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Background: Immune cells from rheumatoid arthritis (RA) patients display a reduced in vitro response to Porphyromonas gingivalis (P. gingivalis), which may have functional immune consequences. The aim of this study was to characterize, by flow cytometry, the frequency/activity of monocytes and naturally occurring myeloid dendritic cells (mDCs) in peripheral blood samples from patients with periodontitis and patients with periodontitis and RA. Methods: The relative frequency of monocytes and mDCs in the whole blood, the frequency of these cells producing TNFα or IL-6 and the protein expression levels for each cytokine, before and after stimulation with lipopolysaccharide (LPS) from Escherichia coli plus interferon-γ (IFN-γ), were assessed by flow cytometry, in peripheral blood samples from 10 healthy individuals (HEALTHY), 10 patients with periodontitis (PERIO) and 17 patients with periodontitis and RA (PERIO+RA). Results: The frequency of monocytes and mDCs producing IL-6 or TNF-α and the expression of IL-6 and TNF-α in the PERIO group were generally higher. Within the PERIO+RA group, P. gingivalis and related antibodies were negatively correlated with the monocyte and mDC expression of IL-6. A subgroup of the PERIO+RA patients that displayed statistically significantly lower frequencies of monocytes producing IL-6 after activation presented statistically significantly higher peptidylarginine deiminase (PAD)2/4 activity, anti-arg-gingipain (RgpB) IgG levels, mean probing depth (PD), periodontal inflamed surface area (PISA) and bleeding on probing (BoP). Conclusions: In the patients with PERIO+RA, innate immune cells seemed to produce lower amounts of pro-inflammatory cytokines, which are correlated with worse periodontitis-related clinical and microbiological parameters.

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OBJECTIVE: Although aging has a strong impact on visual acuity (VA) and falls, their interaction is understudied in generally healthy older adults. This study aimed to examine if and to what extent baseline VA is associated with an increased risk of all and injurious falls over 3 years in generally healthy community-dwelling older adults. DESIGN: Observational analysis of DO-HEALTH, a double-blind, randomized controlled trial. SETTING AND PARTICIPANTS: Multicenter trial with 7 European centers: Zurich, Basel, Geneva (Switzerland), Berlin (Germany), Innsbruck (Austria), Toulouse (France), and Coimbra (Portugal), including 2157 community-dwelling adults aged 70 years and older without any major health events in the 5 years prior to enrollment, sufficient mobility, and good cognitive status. METHODS: The numbers of all and injurious falls were recorded prospectively by diary and in-person assessment every 3 months. Decreased VA at baseline was defined as better-eye VA lower than 1.0. We applied negative binomial regression models for all and injurious falls, adjusted for age, sex, prior falls, treatment allocation, study site, baseline body mass index, and use of walking aids. RESULTS: Among the 2131 participants included in this analysis (mean age: 74.9 years, 61.7% were women, 82.6% at least moderately physically active), 1464 (68.7%) had decreased VA. Overall, 3290 falls including 2116 injurious falls were recorded over 3 years. Decreased VA at baseline was associated with a 22% increased incidence rate of all falls [adjusted incidence rate ratio (aIRR) = 1.22, 95% CI 1.07, 1.38, P = .003] and 20% increased incidence rate of injurious falls (aIRR = 1.20, 95% CI 1.05, 1.37, P = .007). CONCLUSIONS AND IMPLICATIONS: Our findings suggest that decreased VA is an independent predictor of an about 20% increased risk of all and injurious falls, highlighting the importance of regular eye examinations and VA measurements for fall prevention, even in generally healthy and active older adults.

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Vascular involvement in IgG4-related disease (IgG4-RD), is a well-recognized feature and large vessel commitment, especially the aorta, can be the only manifestation of the disease. Being a newly recognized disease, its diagnosis and workup still represents a challenge in clinical practice. A 47-year-old-man with two aortic aneurysms ruptures, one at abdominal and the other at thoracic level, was referred to our rheumatology department. The initial analysis of the surgical specimen obtained 3 years earlier revealed a nonspecific aortitis. Re-evaluation of the biopsy with immunohistology now demonstrated the presence of IgG4 deposits. Evidence-based recommendations regarding diagnosis, treatment and follow-up of IgG4-related large-vessel involvement are lacking. In this particular case, histopathology were crucial. The authors review and discuss vascular involvement in IgG4-RD and respective treatment options.

