Telerehabilitation in Physical Therapist Practice: A Clinical Practice Guideline From the American Physical Therapy Association.

A clinical practice guideline on telerehabilitation was developed by an American Physical Therapy Association volunteer guideline development group consisting of international physical therapists and physiotherapists, a physician, and a consumer. The guideline was based on systematic reviews of current scientific literature, clinical information, and accepted approaches to telerehabilitation in physical therapist practice. Seven recommendations address the impact of, preparation for, and implementation of telerehabilitation in physical therapist practice. Research recommendations identify current gaps in knowledge. Overall, with shared decision-making between clinicians and patients to inform patients of service delivery options, direct and indirect costs, barriers, and facilitators of telerehabilitation, the evidence supports the use of telerehabilitation by physical therapists for both examination and intervention. The Spanish and Chinese versions of this clinical practice guideline, as well as the French version of the recommendations, are available as supplementary material (Suppl. Materials).

Educational competencies for telehealth physical therapy: Results of a modified Delphi process.

BACKGROUND: Telehealth is becoming more prevalent in physical therapy, involving a whole host of clinical services. These services are often provided without structured training in telehealth, and no formal curricula currently exist for this purpose. OBJECTIVE: To develop a set of educational competencies (ECs) to guide instruction of telehealth-related skills in entry-level programs (i.e., Doctor of Physical Therapy), existing programs (i.e., residencies and fellowships), and potential future post-graduate programs specific to telehealth physical therapy. METHODS: Physical therapists and physical therapist assistants from diverse geographic locations and practice areas were invited to participate on an expert panel. A modified Delphi process was then used to evaluate the acceptability of draft ECs gathered from the extant literature by a steering group. Draft ECs were presented to the expert panel on a questionnaire, which asked expert participants to rate each draft EC according to applicability and clarity. Draft ECs were accepted if they met a priori established criteria for acceptability and clarity. Unendorsed ECs were revised by the steering group according to open-ended comments from respondents and presented during a subsequent round. Three rounds of surveys were undertaken. RESULTS: Thirty-eight participants formed the expert panel; 38 participants completed the Round 1 survey, 28 participants completed the Round 2 survey, and 24 participants completed the Round 3 survey. Delphi group members approved 48 ECs in the first round, 23 ECs in the second round, and 2 ECs in the third round. There were 4 ECs that remained unendorsed after the modified Delphi process. Endorsed ECs spanned 7 conceptual areas. Distinct sets of ECs characterized expected end points of first professional degree, existing residency and fellowship, and potential future telehealth physical therapy post-graduate program. CONCLUSIONS: Consensus-based ECs identified in this study may guide instruction in knowledge and skills relevant to physical therapy telehealth.

Management of Familial Hypercholesterolemia: Current Status and Future Perspectives.

Familial hypercholesterolemia (FH) is the most common monogenic disorder associated with premature atherosclerotic cardiovascular disease. Early diagnosis and effective treatment can significantly improve prognosis. Recent advances in the field of lipid metabolism have shed light on the molecular defects in FH and new therapeutic options have emerged. A search of PubMed database up to March 2020 was performed for this review using the following keywords: "familial hypercholesterolemia," "diagnosis," "management," "guideline," "consensus," "genetics," "screening," "lipid lowering agents." The prevalence rate of heterozygous FH is approximately 1 in 200 to 250 and FH is underdiagnosed and undertreated in many parts of the world. Diagnostic criteria have been developed to aid the clinical diagnosis of FH. Genetic testing is now available but not widely used. Cascade screening is recommended to identify affected family members, and the benefits of early interventions are clear. Treatment strategy and target is currently based on low-density lipoprotein (LDL) cholesterol levels as the prognosis of FH largely depends on the magnitude of LDL cholesterol-lowering that can be achieved by lipid-lowering therapies. Statins with or without ezetimibe are the mainstay of treatment and are cost-effective. Addition of newer medications like PCSK9 inhibitors is able to further lower LDL cholesterol levels substantially, but the cost is high. Lipoprotein apheresis is indicated in homozygous FH or severe heterozygous FH patients with inadequate response to cholesterol-lowering therapies. In conclusion, FH is a common, treatable genetic disorder, and although our understanding of this disease has improved, many challenges still remain for its optimal management.

Carbamylated HDL and Mortality Outcomes in Type 2 Diabetes.

