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This study compared the outcomes of cataract surgery with intraocular lens (IOL) implantation in patients with juvenile idiopathic arthritis (JIA)-associated chronic anterior uveitis treated with antimetabolite drugs and systemic corticosteroids (Non-Biological Group) versus patients treated with antimetabolites and biological drugs (Biological Group). A cohort of patients with cataract in JIA-associated uveitis undergoing phacoemulsification with IOL implantation was retrospectively evaluated. The main outcome was a change in corrected distance visual acuity (CDVA) in the two groups. Ocular and systemic complications were also recorded. The data were collected preoperatively and at 1, 12, and 48 months after surgery. Thirty-two eyes of 24 children were included: 10 eyes in the Non-Biological Group and 22 eyes in the Biological Group. The mean CDVA improved from 1.19 ± 0.72 logMAR preoperatively to 0.98 ± 0.97 logMAR at 48 months ( p = 0.45) in the Non-Biological Group and from 1.55 ± 0.91 logMAR preoperatively to 0.57 ± 0.83 logMAR at 48 months ( p = 0.001) in the Biological Group. The postoperative complications, including synechiae, cyclitic membrane, IOL explantation, glaucoma, and macular edema, were not statistically different between the two groups. An immunosuppressive treatment with biological drugs can improve the visual outcome after cataract surgery in patients with JIA-associated uveitis, but it does not significantly reduce postoperative ocular complications.

Objective: To investigate the association between specimen length and number of sections evaluated and the diagnostic yield of temporal artery biopsy (TAB) for giant cell arteritis (GCA)., Methods: A pathologist reviewed all TABs performed for suspected GCA between January 1991 and December 2012. The blocks of all the inadequate and negative biopsy specimens were recut, and further slides at deeper levels were stained with hematoxylin and eosin in order to avoid missing inflammatory changes., Results: In total, findings from 662 TABs were included in the study (71% female; mean age 73.2 years). A total of 427 TAB specimens (65%) were classified as negative, and 235 (35%) were classified as positive for GCA. Compared to those with negative TAB results, patients with positive TAB results were older and more frequently female. There was no difference in postfixation TAB specimen length between TAB specimens negative and positive for GCA (mean 6.5 mm versus 6.9 mm; P = 0.068). Cuts of additional biopsy sections revealed inflammation at deeper levels in 26 of 408 TAB specimens (6.4%) originally reported as uninflamed. The inflamed section was the second in 14 TAB specimens, the third in 9 specimens, and the fourth in 3 specimens. Piecewise logistic regression identified 5 mm as the TAB specimen length change point for diagnostic sensitivity. Compared to a TAB specimen length of <5 mm, the age- and sex-adjusted odds ratio for positive TAB results in samples ≥5 mm long was 1.5 (95% confidence interval 1.0-2.0), P = 0.032., Conclusion: A postfixation TAB specimen length of at least 5 mm should be sufficient to make a histologic diagnosis of GCA. In order not to miss inflammatory changes, at least 3 further sections at deeper levels should be evaluated in all negative TAB specimens., (© 2020, American College of Rheumatology.)

Objectives: To identify predictors of clinical improvement and intubation/death in tocilizumab-treated severe COVID19, focusing on IL6 and CRP longitudinal monitoring., Methods: 173 consecutive patients with severe COVID-19 pneumonia receiving tocilizumab in Reggio Emilia province Hospitals between 11 March and 3 June 2020 were enrolled in a prospective cohort study. Clinical improvement was defined as status improvement on a six-category ordinal scale or discharge from the hospital, whichever came first. A composite outcome of intubation/death was also evaluated. CRP and IL-6 levels were determined before TCZ administration (T0) and after 3 (T3), and 7 (T7) days., Results: At multivariate analysis T0 and T3 CRP levels were negatively associated with clinical improvement (OR 0.13, CI 0.03-0.55 and OR 0.11, CI 0.0-0.46) (p=0.006 and p=0.003) and positively associated with intubation/death (OR 17.66, CI 2.47-126.14 and OR 5.34, CI: 1.49-19.12) (p=0.01 and p=0.004). No significant associations with IL-6 values were observed. General linear model analyses for repeated measures showed significantly different trends for CRP from day 3 to day 7 between patients who improved and those who did not, and between patients who were intubated or died and those who were not (p<0.0001 for both). ROC analysis identified a baseline CRP level of 15.8 mg/dl as the best cut-off to predict intubation/death (AUC = 0.711, sensitivity = 0.67, specificity = 0.71)., Conclusions: CRP serial measurements in the first week of TCZ therapy are useful in identifying patients developing poor outcomes.

Aims: To build a tool to assess the management of inpatients with diabetes mellitus and to investigate its relationship, if any, with clinical outcomes., Materials and Methods: A total of 678 patients from different settings, Internal Medicine (IMU, n = 255), General Surgery (GSU, n = 230) and Intensive Care (ICU, n = 193) Units, were enrolled. A work-flow of clinical care of diabetes was created according to guidelines. The workflow was divided into five different domains: (a) initial assessment; (b) glucose monitoring; (c) medical therapy; (d) consultancies; (e) discharge. Each domain was assessed by a performance score (PS), computed as the sum of the scores achieved in a set of indicators of clinical appropriateness, management and patient empowerment. Appropriate glucose goals were included as intermediate phenotypes. Clinical outcomes included: hypoglycaemia, survival rate and clinical conditions at discharge., Results: The total PS and those of initial assessment and glucose monitoring were significantly lower in GSU with respect to IMU and ICU (P < .0001). The glucose monitoring PS was associated with lower risk of hypoglycaemia (OR = 0.55; P < .0001), whereas both the PSs of glucose monitoring and medical therapy resulted associated with higher in-hospital survival only in the IMU ward (OR = 6.67 P = .001 and OR = 2.38 P = .03, respectively). Instrumental variable analysis with the aid of PS of glucose monitoring showed that hypoglycaemia may play a causal role in in-hospital mortality (P = .04)., Conclusions: The quality of in-hospital care of diabetes may affect patient outcomes, including glucose control and the risk of hypoglycaemia, and through the latter it may influence the risk of in-hospital mortality., (© 2020 John Wiley & Sons Ltd.)

