Del1 Is a Growth Factor for Skeletal Progenitor Cells in the Fracture Callus.

Failure to properly form bone or integrate surgical implants can lead to morbidity and additional surgical interventions in a significant proportion of orthopedic surgeries. While the role of skeletal stem cells (SSCs) in bone formation and repair is well-established, very little is known about the factors that regulate the downstream Bone, Cartilage, Stromal, Progenitors (BCSPs). BCSPs, as transit amplifying progenitor cells, undergo multiple mitotic divisions to expand the pool of lineage committed progenitors allowing stem cells to preserve their self-renewal and stemness. Del1 is a protein widely expressed in the skeletal system, but its deletion led to minimal phenotype changes in the uninjured mouse. In this paper, we demonstrate that Del1 is a key regulator of BCSP expansion following injury. In Del1 knockout mice, there is a significant reduction in the number of BCSPs which leads to a smaller callus and decreased bone formation compared with wildtype (WT) littermates. Del1 serves to promote BCSP proliferation and prevent apoptosis in vivo and in vitro. Moreover, exogenous Del1 promotes proliferation of aged human BCSPs. Our results highlight the potential of Del1 as a therapeutic target for improving bone formation and implant success. Del1 injections may improve the success of orthopedic surgeries and fracture healing by enhancing the proliferation and survival of BCSPs, which are crucial for generating new bone tissue during the process of bone formation and repair.

Sexually dimorphic estrogen sensing in skeletal stem cells controls skeletal regeneration.

Sexually dimorphic tissues are formed by cells that are regulated by sex hormones. While a number of systemic hormones and transcription factors are known to regulate proliferation and differentiation of osteoblasts and osteoclasts, the mechanisms that determine sexually dimorphic differences in bone regeneration are unclear. To explore how sex hormones regulate bone regeneration, we compared bone fracture repair between adult male and female mice. We found that skeletal stem cell (SSC) mediated regeneration in female mice is dependent on estrogen signaling but SSCs from male mice do not exhibit similar estrogen responsiveness. Mechanistically, we found that estrogen acts directly on the SSC lineage in mice and humans by up-regulating multiple skeletogenic pathways and is necessary for the stem cell's ability to self- renew and differentiate. Our results also suggest a clinically applicable strategy to accelerate bone healing using localized estrogen hormone therapy.

Local and Visiting Physician Perspectives on Short Term Surgical Missions in Guatemala: A Qualitative Study.

OBJECTIVE: To explore the impact of short-term surgical missions (STMs) on medical practice in Guatemala as perceived by Guatemalan and foreign physicians. SUMMARY BACKGROUND DATA: STMs send physicians from high-income countries to low and middle-income countries to address unmet surgical needs. Although participation among foreign surgeons has grown, little is known of the impact on the practice of foreign or local physicians. METHODS: Using snowball sampling, we interviewed 22 local Guatemalan and 13 visiting foreign physicians regarding their perceptions of the impact of Guatemalan STMs. Interviews were transcribed verbatim, iteratively coded, and analyzed to identify emergent themes. Findings were validated through triangulation and searching for disconfirming evidence. RESULTS: We identified 2 overarching domains. First, the delivery of surgical care by both Guatemalan and foreign physicians was affected by practice in the STM setting. Differences from usual practice manifested as occasionally inappropriate utilization of skills, management of postoperative complications, the practice of perioperative care versus "pure surgery," and the effect on patient-physician communication and trust. Second, both groups noted professional and financial implications of participation in the STM. CONCLUSIONS: While Guatemalan physicians reported a net benefit of STMs on their careers, they perceived STMs as an imperfect solution to unmet surgical needs. They described missed opportunities for developing local capacity, for example through education and optimal resource planning. Foreign physicians described costs that were manageable and high personal satisfaction with STM work. STMs could enhance their impact by strengthening working relationships with local physicians and prioritizing sustainable educational efforts.

Correction to: Strengthening Surgery Strengthens Health Systems: A New Paradigm and Potential Pathway for Horizontal Development in Low- and Middle-Income Countries.

In the original article, Ziad C. Sifri's first and last names were interchanged. It is correct as reflected here.

Lost in translation: Informed consent in the medical mission setting.

