Telehealth Preferences Among Patients With Advanced Cancer in the Post COVID-19 Vaccine Era.

BACKGROUND: Few studies have examined patient preferences for telehealth in palliative care after the availability of COVID-19 vaccines. We examined patient preferences for video versus in-person visits and factors contributing to preferences in the postvaccine era. METHODS: This is a cross-sectional survey of patients who were seen at our palliative care clinic between April 2021 and March 2022. Patients were surveyed directly their preference for either video or in-person visits for outpatient palliative care (primary outcome). We also surveyed preferences including convenience, cost, wait time, and perceptions of COVID-19 safety regarding their palliative virtual-video visit. We examined clinical factors associated with preferences with multivariate logistic regression. RESULTS: About 200 patients completed the survey. 132 (67%, 95% confidence interval [CI]: 60%, 74%) preferred virtual-video, while 16 (8%) preferred in-person visits during the COVID-19 pandemic. About 120 (61%, 95%CI: 54%, 68%) preferred virtual-video after the pandemic. Patients perceived virtual-video favorably regarding travel and related costs (179 [91%]), convenience (175 [88%]), and wait time (136 [69%]). Multivariable analysis showed concerns for catching COVID-19 from healthcare providers (odds ratio [OR]: 4.20; 95%CI: 1.24-14.25; P = 0.02) and feeling comfortable with computers or mobile devices (OR: 4.59; 95%CI: 1.02, 20.60; P = 0.047) were significantly associated with preferring virtual-video. Patients who were of Hispanic or Latino ethnicity (OR: 0.25; 95%CI: 0.09, 0.71) and had increased dypsnea (OR: 0.74; 95%CI: 0.59, 0.93) were less likely to prefer video over in-person. CONCLUSION: Patients expressed strong preference for video over in-person visits in the outpatient palliative care setting.

Headache Disorders: Differentiating Primary and Secondary Etiologies.

In the initial assessment of a headache patient, several dangerous secondary etiologies must be considered. A thorough history and physical examination, along with a comprehensive differential diagnosis may alert a physician to the diagnosis of a secondary headache particularly when it is accompanied by certain clinical features. Evaluation and workup include a complete neurological examination, consideration of neuroimaging, and serum/spinal fluid analysis if indicated. Careful attention to the patients' history and physical examination will guide the diagnostic work-up and management. In this review, we summarize the diagnostic workup of various primary and secondary headache etiologies. Although most headaches are primary in nature, it is essential to screen for headache "red flags", as they can suggest life threatening secondary etiologies. When secondary causes are suspected, appropriate neuroimaging can further differentiate the underlying cause. The appropriate imaging is dependent on the most likely secondary etiology, which is deduced from history and physical examination. When no red flags are present, primary headaches are more likely. These can be differentiated by frequency, location, duration, triggers, and presence of aura. The different clinical presentations for secondary headaches, as well as the distinguishing features for primary headaches are outlined in this review.

Postvaccine Era COVID-19 Pandemic-Related Distress in Palliative Care Patients With Advanced Cancer.

CONTEXT: The COVID-19 pandemic represents a source of distress in patients with advanced cancer; however, few studies have examined the extent of pandemic-related distress in the postvaccine era. OBJECTIVES: We conducted a cross-sectional survey to examine pandemic-related distress among patients seen by palliative care after vaccine availability. METHODS: Patients at our palliative care clinic were surveyed from April 2021 to March 2022 regarding 1) pandemic-related distress level, 2) potential contributors to pandemic-related distress, 3) coping strategies, 4) demographic factors and symptom burden. Univariate and multivariate analyses identified factors associated with pandemic-related distress. RESULTS: A total of 200 patients completed the survey. Of 79 (40%, 95% confidence interval [CI]: 33%, 46%) reported worse pandemic-related distress. Patients who reported greater distress were more likely to report worse social isolation (67 [86%] vs. 52 [43%]), staying home more often (75 [95%] vs. 95 [79%]), more negative experience staying at home (26 [33%] vs. 11 [9%]), worse stress with child-care duties (14 [19%] vs. 4 [3%]), less seeing family/friends (63 [81%] vs. 72 [60%]), and more difficulty traveling to medical appointments (27 [35%] vs. 20 [17%]). Thirty-seven patients (19%) reported more difficulty getting medical appointments. In multivariable analysis, younger age (odds ratio [OR], 0.97; 95% CI, 0.92-0.99; P = 0.01), worse isolation status (OR, 6.87; 95% CI, 2.76-17.12; P < 0.001), and more negative attitude towards staying home (OR, 4.49; 95% CI, 1.6-12.57; P = 0.004) were associated with pandemic-related distress. CONCLUSIONS: Patients with advanced cancer continued to experience pandemic-related distress in the postvaccine era. Our findings highlight potential opportunities to support patients.

