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Chronic kidney disease (CKD) is an increasingly prevalent disorder that poses a significant global health and socioeconomic burden. East Asian countries such as China, Taiwan, Japan, and South Korea have a higher incidence and prevalence of kidney failure when compared to Western nations, and the reasons for this discrepancy remain unclear. Aldehyde dehydrogenase 2 (ALDH2) is an essential detoxifying enzyme for exogenous and endogenous aldehyde metabolism in mitochondria. Inactivating mutations at E504K and E487K are found in 35-45% of East Asian populations and has been linked to a higher risk of various disorders, including cardiovascular diseases and cancer. However, little is known about the role of ALDH2 in CKD. Here, we characterized the expression pattern of ALDH2 in normal and CKD human and mouse kidneys and demonstrated that ALDH2 expression was significantly reduced, and that the protein level was inversely correlated with the degree of CKD and fibrosis. Further, we treated ALDH2∗2 knock-in mice, a loss of ALDH2 function model, with aristolochic acid and found that these mice showed enhanced fibrosis. Moreover, ALDH2 deficiency was associated with kidney fibrosis involving epithelial cell differentiation process in vivo and in vitro. However, ALDH2 overexpression protected proximal tubule epithelial cells from transforming growth factor-β-induced dedifferentiation or partial epithelial-mesenchymal transdifferentiation in vitro. Thus, our findings yield important clinical information regarding the development and progression of CKD involving ALDH2, especially among East Asian populations., (Copyright © 2024 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Cancer continues to impose a substantial global health burden, particularly among the elderly, where the ongoing global demographic shift towards an ageing population underscores the growing need for early cancer detection. This is essential for enabling personalised cancer care and optimised treatment throughout the disease course to effectively mitigate the increasing societal impact of cancer. Liquid biopsy has emerged as a promising strategy for cancer diagnosis and treatment monitoring, offering a minimally invasive method for the isolation and molecular profiling of circulating tumour-derived components. The expansion of the liquid biopsy approach to include the detection of tumour-derived extracellular vesicles (tdEVs) holds significant therapeutic opportunity. Evidence suggests that tdEVs carry cargo reflecting the contents of their cell-of-origin and are abundant within the blood, exhibiting superior stability compared to non-encapsulated tumour-derived material, such as circulating tumour nucleic acids and proteins. However, despite theoretical promise, several obstacles hinder the translation of extracellular vesicle-based cancer biomarkers into clinical practice. This critical review assesses the current prospects and challenges facing the adoption of tdEV biomarkers in clinical practice, offering insights into future directions and proposing strategies to overcome translational barriers. By addressing these issues, EV-based liquid biopsy approaches could revolutionise cancer diagnostics and management.

Background: While factors associated with long COVID (LC) continue to be illuminated, little is known about recovery. This study used national survey data to assess factors associated with recovery from LC., Methods: We used data from the 2022 National Health Interview Survey, a cross-sectional sample of noninstitutionalized US adults. Survey analysis was used to account for oversampling and nonresponse bias and to obtain nationally representative estimates. A multivariable logistic regression model was used to identify potential predictors of LC recovery., Results: Among those reporting ever having COVID-19, 17.7% or an estimated 17.5 million American adults reported ever having LC, and among those with LC, 48.5% or an estimated 8.5 million reported having recovered. Multivariable logistic regression analysis showed that Hispanic adults were significantly more likely than White adults to report recovery from LC. At the same time, those with severe COVID-19 symptoms and those who had more than a high school degree, were aged 40 years or older, or were female were less likely to report recovery., Conclusion: Significant variations in LC recovery were noted across age, sex, race and ethnicity, education, and severity of COVID-19 symptoms. Further work is needed to elucidate the causes of these differences and identify strategies to increase recovery rates., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Ivabradine is a pharmacologic agent that inhibits the funny current responsible for determining heart rate in the sinoatrial node. Ivabradine's clinical potential has been investigated in the context of heart failure since it is associated with reduced myocardial oxygen demand, enhanced diastolic filling, stroke volume, and coronary perfusion time; however, it is yet to demonstrate definitive mortality benefit. Alternative effects of ivabradine include modulation of the renin-angiotensin-aldosterone system, sympathetic activation, and endothelial function. Here, we review key clinical trials informing the clinical use of ivabradine and explore opportunities for leveraging its potential pleiotropic effects in other diseases, including treatment of hyperadrenergic states and mitigating complications of COVID-19 infection., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The rotator cuff (RC) plays a pivotal role in the performance and health of the shoulder and upper