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OBJECTIVE: The term "invalidation" refers to the patients' perception that their medical condition is not recognized by the social environment. Invalidation can be a major issue in patients' lives, adding a significant burden to symptoms and limitations while increasing the risk of physical and psychological disability. In this study in patients with rheumatic diseases, we investigated the relationship between invalidation and sociodemographic, clinical, psychological, and personality characteristics. METHODS: This international cross-sectional study included 562 adults with rheumatoid arthritis (n = 124), spondyloarthritis (n = 85), systemic lupus erythematosus (n = 112), or fibromyalgia (FM; n = 241). Assessed were the family and health professionals subscales of the Illness Invalidation Inventory (3*I), happiness (Subjective Happiness Scale), personality (Ten-Item Personality Inventory), pain, and loneliness (numerical rating scales). Univariate and multivariate analyses were used to test different models. RESULTS: Invalidation occurred in all rheumatic diseases, but patients with FM reported the most invalidation. Including all correlated variables in the multivariate model, pain remained as a determinant of invalidation by health professionals, but not by family. Regarding psychological variables, loneliness remained as a determinant of invalidation by family, but not by health professionals. FM and low levels of happiness, agreeableness, and conscientiousness were associated with invalidation while taking account of other variables. CONCLUSION: Invalidation occurs in all rheumatic diseases and patients with FM experience the most invalidation. Psychological factors (happiness, agreeableness, and conscientiousness), loneliness, and pain intensity are associated with invalidation, irrespective of the rheumatic disease and may deserve dedicated interventions.

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BACKGROUND: Use of topical nonsteroidal anti-inflammatory drugs (NSAIDs) to treat chronic musculoskeletal conditions has become widely accepted because they can provide pain relief without associated systemic adverse events. This review is an update of 'Topical NSAIDs for chronic musculoskeletal pain in adults', originally published in Issue 9, 2012. OBJECTIVES: To review the evidence from randomised, double-blind, controlled trials on the efficacy and safety of topically applied NSAIDs for chronic musculoskeletal pain in adults. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and our own in-house database; the date of the last search was February 2016. We also searched the references lists of included studies and reviews, and sought unpublished studies by asking personal contacts and searching online clinical trial registers and manufacturers' web sites. SELECTION CRITERIA: We included randomised, double-blind, active or inert carrier (placebo) controlled trials in which treatments were administered to adults with chronic musculoskeletal pain of moderate or severe intensity. Studies had to meet stringent quality criteria and there had to be at least 10 participants in each treatment arm, with application of treatment at least once daily. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion and extracted data. We used numbers of participants achieving each outcome to calculate risk ratio and numbers needed to treat (NNT) or harm (NNH) compared to carrier or other active treatment. We were particularly interested to compare different formulations (gel, cream, plaster) of individual NSAIDs. The primary outcome was 'clinical success', defined as at least a 50% reduction in pain, or an equivalent measure such as a 'very good' or 'excellent' global assessment of treatment, or 'none' or 'slight' pain on rest or movement, measured on a categorical scale. MAIN RESULTS: We identified five new studies for this update, which now has information from 10,631 participants in 39 studies, a 38% increase in participants from the earlier review; 33 studies compared a topical NSAID with carrier. All studies examined topical NSAIDs for treatment of osteoarthritis, and for pooled analyses studies were generally of moderate or high methodological quality, although we considered some at risk of bias from short duration and small size.In studies lasting 6 to 12 weeks, topical diclofenac and topical ketoprofen were significantly more effective than carrier for reducing pain; about 60% of participants had much reduced pain. With topical diclofenac, the NNT for clinical success in six trials (2343 participants) was 9.8 (95% confidence interval (CI) 7.1 to 16) (moderate quality evidence). With topical ketoprofen, the NNT for clinical success in four trials (2573 participants) was 6.9 (5.4 to 9.3) (moderate quality evidence). There was too little information for analysis of other individual topical NSAIDs compared with carrier. Few trials compared a topical NSAID to an oral NSAID, but overall they showed similar efficacy (low quality evidence). These efficacy results were almost completely derived from people with knee osteoarthritis.There was an increase in local adverse events (mostly mild skin reactions) with topical diclofenac compared with carrier or oral NSAIDs, but no increase with topical ketoprofen (moderate quality evidence). Reporting of systemic adverse events (such as gastrointestinal upsets) was poor, but where reported there was no difference between topical NSAID and carrier (very low quality evidence). Serious adverse events were infrequent and not different between topical NSAID and carrier (very low quality evidence).Clinical success with carrier occurred commonly - in around half the participants in studies lasting 6 to 12 weeks. Both direct and indirect comparison of clinical success with oral placebo indicates that response rates with carrier (topical placebo) are about twice those seen with oral placebo.A substantial amount of data from completed, unpublished studies was unavailable (up to 6000 participants). To the best of our knowledge, much of this probably relates to formulations that have never been marketed. AUTHORS' CONCLUSIONS: Topical diclofenac and topical ketoprofen can provide good levels of pain relief beyond carrier in osteoarthritis for a minority of people, but there is no evidence for other chronic painful conditions. There is emerging evidence that at least some of the substantial placebo effects seen in longer duration studies derive from effects imparted by the NSAID carrier itself, and that NSAIDs add to that.

