RANKL inhibition reduces lesional cellularity and Gαs variant expression and enables osteogenic maturation in fibrous dysplasia.

Fibrous dysplasia (FD) is a rare, disabling skeletal disease for which there are no established treatments. Growing evidence supports inhibiting the osteoclastogenic factor receptor activator of nuclear kappa-B ligand (RANKL) as a potential treatment strategy. In this study, we investigated the mechanisms underlying RANKL inhibition in FD tissue and its likely indirect effects on osteoprogenitors by evaluating human FD tissue pre- and post-treatment in a phase 2 clinical trial of denosumab (NCT03571191) and in murine in vivo and ex vivo preclinical models. Histological analysis of human and mouse tissue demonstrated increased osteogenic maturation, reduced cellularity, and reduced expression of the pathogenic Gαs variant in FD lesions after RANKL inhibition. RNA sequencing of human and mouse tissue supported these findings. The interaction between osteoclasts and mutant osteoprogenitors was further assessed in an ex vivo lesion model, which indicated that the proliferation of abnormal FD osteoprogenitors was dependent on osteoclasts. The results from this study demonstrated that, in addition to its expected antiosteoclastic effect, denosumab reduces FD lesion activity by decreasing FD cell proliferation and increasing osteogenic maturation, leading to increased bone formation within lesions. These findings highlight the unappreciated role of cellular crosstalk between osteoclasts and preosteoblasts/osteoblasts as a driver of FD pathology and demonstrate a novel mechanism of action of denosumab in the treatment of bone disease.TRIAL REGISTRATION: ClinicalTrials.gov NCT03571191.

Serum Phosphorus as a Driver of Skeletal Morbidity in Fibrous Dysplasia.

CONTEXT: Fibrous dysplasia (FD) results in fractures, pain, and deformities. Abnormal osteoprogenitor cells overproduce FGF23, leading to hyperphosphaturia in most patients and frank hypophosphatemia in a subset. Studies suggest hypophosphatemia is associated with increased FD-related morbidity. However, the relationship between phosphorus and skeletal complications has not been investigated, and the optimal therapeutic target has not been determined. OBJECTIVE: Characterize the impact of serum phosphorus on FD-related morbidity and identify levels associated with increased skeletal complications. METHODS: Natural history study with 240 subjects at a clinical research center who had ≥1 fasting phosphorus level, determined as age- and sex-adjusted Z-scores. Subjects were categorized based on frank hypophosphatemia (Z-score ≤ -2; n = 48); low-normophosphatemia (> -2 to ≤ -1; n = 66); and high-normophosphatemia (> -1 to ≤ 2; n = 125). Main outcomes were fractures, orthopedic surgeries, and scoliosis. RESULTS: Subjects with frank and low-normophosphatemia had increased fracture and surgery rates vs high-normophosphatemia. The prevalence of moderate to severe scoliosis was similarly higher in the frank and low-normophosphatemia groups. In a subanalysis of patients matched for Skeletal Burden Score ≥35, fracture and surgery rates remained higher in the frank hypophosphatemia group, suggesting association between phosphorus and skeletal complications is not explained by differences in FD burden alone. CONCLUSION: Both frank hypophosphatemia and low-normophosphatemia are associated with increased FD-related complications. This supports FGF23-mediated hypophosphatemia as a driver of skeletal morbidity, which may impact a larger proportion of the FD/McCune-Albright syndrome population than previously recognized. These findings enable clinicians to identify at-risk patients and will inform development of prospective studies to determine optimal therapeutic targets.

Lesion Expansion in Gnathic Fibrous Dysplasia: Natural History, Indicators of Progression, and Response to Bisphosphonates.