Twelve tips for providing academic remediation to widening access learners in medical education.

As medical schools expand access and diversity through widening access initiatives, there is an increasing need to provide academic remediation for learners during their first year in medical school. The previous educational experiences of widening access learners are often mismatched for continuing success in medical school. This article offers 12 tips for providing academic remediation to widening access learners and draws on insights from the learning sciences and research in psychosocial education to support academic development within a holistic framework.

"Community health workers bring value and deserve to be valued too:" Key considerations in improving CHW career advancement opportunities.

Introduction: Community health workers (CHWs) are critical members of the public health workforce, who connect the individuals they serve with resources, advocate for communities facing health and racial inequities, and improve the quality of healthcare. However, there are typically limited professional and career building pathways for CHWs, which contribute to low wages and lack of career advancement, further resulting in turnover, attrition, and workforce instability. Methods: The Center for Community Health Alignment (CCHA), within the Arnold School of Public Health at the University of South Carolina, utilized a mixed-method data collection strategy to provide a more in-depth understanding of this issue and ways that employers, advocates, and CHWs can address it. Results: Themes across data sources emphasized the importance of retaining skilled and experienced CHWs and educating other health professions about CHWs' critical roles, and reported that doing so will result in decreased attrition professional growth, and improved program quality. CHWs and allies concluded that higher wages, valuing lived experience over formal education, and participation in additional training opportunities should be the primary factors considered for career advancement. Discussion: Utilizing input from experienced CHWs and CHW allies nationally, this article describes the importance of supporting CHW career advancement, shares best practices, and suggestions for designing strategies that organizations/employers can use to improve CHW career pathways to better support the CHW workforce and reduce attrition.

Intervenciones para promover la dignificación del fin de vida por estudiantes por estudiantes y profesionales de enfermería / Interventions by nursing students and professionals to promote dignity at the end of life

Introducción: el cuidado es el eje de la enfermería y adquiere especial relevancia en el proceso del fin de vida y muerte, donde deben garantizarse cuidados que dignifiquen a la persona y su entorno. Los profesionales y estudiantes de enfermería deben estar capacitados para ello. Objetivo: identificar intervenciones para promover la dignificación de la persona en el fin de la vida y la muerte, entre estudiantes y profesionales de enfermería. Metodología: revisión integrativa de la literatura. Se realizaron búsquedas en bases de datos: PubMed, CUIDEN Plus, Ovid, Biblioteca Virtual en Salud y ProQuest y se incluyeron artículos derivados de investigación y revisión publicados entre 2016 y 2021. Se efectuó lectura crítica utilizando la herramienta Joanna Briggs Institute (JBI). Estudio sin riesgo ético, según la resolución 8430 de 1993. Resultados: se incluyeron 34 artículos y se construyeron cinco temáticas: dignidad humana, muerte digna en la atención de enfermería, factores que impiden la dignificación del fin de vida, beneficios para estudiantes, profesionales de enfermería, paciente y familia, y estrategias que promueven la dignidad en el fin de vida y muerte. Conclusiones: el fin de la vida y la muerte son procesos complejos a los que deben enfrentarse estudiantes y profesionales de enfermería, ante los cuales puede ser de ayuda implementar intervenciones como las identificadas, dado que contribuyen en el conocimiento, compromiso, trato humanizado y compasión; es necesaria mayor docencia e investigación al respecto.