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Cost-effective intervention thresholds (ITs) based on FRAX(®) were determined for Portugal. Assuming a willingness to pay (WTP) of €32,000 per quality-adjusted life years (QALYs), treatment with generic alendronate is cost effective for men and women aged 50 years or more, with 10-year probabilities for major osteoporotic fractures and hip above 8.8 and 2.5 %, respectively. The aim of the present study was to identify the 10-year probabilities of a major and hip osteoporotic fracture using FRAX(®) validated for Portugal, above which pharmacologic interventions become cost effective in the Portuguese context. A previously developed and validated state transition Markov cohort model was populated with epidemiologic, economic and quality-of-life fracture data from Portugal. Cost-effectiveness of FRAX(®)-based ITs was calculated for generic alendronate and proprietary zoledronic acid, denosumab and teriparatide were compared to "no intervention", assuming a WTP of €32,000 (two times national Gross Domestic Product per capita) per QALYs. In the Portuguese epidemiological and economic context, treatment with generic alendronate was cost effective for men and women aged 50 years or more, with 10-year probabilities at or above 8.8 % for major osteoporotic fractures and 2.5 % for hip fractures. Cost-effective threshold 10-year probabilities for major osteoporotic and hip fractures were higher for zoledronic acid (20.4 and 10.1 %), denosumab (34.9 and 10.1 %) and teriparatide (77.8 and 62.6 %), respectively. A tool is provided to perform the calculation of cost-effective ITs for different medications, according to age group and diverse levels of WTP. Cost-effective ITs, for different medications, age groups and WTP, based on 10-year probabilities of major and hip fracture probabilities calculated with FRAX are provided.

