Time to Publication and Time-Lag Publication Bias for Randomized Trials on Connective Tissue Diseases.

OBJECTIVE: To assess the time from completion to publication of randomized controlled trials (RCTs) on connective tissue diseases (CTDs), investigate the factors associated with, and explore the influence of significance of study results on time to publication (time-lag publication bias). METHODS: We included interventional, phase 2/3, 3, or 4 RCTs on CTDs registered in Clinicaltrials.gov from 2000 to 2016, whose results had been published in a peer-review journal less than 5 years after their completion. Main trial features, including the significance of primary outcome results, were collected. Time to publication was the time from study completion to the earliest publication date. Multivariable linear regression was used to identify factors associated with time to publication. RESULTS: We included 62 studies, mostly phase 3 (61%) trials on pharmacologic treatments (94%); we recruited patients with systemic lupus (55%) or systemic sclerosis (23%) and planned to enroll a median of 131 (IQR [interquartile range]: 61-288) patients. Twenty-two (35%) reported at least a statistically significant primary outcome. Median time to publication was 28 months (IQR: 17-36). In a multivariable analysis, time to publication progressively improved over time (faster publication in recent years, with the average time to publication decreasing by 1.3 [95% CI: 0.3-2.3] months per year) and was not influenced by the significance of primary outcome results, funder, impact factor of the journal, number of recruiting countries, and comparator. CONCLUSION: A high proportion of CTDs-RCTs is published beyond 2 years from completion. We did not find evidence of time-lag publication bias, and time to publication improved over time.

Inflammation modulates intercellular adhesion and mechanotransduction in human epidermis via ROCK2.

Aberrant mechanotransduction and compromised epithelial barrier function are associated with numerous human pathologies including inflammatory skin disorders. However, the cytoskeletal mechanisms regulating inflammatory responses in the epidermis are not well understood. Here we addressed this question by inducing a psoriatic phenotype in human keratinocytes and reconstructed human epidermis using a cytokine stimulation model. We show that the inflammation upregulates the Rho-myosin II pathway and destabilizes adherens junctions (AJs) promoting YAP nuclear entry. The integrity of cell-cell adhesion but not the myosin II contractility per se is the determinative factor for the YAP regulation in epidermal keratinocytes. The inflammation-induced disruption of AJs, increased paracellular permeability, and YAP nuclear translocation are regulated by ROCK2, independently from myosin II activation. Using a specific inhibitor KD025, we show that ROCK2 executes its effects via cytoskeletal and transcription-dependent mechanisms to shape the inflammatory response in the epidermis.

Extent of and Reasons for Discontinuation and Nonpublication of Interventional Trials on Connective Tissue Diseases: An Observational Study.

OBJECTIVE: To assess the proportion, the reasons, and the factors associated with the discontinuation or nonpublication of randomized controlled trials (RCTs) on connective tissue diseases (CTDs). METHODS: We searched all interventional RCTs on CTDs registered in ClinicalTrials.gov since 2000. Two reviewers selected studies according to prespecified eligibility criteria. Completion status, publication status, and reported reasons for discontinuation or nonpublication were retrieved on ClinicalTrials.gov, through literature search, and by contacting investigators. Multivariable logistic regression was used to identify factors associated with study noncompletion and nonpublication. RESULTS: We included 175 studies, mostly phase III, placebo-controlled trials on pharmacologic treatments recruiting patients with systemic lupus erythematosus (51%), systemic sclerosis (20%), Sjögren's syndrome (12%), or other CTDs. Fifty-eight (33%) had been discontinued, mainly for insufficient patient accrual, with no differences in discontinuation rates across the CTDs (P > 0.5). Forty-six (35%) of 130 studies having included at least 1 patient were unpublished, and 86 (65%) were published in a peer-reviewed journal after a median of 24 months (interquartile range 15-41) from completion, with a significantly higher publication rate in completed versus discontinued studies (81% versus 22%; P < 0.001). We were able to obtain reasons for nonpublication in one-third of cases. Small sample size (<100 participants) was the only factor associated with study noncompletion and nonpublication. CONCLUSION: One of 3 registered RCTs on CTDs fails to be completed or published. This represents a waste of resources and raises ethical concerns regarding hidden clinical data and unfruitful participation by patients.

Contribution of keratinocytes to dermal fibrosis.

