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Tripp Leavitt, Michael S Hu, Clement D Marshall, Leandra A Barnes, Michael T Longaker, H Peter Lorenz Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA Abstract: Currently available treatments for chronic wounds are inadequate. A clearly effective therapy does not exist, and treatment is often supportive. This is largely because the cellular and molecular processes underlying failure of wound repair are still poorly understood. With an increase in comorbidities, such as diabetes and vascular disease, as well as an aging population, the incidence of these intractable wounds is expected to rise. As such, chronic wounds, which are already costly, are rapidly growing as a tremendous burden to the health-care system. Stem cells have garnered much interest as a therapy for chronic wounds due to their inherent ability to differentiate into multiple lineages and promote regeneration. Herein, we discuss the types of stem cells used for chronic wound therapy, as well as the proposed means by which they do so. In particular, we highlight mesenchymal stem cells (including adipose-derived stem cells), endothelial progenitor cells, and induced pluripotent stem cells. We include the results of recent in vitro and in vivo studies in both animal models and human clinical trials. Finally, we discuss the current studies to improve stem cell therapies and the limitations of stem cell-based therapeutics. Stem cells promise improved therapies for healing chronic wounds, but further studies that are well-designed with standardized protocols are necessary for fruition. Keywords: stem cells, chronic wounds, cell therapy, wound healing

Bayesian causal inference in randomized experiments usually imposes model-based structure on potential outcomes. Yet causal inferences from randomized experiments are especially credible because they depend on a known assignment process, not a probability model of potential outcomes. In this article, I derive a randomization-based procedure for Bayesian inference of causal effects in a finite population setting. I formally show that this procedure satisfies Bayesian analogues of unbiasedness and consistency under weak conditions on a prior distribution. Unlike existing model-based methods of Bayesian causal inference, my procedure supposes neither probability models that generate potential outcomes nor independent and identically distributed random sampling. Unlike existing randomization-based methods of Bayesian causal inference, my procedure does not suppose that potential outcomes are discrete and bounded. Consequently, researchers can reap the benefits of Bayesian inference without sacrificing the properties that make inferences from randomized experiments especially credible in the first place.

Purpose: In Huntington disease (HD), synonymous variants causing loss or duplication of the interrupting CAA codon in the HTT CAG repeat modify disease onset. These variants are undetectable during HD genetic testing, resulting in inaccurate diagnostic reporting of uninterrupted CAG repeat length. Inaccurate reporting of CAG repeat length results in misdiagnosis of individuals with alleles near diagnostic cut-offs. We present a method to identify variant alleles during CAG repeat genotyping, allowing accurate diagnostic reporting of uninterrupted CAG repeat length., Methods: We used triplet-primed PCR (TP-PCR) to amplify HTT CAG repeat alleles with canonical or noncanonical repeat interruptions and leveraged differences in peak amplification patterns to develop a screening method based on peak height ratio (PHR). We used PHR to screen blood DNA from a cohort of symptomatic individuals with diagnostic CAG repeat lengths of 40 to 41., Results: TP-PCR enables accurate reporting of uninterrupted CAG repeat length in diagnostic testing by detecting HD alleles with loss or duplication of the CAG repeat interruption., Conclusion: PHR screening of TP-PCR traces is a cost-effective screening method for detection, ascertainment of uninterrupted HTT CAG repeat length, and accurate diagnostic reporting for individuals with disease-modifying noncanonical CAG repeat interruptions., Competing Interests: Michael R. Hayden is the CEO of Prilenia Therapeutics, a private company, and serves on the public boards of Ionis Pharmaceuticals, Oxford Biomedica, AbCellera and 89bio. All other authors declare no conflicts of interest., (© 2024 The Authors.)

Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Minimal clinically important differences (MCIDs) quantify the clinical relevance of quality of life results at the individual patient and group level. The aim of this study was to estimate the MCID for the Brief Fatigue Inventory (BFI) and the Worst and Usual Fatigue items in patients with brain or CNS cancer undergoing curative radiotherapy., Methods: Data from a multi-site prospective registry was used. The MCID was calculated using distribution-based and anchor-based approaches. For the anchor-based approach, the fatigue item from the PROMIS-10 served as the anchor to determine if a patient improved, deteriorated, or had no change from baseline to end of treatment (EOT). We compared the unadjusted means on the BFI for the 3 groups to calculate the MCID. For the distribution-based approaches, we calculated the MCID as 0.5 SD of the scores and as 1.96 times the standard error of measurement., Results: Three-hundred and fifty nine patients with brain or CNS tumors undergoing curative radiotherapy filled out the 9-item BFI at baseline and EOT. The MCID for the BFI was 1.33 (ranging from 0.99 to 1.70 across the approaches), 1.51 (ranging from 1.16 to 2.02) and 1.76 (ranging from 1.38 to 2.14) for the usual and worst fatigue items, respectively., Conclusions: This study provides the MCID ranges for the BFI and Worst and Usual fatigue items, which will allow clinically meaningful conclusions to be drawn from BFI scores. These results can be used to select optimal treatments for patients with brain or CNS cancer or to interpret BFI scores from clinical trials., Competing Interests: All authors declare no conflict of interest with respect to this work., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology and the European Association of Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Purpose: Combined targeted muscle reinnervation with regenerative peripheral nerve interfaces ("TMRpni") is a recently described nerve management strategy that leverages beneficial elements of targeted muscle reinnervation (TMR) and regenerative peripheral nerve interface (RPNI) techniques. This study aimed to evaluate the effect of TMRpni on long-term opioid consumption after amputation. We hypothesize that TMRpni decreases chronic opioid consumption in amputees., Methods: This is a retrospective cohort study of all patients who underwent TMRpni between 2019 and 2021. These patients were age-matched at a 1:1 ratio with a control group of patients who underwent amputation without TMRpni. Statistical analysis was performed using SPSS Version 28.0., Results: Thirty-one age-matched pairs of patients in the TMRpni and control groups were included. At 30 days after surgery, there was no significant difference in number of patients who required an additional refill of their opioid prescriptions (45% vs 55%, P = 0.45) or patients who continued to actively use opioids (36% vs 42%, P = 0.60). However, at 90 days after surgery, there was a significantly lower number of patients from the TMRpni group who reported continued opioid use compared with the control group (10% vs 32%, P = 0.03)., Conclusions: This study demonstrates that TMRpni may translate to decreased rates of chronic opiate use. Continued study is indicated to optimize TMRpni techniques and patient selection and to determine its long-term efficacy., Competing Interests: Conflicts of interest and sources of funding: None of the authors have a financial interest in any of the products, devices, or drugs mentioned in this article., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Pediatric tracheostomy for COVID-19 infections is uncommon and requires age-appropriate adaptations. This case adds to a limited body of literature related to tracheostomy placement and management in an adolescent. Thoughtful planning and communication by a dedicated tracheostomy team was crucial in obtaining a successful outcome., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: Oropharyngeal squamous cell carcinoma (OPSCC) recurrence is almost universally fatal. Development of effective therapeutic options requires an improved understanding of recurrent OPSCC biology., Methods: We analyzed paired primary-recurrent OPSCC from Veterans treated at the Michael E. DeBakey Veterans Affairs Medical Center between 2000 and 2020 who received curative intent radiation-based treatment (with or without chemotherapy). Patient tumors were analyzed using standard immunohistochemistry and automated imaging of infiltrating lymphocytes and multinucleated tumor cells coupled to machine learning algorithms., Results: Primary and recurrent tumors demonstrated high concordance via p16 and p53 immunohistochemistry, with comparable levels of multinucleation. In contrast, recurrent tumors demonstrated significantly higher levels of CD8+ tumor infiltrating lymphocytes (p<0.05) and higher levels of PD-L1 expression (p<0.05)., Conclusion: Exposure to chemo-radiation and recurrence following treatment preserves critical features of intrinsic tumor biology and the tumor immune microenvironment suggesting that novel treatment regimens may be as effective in the salvage setting as in the definitive intent setting., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Adult traumatic brachial plexus injuries (TBPIs) are life-altering events that can have detrimental effects on a patient's quality of life., Objective: To examine how social determinants of health (SDOH) disparities influence the risk of developing new psychosocial conditions after TBPIs in previously psychiatric-naïve patients., Methods: Between January 2010 and June 2019, a retrospective analysis was performed using PearlDiver's Mariner, an all-payer claims database, to create 3 cohorts: TBPI disparity cohort: patients with TBPI and presence of at least 1 SDOH disparity before injury, TBPI without disparity cohort: patients with TBPI and the absence of any SDOH disparity, and control cohort: patients without TBPIs., Results: The matched population analyzed in this study consisted of 1176 patients who were equally represented in the TBPI disparity cohort (n = 392, 33.33%), TBPI without disparity cohort (n = 392, 33.33%), and control cohort (n = 392, 33.33%). A total of 301 patients developed any psychosocial condition with 4 years of their injury. Patients in the TBPI disparity cohort had significantly higher rates of developing any psychosocial condition (31.12%, P < .0005), depression (22.70%, P = .0032), anxiety (18.62%, P = .0203), drug abuse (7.91%, P = .0060), and alcohol abuse (4.85%, P = .03499) when compared with the other cohorts. Furthermore, the disparity cohort carried a significantly increased risk of developing any psychosocial condition (hazard ratio 1.42, 95% CI 1.09-1.86). The rates of suicide attempt, post-traumatic stress disorder, and divorce did not significantly differ between groups., Conclusion: TBPI patients with SDOH disparities are at increased risk of developing new-onset psychosocial conditions, such as depression, anxiety, drug abuse, and alcohol abuse. Level of Evidence: Prognostic Level III., (Copyright © Congress of Neurological Surgeons 2023. All rights reserved.)

