Ischemic cardiac stromal fibroblast-derived protein mediators in the infarcted myocardium and transcriptomic profiling at single cell resolution.

This article focuses on screening the major secreted proteins by the ischemia-challenged cardiac stromal fibroblasts (CF), the assessment of their expression status and functional role in the post-ischemic left ventricle (LV) and in the ischemia-challenged CF culture and to phenotype CF at single cell resolution based on the positivity of the identified mediators. The expression level of CRSP2, HSP27, IL-8, Cofilin-1, and HSP90 in the LV tissues following coronary artery bypass graft (CABG) and myocardial infarction (MI) and CF cells followed the screening profile derived from the MS/MS findings. The histology data unveiled ECM disorganization, inflammation and fibrosis reflecting the ischemic pathology. CRSP2, HSP27, and HSP90 were significantly upregulated in the LV-CABG tissues with a concomitant reduction ion LV-MI whereas Cofilin-1, IL8, Nrf2, and Troponin I were downregulated in LV-CABG and increased in LV-MI. Similar trends were exhibited by ischemic CF. Single cell transcriptomics revealed multiple sub-phenotypes of CF based on their respective upregulation of CRSP2, HSP27, IL-8, Cofilin-1, HSP90, Troponin I and Nrf2 unveiling pathological and pro-healing phenotypes. Further investigations regarding the underlying signaling mechanisms and validation of sub-populations would offer novel translational avenues for the management of cardiac diseases.

Operative Treatment of Distal Tibial Fractures in Children Managed With Epiphyseal Screws: A Comparison of Outcomes When Screws Are Retained Versus Removed Following Fracture Union.

BACKGROUND: Fractures of the distal tibial epiphysis in children are often accompanied by articular surface disruption. With increased displacement, internal fixation is frequently performed with an epiphyseal screw to close the fracture gap. Despite limited, high-level clinical evidence to support implant removal, epiphyseal screws are commonly removed after fracture healing due to potentially increased contact forces on the tibiotalar joint. The purpose of this study was to investigate and compare outcomes and complications in children that underwent surgical treatment of distal tibial epiphyseal fractures with placement of an epiphyseal screw(s) and had the implant(s) retained versus removed at a minimum of 2-year postoperative follow-up. METHODS: Children younger than 18 years from two urban tertiary care centers who underwent operative management of distal tibia Salter-Harris III and IV fractures using epiphyseal screws (2013-2020) were divided into two cohorts: retained epiphyseal screws and implant removed. Demographics, intraoperative, postoperative, and radiographic data were collected. Patient-reported outcomes (PROs) using the Foot and Ankle Ability Measure (FAAM) and Single Assessment Numeric Evaluation (SANE) questionnaires were collected at the final follow-up. Statistical analysis, including power analysis, was performed. RESULTS: Fifty-two children were included (30 males, 22 females) with a mean age of 13.3 years at the time of injury (range, 7.7-16.4 years). Thirty-five children retained the implants; seventeen had implants removed. All completed the FAAM questionnaires at a mean follow-up of 4.4 ± 1.9 years, while 29 completed the SANE questionnaire at a mean follow-up of 4.4 ± 1.7 years. No statistically significant difference in patient demographics, surgical variables, or PROs was observed. Six children experienced complications from the initial surgery, including infections and complex regional pain syndrome, with no difference in complication rates between the cohorts ( P =0.08). Furthermore, no complication was observed as a result of implant removal. CONCLUSIONS: Children with retained epiphyseal implants have similar functional outcomes as compared with those who had implants removed after distal tibial epiphyseal fracture fixation and union. LEVEL OF EVIDENCE: Level III-Retrospective comparative study.

Hyperlipidemia in tendon injury: chronicles of low-density lipoproteins.