PURPOSE OF REVIEW: The cellular pathogenesis of fibrotic disorders including systemic sclerosis (SSc) remains largely speculative. Currently, the altered function of endothelial cells and fibroblasts under the influence of an inappropriate immune response are considered central pathogenic events in SSc. Adding to this complexity, novel evidence here reviewed suggests that keratinocytes may concur in the development of skin fibrosis. RECENT FINDINGS: Epidermal equivalents (EE) generated from primary SSc keratinocytes display a distinct gene expression program when compared to healthy donor (HD) EE. SSc-EE, among others, exhibited enhanced oxidative and metabolic response pathways. Immunohistochemical studies demonstrated similarities between SSc-EE and SSc epidermis including altered keratinocyte differentiation, enhanced expression of activation markers, and reduced rate of basal keratinocytes proliferation. SSc-EE supernatants more than HD-EE modified the inflammatory and extracellular matrix deposition/resorption program of dermal fibroblasts. Further evidence indicated that the relative lack rather than the excess of interleukin-25 in keratinocytes may contribute to enhanced dermal fibrotic changes. Overall, these data support keratinocyte-intrinsic SSc-related modifications. SUMMARY: Improved methods for engineering epidermal and skin equivalents are helping to address the question whether keratinocyte alterations in SSc are primary and capable to dysregulate dermal homeostasis or secondary following dermal fibrotic changes.

IL-25 participates in keratinocyte-driven dermal matrix turnover and is reduced in systemic sclerosis epidermis.

OBJECTIVES: Evidence shows that dysfunctional SSc keratinocytes contribute to fibrosis by altering dermal homeostasis. Whether IL-25, an IL-17 family member regulating many epidermal functions, takes part in skin fibrosis is unknown. Here we address the role of IL-25 in skin fibrosis. METHODS: The expression of IL-25 was evaluated by immunofluorescence and in situ hybridization in 10 SSc and seven healthy donor (HD) skin biopsies. Epidermal equivalents (EE) reconstituted by primary HD keratinocytes were used as a model to study transcriptomic changes induced by IL-25 in the epidermis. RNA expression profile in EEs was characterized by RNAseq. The conditioned medium (CM) from primary SSc and HD keratinocytes primed with IL-25 was used to stimulate fibroblasts. IL-6, IL-8, MMP-1, type-I collagen (Col-I), and fibronectin production by fibroblasts was assessed by ELISA. RESULTS: SSc epidermis expressed lower levels of IL-25 compared with HDs. In EEs, IL-25 regulated several molecular pathways related to wound healing and extracellular matrix remodelling. Compared with control CM, the CM from IL-25-primed keratinocytes enhanced the fibroblast production of MMP-1, IL-6 and IL-8, but not of Col-I nor fibronectin. However, IL-25 significantly reduced the production of Col-I when applied directly to fibroblasts. The activation of keratinocytes by IL-25 was receptor-dependent and evident after a very short incubation time (10 min), largely mediated by IL-1, suggesting enhanced and specific release of preformed mediators. CONCLUSIONS: These results show that IL-25 participates in skin homeostasis, and its decreased expression in SSc may contribute to skin fibrosis by favouring extracellular matrix deposition over degradation.

Modeling Performance of Microservices Systems with Growth Theory.

CONTEXT: The microservices architectural style is gaining momentum in the IT industry. This style does not guarantee that a target system can continuously meet acceptable performance levels. The ability to study the violations of performance requirements and eventually predict them would help practitioners to tune techniques like dynamic load balancing or horizontal scaling to achieve the resilience property. OBJECTIVE: The goal of this work is to study the violations of performance requirements of microservices through time series analysis and provide practical instruments that can detect resilient and non-resilient microservices and possibly predict their performance behavior. METHOD: We introduce a new method based on growth theory to model the occurrences of violations of performance requirements as a stochastic process. We applied our method to an in-vitro e-commerce benchmark and an in-production real-world telecommunication system. We interpreted the resulting growth models to characterize the microservices in terms of their transient performance behavior. RESULTS: Our empirical evaluation shows that, in most of the cases, the non-linear S-shaped growth models capture the occurrences of performance violations of resilient microservices with high accuracy. The bounded nature associated with this models tell that the performance degradation is limited and thus the microservice is able to come back to an acceptable performance level even under changes in the nominal number of concurrent users. We also detect cases where linear models represent a better description. These microservices are not resilient and exhibit constant growth and unbounded performance violations over time. The application of our methodology to a real in-production system identified additional resilience profiles that were not observed in the in-vitro experiments. These profiles show the ability of services to react differently to the same solicitation. We found that when a service is resilient it can either decrease the rate of the violations occurrences in a continuous manner or with repeated attempts (periodical or not). CONCLUSIONS: We showed that growth theory can be successfully applied to study the occurences of performance violations of in-vitro and in-production real-world systems. Furthermore, the cost of our model calibration heuristics, based on the mathematical expression of the selected non-linear growth models, is limited. We discussed how the resulting models can shed some light on the trend of performance violations and help engineers to spot problematic microservice operations that exhibit performance issues. Thus, meaningful insights from the application of growth theory have been derived to characterize the behavior of (non) resilient microservices operations.

