Boston Medical Center

BACKGROUND: Thyroid nodules are a common clinical problem, and differentiated thyroid cancer is becoming increasingly prevalent. Since the American Thyroid Association's (ATA's) guidelines for the management of these disorders were revised in 2009, significant scientific advances have occurred in the field. The aim of these guidelines is to inform clinicians, patients, researchers, and health policy makers on published evidence relating to the diagnosis and management of thyroid nodules and differentiated thyroid cancer. METHODS: The specific clinical questions addressed in these guidelines were based on prior versions of the guidelines, stakeholder input, and input of task force members. Task force panel members were educated on knowledge synthesis methods, including electronic database searching, review and selection of relevant citations, and critical appraisal of selected studies. Published English language articles on adults were eligible for inclusion. The American College of Physicians Guideline Grading System was used for critical appraisal of evidence and grading strength of recommendations for therapeutic interventions. We developed a similarly formatted system to appraise the quality of such studies and resultant recommendations. The guideline panel had complete editorial independence from the ATA. Competing interests of guideline task force members were regularly updated, managed, and communicated to the ATA and task force members. RESULTS: The revised guidelines for the management of thyroid nodules include recommendations regarding initial evaluation, clinical and ultrasound criteria for fine-needle aspiration biopsy, interpretation of fine-needle aspiration biopsy results, use of molecular markers, and management of benign thyroid nodules. Recommendations regarding the initial management of thyroid cancer include those relating to screening for thyroid cancer, staging and risk assessment, surgical management, radioiodine remnant ablation and therapy, and thyrotropin suppression therapy using levothyroxine. Recommendations related to long-term management of differentiated thyroid cancer include those related to surveillance for recurrent disease using imaging and serum thyroglobulin, thyroid hormone therapy, management of recurrent and metastatic disease, consideration for clinical trials and targeted therapy, as well as directions for future research. CONCLUSIONS: We have developed evidence-based recommendations to inform clinical decision-making in the management of thyroid nodules and differentiated thyroid cancer. They represent, in our opinion, contemporary optimal care for patients with these disorders.

BACKGROUND: Serum creatinine concentration is widely used as an index of renal function, but this concentration is affected by factors other than glomerular filtration rate (GFR). OBJECTIVE: To develop an equation to predict GFR from serum creatinine concentration and other factors. DESIGN: Cross-sectional study of GFR, creatinine clearance, serum creatinine concentration, and demographic and clinical characteristics in patients with chronic renal disease. PATIENTS: 1628 patients enrolled in the baseline period of the Modification of Diet in Renal Disease (MDRD) Study, of whom 1070 were randomly selected as the training sample; the remaining 558 patients constituted the validation sample. METHODS: The prediction equation was developed by stepwise regression applied to the training sample. The equation was then tested and compared with other prediction equations in the validation sample. RESULTS: To simplify prediction of GFR, the equation included only demographic and serum variables. Independent factors associated with a lower GFR included a higher serum creatinine concentration, older age, female sex, nonblack ethnicity, higher serum urea nitrogen levels, and lower serum albumin levels (P < 0.001 for all factors). The multiple regression model explained 90.3% of the variance in the logarithm of GFR in the validation sample. Measured creatinine clearance overestimated GFR by 19%, and creatinine clearance predicted by the Cockcroft-Gault formula overestimated GFR by 16%. After adjustment for this overestimation, the percentage of variance of the logarithm of GFR predicted by measured creatinine clearance or the Cockcroft-Gault formula was 86.6% and 84.2%, respectively. CONCLUSION: The equation developed from the MDRD Study provided a more accurate estimate of GFR in our study group than measured creatinine clearance or other commonly used equations.

Once foods in the United States were fortified with vitamin D, rickets appeared to have been conquered, and many considered major health problems from vitamin D deficiency resolved. But vitamin D deficiency is common. This review considers the role of vitamin D in skeletal and nonskeletal health and suggests strategies for the prevention and treatment of vitamin D deficiency.