Hyperlipidemia impacts millions of people globally and has been the major risk factor for developing atherosclerosis and cardiovascular disease. Interestingly, hyperlipidemic subjects exhibit increased incidence of rotator cuff tendon injury (RCTI) and disorganization of tendon matrix. Low-density lipoproteins (LDL) and its oxidized form (ox-LDL) play a crucial role in hyperlipidemia-driven pro-inflammatory responses in multiple tissues including the tendon. The signaling of oxLDL upregulates the inflammatory cytokines, chemokines, adhesion molecules, and the activation of monocytes/macrophages/resident tendon cells and matrix metalloproteinases impairing the tendon homeostasis resulting in the alteration of extracellular matrix. In addition, the hyperlipidemia-driven immune response and subsequent oxidative stress promote degenerative responses in the tendon tissue. However, the pathological mechanisms underlying the occurrence of RCTI in hyperlipidemia and the effect of ox-LDL in tendon matrix are currently unknown. The present review focuses on the implications and perspectives of LDL/oxLDL on the increased incidence of RCTI.

Pathological alterations in the expression status of rotator cuff tendon matrix components in hyperlipidemia.

Hyperlipidemia is an important risk factor in the development and progression of tendon pathology, however its role in aggravating rotator cuff tendon injury (RCTI) is largely unknown. We aimed to assess the expression status of key extracellular matrix (ECM) components in the tendon tissues and tenocytes under hyperlipidemia. Shoulder rotator cuff (RC) tendon tissues harvested from the swine model of hyperlipidemia displayed alterations in histomorphometry and the expression status of major ECM component proteins including COL-I, COL-III, COL-IV, COL-V, COL-VI, MMP2, and MMP9. Similarly, the LDL- and oxLDL-challenged tenocytes displayed altered expression of the same proteins at both transcriptional and translational levels. In addition, the lipid uptake and cellular reactive oxygen radicals predominated in the lipid-challenged tenocytes compared to the control. Overall, the LDL-treated cells displayed predominant pathological alterations compared to the ox-LDL-treated cells. Further understanding regarding the underlying molecular mechanisms driving the tendon matrisome alteration and subsequent aggravated RCTI pathology in hyperlipidemia could open novel translational avenues in the management of RCTI.

The Efficacy of Platelet-Rich Plasma for Improving Pain and Function in Lateral Epicondylitis: A Systematic Review and Meta-analysis with Risk-of-Bias Assessment.

PURPOSE: To assess the efficacy of platelet-rich plasma (PRP) for lateral epicondylitis and evaluate its impact on pain and functional outcomes. METHODS: This study followed Preferred Reporting Items and Systematic Reviews and Meta-Analyses guidelines. A comprehensive literature search was conducted in September 2019 and repeated in April 2020 using electronic databases PubMed, MEDLINE, and the Cochrane Library. Baseline and 3-, 6-, and 12-month data were extracted for visual analog scale (VAS), Disabilities of the Arm, Shoulder, and Hand (DASH), and modified Mayo Clinic performance index for the elbow (MAYO) scores. Only level 1 studies with patients who had not undergone surgery were included. Outcomes data, study design, demographic variables, PRP formulation, and comparator treatments were recorded. Statistical analyses of pooled weighted mean differences (WMDs) were performed and compared with estimated minimal clinically important difference (MCID) values. The Coleman Methodology Score (CMS) was used to assess methodological quality, and the Cochrane risk-of-bias assessment was performed. RESULTS: This review included 16 level I studies, 9 of which (581 total patients, 281 receiving single injections of PRP) were quantitatively analyzed. The average age was 41.5 years, 56.8% of patients were female, and mean follow-up was 7.5 months. The mean CMS was 78.94 ± 12.74 (range 59 to 97), and 5 of 16 studies were at low risk for bias. Patients who received PRP had significantly improved VAS scores at 3 months (WMD -0.85; 95% confidence interval [CI] -1.03, -0.66; P < .01) and 6 months (WMD -0.74; 95% CI -0.98, -0.50; P < .01) compared with those who received autologous whole blood, though MAYO scores were statistically equivalent. Comparing PRP to corticosteroids, VAS and DASH scores were not significantly different at 3 months, although PRP was superior at 6 months for VAS (WMD -1.70; 95% CI -2.65, -0.75; P < .01) and DASH (WMD -6.23; 95% CI -10.78, -1.69; P < .01). Most differences in VAS and DASH scores exceeded the 5% absolute difference estimate for their respective MCIDs but fell short of the 10% estimate. CONCLUSION: Considering the small number of comparable studies, lack of quantification of specific PRP content, considerable heterogeneity between randomized control trials, and most effect sizes being equivocal within the framework of 2 estimated MCID values, the authors can neither scientifically support nor discourage the usage of PRP for lateral epicondylitis despite finding statistically significant improvements in pain and functional outcomes. LEVEL OF EVIDENCE: I, prognostic.