Introduction: care is nursing practice axis and is especially relevant through the end-of-life and death process, where care dignifying the patient and his or her environment must be ensured. Nursing professionals and students should be trained for this purpose. Objective: to identify interventions to promote patient dignity at end of life and death, among nursing students and professionals. Methodology: an integrative literature review. The PubMed, CUIDEN Plus, Ovid, Biblioteca Virtual en Salud and ProQuest databases were searched and articles derived from research and review published between 2016 and 2021 were included. Critical reading was conducted using the Joanna Briggs Institute (JBI) tool. This is a study carrying no ethical risk, according to Resolution 8430 of 1993. Results: 34 articles were included, and organized into five topics: human dignity, nursing care for dignified death, barriers to dignifying end of life, benefits for nursing students and professionals, patient and family, and strategies that promote dignity at end of life and death. Conclusions: end of life and death are complex processes which nursing students and professionals must face. Implementing interventions such as those identified herein, may be helpful, since they contribute to knowledge, commitment, humanized treatment, and compassion. Further education and research in this regard is required.

Heterogeneous nuclear ribonucleoprotein K is overexpressed in acute myeloid leukemia and causes myeloproliferation in mice via altered Runx1 splicing.

Acute myeloid leukemia (AML) is driven by numerous molecular events that contribute to disease progression. Herein, we identify hnRNP K overexpression as a recurrent abnormality in AML that negatively correlates with patient survival. Overexpression of hnRNP K in murine fetal liver cells results in altered self-renewal and differentiation potential. Further, murine transplantation models reveal that hnRNP K overexpression results in myeloproliferation in vivo. Mechanistic studies expose a direct functional relationship between hnRNP K and RUNX1-a master transcriptional regulator of hematopoiesis often dysregulated in leukemia. Molecular analyses show that overexpression of hnRNP K results in an enrichment of an alternatively spliced isoform of RUNX1 lacking exon 4. Our work establishes hnRNP K's oncogenic potential in influencing myelogenesis through its regulation of RUNX1 splicing and subsequent transcriptional activity.

Open-Label Placebo for the Treatment of Cancer-Related Fatigue in Patients with Advanced Cancer: A Randomized Controlled Trial.

BACKGROUND: The purpose of this study was to determine the effects of an open-labeled placebo (OLP) compared to a waitlist control (WL) in reducing cancer-related fatigue (CRF) in patients with advanced cancer using Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F). MATERIALS AND METHODS: In this randomized controlled trial, patients with fatigue ≥4/10 on Edmonton Symptom Assessment Scale (ESAS) were randomized to OLP one tablet twice a day or WL for 7 days. On day 8, patients of both arms received a placebo for 3 weeks. Changes in FACIT-F from baseline to day 8 (primary outcome) and at day 29, were assessed. Secondary outcomes included FACT-G, Multidimensional Fatigue Symptom Inventory-SF, Fatigue cluster (defined as a composite of ESAS fatigue, pain, and depression), Center for epidemiologic studies-depression, Godin leisure-time physical activity questionnaire, and global symptom evaluation. RESULTS: A total of 84/90 (93%) patients were evaluable. The mean (SD) FACIT-F change at day 8 was 6.6 (7.6) after OLP, vs. 2.1 (9.4) after WL (P = .016). On days 15 and 29, when all patients received OLP, there was a significant improvement in CRF and no difference between arms. There was also a significant improvement in ESAS fatigue, and fatigue cluster score in the OLP arm on day 8 of the study (0.029, and 0.044, respectively). There were no significant differences in other secondary outcomes and adverse events between groups. CONCLUSIONS: Open-labeled placebo was efficacious in reducing CRF and fatigue clusters in fatigued advanced cancer patients at the end of 1 week. The improvement in fatigue was maintained for 4 weeks. Further studies are needed.

Decorin knockdown is beneficial for aged tendons in the presence of biglycan expression.