OBJECTIVE: Carbamylation is part of the aging process and causes adverse changes in the structure and function of proteins. Lipoproteins are subjected to carbamylation. We investigated the usefulness of carbamylated HDL as a prognostic indicator of survival in patients with type 2 diabetes and the association with mortality outcomes. RESEARCH DESIGN AND METHODS: Baseline plasma carbamylated HDL was measured by ELISA in a cohort of 1,517 patients with type 2 diabetes. The primary outcome was all-cause mortality, and the secondary outcomes were cause-specific deaths, including cardiovascular, renal, infection, and cancer related. RESULTS: Over a median follow-up of 14 years, 292 patients died, and the mortality rate was 14.5 per 1,000 person-years. Plasma carbamylated HDL level was higher in those with a fatal outcome (46.1 ± 17.8 µg/mL vs. 32.9 ± 10.7; P < 0.01). Patients in the third (hazard ratio [HR] 2.11; 95% CI 1.40-3.17; P < 0.001) and fourth quartiles (HR 6.55; 95% CI 4.67-9.77; P < 0.001) of carbamylated HDL had increased mortality risk. After adjustment for conventional risk factors, elevated carbamylated HDL was independently associated with all-cause mortality (HR 1.39; 95% CI 1.28-1.52; P < 0.001) as well as with all the cause-specific mortalities. Adding plasma carbamylated HDL level improved the power of the multivariable models for predicting all-cause mortality, with significant increments in C index (from 0.78 to 0.80; P < 0.001), net reclassification index, and integrated discrimination improvement. CONCLUSIONS: Carbamylation of HDL renders HDL dysfunctional, and carbamylated HDL is independently associated with mortality outcomes in patients with type 2 diabetes.

Connecting at the Webside: Rapid Telehealth Implementation for Musculoskeletal Clinicians.

SYNOPSIS: Telehealth is rapidly being implemented during the COVID-19 pandemic. Despite evidence for the effectiveness of telehealth for musculoskeletal examination and treatment, there is a lack of clear guidance related to implementation. We provide recommendations on practical concerns related to delivering telehealth, including choice of platform; legal, ethical, and administrative considerations; building a "webside manner"; and implications for musculoskeletal examination and treatment. J Orthop Sports Phys Ther 2021;51(1):8-11. doi:10.2519/jospt.2021.9902.

Association Between Treatment With Apixaban, Dabigatran, Rivaroxaban, or Warfarin and Risk for Osteoporotic Fractures Among Patients With Atrial Fibrillation: A Population-Based Cohort Study.

BACKGROUND: It is unclear whether anticoagulant type is associated with the risk for osteoporotic fracture, a deleterious complication of anticoagulants among patients with atrial fibrillation (AF). OBJECTIVE: To compare the risk for osteoporotic fracture between anticoagulants. DESIGN: Population-based cohort study. SETTING: Territory-wide electronic health record database of the Hong Kong Hospital Authority. PARTICIPANTS: Patients newly diagnosed with AF between 2010 and 2017 who received a new prescription for warfarin or a direct oral anticoagulant (DOAC) (apixaban, dabigatran, or rivaroxaban). Follow-up ended on 31 December 2018. MEASUREMENTS: Osteoporotic hip and vertebral fractures in anticoagulant users were compared using propensity score-weighted cumulative incidence differences (CIDs). RESULTS: There were 23 515 patients identified (3241 apixaban users, 6867 dabigatran users, 3866 rivaroxaban users, and 9541 warfarin users). Overall mean age was 74.4 years (SD, 10.8), ranging from 73.1 years (warfarin) to 77.9 years (apixaban). Over a median follow-up of 423 days, 401 fractures were identified (crude event number [weighted rate per 100 patient-years]: apixaban, 53 [0.82]; dabigatran, 95 [0.76]; rivaroxaban, 57 [0.67]; and warfarin, 196 [1.11]). After 24-month follow-up, DOAC use was associated with a lower risk for fracture than warfarin use (apixaban CID, -0.88% [95% CI, -1.66% to -0.21%]; dabigatran CID, -0.81% [CI, -1.34% to -0.23%]; and rivaroxaban CID, -1.13% [CI, -1.67% to -0.53%]). No differences were seen in all head-to-head comparisons between DOACs at 24 months (apixaban vs. dabigatran CID, -0.06% [CI, -0.69% to 0.49%]; rivaroxaban vs. dabigatran CID, -0.32% [CI, -0.84% to 0.18%]; and rivaroxaban vs. apixaban CID, -0.25% [CI, -0.86% to 0.40%]). LIMITATION: Residual confounding is possible. CONCLUSION: Among patients with AF, DOAC use may result in a lower risk for osteoporotic fracture compared with warfarin use. Fracture risk does not seem to be altered by the choice of DOAC. These findings may help inform the benefit-risk assessment when choosing between anticoagulants. PRIMARY FUNDING SOURCE: The University of Hong Kong and University College London Strategic Partnership Fund.

