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Hypoparathyroidism is the only endocrine deficiency for which hormone replacement therapy is not the standard of care. Although conventional treatments may control hypocalcaemia, other complications such as hyperphosphatemia, kidney stones, peripheral calcifications, and bone disease remain unmet needs. This meta-analysis (PROSPERO registration number CRD42019126881) aims to evaluate and compare the efficacy and safety of PTH

Background On December 2017 the Italian Parliament approved law n. 219/2017 “Provisions for informed consent and advance directives” regarding challenging legal and bioethical issues related to healthcare decisions and end-of-life choices. The law does not contain an explicit reference to Ethics Committees (ECs), but they could still play a role in implementing the law. Methods A questionnaire-based survey was performed among the ECs of the Italian Institute for Research and Care belonging to the Network of neuroscience and neurorehabilitation, with the aim of (1) knowing whether the ECs participated and, if so, how in the process of implementation of law n. 219/2017 in the referring institutes; (2) investigating the point of view of the ECs regarding their possible involvement in the process; (3) exploring the contribution ECs can provide to give effective implementation to the law principles and provisions. Results Seventeen ECs out of thirty took part in the survey; the characteristics of the responding and non-responding committees are similar, so the responding ECs can be regarded as representative of all ECs in the Network. Nine ECs did not discuss the law in anyway: the main reason for this is that the referring institutions (6) and the health care professionals (3) did not ask for an EC intervention. Nevertheless, the large majority of the ECs believe that their involvement in the implementation of the law as a whole is appropriate (8) or absolutely appropriate (6), while 3 of them are neutral. No EC believes that the involvement is inappropriate. The aspect of the law on which the 14 ECs converge in considering the EC involvement appropriate/absolutely appropriate is the one related to the health facilities obligation to guarantee the full and proper implementation of the principles of the law. Conclusions Our survey confirms that ECs believe they can play a role in the implementation of law n. 219/2017, although this does not entirely correspond to what the committees have actually done in reality. This role could be better exercised by ECs specifically established for clinical practice, which would have a composition, functioning and a mandate better suited to the purpose. This supports the call for a national regulation of ECs for clinical practice.

In healthy women, the cervicovaginal microbiota is characterized by the predominance of

Cyclic GMP–phosphodiesterase type 5 (PDE5) inhibition has been shown to counteract maladaptive cardiac changes triggered by diabetes in some but not all studies. We performed a single-center, 20-week, double-blind, randomized, placebo-controlled trial (NCT01803828) to assess sex differences in cardiac remodeling after PDE5 inhibition in patients with diabetic cardiomyopathy. A total of 122 men and women (45 to 80 years) with long-duration (>3 years) and well-controlled type 2 diabetes mellitus (T2DM; HbA1c < 86 mmol/mol) were selected according to echocardiographic signs of cardiac remodeling. Patients were randomly assigned (1:1) to placebo or oral tadalafil (20 mg, once daily). The primary outcome was to evaluate sex differences in cardiac torsion change. Secondary outcomes were changes in cardiovascular, metabolic, immune, and renal function. At 20 weeks, the treatment-by-sex interaction documented an improvement in cardiac torsion (−3.40°, −5.96; −0.84, P = 0.011) and fiber shortening (−1.19%, −2.24; −0.14, P = 0.027) in men but not women. The primary outcome could not be explained by differences in cGMP concentrations or tadalafil pharmacodynamics. In both sexes, tadalafil improved hsa-miR-199-5p expression, biomarkers of cardiovascular remodeling, albuminuria, renal artery resistive index, and circulating Klotho concentrations. Immune cell profiling revealed an improvement in low-grade chronic inflammation: Classic CD14 ++ CD16 − monocytes reduced, and Tie2 + monocytes increased. Nine patients (14.5%) had minor adverse reactions after tadalafil administration. Continuous PDE5 inhibition could offer a strategy to target cardiorenal complications of T2DM, with sex- and tissue-specific responses. Further studies are needed to confirm Klotho and hsa-miR-199-5p as markers for T2DM complications.