Fibrous dysplasia (FD) is characterized by expansile fibro-osseous lesions that may occur in association with endocrinopathies as part of McCune-Albright syndrome (MAS). Craniofacial FD is a significant source of morbidity and most commonly involves the gnathic bones. There is a critical need to understand the natural history and risk factors for gnathic FD progression to develop preventative trials and identify candidates for intervention. The purpose of this study was to characterize gnathic FD lesion expansion and to identify risk factors associated with lesion growth. Patients with gnathic FD and serial CT imaging were evaluated. Volumetric analyses of CT scans were performed using MIM Encore software. Generalized mixed model analysis was used to account for intra-subject correlation, with FD lesion volume as the dependent variable. In addition to age, effects of MAS-associated endocrinopathies, sex, disease severity, and bisphosphonate treatment were evaluated. A total of 104 total lesions in 52 patients were characterized longitudinally. Median age at initial scan was 8.8 years (range 3.4-18.8), and median age at final scan was 16.8 years (range 6.9-33.4 years). The median number of scans per subject was 4 (range 2-14). FD lesion volume increased with age (2.50 cm3 /yr, 95% confidence interval [CI] 1.95-3.04, p < 0.001). However, lesion expansion rate decreased over time (-0.05 cm3 /yr, 95% CI -0.07 to 0.04, p < 0.001). Mandibular lesions tended to expand at a greater rate than maxillary lesions (p < 0.001). Growth hormone excess was associated with accelerated expansion rate (p = 0.002). Other MAS-associated endocrinopathies, pubertal status, sex, weight, lesion density, disease severity, and bisphosphonate treatment were not associated with lesion volume or expansion. Gnathic FD lesion expansion is most rapid in younger children and declines as patients approach adulthood. The availability of quantitative natural history data will guide clinicians in identifying patients who are candidates for medical and surgical interventions and clinical trials for preventative therapies. Published 2023. This article is a U.S. Government work and is in the public domain in the USA.

Craniofacial Fibrous Dysplasia: Clinical and Therapeutic Implications.

PURPOSE OF REVIEW: This study aims to review diagnosis, potential complications, and clinical management in craniofacial fibrous dysplasia. RECENT FINDINGS: Fibrous dysplasia (FD) is a rare mosaic disorder in which normal bone and marrow are replaced with expansile fibro-osseous lesions. Disease presents along a broad spectrum and may be associated with extraskeletal features as part of McCune-Albright syndrome (MAS). The craniofacial skeleton is one of the most commonly impacted areas in FD, and its functional and anatomical complexities create unique challenges for diagnosis and management. This review summarizes current approaches to diagnosis and management in FD/MAS, with emphasis on the clinical and therapeutic implications for the craniofacial skeleton.

Prioritization of Evidence-Based and Evidence-Informed Interventions for Retention in Medical Care for Persons with HIV.

Up to 50% of those diagnosed with HIV in the U.S. are not retained in medical care. Care retention provides opportunity to monitor benefits of HIV therapy and enable viral suppression. To increase retention, there is a need to prioritize best practices appropriate for translation and dissemination for real-world implementation. Eighteen interventions from CDC's Compendium of Evidence-Based Interventions were scored using the RE-AIM framework to determine those most suitable for dissemination. A CDC Division of HIV Prevention workgroup developed a RE-AIM scale with emphasis on the Implementation and Maintenance dimensions and less emphasis on the Efficacy dimension since all 18 interventions were already identified as evidence-based or evidence-informed. Raters referenced primary efficacy publications and scores were averaged for a ranked RE-AIM score for interventions. Of 18 interventions, four included care linkage and 7 included viral suppression outcomes. Interventions received between 20.6 and 35.3 points (45 maximum). Scores were converted into a percentage of the total possible with ranges between 45.8 and 78.4%. Top four interventions were ARTAS (78.4%); Routine Screening for HIV (RUSH) (73.2%); Optn4Life (67.4%) and Virology Fast Track (65.9%). All four scored high on Implementation and Maintenance dimensions. Select items within the scale were applicable to health equity, covering topics such as reaching under-served focus populations and acceptability to that population. Navigation-enhanced Case Management (NAV) scored highest on the health equity subscale. RE-AIM prioritization scores will inform dissemination and translation efforts, help clinical staff select feasible interventions for implementation, and support sustainability for those interventions.

RESUMEN: Hasta el 50% de las personas diagnosticadas con VIH en USA no son retenidos en cuidados médicos impactando su monitoreo y supresión viral. Dieciocho intervenciones de retención fueron evaluadas utilizando el marco RE-AIM para determinar su adecuación para la difusión. Evaluadores promediaron las intervenciones. Cuatro intervenciones incluyeron enlace de atención y 7 supresión viral. Las cuatro intervenciones principales fueron ARTAS, detección de rutina para el VIH, Optn4Life y Vía rápida de virología. Elementos del marco fueron usados para evaluar equidad en salud y cubrieron temas de cómo llegar a las poblaciones desatendidas y la aceptabilidad de esa población. La intervención gestión de casos para mejorar con navegación (NAV) obtuvo la puntuación más alta en la subescala de equidad. RE-AIM y los puntajes de priorización de equidad informarán los esfuerzos de difusión y traducción, ayudarán al personal clínico a seleccionar las intervenciones para la implementación y apoyarán la sostenibilidad.