extremity. Blood flow restriction training (BFRT) is a modality to improve strength and muscle hypertrophy with even low-load training in healthy and injured individuals. There is minimal evidence examining its effect proximal to the occluded area, and particularly on the RC., Hypothesis & Purpose: The purpose of this case series is to explore the effects of low-load BFRT on RC strength, hypertrophy, and tendon thickness in asymptomatic individuals., Study Design: Case series., Methods: Fourteen participants with asymptomatic, untrained shoulders were recruited to participate. They performed an eight-week low-load shoulder exercise regimen where BFR was applied to the dominant arm only during exercise. The dependent variables were maximal isometric strength of the shoulder external rotators(ER) and elevators (in the scapular plane in full can position) (FC) measured via handheld dynamometry, cross sectional area (CSA) of the supraspinatus and infraspinatus muscles, and supraspinatus tendon thickness measured via ultrasound imaging (US). Mean changes within and between arms were compared after training using paired t-tests. Cohen's d was used to determine effect sizes., Results: All participants were able to complete the BFRT regimen without adverse effects. Mean strength and CSA increased for all variables in both arms, however this increase was only significant (p\<0.01) for FC strength bilaterally and CSA for the supraspinatus and infraspinatus on the BFRT side. The effect sizes for increased supraspinatus and infraspinatus CSA on the BFRT side were 0.40 (9.8% increase) and 0.46 (11.7% increase) respectively. There were no significant differences when comparing the mean changes of the BFRT side to the non-BFRT side for strength or muscle CSA. There were no significant changes to supraspinatus tendon thickness., Conclusion: These results suggest variability in response of the RC musculature to low-load BFRT in asymptomatic individuals. The potential for a confounding systemic response in the study design makes determining whether low-load BFRT is more beneficial than low-load non-BFRT difficult. The hypertrophy seen on the BFRT side warrants further study., Level of Evidence: 4., Competing Interests: All authors, their immediate family, and any research foundation with which they are affiliated did not receive any financial payments or other benefits from any commercial entity related to the subject of this article., (© The Author(s).)

Background: Currently, there are limited reviews in the dermatology literature on how to approach reconstruction of nasal lining in full-thickness nasal defects resulting from Mohs micrographic surgery. Given variable training and experience, dermatologic surgeons may seek additional references to help reconstruct certain advanced defects. We sought to synthesize literature from dermatologic surgery, plastic surgery, and otolaryngology to review repair options and considerations for repair of nasal lining defects., Objective: To present a comprehensive literature review of repair options for nasal lining reconstruction and discuss advantages, disadvantages, specific anatomic considerations, and techniques to execute such options., Materials and Methods: Articles from several different reconstructive specialties including dermatologic/Mohs surgery, otolaryngology, and plastic and reconstructive surgery were reviewed. Instructive images were compiled to illustrate several techniques, with additional medical illustration recreations included to help showcase important reconstructive approaches., Results: A comprehensive descriptive review of nasal lining repair options for the reconstructive surgeon., Conclusion: Advanced tumors can result in full-thickness nasal defects, and this review describes various reconstructive options for reconstruction based on the extent of the defect., (Copyright © 2024 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Background: Following prenatal diagnosis of critical congenital heart disease (CCHD), parents encounter emotional distress while facing caregiving challenges. Supportive psycho-educational interventions using mobile health (mHealth) can make care more accessible., Objectives: We tested a novel nurse-guided mHealth care program, Preparing Heart and Mind ™ (PHM ™ ), with the objectives of examining feasibility and estimating the effect of the intervention on parents' emotional distress., Methods: This pilot study design randomized participants using a 2:1 intervention to control ratio. Analysis involved description of retention, and intervention attendance and engagement, and adjusted linear mixed models to estimate group differences in depressive (CES-D), anxiety (STAI-S), and traumatic stress (IES-r) symptoms., Results: The sample included 55 parents (n=38 PHM ™ group, n=17 control). Complete retention of 37 (67%) parents included 29 (76%) in the PHM ™ group and 8 (47%) control. Most attrition was due to infant death (7 parents), transplant referral (2 parents), or postnatal diagnostic ineligibility (4 parents). For the PHM ™ group, ≥96% of parents attended pre- and postnatal sessions and most (65%) messaged with the nurse. mHealth engagement was highest prenatally, with handling uncertainty the most viewed topic (average 94% pages viewed). In linear mixed models analyses, the PHM ™ group had on average 4.84 points lower depression (95% CI: -10.68-1.04), 6.56 points lower anxiety (-14.04-0.92), and 6.28 points lower trauma (-14.44-1.88) scores by study end., Conclusion: Findings suggest that a nurse-guided mHealth approach is feasible and may contribute to a clinically important reduction in parents' emotional distress.