Decorin and biglycan are two major small leucine-rich proteoglycans (SLRPs) present in the tendon extracellular matrix that facilitate collagen fibrillogenesis, tissue turnover, and cell signal transduction. Previously, we demonstrated that knockout of decorin prevented the decline of tendon mechanical properties that are associated with aging. The objective of this study was to determine the effects of decorin and biglycan knockdown on tendon structure and mechanics in aged tendons using tamoxifen-inducible knockdown models. We hypothesized that the knockdown of decorin and compound knockdown of decorin and biglycan would prevent age-related declines in tendon mechanics and structure compared to biglycan knockdown and wild-type controls, and that these changes would be exacerbated as the tendons progress towards geriatric ages. To achieve this objective, we created tamoxifen-inducible mouse knockdown models to target decorin and biglycan gene inactivation without the abnormal tendon development associated with traditional knockout models. Knockdown of decorin led to increased midsubstance modulus and decreased stress relaxation in aged tendons. However, these changes were not sustained in the geriatric tendons. Knockdown in biglycan led to no changes in mechanics in the aged or geriatric tendons. Contrary to our hypothesis, the compound decorin/biglycan knockdown tendons did not resemble the decorin knockdown tendons, but resulted in increased viscoelastic properties in the aged and geriatric tendons. Structurally, knockdown of SLRPs, except for the 570d I-Dcn -/- /Bgn -/- group, resulted in alterations to the collagen fibril diameter relative to wild-type controls. Overall, this study identified the differential roles of decorin and biglycan throughout tendon aging in the maintenance of tendon structural and mechanical properties and revealed that the compound decorin and biglycan knockdown phenotype did not resemble the single gene decorin or biglycan models and was detrimental to tendon properties throughout aging.

Understanding unidentified human remains investigations through the United States census data.

Each year, thousands of unidentified human remains (UHR) cases are reported in the U.S. Technological advances have greatly enhanced the forensic community's capacity and capability to solve UHR cases, but little is known about the extent to which these resources are used by medical examiners and coroners (MECs). Using public datasets, the study purpose is to describe the current state MEC system with respect to UHR cases, the resources used to investigate these cases, and the evidence retention polices in place. There was an overall decline in UHR cases reported between 2004 and 2018. Less than half of MECs in both study years reported having established written final disposition and evidence retention policies for UHR cases. National missing persons databases were underused. This study provides an important window into the present state of UHRs being handled by our Nation's MEC offices and the resources available to solve these difficult cases.

Increasing Vascular Response to Injury Improves Tendon Early Healing Outcome in Aged Rats.

Tendon injuries positively correlate with patient age, as aging has significant effects on tendon homeostatic maintenance and healing potential after injury. Vascularity is also influenced by age, with both clinical and animal studies demonstrating reduced blood flow in aged tissues. However, it is unknown how aging effects vascularity following tendon injury, and if this vascular response can be modulated through the delivery of angiogenic factors. Therefore, the objective of this study is to evaluate the vascular response following Achilles tendon injury in adult and aged rats, and to define the alterations to tendon healing in an aged model following injection of angiogenic factors. It was determined that aged rat Achilles tendons have a reduced angiogenesis following injury. Further, the delivery of vascular endothelial growth factor, VEGF, caused an increase in vascular response to tendon injury and improved mechanical outcome in this aged population. This work suggests that reduced angiogenic potential with aging may be contributing to impaired tendon healing response and that the delivery of angiogenic factors can rescue this impaired response. This study was also the first to relate changes in vascular response in an aged model using in vivo measures of blood perfusion to alterations in healing properties.

Biglycan has a major role in maintenance of mature tendon mechanics.