Background: Acute appendicitis is one of the most common surgical emergencies worldwide. Preoperative assessment of the risk of complicated appendicitis may aid in treatment planning. We sought to investigate the association between pre-appendectomy hyponatremia and diagnosis of complicated appendicitis., Methods: The TriNetX platform, a federated health research network that aggregates de-identified electronic health record data of over 90 million patients across the United States, was queried for patients who underwent appendectomy starting January 2019 and who had at least one sodium value from the preoperative period. The study population was stratified into three age groups: pediatric (age < 18), adult (age 18-64), and older adult (age ≥ 65). These groups were subdivided into patients with preoperative hyponatremia (<135 mmol/L) and normonatremia (135-145 mmol/L)., Results: Among the 61,245 patients who met inclusion criteria, 17,546 were included for analysis following propensity score matching. The odds of complicated appendicitis were highest in pediatric patients (age < 18) with pre-appendectomy hyponatremia (odds ratio [OR] = 2.91, 95 % CI [2.53, 3.35]). Patients age 18-64 and aged ≥ 65 with preoperative hyponatremia also demonstrated increased odds of a complicated appendicitis diagnosis, but to a lesser extent (OR = 2.11, 95 % CI [1.92, 2.32] (OR = 1.49, 95 % CI [1.25, 1.77], respectively)., Conclusions: In a large analysis of matched patients with acute appendicitis, we found an association between immediate preoperative hyponatremia and complicated appendicitis. Future studies are indicated to further evaluate the role of hyponatremia as a potential diagnostic marker for complicated appendicitis in all age groups., Key Message: This study suggests a role of hyponatremia as one of multiple variables to incorporate into future clinical decision tools for complicated acute appendicitis., Competing Interests: Luis E. Tollinche is a grant recipient through Merck Investigator Studies Program (MISP) to fund a clinical trial at MSKCC (NCT03808077). LET serves a consultancy and advisory role for Merck & Co. Pharmaceutical Company. LET serves a consultancy and advisory role for GE Healthcare. LET receives stipend for his role as examiner with The American Board of Anesthesiology. These relationships have not conflicted with the quality or integrity of the work presented. The other authors have no competing interests to declare., (© 2023 The Authors.)

Objective: Evaluate Elementary Education college students' familiarity and perceptions of Breakfast in the Classroom (BIC) before and after an educational video intervention., Methods: A 5-minute educational video was developed as an intervention in a pilot study. Quantitative data were collected from Elementary Education students using preintervention and postintervention surveys and analyzed using paired sample t tests (P < 0.001)., Results: A total of 68 participants completed preintervention and postintervention surveys. Postintervention survey scores indicated that participants' perceptions of BIC improved after watching the video. Paired sample t tests also showed an increase in preference for BIC, familiarity with the 5 school breakfast service models, and confidence to implement BIC in future classrooms., Conclusions and Implications: An educational video intervention effectively improves Elementary Education students' perceptions of BIC. Elementary Education students who gain a positive perception of BIC may influence the program's success and ability to benefit students., (Copyright © 2023 Society for Nutrition Education and Behavior. Published by Elsevier Inc. All rights reserved.)

Purpose: Patient-reported outcomes provide quality of life (QOL) data during and after radiation. When pediatric patients are unable to complete patient-reported outcomes, it is unknown whether caregiver responses are an accurate surrogate. We assessed whether caregiver scores for the Pediatric Quality of Life Inventory (PedsQL) Core and Brain Tumor Module questionnaires can substitute for missing child scores., Methods and Materials: From 2016 to 2018, pediatric patients treated with radiation were followed in a prospective, institutional registry. Child and caregiver Core and Tumor PedsQL surveys were obtained at pretreatment, end of treatment, and in regular follow-up. The differences between the 2 scores at each time point were quantified using a linear mixed-model and the level of agreement was estimated with intraclass correlation coefficient (ICC). An ICC 95% confidence interval (CI) lower limit exceeding 0.75 was considered an acceptable threshold for using caregiver scores as imputed values for missing child scores., Results: Ninety-one children completed 403 surveys. Caregivers underestimated QOL scores at baseline, but not at end of treatment or any follow-up time. The PedsQL Core total score had an ICC of 0.88 (95% CI, 0.81-0.92), and the emotional, physical, school, and social function subdomain scores were 0.81 (0.72-0.88), 0.72 (0.58-0.82), 0.79 (0.68-0.86), and 0.75 (0.62-0.83), respectively. The tumor total score ICC was 0.91 (0.85, 0.94), and each of the subdomains (cognitive problems, communication, movement and balance, nausea, pain and hurt, perceived physical appearance, procedural anxiety, treatment anxiety, and worry) had ICC lower bound 95% CI ≥0.75 except for communication (0.83, 0.74-0.89). Bland-Altman analysis demonstrated no visual change in discrepancy between child and caregiver estimates as overall QOL improved., Conclusions: Agreement between child- and caregiver-reported QOL was generally strong in the acute period after radiation, implying that caregiver scores may be imputed for child scores in future protocols and analyses of pediatric QOL., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Flap-based reconstruction following abdominoperineal resection has been used to address the resultant soft tissue defect and reduce postoperative wound complications. Vertical rectus abdominis myocutaneous flaps have been the traditional choice, but locoregional flaps have attracted attention in minimally invasive resection because they avoid additional abdominal dissection. However, few data exist comparing flap types., Objective: To compare outcomes for different types of perineal reconstruction in patients undergoing abdominoperineal resection exclusively for anorectal pathology., Design: This was a retrospective comparative study., Setting: This study was conducted at a large, tertiary referral institution., Patients: Following Institutional Review Board approval, prospectively maintained clinical and financial databases were interrogated and cross-referenced for patients undergoing proctectomy or abdominoperineal resection with flap reconstruction from 2007 to 2018. Patients with primary gynecological or urological pathology were excluded., Main Outcome Measures: The primary outcome was flap complication rate. Secondary outcomes included perineal hernia rate, donor site complications, emergency department consult after discharge, readmission <90 days, and length of stay. Data were analyzed using univariate and multivariate techniques., Results: A total of 135 patients (79 female, median age 58 years) were included: 68 rectus, 52 gluteal, and 15 gracilis flap reconstructions. Median follow-up was 46 months. Rates of both major and minor flap complications were similar for rectus and gluteal flaps, even when controlling for differences between groups via multivariate analysis ( p > 0.9), including extent of resection and use of mesh. For all flaps, American Society of Anesthesiology score ≥3 was the only independent predictor of major, but not minor, flap complications. For rectus and gluteal flaps, smoking, female sex, and American Society of Anesthesiology score ≥3 were independent predictors of major flap complications ( p < 0.05)., Limitations: This study was limited by its retrospective nature and potential selection bias associated with flap choice; it was also impossible to quantify defect size., Conclusion: Gluteal flaps have similar complication rates to rectus flaps and may be considered for patients who are otherwise suitable for minimally invasive abdominoperineal resection. See Video Abstract at http://links.lww.com/DCR/B866 .Una comparación de los colgajos miocutáneos perineales después de la escisión abdominoperineal del recto para patología anorectal., Antecedentes: La reconstrucción con colgajo después de la resección abdominoperineal se ha utilizado para abordar el defecto de tejido blando resultante y reducir las complicaciones postoperatorias de la herida. Los colgajos miocutáneos verticales del recto abdominal han sido la elección tradicional, pero los colgajos locorregionales han atraído la atención en la resección mínimamente invasiva porque evitan la disección abdominal adicional. Sin embargo, existen pocos datos que comparen los tipos de colgajos., (Copyright © The ASCRS 2021.)