Objective: To evaluate characteristics and predictors of relapses and long-term remission in an Italian cohort of patients with large-vessel (LV) giant cell arteritis (GCA)., Methods: We evaluated 87 consecutive patients with LV-GCA followed up at the Rheumatology Unit of Reggio Emilia Hospital (Italy) for at least 2 years. Patients with relapses and long-term remission were compared to those without. A group of 34 patients with biopsy proven GCA without LV vasculitis (LVV) at diagnosis was considered for comparison., Patients: 37 patients (42.5%) experienced one or more relapses. Nineteen (37.2%) of the 51 relapses were experienced during the first year after diagnosis. The majority of relapses occurred with doses of prednisone (PDN) ≤ 10 mg/day (74.5%). Polymyalgia rheumatica (PMR) (41.2%) and worsening at imaging of LVV (39.2%) were the most frequently observed relapsing manifestations. The total cumulative prednisone dose was significantly higher (p < 0.0001) and the total duration of PDN treatment longer (p < 0.0001) in relapsing patients compared to those without relapses. Relapsing patients had at diagnosis more frequently fever ≥ 38°C (p = 0.03) and visual manifestations (p = 0.03), and less frequently long-term remission (p = 0.002). In the multivariate model fever ≥ 38°C (HR 2.30, 95%CI:1.11-4.78) and total cumulative PDN dose (HR 1.18, 95%CI: 1.08-1.30) were significantly associated with an increased risk of relapses, while aortic arch involvement at imaging at diagnosis (HR 0.26, 95%CI: 0.11-0.59) and long-term remission (HR 0.27, 95%CI: 0.11-0.65) with a reduced risk. 35/84 patients (41.6%) experienced long-term remission. PMR and disease relapses were less frequently observed (p = 0.04 and p = 0.002, respectively), and the total cumulative prednisone dose was lower (p < 0.001) in patients with long-term remission compared to those without. In the multivariate model the presence of relapses (HR 0.21, 95%CI: 0.07-0.62) and the total cumulative PDN dose (HR 0.85, 95%CI: 0.77-0.95) were significantly negatively associated with long-term remission., Conclusion: In our cohort of patients with LV GCA we identified predictors of a relapsing course and long-term remission, which were observed in around half of the patients., Competing Interests: Declaration of Competing Interests None., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: Most thyroid cancer are incidentally diagnosed. However, little is known on the different modalities of incidental diagnosis in adult versus older patients., Methods: We retrospectively analyzed data from 440 patients consecutively diagnosed with differentiated thyroid cancer (DTC) in a single institution. Modalities of diagnosis were categorized as follows: (A) clinically diagnosed, nonincidental cases; (B) incidental during carotid power-duplex (CPD); (C) incidental during neck imaging other than carotid power-duplex; (D) incidental during imaging workup of thyroid dysfunction or at histological examination after thyroidectomy for benign lesions. Demographics, histology and follow-up were compared between adult (<65 years) and older (≥65 years) patients according to the different modalities of diagnosis., Results: A total of 363 and 67 cases were recorded in adult and older patients, respectively with incidental proportions of 79% and 85%, respectively. A P < 0.001 significant difference in the modality of diagnosis was found between adult and older subjects, the latter presenting with a higher prevalence of Group B. In the nonincidental group, papillary histotype, larger size, and extrathyroidal invasion were more frequently observed in older subjects. Disease-free survival was comparable between adult and older subjects in the incidental cases, whereas it was reduced, though not significantly, in older subjects., Conclusion: Incidental cases of DTC are more frequently diagnosed in the old subjects and are mainly due to CPD. Disease-free survival is comparable between adult and older subjects in both incidental and nonincidental cases, although it may be slightly reduced in nonincidentally diagnosed older patients.

The extract of the seeds from Indian celery, Apium greaveolens (CSE), tested in experimental animals (rodents), and in humans affected by chronic osteoarthritic diseases, exhibits anti-inflammatory effects that can be compared, to some degree, to those of non-steroid anti-inflammatory drugs (NSAID). In view of a potential use of CSE in the equine species, it was tested on horses affected by chronic articular pathologies. The trial was performed on 20 horses divided into three different groups, orally treated with 0 (controls), 7.0 or 30 g of CSE BID. Basic orthopedic examinations were conducted, vital signs were observed, and blood samples collected. Improvement was observed at the highest dosage tested (30 g of CSE BID), as reflected in the score values of three clinical parameters, (i) amplitude and (ii) sensitivity to passive flexion and (iii) flexion test. Since the improvement of these parameters can be correlated with a lower perception of the pain, the present data suggest that the CSE treatment can have an analgesic effect in horses affected by chronic osteoarthritic diseases., Competing Interests: The authors declare no conflict of interest.

Objective: The purpose of the ULISSE study was to evaluate the prevalence of clinical and ultrasonographic (US) entheseal involvement in patients with psoriatic arthritis (PsA), psoriasis, and fibromyalgia syndrome (FMS)., Methods: In this cross-sectional multicenter study, patients with PsA and psoriasis (not taking systemic therapy) and FMS underwent a clinical evaluation of the entheses, and a B-mode and power Doppler examination of 6 pairs of entheses., Results: The study analyzed 140 patients with PsA, 51 with psoriasis, and 51 with FMS. Clinical and US examinations were performed in 1960 and 1680 entheses in the PsA group, and 714 and 612 entheses both in the psoriasis group and in the FMS group. In both per-patient and per-enthesis evaluation, the frequency of entheseal tenderness was higher in patients with FMS (92% of the patients and 46% of the entheses, compared with 66%/23% in the PsA group and 59%/18% in the psoriasis group). With US examination, signs of entheseal involvement were more frequent in both the per-patient and per-enthesis evaluation in PsA and psoriasis (about 90% of patients in both the PsA and psoriasis groups and 75% of patients in the FMS group had at least 1 site affected, and 54%, 41%, and 27% of the pairs of entheses in, respectively, PsA, psoriasis, and FMS patients showed at least 1 enthesis involved)., Conclusion: The ULISSE study indicated that enthesitis is a common feature in patients with PsA, those with psoriasis, and in those with FMS if only clinical examination is used. US entheseal assessment showed findings more consistent with the 3 disorders.