Decorin and biglycan are two small leucine-rich proteoglycans (SLRPs) that regulate collagen fibrillogenesis and extracellular matrix assembly in tendon. The objective of this study was to determine the individual roles of these molecules in maintaining the structural and mechanical properties of tendon during homeostasis in mature mice. We hypothesized that knockdown of decorin in mature tendons would result in detrimental changes to tendon structure and mechanics while knockdown of biglycan would have a minor effect on these parameters. To achieve this objective, we created tamoxifen-inducible mouse knockdown models targeting decorin or biglycan inactivation. This enables the evaluation of the roles of these SLRPs in mature tendon without the abnormal tendon development caused by conventional knockout models. Contrary to our hypothesis, knockdown of decorin resulted in minor alterations to tendon structure and no changes to mechanics while knockdown of biglycan resulted in broad changes to tendon structure and mechanics. Specifically, knockdown of biglycan resulted in reduced insertion modulus, maximum stress, dynamic modulus, stress relaxation, and increased collagen fiber realignment during loading. Knockdown of decorin and biglycan produced similar changes to tendon microstructure by increasing the collagen fibril diameter relative to wild-type controls. Biglycan knockdown also decreased the cell nuclear aspect ratio, indicating a more spindle-like nuclear shape. Overall, the extensive changes to tendon structure and mechanics after knockdown of biglycan, but not decorin, provides evidence that biglycan plays a major role in the maintenance of tendon structure and mechanics in mature mice during homeostasis.

Mechanical properties of the different rotator cuff tendons in the rat are similarly and adversely affected by age.

Rotator cuff tendon tears and tendinopathies are common injuries affecting a large portion of the population and can result in pain and joint dysfunction. Incidence of rotator cuff tears significantly increases with advancing age, and up to 90% of these tears involve the supraspinatus. Previous literature has shown that aging can lead to inferior mechanics, altered composition, and changes in structural properties of the supraspinatus. However, there is little known about changes in supraspinatus mechanical properties in context of other rotator cuff tendons. Alterations in tendon mechanical properties may indicate damage and an increased risk of rupture, and thus, the purpose of this study was to use a rat model to define age-related alterations in rotator cuff tendon mechanics to determine why the supraspinatus is more susceptible to tears due to aging than the infraspinatus, subscapularis, and teres minor. Fatigue, viscoelastic, and quasi-static properties were evaluated in juvenile, adult, aged, and geriatric rats. Aging ubiquitously and adversely affected all rotator cuff tendons tested, particularly leading to increased stiffness, decreased stress relaxation, and decreased fatigue secant and tangent moduli in geriatric animals, suggesting a common intrinsic mechanism due to aging in all rotator cuff tendons. This study demonstrates that aging has a significant effect on rotator cuff tendon mechanical properties, though the supraspinatus was not preferentially affected. Thus, we are unable to attribute the aging-associated increase in supraspinatus tears to its mechanical response alone.

Biomechanical Parameters of Mesh Reinforcement and Analysis of a Novel Device for Incisional Hernia Prevention.

BACKGROUND: Prophylactic mesh augmentation (PMA) is an effective technique utilized to reduce the risk of incisional hernia. This study analyzes the biomechanical characteristics of a mesh-reinforced closure and evaluates a novel prophylactic mesh implantation device (SafeClose Roller System; SRS). MATERIALS AND METHODS: A total of eight senior-level general surgery trainees (≥4 years of training) from the University of Pennsylvania Health System participated in the study. Biomechanical strength, mesh stiffness, mesh uniformity, and time efficiency for fixation were compared among hand-sewn mesh fixation, SRS mesh fixation and a no-mesh fixation control. Porcine abdominal wall specimens served as simulated laparotomy models. RESULTS: Biomechanical load strength was significantly higher for mesh reinforced repairs (P = 0.009). The SRS resulted in a stronger biomechanical force than hand-sewn mesh (21.2 N stronger, P = 0.317), with more uniform mesh placement (P < 0.01), faster time of fixation (P < 0.001) and with less discrete hand-movements (P < 0.001). CONCLUSIONS: Mesh reinforcement for incisional reinforcement has a significant impact on the strength of the closure. The utilization of a mesh-application system has the potential to amplify the advantages of mesh reinforcement by providing efficiency and consistency to fixation methods, with similar biomechanical strength to hand-sewn mesh. Additional in vivo analysis and randomized controlled trials are needed to further assess clinical efficacy.