Purpose: To characterize the significance of patient-level influences, including smoking history, on oncologic outcomes in human papillomavirus (HPV)-mediated oropharyngeal cancer (OPC)., Materials and Methods: A bi-institutional retrospective cohort study of previously untreated, HPV+ OPC patients who underwent curative treatment from 1/1/2008 to 7/1/2018 was performed. The primary outcome was disease-free survival (DFS) and the primary exposure was ≤10 versus >10-pack-year (PY)-smoking history., Results: Among 953 OPC patients identified, 342 individuals with HPV+ OPC were included. The median patient age was 62 years, 33.0% had a > 10-PY-smoking history, 60.2% had AJCC8 stage I disease, and 35.0% underwent primary surgery. The median follow-up was 49 months (interquartile range [IQR] 32-75 months). Four-year DFS-estimates were similar among patients with ≤10-PY-smoking history (78.0%, 95% CI:71.7%-83.1%) compared to >10-PYs (74.8%; 95% CI:65.2%-82.0%; log-rank:p = 0.53). On univariate analysis, >10-PY-smoking history did not correlate with DFS (hazard ratio[HR]:1.15;95% CI:0.74-1.79) and remained nonsignificant when forced into the multivariable model. On adjusted analyses, stage, treatment paradigm, and age predicted DFS. Neither >10-PYs, nor any other definition of tobacco use (e.g., current smoker or > 20-PYs) was predictive of DFS, overall survival, or disease-specific survival. Conversely, age nonsignificantly and significantly predicted adjusted DFS (adjusted HR[aHR]:1.02,95% CI:0.997-1.05, p = 0.08), overall survival (aHR 1.05; 95% CI: 1.02-1.08; p = 0.002) and disease-specific survival (aHR 1.04;95% CI: 0.99-1.09;p = 0.09)., Conclusion: Other than age, patient-level influences may not be primary drivers of HPV+ OPC outcomes. Although limited by its modest sample size, our study suggests the significance of smoking has been overstated in this disease. These findings and the emerging literature collectively do not support risk-stratification employing the >10-PY threshold., Level of Evidence: Level 4., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objectives: To determine predictors of obstructive sleep apnea (OSA) in underweight children and to describe the demographic, clinical, and polysomnographic characteristics of an ethnically diverse population of underweight children with OSA., Study Design: Case-control study., Setting: University of Texas Southwestern Medical Center and Children's Medical Center of Dallas., Methods: Underweight children aged 2 to 18 years who underwent a polysomnogram for suspected OSA between January 2014 and December 2020 were included. Underweight was defined as body mass index <5th percentile per Centers for Disease Control and Prevention guidelines. Children with apnea-hypopnea index <1.0 served as a control group. Univariate and multiple logistic regression analysis was used to determine the predictors of OSA. Significance was set at P < .05., Results: An overall 124 children met inclusion criteria: mean age, 6.4 years; 50% female; 44% Hispanic, 31% African American, and 18% Caucasian. A total of 83 children had OSA (apnea-hypopnea index ≥1.0). Height was negatively correlated with OSA (odds ratio, 0.94; 95% CI, 0.88-0.99; P = .02) while allergic rhinitis (odds ratio, 2.97; 95% CI, 1.24-7.08; P = .01) and tonsillar hypertrophy (odds ratio, 3.38; 95% CI, 1.42-8.02; P = .01) were predictors for the presence of OSA. No demographic or clinical characteristics were predictors for severe OSA., Conclusion: Underweight children with OSA, as compared with those without OSA, are more likely to have decreased height, tonsillar hypertrophy, and allergic rhinitis. There are no predictors of severe OSA in underweight children. We recommend polysomnography for the diagnosis of OSA in symptomatic underweight children with large tonsils, especially when they have a history of allergies.