The impact of nonrheumatic atrial fibrillation, hypertension, coronary heart disease, and cardiac failure on stroke incidence was examined in 5,070 participants in the Framingham Study after 34 years of follow-up. Compared with subjects free of these conditions, the age-adjusted incidence of stroke was more than doubled in the presence of coronary heart disease (p less than 0.001) and more than trebled in the presence of hypertension (p less than 0.001). There was a more than fourfold excess of stroke in subjects with cardiac failure (p less than 0.001) and a near fivefold excess when atrial fibrillation was present (p less than 0.001). In persons with coronary heart disease or cardiac failure, atrial fibrillation doubled the stroke risk in men and trebled the risk in women. With increasing age the effects of hypertension, coronary heart disease, and cardiac failure on the risk of stroke became progressively weaker (p less than 0.05). Advancing age, however, did not reduce the significant impact of atrial fibrillation. For persons aged 80-89 years, atrial fibrillation was the sole cardiovascular condition to exert an independent effect on stroke incidence (p less than 0.001). The attributable risk of stroke for all cardiovascular contributors decreased with age except for atrial fibrillation, for which the attributable risk increased significantly (p less than 0.01), rising from 1.5% for those aged 50-59 years to 23.5% for those aged 80-89 years. While these findings highlight the impact of each cardiovascular condition on the risk of stroke, the data suggest that the elderly are particularly vulnerable to stroke when atrial fibrillation is present.(ABSTRACT TRUNCATED AT 250 WORDS)

BACKGROUND: Thyroid nodules are a common clinical problem, and differentiated thyroid cancer is becoming increasingly prevalent. Since the publication of the American Thyroid Association's guidelines for the management of these disorders was published in 2006, a large amount of new information has become available, prompting a revision of the guidelines. METHODS: Relevant articles through December 2008 were reviewed by the task force and categorized by topic and level of evidence according to a modified schema used by the United States Preventative Services Task Force. RESULTS: The revised guidelines for the management of thyroid nodules include recommendations regarding initial evaluation, clinical and ultrasound criteria for fine-needle aspiration biopsy, interpretation of fine-needle aspiration biopsy results, and management of benign thyroid nodules. Recommendations regarding the initial management of thyroid cancer include those relating to optimal surgical management, radioiodine remnant ablation, and suppression therapy using levothyroxine. Recommendations related to long-term management of differentiated thyroid cancer include those related to surveillance for recurrent disease using ultrasound and serum thyroglobulin as well as those related to management of recurrent and metastatic disease. CONCLUSIONS: We created evidence-based recommendations in response to our appointment as an independent task force by the American Thyroid Association to assist in the clinical management of patients with thyroid nodules and differentiated thyroid cancer. They represent, in our opinion, contemporary optimal care for patients with these disorders.

NHANES III measured serum TSH, total serum T(4), antithyroperoxidase (TPOAb), and antithyroglobulin (TgAb) antibodies from a sample of 17,353 people aged > or =12 yr representing the geographic and ethnic distribution of the U.S. population. These data provide a reference for other studies of these analytes in the U.S. For the 16,533 people who did not report thyroid disease, goiter, or taking thyroid medications (disease-free population), we determined mean concentrations of TSH, T(4), TgAb, and TPOAb. A reference population of 13,344 people was selected from the disease-free population by excluding, in addition, those who were pregnant, taking androgens or estrogens, who had thyroid antibodies, or biochemical hypothyroidism or hyperthyroidism. The influence of demographics on TSH, T(4), and antibodies was examined. Hypothyroidism was found in 4.6% of the U.S. population (0.3% clinical and 4.3% subclinical) and hyperthyroidism in 1.3% (0.5% clinical and 0.7% subclinical). (Subclinical hypothyroidism is used in this paper to mean mild hypothyroidism, the term now preferred by the American Thyroid Association for the laboratory findings described.) For the disease-free population, mean serum TSH was 1.50 (95% confidence interval, 1.46-1.54) mIU/liter, was higher in females than males, and higher in white non-Hispanics (whites) [1.57 (1.52-1.62) mIU/liter] than black non-Hispanics (blacks) [1.18 (1.14-1.21) mIU/liter] (P < 0.001) or Mexican Americans [1.43 (1.40-1.46) mIU/liter] (P < 0.001). TgAb were positive in 10.4 +/- 0.5% and TPOAb, in 11.3 +/- 0.4%; positive antibodies were more prevalent in women than men, increased with age, and TPOAb were less prevalent in blacks (4.5 +/- 0.3%) than in whites (12.3 +/- 0.5%) (P < 0.001). TPOAb were significantly associated with hypo or hyperthyroidism, but TgAb were not. Using the reference population, geometric mean TSH was 1.40 +/- 0.02 mIU/liter and increased with age, and was significantly lower in blacks (1.18 +/- 0.02 mIU/liter) than whites (1.45 +/- 0.02 mIU/liter) (P < 0.001) and Mexican Americans (1.37 +/- 0.02 mIU/liter) (P < 0.001). Arithmetic mean total T(4) was 112.3 +/- 0.7 nmol/liter in the disease-free population and was consistently higher among Mexican Americans in all populations. In the reference population, mean total T(4) in Mexican Americans was (116.3 +/- 0.7 nmol/liter), significantly higher than whites (110.0 +/- 0.8 nmol/liter) or blacks (109.4 +/- 0.8 nmol/liter) (P < 0.0001). The difference persisted in all age groups. In summary, TSH and the prevalence of antithyroid antibodies are greater in females, increase with age, and are greater in whites and Mexican Americans than in blacks. TgAb alone in the absence of TPOAb is not significantly associated with thyroid disease. The lower prevalence of thyroid antibodies and lower TSH concentrations in blacks need more research to relate these findings to clinical status. A large proportion of the U.S. population unknowingly have laboratory evidence of thyroid disease, which supports the usefulness of screening for early detection.