In Lieu of Smoking: Are Smokers More Likely to Enact Certain Types of Implementation Intention Plans During a JIT Smoking Cessation?

BACKGROUND: To identify actionable and effective implementation intention (II) plans, we examined whether (a) IIs suggesting food or nicotine-based substitution strategies to help quit smoking cigarettes would be more likely to be enacted in real time, (b) IIs reminding participants to cognitively motivate themselves or engage in solitary activity would be more likely to be enacted than those suggesting seeking social support, and (c) II plan enactment based on the above strategies would be associated with reporting momentary lapse avoidance. METHOD: A sample of 57 Asian American young adult (18-25 years) smokers participated in a 4-week, mobile-based smoking cessation intervention, implemented in a Just-In-Time framework. User-specified IIs were categorized into nature of activity (cognitively motivate themselves, engage in solitary activity, seek social support) and type of substitution strategy (food, nicotine, no substitution). Outcome variable was momentary enactment of the given II. Generalized mixed linear models were used for analyses. RESULTS: IIs reminding participants to cognitively motivate themselves and/or engage in solitary activities were more likely to be enacted than IIs recommending seeking social support. IIs recommending nicotine-based substitution were more likely to be enacted than IIs that did not specify any substitution. IIs suggesting food-based substitution, however, were less likely to be enacted than those not suggesting a specific substitution. II plan enactment based on the above strategies was significantly associated with avoiding momentary lapses compared to when momentary lapses occurred. CONCLUSION: Specifying II recommendations found to be helpful with avoiding lapses in a smoking cessation context, can increase chances of II enactment, and improve overall health intervention outcomes.

Zinc sulfide nanoparticles improve skin regeneration.

Wound healing has been intensely studied to expedite recovery times and reduce scarring. However, current technologies fail to achieve regenerative capabilities, leaving wounds with scarring and lack of skin accessories. The recent emergence of nanotechnology has provided a new clinical modality of zinc nanoparticles in wound care. This present study investigated Zinc Sulfide nanoparticles (ZnS-NP) on wound healing in vitro with 2D and 3D models and in vivo with rat full-thickness wound model. ZnS-NP inhibited fetal bovine serum-stimulated rat skin fibroblast cell proliferation, altered cytoskeletal organization, and reduced collagen synthesis as well as contractile activity. ZnS-NP regulated redox homeostatsis and promoted fibroblast viability in 3D hypoxia conditions. In the rat full-thickness wound model, ZnS-NP reduced wound contraction, enhanced re-epithelization, and promoted skin appendage formation. The biological activities of ZnS-NPs determined in our current study may suggest promising practical applications for topical or systemic treatment for wound repair.

Governmental Regulations and Increasing Food and Drug Administration Oversight of Regenerative Medicine Products: What's New in 2020?

The United States Food and Drug Administration (FDA) is responsible for protecting and promoting public health through rules and regulations. Over the past few years, the field of regenerative medicine and cell therapy have garnered significant interest, and this evolving new biology is changing fast and challenging regulatory bodies. The FDA has published a series of guidance documents outlining steps to protect consumers against potentially dangerous and unproven treatments. The agency has offered a grace period for "stem cell clinics" until November 2020 to come into compliance by obtaining Investigational New Drug applications and working to secure premarket approval of their products. With the documentation of hundreds of "stem cell clinics," the FDA needs to enforce the adherence to their outlined standards to protect patients. The aim of this review was to provide an overview of these FDA regulations and some current issues within the industry. The purpose is to educate and inform the musculoskeletal community about the current government regulations of this new expanding biology. LEVEL OF EVIDENCE: Level V, expert opinion.