Objectives: Fatigue in multiple sclerosis (MS) is a frequent and invalidating symptom, which can be relieved by non-invasive neuromodulation, which presents only negligible side effects. A 5-day transcranial direct-current stimulation, 15 min per day, anodically targeting the somatosensory representation of the whole body against a larger occipital cathode was efficacious against MS fatigue (fatigue relief in multiple sclerosis, Faremus treatment). The present proof-of-concept study tested the working hypothesis that Faremus S1 neuromodulation modifies the homology of the dominant and non-dominant corticospinal (CST) circuit recruitment. Methods: CST homology was assessed via the Fréchet distance between the morphologies of motor potentials (MEPs) evoked by transcranial magnetic stimulation in the homologous left- and right-hand muscles of 10 fatigued MS patients before and after Faremus. Results: In the absence of any change in MEP features either as differences between the two body sides or as an effect of the treatment, Faremus changed in physiological direction the CST’s homology. Faremus effects on homology were more evident than recruitment changes within the dominant and non-dominant sides. Conclusions: The Faremus-related CST changes extend the relevance of the balance between hemispheric homologs to the homology between body sides. With this work, we contribute to the development of new network-sensitive measures that can provide new insights into the mechanisms of neuronal functional patterning underlying relevant symptoms.

Introduction: The short forms of MacArthur-Bates Communicative Development Inventories (MB-CDI) are widely used for assessing communicative and linguistic development in infants and toddlers. Italian norms for the Words and Gestures (WG) and Words and Sentences (WS) short forms overlap between 18 and 24 months. Objective: To evaluate the agreement between these two forms. Methods: Parents of 104 children aged 18–24 months filled in both questionnaires. Results: The two questionnaires showed high agreement in measuring expressive vocabulary size and the percentile of lexical production and good agreement in identifying children at-risk for language delay (75% of the cases were accurately identified). Both short forms include a list of 100 words and a set of questions investigating potential risk factors for communication and language disorders. Ten children with an expressive vocabulary Conclusions: Short forms of the Italian MB-CDI can be used interchangeably for evaluating lexical production, but each one offers different quantitative and qualitative information on the behaviours related to language acquisition.

Objective Neurosurgery is the first-line treatment for acromegaly. Whether metabolic disorders are reversible after neurosurgery is still debated. The meta-analysis aimed to address the following questions: (i) Does neurosurgery affect glycolipid metabolism? (ii) Are these effects related to disease control or follow-up length? Design A meta-analysis and systematic review of the literature. Methods Three reviewers searched databases until August 2019 for prospective trials reporting glycometabolic outcomes after neurosurgery. Three other extracted outcomes, all assessed the risk of bias. Results Twenty studies were included. Neurosurgery significantly reduced fasting plasma glucose (FPG) (effect size (ES): −0.57 mmol/L, 95% CI: −0.82 to −0.31; P < 0.001), glucose load (ES: −1.10 mmol/L, 95% CI: −1.66 to −0.53; P < 0.001), glycosylated haemoglobin (HbA1c) (ES: −0.28%, 95% CI: −0.42 to −0.14; P < 0.001), fasting plasma insulin (FPI) (ES: −10.53 mU/L, 95% CI: −14.54 to −6.51; P < 0.001), homeostatic model assessment of insulin resistance (HOMA-IR) (ES: −1.98, 95% CI: −3.24 to −0.72; P = 0.002), triglycerides (TGDs) (ES: −0.28 mmol/L, 95% CI: −0.36 to −0.20; P < 0.001) and LDL-cholesterol (LDLC) (ES: −0.23 mmol/L, 95% CI: −0.45 to −0.02 mmol/L); P = 0.030) and increased HDL-cholesterol (HDLC) (ES: 0.21 mmol/L, 95% CI: 0.14 to 0.28; P < 0.001). Meta-regression analysis showed that follow-up length – not disease control – had a significant effect on FPG, with the greatest reduction in the shortest follow-up (beta = 0.012, s.e. = 0.003; P = 0.001). Conclusions Neurosurgery improves metabolism with a significant decrease in FPG, glucose load, HbA1c, FPI, HOMA-IR, TGDs, and LDLC and increase in HDLC. The effect on FPG seems to be more related to follow-up length than to disease control.