Objective: To evaluate aortic diameter and predictors of aortic dilatation using 18 FDG-PET/CT in a longitudinally followed cohort of patients with large vessel vasculitis (LVV) compared with controls., Methods: All consecutive patients with LVV who underwent at least 2 PET/CT scans between January 2008 and May 2015 were included. The first and last PET/CT study was evaluated by a radiologist and a nuclear medicine physician. Diameter and FDG uptake of the aorta was measured at 4 different levels: ascending, descending thoracic, suprarenal and infrarenal abdominal aorta. Twenty-nine age- and sex-matched patients with lymphoma who underwent at least 2 PET/CT scans in the same time interval were selected as controls., Results: 93 patients with LVV were included in the study. In the time interval between first and last PET/CT study (median time 31 months), the diameter of the ascending, descending thoracic and suprarenal abdominal aorta significantly increased in LVV patients but not in controls. At last PET/CT, patients with LVV compared with controls had higher diameter of ascending [35.41 (5.54) vs 32.97 (4.11) mm, p = 0.029], descending thoracic [28.42 (4.82) vs 25.72 (3.55) mm, p = 0.007] and suprarenal abdominal aorta, mean [25.34 (7.01) vs 22.16 (3.26) mm, p = 0.005] and more frequently had aortic dilatation [19% vs 3%, p = 0.023]. Significant predictors of aortic dilatation were male sex [OR 7.27, p = 0.001] and, only for GCA, hypertension [OR 6.30, p = 0.031]. Finally, GCA patients with aortic FDG uptake grade 3 at first PET/CT, compared to those with aortic FDG uptake ≤2, had significantly higher aortic diameter., Conclusions: Patients with LVV are at increased risk of aortic dilatation compared with age- and sex-matched controls. Significant predictors of aortic dilatation are male sex and, only for GCA, hypertension. GCA patients with aortic FDG uptake grade 3 are at increased risk of aortic dilatation., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objectives: We investigated the clinical, electrocardiographic, and echocardiographic determinants of the cardiac status in nonagenarian patients., Methods: We consecutively examined 654 Caucasian patients (232 males and 422 females) aged ≥90 years. All patients underwent clinical examination, ECG, and transthoracic echocardiography., Results: Their average age was 92.5 ± 2.5 years. Patients were predominately female of older age (p < 0.0001 and p = 0.02, respectively). A history of cardiovascular disease was present in 78.4% of the participants. One third of the patients was hospitalized for cardiovascular causes, with females being twice as many (p < 0.0001). Females showed higher levels of serum cholesterol, triglycerides, and glycemia (p < 0.0001, p< 0.0001, and p = 0.04 respectively). Sinus rhythm was detected in 65%, and atrial fibrillation in 31% of the overall population. Heart rate, PR and corrected QT (QTc) intervals, right bundle branch block (RBBB) and RBBB associated with left anterior fascicular block (LAFB) were higher in males (p < 0.0001, p = 0.036, p = 0.009, p = 0.001, and p = 0.004, respectively). Aortic root dimension, left ventricular (LV) mass index, and indexed LV systolic-diastolic volumes were higher in males (p < 0.001, p < 0.0001, p < 0.001, and p < 0.0001, respectively). Women showed fewer LV segmental kinetic disorders (p = 0009) and higher LV ejection fraction (LVEF; p< 0.0001). Hyperuricemia was positively associated with a history of cardiovascular disease (r = 0.15), glycemia (r = 19), creatininemia (r = 0.50), uremia (r = 0.51), triglycerides (r = 0.19), PR interval (r = 0.14), and left bundle branch block (r = 0.11), and inversely associated with sinus rhythm (r = -0.14) and LVEF (r = -0.17). Diabetes was positively correlated with PR and QTc intervals (r = 0.14 and r = 0.10, respectively), and RBBB with LFAB (r = 0.10), and inversely correlated with LVEF (r = -0.10)., Conclusions: We found a remarkable presence of cardiovascular risk factors, ECG, and structural alterations in hospitalized nonagenarians, which presents more commonly in males., (© 2019 S. Karger AG, Basel.)

Purpose: To assess the usefulness of spectral-domain optical coherence tomography (SD-OCT) peripapillary retinal nerve fiber layer (RNFL) thickness measurement in discriminating early phase optic disc edema (ODE) from pseudoedema (PODE)., Methods: Hospital-based, multicenter, cross-sectional study involving external patients referred for recent identification of "presumed ODE". Patients underwent SD-OCT optic nerve head (ONH) RNFL thickness measurement at their first evaluation. In 155 of these, the causative etiology was subsequently ascertained and the respective eyes (one per patient) were assigned to the ODE (95 eyes) or PODE (60 eyes) group. Admission SD-OCT data were retrieved and used for the analysis. ROC curve analysis was used to calculate specificity, sensitivity and predictive value (PV) of the RNFL values., Results: The PODE group was significantly younger than the ODE group (p = 0.007). The average and any single-quadrant RNFL thickness was significantly higher in the ODE group compared with the PODE and control groups. The average and the inferior quadrant thicknesses tested the most powerful parameters to differentiate ODE from PODE. A cutoff value of ≥ 110 μm for the average area, or of ≥ 150 μm for the inferior quadrant was associated with maximal sensitivity and specificity with positive PV greater than 80%., Conclusions: The SD-OCT evaluation of the peripapillary RNFL achieved good specificity, sensitivity and positive PV in discriminating between ODE and PODE. Despite the correct differential diagnosis between these categories still relies on a careful medical history taking and other ancillary testing, we proved the usefulness of SD-OCT RNFL measurement in supporting the diagnostic process., Competing Interests: The authors have declared that no competing interests exist.