Dysfunctional Keratinocytes Increase Dermal Inflammation in Systemic Sclerosis: Results From Studies Using Tissue-Engineered Scleroderma Epidermis.

OBJECTIVE: Evidence suggests that keratinocyte-fibroblast interactions are abnormal in systemic sclerosis (SSc). The present study was undertaken to investigate potential epidermal dysfunction in SSc and its effects on dermal homeostasis. METHODS: Epidermal equivalents (EEs) were generated using keratinocytes from 6 healthy donors and 4 individuals with SSc. Skin and EE expression of markers of proliferation, differentiation, and activation was evaluated by immunohistochemistry. The transcriptomic profile of SSc EEs and healthy donor EEs was identified by RNA sequencing. EE conditioned medium (CM) was used to stimulate fibroblasts, and their production of interleukin-6 (IL-6), IL-8, matrix metalloproteinase 1 (MMP-1), type I collagen, and fibronectin was assessed by enzyme-linked immunosorbent assay. RESULTS: Compared to healthy donor EEs, SSc EEs exhibited aberrant differentiation, enhanced expression of activation markers, and a lower rate of basal keratinocyte mitosis, reproducing most of the abnormalities observed in SSc epidermis. RNA sequencing analysis revealed that, compared to healthy donor EEs, SSc EEs were characterized by lower expression of homeobox gene family members and by enhanced metabolic and oxidative stress molecular pathways. EE CM enhanced fibroblast production of IL-6, IL-8, MMP-1, type I collagen, and fibronectin (P < 0.05). Except for type I collagen and fibronectin, this effect was 2-fold higher in the presence of CM generated form SSc EEs. IL-1 was responsible, at least in part, for keratinocyte-dependent fibroblast activation. CONCLUSION: SSc EEs recapitulate the in vivo characteristics of SSc epidermis, demonstrating that SSc keratinocytes have an intrinsically altered differentiation program, possibly due to the dysregulation of genes from the homeobox family. The increased metabolic and oxidative stress associated with SSc epidermis may contribute to chronic inflammation and fibrosis of the dermis.

Interplay Between Keratinocytes and Fibroblasts: A Systematic Review Providing a New Angle for Understanding Skin Fibrotic Disorders.

Background/Objective: Skin fibrosis is the result of aberrant processes leading to abnormal deposition of extracellular matrix (ECM) in the dermis. In healthy skin, keratinocytes participate to maintain skin homeostasis by actively crosstalking with fibroblasts. Within the wide spectrum of fibrotic skin disorders, relatively little attention has been devoted to the role of keratinocytes for their capacity to participate to skin fibrosis. This systematic review aims at summarizing the available knowledge on the reciprocal interplay of keratinocytes with fibroblasts and their soluble mediators in physiological states, mostly wound healing, and conditions associated with skin fibrosis. Methods: We performed a systematic literature search on PubMed to identify in vitro and ex vivo human studies investigating the keratinocyte characteristics and their interplay with fibroblasts in physiological conditions and within fibrotic skin disorders including hypertrophic scars, keloids, and systemic sclerosis. Studies were selected according to pre-specified eligibility criteria. Data on study methods, models, stimuli and outcomes were retrieved and summarized according to pre-specified criteria. Results: Among the 6,271 abstracts retrieved, 73 articles were included, of which 14 were specifically dealing with fibrotic skin pathologies. Fifty-six studies investigated how keratinocyte may affect fibroblast responses in terms of ECM-related genes or protein production, phenotype modification, and cytokine production. Most studies in both physiological conditions and fibrosis demonstrated that keratinocytes stimulate fibroblasts through the production of interleukin 1, inducing keratinocyte growth factor (KGF) and metalloproteinases in the fibroblasts. When the potential of keratinocytes to modulate collagen synthesis by healthy fibroblasts was explored, the results were controversial. Nevertheless, studies investigating keratinocytes from fibrotic skin, including keloids, hypertrophic scar, and scleroderma, suggested their potential involvement in enhancing ECM deposition. Twenty-three papers investigated keratinocyte proliferation differentiation and production of soluble mediators in response to interactions with fibroblasts. Most studies showed that fibroblasts modulate keratinocyte viability, proliferation, and differentiation. The production of KGF by fibroblast was identified as key for these functions. Conclusions: This review condenses evidence for the active interaction between keratinocytes and fibroblasts in maintaining skin homeostasis and the altered homeostatic interplay between keratinocytes and dermal fibroblasts in scleroderma and scleroderma-like disorders.

