Establishing Sustainable Arthroscopy Capacity in Low- and Middle-Income Countries (LMICs) through High-Income Country/LMIC Partnerships: A Qualitative Analysis.

Disparities exist in treatment modalities, including arthroscopic surgery, for orthopaedic injuries between high-income countries (HICs) and low- and middle-income countries (LMICs). Arthroscopy training is a self-identified goal of LMIC surgeons to meet the burden of musculoskeletal injury. The aim of this study was to determine the necessary "key ingredients" for establishing arthroscopy centers in LMICs in order to build capacity and expand training in arthroscopy in lower-resource settings. Methods: This study utilized semi-structured interviews with orthopaedic surgeons from both HICs and LMICs who had prior experience establishing arthroscopy efforts in LMICs. Participants were recruited via referral sampling. Interviews were qualitatively analyzed in duplicate via a coding schema based on repeated themes from preliminary interview review. Subgroup analysis was conducted between HIC and LMIC respondents. Results: We identified perspectives shared between HIC and LMIC stakeholders and perspectives unique to 1 group. Both groups were motivated by opportunities to improve patients' lives; the LMIC respondents were also motivated by access to skills and equipment, and the HIC respondents were motivated by teaching opportunities. Key ingredients identified by both groups included an emphasis on teaching and the need for high-cost equipment, such as arthroscopy towers. The LMIC respondents reported single-use materials as a key ingredient, while the HIC respondents reported local champions as crucial. The LMIC respondents cited the scarcity of implants and shaver blades as a barrier to the continuity of arthroscopy efforts. Conclusions: Incorporation of the identified key ingredients, along with leveraging the motivations of the host and the visiting participant, will allow future international arthroscopy partnerships to better match proposed interventions with the host-identified needs. Clinical Relevance: Arthroscopy is an important tool for treatment of musculoskeletal injury. Increasing access to arthroscopy is an important goal to achieve greater equity in musculoskeletal care globally. Developing successful partnerships between HICs and LMICs to support arthroscopic surgery requires sustained relationships that address local needs.

Recomendaciones para la sedación y la analgesia por médicos no anestesiólogos y odontólogos de pacientes mayores de 12 años / Sedation and analgesia recommendations for non-anesthesiologist physicians and dentists in patients over 12 years old

Las complicaciones relacionadas con la sedación son, en su enorme mayoría, prevenibles. El presente documento establece unas recomendaciones para que los no anestesiólogos puedan realizar sedaciones nivel I y II con un buen nivel de seguridad. Sus aspectos másimportantes son: administración de la sedación por una persona diferente del operador; recomendaciones en cuanto a la capacitación, la monitorización, el uso de un solo medicamento para la sedación y la disponibilidad de medicamentos y equipos de respaldo;la necesidad de realizar una evaluación previa a la sedación, así como el consentimiento informado y el registro durante el procedimiento; y recomendaciones para considerar un bajo umbral con el fin de solicitar el apoyo de un anestesiólogo.

Most of the complications related to sedation are preventable. This document defines some recommendations for non-anesthesiologists so that they can provide sedation level I and II with adequate safety. The most important recommendations are: that the sedation be provided by someone different from the person who performs the surgical procedure; designation of the training and monitoring of thje person who sedates; the use of only one medication for sedation, and the availability of medications and equipment to manage complications; the mandatory need of an assessment prior to the sedation, as well as informed consent and record of events during the procedure; and the recommendation of having a low threshold to request the support of an anesthesiologist.

TWEAK stimulation of kidney resident cells in the pathogenesis of graft versus host induced lupus nephritis.

The cytokine TWEAK demonstrates potent kidney proinflammatory and proliferative effects. Recently, we have shown that interactions of TWEAK with its receptor Fn14 are instrumental in the pathogenesis of nephritis in the chronic graft-versus-host (cGVH) induced model of lupus. Fn14 is expressed by macrophages and resident kidney cells; we hypothesized that TWEAK binding to both cell types contributes to the pathogenesis of lupus nephritis. To address this question, we generated bone marrow chimaeras and compared the progression of nephritis during cGVH induced lupus in mice expressing Fn14 only on bone marrow-derived cells, versus mice displaying Fn14 only on non-bone marrow-derived cells. While Fn14 deficiency did not significantly affect autoantibody titers, Fn14 deficiency on bone marrow-derived cells did not inhibit nephritis initiation in mice with Fn14 sufficient non-hematopoeitic cells. Conversely, expression of Fn14 only on bone marrow-derived cells resulted in a delayed, milder disease course. To further explore the role of macrophages, we depleted macrophages during cGVH induction. Surprisingly, we found that macrophage depleted mice displayed significantly increased titers of anti-DNA antibodies and worse kidney disease. We conclude that the presence of Fn14 on resident kidney cells alone may be sufficient to initiate nephritis in this murine model of lupus.