Objectives: To compare patterns of vascular involvement using 18F-fluorodeoxyglucose-positron emission tomography computed tomography (FDG PET/CT) in patients with giant cell arteritis (GCA) and Takayasu's arteritis (TAK)., Methods: A total of 130 consecutive 18F-FDG PET/CT scans performed during the disease course for evaluating disease activity in 15 GCA and 13 TAK patients were retrospectively examined by two nuclear physicians blinded to clinical data. Standardised uptake values (SUVmax) in 14 vascular districts including all the aortic segments and the main tributaries were measured. The average SUVmax value for each vascular district was also calculated. Principal component analysis (PCA) and agglomerative hierarchical cluster analysis (CA) were used to explore distribution patterns of vascular FDG uptake., Results: The aortic segments showed the highest SUV max values among the different districts in both GCA and TAK. SUV max values measured in the different districts were significantly higher in GCA compared to TAK, except for the axillary arteries. Regarding thoracic and abdominal aorta, ascending aorta and aortic arch had the highest correlation in both vasculitis (p<0.0001). CA confirmed that carotid, axillary, subclavian, iliac and femoral arteries clustered with their contralateral counterpart in both vasculitis. The 3 components of thoracic aorta clustered with abdominal aorta in TAK, while aortic arch clustered only with ascending aorta, and descending and abdominal aorta grouped together with iliac and femoral arteries in GCA. PCA analysis identified 3 different components for TAK and GCA explaining 72% and 71% of the total variance respectively in these two vasculitis. Confirming CA, a component including the entire aortic district was identified in TAK, but not in GCA. Similar results in PCA using averaged data were observed., Conclusions: Strong similarities, but also a subtle skewing in terms of distribution patterns of arterial involvement assessed by SUVmax values were observed between GCA and TAK.

Purpose: Describe patient characteristics, treatment, and vision outcomes of Listeria monocytogenes endophthalmitis, an exceedingly rare form of listeriosis., Methods: L. monocytogenes endophthalmitis cases in human adults, located through Medline (32) and from disease surveillance centers (11). L. monocytogenes conjunctivitis and keratitis were excluded., Results: Most cases occurred in 2000-2015 (22/43), and almost all in Europe or North America (40/43). Patients were a median 61 years, 57% male (24/42) and half were immunosuppressed. Median days from entering care to diagnosis was 8 (IQR = 5-17). Only four were exogenous infections. L. monocytogenes was identified in 31/35 of anterior eye fluid samples (89%). Antibiotic regimens varied markedly (mostly ≥3 drugs). At diagnosis, most were blind in the affected eye (85%, 28/33), only a third regained normal vision (12/36). Older patients had poorer outcomes., Conclusions: Cases increased over time. Diagnostic delays were common and visual impairment often refractory to treatment, especially in older adults. The condition's rarity and variation in treatment makes it difficult to identify optimum therapy.

Purpose: To assess the ability of swept-source (SS) optical coherence tomography (OCT) of the anterior segment (AS) to measure anterior chamber (AC) inflammation (both flare and cells) objectively. To compare OCT-derived inflammatory indices with standard techniques., Design: Prospective evaluation of a diagnostic test., Participants: Patients diagnosed with anterior uveitis (active or inactive) and controls., Methods: Participants underwent an AC inflammation evaluation including: clinical cell and flare grading and laser flare photometry (LFP). Uveitis patients were divided into active or inactive uveitis status according to clinical grading. Anterior segment SS-OCT scans were obtained for each participant. Tomographic images were analyzed to count the AC cells, and to calculate to absolute measurements of aqueous signal intensity. The absolute values were compared with the signal measured by the scan outside the eye, generating an optical density ratio (aqueous-to-air relative intensity [ARI] index). Correlations between OCT-derived AC inflammatory indexes and LFP, clinical grading, participant category (active or inactive uveitis, control), age, gender, and central corneal thickness (CCT) were assessed., Main Outcome Measures: Correlation between OCT-derived AC inflammatory indexes (ARI index and AC cells on OCT) and standard clinical techniques (LFP, clinical cell grading)., Results: Two hundred thirty-seven eyes (70 active uveitis, 97 inactive uveitis, and 70 controls) were included. Anterior chamber cells count on OCT did not differ between inactive uveitis and controls, but was significantly higher in active uveitis compared to the other categories (both P < 0.0001). All groups had different LFP (all P < 0.0001). Active uveitis had significantly higher ARI index compared with inactive uveitis and controls (both P < 0.0001). Interobserver agreement (intraclass correlation coefficient) for ARI index was 0.78. The ARI index correlated positively with age (P = 0.043) and negatively with CCT (P = 0.006). The ARI index correlated with LFP in the active uveitis group (P < 0.0001), but not in the others. Anterior chamber cells on OCT increased among all cell clinical grades (P < 0.0001). The ARI index increased among all flare clinical grades (P < 0.005)., Conclusions: Anterior segment SS-OCT could be used for a comprehensive assessment of AC inflammation, providing objective measurements of inflammatory cells and aqueous flare., (Copyright © 2017 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

To evaluate the causes of the first referral to an endocrine visit of patients with thyroid cancer in a mildly iodine-deficient area and to correlate them with prognostic features. We studied 298 consecutive patients (64 M and 234 F) with thyroid cancer. Of these, 281 had differentiated thyroid cancer. The causes of referral were categorized as follows: (Group A) clinical evidence of a neck lump; (Group B) incidental imaging in subjects without known thyroid diseases; (Group C) incidental imaging during a workup of thyroid disorders. Also, in differentiated thyroid cancer cases, clinical, histomorphologic, and prognostic parameters were compared among the three different groups of referral causes. In both total thyroid cancer and differentiated thyroid cancer cohorts, Group A, B, and C accounted for about 25, 35, and 40 % of causes, respectively. Considering the differentiated thyroid cancer, in Group B, ultrasound accounted for 94 % of cases, with 73 % resulting from screening or serendipitous study. Within a median follow-up of 5.6 [IQR: 2.7-9.5] years, disease-free survival was significantly lower in patients of Group A (Log-Rank test p = 0.030 vs. the other groups of causes). However, at the Cox multivariate analysis only male sex (p = 0.002) and stage (p = 0.005), but not referral cause, resulted independent predictors of events. In patients without known thyroid disease, unjustified thyroid ultrasound represents the main cause of referral of thyroid cancer patients to the first endocrine visit. The fact that this is not related to the disease-free survival strengthens the concept of the uselessness of thyroid cancer screening.