BACKGROUND: Informed consent is a fundamental tenet of ethical care, but even under favorable conditions, patient comprehension of consent conversations may be limited. Little is known about providing informed consent in more uncertain situations such as medical missions. We sought to examine the informed consent process in the medical mission setting. METHODS: We studied informed consent for adult patients undergoing inguinal herniorrhaphy during a medical mission to Guatemala using a convergent mixed-methods design. We audiotaped informed consents during preoperative visits and immediately conducted separate surveys to elicit comprehension of risks. Informed consent conversations and survey responses were translated and transcribed. We used descriptive statistics to examine informed consent content, including information provided by surgeon, the translation of information, and patient comprehension, and used thematic analysis to examine the consent process. RESULTS: Thirteen adult patients (median age 53 years, 69% male) participated. Surgeons conveyed 4 standard risks in 10 out of 13 encounters (77%); all 4 risks were translated to patients in 10 out of 13 encounters (77%). No patient could recall all 4 risks. Qualitative themes regarding the informed consent process included limited physician language skills, verbal domination by physicians and interpreters, and mistranslation of risks. Patients relied on faith and prior or vicarious experiences to qualify surgical risks instead of consent conversations. Many patients restated surgical instructions when asked about risks. CONCLUSION: Despite physicians' attempts to provide informed consent, medical mission patients did not comprehend surgical risks. Our data reveal a critical need to develop more effective methods for communicating surgical risks during medical missions.

Strengthening Surgery Strengthens Health Systems: A New Paradigm and Potential Pathway for Horizontal Development in Low- and Middle-Income Countries.

Global health is transitioning toward a focus on building strong and sustainable health systems in developing countries; however, resources, funding, and agendas continue to concentrate on "vertical" (disease-based) improvements in care. Surgical care in low- and middle-income countries (LMICs) requires the development of health systems infrastructure and can be considered an indicator of overall system readiness. Improving surgical care provides a scalable gateway to strengthen health systems in multiple domains. In this position paper by the Society of University Surgeons' Committee on Global Academic Surgery, we propose that health systems development appropriately falls within the purview of the academic surgeon. Partnerships between academic surgical institutions and societies from high-income and resource-constrained settings are needed to strengthen advocacy and funding efforts and support development of training and research in LMICs.

DEL1 protects against chondrocyte apoptosis through integrin binding.

BACKGROUND: Osteoarthritis (OA) is a debilitating disease process, affecting mobility and overall health of millions. Current treatment is for symptomatic relief and discovery of approaches to halt or reverse damage is imperative. Deletion of developmental endothelial locus-1 (Del1) has been shown to increase severity of OA in knockout mice. We examined the intracellular pathways involved in the ability of DEL1 to protect chondrocytes from apoptosis and anoikis and hypothesized that it functioned via integrin signaling. MATERIALS AND METHODS: Primary human chondrocytes were treated with various inducers of apoptosis, including anoikis, in the presence of added DEL1 or bovine serum albumin as control. Various inhibitors of integrin binding were examined for their effect on DEL1 activity. Downstream signaling pathway components were detected by immunoblotting. RESULTS: The addition of DEL1 protected chondrocytes from multiple inducers of apoptosis as measured by cell survival, terminal deoxynucleotidyl transferase dUTP nick end labeling and caspase 3/7 assays (P < 0.05). The effect of DEL1 was blocked by RGD peptides and by antibodies directed to integrin αVß3, but not by controls or antibody to integrin α1 (P < 0.05). Treatment with DEL1 promoted ERK and AKT activation when cells were attached, but only AKT activation under conditions of anoikis. CONCLUSIONS: DEL1 protected chondrocytes from apoptosis in response to activators of either the intrinsic or extrinsic pathways, and to anoikis. This effect was mediated primarily through integrin αVß3. This represents a therapeutic target for therapies to prevent cartilage degeneration in OA.

Global Surgery: Effective Involvement of US Academic Surgery: Report of the American Surgical Association Working Group on Global Surgery.