TWEAK/Fn14 interactions are instrumental in the pathogenesis of nephritis in the chronic graft-versus-host model of systemic lupus erythematosus.

TNF-like weak inducer of apoptosis (TWEAK), a member of the TNF superfamily, is a prominent inducer of proinflammatory cytokines in vitro and in vivo. We previously found that kidney cells display the TWEAK receptor Fn14, and that TWEAK stimulation of mesangial cells and podocytes induces a potent proinflammatory response. Several of the cytokines up-regulated in the kidney in response to TWEAK are instrumental in Lupus nephritis; we therefore hypothesized that TWEAK/Fn14 interactions may be important in the cascade(s) leading to renal damage in systemic Lupus erythematosus. In this study, we analyzed the effects of Fn14 deficiency in the chronic graft-vs-host model of SLE, and the benefits of treatment with an anti-TWEAK mAb in this mouse model. We found that anti-nuclear Ab titers were no different between C57BL/6 Fn14 wild-type and deficient mice injected with alloreactive bm12 splenocytes. However, kidney disease was significantly less severe in Fn14 knockout mice. Furthermore, kidney IgG deposition, IL-6, MCP-1, RANTES, and IP-10, as well as macrophage infiltration, were significantly decreased in Fn14-deficient mice with induced lupus. Similarly, mice with induced Lupus treated with an anti-TWEAK neutralizing mAb had significantly diminished kidney expression of IL-6, MCP-1, IL-10, as well as proteinuria, but similar autoantibody titers, as compared with control-treated mice. We conclude that TWEAK is an important mediator of kidney damage that acts by promoting local inflammatory events, but without impacting adaptive immunity in this experimental LN model. Thus, TWEAK blockade may be a novel therapeutic approach to reduce renal damage in SLE.

Expansion and hyperactivity of CD1d-restricted NKT cells during the progression of systemic lupus erythematosus in (New Zealand Black x New Zealand White)F1 mice.

CD1d-restricted NKT cells expressing invariant TCR alpha-chain rearrangements (iNKT cells) have been reported to be deficient in humans with a variety of autoimmune syndromes and in certain strains of autoimmune mice. In addition, injection of mice with alpha-galactosylceramide, a specific glycolipid agonist of iNKT cells, activates these T cells and ameliorates autoimmunity in several different disease models. Thus, deficiency and reduced function in iNKT cells are considered to be risk factors for the development of such diseases. In this study we report that the development of systemic lupus erythematosus in (New Zealand Black (NZB) x New Zealand White (NZW))F(1) mice was paradoxically associated with an expansion and activation of iNKT cells. Although young (NZB x NZW)F(1) mice had normal levels of iNKT cells, these expanded with age and became phenotypically and functionally hyperactive. Activation of iNKT cells in (NZB x NZW)F(1) mice in vivo or in vitro with alpha-galactosylceramide indicated that the immunoregulatory role of iNKT cells varied over time, revealing a marked increase in their potential to contribute to production of IFN-gamma with advancing age and disease progression. This evolution of iNKT cell function during the progression of autoimmunity may have important implications for the mechanism of disease in this model of systemic lupus erythematosus and for the development of therapies using iNKT cell agonists.

T cell recognition of an engineered MHC class I molecule: implications for peptide-independent alloreactivity.

Previously, we described H-2K(bW9) (K(bW9)), an engineered variant of the murine MHC class I molecule H-2K(b) (K(b)), devoid of the central anchor ("C") pocket owing to a point mutation on the floor of the peptide binding site; this substitution drastically altered selection of bound peptides, such that the peptide repertoires of K(b) and K(bW9) are largely nonoverlapping in vivo. On the basis of these observations, we used K(bW9) and K(b) to revisit the role of peptides in alloreactive T cell recognition. We first compared Ab and TCR recognition of K(bW9) and K(b). Six of six K(b)-specific mAbs, directed against different parts of the molecule, recognized K(bW9) well, albeit at different levels than K(b). Furthermore, K(bW9) readily served as a restriction element for a peptide-specific syngeneic CTL response. Therefore, K(bW9) mutation did not result in gross distortions of the TCR-interacting surface of class I, which was comparable between K(b) and K(bW9). Interestingly, when K(bW9) was used to stimulate allogeneic T cells, it induced an infrequent CTL population that cross-reacted against K(b) and was specific for peptide-independent MHC epitopes. By contrast, K(b)-induced alloreactive CTLs recognized K(b) in a peptide-specific manner, did not cross-react on K(bW9), and were present at much higher frequencies than those induced by K(bW9). Thus, induction of rare peptide-independent CTLs depended on unique structural features of K(bW9), likely due to the elevated floor of the peptide-binding groove and the consequent protruding position of the peptide. These results shed new light on the relationship between TCR and peptide-MHC complex in peptide-independent allorecognition.