Background : : Ferric carboxymaltose (FCM) is a parenteral, dextran-free iron formulation designed to overcome the limitations of existing iron preparations. The main aim of this study was to retrospectively examine results obtained from a long period of FCM therapy in hemodialysis patients who have been previously treated with ferric gluconate (FX). Markers of iron metabolism, erythropoietin (EPO) doses, and effects on anemic status have been analysed. Methods : : The study was performed with a follow up period of 4 years, when patients were treated before with FX and then switched to FCM. A total of 25 patients were included in the study. Results : : FCM increased transferrin saturation (TSAT) levels by 11.9% (P < 0.001) with respect to FX. Events of TSAT less than 20% were reduced during FCM. The monthly dose of EPO was reduced in the FCM period (-6,404.1 international unit [IU]; 95% confidence interval, -10,643.5 IU; -2,164.6 IU; P = 0.003), as well as the erythropoietin resistance index (P = 0.004). During the period with FCM, ferritin levels were higher than during FX (P < 0.001), while transferrin was reduced (P = 0.001). Conclusion : : During FCM treatment, minor doses of EPO were administered if compared to those delivered during FX therapy. Stable and on target levels of hemoglobin were maintained with better control of anemia through high levels of ferritin and TSAT.

Objectives: The homology of hemispheric cortical areas plays a crucial role in brain functionality. Here, we extend this concept to the homology of the dominant and non-dominant hemi-bodies, investigating the relationship of the two corticospinal tracts (CSTs). The evoked responses provide an estimate of the number of in-phase recruitments via their amplitude as a suitable indicator of the neuronal projections’ integrity. An innovative concept derived from experience in the somatosensory system is that their morphology reflects the recruitment pattern of the whole circuit. Methods: CST homology was assessed via the Fréchet distance between the morphologies of motor-evoked potentials (MEPs) using a transcranial magnetic stimulation (TMS) in the homologous left- and right-hand first dorsal interosseous muscles of 40 healthy volunteers (HVs). We tested the working hypothesis that the inter-side Fréchet distance was higher than the two intra-side distances. Results: In addition to a clear confirmation of the working hypothesis (p < 0.0001 for both hemi-bodies) verified in all single subjects, we observed that the intra-side Fréchet distance was higher for the dominant than the non-dominant one. Interhemispheric morphology similarity increased with right-handedness prevalence (p = 0.004). Conclusions: The newly introduced measure of circuit recruitment patterning represents a potential benchmark for the evaluation of inter-lateral mechanisms expressing the relationship between homologous hemilateral structures subtending learning and suggests that variability in recruitment patterning physiologically increases in circuits expressing greater functionality.

Neural oscillations can be modulated by non-invasive brain stimulation techniques, including transcranial alternating current stimulation (tACS). However, direct evidence of tACS effects at the cortical level in humans is still limited. In a tACS-electroencephalography co-registration setup, we investigated the ability of tACS to modulate cortical somatosensory information processing as assessed by somatosensory-evoked potentials (SEPs). To better elucidate the neural substrates of possible tACS effects we also recorded peripheral and spinal SEPs components, high-frequency oscillations (HFOs), and long-latency reflexes (LLRs). Finally, we studied whether changes were limited to the stimulation period or persisted thereafter. SEPs, HFOs, and LLRs were recorded during tACS applied at individual mu and beta frequencies and at the theta frequency over the primary somatosensory cortex (S1). Sham-tACS was used as a control condition. In a separate experiment, we assessed the time course of mu-tACS effects by recording SEPs before (T0), during (T1), and 1 min (T2) and 10 min (T3) after stimulation. Mu-tACS increased the amplitude of the N20 component of SEPs compared to both sham and theta-tACS. No differences were found between sham, beta-, and theta-tACS conditions. Also, peripheral and spinal SEPs, P25, HFOs, and LLRs did not change during tACS. Finally, mu-tACS-induced modulation of N20 amplitude specifically occurred during stimulation (T1) and vanished afterwards (i.e., at T2 and T3). Our findings suggest that TACS applied at the individual mu frequency is able to modulate early somatosensory information processing at the S1 level and the effect is limited to the stimulation period.