In some patients who are hospitalized for acute illness, we have noted a reversible syndrome of headache, altered mental functioning, seizures, and loss of vision associated with findings indicating predominantly posterior leukoencephalopathy on imaging studies. To elucidate this syndrome, we searched the log books listing computed tomographic (CT) and magnetic resonance imaging (MRI) studies performed at the New England Medical Center in Boston and Hôpital Sainte Anne in Paris; we found 15 such patients who were evaluated from 1988 through 1994.

BACKGROUND: The leading cause of death in patients hospitalized for acute myocardial infarction is cardiogenic shock. We conducted a randomized trial to evaluate early revascularization in patients with cardiogenic shock. METHODS: Patients with shock due to left ventricular failure complicating myocardial infarction were randomly assigned to emergency revascularization (152 patients) or initial medical stabilization (150 patients). Revascularization was accomplished by either coronary-artery bypass grafting or angioplasty. Intraaortic balloon counterpulsation was performed in 86 percent of the patients in both groups. The primary end point was mortality from all causes at 30 days. Six-month survival was a secondary end point. RESULTS: The mean age of the patients was 66+/-10 years, 32 percent were women and 55 percent were transferred from other hospitals. The median time to the onset of shock was 5.6 hours after infarction, and most infarcts were anterior in location. Ninety-seven percent of the patients assigned to revascularization underwent early coronary angiography, and 87 percent underwent revascularization; only 2.7 percent of the patients assigned to medical therapy crossed over to early revascularization without clinical indication. Overall mortality at 30 days did not differ significantly between the revascularization and medical-therapy groups (46.7 percent and 56.0 percent, respectively; difference, -9.3 percent; 95 percent confidence interval for the difference, -20.5 to 1.9 percent; P=0.11). Six-month mortality was lower in the revascularization group than in the medical-therapy group (50.3 percent vs. 63.1 percent, P=0.027). CONCLUSIONS: In patients with cardiogenic shock, emergency revascularization did not significantly reduce overall mortality at 30 days. However, after six months there was a significant survival benefit. Early revascularization should be strongly considered for patients with acute myocardial infarction complicated by cardiogenic shock.