Background: The chondrogenic differentiation of mesenchymal stem cells (MSCs) to enhance cartilage repair and regeneration is a promising strategy to alleviate osteoarthritis (OA) progression., Method: The potency of JD-312 in inducing chondrogenic differentiation of MSCs was assessed and verified. The efficacy of JD-312-treated MSCs was evaluated using a Sprague-Dawley rat DMM model. Additionally, the capacity of JD-312 to successfully recruit bone marrow-derived mesenchymal stem cells (BMSCs) for the treatment of OA in vitro was confirmed via intra-articular injection. The repair status of the articular cartilage was analyzed in vivo through histological examination., Result: In this study, we identify JD-312 as a novel non-toxic small molecule that can promote chondrogenic differentiation in human umbilical cord-derived MSCs (hUCMSCs) and human bone marrow MSCS (hBMSCs) in vitro . We also show that transient differentiation of MSCs with JD-312 prior to in vivo administration remarkably improves the regeneration of cartilage and promotes Col2a1 and Acan expression in rat models of DMM, in comparison to kartogenin (KGN) pre-treatment or MSCs alone. Furthermore, direct intra-articular injection of JD-312 in murine model of OA showed reduced loss of articular cartilage and improved pain parameters. Lastly, we identified that the effects of JD-312 are at least in part mediated via upregulation of genes associated with the focal adhesion, PI3K-Akt signaling and the ECM-receptor interaction pathways, and specifically cartilage oligomeric matrix protein (COMP) may play a vital role., Conclusion: Our study demonstrated that JD-312 showed encouraging repair effects for OA in vivo ., The Translational Potential of This Article: Together, our findings demonstrate that JD-312 is a promising new therapeutic molecule for cartilage regeneration with clinical potential., Competing Interests: No confict of interest., (© 2023 The Authors.)

Diabetic kidney disease (DKD), or diabetic nephropathy (DN), is one of the most prevalent complications of type 2 diabetes mellitus (T2DM) and causes severe burden on the general welfare of T2DM patients around the world. While several new agents have shown promise in treating this condition and potentially halting the progression of the disease, more work is needed to understand the complex regulatory network involved in the disorder. Recent studies have provided new insights into the connection between autophagy, a physiological metabolic process known to maintain cellular homeostasis, and the pathophysiological pathways of DKD. Typically, autophagic activity plays a role in DKD progression mainly by promoting an inflammatory response to tissue damage, while both overactivated and downregulated autophagy worsen disease outcomes in different stages of DKD. This correlation demonstrates the potential of autophagy as a novel therapeutic target for the disease, and also highlights new possibilities for utilizing already available DN-related medications. In this review, we summarize findings on the relationship between autophagy and DKD, and the impact of these results on clinical management strategies.