Background: Nephrolithiasis in allograft kidneys is rare, but this diagnosis may lead to allograft complications and patient morbidity. Previous studies that have evaluated nephrolithiasis posttransplant have focused on surgical stone management, with limited data on urine metabolic risk factors and the presence of stones after follow-up., Methods: We retrospectively evaluated kidney transplant recipients who were diagnosed with transplant nephrolithiasis between 2009 and 2019. Computed tomography and ultrasound imaging were used to confirm stone presence., Results: The incidence of allograft kidney stone formation was 0.86% of 6548 kidney transplant recipients. Of the 56 cases identified, 17 (30%) had a pretransplant history of nephrolithiasis. Only four (7%) patients received a known kidney stone at the time of allograft implantation. Of the 56 cases, 34 had a 24-h supersaturation study. The urine supersaturation study showed 32 patients (94%) had a urine citrate of <450 mg excreted in 24 h (median 124.5 mg/24 h, reference range >500 mg/24 h), along with 22 patients (61%) having a urine oxalate excretion of ≥30 mg in 24 h (median 34.4 mg/24 h, reference range <30 mg/24 h). Calcium oxalate composition was most common (91% with >1 supersaturation for calcium oxalate crystals), with normal median urine calcium levels (median urine calcium 103.5 mg/24 h, reference range <200 mg/24 h). After a 4-year follow-up, 50% ( n = 28) required surgical intervention and 43 (77%) patients continued to have evidence of transplant nephrolithiasis on imaging., Conclusions: This is the largest study of transplant nephrolithiasis confirming that hypocitraturia and hyperoxaluria were the most significant urine metabolic risk factors associated with allograft nephrolithiasis and that hyperoxaluria was the most prevalent driver for calcium oxalate stone composition. Our study is first to show low stone-free rates at the last follow-up and a significant proportion requiring surgical intervention., (© The Author(s) 2021. Published by Oxford University Press on behalf of the ERA.)

Objective: The aim of this study was to determine the interaction of full thickness excisional wounds and tumors in vivo., Summary of Background Data: Tumors have been described as wounds that do not heal due to similarities in stromal composition. On the basis of observations of slowed tumor growth after ulceration, we hypothesized that full thickness excisional wounds would inhibit tumor progression in vivo., Methods: To determine the interaction of tumors and wounds, we developed a tumor xenograft/allograft (human head and neck squamous cell carcinoma SAS/mouse breast carcinoma 4T1) wound mouse model. We examined tumor growth with varying temporospatial placement of tumors and wounds or ischemic flap. In addition, we developed a tumor/wound parabiosis model to understand the ability of tumors and wounds to recruit circulating progenitor cells., Results: Tumor growth inhibition by full thickness excisional wounds was dose-dependent, maintained by sequential wounding, and relative to distance. This effect was recapitulated by placement of an ischemic flap directly adjacent to a xenograft tumor. Using a parabiosis model, we demonstrated that a healing wound was able to recruit significantly more circulating progenitor cells than a growing tumor. Tumor inhibition by wound was unaffected by presence of an immune response in an immunocompetent model using a mammary carcinoma. Utilizing functional proteomics, we identified 100 proteins differentially expressed in tumors and wounds., Conclusion: Full thickness excisional wounds have the ability to inhibit tumor growth in vivo. Further research may provide an exact mechanism for this remarkable finding and new advances in wound healing and tumor biology., Competing Interests: The authors have declared that no conflict of interest exists., (Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.)

Fibroblast heterogeneity has been shown within the unwounded mouse dorsal dermis, with fibroblast subpopulations being identified according to anatomical location and embryonic lineage. Using lineage tracing, we demonstrate that paired related homeobox 1 (Prrx1)-expressing fibroblasts are responsible for acute and chronic fibroses in the ventral dermis. Single-cell transcriptomics further corroborated the inherent fibrotic characteristics of Prrx1 fibroblasts during wound repair. In summary, we identify and characterize a fibroblast subpopulation in the mouse ventral dermis with intrinsic scar-forming potential., Competing Interests: Declaration of Interests H.Y.C. is a co-founder of Accent Therapeutics and Boundless Bio and an advisor to 10x Genomics, Arsenal Bioscience, and Spring Discovery., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Not all women undergo post-mastectomy breast reconstruction due to medical comorbidities or personal preference. An aesthetically pleasing closure and contour of the chest wall is still desired, though may be technically difficult to achieve in some patients. By combining techniques and lessons learned from breast reductions and female-to-male mastectomies (FTTM), we present a technical approach to aesthetic primary closure post-mastectomy that can be utilized in patients regardless of preoperative breast size., Methods: After mastectomy, excess cranial/caudal tissue is determined and the lower flap is de-epithelialized to allow for bulk in the reconstructed breast. Excess tissue in the horizontal plane is assessed, and axillary, nonbreast tissue is medialized. Excess skin in the horizontal plane is removed with a small lateral incision similar to a wise-pattern closure., Results: We have performed this technique with good aesthetic results and satisfied patients postoperatively., Conclusion: When performing post-mastectomy closure without reconstruction, attention to tissue excess, medialization of axillary tissue and providing bulk with lateral and caudal tissue allows for an easy, reproducible, and aesthetic closure., (© 2019 Wiley Periodicals, Inc.)