Modulation of vascular response after injury in the rat Achilles tendon alters healing capacity.

Tendons are relatively hypovascular but become hypervascular during both injury and degeneration. This is due to the angiogenic response, or the formation of new blood vessels, to tissue injury. The objective of this study was to evaluate the effect of vascular modulation in the rat Achilles tendons during healing. Fischer rats received a bilateral Achilles incisional injury followed by local injections of vascular endothelial growth factor (VEGF), anti-VEGF antibody (B20.4-1-1), or saline either early or late during the healing process. Vascular modulation and healing were evaluated using multiple in vivo ultrasound imaging modalities, in vivo functional assessment, and ex vivo measures of tendon compositional and mechanical properties. The late delivery of anti-VEGF antibody, B20, caused a temporary reduction in healing capacity during a time point where vascularity was also decreased, and then an improvement during a later time point where vascularity was increased relative to control. However, VEGF delivery had a minimal impact on healing and vascular changes in both early and late delivery times. This study was the first to evaluate vascular changes using both in vivo imaging methods and ex vivo histological methods, as well as functional and mechanical outcomes associated with these vascular changes. Clinical significance: this study demonstrates that the alteration of vascular response through the delivery of angiogenic growth factors has the ability to alter tendon healing properties.

Amplifying Bone Marrow Progenitors Expressing α-Smooth Muscle Actin Produce Zonal Insertion Sites During Tendon-to-Bone Repair.

Traditional tendon-to-bone repair where the tendon is reattached to bone via suture anchors often results in disorganized scar production rather than the formation of a zonal insertion. In contrast, ligament reconstructions where tendon grafts are passed through bone tunnels can yield zonal tendon-to-bone attachments between the graft and adjacent bone. Therefore, ligament reconstructions can be used to study mechanisms that regulate zonal tendon-to-bone repair in the adult. Anterior cruciate ligament (ACL) reconstructions are one of the most common reconstruction procedures and while we know that cells from outside the graft produce the attachments, we have not yet established specific cell populations that give rise to this tissue. To address this knowledge gap, we performed ACL reconstructions in lineage tracing mice where α-smooth muscle actin (αSMACreERT2) was used to label αSMA-expressing progenitors within the bone marrow that produced zonal attachments. Expression of αSMA was increased during early stages of the repair process such that the contribution of SMA-labeled cells to the tunnel integration was highest when tamoxifen was delivered in the first week post-surgery. The zonal attachments shared features with normal entheses, including tidemarks oriented perpendicularly to collagen fibers, Col1a1-expressing cells, alkaline phosphatase activity, and proteoglycan-rich staining. Finally, the integration strength increased with time, requiring 112% greater force to remove the graft from the tunnel at 28 days compared with 14 days post-surgery. Future studies will target these progenitor cells to define the pathways that regulate zonal tendon-to-bone repair in the adult. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:105-116, 2020.

A turn for the worse: Turning performance in Parkinson's disease and Essential tremor.

BACKGROUND: Turning is an activity of daily living known to elicit falls in older adults and particularly in persons with movement disorders. Specifically, those with Parkinson's disease have marked impairments in forward walking and turning. Although recent work has identified gait impairment in those with Essential tremor, turning has not been extensively evaluated. As the cerebellum is key in the pathophysiology of Essential tremor, complex tasks like turning, may be impaired for this population. The purpose of this study was to investigate turning behavior and falls in those with Essential tremor and Parkinson's disease. METHODS: 15 persons with Essential tremor and 15 persons with Parkinson's disease performed forward walking and turns on an instrumented walkway. t-tests compared groups and a regression was performed to predict fall frequency. FINDINGS: During turning, those with Essential tremor had lower cadence (p = .042) and took more time (p = .05). No other variables, including forward walking variables, differed between groups. When pooling groups, the significant fall frequency predictor model (p = .003) included decreased forward cadence, increased turning cadence, and female sex. Overall, the model explained 40.7% of the variance. INTERPRETATION: While forward gait performance was similar between groups, those with Essential tremor had increased turn time, a measure often associated with turning impairment. Together, these results suggest overall gait impairment in Essential tremor is more prevalent than recognized. Walking performance, both turning and forward, and sex were predictive of fall frequency. Therapeutic interventions in these populations should include both forward walking and turns to mitigate fall risk.