Objective: To identify factors that support or limit human milk (HM) feeding and direct breastfeeding (BF) for infants with single ventricle congenital heart disease at neonatal stage 1 palliation (S1P) discharge and at stage 2 palliation (S2P) (∼4-6 months old)., Study Design: Analysis of the National Pediatric Cardiology Quality Improvement Collaborative (NPC-QIC) registry (2016-2021; 67 sites). Primary outcomes were any HM, exclusive HM, and any direct BF at S1P discharge and at S2P. The main analysis involved multiple phases of elastic net logistic regression on imputed data to identify important predictors., Results: For 1944 infants, the strongest predictor domain areas included preoperative feeding, demographics/social determinants of health, feeding route, clinical course, and site. Significant findings included: preoperative BF was associated with any HM at S1P discharge (OR = 2.02, 95% CI = 1.74-3.44) and any BF at S2P (OR = 2.29, 95% CI = 1.38-3.80); private/self-insurance was associated with any HM at S1P discharge (OR = 1.91, 95% CI = 1.58-2.47); and Black/African-American infants had lower odds of any HM at S1P discharge (OR = 0.54, 95% CI = 0.38-0.65) and at S2P (0.57, 0.30-0.86). Adjusted odds of HM/BF practices varied among NPC-QIC sites., Conclusions: Preoperative feeding practices predict later HM and BF for infants with single ventricle congenital heart disease; therefore, family-centered interventions focused on HM/BF during the S1P preoperative time are needed. These interventions should include evidence-based strategies to address implicit bias and seek to minimize disparities related to social determinants of health. Future research is needed to identify supportive practices common to high-performing NPC-QIC sites., Competing Interests: Declaration of Competing Interest This study was supported by the National Institutes of Health (NINR, Award #F31NR020577). Content is the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. D.L.S is a member of the Advisory Board for Medela Healthcare US. The other authors have no conflicts of interest to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background Infants with single ventricle congenital heart disease undergo 3 staged surgeries/interventions, with risk for morbidity and mortality. We estimated the effect of human milk (HM) and direct breastfeeding on outcomes including necrotizing enterocolitis, infection-related complications, length of stay, and mortality. Methods and Results We analyzed the National Pediatric Cardiology Quality Improvement Collaborative (NPC-QIC) registry (2016-2021), examining HM/breastfeeding groups during stage 1 and stage 2 palliations. We calculated propensity scores for feeding exposures, then fitted Poisson and logistic regression models to compare outcomes between propensity-matched cohorts. Participants included 2491 infants (68 sites). Estimates for all outcomes were better in HM/breastfeeding groups. Infants fed exclusive HM before stage 1 palliation (S1P) had lower odds of preoperative necrotizing enterocolitis (odds ratio [OR], 0.37 [95% CI, 0.17-0.84]; P =0.017) and shorter S1P length of stay (rate ratio [RR], 0.87 [95% CI, 0.78-0.98]; P =0.027). During the S1P hospitalization, infants with high HM had lower odds of postoperative necrotizing enterocolitis (OR, 0.28 [95% CI, 0.15-0.50]; P <0.001) and sepsis (OR, 0.29 [95% CI, 0.13-0.65]; P =0.003), and shorter S1P length of stay (RR, 0.75 [95% CI, 0.66-0.86]; P <0.001). At stage 2 palliation, infants with any HM (RR, 0.82 [95% CI, 0.69-0.97]; P =0.018) and any breastfeeding (RR, 0.71 [95% CI, 0.57-0.89]; P =0.003) experienced shorter length of stay. Conclusions Infants with single ventricle congenital heart disease in high-HM and breastfeeding groups experienced multiple significantly better outcomes. Given our findings of improved health, strategies to increase the rates of HM/breastfeeding in these patients should be implemented. Future research should replicate these findings with granular feeding data and in broader congenital heart disease populations, and should examine mechanisms (eg, HM components, microbiome) by which HM/breastfeeding benefits these infants.

Competing Interests: Conflicts of interest None disclosed.