T-Cell Proapoptotic and Antifibrotic Activity Against Autologous Skin Fibroblasts in vitro Is Associated With IL-17A Axis Upregulation in Systemic Sclerosis.

Background: Systemic sclerosis (SSc) T cells can induce apoptosis of autologous skin fibroblasts in vitro. Th17 cells have been reported to increase in SSc patients, and interleukin-17A (IL-17A) has a profibrotic function. We used a system based on T-cell-autologous fibroblast co-cultures to further investigate a possible role of IL-17A in SSc. Methods: T cells from diffuse SSc patients were co-cultured with autologous skin fibroblasts. IL17A mRNA was assessed by real-time PCR in co-cultured and control T cells, while IL17RA, CXCL1, CCL2, CCL3, COL1A1, COL3A1, CTGF, TGFBR2, and SMAD3 mRNAs were assessed in co-cultured and control fibroblasts. In subset experiments, co-cultures and control cells were treated with either IL-17A or IL-17A plus anti-IL17 receptor monoclonal antibody (α-IL-17RA mAb). Chemokine and procollagen type I (PCI) production was further investigated at the protein level in cell culture supernatants by multiple suspension immunoassay and sandwich ELISA, respectively. Co-cultured and control fibroblasts were also stained with Annexin V and analyzed by flow cytometry. Results: T cell-fibroblast co-cultures overexpressed IL17A and IL17RA. Furthermore, co-cultured fibroblasts upregulated IL-17A targets CXCL1, CCL2, and CCL3, while COL1A1, COL3A1, CTGF, and two key effectors of the TGF-ß signaling, TGFBR2 and SMAD3, were found downregulated. Consistently, chemokine concentrations were increased in co-culture supernatants, while PCI levels were reduced, especially after stimulation with ectopic IL-17A. Finally, simultaneous α-IL-17RA mAb treatment restored PCI levels and reduced fibroblast apoptosis in IL-17A-stimulated co-cultures. Conclusion: These data suggest that IL-17A upregulation might play a role in modulating T cell-mediated antifibrotic and proapoptotic effects in co-cultured autologous skin fibroblasts.

Utilidad de las imágenes híbridas SPECT/TC en el infarto óseo / Utility of single-photon emission computed tomography and computed tomography imaging in bone infarction

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Performance of a new quantitative computed tomography index for interstitial lung disease assessment in systemic sclerosis.

Quantitative high resolution computed tomography (HRCT) may objectively assess systemic sclerosis (SSc)-interstitial lung disease (ILD) extent, using three basic densitometric measures: mean lung attenuation (MLA), skewness, and kurtosis. This prospective study aimed to develop a composite index - computerized integrated index (CII) - that accounted for MLA, skewness, and kurtosis by means of Principal Component Analysis over HRCTs of 83 consecutive SSc subjects, thus eliminating redundancies. Correlations among CII, cardiopulmonary function and immune-inflammatory biomarkers (e.g. sIL-2Rα and CCL18 serum levels) were explored. ILD was detected in 47% of patients at visual HRCT assessment. These patients had worse CII values than patients without ILD. The CII correlated with lung function at both baseline and follow-up, and with sIL-2Rα and CCL18 serum levels. The best discriminating CII value for ILD was 0.1966 (AUC = 0.77; sensitivity = 0.81 [95%CI:0.68-0.92]; specificity = 0.66 [95%CI:0.52-0.80]). Thirty-four percent of patients without visual trace of ILD had a CII lower than 0.1966, and 67% of them had a diffusing lung capacity for CO <80% of predicted. We showed that this new composite CT index for SSc-ILD assessment correlates with both lung function and immune-inflammatory parameters and could be sufficiently sensitive for capturing early lung density changes in visually ILD-free patients.