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OBJECTIVES: To evaluate ultrasound Virtual Touch Imaging and Quantification (VTIQ) as a method for determining absolute skin stiffness in patients with systemic sclerosis (SSc). METHODS: Skin thickness, assessed by the modified Rodnan Skin Score (mRSS) and absolute skin stiffness, using VTIQ, were measured at all mRSS anatomical sites to quantify the shear wave velocity (in m/s) in 26 SSc patients and in 17 age- and gender-matched controls. Correlations between mRSS and absolute skin stiffness, and comparisons between patients and controls were analysed statistically using Mann-Whitney U tests and correlations between variables using Pearson's. P values <0.05 were considered significant. RESULTS: Shear wave velocity as a measure of skin stiffness was significantly higher in SSc than in controls in 11 out of 16 mRSS sites investigated. Shear-wave velocity was strongly correlated with the local mRSS in the following anatomical sites: forearm, hand, phalanx, and thigh. In the patient group, clinically unaffected skin could also be differentiated from healthy skin using shear-wave velocity. CONCLUSIONS: VTIQ represents an innovative and promising technique that provides, for the first time, a non-invasive, absolute quantification of skin stiffness. Further studies of VTIQ are required, but this early study supports the clinical and scientific potential of this new measure of skin involvement in SSc.

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BACKGROUND: The aim of our work was to replicate, in a Southern European population, the association reported in Northern populations between PTPRC locus and response to anti-tumor necrosis factor (anti-TNF) treatment in rheumatoid arthritis (RA). We also looked at associations between five RA risk alleles and treatment response. METHODS: We evaluated associations between anti-TNF treatment responses assessed by DAS28 change and by EULAR response at six months in 383 Portuguese patients. Univariate and multivariate linear and logistic regression analyses were performed. In a second step to confirm our findings, we pooled our population with 265 Spanish patients. RESULTS: No association was found between PTPRC rs10919563 allele and anti-TNF treatment response, neither in Portuguese modeling for several clinical variables nor in the overall population combining Portuguese and Spanish patients. The minor allele for RA susceptibility, rs3761847 SNP in TRAF1/C5 region, was associated with a poor response in linear and logistic univariate and multivariate regression analyses. No association was observed with the other allellic variants. Results were confirmed in the pooled analysis. CONCLUSION: This study did not replicate the association between PTPRC and the response to anti-TNF treatment in our Southern European population. We found that TRAF1/C5 risk RA variants potentially influence anti-TNF treatment response.

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Glucocorticoids are one of the most effective treatments for rheumatoid arthritis, with well-established efficacy in controlling the disease symptoms and structural progression. Fears regarding their toxicity are reflected in common recommendations for the use of the lowest possible dose for the shortest possible time. We herein review toxicity data obtained in randomized clinical trials of low-dose glucocorticoid in rheumatoid arthritis, given that observational studies cannot guarantee the avoidance of bias by indication. Seven eligible randomized controlled trials were identified. These publications do not identify any strong signal of relevant toxicity of glucocorticoid in doses of up to 10 mg of prednisone equivalent/day for up to 2 years. However, the quantity (1,100 patient years of exposure) and especially the quality of evidence are too limited to establish conclusions. A large prospective trial dedicated to the toxicity of low-dose glucocorticoid is dearly needed. Meanwhile, adherence to recommendations on standardized methodologies for the registration and report of glucocorticoid adverse events is essential to improve our knowledge and competence in the best management of these important medications.

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Low- to medium-dose glucocorticoids have been shown to have not only anti-inflammatory but also disease-modifying properties in rheumatoid arthritis. The evidence for the benefit of its early use in combination with disease-modifying antirheumatic drugs underlines the need for a close evaluation of their risk-benefit ratio. Over time, numerous myths and fears about glucocorticoid toxicity in rheumatoid arthritis have arisen from observational studies, and many concerns have been unduly extrapolated from observations with higher-dose treatment. Furthermore, we cannot exclude the possibility of a powerful effect of bias by indication in these studies. Low- to medium-dose glucocorticoid regimens continued to be evaluated in randomized clinical trials, particularly in early disease, but these studies also have relevant methodological limitations in assessing safety, particularly due to small size and/or short duration. At present, the evidence on which to support clear recommendations about glucocorticoid toxicity remains remarkably weak. A large prospective pragmatic trial dedicated to the toxicity of low-dose glucocorticoids is dearly needed. Meanwhile, adherence to recommendations on standardized methodologies for registration and report of glucocorticoid adverse events is essential for improving our knowledge and competence in the best management of these important medications.