People who inject drugs (PWID) constitute the largest reservoir of hepatitis C virus (HCV). Although effective medications are available and access to care is universal in Italy, the proportion of PWID receiving appropriate care remains low.To identify the major barriers for PWID to HCV treatment we surveyed a large sample of practitioners working in outpatient addiction centres (SerDs). The survey was conducted in two stages and involved 30.3% of SerDs operating in Italy. In the first, SerD physicians completed a questionnaire designed with a Delphi structure. In the second, SerD practitioners completed a targeted questionnaire to identify barriers to four SerD services in HCV management: screening, referral, treatment and harm reduction.The first-stage questionnaire, in which a Delphi and RAND-UCLA method was used, revealed a lack of agreement among the physicians about barriers to health care. The more detailed second-stage questionnaire indicated the barriers to delivering specific SerD services. As regarded the delivery of all four services, the major reasons for treating50% of patients were: physician and nurse understaffing, technical, economic and logistic issues. In contrast, the practitioners who responded that they follow protocol recommendations often deliver all four services to50% of patients.HCV treatment remains out of reach for many PWID attending a drug treatment centre in Italy. To meet the World Health Organisation (WHO) target, there is a need to increase economic, technical and staff support at treatment centres using the protocols and the universal health care already in place.

Purpose There is a lack of consensus on the most appropriate early diagnostic strategy, criteria for early access to treatment and follow-up approach for patients with COPD. Materials and methods A Delphi consensus project investigated the early management of COPD. We formulated two questionnaires for completion by pneumologists in Italy. Results A total of 207 specialists completed questionnaire 1 and 184 of them questionnaire 2, between November 2016 and October 2017. Early diagnosis of COPD was considered uncommon for 93.2% of the expert panel. Regardless of the definition of "early diagnosis" - a diagnosis made before the clinical manifestation of the disease for most responders (60.4%) - experts were confident of the positive effects of early disease management, which they consider is effective in modifying the natural history of the disease. Lack of awareness of the disease was considered the first limiting factor to early COPD management for 78% of respondents. The most effective steps to reduce functional decline were considered to be smoking cessation, followed by long-acting β2-agonist (LABA)/long-acting muscarinic antagonist (LAMA), LAMA, LABA, and finally inhaled corticosteroid/LABA (P

Several treatment options are available for chronic lymphocytic leukemia (CLL) and, for this reason, treatment choice can result challenging after introducing oral targeted agents. This study aims at comparing patients' and hematologists' preferences for attributes of CLL treatments. An online cross-sectional survey has been delivered to clinicians and patients affected by CLL in Italy. A discrete choice experiment has been conducted so to estimate each attribute's relative importance (RI) and assess the preference weight for each level of each attribute. An expert panel agreed on investigating the following attributes: progression-free survival (PFS) and measurable residual disease, route of administration/therapy duration and follow-up frequency, incidence of diarrhea (episodes/day), serious infections (grade 3 or 4), and atrial fibrillation. Overall, 746 patients and 109 clinicians accessed the survey, and 215 and 69, respectively, filled it in. The most important attributes were PFS (RI 30%) for hematologists and the risk of severe infections (RI 24%) for patients. Clinicians rated preference for maximum efficacy and lowest risk of severe infection very high (30%). Both patients and clinicians preferred oral administration while considering duration of therapy less relevant. The frequency of hospital appointments was negligible for patients, while clinicians preferred a quarterly frequency. Considering all attributes, diarrhea was weighted more by clinicians than by patients. Atrial fibrillation was not relevant for clinicians, while it was not negligible for patients. In conclusion, clinicians and patients favor an oral therapy, including continuous treatment, if associated with prolonged PFS, albeit with particular attention to the risk of serious infections.

In healthy women, the cervicovaginal microbiota is characterized by the predominance of Lactobacillus spp., whereas the overgrowth of anaerobic bacteria leads to dysbiosis, known to increase the risk of acquiring genital infections like Chlamydia trachomatis. In the last decade, a growing body of research has investigated the composition of the cervicovaginal microbiota associated with chlamydial infection via 16s rDNA sequencing, with contrasting results. A systematic review and a meta-analysis, performed on the alpha-diversity indices, were conducted to summarize the scientific evidence on the cervicovaginal microbiota composition in C. trachomatis infection. Databases PubMed, Scopus and Web of Science were searched with the following strategy: “Chlamydia trachomatis” AND “micro*”. The diversity indices considered for the meta-analysis were Operational Taxonomic Unit (OTU) number, Chao1, phylogenetic diversity whole tree, Shannon’s, Pielou’s and Simpson’s diversity indexes. The search yielded 425 abstracts for initial review, of which 16 met the inclusion criteria. The results suggested that the cervicovaginal microbiota in C. trachomatis-positive women was characterized by Lactobacillus iners dominance, or by a diverse mix of facultative or strict anaerobes. The meta-analysis, instead, did not show any difference in the microbial biodiversity between Chlamydia-positive and healthy women. Additional research is clearly required to deepen our knowledge on the interplay between the resident microflora and C. trachomatis in the genital microenvironment.