Osteoarthritis (OA) is one of the most common chronic diseases in the world. However, current treatment modalities mainly relieve pain and inhibit cartilage degradation, but do not promote cartilage regeneration. In this study, we show that G protein-coupled receptor class C group 5 member B (GPRC5B), an orphan G-protein-couple receptor, not only inhibits cartilage degradation, but also increases cartilage regeneration and thereby is protective against OA. We observed that Gprc5b deficient chondrocytes had an upregulation of cartilage catabolic gene expression, along with downregulation of anabolic genes in vitro . Furthermore, mice deficient in Gprc5b displayed a more severe OA phenotype in the destabilization of the medial meniscus (DMM) induced OA mouse model, with upregulation of cartilage catabolic factors and downregulation of anabolic factors, consistent with our in vitro findings. Overexpression of Gprc5b by lentiviral vectors alleviated the cartilage degeneration in DMM-induced OA mouse model by inhibiting cartilage degradation and promoting regeneration. We also assessed the molecular mechanisms downstream of Gprc5b that may mediate these observed effects and identify the role of protein kinase B (AKT)-mammalian target of rapamycin (mTOR)-autophagy signaling pathway. Thus, we demonstrate an integral role of GPRC5B in OA pathogenesis, and activation of GPRC5B has the potential in preventing the progression of OA., (© 2023 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)

Approximately 30-50% of infants undergoing neonatal surgery for congenital heart disease (CHD) cannot meet oral feeding goals by discharge and require feeding tube support at home. Feeding tubes are associated with increased readmission rates and consequent hospital, payer, and family costs, and are a burden for family caregivers. Identification of modifiable risk factors for oral feeding problems could support targeted care for at-risk infants. Therefore, the aim of this systematic review is to determine risk factors for tube feeding at discharge in infants undergoing neonatal surgery for CHD. Following Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines, a search was conducted using MEDLINE, CINAHL, and Cochrane Database of Systematic Reviews. Studies published before 2010 were excluded. The search resulted in 607 records, of which 18 were included. Studies were primarily retrospective cohort designs and results were often inconsistent. Study quality was assessed using the Joanna Briggs Critical Appraisal Tools. As a group, the studies exhibited substantial risk for bias. Based on the findings, infants who struggle with feeding preoperatively, experience increased nil per os duration and/or low oral feeding volume postoperatively, experience increased duration of mechanical ventilation, or have vocal cord dysfunction may be at risk for tube feeding at hospital discharge. Factors warranting further examination include cardiac physiology (e.g., aortic arch obstruction) and the relationship between neurodevelopment and oral feeding. Clinicians should use caution in assuming risk for an individual and prioritize early implementation of interventions that facilitate oral feeding development., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Infants with single-ventricle (SV) congenital heart disease (CHD) undergo staged surgical and/or catheter-based palliation and commonly experience feeding challenges and poor growth. Little is known about human milk (HM) feeding or direct breastfeeding (BF) in this population. Aim: To determine (1) HM and BF prevalence for infants with SV CHD, and (2) whether BF at neonatal stage 1 palliation (S1P) discharge is associated with any HM at stage 2 palliation (S2P; ∼4-6 months old). Materials and Methods: Analysis of the National Pediatric Cardiology Quality Improvement Collaborative registry (2016-2021) using (1) descriptive statistics for prevalence, and (2) logistic regression adjusted for multiple variables (e.g., prematurity, insurance, length of stay) to examine early BF/later HM feeding. Results: Participants included 2,491 infants from 68 sites. HM prevalence ranged from 49.3% any/41.5% exclusive before S1P to 37.1% any/7.0% exclusive at S2P. Direct BF ranged from 16.1% any/7.9% exclusive before S1P to 9.2% any/3.2% exclusive at S2P discharge. Prevalence varied among sites; for example, 0-100% any HM before S1P. Infants BF at S1P discharge had greater odds of any HM (odds ratio = 4.11, 95% confidence interval [CI] = 2.79-6.07, p  < 0.001) and exclusive HM (1.85, 95% CI 1.03-3.30, p  = 0.039) at S2P. Conclusions: The prevalence of HM and BF for infants with SV CHD was low and declined over time. Direct BF at S1P discharge was associated with increased odds of any HM at S2P. Wide variation suggests that site-specific practices impact feeding outcomes. HM and BF prevalence are suboptimal in this population, and identification of supportive institutional practices is needed.