BACKGROUND: Patisiran, an investigational RNA interference therapeutic agent, specifically inhibits hepatic synthesis of transthyretin. METHODS: In this phase 3 trial, we randomly assigned patients with hereditary transthyretin amyloidosis with polyneuropathy, in a 2:1 ratio, to receive intravenous patisiran (0.3 mg per kilogram of body weight) or placebo once every 3 weeks. The primary end point was the change from baseline in the modified Neuropathy Impairment Score+7 (mNIS+7; range, 0 to 304, with higher scores indicating more impairment) at 18 months. Other assessments included the Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) questionnaire (range, -4 to 136, with higher scores indicating worse quality of life), 10-m walk test (with gait speed measured in meters per second), and modified body-mass index (modified BMI, defined as [weight in kilograms divided by square of height in meters]×albumin level in grams per liter; lower values indicated worse nutritional status). RESULTS: A total of 225 patients underwent randomization (148 to the patisiran group and 77 to the placebo group). The mean (±SD) mNIS+7 at baseline was 80.9±41.5 in the patisiran group and 74.6±37.0 in the placebo group; the least-squares mean (±SE) change from baseline was -6.0±1.7 versus 28.0±2.6 (difference, -34.0 points; P<0.001) at 18 months. The mean (±SD) baseline Norfolk QOL-DN score was 59.6±28.2 in the patisiran group and 55.5±24.3 in the placebo group; the least-squares mean (±SE) change from baseline was -6.7±1.8 versus 14.4±2.7 (difference, -21.1 points; P<0.001) at 18 months. Patisiran also showed an effect on gait speed and modified BMI. At 18 months, the least-squares mean change from baseline in gait speed was 0.08±0.02 m per second with patisiran versus -0.24±0.04 m per second with placebo (difference, 0.31 m per second; P<0.001), and the least-squares mean change from baseline in the modified BMI was -3.7±9.6 versus -119.4±14.5 (difference, 115.7; P<0.001). Approximately 20% of the patients who received patisiran and 10% of those who received placebo had mild or moderate infusion-related reactions; the overall incidence and types of adverse events were similar in the two groups. CONCLUSIONS: In this trial, patisiran improved multiple clinical manifestations of hereditary transthyretin amyloidosis. (Funded by Alnylam Pharmaceuticals; APOLLO ClinicalTrials.gov number, NCT01960348 .).

BACKGROUND: Although disuse of skeletal muscle and undernutrition are often cited as potentially reversible causes of frailty in elderly people, the efficacy of interventions targeted specifically at these deficits has not been carefully studied. METHODS: We conducted a randomized, placebo-controlled trial comparing progressive resistance exercise training, multinutrient supplementation, both interventions, and neither in 100 frail nursing home residents over a 10-week period. RESULTS: The mean (+/- SE) age of the 63 women and 37 men enrolled in the study was 87.1 +/- 0.6 years (range, 72 to 98); 94 percent of the subjects completed the study. Muscle strength increased by 113 +/- 8 percent in the subjects who underwent exercise training, as compared with 3 +/- 9 percent in the nonexercising subjects (P < 0.001). Gait velocity increased by 11.8 +/- 3.8 percent in the exercisers but declined by 1.0 +/- 3.8 percent in the nonexercisers (P = 0.02). Stair-climbing power also improved in the exercisers as compared with the nonexercisers (by 28.4 +/- 6.6 percent vs. 3.6 +/- 6.7 percent, P = 0.01), as did the level of spontaneous physical activity. Cross-sectional thigh-muscle area increased by 2.7 +/- 1.8 percent in the exercisers but declined by 1.8 +/- 2.0 percent in the nonexercisers (P = 0.11). The nutritional supplement had no effect on any primary outcome measure. Total energy intake was significantly increased only in the exercising subjects who also received nutritional supplementation. CONCLUSIONS: High-intensity resistance exercise training is a feasible and effective means of counteracting muscle weakness and physical frailty in very elderly people. In contrast, multi-nutrient supplementation without concomitant exercise does not reduce muscle weakness or physical frailty.

