Adrenalectomy Improves Blood Pressure and Metabolic Control in Patients With Possible Autonomous Cortisol Secretion: Results of a RCT.

Objective: The best approach to patients with adrenal incidentaloma (AI) and possible autonomous cortisol secretion (PACS) is debated. The aim of this study was to assess the metabolic effect of adrenalectomy in AI patients with PACS in relation to cortisol secretion parameters, peripheral activation, and glucocorticoid sensitivity. Design: This is a multicenter randomized study (NCT number: NCT04860180). Methods: Sixty-two AI outpatients (40-75 years) with AI >1 cm and cortisol after overnight dexamethasone suppression test (F-1mgDST) between 50 and 138 nmol/L were randomized to adrenalectomy (Arm A) or a conservative approach (Arm B). Fifty-five patients completed the 6-month follow-up, 25 patients in Arm A (17 female patients, aged 62.5 ± 10.4 years) and 30 patients in Arm B (24 female patients, 66.1 ± 9.1 years). Plasma adrenocorticotroph hormone (ACTH), 24-h urinary free cortisol, 24-h urinary free cortisone, F-1mgDST, glucose, lipids, glycated hemoglobin (HbA1c) levels, blood pressure (BP), body weight, and treatment variations were assessed. The 24-h urinary free cortisol/cortisone ratio (an 11-beta hydroxysteroid dehydrogenase type 2 activity marker), BclI, and the N363S variants of glucocorticoid receptor (GR) polymorphisms were also evaluated. Results: BP control improved in 68% and 13% of the subjects in Arm A and Arm B, respectively (p = 0.001), and the glycometabolic control improved in 28% and 3.3% of the subjects in Arm A and Arm B patients, respectively (p = 0.02). Arm A subjects more rarely showed the BP and/or glycometabolic control worsening than Arm B patients (12% and 40%, respectively, p = 0.03). The surgical approach was independently associated with BP amelioration (OR 3.0, 95% CI 3.8-108.3, p < 0.001) but not with age, F-1mgDST levels, BMI, and hypertension and diabetes mellitus presence at baseline. The 24-h urinary free cortisol/cortisone ratio and the presence of sensitizing GR polymorphisms were not associated with the surgical outcome. The receiver operating characteristic (ROC) curve analysis showed that the BP control amelioration was associated with F-1mgDST [area under the curve (AUC), 0.82 ± 0.09 p = 0.012]. The F-1mgDST cutoff with the best compromise in predicting the BP amelioration was set at 75 nmol/L (sensitivity 77%, specificity 75%). Conclusions: AI patients with PACS benefit from surgery in terms of BP and glycometabolic control.

Comparison of the ability of the King's and MiToS staging systems to predict disease progression and survival in amyotrophic lateral sclerosis.

Background: Assessing clinical progression in amyotrophic lateral sclerosis (ALS) remains a challenge. We evaluated the validity and predictive capabilities of the King's and Milano-Torino Staging (MiToS) systems in a cohort of patients with ALS to demonstrate their benefit in clinical practice.Methodology: A cohort study was performed by including ALS incident cases in a referral center from 2007 to 2016. The staging systems were determined at time of diagnosis and follow-up. The standardized median times to reach each stage were computed. A multi-state model in the framework of the Cox model evaluated the predictive value of measurements. The survival C-statistic was reported as a measure of prediction ability.Results: Overall, 298 incident cases were included. The King's and MiToS systems described a progressive increase in the risk of dying with each elapsed stage. However, a lower resolution for late disease description for the King's system was observed, and late stages overlapped for the MiToS system. Slight variations in the staging systems appeared to improve performance based on validity and prediction abilities: (i) in the King's (C-statistic = 0.783), by adding a new stage involving the need for both gastrostomy and NIV: (ii) in the MiToS (C-statistic = 0.792), by merging stage 3 and stage 4 into a single stage 3.Conclusion: Both King's and MiToS are valid systems but have certain limitations. Variations in the staging systems may provide a more suitable framework for describing progression and survival. Further research is needed to evaluate the variations in the staging systems.