DSM-5 describe three forms of restrictive and selective eating: Anorexia Nervosa-Restrictive (AN-R), Anorexia Nervosa-Atypical (AN-A), and Avoidant/Restrictive Food Intake Disorder (ARFID). While AN is widely studied, the psychopathological differences among these three diseases are not clear. The aim of this study was to (i) compare the clinical features of AN-R, AN-A, and ARFID, in a clinical sample recruited from a specialized EDs program within a tertiary care children’s Hospital; (ii) identifying three specific symptom profiles, to better understand if restrictive ED share a common psychopathological basis. Data were collected retrospectively. Psychometric assessment included: the Children’s Depression Inventory (CDI), the Multidimensional Anxiety Scale for Children (MASC), the Child Behavior Checklist (CBCL), and the Eating Disorder Inventory-3 (EDI-3). A final sample of 346 children and adolescent patients were analyzed: AN-R was the most frequent subtype (55.8%), followed by ARFID (27.2%) and AN-A (17%). Patients with ARFID presented different features from AN-R and AN-A, characterized by lower weight and medical impairment, younger age at onset, and a frequent association with separation anxiety and ADHD symptoms. EDI-3 profiles showed specific different impairment for both AN groups compared to ARFID. However, no differences was detected for items: ‘Interpersonal Insecurity’, “Interoceptive Deficits”, “Emotional Dysregulation”, and “Maturity Fears”. Different ED profiles was found for the three groups, but they share the same general psychopathological vulnerability, which could be at the core of EDs in adolescence. III. Evidence obtained from case–control analytic studies.

Background: Cardiovascular disease is the leading cause of morbidity and mortality in type 2 diabetes (T2DM) patients. Cyclic GMP-phosphodiesterase type 5 (PDE5) inhibition was shown to counteract maladaptive cardiac changes triggered by diabetes in some studies. Our aim was to assess sex differences in cardiac remodeling after PDE5 inhibition in patients with diabetic cardiomyopathy (DCM). Methods: We performed a 20-week, double-blind, randomized, placebo-controlled trial. Men and women (45–80 years) with controlled T2DM and echocardiographic (ECG) signs of cardiac remodeling were randomly assigned (1:1) to placebo or tadalafil 20 mg once daily. The primary outcome was analyzing the sex-difference in cardiac torsion change, from baseline to 20 weeks. Secondary outcomes included changes in cardiovascular, metabolic, immune and renal function. Efficacy analyses included all patients who received at least one dose of treatment. Findings: Between May 2014 and July 2018, we screened 220 diabetic subjects; 122 met the inclusion criteria and were randomized to tadalafil (n=61) or placebo (n=61). At 20 weeks, the sex-by-treatment interaction documented an improvement in cardiac torsion [-3·40°(-5·96;-0·84, p =0·011)], paralleled by a consensual increase in fiber shortening, in men but not women. Biomarkers of cardiovascular remodeling , titin and hsa-miR-199-5p, improved accordingly. In both sexes, tadalafil reduced TGF-beta and improved albuminuria, renal artery’s resistive index, Klotho , and symmetric-di-methyl-arginine markers . Five months of 20 mg daily tadalafil in patients with DCM was proven safe. The most common adverse reactions were myalgia (9[14·5%]), gastric reflux (6[9·7%]), headache (4[6·4%]) and flushing (2[3·8%]); one SAE occurred in the placebo arm. Interpretation: Continuous PDE5 inhibition could represent a new treatment strategy to target cardiac and renal complications of T2DM, with a different tissue-specific response in men and women. Klotho and hsa-miR-199-5p appear as novel players linking renal disease to DCM progression. Trial Registration: NCT01803828. Funding Statement: Italian Ministry of University and Research, SIR RBSI141LY2. Declaration of Interests: Prof. Isidori reports personal fees from Takeda; non-financial support from Takeda and Ipsen; and grants from Shire and Pfizer outside the submitted work; Prof. Pozzilli reports research contracts and consulting from Eli Lilly, Sanofi, Merck, Merck Sharpt Dohme, Astra Zeneca, Medtronic, Abbott; Dr. Defeudis reports grants from Ibsa, personal fees from Abbott, grants from Novo Nordisk, grants from Kyowa Kirin , personal fees from Roche, outside the submitted work; Prof. Badagliacca reports personal fees from Bayer, personal fees from MSD, personal fees from Dompe, personal fees from GSK, personal fees from Ferrer, personal fees from United Therapeutics, personal fees from Galenica, personal fees from Janssen, outside the submitted work; all others have nothing to disclose. Ethics Approval Statement: The study was performed in the Policlinico Umberto I in Rome (Italy) and approved by the local ethical review board (3083/14), published on public registries (NCT01803828, EUDRACT 2014-000077-39), and conducted under the Declaration of Helsinki and good clinical practice.