BACKGROUND: Cyclophosphamide and glucocorticoids have been the cornerstone of remission-induction therapy for severe antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis for 40 years. Uncontrolled studies suggest that rituximab is effective and may be safer than a cyclophosphamide-based regimen. METHODS: We conducted a multicenter, randomized, double-blind, double-dummy, noninferiority trial of rituximab (375 mg per square meter of body-surface area per week for 4 weeks) as compared with cyclophosphamide (2 mg per kilogram of body weight per day) for remission induction. Glucocorticoids were tapered off; the primary end point was remission of disease without the use of prednisone at 6 months. RESULTS: Nine centers enrolled 197 ANCA-positive patients with either Wegener's granulomatosis or microscopic polyangiitis. Baseline disease activity, organ involvement, and the proportion of patients with relapsing disease were similar in the two treatment groups. Sixty-three patients in the rituximab group (64%) reached the primary end point, as compared with 52 patients in the control group (53%), a result that met the criterion for noninferiority (P<0.001). The rituximab-based regimen was more efficacious than the cyclophosphamide-based regimen for inducing remission of relapsing disease; 34 of 51 patients in the rituximab group (67%) as compared with 21 of 50 patients in the control group (42%) reached the primary end point (P=0.01). Rituximab was also as effective as cyclophosphamide in the treatment of patients with major renal disease or alveolar hemorrhage. There were no significant differences between the treatment groups with respect to rates of adverse events. CONCLUSIONS: Rituximab therapy was not inferior to daily cyclophosphamide treatment for induction of remission in severe ANCA-associated vasculitis and may be superior in relapsing disease. (Funded by the National Institutes of Allergy and Infectious Diseases, Genentech, and Biogen; ClinicalTrials.gov number, NCT00104299.)

This paper is a revision and update of the recommendations developed following the 1st (Vienna 2001), 2nd (Prague 2004) and 3rd (Zurich 2008) International Consensus Conferences on Concussion in Sport and is based on the deliberations at the 4th International Conference on Concussion in Sport held in Zurich, November 2012.1–3&#13;\n&#13;\nThe new 2012 Zurich Consensus statement is designed to build on the principles outlined in the previous documents and to develop further conceptual understanding of this problem using a formal consensus-based approach. A detailed description of the consensus process is outlined at the end of this document under the Background section. This document is developed primarily for use by physicians and healthcare professionals who are involved in the care of injured athletes, whether at the recreational, elite or professional level.

Spatial positions of cells in tissues strongly influence function, yet a high-throughput, genome-wide readout of gene expression with cellular resolution is lacking. We developed Slide-seq, a method for transferring RNA from tissue sections onto a surface covered in DNA-barcoded beads with known positions, allowing the locations of the RNA to be inferred by sequencing. Using Slide-seq, we localized cell types identified by single-cell RNA sequencing datasets within the cerebellum and hippocampus, characterized spatial gene expression patterns in the Purkinje layer of mouse cerebellum, and defined the temporal evolution of cell type-specific responses in a mouse model of traumatic brain injury. These studies highlight how Slide-seq provides a scalable method for obtaining spatially resolved gene expression data at resolutions comparable to the sizes of individual cells.

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.

The study of T regulatory cells (T reg cells) has been limited by the lack of specific surface markers and an inability to define mechanisms of suppression. We show that the expression of CD39/ENTPD1 in concert with CD73/ecto-5'-nucleotidase distinguishes CD4(+)/CD25(+)/Foxp3(+) T reg cells from other T cells. These ectoenzymes generate pericellular adenosine from extracellular nucleotides. The coordinated expression of CD39/CD73 on T reg cells and the adenosine A2A receptor on activated T effector cells generates immunosuppressive loops, indicating roles in the inhibitory function of T reg cells. Consequently, T reg cells from Cd39-null mice show impaired suppressive properties in vitro and fail to block allograft rejection in vivo. We conclude that CD39 and CD73 are surface markers of T reg cells that impart a specific biochemical signature characterized by adenosine generation that has functional relevance for cellular immunoregulation.

The purpose of this new classification compendium is to republish the Orthopaedic Trauma Association's (OTA) classification. The OTA classification was originally published in a compendium of the Journal of Orthopaedic Trauma in 1996. It adopted The Comprehensive Classification of the Long Bones developed by Müller and colleagues and classified the remaining bones. In this compendium, the introductory chapter reviews new scientific information about classifying fractures that has been published in the last 11 years. The classification is presented in a revised format that is easier to follow. The OTA and AO classification will now have a unified alpha-numeric code eliminating the differences that have existed between the 2 codes. The code was significantly revised for the clavicle and scapula, foot and hand, and patella. Dislocations have been expanded on an anatomic basis and for most joints will be coded separately. This publication should stimulate new developments and interest in a unified language to code and classify fractures. Further improvements in classification will result in better patient care and clinical research.