Home and Community-Based Physical Therapist Management of Adults With Post-Intensive Care Syndrome.

More than 4 million adults survive a stay in the intensive care unit each year, with many experiencing new or worsening physical disability, mental health problems, and/or cognitive impairments, known as post-intensive care syndrome (PICS). Given the prevalence and magnitude of physical impairments after critical illness, many survivors, including those recovering from COVID-19, could benefit from physical therapist services after hospital discharge. However, due to the relatively recent recognition and characterization of PICS, there may be limited awareness and understanding of PICS among physical therapists practicing in home health care and community-based settings. This lack of awareness may lead to inappropriate and/or inadequate rehabilitation service provision. While this perspective article provides information relevant to all physical therapists, it is aimed toward those providing rehabilitation services outside of the acute and postacute inpatient settings. This article reports the prevalence and clinical presentation of PICS and provides recommendations for physical examination and outcomes measures, plan of care, and intervention strategies. The importance of providing patient and family education, coordinating community resources including referring to other health care team members, and community-based rehabilitation service options is emphasized. Finally, this perspective article discusses current challenges for optimizing outcomes for people with PICS and suggests future directions for research and practice.

Carbamylated Lipoproteins and Progression of Diabetic Kidney Disease.

BACKGROUND AND OBJECTIVES: Protein carbamylation is a consequence of uremia and carbamylated lipoproteins contribute to atherogenesis in CKD. Proteins can also be carbamylated by a urea-independent mechanism, and whether carbamylated lipoproteins contribute to the progression of CKD has not been investigated. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A case-control study was performed to determine whether there were changes in plasma levels of carbamylated lipoproteins in individuals with type 2 diabetes with eGFR >60 ml/min per 1.73 m2 compared with a group of age- and sex-matched healthy controls. A cohort of 1320 patients with type 2 diabetes with baseline eGFR ≥30 ml/min per 1.73 m2 was longitudinally followed up to evaluate the association between carbamylated lipoproteins and progression of CKD. The primary kidney outcome was defined as doubling of serum creatinine and/or initiation of KRT during follow-up. Plasma carbamylated LDLs and HDLs was measured by ELISA. RESULTS: In individuals with diabetes with eGFR >60 ml/min per 1.73 m2, both plasma carbamylated LDL and HDL levels were higher compared with healthy controls (P<0.001). After a mean follow-up of 9 years of the diabetic cohort, individuals in the top quartile of carbamylated LDL (hazard ratio, 2.21; 95% confidence interval, 1.42 to 3.46; P<0.001) and carbamylated HDL (hazard ratio, 4.53; 95% confidence interval, 2.87 to 7.13; P<0.001) had higher risk of deterioration of kidney function compared with those in the lowest quartile. On multivariable Cox regression analysis, plasma carbamylated LDL was no longer associated with kidney outcome after adjusting for baseline eGFR and potential confounding factors. However, the association between plasma carbamylated HDL and kidney outcome remained significant and was independent of HDL cholesterol. CONCLUSIONS: Plasma carbamylated HDL but not carbamylated LDL was independently associated with progression of CKD in patients with type 2 diabetes.

A young Chinese man with nephrotic syndrome due to lipoprotein glomerulopathy.

Lipoprotein glomerulopathy (LPG) is a rare autosomal dominant renal disease with incomplete penetrance, associated with specific protein-modifying mutations in the APOE gene. LPG is associated with poor renal prognosis, in which lipoprotein thrombi are seen in the glomerular capillaries. Dyslipidemia in LPG generally resembles type III hyperlipoproteinemia with elevated serum apolipoprotein E level. Fibrate is the most frequently reported lipid-lowering therapy in LPG as hypertriglyceridemia is common in these individuals. There are few existing case reports on effectiveness of statin monotherapy for LPG. We report a 32-year-old Chinese man who presented with nephrotic syndrome, renal impairment, severe hypercholesterolemia without hypertriglyceridemia, and hypertension. Renal biopsy confirmed lipoprotein glomerulopathy. Genetic testing confirmed APOE Kyoto mutation. Anti-hypertensive therapy, including angiotensin receptor blocker, and statin were initiated. Concomitant with normalization of lipid profile, his proteinuria markedly improved, and his renal function has remained stable up to 3 years, demonstrating sustained benefit with statin monotherapy in LPG.