Increased non high-density lipoprotein (HDL)/low-density lipoprotein (LDL) cholesterol levels are independent risk factors for cardiovascular (CV) mortality with no documented threshold. A new combination of nutraceuticals (berberine 200 mg, monacolin K 3 mg, chitosan 10 mg and coenzyme Q 10 mg) with additive lipid-lowering properties has become available. The aim of the study is to test the efficacy of the nutraceutical formulation (one daily) in lowering non-HDL cholesterol vs. placebo at 12 weeks in individuals with non-HDL-cholesterol levels ≥160 mg/dL. 39 subjects (age 52 ± 11 years; 54% females; body mass index 27 ± 4 kg/m²) were randomized (3:1) in a double blind phase II placebo-controlled study. At baseline, 4 and 12 weeks main clinical/biohumoral parameters, pro-inflammatory cytokines, (gut)-hormones, proprotein convertase subtilisin/kexin type 9 (PCSK9) levels and endothelial progenitor cell (EPC) number were assessed. Baseline characteristics were comparable in the two groups. The intervention significantly decreased non-HDL cholesterol (-30 ± 20 mg/dL; p = 0.012), LDL cholesterol (-31 ± 18 mg/dL, p = 0.011) and apolipoprotein (Apo) B (-14 ± 12 mg/dL, p = 0.030) levels compared to the placebo. Pro-inflammatory, hormonal, PCSK9 and EPC levels remained stable throughout the study in both groups. The intervention was well tolerated. Three adverse events occurred: Epstein Barr virus infection, duodenitis and asymptomatic but significant increase in creatine phosphokinase (following intense physical exercise) which required hospitalization. The tested nutraceutical formulation may represent a possible therapeutic strategy in dyslipidemic individuals in primary prevention., Competing Interests: Valentina Spigoni, Federica Fantuzzi, Eleonora Derlindati, Maria Maddalena Micheli, Monica Antonini, Monica Antonini, and Ivana Zavaroni have no disclosures. Alessandra Dei Cas is an invited speaker for Doc generic, Merck Sharp & Dohme, Astra Zeneca, Sanofi, Eli Lilly Ltd., and consultant to Eli Lilly Ltd. and Boeringher. Riccardo C. Bonadonna is a member of the following board/advisory panel: MSD, Eli Lilly Ltd., Amgen, Sanofi and invited speaker for Sanofi, MSD, Bristol-Myers Squibb, Eli Lilly Ltd, Astra Zeneca, Janssen. Andrea Fratter is the head of the Research and Innovation Technology Department in Labomar, the company that has developed and patented Coleosoma, the main technological matrix employed in the clinical test. Marzia Pellizzato is the head of the Nutraceutical Formulation Department in Labomar, the company that has developed and patented Coleosoma, the main technological matrix employed in the clinical test. The founding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.

Background: Fewer circulating endothelial progenitor cells (EPCs) and increased plasma (C-term) stromal cell-derived factor 1α (SDF-1α), a substrate of DPP-4, are biomarkers, and perhaps mediators, of cardiovascular risk and mortality. Short-term/acute treatment with DPP-4 inhibitors improve EPC bioavailability; however, long-term effects of DPP-4i on EPCs bioavailability/plasma (C-term) SDF-1α are unknown., Methods: Randomized (2:1) open-label trial to compare the effects of vildagliptin (V) (100 mg/day) vs glibenclamide (G) (2.5 mg bid to a maximal dose of 5 mg bid) on circulating EPC levels at 4 and 12 months of treatment in 64 patients with type 2 diabetes in metformin failure. At baseline, and after 4 and 12 months, main clinical/biohumoral parameters, inflammatory biomarkers, concomitant therapies, EPC number (CD34 + /CD133 + /KDR + /10 6 cytometric events) and plasma (C-term) SDF-1α (R&D system) were assessed., Results: Baseline characteristics were comparable in the two groups. V and G similarly and significantly (p < 0.0001) improved glucose control. At 12 months, V significantly increased EPC number (p < 0.05) and significantly reduced (C-term) SDF-1α plasma levels (p < 0.01) compared to G, with no differences in inflammatory biomarkers., Conclusions: V exerts a long-term favorable effect on EPC and (C-term) SDF-1α levels at glucose equipoise, thereby implying a putative beneficial effect on vascular integrity. Trial registration Clinical Trials number: NCT01822548; name: Effect of Vildagliptin vs. Glibenclamide on Circulating Endothelial Progenitor Cell Number Type 2 Diabetes. Registered 28 March, 2013.

Objective: To evaluate the frequency of long-term remission after glucocorticoids (GCs) suspension in an Italian cohort of patients with biopsy-proven GCA and to identify factors that may predict long-term remission., Methods: We evaluated 131 patients with biopsy-proven transmural GCA diagnosed and followed up at the Rheumatology Unit of Reggio Emilia Hospital (Italy) for whom sufficient information was available from the time of diagnosis until at least 18 months of follow-up. Long-term remission was defined as complete clinical remission without elevation of inflammatory markers for at least one year after the GC withdrawal., Results: 73 patients (56%) experienced long-term remission. Disease flares were less frequently observed in patients with long-term remission compared to those without (p = 0.002). The cumulative doses of prednisone at 1 year and for the entire followup duration were significantly lower (p < 0.0001 for both parameters) in patients with long-term remission; similarly, the duration of prednisone treatment was also significantly lower (p < 0.0001). The presence of PMR at diagnosis (HR 0.46) was significantly negatively associated with long-term remission (p = 0.008), while hemoglobin levels (HR 1.48) were significantly positively associated (p < 0.0001). Patients with long-term remission were able to reach 10 mg/day and 5 mg/day of prednisone sooner than the patients without (p = 0.02 and p < 0.0001, respectively)., Conclusion: In our cohort of GCA patients around half of the patients were able to attain long-term remission. Recognition of findings which predict disease course may aid decisions regarding therapy., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Aims: Individuals with type 2 diabetes show shorter leukocyte telomere length (LTL) compared to people without diabetes. Reduced LTL is associated with increased carotid intima-media thickness (IMT) in healthy subjects. The aim of the study is to assess whether LTL also correlates with IMT in patients with diabetes., Methods: In a cohort of 104 subjects with type 2 diabetes and atherogenic dyslipidemia, we assessed anthropometric, hemodynamic and metabolic parameters. Common carotid IMT was expressed as the maximum IMT. LTL was assessed by a specific real-time PCR reaction., Results: At univariate analysis, IMT values were positively correlated with age (p < 0.001), previous history of cardiovascular events (p < 0.005), fasting plasma glucose (p < 0.01), HbA1c (p < 0.05) and negatively correlated with LTL (p < 0.05). In a multivariate model, age (p < 0.001) and LTL (p < 0.05) were the only independent predictors of maximum IMT, with an adjusted R (2) of 0.22., Conclusions: LTL is an independent predictor of subclinical atherosclerosis pointing to a role of LTL as an early marker of vascular burden and cardiovascular disease also in type 2 diabetes.

