Total Joint Arthroplasty in HIV-Positive Patients in Malawi: Outcomes from the National Arthroplasty Registry of the Malawi Orthopaedic Association.

In this observational study, we describe the medium-term outcomes of total joint arthroplasty (TJA) in human immunodeficiency virus (HIV)-positive patients in Malawi, a low-income country. With a high prevalence of HIV and increasing arthroplasty rates in low and middle-income countries, understanding the outcomes of TJA in this unique cohort of patients is essential to ensure that surgical practice is evidence-based. Data for all HIV-positive patients who had TJA from January 2005 to March 2020 were extracted from the National Arthroplasty Registry of the Malawi Orthopaedic Association (NARMOA). From January 2005 to March 2020, a total of 102 total hip arthroplasties (THAs) and 20 total knee arthroplasties (TKAs) were performed in 97 patients who were HIV-positive and without hemophilia or a history of intravenous drug use. The mean length of follow-up was 4 years and 3 months (range, 6 weeks to 15 years) in the THA group and 4 years and 9 months (range, 6 weeks to 12 years) in the TKA group. The mean patient age was 50 years (range, 21 to 76 years) and 64 years (range, 48 to 76 years) at the time of THA and TKA, respectively. The primary indication for THA was osteonecrosis (66 hips). In the THA group, the mean preoperative Oxford Hip Score and Harris hip score were 14.0 (range, 2 to 33) and 29.4 (range, 1 to 64), respectively, and improved to 46.6 (range, 23 to 48) and 85.0 (range, 28 to 91) postoperatively. The primary indication for TKA was osteoarthritis (19 knees). The mean preoperative Oxford Knee Score was 14.9 (range, 6 to 31) and increased to 46.8 (range, 40 to 48) postoperatively. In patients who underwent THA, there was 1 deep infection (1 of 102 procedures), and 6 patients developed aseptic loosening (6 of 102). There was 1 postoperative superficial infection following TKA (1 of 20 procedures), and 1 patient developed aseptic loosening (1 of 20). Postoperative 6-week mortality among all patients was zero. To our knowledge this is the largest medium-term follow-up of HIV-positive patients, without hemophilia or a history of intravenous drug use, who have had TJA in a low-income country. This study demonstrated good medium-term results among HIV-positive patients undergoing TJA, low complication rates, and improvements in patient-reported outcome measures. Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence

Genetic errors of immunity distinguish pediatric non-malignant lymphoproliferative disorders

Background Pediatric non-malignant lymphoproliferative disorders (PLPD) are clinically and genetically heterogeneous. Long-standing immune dysregulation and lymphoproliferation in children may be life-threatening, and a paucity of data exists to guide evaluation and treatment of children with PLPD. Objective The primary objective of this study was to ascertain the spectrum of genomic immunologic defects in PLPD. Secondary objectives included characterization of clinical outcomes and associations between genetic diagnoses and those outcomes. Methods PLPD was defined by persistent lymphadenopathy, lymph organ involvement, or lymphocytic infiltration for more than 3 months, with or without chronic or significant EBV infection. Fifty-one subjects from 47 different families with PLPD were analyzed using whole exome sequencing (WES). Results WES identified likely genetic errors of immunity in 51% to 62% of families (53% to 65% of affected children). Presence of a genetic etiology was associated with younger age and hemophagocytic lymphohistiocytosis. Ten-year survival for the cohort was 72.4%, and patients with viable genetic diagnoses had a higher survival rate (82%) compared to children without a genetic explanation (48%, p = 0.03). Survival outcomes for individuals with EBV-associated disease and no genetic explanation were particularly worse than outcomes for subjects with EBV-associated disease and a genetic explanation (17% vs. 90%; p = 0.002). Ascertainment of a molecular diagnosis provided targetable treatment options for up to 18 individuals and led to active management changes for 12 patients. Conclusion PLPD therefore defines children with high risk for mortality, and WES informs clinical risks and therapeutic opportunities for this diagnosis

Total Knee Arthroplasty in a Low-Income Country: Short-Term Outcomes from a National Joint Registry.

