement. Synovial Prg4+ lineage progenitors are exquisitely responsive to acute injury and may represent pioneers in joint tissue repair.

Chalcogenide glass waveguides with paper-based fluidics for mid-infrared absorption spectroscopy.

We demonstrate the integration of paper fluidics with mid-infrared (MIR) chalcogenide waveguides to introduce liquid samples to the waveguide evanescent field for analysis. Spectroscopy of model analytes (water and isopropyl alcohol) having well-defined mid-IR absorptions, on a ZnSe rib waveguide fabricated on silicon, is demonstrated in the wavelength range of 2.6-3.7 µm, showing their O-H and C-H stretching absorptions. The results are compared with a theoretical waveguide model, achieving good agreement. It is concluded that the presence of paper in the evanescent field does not interfere with the waveguide measurements, opening up opportunities to combine low-cost paper-based fluidics and integrated photonic technologies.

Associations between metabolic syndrome components and markers of inflammation in Welsh school children.

We investigated the multivariate dimensionality and strength of the relationship between metabolic syndrome (MetS) and inflammation in children. Caucasian school children (N = 229; 12-14 years) from Wales were tested on several health indicators including measures of body composition, inflammation, fasting glucose regulation, blood pressure, and lipids. The multivariate association between MetS and inflammation was investigated via canonical correlation analysis. Data were corrected for non-normality by log transformation, and sex-specific z-scores computed for variables where there was a significant sex difference. Structure r's were interpreted to determine the dimensions of MetS and inflammation responsible for significant canonical variates. The overall multivariate association between MetS and inflammation was significant (Wilks' Lambda = 0.54, p < 0.001). The relationship was explained primarily by the waist circumference dimension of MetS (CC = 0.87) and inflammatory markers of fibrinogen (CC = 0.52) and C-reactive protein (CC = 0.50). The pattern of results was similar regardless of whether variables were adjusted for sex differences. CONCLUSION: Central adiposity is the strongest predictor of the inflammatory aspect of cardiovascular disease risk in Caucasian adolescents. Future research into MetS and cardiometabolic risk should consider multivariate statistical approaches, in order to identify the separate contributions of each dimension in interrelationships and to identify which dimensions are influenced by preventive interventions. What is Known: • Metabolic syndrome (MetS) is associated with increased risk of cardiovascular disease (CVD) and type 2 diabetes. Markers of inflammation are also potential predictors of later development of CVD and type 2 diabetes. • The contribution of individual markers in interrelationships between MetS and inflammation is unknown. What is New: • We uniquely demonstrate that within a multivariate model, waist circumference is the primary link between MetS variables and markers of inflammation in children. • Waist circumference may therefore be a useful population-level screening tool to identify future risk of CVD.

Screening Gene Knockout Mice for Variation in Bone Mass: Analysis by µCT and Histomorphometry.

PURPOSE OF REVIEW: The international mouse phenotyping consortium (IMPC) is producing defined gene knockout mouse lines. Here, a phenotyping program is presented that is based on micro-computed tomography (µCT) assessment of distal femur and vertebra. Lines with significant variation undergo a computer-based bone histomorphometric analysis. RECENT FINDINGS: Of the 220 lines examined to date, approximately 15% have a significant variation (high or low) by µCT, most of which are not identified by the IMPC screen. Significant dimorphism between the sexes and bone compartments adds to the complexity of the skeletal findings. The µCT information that is posted at www.bonebase.org can group KOMP lines with similar morphological features. The histological data is presented in a graphic form that associates the cellular features with a specific anatomic group. The web portal presents a bone-centric view appropriate for the skeletal biologist/clinician to organize and understand the large number of genes that can influence skeletal health. Cataloging the relative severity of each variant is the first step towards compiling the dataset necessary to appreciate the full polygenic basis of degenerative bone disease.

Effectiveness of active school transport interventions: a systematic review and update.