Repair of Rotator Cuff Tendon Defects in Aged Rats Using a Growth Factor Injectable Gel Scaffold.

PURPOSE: To determine if the tendon-specific crosslinking gelatin (Col-Tgel) impregnated with growth factors promotes tendon healing at the bone interface and in a tendon window model. METHODS: Two different Col-Tgel formulations were first tested in vitro by evaluating cell morphology and tendogenic differentiation. After the optimum formulation was determined, the gel was mixed with either transforming growth factor-ß3 (TGF-ß3) or growth differentiation factor-7 (GDF-7) growth factor and prepared for injections. Window defects were induced in 12 animals, which were randomized into the following treatments: (1) sham, (2) empty Col-Tgel, (3) Col-Tgel containing TGF-ß3, or (4) Col-Tgel containing GDF-7. Based on these results, the sham, empty Col-Tgel, and Col-Tgel containing TGF-ß3 were applied to the supraspinatus repair interface. Tendons were analyzed biomechanically and histologically using hematoxylin and eosin and Masson's trichrome staining. RESULTS: In the window defect model, histologic scores were the best in rats treated with TGF-ß3 containing Col-Tgel, followed by the empty Col-Tgel scaffold, and finally the sham control. The GDF-7 Col-Tgel was not further tested because occasional ectopic cartilage and bone formation was found in the prior window defect model. In the supraspinatus repair model, there was no statistical difference (P > .05) in the biomechanical strength among the 3 treatment groups, but load-to-failure ratio improved when TGF-ß3 was added to the scaffold, suggesting improved tendon healing. CONCLUSIONS: This pilot study evaluated the performance of an injectable gel tendon graft in a population of retired breeder rats. The results suggest that Col-Tgel containing TGF-ß3 may be a useful adjunctive treatment for surgical repair of full-thickness rotator cuff tears. Histologic and biomechanical scores suggest that Col-Tgel containing TGF-ß3 promotes tendon healing. CLINICAL RELEVANCE: The results of this study suggest that shoulders injected with Col-Tgel may be a useful adjunctive treatment for repair of rotator cuff tears.

"Ene" Reactions of Singlet Oxygen at the Air-Water Interface.

Prenylsurfactants [(CH3)2C═CH(CH2)nSO3(-) Na(+) (n = 4, 6, or 8)] were designed to probe the "ene" reaction mechanism of singlet oxygen at the air-water interface. Increasing the number of carbon atoms in the hydrophobic chain caused an increase in the regioselectivity for a secondary rather than tertiary surfactant hydroperoxide, arguing for an orthogonal alkene on water. The use of water, deuterium oxide, and H2O/D2O mixtures helped to distinguish mechanistic alternatives to homogeneous solution conditions that include dewetting of the π bond and an unsymmetrical perepoxide transition state in the hydroperoxide-forming step. The prenylsurfactants and a photoreactor technique allowed a certain degree of interfacial control of the hydroperoxidation reaction on a liquid support, where the oxidant (airborne (1)O2) is delivered as a gas.

Utilization of minimally invasive burr for surgical correction of calcaneus fracture malunion: A case report describing a novel technique.

INTRODUCTION: Calcaneus fractures pose a significant treatment challenge to orthopaedic surgeons. Nonoperative treatment frequently leads to malunion, persistent pain, and development of subtalar arthritis, while operative treatment increases the risk of surgical-related complications, such as surgical site infection, without demonstrating superior outcomes. PRESENTATION OF CASE: A 58-year-old male laborer presented three months after sustaining a left joint-depression type calcaneus fracture. He was initially treated nonoperatively but suffered from significant pain and dysfunction interfering with activities of daily living and inability to return to work. The patient was treated with a novel technique utilizing a minimally invasive burr to correct calcaneus fracture malunion. There were no reported post-operative complications, including infection or additional malunion, patient has returned to normal shoewear and his physically demanding career. DISCUSSION: This is one of few studies documenting utilization of a minimally invasive burr for surgical correction of calcaneus fracture malunion. Restoration of calcaneal height and hindfoot alignment were achieved without evidence of subtalar arthritis on postoperative radiographs. Minimally invasive surgical procedures, especially with smaller incisions, have been found to be just as effective as open, though with significantly fewer wound and nerve complications. CONCLUSION: Minimally invasive correction of calcaneus fracture malunion may be a viable option for surgical intervention, even in patients who are at higher risk of surgical complications such as infection. The indications for minimally invasive techniques are rapidly expanding and further studies are warranted to evaluate the use of minimally invasive techniques in foot and ankle surgery.