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OBJECTIVE: SLE has a relapsing-remitting course with disease activity flares over time. This study aims to identify clinical predictors of SLE flares. METHODS: This prospective cohort study over 24 months included all SLE patients on follow-up at one academic lupus clinic. Flare was defined as an increase in SLEDAI-2K score ≥4 points. Baseline clinical and demographic parameters were compared using survival analysis for time-to-flare outcome with univariate log-rank tests. Variables with significant differences were further evaluated as predictors with multivariate Cox regression models adjusting for potential confounding or contributing factors and hazard ratio (HR) calculation. RESULTS: A total of 202 SLE patients were included. Over the follow-up period, 1083 visits were documented and 16.8% of patients presented with flares. In multivariate analysis, the following parameters emerged as flare predictors: SLE diagnosis up to 25 years of age (HR = 2.14, P = 0.03), lupus nephritis previous to baseline visit (HR = 4.78, P < 0.0001) and immunosuppressor treatment for severe SLE (HR = 3.22, P < 0.001). Baseline disease activity, disease duration and treatment with prednisone or HCQ were not predictive factors. CONCLUSION: Patients with an SLE diagnosis before age 25 years, lupus nephritis or immunosuppressor treatment for severe SLE present greater HRs for flares, suggesting the need for tighter clinical monitoring. Current immunosuppressive strategies seem to be inefficient in providing flare prevention.

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This chapter discusses how doctors in key European countries develop and maintain professional standards of clinical knowledge in their specialism, rheumatology, with particular reference to how they are assessed in the workplace. The authors discuss key educational theories related to learning and assessment, including experiential learning, reflective practice, how formative and summative assessments drive experiential learning and the essential principles of reliability and validity. This chapter also considers the challenge of ensuring that professional attitudes towards assessment and reflective practice are developed alongside cognitive and practical skills, with reference to current frameworks, including the UK and North America. The chapter lists, describes and explains the main summative assessments used in postgraduate medicine in the UK. We advocate the development of the professional reflective-practitioner attitude as the best way of approaching the range of work-based assessments that trainees need to engage in. Our account concludes by briefly discussing the barriers that may impede professional approaches to assessing competence in rheumatology. A summary states how individual practitioners may contribute to a more effective process in their roles as assessors and trainees.

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OBJECTIVES: To evaluate the level of education and participation in an internship abroad and to European league against rheumatism (EULAR) on line course of young rheumatologists. To define new tools for learning. METHODS: Questionnaires were administered to 170 trainees and young specialists in 2008-2009 during official EULAR meetings or using the mailing list of European young rheumatologists in training. The questions with related visual analogical scale (VAS score 0-10) for satisfaction encompassed the following issues: languages, computer, daily hours employed, different items of medical culture, internship abroad, EULAR on-line course and bursaries. VAS>6 was considered a good level of satisfaction. RESULTS: 170 young rheumatologists (113 trainees and 57 specialists, 33±4.2 years old) from 32 EULAR countries did not approve their own national training (42.3%), believed in an European common education system (90.5%), had a good knowledge of English (85.7%) and computer (90.5%) and spent the majority of time in clinical practice (57.5%) in comparison with study and research. The young rheumatologists had higher competence in drug management (93.5%) than in clinical assessment and knowledge of imaging and anatomy, and mostly suggested new ways of communication (61.4% on-line courses and 66.1% DVD) to improve their education. 38% made stage abroad and participated to EULAR on-line course, with high satisfaction, but only half of them were granted by bursaries. CONCLUSIONS: Young rheumatologists are low confident in their own education and believe that visits to other training centers and new ways of learning (on line and DVD) might improve their competence.

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Most authorities recommend starting biological agents upon failure of at least one disease-modifying agent in patients with rheumatoid arthritis. However, owing to the absence of head-to-head studies, there is little guidance about which biological to select. Still, the practicing clinician has to decide. This review explores the application of published evidence to practice, discussing the goals of treatment, the (in) ability to predict individual responses to therapy, and the potential value of indirect comparisons. We suggest that cycling of biological agents, until remission is achieved or until the most effective agent for that individual patient is determined, deserves consideration in the current stage of knowledge.