Aims: Several drug classes are now available to achieve a satisfactory metabolic control in patients with type 2 diabetes (T2DM), but patients’ preferences may differ. Methods: In a discrete-choice experiment, we tested T2DM patients’ preferences for recent antidiabetic drugs, in the event that their treatment might require intensification. The following attributes were considered: (a) route of administration; (b) type of delivery; (c) timing; (d) risk of adverse events; (e) effects on body weight. Twenty-two possible scenarios were built, transferred into 192 paired choices and proposed to 491 cases naïve to injectable treatments and 171 treated by GLP-1 receptor agonists (GLP-1RAs). Analyses were performed by descriptive statistics and random effects logit regression model. Results: Preferences according to dosing frequency, risk of nausea and urinary tract infections (UTls) were similar across groups, age, sex and BMI. Administration route and delivery type accounted for 1/3 of relative importance; the risk of UTIs, nausea and dosing frequency for ≈ 20% each, and weight loss for only 6%. Two significant interactions emerged (p < 0.01): type of delivery × group, and weight change × BMI class. Irrespective of previous treatment, the three preferred choices were injectable, coupled with weekly dosing and a ready-to-use device (first two choices). In a regression model, being naïve or non-naïve changed the ranking of preferences (p < 0.001), and the order was systematically shifted towards injectable medications in non-naïve subjects. Conclusion: Easy-to-deliver, injectable treatment is preferred in T2DM, independently of treatment history, and previous experience with GLP-1RAs strengthens patients’ willingness to accept injectable drugs.

Context Somatostatin analogs (SSAs) effectively control growth hormone secretion in first- and second-line treatment of acromegaly. Their effect on glucose metabolism is still debated. Objective To address the following questions: (1) Do SSAs affect fasting plasma glucose (FPG), fasting plasma insulin, glycosylated hemoglobin (HbA1c), glucose load (glucose levels after 2-hour oral glucose tolerance test), homeostatic model assessment of insulin resistance (HOMA-I), homeostatic model assessment of pancreatic β-cell function (HOMA-β), triglycerides, weight, or body mass index? (2) Do lanreotide and octreotide affect metabolism differently? (3) Does their effect depend on disease control? Design We performed a meta-analysis of prospective interventional trials treating acromegaly with SSAs. Inclusion criteria: all studies reporting glycometabolic outcomes before and after SSAs with a minimum 6-month follow-up. Results The inclusion criteria were met by 47 studies treating 1297 subjects (631 females). SSA treatment effectively lowered fasting plasma insulin [effect size (ES), −6.67 mU/L; 95% confidence interval (CI), −8.38 to −4.95 mU/L; P < 0.001], HOMA-I (ES, −1.57; CI, −2.42 to −0.72; P < 0.001), HOMA-β (ES, −47.45; CI, −73.15 to −21.76; P < 0.001), and triglycerides (ES, −0.37 mmol/L; CI, −0.47 to −0.27 mmol/L; P < 0.001). SSAs worsened glucose levels after a 2-hour oral glucose tolerance test (ES, 0.59 mmol/L; CI, 0.05 to 1.13 mmol/L; P = 0.032), but not FPG. A mild but significant increase in HbA1c (ES, 0.12%; CI, 0.00% to 0.25%; P = 0.044) was found in subjects treated with octreotide. Conclusions SSA treatment in acromegaly patients, while improving disease control, reduces insulin levels, increases after-load glucose, and, ultimately, increases HbA1c levels without affecting FPG. The findings suggest that clinicians treating acromegaly with SSAs should consider targeting postprandial glucose.