: There is an unacceptably high burden of death and disability from conditions that are treatable by surgery, worldwide and especially in low- and middle-income countries (LMICs). The major actions to improve this situation need to be taken by the surgical communities, institutions, and governments of the LMICs. The US surgical community, including the US academic surgical community, has, however, important roles to play in addressing this problem. The American Surgical Association convened a Working Group to address how US academic surgery can most effectively decrease the burden from surgically treatable conditions in LMICs. The Working Group believes that the task will be most successful (1) if the epidemiologic pattern in a given country is taken into account by focusing on those surgically treatable conditions with the highest burdens; (2) if emphasis is placed on those surgical services that are most cost-effective and most feasible to scale up; and (3) if efforts are harmonized with local priorities and with existing global initiatives, such as the World Health Assembly with its 2015 resolution on essential surgery. This consensus statement gives recommendations on how to achieve those goals through the tools of academic surgery: clinical care, training and capacity building, research, and advocacy. Through all of these, the ethical principles of maximally and transparently engaging with and deferring to the interests and needs of local surgeons and their patients are of paramount importance. Notable benefits accrue to US surgeons, trainees, and institutions that engage in global surgical activities.

Review of the Current Management of Pressure Ulcers.

Significance: The incidence of pressure ulcers is increasing due to our aging population and the increase in the elderly living with disability. Learning how to manage pressure ulcers appropriately is increasingly important for all professionals in wound care. Recent Advances: Many new dressings and treatment modalities have been developed over the recent years and the goal of this review is to highlight their benefits and drawbacks to help providers choose their tools appropriately. Critical Issues: Despite an increased number of therapies available on the market, none has demonstrated any clear benefit over the others and pressure ulcer treatment remains frustrating and time-consuming. Future Directions: Additional research is needed to develop products more effective in prevention and treatment of pressure ulcers.

An academic career in global surgery: a position paper from the Society of University Surgeons Committee on Academic Global Surgery.

In recent years, as the high burden of surgical disease and poor access to surgical care in low- and middle-income countries have gained recognition as major public health problems, interest in global health has surged among surgical trainees and faculty. Traditionally, clinical volunteerism was at the forefront of the high-income country response to the significant burden of surgical disease in low- and middle-income countries. However, sustainable strategies for providing surgical care in low- and middle-income countries increasingly depend on bilateral clinical, research, and education collaborations to ensure effective resource allocation and contextual relevance. Academic global surgery creates avenues for interested surgeons to combine scholarship and education with their clinical global surgery passions through incorporation of basic/translational, education, clinical outcomes, or health services research with global surgery. Training in global health, either within residency or through advanced degrees, can provide the necessary skills to develop and sustain such initiatives. We further propose that creating cross-continental, bidirectional collaborations can maximize funding opportunities. Academic institutions are uniquely positioned to lead longitudinal and, importantly, sustainable global surgery efforts. However, for the individual global surgeon, the career path forward may be unclear. This paper reviews the development of academic global surgery, delineates the framework and factors critical to training global surgeons, and proposes models for establishing an academic career in this field. Overall, with determination, the academic global surgeon will not only carve out a niche of expertise but will define this critical field for future generations.

Guide to research in academic global surgery: A statement of the Society of University Surgeons Global Academic Surgery Committee.

Global surgery is an emerging academic discipline that is developing in tandem with numerous policy and advocacy initiatives. In this regard, academic global surgery will be crucial for measuring the progress toward improving surgical care worldwide. However, as a nascent academic discipline, there must be rigorous standards for the quality of work that emerges from this field. In this white paper, which reflects the opinion of the Global Academic Surgery Committee of the Society for University Surgeons, we discuss the importance of research in global surgery, the methodologies that can be used in such research, and the challenges and benefits associated with carrying out this research. In each of these topics, we draw on existing examples from the literature to demonstrate our points. We conclude with a call for continued, high-quality research that will strengthen the discipline's academic standing and help us move toward improved access to and quality of surgical care worldwide.

Why do patients receive care from a short-term medical mission? Survey study from rural Guatemala.