This study evaluated the frequency, timing, and characteristics of flares in a large cohort of Italian patients with biopsy-proven giant cell arteritis (GCA) and to identify factors at diagnosis able to predict the occurrence of flares. We evaluated 157 patients with biopsy-proven transmural GCA diagnosed and followed at the Rheumatology Unit of Reggio Emilia Hospital (Italy) for whom sufficient information was available from the time of diagnosis until at least 4 years of follow-up. Fifty-seven patients (36.5%) experienced ≥1 flares. Fifty-one (46.4%) of the 110 total flares (88 relapses and 22 recurrences) were experienced during the first 2 years after diagnosis. The majority of relapses occurred with doses of prednisone ≤ 10 mg/day (82.9%), whereas only 3.4% of relapses occurred for doses ≥ 25 mg/day. Polymyalgia rheumatica (46.5%) and cranial symptoms (41.9%) were the most frequent manifestations at the time of the first relapse. Cumulative prednisone dose during the first year and total cumulative prednisone dose were significantly higher in flaring patients compared with those without flares (7.8 ± 2.4 vs 6.7 ± 2.4 g, P = 0.02; 15.5 ± 8.9 vs 10.0 ± 9.2 g, P = 0.0001, respectively). The total duration of prednisone treatment was longer in flaring patients (58 ± 44 vs 30 ± 30 months, P = 0.0001).Patients with disease flares had at diagnosis more frequently systemic manifestations (P = 0.02) and fever ≥ 38°C (P = 0.02), significantly lower hemoglobin levels (P = 0.05), more frequent presence at temporal artery biopsy (TAB) specimens of giant cells (P = 0.04) and intraluminal acute thrombosis (P = 0.007), and more moderate/severe arterial inflammation (P = 0.009) compared with those without flares. In the multivariate model fever ≥ 38 °C (hazard ratio 2.14; 95% confidence interval, 1.06-4.32, P = 0.03) and the severity of inflammatory infiltrate (moderate/severe versus mild) (hazard ratio 5.41; 95% confidence interval, 1.64-17.87, P = 0.006) were significantly associated with an increased risk of flares. In conclusion, a flaring course is common in GCA and it is associated with prolonged GC requirements. Fever at diagnosis and severity of inflammation at TAB appear to predict the development of disease flares.

Objective: To correlate histopathological features of positive temporal artery biopsy (TAB) and clinical manifestations of the disease in a large single-center population-based cohort of patients with biopsy-proven giant cell arteritis (GCA)., Methods: A pathologist with expertise in vasculitis and blinded to clinical data and final diagnosis reviewed all TABs performed for suspected GCA at our hospital between January 1986 and December 2013. Histopathologic features evaluated were: the severity of inflammation and intimal hyperplasia, both graded on a semiquantitative scale (mild = 1, moderate = 2, severe = 3), the presence of intraluminal acute thrombosis, calcifications, giant cells, fibrinoid necrosis and laminar necrosis., Results: 274 patients had a final diagnosis of biopsy-proven GCA and were included in the study. Cranial ischemic events (CIEs) were observed in 161 (58.8%), visual manifestations in 79 (28.8%) and permanent (partial or complete) visual loss in 51 (18.6%) patients. Predictors for the development of CIEs were older age (OR = 1.057, 95% CI 1.019-1.097, p = 0.003), lower ESR values (OR = 0.990, 95% CI 0.981-0.999, p = 0.026) as well as the presence of giant cells (OR = 1.848, 95% CI 1.045-3.269, p = 0.035) and laminar necrosis at TAB (OR = 2.334, 95% CI 1.187-4.587, p = 0.014). Predictors for the development of permanent visual loss were lower CRP values (OR = 0.906, 95% CI 0.827-0.992, p = 0.033) and the presence of calcifications at TAB (OR = 3.672, 95% CI 1.479-9.121, p = 0.005). Fibrinoid necrosis was not observed in any of the TABs evaluated., Conclusion: Pathological features of TAB may predict some manifestations of GCA. These findings may have implications for patients' management., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Considering the role of carcinoembryonic antigen (CEA) serum levels as potential useful predictive marker during chemotherapy treatment, we studied its applicability in advanced non-small cell lung cancer (NSCLC) patients treated with epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitors (TKIs). Our retrospective cohort consists of 79 patients (33 EGFR mutated and 46 EGFR wild type or unknown) affected by advanced NSCLC, for whom CEA serum values at the beginning of TKI therapy and after the first month of treatment were available, regardless of treatment line. Baseline CEA value, percentage of CEA reduction after 1 month, and percentage of patients with ≥20 % CEA decrease after 1 month (CEA response) were correlated with disease control rate (DCR), progression-free (PFS), and overall (OS) survival, according to EGFR mutational status. Median baseline CEA levels were significantly higher in EGFR mutated (40.9 ng/ml; interquartile range (IQR) 8.9-197.6) than in wild-type cases (6.2 ng/ml; IQR 2.8-12.8; p = 0.003). Both percentage reduction in CEA levels (-10.7 vs. +13.4 %) and percentage of cases with CEA response (42 vs. 20 %) were significantly higher in mutated vs. wild-type/unknown patients (p = 0.007 and p = 0.027, respectively). In wild-type/unknown patients, CEA response was significantly correlated with DCR (p = 0.001) and resulted as a significant predictor of PFS both in univariate (p = 0.002) and in multivariate analyses (hazard ratio (HR) 0.27; 95 % confidence interval (CI) 0.11-0.66; p = 0.004); only a trend was found for OS prediction (p = 0.082). In EGFR-mutated group, CEA reduction did not show any correlation either with PFS or OS. CEA response after 1 month of EGFR-TKI therapy could be a useful marker, worthy to further studies, as early predictor of treatment outcome in EGFR wild-type/unknown unselected NSCLC cases for which no molecular predictor is yet available.