Introduction Noonan syndrome (NS) is an autosomal dominant disorder characterized by short stature, skeletal and haematological/lymphatic defects, distinctive facies, cryptorchidism, and a wide spectrum of congenital heart defects. Recurrent features also include variable cognitive deficits and behavioural problems. Recent research has been focused on the assessment of prevalence, age of onset and characterization of psychiatric features in this disorder. Herein, we evaluated the prevalence of attention deficit and hyperactivity disorder (ADHD), anxiety and depressive symptoms and syndromes in a cohort of individuals with clinical and molecular diagnosis of NS. Methods The Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children Present and Lifetime version (K-SADS PL) has been used for the assessment of psychiatric disorders according to Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). Multidimensional Anxiety Scale for Children (MASC) and the Children's Depression Inventory (CDI) have been assessed for the evaluation of anxiety and depressive symptoms and syndromes, whereas Conners Teacher and Parent Rating Scales-long version (CRS-R) have been used to evaluate ADHD. Results The study included 27 individuals (67% males) with an average age of 10.4 years (range 6–18 years) receiving molecular diagnosis of NS or a clinically related condition, evaluated and treated at the Neuropsychiatric Unit of Children's Hospital Bambino Gesu and at the Center for Rare Diseases of Fondazione Policlinico Universitario Agostino Gemelli, in Rome. Twenty individuals showed mutations in PTPN11, five in SOS1 and two in SHOC2. The mean IQ was 94 (Standard Deviation = 17, min = 56, max = 130). Seventy percent of the individuals (n = 19; 95% Confidence Interval = 52–85%) showed ADHD features, with six individuals reaching DSM-IV-TR criteria for ADHD disorder, and thirteen showing subsyndromal traits. Symptoms or syndrome of anxiety were present in 37% of the cohort (n = 10; 95% Confidence Interval = 19–56%), with two individuals showing anxiety disorder and eight cases exhibiting subsyndromal traits. Conclusion Our results show individuals with NS do present a very high risk to develop psychiatric disorders or symptoms during paediatric age. Based on these findings, preschool assessment of inattentive, hyperactivity/impulsivity and anxiety/depressive symptoms is recommended in order to plan a personalized treatment for psychological/psychiatric issues in affected individuals. Dedicated prospective studies are required to confirm the present data and better characterize the psychopathological profile in NS.

Social and occupational impairments are present in the schizophrenia prodrome, and poor social functioning predicts transition to psychosis in Ultra-High Risk (UHR) individuals. We aimed to: 1) validate the Italian version of the Global Functioning: Social (GF: S) and Global Functioning: Role (GF: S) scales; 2) evaluate their association with UHR criteria. Participants were 12-21-years-old (age, mean=15.2, standard deviation=2.1, male/female ratio=117/120) nonpsychotic help-seekers, meeting (N=39) or not (N=198) UHR criteria. Inter-rater reliability was excellent for both scales, which also showed good to excellent concurrent validity, as measured by correlation with Global Assessment of Functioning (GAF) scores. Furthermore, GF:S and GF: R were able to discriminate between UHRs and non-UHRs, with UHRs having lower current scores. After adjusting for current GAF scores, only current GF:S scores independently differentiated UHR from non-UHR (OR=1.33, 95%CI: 1.02-1.75, p=0.033). Finally, UHR participants showed a steeper decrease from highest GF:S and GF: R scores in the past year to their respective current scores, but not from highest past year GAF scores to current scores. GF:S/GS: R scores were not affected by age or sex. GF:S/GF: R are useful functional level and outcome measures, having the advantage over the GAF to not confound functioning with symptom severity. Additionally, the GF:S may be helpful in identifying UHR individuals.