Background We describe our 10-year experience with total knee arthroplasty in patients who are included in the Malawi National Joint Registry. Methods A total of 127 patients underwent 153 total knee arthroplasties (TKAs) between 2005 and 2015. The mean duration of follow-up was 4 years and 3 months (range, 6 months to 10 years and 6 months). The study group included 98 women and 29 men with a mean age of 65.3 years (range, 24 to 84 years). Nine patients were human immunodeficiency virus (HIV)-positive. Results The primary indication for surgery was osteoarthritis (150 knees), and the mean preoperative and postoperative Oxford Knee Scores were 16.81 (range, 4 to 36) and 45.61 (range, 29 to 48), respectively. Four knees (2.6%) were revised because of early periprosthetic joint infection (1 knee), aseptic loosening (1 knee), and late periprosthetic joint infection (2 knees). There were no perioperative deaths. In the group of 9 patients who were HIV-positive, there were no early or late complications and the mean Oxford Knee Score was 47 (range, 42 to 48) at the time of the latest follow-up. Conclusions This study demonstrated good short-term results following 153 primary TKAs performed in a low-income country. Level of Evidence Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence

Topics, Skills, and Cases for an Undergraduate Musculoskeletal Curriculum in Southern Africa

Background: Most patients with orthopaedic pathology in low to middle-income countries are treated by nonspecialists. A curriculum to prepare undergraduate medical students for this duty should reflect the local pathology and skills that are required to manage patients in a resource-restricted environment. The aim of this study was to establish and prioritize a list of core orthopaedic-related knowledge topics, clinical cases, and skills that are relevant to medical students in southern Africa and areas with a similar clinical context. Methods: A modified Delphi consensus study was conducted with 3 interactive iterative rounds of communication and prioritization of items by experts from Africa, Europe, and North America. Preferred priorities were selected but were limited to 50% of all of the possible items. Percent agreement of ≥75% was defined as consensus on each of these items. Results: Most of the 43 experts who participated were orthopaedic surgeons from 7 different countries in southern Africa, but 28% were general practitioners or doctors working in primary or secondary-level facilities. Experts prioritized cases such as patients with multiple injuries, a limping child, and orthopaedic emergencies. Prioritized skills were manipulation and immobilization of dislocations and fractures. The most important knowledge topics included orthopaedic infections, the treatment of common fractures and dislocations, any red flags alerting to specialist referral, and back pain. Surgical skills for the treatment of urgent care conditions were included by some experts who saw a specific need in their clinical practice, but these were ranked lower. Conclusions: A wide geographic, academic, and expertise-specific footprint of experts informed this international consensus through their various clinical and academic circumstances. Knowledge topics, skills, and cases concerning orthopaedic trauma and infection were prioritized by the highest percent agreement. Acute primary care for fractures and dislocations ranked high. Furthermore, the diagnosis and the treatment of conditions not requiring specialist referral were prioritized. This study can inform national curricula in southern Africa and assist in the allocation of student clinical rotations

CNS Langerhans cell histiocytosis: Common hematopoietic origin for LCH-associated neurodegeneration and mass lesions.

BACKGROUND: Central nervous system Langerhans cell histiocytosis (CNS-LCH) brain involvement may include mass lesions and/or a neurodegenerative disease (LCH-ND) of unknown etiology. The goal of this study was to define the mechanisms of pathogenesis that drive CNS-LCH. METHODS: Cerebrospinal fluid (CSF) biomarkers including CSF proteins and extracellular BRAFV600E DNA were analyzed in CSF from patients with CNS-LCH lesions compared with patients with brain tumors and other neurodegenerative conditions. Additionally, the presence of BRAFV600E was tested in peripheral mononuclear blood cells (PBMCs) as well as brain biopsies from LCH-ND patients, and the response to BRAF-V600E inhibitor was evaluated in 4 patients with progressive disease. RESULTS: Osteopontin was the only consistently elevated CSF protein in patients with CNS-LCH compared with patients with other brain pathologies. BRAFV600E DNA was detected in CSF of only 2/20 (10%) cases, both with LCH-ND and active lesions outside the CNS. However, BRAFV600E+ PBMCs were detected with significantly higher frequency at all stages of therapy in LCH patients who developed LCH-ND. Brain biopsies of patients with LCH-ND demonstrated diffuse perivascular infiltration by BRAFV600E+ cells with monocyte phenotype (CD14+ CD33+ CD163+ P2RY12- ) and associated osteopontin expression. Three of 4 patients with LCH-ND treated with BRAF-V600E inhibitor experienced significant clinical and radiologic improvement. CONCLUSION: In LCH-ND patients, BRAFV600E+ cells in PBMCs and infiltrating myeloid/monocytic cells in the brain is consistent with LCH-ND as an active demyelinating process arising from a mutated hematopoietic precursor from which LCH lesion CD207+ cells are also derived. Therapy directed against myeloid precursors with activated MAPK signaling may be effective for LCH-ND. Cancer 2018;124:2607-20. © 2018 American Cancer Society