Galectin-3 and risk of cardiovascular events and all-cause mortality in type 2 diabetes.

AIMS: Recent clinical studies have shown that galectin-3 is a prognostic indicator in patients with coronary heart disease and in patients with heart failure. Experimental data suggest that galectin-3 may play a role in atherogenesis. We have evaluated whether serum galectin-3 level is associated with cardiovascular outcome in type 2 diabetes. MATERIALS AND METHODS: Galectin-3 was measured in baseline samples in 1495 persons with type 2 diabetes. The primary cardiovascular outcome, incident cardiovascular events, was defined as first non-fatal myocardial infarction, non-fatal stroke, coronary revascularization, or death from cardiovascular cause. The secondary outcome was all-cause mortality. RESULTS: At baseline, 12% of the subjects had prevalent cardiovascular disease. Serum galectin-3 was increased in the group with incident cardiovascular events compared with those who remained free of events during follow up (9.03 ± 2.98 ng/mL vs 8.15 ± 2.76, P < 0.01). Serum galectin-3 was also significantly increased in those subjects with a fatal outcome. The hazard ratios (HR) for cardiovascular events and all-cause mortality for individuals in the top quartile were 2.50 (95% CI 1.87, 3.36, P < 0.001) and 3.92 (95%CI 2.55, 6.01, P < 0.001), respectively. In a multivariate Cox regression analysis including traditional risk factors, log (eGFR), baseline albuminuria, and cardiovascular disease status, the HR per standard deviation change in galectin-3 was 1.13 (95% CI 1.02, 1.26, P = 0.02) for cardiovascular events and 1.17 (95% CI 1.01, 1.35, P = 0.04) for all-cause mortality. CONCLUSIONS: Serum galectin-3 is associated with adverse cardiovascular outcomes in persons with type 2 diabetes independent of traditional risk factors.

Telehealth Physical Therapy in Musculoskeletal Practice.

Telehealth physical therapy has the potential to transform many critical areas of care in musculoskeletal practice. However, the amount of hype around telehealth needs to be carefully examined, because widespread implementation has been stalled by payment and regulatory barriers in physical therapy. The purposes of this Viewpoint are to highlight (1) the current level of implementation, (2) telehealth musculoskeletal evidence, and (3) future opportunities in the digital age. J Orthop Sports Phys Ther 2018;48(10):736-739. doi:10.2519/jospt.2018.0613.

Physical Impairments Associated With Post-Intensive Care Syndrome: Systematic Review Based on the World Health Organization's International Classification of Functioning, Disability and Health Framework.

Background: Post-intensive care syndrome (PICS) is a constellation of new or worsening impairments in physical, mental, or cognitive abilities or a combination of these in individuals who have survived critical illness requiring intensive care. Purpose: The 2 purposes of this systematic review were to identify the scope and magnitude of physical problems associated with PICS during the first year after critical illness and to use the World Health Organization's International Classification of Functioning, Disability and Health (ICF) framework to elucidate impairments of body functions and structures, activity limitations, and participation restrictions associated with PICS. Data Sources: Ovid MEDLINE, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, CINAHL Plus with Full Text (EBSCO), Web of Science, and Embase were searched from inception until March 7, 2017. Study Selection: Two reviewers screened titles, abstracts, and full text to independently determine study eligibility based on inclusion and exclusion criteria. Data Extraction: Study methodological quality was assessed using the Newcastle-Ottawa Scale. Data describing study methods, design, and participant outcomes were extracted. Data Synthesis: Fifteen studies were eligible for review. Within the first year following critical illness, people who had received intensive care experienced impairments in all 3 domains of the ICF (body functions and structures, activity limitations, and participation restrictions). These impairments included decreased pulmonary function, reduced strength of respiratory and limb muscles, reduced 6-minute walk test distance, reduced ability to perform activities of daily living and instrumental activities of daily living, and reduced ability to return to driving and paid employment. Limitations: The inclusion of only 15 observational studies in this review may limit the generalizability of the findings. Conclusions: During the first year following critical illness, individuals with PICS experienced physical impairments in all 3 domains of the ICF.

Galectin-3 is independently associated with progression of nephropathy in type 2 diabetes mellitus.