Decreasing Time from Decision to Intubation in Premedicated Neonates: A Quality Improvement Initiative.

Endotracheal intubation carries the risk of discomfort, decompensation, oral trauma, and endotracheal tube malposition. Treatment with premedications reduces complications, increases overall intubation safety, improves pain control, and improves first-pass success. However, time is frequently a barrier to administration. We aimed to decrease the decision-to-intubation time interval from a baseline of 40 minutes to less than 35 minutes over 6 months. METHODS: We used the Model for Improvement with multiple plan-do-study-act cycles to reduce the time from decision to successful intubation in nonemergent neonatal intubations. Key drivers were timely administration of medications, availability of skilled personnel and equipment, and efficient use of time. RESULTS: During this project, time from the decision to successful intubation decreased from a historical mean of 40 minutes to a new baseline of 27 minutes. This change represents a 33% decrease, with 80% of intubations occurring within 35 minutes. During this time, success rates remained stable, and medication errors and side effects did not increase. CONCLUSIONS: Standard processes to prepare and administer premedications decreased the time from decision to intubation without significant adverse effects, allowing the benefit of premedication administration in a safe and timely manner in nonemergent neonatal intubations.

Dynamic Loading and Tendon Healing Affect Multiscale Tendon Properties and ECM Stress Transmission.

The extracellular matrix (ECM) is the primary biomechanical environment that interacts with tendon cells (tenocytes). Stresses applied via muscle contraction during skeletal movement transfer across structural hierarchies to the tenocyte nucleus in native uninjured tendons. Alterations to ECM structural and mechanical properties due to mechanical loading and tissue healing may affect this multiscale strain transfer and stress transmission through the ECM. This study explores the interface between dynamic loading and tendon healing across multiple length scales using living tendon explants. Results show that macroscale mechanical and structural properties are inferior following high magnitude dynamic loading (fatigue) in uninjured living tendon and that these effects propagate to the microscale. Although similar macroscale mechanical effects of dynamic loading are present in healing tendon compared to uninjured tendon, the microscale properties differed greatly during early healing. Regression analysis identified several variables (collagen and nuclear disorganization, cellularity, and F-actin) that directly predict nuclear deformation under loading. Finite element modeling predicted deficits in ECM stress transmission following fatigue loading and during healing. Together, this work identifies the multiscale response of tendon to dynamic loading and healing, and provides new insight into microenvironmental features that tenocytes may experience following injury and after cell delivery therapies.

Tendon healing affects the multiscale mechanical, structural and compositional response of tendon to quasi-static tensile loading.

Tendon experiences a variety of multiscale changes to its extracellular matrix during mechanical loading at the fascicle, fibre and fibril levels. For example, tensile loading of tendon increases its stiffness, with organization of collagen fibres, and increases cell strain in the direction of loading. Although applied macroscale strains correlate to cell and nuclear strains in uninjured tendon, the multiscale response during tendon healing remains unknown and may affect cell mechanosensing and response. Therefore, this study evaluated multiscale structure-function mechanisms in response to quasi-static tensile loading in uninjured and healing tendons. We found that tendon healing affected the macroscale mechanical and structural response to mechanical loading, evidenced by decreases in strain stiffening and collagen fibre realignment. At the micro- and nanoscales, healing resulted in increased collagen fibre disorganization, nuclear disorganization, decreased change in nuclear aspect ratio with loading, and decreased indentation modulus compared to uninjured tendons. Taken together, this work supports a new concept of nuclear strain transfer attenuation during tendon healing and identifies several multiscale properties that may contribute. Our work also provides benchmarks for the biomechanical microenvironments that tendon cells may experience following cell delivery therapies.