During both embryonic development and adult tissue regeneration, changes in chromatin structure driven by master transcription factors lead to stimulus-responsive transcriptional programs. A thorough understanding of how stem cells in the skeleton interpret mechanical stimuli and enact regeneration would shed light on how forces are transduced to the nucleus in regenerative processes. Here we develop a genetically dissectible mouse model of mandibular distraction osteogenesis-which is a process that is used in humans to correct an undersized lower jaw that involves surgically separating the jaw bone, which elicits new bone growth in the gap. We use this model to show that regions of newly formed bone are clonally derived from stem cells that reside in the skeleton. Using chromatin and transcriptional profiling, we show that these stem-cell populations gain activity within the focal adhesion kinase (FAK) signalling pathway, and that inhibiting FAK abolishes new bone formation. Mechanotransduction via FAK in skeletal stem cells during distraction activates a gene-regulatory program and retrotransposons that are normally active in primitive neural crest cells, from which skeletal stem cells arise during development. This reversion to a developmental state underlies the robust tissue growth that facilitates stem-cell-based regeneration of adult skeletal tissue.

In the original version of this Article, the authors inadvertently omitted Elizabeth A. Brett, who contributed to the generation of the histology figures, from the author list.This has now been corrected in both the PDF and HTML versions of the Article.

Stem cell regulation and hierarchical organization of human skeletal progenitors remain largely unexplored. Here, we report the isolation of a self-renewing and multipotent human skeletal stem cell (hSSC) that generates progenitors of bone, cartilage, and stroma, but not fat. Self-renewing and multipotent hSSCs are present in fetal and adult bones and can also be derived from BMP2-treated human adipose stroma (B-HAS) and induced pluripotent stem cells (iPSCs). Gene expression analysis of individual hSSCs reveals overall similarity between hSSCs obtained from different sources and partially explains skewed differentiation toward cartilage in fetal and iPSC-derived hSSCs. hSSCs undergo local expansion in response to acute skeletal injury. In addition, hSSC-derived stroma can maintain human hematopoietic stem cells (hHSCs) in serum-free culture conditions. Finally, we combine gene expression and epigenetic data of mouse skeletal stem cells (mSSCs) and hSSCs to identify evolutionarily conserved and divergent pathways driving SSC-mediated skeletogenesis. VIDEO ABSTRACT., (Published by Elsevier Inc.)

Purpose: To determine whether differential kinematics, kinetics, rates of energy use, and cardiopulmonary responses occur during running with water bottles and bottle belt holders compared with running only., Methods: Trained runners (N = 42; age 27.2 [6.4] y) ran on an instrumented treadmill for 4 conditions in a randomized order: control run (CON), handheld full water bottle (FULL; 16.9 fluid oz; 454 g), handheld half-full water bottle (HALF; 8.4 fluid oz; 227 g), and waist-worn bottle belt holder (BELT; hydration belt; 676 g). Gas exchange was measured using a portable gas analyzer. Kinetic and kinematic responses were determined by standard 3-dimensional videographic techniques. Interactions of limb side (right and left) by study condition (CON, FULL, HALF, and BELT) were tested for rates of oxygen use and energy expenditure and kinematic and kinetic parameters., Results: No significant limb-side × condition interactions existed for rates of oxygen use or energy expenditure. A significant interaction occurred with sagittal elbow flexion (P < .001). Transverse pelvic-rotation excursions differed on average 3.8° across conditions. The minimum sagittal hip-flexion moment was higher in the right leg in the HALF and BELT conditions compared with CON (P < .001)., Conclusions: Carrying water by hand or on the waist does not significantly change the kinematics of running motion, rates of oxygen use and energy expenditure, or cardiopulmonary measures over short durations. Runners likely make adjustments to joint moments and powers that preserve balance and protect the lower-extremity joints while maintaining rates of oxygen use and energy expenditure.

Targeted genetic dissection of tissues to identify precise cell populations has vast biological and therapeutic applications. Here we develop an approach, through the packaging and delivery of 4-hydroxytamoxifen liposomes (LiTMX), that enables localized induction of CreER T2 recombinase in mice. Our method permits precise, in vivo, tissue-specific clonal analysis with both spatial and temporal control. This technology is effective using mice with both specific and ubiquitous Cre drivers in a variety of tissue types, under conditions of homeostasis and post-injury repair, and is highly efficient for lineage tracing and genetic analysis. This methodology is directly and immediately applicable to the developmental biology, stem cell biology and regenerative medicine, and cancer biology fields.