Primary bone cancer (PBC) comprises several subtypes each underpinned by distinctive genetic drivers. This driver diversity produces novel morphological features and clinical behaviour that serendipitously makes PBC an excellent metastasis model. Here, we report that some transfer RNA-derived small RNAs termed tRNA fragments (tRFs) perform as a constitutive tumour suppressor mechanism by blunting a potential pro-metastatic protein-RNA interaction. This mechanism is reduced in PBC progression with a gradual loss of tRNAGly TCC cleavage into 5' end tRF-Gly TCC when comparing low-grade, intermediate-grade and high-grade patient tumours. We detected recurrent activation of miR-140 leading to upregulated RUNX2 expression in high-grade patient tumours. Both tRF-Gly TCC and RUNX2 share a sequence motif in their 3' ends that matches the YBX1 recognition site known to stabilise pro-metastatic mRNAs. Investigating some aspects of this interaction network, gain- and loss-of-function experiments using small RNA mimics and antisense LNAs, respectively, showed that ectopic tRF-Gly TCC reduced RUNX2 expression and dispersed 3D micromass architecture in vitro . iCLIP sequencing revealed YBX1 physical binding to the 3' UTR of RUNX2 . The interaction between YBX1, tRF-Gly TCC and RUNX2 led to the development of the RUNX2 inhibitor CADD522 as a PBC treatment. CADD522 assessment in vitro revealed significant effects on PBC cell behaviour. In xenograft mouse models, CADD522 as a single agent without surgery significantly reduced tumour volume, increased overall and metastasis-free survival and reduced cancer-induced bone disease. Our results provide insight into PBC molecular abnormalities that have led to the identification of new targets and a new therapeutic., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Author(s).)

Aging is a complex process involving transcriptomic changes associated with deterioration across multiple tissues and organs, including the brain. Recent studies using heterochronic parabiosis have shown that various aspects of aging-associated decline are modifiable or even reversible. To better understand how this occurs, we performed single-cell transcriptomic profiling of young and old mouse brains after parabiosis. For each cell type, we cataloged alterations in gene expression, molecular pathways, transcriptional networks, ligand-receptor interactions and senescence status. Our analyses identified gene signatures, demonstrating that heterochronic parabiosis regulates several hallmarks of aging in a cell-type-specific manner. Brain endothelial cells were found to be especially malleable to this intervention, exhibiting dynamic transcriptional changes that affect vascular structure and function. These findings suggest new strategies for slowing deterioration and driving regeneration in the aging brain through approaches that do not rely on disease-specific mechanisms or actions of individual circulating factors., (© 2023. The Author(s).)

Objective: The purpose of this study was to determine the feasibility, reliability, validity, and responsiveness of the Timed Functional Arm and Shoulder Test (TFAST) in patients with shoulder problems., Methods: This study was a repeated-measures clinical measurement observational cohort study. A total of 104 patients who were symptomatic participated in this study. The TFAST was collected as part of an patient's outpatient physical therapist care at 6 different sites. The test and data collection were performed at 3 time points: baseline (initial evaluation), follow-up at the patient's first return visit within 7 days of evaluation, and discharge at the patient's final visit for care., Results: All participants were able to perform the TFAST at baseline, with 1 exception, and 67 participants completed data collection at all 3 time points. There were no adverse effects in any participant related to performing the TFAST. Intrarater intersession reliability, reported as ICC(2,1), was 0.91 (95% CI = 0.79-0.95). The mean difference in TFAST scores for the affected arm was 23.2 repetitions (77.4 at baseline to 100.6 at discharge). The Cohen d effect size was 1.02, and the standardized response mean was 0.95. The minimal clinically important difference was determined to be 21 repetitions., Conclusion: The TFAST seems to be feasible and appropriate for use in a wider population than other existing shoulder performance measures. The TFAST has demonstrated adequate reliability, validity, and responsiveness in patients with shoulder problems. Clinicians may consider using the TFAST to objectively assess patient performance., Impact: The TFAST may be used to expand measurement of objective shoulder performance in a wide population of patients with shoulder problems. This test may provide information beyond an patient's self-report and contribute to clinical decision-making., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Physical Therapy Association. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The nail unit and genitalia represent rare locations where malignant tumors may arise. Human papillomavirus has emerged as a causative agent of the development of the most common malignancies in these sites. Tissue preservation with surgery is of utmost importance, and tissue-sparing approaches are increasingly emphasized in the dermatology, urology, and gynecology literature. In addition to its tissue-sparing nature, Mohs micrographic surgery allows the complete evaluation of histologic margins to ensure tumor extirpation and may be the ideal treatment modality. The authors herein present approaches for the evaluation and treatment of malignant tumors of the nail unit and genitalia., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Over the last 40 years osteosarcoma (OS) survival has stagnated with patients commonly resistant to neoadjuvant MAP chemotherapy involving high dose methotrexate, adriamycin (doxorubicin) and platinum (cisplatin). Due to the rarity of OS, the generation of relevant cell models as tools for drug discovery is paramount to tackling this issue. Four literature databases were systematically searched using pre-determined search terms to identify MAP resistant OS cell lines and patients. Drug exposure strategies used to develop cell models of resistance and the impact of these on the differential expression of resistance associated genes, proteins and non-coding RNAs are reported. A comparison to clinical studies in relation to chemotherapy response, relapse and metastasis was then made. The search retrieved 1891 papers of which 52 were relevant. Commonly, cell lines were derived from Caucasian patients with epithelial or fibroblastic subtypes. The strategy for model development varied with most opting for continuous over pulsed chemotherapy exposure. A diverse resistance level was observed between models (2.2-338 fold) with 63% of models exceeding clinically reported resistance levels which may affect the expression of chemoresistance factors. In vitro p-glycoprotein overexpression is a key resistance mechanism; however, from the available literature to date this does not translate to innate resistance in patients. The selection of models with a lower fold resistance may better reflect the clinical situation. A comparison of standardised strategies in models and variants should be performed to determine their impact on resistance markers. Clinical studies are required to determine the impact of resistance markers identified in vitro in poor responders to MAP treatment, specifically with respect to innate and acquired resistance. A shift from seeking disputed and undruggable mechanisms to clinically relevant resistance mechanisms may identify key resistance markers that can be targeted for patient benefit after a 40-year wait., (© 2022. The Author(s).)

Background: During the coronavirus disease 2019 pandemic, national guidelines recommended that elective surgery for esophageal cancer be deferred by 3 months when hospital resources are limited. The impact of this delay on patient outcomes is unknown. We sought to evaluate the survival of patients with stage I and II/III esophageal cancer who undergo early vs delayed treatment., Study Design: Using the National Cancer Database from 2010 to 2017, multivariable Cox proportional hazards modeling and propensity score-matched analysis were employed to compare survival of patients with stage I esophageal cancer who received early (0 to 4 weeks after diagnosis) vs delayed esophagectomy (12 to 16 weeks) and of patients with stage II/III esophageal cancer who-after receiving timely chemoradiation (0 to 4 weeks after diagnosis)-underwent early (9 to 17 weeks) vs delayed esophagectomy (21 to 29 weeks)., Results: For stage I esophageal cancer, 226 (41.7%) patients underwent early esophagectomy, and 316 (58.3%) patients underwent delayed esophagectomy. Propensity score matching created 2 groups of 134 patients with early or delayed esophagectomy, whose 5-year survival was comparable (hazard ratio [HR] 65.0% [95% confidence interval (CI) 55.2% to 73.2%] vs HR 65.1% [95% CI 55.6% to 73.1%], p = 0.50). For stage II/III esophageal cancer, 1,236 (86.1%) patients underwent early esophagectomy, and 200 (13.9%) underwent delayed esophagectomy. Propensity score matching created 2 groups of 130 patients; the early esophagectomy group had improved 5-year survival compared with the delayed esophagectomy group (HR 41.6% [95% CI 32.1% to 50.8%] vs HR 22.9% [95% CI 14.9% to 31.8%], p = 0.006)., Conclusions: Early esophagectomy was associated with similar survival compared with delayed esophagectomy for patients with stage I esophageal cancer. For patients with stage II/III esophageal cancer, early esophagectomy was associated with improved survival relative to delayed esophagectomy., (Copyright © 2022 by the American College of Surgeons. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Background: Infants with congenital heart disease (CHD) are at risk for feeding-related morbidity and mortality, with growth failure and oral feeding problems associated with poor outcomes. The benefits of human milk (HM) for preterm infants have been well documented, but evidence on HM for infants with CHD has recently begun to emerge. Objectives: Our primary aim was to examine the impact of HM feeding on outcomes for infants with CHD. Methods: Following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines, a search was conducted using MEDLINE, CINAHL, and Cochrane Database of Systematic Reviews. The quality of each study was assessed using the Joanna Briggs Critical Appraisal Tools. A total of 16 studies were included. Results: There was evidence that an exclusive HM diet reduces the risk of necrotizing enterocolitis (NEC) for infants with CHD. Evidence with a higher risk for bias indicated that a well-managed HM diet may be associated with improved growth, shorter length of stay, and improved postoperative feeding and nutritional outcomes. Chylothorax outcomes were similar between modified HM and medium-chain triglyceride formula. The studies had significant limitations related to power, lack of control for covariates, and inconsistent delineation of feeding groups. Conclusions: Based on the reduced risk for NEC and given the conclusive benefits in other vulnerable populations, we recommend that clinicians and institutions prioritize programs to support HM feeding for infants with CHD. Large high-quality studies are needed to validate these results. Future work should clarify best practices in managing an HM diet to support optimal growth and development for these infants.