Background: Macrophages are a heterogeneous cell population which in response to the cytokine milieu polarize in either classically activated macrophages (M1) or alternatively activated macrophages (M2). This plasticity makes macrophages essential in regulating inflammation, immune response and tissue remodeling and a novel therapeutic target in inflammatory diseases such as atherosclerosis. The aim of the study was to describe the transcriptomic profiles of differently polarized human macrophages to generate new hypotheses on the biological function of the different macrophage subtypes., Methods and Results: Polarization of circulating monocytes/macrophages of blood donors was induced in vitro by IFN-γ and LPS (M1), by IL-4 (M2a), and by IL-10 (M2c). Unstimulated cells (RM) served as time controls. Gene expression profile of M1, M2a, M2c and RM was assessed at 6, 12 and 24h after polarization with Whole Human Genome Agilent Microarray technique. When compared to RM, M1 significantly upregulated pathways involved in immunity and inflammation, whereas M2a did the opposite. Conversely, decreased and increased expression of mitochondrial metabolism, consistent with insulin resistant and insulin sensitive patterns, was seen in M1 and M2a, respectively. The time sequence in the expression of some pathways appeared to have some specific bearing on M1 function. Finally, canonical and non-canonical Wnt genes and gene groups, promoting inflammation and tissue remodeling, were upregulated in M2a compared to RM., Conclusion: Our data in in vitro polarized human macrophages: 1. confirm and extend known inflammatory and anti-inflammatory gene expression patterns; 2. demonstrate changes in mitochondrial metabolism associated to insulin resistance and insulin sensitivity in M1 and M2a, respectively; 3. highlight the potential relevance of gene expression timing in M1 function; 4. unveil enhanced expression of Wnt pathways in M2a suggesting a potential dual (pro-inflammatory and anti-inflammatory) role of M2a in inflammatory diseases.

Background: To characterise the polyspecific intraocular antibody synthesis in aqueous humor of patients with Fuchs uveitis and other types of non-infectious uveitis., Methods: Aqueous and serum samples collected from 24 patients with Fuchs uveitis, 21 patients with non-infectious uveitis, and 27 healthy subjects undergoing elective cataract surgery (control group) were analysed. In addition, vitreous samples, collected from seven uveitis patients (five Fuchs and two panuveitis) during retinal surgery, were examined. Specific immunoglobulin G antibodies against cytomegalovirus (CMV), rubella virus, herpes simplex virus (HSV), and varicella zoster virus (VZV) were investigated, and Goldmann-Witmer coefficients (GWCs) were calculated. Real-time PCR was performed to detect viral genome for HSV, VZV, and CMV, while nested PCR was conducted to detect rubella RNA., Results: None of the control samples tested positive for any of the viral antibodies investigated. Intraocular antibody production was found in eight samples of patients affected by Fuchs uveitis (6/8 positive for rubella virus and 2/8 positive for herpes virus). Among patients with non-infectious uveitis, three tested positive for intraocular antibody production (one RV, one HSV and one for VZV). PCR was positive for RV in two patients with Fuchs uveitis, in three patients with non-infectious uveitis (one for RV and two for HSV), and in three control subjects (one for CMV and one for HSV)., Conclusions: Our series confirmed the presence of specific viral antibodies, especially against rubella virus, in the subgroup of patients affected by Fuchs uveitis, suggesting that this virus may be responsible for this chronic inflammatory condition. Rubella virus is probably the main causative agent of Fuchs uveitis, but other viruses may also be involved in the pathogenesis of this disease.

Our purpose was to examine toxoplasmic serology in relation to episodes of suspected acute toxoplasmic retinochoroiditis and evaluate its use in the appraisal of patients. The mean values of enzymatic immunoassay (EIA) titers for toxoplasmic antibodies were retrospectively compared in patients with active and inactive toxoplasmosis and in a third group of uveitis cases not caused by toxoplasmosis. The proportion of cases under and above a predefined serology value above cut-off was compared in all groups. Between 1995 and 2010, 97 out of 1,276 new uveitis cases seen at the Centre for Ophthalmic Specialized Care (COS), Lausanne, Switzerland were diagnosed as toxoplasmic retinochoroiditis, of which 51 had documented serology available. The mean EIA values for immunoglobulin (Ig) G were 147.75 ± 259.4 IU/ml for patients with active disease, 18.93 ± 23.09 (p < 0.05) for patients with inactive toxoplasmosis and 18.35 ± 20.82 for controls (p < 0.017). The proportion of cases under the designated limit value were 2/51 (4%) in the active retinitinochoroiditis group, 14/27 (52%) (p < 0.05) in the control group, and 7/7 (100%) in the inactive toxoplasmic group (p < 0.001). Three out of 51 cases showed high IgM values in addition to IgG elevation and were primary infections. Toxoplasmosis serology, contrary to popular belief, is useful to confirm active toxoplasmic retinochoroiditis; it is easy to perform, cheap and supports clinical diagnosis in up to 96% of cases, not only by showing positivity but by also showing a significant elevation of titers. In atypical cases serology is not only useful but essential.

Purpose: To investigate potential associations of the ICAM-1 gene polymorphisms and Fuchs uveitis in a cohort of Italian patients., Methods: Seventy-one consecutive Italian patients affected by Fuchs uveitis were observed at the Ocular Immunology Unit, Arcispedale S. Maria Nuova (Reggio Emilia, Italy) from 2002 to 2008. Two hundred twenty-six healthy Italian blood donors from the same geographic area were selected as the control group. All Fuchs uveitis patients and control subjects were genotyped by polymerase chain reaction (PCR) and allele-specific oligonucleotide techniques for ICAM-1 polymorphisms at codon 241 (exon 4)., Results: The frequency of the ICAM-1 G/R 241 polymorphism was significantly higher in Fuchs uveitis than in the control subjects (16.9% vs. 5.8%; P=0.006, Pcorr=0.012; odds ratio, 3.3; 95% confidence interval, 1.4-7.7). No significant association between clinical features and ICAM-1 polymorphisms was found., Conclusions: This study demonstrates for the first time that the ICAM-1 G/R 241 polymorphism may represent a candidate gene for Fuchs uveitis susceptibility.