CNS Langerhans cell histiocytosis: Common hematopoietic origin for LCH-associated neurodegeneration and mass lesions

BACKGROUND: Central nervous system Langerhans cell histiocytosis (CNS-LCH) brain involvement may include mass lesions and/or a neurodegenerative disease (LCH-ND) of unknown etiology. The goal of this study was to define the mechanisms of pathogenesis that drive CNS-LCH. METHODS: Cerebrospinal fluid (CSF) biomarkers including CSF proteins and extracellular BRAFV600E DNA were analyzed in CSF from patients with CNS-LCH lesions compared with patients with brain tumors and other neurodegenerative conditions. Additionally, the presence of BRAFV600E was tested in peripheral mononuclear blood cells (PBMCs) as well as brain biopsies from LCH-ND patients, and the response to BRAF-V600E inhibitor was evaluated in 4 patients with progressive disease. RESULTS: Osteopontin was the only consistently elevated CSF protein in patients with CNS-LCH compared with patients with other brain pathologies. BRAFV600E DNA was detected in CSF of only 2/20 (10%) cases, both with LCH-ND and active lesions outside the CNS. However, BRAFV600E+ PBMCs were detected with significantly higher frequency at all stages of therapy in LCH patients who developed LCH-ND. Brain biopsies of patients with LCH-ND demonstrated diffuse perivascular infiltration by BRAFV600E+ cells with monocyte phenotype (CD14+ CD33+ CD163+ P2RY12- ) and associated osteopontin expression. Three of 4 patients with LCH-ND treated with BRAF-V600E inhibitor experienced significant clinical and radiologic improvement. CONCLUSION: In LCH-ND patients, BRAFV600E+ cells in PBMCs and infiltrating myeloid/monocytic cells in the brain is consistent with LCH-ND as an active demyelinating process arising from a mutated hematopoietic precursor from which LCH lesion CD207+ cells are also derived. Therapy directed against myeloid precursors with activated MAPK signaling may be effective for LCH-ND. Cancer 2018;124:2607-20. © 2018 American Cancer Society

CNS Langerhans cell histiocytosis: Common hematopoietic origin for LCH-associated neurodegeneration and mass lesions.

BACKGROUND: Central nervous system Langerhans cell histiocytosis (CNS-LCH) brain involvement may include mass lesions and/or a neurodegenerative disease (LCH-ND) of unknown etiology. The goal of this study was to define the mechanisms of pathogenesis that drive CNS-LCH. METHODS: Cerebrospinal fluid (CSF) biomarkers including CSF proteins and extracellular BRAFV600E DNA were analyzed in CSF from patients with CNS-LCH lesions compared with patients with brain tumors and other neurodegenerative conditions. Additionally, the presence of BRAFV600E was tested in peripheral mononuclear blood cells (PBMCs) as well as brain biopsies from LCH-ND patients, and the response to BRAF-V600E inhibitor was evaluated in 4 patients with progressive disease. RESULTS: Osteopontin was the only consistently elevated CSF protein in patients with CNS-LCH compared with patients with other brain pathologies. BRAFV600E DNA was detected in CSF of only 2/20 (10%) cases, both with LCH-ND and active lesions outside the CNS. However, BRAFV600E CONCLUSION: In LCH-ND patients, BRAFV600