Time-trend evolution and determinants of sex ratio in Amyotrophic Lateral Sclerosis: a dose-response meta-analysis.

BACKGROUND: A noticeable change of the male-to-female sex ratio (SR) has been observed in Amyotrophic Lateral Sclerosis (ALS) leading to an apparent regression of SR with time (SR close to 1:1). OBJECTIVE: To provide a global SR estimate and investigate its relation with respect to population age. METHODS: A systematic review and meta-analysis was conducted including only population-based studies with a high-quality methodology in European ancestral origin population. Male-to-female SR was estimated by three different measures: SR number, SR crude incidence and SR standardized incidence. Standard and dose-response meta-analyses were performed to assess the pooled SR measures (irrespective of population age) and the evolution of the SR measures with respect to population age, respectively. Potential sources of heterogeneity were investigated via meta-regression. RESULTS: Overall, 3254 articles were retrieved in the literature search. Thirty-nine studies stratified by time periods were included. The overall pooled male-to-female ratio was 1.28 (95% CI 1.23-1.32) for SR number, 1.33 (95% CI 1.29-1.38) for SR crude incidence and 1.35 (95% CI 1.31-1.40) for SR standardized incidence. The SR number with respect to population age reveals a progressive reduction of SR at increasing age, while the SR crude incidence in relation to age displays a U-shaped curve. CONCLUSIONS: The number and the incidence of ALS cases were consistently higher in males than females. Dose-response meta-analysis showed that SR measures change with respect to population age. Further original research is needed to clarify if our findings are reproducible in other populations.

Age-specific ALS incidence: a dose-response meta-analysis.

To evaluate the association between worldwide ALS incidence rates and age, using a dose-response meta-analysis. We reviewed Medline and Embase up to July 2016 and included all population-based studies of newly-diagnosed cases, using multiple sources for case ascertainment. A dose-response meta-analysis was performed. A meta-regression investigated potential sources of heterogeneity. Of 3254 articles identified in the literature, we included 41 incidence studies covering 42 geographical areas. Overall, the fit between observed and predicted age-specific rates was very good. The expected variation of ALS incidence with age was characterized, in each study, by a progressive increase in the incidence from the 40s leading to a peak in the 60s or 70s, followed by a sharp decrease. Cochran's Q test suggested a significant heterogeneity between studies. Overall, estimated patterns of ALS age-specific incidence (at which the peak was reached) were similar among subcontinents of Europe and North America: peak of ALS incidence ranged in these areas between 6.98 and 8.17/100,000 PYFU, which referred to age in the range 71.6-77.4 years. The relationship between age and ALS incidence appeared different for Eastern Asia which was characterized by a peak of ALS incidence at 2.20/100,000 PYFU around 75 years of age. This study confirms the consistency of the age-specific ALS incidence pattern within different subcontinents. Age-specific incidence appears lower in Eastern Asia as compared to Europe and North America.

Variation in worldwide incidence of amyotrophic lateral sclerosis: a meta-analysis.

Background: To assess the worldwide variation of amyotrophic lateral sclerosis (ALS) incidence, we performed a systematic review and meta-analysis of population-based data published to date. Methods: We reviewed Medline and Embase up to June 2015 and included all population-based studies of newly diagnosed ALS cases, using multiple sources for case ascertainment. ALS crude and standardized incidence (on age and sex using the US 2010 population) were calculated. Random effect meta-analysis and meta-regression were performed using the subcontinent as the main study level covariate. Sources of heterogeneity related to the characteristics of the study population and the study methodology were investigated. Results: Among 3216 records, 44 studies were selected, covering 45 geographical areas in 11 sub-continents. A total of 13 146 ALS cases and 825 million person-years of follow-up (PYFU) were co-nsidered. The overall pooled worldwide crude ALS incidence was at 1.75 (1.55-1.96)/100 000 PYFU; 1.68 (1.50-1.85)/100 000 PYFU after standardization. Heterogeneity was identified in ALS standardized incidence between North Europe [1.89 (1.46-2.32)/100 000 PYFU] and East Asia [0.83 (0.42-1.24)/100 000 PYFU, China and Japan P = 0.001] or South Asia [0.73 (0.58-0.89)/100 000/PYFU Iran, P = 0.02]. Conversely, homogeneous rates have been reported in populations from Europe, North America and New Zealand [pooled ALS standardized incidence of 1.81 (1.66-1.97)/100 000 PYFU for those areas]. Conclusion: This review confirms a heterogeneous distribution worldwide of ALS, and sets the scene to sustain a collaborative study involving a wide international consortium to investigate the link between ancestry, environment and ALS incidence.