ActivinA: a new leukemia-promoting factor conferring migratory advantage to B-cell precursor-acute lymphoblastic leukemic cells.

B-cell precursor-acute lymphoblastic leukemia modulates the bone marrow (BM) niche to become leukemia-supporting and chemo-protective by reprogramming the stromal microenvironment. New therapies targeting the interplay between leukemia and stroma can help improve disease outcome. We identified ActivinA, a TGF-ß family member with a well-described role in promoting several solid malignancies, as a factor favoring leukemia that could represent a new potential target for therapy. ActivinA resulted over-expressed in the leukemic BM and its production was strongly induced in mesenchymal stromal cells after culture with leukemic cells. Moreover, MSCs isolated from BM of leukemic patients showed an intrinsic ability to secrete higher amounts of ActivinA compared to their normal counterparts. The pro-inflammatory leukemic BM microenvironment synergized with leukemic cells to induce stromal-derived ActivinA. Gene expression analysis of ActivinA-treated leukemic cells showed that this protein was able to significantly influence motility-associated pathways. Interestingly, ActivinA promoted random motility and CXCL12-driven migration of leukemic cells, even at suboptimal chemokine concentrations, characterizing the leukemic niche. Conversely, ActivinA severely impaired CXCL12-induced migration of healthy CD34+ cells. This opposite effect can be explained by the ability of ActivinA to increase intracellular calcium only in leukemic cells, boosting cytoskeleton dynamics through a higher rate of actin polymerization. Moreover, by stimulating the invasiveness of the leukemic cells, ActivinA was found to be a leukemia-promoting factor. Importantly, the ability of ActivinA to enhance BM engraftment and the metastatic potential of leukemic cells was confirmed in a xenograft mouse model of the disease. Overall, ActivinA was seen to be a key factor in conferring a migratory advantage to leukemic cells over healthy hematopoiesis within the leukemic niche.

Interleukin-6 and Type-I Collagen Production by Systemic Sclerosis Fibroblasts Are Differentially Regulated by Interleukin-17A in the Presence of Transforming Growth Factor-Beta 1.

Functional cytokine networks have been poorly characterized in systemic sclerosis (SSc). While interleukin-17A (IL-17A) is increased in SSc skin and other organs, its role is still debated, particularly considering fibrogenesis. We uncover here a dual function of IL-17A in the presence of transforming growth factor-ß 1 (TGF-ß), the master pro-fibrotic cytokine. In the one hand, we report an unexpected synergic activity resulting in enhanced production of IL-6 by dermal fibroblasts; in the other hand, a substantial inhibition of type I collagen (col-I) production. IL-17A or TGF-ß enhanced the production of IL-6 by 8- to 16-folds when compared to control in healthy donors (HD) and SSc cultures. However, the joint presence of IL-17A and TGF-ß resulted in robustly exuberant responses with levels of IL-6 up to 100-folds higher than those observed in untreated cells. Inhibition of NFκB signaling pathway preferentially inhibited the production of IL-6 driven by IL-17A in HD fibroblasts, while inhibition of PI3K preferentially inhibited the production of IL-6 driven by TGF-ß. Interestingly, when p38 MAPK was inhibited, substantial reduction of IL-6 production was observed for both IL-17A and TGF-ß. Consistently with the inhibition experiments, the combined stimulation of fibroblasts by IL-17A and TGF-ß resulted in 1.8-fold increase in p38 MAPK phosphorylation (P = 0.025), when compared to levels of phosphorylated p38 MAPK induced by IL-17A alone. Furthermore, the enhanced phosphorylation of p38 MAPK in the joint presence of IL-17A and TGF-ß was unique among the signaling molecules we examined. As expected, TGF-ß induced SMAD2 phosphorylation and col-I production. However, in fibroblasts cultured in the joint presence of TGF-ß and IL-17A, SMAD2 phosphorylation was decreased by 0.6-folds (P = 0.022) when compared to that induced by TGF-ß alone. Remarkably, in this condition, the production of col-I and fibronectin was significantly decreased in both HD and SSc. Thus, IL-17A and TGF-ß reciprocally influence each other effector functions in fibroblasts. Intracellular molecular switches may favor synergic or antagonistic activities, which are revealed by specific readouts. The implications of these data in the context of SSc are far reaching, particularly in terms of therapeutic approaches since IL-6, IL-17A, and TGF-ß are all putative targets of treatment.