Investigating particulate production in the operating suite following the use of waterless alcohol based dry scrub versus traditional hand washing and drying with commonly used surgical towels: An experimental study.

BACKGROUND: An often-overlooked item that could cause contamination in the operating suite are the towels used for hand drying following surgical scrub. The purpose of this current study was to determine if there was a difference in the particulate count from different hand drying methods following surgical hand preparation. METHODS: Three simulated hand drying groups were established: disposable sterilized surgical towels, reusable sterilized surgical towels, and a waterless alcohol-based dry rub. Particle size measurements of 0.3 µm, 5.0 µm, and 10.0 µm were collected at time zero and repeated every minute for 5 minutes for a total of 10 trials each. RESULTS: Both the reusable and disposable towels produced significantly more particle matter in all size groups compared to the alcohol scrub control group. A comparison analysis and ANOVA testing demonstrated that alcohol dry scrub produced significantly fewer particles compared to both the disposable blue towels (P < .01) and the reusable green towels (P < 0.01). Disposable towels produced significantly more particles in the 0.3 µm count compared to reusable towels (P < .05). CONCLUSIONS: An alcohol-based dry rub without using a towel yielded the lowest amount of particulate formation in this experimental model, while reusable surgical towels produced the highest number of particles. LEVEL OF EVIDENCE: Level II Experimental Study.

Orthopedic Resident and Patient Perception of Electronic Medical Record Use During the Clinic Visit.

Background The transition from paper charts to electronic medical records (EMRs) has resulted in greater efficiency and reduced medical errors. This study aimed to examine the perception of patients and orthopedic residents regarding computer use during the clinic visit. Methodology This study utilized a cross-sectional cluster design. Orthopedic resident physicians were given a one-time general pre-visit survey. Additional surveys were given to patients and resident physicians post-visit. Surveys included questions that assessed satisfaction and the perceived impact of computer usage on doctor-patient interactions. Logistic generalized estimating equations were run to determine if there was an association between patient response and clinician assessment, adjusting for repeated measures within clinicians. Results A total of 80 patients and 15 residents completed the surveys. Results from the physician pre-visit survey showed that more residents perceived the computer as having a "negative" (47%) than "positive" (26%) effect on their relationship with patients. According to the post-visit analysis, patients perceived the residents' use of the EMR as having an overall positive effect on their ability to establish a personal connection and having a positive effect on their ability to give them attention. Conclusions Overall, there was little correlation between patient and resident perception of the computer's effect on their relationship. Patients generally perceived the computer as having a positive effect on their interaction with the residents even when residents had a negative perception of the computer's effect on their interaction.

Nowarta110 Topical Versus Placebo for the Treatment of Plantar Warts: A Phase I/II Randomized Controlled Clinical Trial.

BACKGROUND/AIM: Plantar warts are cutaneous lesions on the plantar aspect of the foot caused by the infection of keratinocytes with the human papillomavirus (HPV). The severity and magnitude of warts can vary, but they cause pain and discomfort for all age groups. The treatment for plantar warts remains a continuing challenge. The purpose of this research was to compare the efficacy and safety of naturally derived Nowarta110 topical formula versus a matching placebo in treating plantar warts. PATIENTS AND METHODS: The study is a randomized, double-blind, parallel assignment control interventional phase I/II clinical trial. This study included 54 patients with plantar warts. Patients were randomized to two groups: the placebo group, which included 26 patients treated with a matching placebo and the Nowarta110 group, which included 28 patients who received topical Nowarta110. The diagnosis of plantar warts was made by clinical examination. The treatment's efficacy and safety were assessed every week and after 6 weeks from the initiation of the intervention. RESULTS: In the Nowata110 group, 18 patients (64.3%) were completely cleared of their warts, and 10 patients (35.7%) partially responded to the therapy with a 20% to 80% decrease in warts dimensions. In the placebo group, only 2 patients (7.7%) were completely cleared of their warts, and 3 patients (11.5%) partially responded to the intervention with a 10% to 35% decrease in warts dimensions. The difference was highly significant between the two groups. There was 1 event with minor pain as a side effect in the Nowarta110 group and 9 events of non-serious local side effects in the placebo group, which included 2 patients who dropped out. CONCLUSION: Topical Nowarta110 is a safe, well-tolerated, and highly effective therapeutic modality in treating refractory and recurrent plantar warts. The breakthrough findings of the study encourage further extensive clinical trials to fully explore the prospect of Nowarta110 in managing all types of warts and HPV-related diseases.