BACKGROUND: Active school transport (AST) is a promising strategy to increase children's physical activity. A systematic review published in 2011 found large heterogeneity in the effectiveness of interventions in increasing AST and highlighted several limitations of previous research. We provide a comprehensive update of that review. METHODS: Replicating the search of the previous review, we screened the PubMed, Web of Science, Cochrane, Sport Discus and National Transportation Library databases for articles published between February 1, 2010 and October 15, 2016. To be eligible, studies had to focus on school-aged children and adolescents, include an intervention related to school travel, and report a measure of travel behaviors. We assessed quality of individual studies with the Effective Public Health Practice Project quality assessment tool, and overall quality of evidence with the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) approach. We calculated Cohen's d as a measure of effect size. RESULTS: Out of 6318 potentially relevant articles, 27 articles reporting 30 interventions met our inclusion criteria. Thirteen interventions resulted in an increase in AST, 8 found no changes, 4 reported inconsistent results, and 5 did not report inferential statistics. Cohen's d ranged from -0.61 to 0.75, with most studies reporting "trivial-to-small" positive effect sizes. Three studies reported greater increases in AST over longer follow-up periods and two Safe Routes to School studies noted that multi-level interventions were more effective. Study quality was rated as weak for 27/30 interventions (due notably to lack of blinding of outcome assessors, unknown psychometric properties of measurement tools, and limited control for confounders), and overall quality of evidence was rated as low. Evaluations of implementation suggested that interventions were limited by insufficient follow-up duration, incomplete implementation of planned interventions, and limited access to resources for low-income communities. CONCLUSIONS: Interventions may increase AST among children; however, there was substantial heterogeneity across studies and quality of evidence remains low. Future studies should include longer follow-ups, use standardized outcome measures (to allow for meta-analyses), and examine potential moderators and mediators of travel behavior change to help refine current interventions. TRIAL REGISTRATION: Registered in PROSPERO: CRD42016033252.

Cutaneous Squamous Cell Carcinoma With Sclerosing Features: An Uncommon and Potentially Aggressive Variant.

Sclerosing squamous cell carcinoma (SCC), also known as "desmoplastic" SCC, is a rare subtype of cutaneous malignancy. This variant is clinically significant because it is associated with an increased risk of local recurrence and metastasis. We herein present 16 examples of sclerotic SCC of the skin in 8 men and 3 women, with a median age of 66 years. The most common site of origin for this tumor is the skin of the head and neck, including the scalp (5 tumors in 2 different patients), forehead (3 cases), nasal ala (2 cases), neck (2 cases in the same patient), ear (2 cases), cheek (1 case), and chest (1 case). Microscopically, sclerosing SCCs are characterized by cellular cords, nests, and islands, as well as scattered single cells infiltrating densely desmoplastic and collagenized connective tissue. The differential diagnosis principally includes sclerosing basal cell carcinoma, microcystic adnexal carcinoma, and desmoplastic trichoepithelioma. The main goals of this study are to further characterize these lesions pathologically, and increase general awareness of this SCC subtype.

How fast is fast enough? Walking cadence (steps/min) as a practical estimate of intensity in adults: a narrative review.

BACKGROUND: Cadence (steps/min) may be a reasonable proxy-indicator of ambulatory intensity. A summary of current evidence is needed for cadence-based metrics supporting benchmark (standard or point of reference) and threshold (minimums associated with desired outcomes) values that are informed by a systematic process. OBJECTIVE: To review how fast, in terms of cadence, is enough, with reference to crafting public health recommendations in adults. METHODS: A comprehensive search strategy was conducted to identify relevant studies focused on walking cadence and intensity for adults. Identified studies (n=38) included controlled (n=11), free-living observational (n=18) and intervention (n=9) designs. RESULTS: There was a strong relationship between cadence (as measured by direct observation and objective assessments) and intensity (indirect calorimetry). Despite acknowledged interindividual variability, ≥100 steps/min is a consistent heuristic (e.g, evidence-based, rounded) value associated with absolutely defined moderate intensity (3 metabolic equivalents (METs)). Epidemiological studies report notably low mean daily cadences (ie, 7.7 steps/min), shaped primarily by the very large proportion of time (13.5 hours/day) spent between zero and purposeful cadences (<60 steps/min) at the population level. Published values for peak 1-min and 30-min cadences in healthy free-living adults are >100 and >70 steps/min, respectively. Peak cadence indicators are negatively associated with increased age and body mass index. Identified intervention studies used cadence to either prescribe and/or quantify ambulatory intensity but the evidence is best described as preliminary. CONCLUSIONS: A cadence value of ≥100 steps/min in adults appears to be a consistent and reasonable heuristic answer to 'How fast is fast enough?' during sustained and rhythmic ambulatory behaviour. TRIAL REGISTRATION NUMBER: NCT02650258.