BACKGROUND: Hospital de la Familia was established to serve the indigent population in the western highlands of Guatemala and has a full-time staff of Guatemalan primary care providers supplemented by short-term missions of surgical specialists. The reasons for patients seeking surgical care in this setting, as opposed to more consistent care from local institutions, are unclear. We sought to better understand motivations of patients seeking mission-based surgical care. METHODS: Patients presenting to the obstetric and gynecologic, plastic, ophthalmologic, general, and pediatric surgical clinics at the Hospital de la Familia from July 27 to August 6, 2015 were surveyed. The surveys assessed patient demographics, surgical diagnosis, location of home, mode of travel, and reasons for seeking care at this facility. RESULTS: Of 252 patients surveyed, 144 (59.3%) were female. Most patients reported no other medical condition (67.9%, n = 169) and no consistent income (83.9%, n = 209). Almost half (44.9%, n = 109) traveled >50 km to receive care. The most common reasons for choosing care at this facility were reputation of high quality (51.8%, n = 130) and affordability (42.6%, n = 102); the least common reason was a lack of other options (6.4%, n = 16). CONCLUSIONS: Despite long travel distances and the availability of other options, reputation and affordability were primarily cited as the most common reasons for choosing to receive care at this short-term surgical mission site. Our results highlight that although other surgical options may be closer and more readily available, reputation and cost play a large role in choice of patients seeking care.

Laboratory Models for the Study of Normal and Pathologic Wound Healing.

Current knowledge of wound healing is based on studies using various in vitro and in vivo wound models. In vitro models allow for biological examination of specific cell types involved in wound healing. In vivo models generally provide the full spectrum of biological responses required for wound healing, including inflammation and angiogenesis, and provide cell-cell interactions not seen in vitro. In this review, the authors aim to delineate the most relevant wound healing models currently available and to discuss their strengths and limitations in their approximation of the human wound healing processes to aid scientists in choosing the most appropriate wound healing models for designing, testing, and validating their experiments.

Inhibition of IRE1 results in decreased scar formation.

Wound healing is characterized by the production of large amounts of protein necessary to replace lost cellular mass and extracellular matrix. The unfolded protein response (UPR) is an important adaptive cellular response to increased protein synthesis. One of the main components of the UPR is IRE1, an endoplasmic reticulum transmembrane protein with endonuclease activity that produces the activated form of the transcription factor XBP1. Using luciferase reporter mice for Xbp1 splicing, we showed that IRE1 was up-regulated during excisional wound healing at the time in wound healing consistent with that of the proliferative phase, when the majority of protein synthesis for cellular proliferation and matrix deposition occurs. Furthermore, using a small molecule inhibitor of IRE1 we demonstrated that inhibition of IRE1 led to decreased scar formation in treated mice. Results were recapitulated in a hypertrophic scar mouse model. These data help provide a cellular pathway to target in the treatment of hypertrophic scarring and keloid disorders.

Del1 Knockout Mice Developed More Severe Osteoarthritis Associated with Increased Susceptibility of Chondrocytes to Apoptosis.

OBJECTIVE: We identified significant expression of the matricellular protein, DEL1, in hypertrophic and mature cartilage during development. We hypothesized that this tissue-specific expression indicated a biological role for DEL1 in cartilage biology. METHODS: Del1 KO and WT mice had cartilage thickness evaluated by histomorphometry. Additional mice underwent medial meniscectomy to induce osteoarthritis, and were assayed at 1 week for apoptosis by TUNEL staining and at 8 weeks for histology and OA scoring. In vitro proliferation and apoptosis assays were performed on primary chondrocytes. RESULTS: Deletion of the Del1 gene led to decreased amounts of cartilage in the ears and knee joints in mice with otherwise normal skeletal morphology. Destabilization of the knee led to more severe OA compared to controls. In vitro, DEL1 blocked apoptosis in chondrocytes. CONCLUSION: Osteoarthritis is among the most prevalent diseases worldwide and increasing in incidence as our population ages. Initiation begins with an injury resulting in the release of inflammatory mediators. Excessive production of inflammatory mediators results in apoptosis of chondrocytes. Because of the limited ability of chondrocytes to regenerate, articular cartilage deteriorates leading to the clinical symptoms including severe pain and decreased mobility. No treatments effectively block the progression of OA. We propose that direct modulation of chondrocyte apoptosis is a key variable in the etiology of OA, and therapies aimed at preventing this important step represent a new class of regenerative medicine targets.