Successful Phytotherapy for Acute Refractory Radiation Cystitis in a Cervical Cancer Patient: A Case Report.

BACKGROUND/AIM: Radiation cystitis is a frequent complication that can occur after therapeutic irradiation of pelvic cancers. The current treatment for this condition is complex and often ineffective. CASE REPORT: We present a clinical case of a 54-year-old patient diagnosed with small cell cervical cancer FIGO stage IIIC who developed grade 2-3 radiation cystitis following post-operational chemoradiation therapy. The patient exhibited increased urinary urgency and frequency, dysuria, and low abdominal pain, which failed to respond to acupuncture and corticosteroid treatments. A course of Ich Nieu Khang phytotherapy tablets, resulted in significant improvement of symptoms within 24 hours of initiation. The symptoms resolved completely within 10 days, and ultrasonography documented a marked decrease in bladder wall thickening and improved bladder evacuation function. The phytotherapy was well-tolerated, and no side-effects were observed during the 60-day treatment period. CONCLUSION: These findings suggest that phytotherapy may be viable for managing radiation cystitis. However, further controlled clinical trials are needed to confirm the efficacy of Ich Nieu Khang and promote its broader clinical applications.

Enhancement of Chondrogenic Markers by Exosomes Derived from Cultured Human Synovial Fluid-Derived Cells: A Comparative Analysis of 2D and 3D Conditions.

OBJECTIVE: The goal of this pilot study was to investigate the effects of exosomes derived from synovial fluid-derived cells (SFDCs) cultured under normoxic conditions in a two-dimensional (2D) monolayer or encapsulated within a three-dimensional (3D) matrix for chondrogenic differentiation in vitro and cartilage defect repair in vivo. DESIGN: Synovial fluid samples were obtained from three patients, and SFDCs were isolated and expanded either in a 2D monolayer culture or seeded within a transglutaminase cross-linked gelatin (Col-Tgel) to create a 3D gel culture. Exosomes derived from each environment were isolated and characterized. Then, their effects on cartilage-cell proliferation and chondrogenic differentiation were assessed using an in vitro organoid model, and their potential for enhancing cartilage repair was evaluated using a rat cartilage defect model. RESULTS: SFDCs obtained from different donors reached a state of senescence after four passages in 2D culture. However, transferring these cells to a 3D culture environment mitigated the senescence and improved cell viability. The 3D-cultured exosomes exhibited enhanced potency in promoting chondrogenic differentiation, as evidenced by the increased expression of chondrogenic genes and greater deposition of cartilage-specific extracellular matrix. Furthermore, the 3D-cultured exosomes demonstrated superior effectiveness in enhancing cartilage repair and exhibited better healing properties compared to exosomes derived from a 2D culture. CONCLUSIONS: The optimized 3D culture provided a more favorable environment for the proliferation of human synovial cells and the secretion of exosomes compared to the 2D culture. The 3D-cultured exosomes exhibited greater potential for promoting chondrogenic gene expression in vitro and demonstrated improved healing properties in repairing cartilage defects compared to exosomes derived from the 2D culture.

The Rationality of Implementation of Dimethyl Sulfoxide as Differentiation-inducing Agent in Cancer Therapy.