AIMS/HYPOTHESIS: Galectin-3 has been implicated in cardiac and renal fibrosis and serves as a prognostic clinical indicator in heart failure. The aim of the present study was to evaluate whether serum galectin-3 level is associated with progressive kidney disease in type 2 diabetes. METHODS: Galectin-3 was measured in baseline samples by ELISA in 1320 participants with type 2 diabetes with eGFR ≥30 ml min-1 1.73 m-2. The primary outcome was defined as doubling of serum creatinine and/or initiation of renal replacement therapy during follow-up. The secondary outcome was progression to macroalbuminuria in individuals with normo- or microalbuminuria at baseline. RESULTS: Serum galectin-3 levels were significantly increased in a random subgroup of 270 type 2 diabetic individuals with eGFR >60 ml min-1 1.73 m-2 compared with an age- and sex-matched non-diabetic control group (7.58 ± 2.29 ng/ml vs 6.10 ± 1.91 ng/ml, respectively, p < 0.01). In the whole diabetic cohort, after a mean follow-up of 9 years, galectin-3 was independently associated with doubling of serum creatinine (HR 1.19; 95% CI 1.14, 1.24, p < 0.001) and incident macroalbuminuria (HR 1.20; 95% CI 1.12, 1.30, p < 0.001), even after adjusting for traditional risk factors, baseline eGFR and albuminuria status. Individuals with galectin-3 levels in the highest quartile had a fourfold risk of renal function loss and threefold risk of incident macroalbuminuria. CONCLUSIONS/INTERPRETATION: Serum galectin-3 was independently associated with progressive renal disease in type 2 diabetes. Further mechanistic studies are warranted to determine whether galectin-3 is simply a disease biomarker or is also a mediator of the development and progression of diabetic nephropathy.

Exercise Perception and Behaviors in Individuals Living with Primary Immunodeficiency Disease.

BACKGROUND: Routine exercise has been established as an effective way to improve overall health. The value of exercise has been established in many diseases, however, there are no studies investigating the impact of exercise for individuals with primary immunodeficiency disease (PID). The purpose of this study was to investigate exercise perceptions and behaviors in individuals diagnosed with PID. METHODS: An online survey was distributed over a four-week period. RESULTS: Of the 264 responses collected, most were females, 45-54 years old. Respondents reported a measurable loss of function impairing their daily activities due to loss of mobility/physical activity (41.32%), or loss of lung/pulmonary function (40.08%,). They felt exercise decreased stress level and improved their mental well-being (46.25%). Some indicated they participate in exercise (33.20%), while 36.84% had not participated in exercise for at least 1 year. Exercise was limited primarily due to fatigue (86.97%). CONCLUSION: Exercise is important for those with chronic medical conditions. Most individuals living with PID can participate in low/moderate physical activity, but struggle with vigorous physical activity, since fatigue is the greatest barrier. Respondents view exercise as beneficial, and would like to increase participation in an exercise program.

Validity of major osteoporotic fracture diagnosis codes in the Clinical Data Analysis and Reporting System in Hong Kong.

PURPOSE: Large medical record databases facilitate epidemiology research in fracture. However, the validity of fracture in the databases is needed to ensure the reliability of data. We aimed to assess the validity of International Classification of Diseases, 9th Revision (ICD-9) code algorithms for identifying major osteoporotic fracture in the Clinical Data Analysis and Reporting System (CDARS) in Hong Kong. METHODS: The CDARS is a database developed by the Hong Kong Hospital Authority for research purpose. We used ICD-9 code algorithm for identifying major osteoporotic fracture, including vertebral fracture, humerus fracture, forearm/wrist fracture, and hip fracture, in CDARS in 2005-2016. As high positive predictive value (PPV) is critically important in epidemiology research, we sought to determine the PPV of fracture diagnostic code in terms of ICD-9 relative to the radiography imaging and clinical notes. A total of 380 major osteoporotic fracture cases (vertebral fracture: 101 cases; humerus fracture: 81 cases; forearm/wrist fracture: 94 cases; and hip fracture: 104 cases) were randomly selected and validated. RESULTS: In 380 fracture cases, the overall PPV was 96.8%. In subgroup analysis, PPV of 100% was observed for hip, humerus, and forearm/wrist fractures, whereas PPV of 86% was observed for vertebral fracture. CONCLUSIONS: The use of ICD-9 code algorithm to identify major osteoporotic fracture in CDARS is a valid tool with a very high PPV. However, cautious interpretation is required when the study focuses on incident vertebral fracture. Copyright © 2017 John Wiley & Sons, Ltd.