Skeletal Disease Acquisition in Fibrous Dysplasia: Natural History and Indicators of Lesion Progression in Children.

Fibrous dysplasia (FD) is a rare mosaic disorder resulting in fractures, pain, and disability. Bone lesions appear during childhood and expand during skeletal growth. The rate at which FD lesions progress and the biochemical determinants of FD lesion formation have not been established, making it difficult to investigate and implement preventative therapies. The purpose of this study was to characterize FD lesion progression in children, and to identify clinical variables associated with progressive disease. Clinical data and imaging from an ongoing natural history study at the National Institutes of Health (NIH) were reviewed. 99m-Technetium methylene diphosphonate (99Tc-MDP) scans were used to determine Skeletal Burden Score (SBS), a validated quantitative scoring system. FD progression rate was determined by the change in the SBS in each patient per year. Thirty-one children had serial 99Tc-MDP scans, with a median age at first scan of 6 years (interquartile range [IQR] 4-8, range 2-10), and median follow-up 1.1 years (IQR 1.1-2.1, range 0.7-11.2). The median FD progression rate for the total group was 2.12 SBS units/year (IQR 0.81-2.94, range 0.05-7.81). FD progression rates were highest in children under age 8 years and declined with age (p = 0.03). Baseline disease severity was associated with subsequent disease progression (p = 0.009), with the highest FD progression rates in patients with moderate disease (baseline SBS 16-30), and lowest progression rates in those with severe disease (SBS ≥50). Serum levels of the bone formation marker osteocalcin were positively correlated with subsequent FD progression rate (p = 0.01, R = 0.58). There was no association between FD progression and baseline endocrinopathies, fractures, or surgery rates. FD lesions progress during childhood, particularly in younger children and those with moderate involvement. Osteocalcin may potentially serve as a biomarker for progressive disease. These findings may allow clinicians to investigate preventative therapies, and to identify children with FD who are candidates for early interventions. Published 2022. This article is a U.S. Government work and is in the public domain in the USA.

Looks can be Deceiving: A Challenging Case of Anti-Neutrophil Cytoplasmic Autoantibody Associated Vasculitis.

[Anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis] (AAV) is an autoimmune disease characterized by systemic vascular inflammation. We present a case of a 76-year-old man who presented with shortness of breath, fatigue, and weakness. He was eventually diagnosed with hydralazine-induced ANCA-associated renal limited glomerulonephritis. The presentation of this case was unique for a few reasons; the patient showed an initial improvement in kidney function, was non-oliguric, and had no systemic signs of vasculitis. This led to the patient being discharged prematurely with the diagnosis of acute tubular necrosis. We discuss educational features of this case and warn future clinicians about the possibility of waxing and waning renal function in these patients, as well as the importance of having a higher index of suspicion for glomerulonephritis in patients who take hydralazine.

Hypokalemic Periodic Paralysis Precipitated by Thyrotoxicosis and Renal Tubular Acidosis.

BACKGROUND: Hypokalemic periodic paralysis is a rare neuromuscular disorder characterized by transient episodes of flaccid paralysis due to a defect in muscle ion channels. Most cases are hereditary, but it can be acquired. We present a case of acquired hypokalemic periodic paralysis associated with hyperthyroidism and renal tubular acidosis. Clinical Case. A 38-year-old female with a history of Graves' disease presented to the emergency department with generalized weakness and associated nausea, vomiting, and weight loss. Examination was significant for diffuse weakness in all extremities. Labs showed hypokalemia, hyperthyroidism, and nonanion gap metabolic acidosis with a positive urine anion gap. She was treated for hypokalemic periodic paralysis and renal tubular acidosis. Potassium replacement, propranolol, methimazole, and sodium bicarbonate were initiated. Her potassium gradually corrected with resolution of her symptoms. Further investigation revealed a history of dry eyes, dry mouth, and recurrent dental carries. She had positive ANA, SS-A, and SS-B antibodies. She was diagnosed with Sjögren's syndrome, which may have been associated with her Graves' disease and thus contributed to both her RTA and hyperthyroidism. CONCLUSION: Early recognition and treatment of thyrotoxic periodic paralysis are important to prevent cardiac complications. Management includes potassium replacement with careful monitoring to prevent rebound hyperkalemia. The definitive treatment is to achieve euthyroid status.