One of the major hallmarks of many cancer cells is dedifferentiated cells (immature cells) with little or no resemblance to normal cells. Besides the poor differentiation, malignant cells also have important features such as aggressiveness and resistance to different therapeutics. Differentiation potentiators hold great promise for cancer treatment. Dimethyl sulfoxide (DMSO) is a well-characterized pharmaceutical solvent. It is used as a component of numerous cancer therapeutic approaches, including cancer treatment and several approved cancer immune therapeutics such as Car-T cell therapy and the FDA-approved drug Mekinist (trametinib DMSO) for melanoma treatment. It is also biologically recognized as a pharmaceutical solvent and cryoprotectant. In the current literature, there are no mentions of DMSO's possible ability to potentiate therapeutic activity as a component of these cancer treatments. This review aimed to summarize scientific evidence and substantiate the concept that DMSO can contribute positively to the overall efficacy of cancer treatment as an adjuvant that is safe, inexpensive, and an effective differentiation-inducing therapeutic agent.

Targeting Skeletal Muscle Dysfunction With L-Carnitine for the Treatment of Patients With Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD) is a major medical problem and the world's third leading cause of death. COPD is a chronic disease with heterogeneous clinical symptoms, disease progression, and treatment responses. Besides pulmonary symptomatology, the common systemic clinical manifestations are cachexia, muscle weakness, and widespread comorbidities such as cardiovascular diseases, diabetes, osteoporosis, and infections. The adverse effects of pharmaceutical therapies contribute to the difficulty of health risk assessment and management of COPD patients. This review shows how skeletal muscle dysfunction and metabolic abnormalities contribute significantly to COPD patients' symptoms, functional activities, quality of life, and overall disease outcomes. Based on the clinical evidence of L-carnitine and derivatives as metabolic and muscle bioenergetic enhancers, we propose broader research and implementation of this nutraceutical agent as an effective, inexpensive, and safe adjuvant therapeutic for the long-term management of COPD patients. Moreover, we believe the management of COPD as a chronic disease should be shifted from symptomatic reactive pharmaceutical intervention to more constructive and non-toxic approaches using a single or combination of natural and nutritional agents with potential muscle metabolic enhancing and immunomodulating activities to achieve a better overall outcome for the patients in terms of morbidity, mortality, and medical cost-reduction.

"Smart Exosomes": A Smart Approach for Tendon Regeneration.

Shoulder tendon injuries are the common musculoskeletal disorder resulting in significant pain and disability. These injuries are characterized by chronic inflammation and tissue degeneration. Tendon pathology exhibits poor innate healing ability, enhanced inflammation, disorganized collagen fibers, calcification, and scar tissue formation affecting the normal healing process. Extracellular vesicle, especially exosomes, treatment has been emerging as a potential regenerative strategy improving the outcomes and biomechanical properties, accelerating tenocyte proliferation and migration, reducing inflammation, and facilitating the healing at tendon-bone interface. In this article, we critically reviewed the potential role of exosomes in tendon regeneration and their applications to accelerate the healing response following injury. In addition, the article provides novel insights on the concept of "Smart Exosomes" by programming/manipulating the secretome contents and functions of exosomes in the management of shoulder tendon injury. Impact statement The exosomes pose tremendous regenerative capacity in otherwise inherently poor tendon healing following shoulder injury. Understanding the exosome biology in the context of tendon injury offers immense opportunities for developing novel regenerative approaches. Herein, we focus on the novel concept of "Smart Exosomes" by programming the regenerative properties of exosomes as a next-generation management strategy for shoulder tendon injury.

Bilateral Calcaneus Transfers for the Treatment of Congenital Tibial Deficiencies: A Novel Surgical Technique and Case Report.

Tibial deficiency (also known as tibial hemimelia) is a rare condition with variable presentation. A 2-month-old patient presented with absent bilateral tibias. When the patient was 1 year, a novel reconstructive surgery was done. A bilateral fibular resection with pedicled calcaneus transfer was done, allowing for transfer of the calcaneus along with the overlying glabrous skin and soft tissues to the end of the femur. The patient was permitted to weight-bear after the 4-week postoperative follow-up. At the six-month follow-up, the patient was able to pull to stand and walk with assistance without any reports of pain.