International consensus: What else can we do to improve diagnosis and therapeutic strategies in patients affected by autoimmune rheumatic diseases (rheumatoid arthritis, spondyloarthritides, systemic sclerosis, systemic lupus erythematosus, antiphospholipid syndrome and Sjogren's syndrome)?: The unmet needs and the clinical grey zone in autoimmune disease management.

Autoimmune diseases are a complex set of diseases characterized by immune system activation and, although many progresses have been done in the last 15years, several unmet needs in the management of these patients may be still identified. Recently, a panel of international Experts, divided in different working groups according to their clinical and scientific expertise, were asked to identify, debate and formulate a list of key unmet needs within the field of rheumatology, serving as a roadmap for research as well as support for clinicians. After a systematic review of the literature, the results and the discussions from each working group were summarised in different statements. Due to the differences among the diseases and their heterogeneity, a large number of statements was produced and voted by the Experts to reach a consensus in a plenary session. At all the steps of this process, including the initial discussions by the steering committee, the identification of the unmet needs, the expansion of the working group and finally the development of statements, a large agreement was attained. This work confirmed that several unmet needs may be identified and despite the development of new therapeutic strategies as well as a better understanding of the effects of existing therapies, many open questions still remain in this field, suggesting a research agenda for the future and specific clinical suggestions which may allow physicians to better manage those clinical conditions still lacking of scientific clarity.

Outcome of a glucocorticoid discontinuation regimen in patients with inactive systemic sclerosis.

Glucocorticoids (GC) are widely used to treat systemic sclerosis (SSc). The lack of efficacy data and patient/physician concerns may prompt therapy discontinuation. The aim of this study is to identify factors hampering GC discontinuation in patients with stable disease on oral GC for longer than 12 months. Consecutive patients fulfilling the 2013 ACR/EULAR criteria for SSc and with stable disease were prescribed a slow tapering GC regimen to achieve discontinuation. At study entry and 6 months later (T6), patients were assessed for disease activity and severity. Moreover, the Short-Form-36; the Health Assessment Questionnaire Disability Index (HAQ-DI); and visual analog scales for fatigue, pain, and general health were completed. Reasons for stopping the discontinuation regimen were recorded. Forty-eight patients (46 females, 9 diffuse SSc), with a mean ± SD age of 56±14 years and a median disease duration of 10 years (range 2-22), were enrolled. The median daily GC dose was 5 mg (range 5-10; all patients treated with prednisone). At T6, 33 (68.7 %) patients had discontinued GC. The remaining 15 patients could not discontinue GC because of arthralgia in eight, arthritis in two, puffy fingers in two, increased creatine-kinase in two, and bursitis in one patient. At multiple logistic analysis, a higher baseline HAQ-DI was the only independent factor associated with GC need (OR 2.98, 95 % CI 1.20-7.41; p = 0.01). About one third of SSc patients did not achieve a GC-free regimen. Disability as assessed by HAQ-DI was the leading factor hindering GC discontinuation. A low HAQ-DI score can identify candidates for GC discontinuation.

Impact of obesity and acquisition protocol on (123)I-metaiodobenzylguanidine indexes of cardiac sympathetic innervation.

BACKGROUND: This study was designed to assess the impact of obesity and acquisition protocol on (123)I-metaiodobenzylguanidine (MIBG) indexes of cardiac sympathetic innervation. METHODS: Forty-five patients with heart failure (HF) (38 men, age 58±15 years) underwent (123)I-MIBG cardiac imaging. Of these patients, 10 were obese [body mass index (BMI) ≥30 kg/m(2)]. Ten-minute planar images of the thorax in anterior view were performed 15 minutes ("early" image) and 3 hours and 50 minutes ("late" image) after tracer administration in both supine- and prone-position. Early and late (123)I-MIBG heart-to-mediastinum (H/M) ratios and washout rate were computed. RESULTS: In overall study population, early and late (123)I-MIBG H/M ratios and washout rate were comparable between supine- and prone-position acquisitions. Obese patients had a lower early and late (123)I-MIBG H/M ratios both in supine (P<0.01) and prone (P<0.05) positions compared to non-obese subjects. CONCLUSIONS: Our results indicate that in HF patients, obesity has a significant impact on (123)I-MIBG indexes of cardiac sympathetic innervation. Prone-position did not change early and late (123)I-MIBG H/M ratios and washout rate compared to supine position both in obese and non-obese HF patients.