Prostaglandin E2 (PGE2), a major cyclooxygenase-2 (COX-2) product, is highly secreted by the osteoblast lineage in the subchondral bone tissue of osteoarthritis (OA) patients. However, NSAIDs, including COX-2 inhibitors, have severe side effects during OA treatment. Therefore, the identification of novel drug targets of PGE2 signaling in OA progression is urgently needed. Osteoclasts play a critical role in subchondral bone homeostasis and OA-related pain. However, the mechanisms by which PGE2 regulates osteoclast function and subsequently subchondral bone homeostasis are largely unknown. Here, we show that PGE2 acts via EP4 receptors on osteoclasts during the progression of OA and OA-related pain. Our data show that while PGE2 mediates migration and osteoclastogenesis via its EP2 and EP4 receptors, tissue-specific knockout of only the EP4 receptor in osteoclasts (EP4 LysM ) reduced disease progression and osteophyte formation in a murine model of OA. Furthermore, OA-related pain was alleviated in the EP4 LysM mice, with reduced Netrin-1 secretion and CGRP-positive sensory innervation of the subchondral bone. The expression of platelet-derived growth factor-BB (PDGF-BB) was also lower in the EP4 LysM mice, which resulted in reduced type H blood vessel formation in subchondral bone. Importantly, we identified a novel potent EP4 antagonist, HL-43, which showed in vitro and in vivo effects consistent with those observed in the EP4 LysM mice. Finally, we showed that the Gαs/PI3K/AKT/MAPK signaling pathway is downstream of EP4 activation via PGE2 in osteoclasts. Together, our data demonstrate that PGE2/EP4 signaling in osteoclasts mediates angiogenesis and sensory neuron innervation in subchondral bone, promoting OA progression and pain, and that inhibition of EP4 with HL-43 has therapeutic potential in OA., (© 2022. The Author(s).)

Articular cartilage repair and regeneration is an unmet clinical need because of the poor self-regeneration capacity of the tissue. In this study, we found that the expression of prostaglandin E receptor 4 (PTGER4 or EP4) was largely increased in the injured articular cartilage in both humans and mice. In microfracture (MF) surgery-induced cartilage defect (CD) and destabilization of the medial meniscus (DMM) surgery-induced CD mouse models, cartilage-specific deletion of EP4 remarkably promoted tissue regeneration by enhancing chondrogenesis and cartilage anabolism, and suppressing cartilage catabolism and hypertrophy. Importantly, knocking out EP4 in cartilage enhanced stable mature articular cartilage formation instead of fibrocartilage, and reduced joint pain. In addition, we identified a novel selective EP4 antagonist HL-43 for promoting chondrocyte differentiation and anabolism with low toxicity and desirable bioavailability. HL-43 enhanced cartilage anabolism, suppressed catabolism, prevented fibrocartilage formation, and reduced joint pain in multiple pre-clinical animal models including the MF surgery-induced CD rat model, the DMM surgery-induced CD mouse model, and an aging-induced CD mouse model. Furthermore, HL-43 promoted chondrocyte differentiation and extracellular matrix (ECM) generation, and inhibited matrix degradation in human articular cartilage explants. At the molecular level, we found that HL-43/EP4 regulated cartilage anabolism through the cAMP/PKA/CREB/Sox9 signaling. Together, our findings demonstrate that EP4 can act as a promising therapeutic target for cartilage regeneration and the novel EP4 antagonist HL-43 has the clinical potential to be used for cartilage repair and regeneration., (© 2022. The Author(s).)