Vital Signs: Deaths Among Persons with Diagnosed HIV Infection, United States, 2010-2018.

BACKGROUND: Life expectancy for persons with human immunodeficiency virus (HIV) infection who receive recommended treatment can approach that of the general population, yet HIV remains among the 10 leading causes of death among certain populations. Using surveillance data, CDC assessed progress toward reducing deaths among persons with diagnosed HIV (PWDH). METHODS: CDC analyzed National HIV Surveillance System data for persons aged ≥13 years to determine age-adjusted death rates per 1,000 PWDH during 2010-2018. Using the International Classification of Diseases, Tenth Revision, deaths with a nonmissing underlying cause were classified as HIV-related or non-HIV-related. Temporal changes in total deaths during 2010-2018 and deaths by cause during 2010-2017 (2018 excluded because of delays in reporting), by demographic characteristics, transmission category, and U.S. Census region of residence at time of death were calculated. RESULTS: During 2010-2018, rates of death decreased by 36.6% overall (from 19.4 to 12.3 per 1,000 PWDH). During 2010-2017, HIV-related death rates decreased 48.4% (from 9.1 to 4.7), whereas non-HIV-related death rates decreased 8.6% (from 9.3 to 8.5). Rates of HIV-related deaths during 2017 were highest by race/ethnicity among persons of multiple races (7.0) and Black/African American persons (5.6), followed by White persons (3.9) and Hispanic/Latino persons (3.9). The HIV-related death rate was highest in the South (6.0) and lowest in the Northeast (3.2). CONCLUSION: Early diagnosis, prompt treatment, and maintaining access to high-quality care and treatment have been successful in reducing HIV-related deaths and remain necessary for continuing reductions in HIV-related deaths.

Effectively Communicating About HIV and Other Health Disparities: Findings From a Literature Review and Future Directions.

Despite significant progress in the prevention and treatment of HIV, disparities in rates of infection remain among key groups in the United States, including blacks and African Americans; Hispanics/Latinos; and men who have sex with men (MSM). The U.S. Department of Health and Human Services' initiative, Ending the HIV Epidemic: A Plan for America, calls for addressing HIV-related disparities and reducing stigma and discrimination associated with HIV. The goal of this literature review was to identify approaches for effectively communicating about health disparities across the HIV care continuum. We reviewed the literature to investigate strategies used to communicate health disparities and to identify potential unintended adverse effects resulting from this messaging. Messages about health disparities often target subgroups at higher risk and can be framed in a variety of ways (e.g., social comparison, progress, impact, etiological). Studies have examined the effects of message framing on the risk perceptions, emotional reactions, and behaviors of individuals exposed to the messaging. The evidence points to several potential unintended adverse effects of using social comparison framing and individual responsibility framing to communicate about health disparities, and visual images and exemplars to target messages to higher-risk subgroups. There is not yet a clear evidence-based approach for communicating about health disparities and avoiding potential unintended effects. However, we offer recommendations for communicating about HIV-related disparities based on our findings. Because we found limited literature that addressed our research questions in the context of HIV, we propose a research agenda to build an evidence base for developing effective messages about HIV-related disparities.

Changes in the administrative prevalence of autism spectrum disorders: contribution of special education and health from 2002-2008.

This study examined changes in the administrative prevalence of autism spectrum disorders (ASD) in Utah children from 2002 to 2008 by record source (school and health), age (four, six, and eight), and special education classification. Prevalence increased 100% with 1 in 77 children aged eight identified with ASD by 2008. Across study years and age groups rates were higher when health and school data were combined with a greater proportion of cases ascertained from health. The proportion of children with both a health ASD diagnosis and a special education autism classification did not significantly change. Most children with an ASD health diagnosis did not have an autism special education classification. Findings highlight the growing health and educational impact of ASD.