Background: Cardiorespiratory fitness (CRF) is the only major risk factor that is not routinely assessed in the clinical setting, for preventive medicine. A valid and practical CRF test is needed for use in the clinics. The objective of this study is to demonstrate the validity of a 3-minute squat test to assess CRF in primary care., Methods: A cross-sectional study in which the participants performed both the Ruffier squat test and the Balke maximal treadmill test. The study was conducted in a clinical setting from September 2016 to March 2017. We recruited a convenient sample of 40 adults between 18 and 64 years from the general U.S. population. Participants completed 30 squats in 45 seconds, paced by a metronome. Heart rate was measured at rest (P1), immediately after the test (P2), one minute after the test (P3). [Formula: see text] was measured using the Balke maximal treadmill fitness test., Results: Of the 40 participants, there were 18 men and 22 women. Mean age was 31.2 years (SD = 9.9). We found that the best [Formula: see text] predictors were HR features P1/height and (P2-P3)/age3. Our best-performing model using these two features predicted individuals' CRF levels with an adjusted R2 of 0.637, sensitivity of 0.79, and specificity of 0.56., Conclusions: The study provided strong evidence for the validity of the squat test in the clinical setting. Further, the equation of our model along with [Formula: see text] normative tables provides an efficient and easy way to assess CRF in a primary care setting., Competing Interests: The authors have declared that no competing interests exist.

Significance: Excessive scarring is major clinical and financial burden in the United States. Improved therapies are necessary to reduce scarring, especially in patients affected by hypertrophic and keloid scars. Recent Advances: Advances in our understanding of mechanical forces in the wound environment enable us to target mechanical forces to minimize scar formation. Fetal wounds experience much lower resting stress when compared with adult wounds, and they heal without scars. Therapies that modulate mechanical forces in the wound environment are able to reduce scar size. Critical Issues: Increased mechanical stresses in the wound environment induce hypertrophic scarring via activation of mechanotransduction pathways. Mechanical stimulation modulates integrin, Wingless-type, protein kinase B, and focal adhesion kinase, resulting in cell proliferation and, ultimately, fibrosis. Therefore, the development of therapies that reduce mechanical forces in the wound environment would decrease the risk of developing excessive scars. Future Directions: The development of novel mechanotherapies is necessary to minimize scar formation and advance adult wound healing toward the scarless ideal. Mechanotransduction pathways are potential targets to reduce excessive scar formation, and thus, continued studies on therapies that utilize mechanical offloading and mechanomodulation are needed.

Significance: Scarring of the skin from burns, surgery, and injury constitutes a major burden on the healthcare system. Patients affected by major scars, particularly children, suffer from long-term functional and psychological problems. Recent Advances: Scarring in humans is the end result of the wound healing process, which has evolved to rapidly repair injuries. Wound healing and scar formation are well described on the cellular and molecular levels, but truly effective molecular or cell-based antiscarring treatments still do not exist. Recent discoveries have clarified the role of skin stem cells and fibroblasts in the regeneration of injuries and formation of scar. Critical Issues: It will be important to show that new advances in the stem cell and fibroblast biology of scarring can be translated into therapies that prevent and reduce scarring in humans without major side effects. Future Directions: Novel therapies involving the use of purified human cells as well as agents that target specific cells and modulate the immune response to injury are currently undergoing testing. In the basic science realm, researchers continue to refine our understanding of the role that particular cell types play in the development of scar.

Significance: Wound healing requires a highly orchestrated coordination of processes that are not yet fully understood. Therefore, available clinical therapies are thus far limited in their efficacy in preventing and treating both chronic wounds and scars. Current gene-based therapeutics is largely based on our understanding of the protein-coding genome and proteins involved in known wound healing pathways. Recent Advances: Noncoding RNAs such as microRNAs and long noncoding RNAs have recently been found to be significant modulators of gene expression in diverse cellular pathways. Research has now implicated noncoding RNAs in nearly every stage of the wound healing process, suggesting that they may serve as clinical therapeutic targets. Noncoding RNAs are critical regulators in processes such as angiogenesis and cutaneous cell migration and proliferation, including classically described biological pathways previously attributed to mostly protein constituents. Critical Issues: The complexity and diversity of the interactions of noncoding RNAs with their targets and other binding partners require thorough characterization and understanding of their functions before they may be altered to modulate human wound healing pathways. Future Directions: Research in the area of noncoding RNAs continues to rapidly expand our understanding of their potential roles in physiological and pathological wound healing. Coupled with improving technologies to enhance or suppress target noncoding RNA in vivo , these advances hold great promise in the development of new therapies for wound healing.

Objective: Splinting full-thickness cutaneous wounds in mice has allowed for a humanized model of wound healing. Delineating the epithelial edge and assessing time to closure of these healing wounds via macroscopic visualization have remained a challenge. Approach: Double transgenic mice were created by crossbreeding K14-Cre and ROSA mT/mG reporter mice. Full-thickness excisional wounds were created in K14-Cre/ROSA mT/mG mice ( n  = 5) and imaged using both normal and fluorescent light on the day of surgery, and every other postoperative day (POD) until wound healing was complete. Ten blinded observers analyzed a series of images from a single representative healing wound, taken using normal or fluorescent light, to decide the POD when healing was complete. K14-Cre/ROSA mT/mG mice ( n  = 4) were subsequently sacrificed at the four potential days of rated wound closure to accurately determine the histological point of wound closure using microscopic fluorescence imaging. Results: Average time to wound closure was rated significantly longer in the wound series images taken using normal light, compared with fluorescent light (mean POD 13.6 vs. 11.6, * p  = 0.008). Fluorescence imaging of histological samples indicated that reepithelialization was complete at 12 days postwounding. Innovation: We describe a novel technique, using double transgenic mice K14-Cre/ROSA mT/mG and fluorescence imaging, to more accurately determine the healing time of wounds in mice upon macroscopic evaluation. Conclusion: The accuracy by which wound healing can be macroscopically determined in vivo in mouse models of wound healing is significantly enhanced using K14-Cre/ROSA mT/mG double transgenic mice and fluorescence imaging.