Strong evidence of sexual dimorphic effect of adiposity excess on insulin sensitivity.

AIMS: Our aims were to investigate in several large samples, with a wide range of adiposity, whether: (1) the effect of BMI on insulin sensitivity is different between sexes; (2) also waist circumference plays a sex-specific role on insulin sensitivity; and (3) serum adiponectin and resistin are mediators of such sex-dimorphic effect. METHODS: Samples used were: Gargano study 1 (GS1), GS2 and Catania study (CS) comprising 3274 individuals. Adiponectin and resistin were measured by ELISA. Associations between variables were tested by linear models. RESULTS: In all samples, relationship between BMI and HOMAIR was steeper in males than in females (BMI-by-sex interaction p = 0.04-0.0007). No interaction was observed on serum adiponectin and resistin (p = 0.40-059), which are therefore unlikely to mediate the sex-dimorphic effect of BMI on insulin resistance. Relationship between waist circumference and HOMAIR was similar between sexes in GS1 and GS2 but not in CS (waist-by-sex interaction p = 0.01), comprising much heavier individuals. This suggests that a sex-dimorphic effect of abdominal adiposity on insulin resistance is observable only in the context of high BMI. CONCLUSIONS: Our findings represent a proof of concept that BMI and insulin sensitivity are associated in a sex-specific manner. This may explain why females are protected from diabetes and cardiovascular disease, compared to males of similar BMI.

Cortical abnormalities in patients with migraine: a surface-based analysis.

PURPOSE: To explore the patterns of cortical thickness and cortical surface area abnormalities in patients with migraine (with the expectation of seeing reduced cortical thickness and surface area in regions subserving nociception and increased cortical thickness and surface area in regions involved in migraine pathogenesis) and to assess their correlation with clinical and radiologic manifestations of the disease. MATERIALS AND METHODS: Approval of the local ethical committee was obtained, as well as written informed consent from each participant. T2-weighted and three-dimensional T1-weighted magnetic resonance images of the brain were acquired in 63 migraineurs and 18 matched healthy control subjects. Cortical thickness and cortical surface area were estimated. By using a general linear model approach, a vertex-by-vertex statistical analysis (P < .01) was used to assess between-group comparisons (migraineurs vs control subjects, the aura effect, the effect of white matter hyperintensities [WMHs]) and the correlations between cortical thickness and surface area measurements and patients' clinical and radiologic characteristics. RESULTS: Compared with control subjects, patients with migraine showed reduced cortical thickness and surface area in regions subserving pain processing (P < .01). These two metrics were increased in regions involved in executive functions and visual motion processing (P < .01). The anatomic overlap of cortical thickness and cortical surface area abnormalities was only minimal, with cortical surface area abnormalities being more pronounced and more widely distributed than cortical thickness abnormalities. Cortical thickness and surface area abnormalities were related to aura and WMHs (P < .01) but not to disease duration and attack frequency. CONCLUSION: Cortical abnormalities occur in migraineurs and may represent the results of a balance between an intrinsic predisposition, as suggested by cortical surface area abnormalities, and disease-related processes, as indicated by cortical thickness abnormalities.