Background: Over the last decade ocular involvement due to tuberculosis has re-emerged. In non-endemic areas the low frequency of active tuberculosis is at the origin of an underestimation of the disease. The purpose of this study is to report a group of patients with presumed tuberculous uveitis and to analyse the pre-diagnostic course, the diagnostic delay and the evolution of ocular inflammation after diagnosis and anti-tuberculous treatment., Methods: Criteria for presumed tuberculous uveitis included the presence of a hyperpositive tuberculin skin test with compatible uveitis and the exclusion of other possible etiologies., Results: Thirty-five patients fulfilled the diagnostic criteria for presumed tuberculous uveitis and were included in the study. The diagnosis was performed at presentation in only seven patients, while the correct diagnosis was delayed in the other 30 patients. The mean diagnostic delay was 5.7 +/- 4 years. Anti-tuberculous therapy was given for a minimum of 6 to a maximum of 24 months. Post-diagnostic mean follow-up was 30.4 +/- 13.4 months. Anti-tuberculous therapy resulted in a highly significant increase in visual acuity, from 0.53 to 0.78 (P < 0.001), a highly significant decrease of recurrences, from 100 to 10% (P < 0.001), with only three recurrences observed during the follow-up, and a highly significant decrease in intra-ocular pressure, from 18.3 to 13.7 (P < 0.001)., Conclusions: Our study tends to confirm the existence of tuberculous uveitis and supports the validity of the proposed diagnostic criteria. Recognition of the correct diagnosis and specific therapy, even with substantial delay, avoids recurrences, improves visual acuity and intra-ocular inflammation and decreases intra-ocular pressure.

Background/aims: To determine the levels of cyclosporin A (CsA) in tears and the anterior segment of the eye following long-term oral intake for autoimmune diseases., Methods: Subjects taking oral CsA to treat relapsing autoimmune ocular inflammation were included in this study. All of the patients had been quiescent for at least 6 months. In patients scheduled for cataract extraction (group A), the CsA levels in the blood, aqueous humour and anterior capsule of the lens were determined. In subjects not requiring surgical intervention (group B), CsA was measured in tears and blood. The samples were analysed using turbulent flow chromatography coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS)., Results: There were 19 subjects in group A and 43 subjects in group B. CsA was detectable in all of the tear samples with a mean value of 22.4 +/- 20.2 ng/ml and there was a significant positive correlation between the CsA levels in tears and blood (P = 0.012). CsA was not detected in any of the surgical samples., Conclusion: LC-MS/MS proved very sensitive for detecting CsA in low-volume biological samples. CsA was present in human tears in proportion to the blood level after an average of 12 hours from the last oral intake.

Purpose: To evaluate selected functional and physical properties of 2 models of accommodative intraocular lenses (IOLs) compared with those of a standard monofocal IOL., Design: Prospective randomized comparative trial., Participants: Subjects were divided into 3 groups. In group 1, 30 eyes (19 subjects) received 1CU IOL implantation; in group 2, 29 eyes (19 subjects) received AT-45 IOL implantation; and in group 3, 21 eyes (21 subjects) were implanted with a monofocal IOL as a control., Intervention: Cataract surgery with implantation of the 1CU and AT-45 accommodative IOL models in the study groups, and the ACR6D monofocal IOL in the control group., Main Outcome Measures: Far and near distance visual parameters were assessed at 1, 6, and 12 months after surgery in the accommodative IOL groups, and at 1 and 12 months in the control group. Anterior segment anatomy was investigated by ultrasound biomicroscopy, with and without visual accommodative stimulation., Results: The accommodative IOL groups significantly differed from the controls in terms of lower near-distance refractive addition (NDRA) and better distance-corrected near visual acuity (DCNVA), with P<0.001 at 1 year. The anterior IOL displacement during accommodation (DeltaACD) was significantly larger in the study groups, and this correlated with DCNVA. Until 6 months, the DeltaACD correlated with the solicited sclerociliary process rotation only in the study groups., Conclusion: This 12-month study demonstrated that the accommodating IOLs achieved better clinical results than the monofocal IOL in terms of DCNVA and NDRA. These results support the hypothesis that accommodative IOLs proportionally react to ciliary body rotation, although this relationship became less evident at 12 months.

Purpose: To investigate possible associations between sequence changes in the galactokinase gene (GALK1) and age-related cataract in a European population., Methods: Persons without lens opacities and persons with clinically significant age-related cataract were selected from those participating in the Collaborative Italian-American Clinical Trial of Nutritional Supplements and Age-Related Cataract or from those attending the Section of Ophthalmology of the University of Parma for cataract surgery. Type and severity of the opacities were assessed by slit-lamp and retro-illumination lens photographs. Mutations in GALK1 were identified by PCR amplification of individual exons and flanking sequences and sequencing using fluorescent terminator technology in an ABI 377 Prism or 3100 automated DNA sequencer., Results: DNA samples were obtained from 115 individuals with clear lenses and from 185 individuals with cataract (106 with any nuclear, 88 with any cortical, and 25 with any posterior sub capsular cataract). 157 of the 185 patients with cataract (85%) were age-matched with a control within an age range of plus or minus 1 year. SNPs causing amino acid changes in the galactokinase protein were identified in exon 4; I184M, 1/115 control versus 0/185 cataractous individuals, p=0.38, exon 6; G274D, 0/115 control versus 1/185 cataractous individuals, p>0.99, and exon 7; V338A, 0/115 control versus 1/185 cataractous individuals, p>0.99. Thus, there were no significant differences in the distribution of sequence alterations resulting in amino acid changes between control and cataractous individuals. Eighty samples showed a C to T transition 43 bases into intron 7 (46 cataracts and 34 controls). Testing the distribution of the intron 7 findings showed Hardy-Weinberg equilibrium for both cases (p=0.73) and controls (p=0.51). There was no difference in C/T distribution between cases and controls (p=0.27)., Conclusions: In this northern Italian population age-related cataract does not appear to be associated with GALK1 alleles. Since this is due to a lack of sequence changes in both affected and control individuals, this study cannot rule out the possibility of an association in other populations.