The monocyte lineage is essential to normal wound healing. Macrophage inhibition or knockout in mice results in impaired wound healing through reduced neovascularization, granulation tissue formation, and reepithelialization. Numerous studies have either depleted macrophages or reduced their activity in the context of wound healing. Here, we demonstrate that by increasing the number of macrophages or monocytes in the wound site above physiologic levels via pullulan-collagen composite dermal hydrogel scaffold delivery, the rate of wound healing can be significantly accelerated in both wild-type and diabetic mice, with no adverse effect on the quality of repair. Macrophages transplanted onto wounds differentiate into M1 and M2 phenotypes of different proportions at various time points, ultimately increasing angiogenesis. Given that monocytes can be readily isolated from peripheral blood without in vitro manipulation, these findings hold promise for translational medicine aimed at accelerating wound healing across a broad spectrum of diseases.

Background: Regular physical activity can not only help with weight management, but also lower cardiovascular risks, cancer rates, and chronic disease burden. Yet, only approximately 20% of Americans currently meet the physical activity guidelines recommended by the US Department of Health and Human Services. With the rapid development of mobile technologies, mobile apps have the potential to improve participation rates in exercise programs, particularly if they are evidence-based and are of sufficient content quality., Objective: The goal of this study was to develop and test an instrument, which was designed to score the content quality of exercise program apps with respect to the exercise guidelines set forth by the American College of Sports Medicine (ACSM)., Methods: We conducted two focus groups (N=14) to elicit input for developing a preliminary 27-item scoring instruments based on the ACSM exercise prescription guidelines. Three reviewers who were no sports medicine experts independently scored 28 exercise program apps using the instrument. Inter- and intra-rater reliability was assessed among the 3 reviewers. An expert reviewer, a Fellow of the ACSM, also scored the 28 apps to create criterion scores. Criterion validity was assessed by comparing nonexpert reviewers' scores to the criterion scores., Results: Overall, inter- and intra-rater reliability was high with most coefficients being greater than .7. Inter-rater reliability coefficients ranged from .59 to .99, and intra-rater reliability coefficients ranged from .47 to 1.00. All reliability coefficients were statistically significant. Criterion validity was found to be excellent, with the weighted kappa statistics ranging from .67 to .99, indicating a substantial agreement between the scores of expert and nonexpert reviewers. Finally, all apps scored poorly against the ACSM exercise prescription guidelines. None of the apps received a score greater than 35, out of a possible maximal score of 70., Conclusions: We have developed and presented valid and reliable scoring instruments for exercise program apps. Our instrument may be useful for consumers and health care providers who are looking for apps that provide safe, progressive general exercise programs for health and fitness., (©Yi Guo, Jiang Bian, Trevor Leavitt, Heather K Vincent, Lindsey Vander Zalm, Tyler L Teurlings, Megan D Smith, François Modave. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 07.03.2017.)

Invasive cancers, major injuries, and infection can cause bone defects that are too large to be reconstructed with preexisting bone from the patient's own body. The ability to grow bone de novo using a patient's own cells would allow bony defects to be filled with adequate tissue without the morbidity of harvesting native bone. There is interest in the use of adipose-derived stromal cells (ASCs) as a source for tissue engineering because these are obtained from an abundant source: the patient's own adipose tissue. However, ASCs are a heterogeneous population and some subpopulations may be more effective in this application than others. Isolation of the most osteogenic population of ASCs could improve the efficiency and effectiveness of a bone engineering process. In this protocol, ASCs are obtained from subcutaneous fat tissue from a human donor. The subpopulation of ASCs expressing the marker BMPR-IB is isolated using FACS. These cells are then applied to an in vivo calvarial defect healing assay and are found to have improved osteogenic regenerative potential compared with unsorted cells.

Background: Sanativo is an over-the-counter Brazilian product derived from Amazon rainforest plant extract that is purported to improve the healing of skin wounds. Two experimental studies have shown accelerated closure of nonsplinted excisional wounds in rat models. However, these models allow for significant contraction of the wound and do not approximate healing in the tight skin of humans., Methods: Full-thickness excisional wounds were created on the dorsal skin of mice and were splinted with silicone rings, a model that forces the wound to heal by granulation and reepithelialization. Sanativo or a control solution was applied either daily or every other day to the wounds. Photographs were taken every other day, and the degree of reepithelialization of the wounds was determined., Results: With both daily and every-other-day applications, Sanativo delayed reepithelialization of the wounds. Average time to complete healing was faster with control solution versus Sanativo in the daily application group (9.4 versus 15.2 days; p < 0.0001) and the every-other-day application group (11 versus 13 days; p = 0.017). The size of visible scar at the last time point of the study was not significantly different between the groups, and no differences were found on histologic examination., Conclusions: Sanativo wound healing compound delayed wound reepithelialization in a mouse splinted excisional wound model that approximates human wound healing. The size of visible scar after complete healing was not improved with the application of Sanativo. These results should cast doubt on claims that this product can improve wound healing in humans.