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Estrogens at physiological concentrations are thought to play an immune-stimulating role, whereas androgens have an anti-inflammatory impact. However, their role on cytokine secretion in the presence or absence of cortisol has not been investigated. Furthermore, the role of hydroxylated estrogens downstream of 17beta-estradiol (E2) on secretion of tumor necrosis factor (TNF) is not known. In this study on peripheral blood leukocytes of healthy male subjects, we scrutinized the influence of prior sex hormones (for 24 h) with and without later addition of cortisol (for another 24 h) on stimulated secretion of TNF, IL-2, IL-4, IL-6, IL-10, and interferon-gamma (IFN-gamma). E2 stabilized or increased immune stimuli-induced secretion of TNF, IL-2, IL-4, IL-6, IL-10, and IFNgamma in relation to testosterone. Testosterone, in contrast, inhibited (IL-2, IL-4, IL-10) or tended to inhibit stimulated secretion of these cytokines (TNF, IFNgamma). This effect of E2 was pronounced at a concentration of 10(-10) M (testosterone: 10(-7) M) in the presence of cortisol. E2 (10(-8) M, 10(-10) M) and testosterone (10(-7) M) did not change glucocorticoid receptor expression. The downstream estrogens 2OH-estradiol(one), 4OH-estradiol(one), and 16OH-estradiol(one) did not stimulate TNF secretion at 10(-10) M, but even inhibited its secretion at 10(-11) M. However, the combination of 16OH-estradiol(one) on one side and 2OH-estradiol(one) or 4OH-estradiol(one) on the other side markedly stimulated TNF secretion that was only observable in the presence of cortisol. In conclusion, at physiological concentrations, E2 and a combination of downstream estrogens stabilized or increased immune stimuli-induced TNF secretion. These effects are dependent on the presence of physiological concentrations of cortisol. This study underlines the proinflammatory role of E2, which is probably dependent on conversion to a proinflammatory cocktail of downstream estrogens and the presence of cortisol.

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Soft tissue rheumatism includes a wide spectrum of common lesions of the tendons, enthesis, tendon sheaths, bursae, ligaments and fasciae as well as nerve compression syndromes. Studies on the pathogenesis of these lesions do not support a major role for inflammation, thus questioning the rationale for glucocorticoid injections. This chapter reviews current indications for local glucocorticoid injections and available evidence on its efficacy, as well as contraindications and potential risks. Randomised controlled studies of good methodological quality are rare and there is limited scientific evidence to support the superiority of glucocorticoid injections over alternative treatments. The basic principles of the glucocorticoid injection method are outlined, together with a description of the practical procedure for the more common conditions.

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Evidence from experimental animal studies show that sex hormones influence the glucocorticoid response to a variety of inflammatory and noninflammatory stimuli. In this study we assessed gender differences in the response of ACTH and cortisol in normal young male and female humans following intravenous infusion of human IL-6 in various dosages. Males presented a significantly stronger ACTH production in response to IL-6 than females. Peak cortisol response, however, was similar in males and females. Cortisol/ACTH ratios were significantly higher in females than in males, both at baseline and after each of the IL-6 dosages. These results suggest that an effective glucocorticoid response requires similar levels of IL-6 in males and females. However, they also suggest that the adrenals of males and females have different sensitivities to ACTH (higher in females) and possibly also to direct IL-6 stimulation.

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Gender and sex hormones are strongly related to the incidence and progression of autoimmune rheumatic diseases. Although sex steroids have been shown to have direct effects on the immune system, their influence in vivo may be mediated via interactions with third party systems including the hypothalamic-pituitary-adrenal axis. Such interactions are well demonstrated in experimental animals. In humans, there is increasing, although indirect, evidence that these interactions also occur. Possible interactions at the cell and gene level, with mutual antagonism or synergy between cortico- and gonadal steroids, open new exciting hypotheses that await clarification.

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