BACKGROUND: Sildenafil is a potent inhibitor of cyclic guanosine monophosphate hydrolysis [corrected] in the corpus cavernosum and therefore increases the penile response to sexual stimulation. We evaluated the efficacy and safety of sildenafil, administered as needed in two sequential double-blind studies of men with erectile dysfunction of organic, psychogenic, and mixed causes. METHODS: In a 24-week dose-response study, 532 men were treated with oral sildenafil (25, 50, or 100 mg) or placebo. In a 12-week, flexible dose-escalation study, 329 different men were treated with sildenafil or placebo, with dose escalation to 100 mg based on efficacy and tolerance. After this dose-escalation study, 225 of the 329 men entered a 32-week, open-label extension study. We assessed efficacy according to the International Index of Erectile Function, a patient log, and a global-efficacy question. RESULTS: In the dose-response study, increasing doses of sildenafil were associated with improved erectile function (P values for increases in scores for questions about achieving and maintaining erections were <0.001). For the men receiving 100 mg of sildenafil, the mean score for the question about achieving erections was 100 percent higher after treatment than at base line (4.0 vs. 2.0 of a possible score of 5). In the last four weeks of treatment in the dose-escalation study, 69 percent of all attempts at sexual intercourse were successful for the men receiving sildenafil, as compared with 22 percent for those receiving placebo (P<0.001). The mean numbers of successful attempts per month were 5.9 for the men receiving sildenafil and 1.5 for those receiving placebo (P<0.001). Headache, flushing, and dyspepsia were the most common adverse effects in the dose-escalation study, occurring in 6 percent to 18 percent of the men. Ninety-two percent of the men completed the 32-week extension study. CONCLUSIONS: Oral sildenafil is an effective, well-tolerated treatment for men with erectile dysfunction.

Evidence-based guidelines for the management of patients with Lyme disease, human granulocytic anaplasmosis (formerly known as human granulocytic ehrlichiosis), and babesiosis were prepared by an expert panel of the Infectious Diseases Society of America. These updated guidelines replace the previous treatment guidelines published in 2000 (Clin Infect Dis 2000; 31[Suppl 1]:1-14). The guidelines are intended for use by health care providers who care for patients who either have these infections or may be at risk for them. For each of these Ixodes tickborne infections, information is provided about prevention, epidemiology, clinical manifestations, diagnosis, and treatment. Tables list the doses and durations of antimicrobial therapy recommended for treatment and prevention of Lyme disease and provide a partial list of therapies to be avoided. A definition of post-Lyme disease syndrome is proposed.

Peer Reviewed

BACKGROUND: Cardiac transthyretin (ATTR) amyloidosis is a progressive and fatal cardiomyopathy for which several promising therapies are in development. The diagnosis is frequently delayed or missed because of the limited specificity of echocardiography and the traditional requirement for histological confirmation. It has long been recognized that technetium-labeled bone scintigraphy tracers can localize to myocardial amyloid deposits, and use of this imaging modality for the diagnosis of cardiac ATTR amyloidosis has lately been revisited. We conducted a multicenter study to ascertain the diagnostic value of bone scintigraphy in this disease. METHODS AND RESULTS: Results of bone scintigraphy and biochemical investigations were analyzed from 1217 patients with suspected cardiac amyloidosis referred for evaluation in specialist centers. Of 857 patients with histologically proven amyloid (374 with endomyocardial biopsies) and 360 patients subsequently confirmed to have nonamyloid cardiomyopathies, myocardial radiotracer uptake on bone scintigraphy was >99% sensitive and 86% specific for cardiac ATTR amyloid, with false positives almost exclusively from uptake in patients with cardiac AL amyloidosis. Importantly, the combined findings of grade 2 or 3 myocardial radiotracer uptake on bone scintigraphy and the absence of a monoclonal protein in serum or urine had a specificity and positive predictive value for cardiac ATTR amyloidosis of 100% (positive predictive value confidence interval, 98.0-100). CONCLUSIONS: Bone scintigraphy enables the diagnosis of cardiac ATTR amyloidosis to be made reliably without the need for histology in patients who do not have a monoclonal gammopathy. We propose noninvasive diagnostic criteria for cardiac ATTR amyloidosis that are applicable to the majority of patients with this disease.