Association Between Dabigatran vs Warfarin and Risk of Osteoporotic Fractures Among Patients With Nonvalvular Atrial Fibrillation.

Importance: The risk of osteoporotic fracture with dabigatran use in patients with nonvalvular atrial fibrillation (NVAF) is unknown. Objective: To investigate the risk of osteoporotic fracture with dabigatran vs warfarin in patients with NVAF. Design, Setting, and Participants: Retrospective cohort study using a population-wide database managed by the Hong Kong Hospital Authority. Patients newly diagnosed with NVAF from 2010 through 2014 and prescribed dabigatran or warfarin were matched by propensity score at a 1:2 ratio with follow-up until July 31, 2016. Exposures: Dabigatran or warfarin use during the study period. Main Outcomes and Measures: Risk of osteoporotic hip fracture and vertebral fracture was compared between dabigatran and warfarin users using Poisson regression. The corresponding incidence rate ratio (IRR) and absolute risk difference (ARD) with 95% CIs were calculated. Results: Among 51 496 patients newly diagnosed with NVAF, 8152 new users of dabigatran (n = 3268) and warfarin (n = 4884) were matched by propensity score (50% women; mean [SD] age, 74 [11] years). Osteoporotic fracture developed in 104 (1.3%) patients during follow-up (32 dabigatran users [1.0%]; 72 warfarin users [1.5%]). Results of Poisson regression analysis showed that dabigatran use was associated with a significantly lower risk of osteoporotic fracture compared with warfarin (0.7 vs 1.1 per 100 person-years; ARD per 100 person-years, -0.68 [95% CI, -0.38 to -0.86]; IRR, 0.38 [95% CI, 0.22 to 0.66]). The association with lower risk was statistically significant in patients with a history of falls, fractures, or both (dabigatran vs warfarin, 1.6 vs 3.6 per 100 person-years; ARD per 100 person-years, -3.15 [95% CI, -2.40 to -3.45]; IRR, 0.12 [95% CI, 0.04 to 0.33]), but not in those without a history (0.6 vs 0.7 per 100 person-years; ARD per 100 person-years, -0.04 [95% CI, 0.67 to -0.39]; IRR, 0.95 [95% CI, 0.45 to 1.96]) (P value for interaction, <.001). Conclusions and Relevance: Among adults with NVAF receiving anticoagulation, the use of dabigatran compared with warfarin was associated with a lower risk of osteoporotic fracture. Additional study, perhaps including randomized clinical trials, may be warranted to further understand the relationship between use of dabigatran vs warfarin and risk of fracture.

Serum Level of Soluble Receptor for Advanced Glycation End Products Is Associated with A Disintegrin And Metalloproteinase 10 in Type 1 Diabetes.

BACKGROUND: The receptor for advanced glycation end products (RAGE) is involved in the pathogenesis of diabetic complications, and soluble forms of the receptor (sRAGE) can counteract the detrimental action of the full-length receptor by acting as decoy. Soluble RAGE is produced by alternative splicing [endogenous secretory RAGE (esRAGE)] and/or by proteolytic cleavage of the membrane-bound receptor. We have investigated the role of A Disintegrin And Metalloproteinase 10 (ADAM10) in the ectodomain shedding of RAGE. METHODS: Constitutive and insulin-induced shedding of RAGE in THP-1 macrophages by ADAM10 was evaluated using an ADAM10-specific metalloproteinase inhibitor. Serum ADAM10 level was measured in type 1 diabetes and control subjects, and the association with serum soluble RAGE was determined. Serum total sRAGE and esRAGE were assayed by ELISA and the difference between total sRAGE and esRAGE gave an estimated measure of soluble RAGE formed by cleavage (cRAGE). RESULTS: RAGE shedding (constitutive and insulin-induced) was significantly reduced after inhibition of ADAM10 in macrophages, and insulin stimulated ADAM10 expression and activity. Diabetic subjects have higher serum total sRAGE and esRAGE (p<0.01) than controls, and serum ADAM10 was also increased (p<0.01). Serum ADAM10 correlated with serum cRAGE in type 1 diabetes (r = 0.40, p<0.01) and in controls (r = 0.31. p<0.01) but no correlations were seen with esRAGE. The association remained significant after adjusting for age, gender, BMI, smoking status and HbA1c. CONCLUSION: Our data suggested that ADAM10 contributed to the shedding of RAGE. Serum ADAM10 level was increased in type 1 diabetes and was a significant determinant of circulating cRAGE.