Cognitive dysfunction affects 40–65% of multiple sclerosis (MS) patients and can occur in the early stages of the disease. This study aimed to explore cognitive functions by means of the Italian version of the minimal assessment of cognitive function in MS (MACFIMS) in relapsing-remitting MS (RRMS) patients with very mild clinical disability to identify the primarily involved cognitive functions. Ninety-two consecutive RRMS patients with Expanded Disability Status Scale (EDSS) scores ≤ 2.5 and forty-two healthy controls (HC) were investigated. Our results show that 51.1% of MS patients have cognitive dysfunction compared to HC. An impairment of verbal and visual memory, working memory, and executive functions was found in the RRMS group. After subgrouping RRMS by EDSS, group 1 (EDSS ≤ 1.5) showed involvement of verbal memory and executive functions; moreover, group 2 (2 ≤ EDSS ≤ 2.5) patients were also impaired in information processing speed and visual memory. Our results show that utilizing a comprehensive neuropsychological assessment, approximately half of MS patients with very mild physical disability exhibit cognitive impairment with a primary involvement of prefrontal cognitive functions. Detecting impairment of executive functions at an early clinical stage of disease could be useful to promptly enroll MS patients in targeted rehabilitation.

OBJECTIVE To clarify whether the clinical response after the first 2 cycles with Onabotulinumtoxin A can accurately predict the long-term response. BACKGROUND Onabotulinumtoxin-A (OBT-A) is an approved preventive treatment option for chronic migraine (CM). Nowadays, it remains to be clarified if the treatment has to be prolonged for at least an entire year (4 injections every 3 months - ie, quarterly, as proposed in the PREEMPT trials) or it can be halted after the second or third injection if not clinically effective. DESIGN AND METHODS We conducted a multicenter observational cohort study based on real-life data on the usage of OBT-A in CM patients from 2 Italian headache centers, Roma Campus Bio-Medico and Milano Besta, adopting the whole 4-injections protocol. We performed a retrospective analysis of medical records of consecutive patients treated in the 2 centers. The main statistical analysis aimed to evaluate longitudinal measures related to headache (monthly headache frequency, monthly number of analgesic drugs, MIDAS). We hypothesized from our clinical practice with OBT-A that only 2 cycles of treatment were not enough to actually define the non-responder status to botulinum toxin A and that probably a longer time of treatment is needed to get the condition of long-term (delayed) responder. RESULTS We considered 115 patients from the 2 centers: 53 in Roma and 62 in Milano. Regarding the main analysis, a clear improvement in each measure was obtained at the 6 months assessment and maintained up to 12 months. Comparing patients with

One of the most popular and widely used parent report instruments for assessing early language acquisition is the MacArthur-Bates Communicative Development Inventories (MB-CDI). This study compares normative data of the Italian Words and Sentences complete form (WS-CF) and short form (WS-SF). The samples included 752 children for the WS-CF and 816 children for the WS-SF designed for children aged 18–36 months. The concordance between WS-SF and WS-CF is analyzed in a subgroup of 65 children. The results revealed strong correlations between WS-CF and WS-SF in both lexical and grammar skills as well as strong relationship between lexical and grammar skills. There was a high percentage agreement (97%) between the two forms for scores below the 10th percentile, suggesting that the two forms may be used interchangeably in order to describe vocabulary and grammatical development.

Chlamydia trachomatis, the leading cause of bacterial sexually transmitted diseases in developed countries, with around 127 million new cases per year, is mainly responsible for urethritis and cervicitis in women, and urethritis and epididymitis in men. Most C. trachomatis infections remain asymptomatic (>50%) and, hence, untreated, leading to severe reproductive complications in both women and men, like infertility. Therefore, the detection of C. trachomatis as well as the antimicrobial susceptibility testing becomes a priority, and, along the years, several methods have been recommended, like cell culture and direct immunofluorescence (DFA) on cell cultures. Herein, we described the application of In-Cell Western assay (ICW) via Odyssey CLx as a fast, more accessible, and high-throughput platform for the quantification of C. trachomatis and the screening of anti-chlamydial drugs. As a first step, we set up a standard curve by infecting cell monolayers with 2-fold serial dilutions of C. trachomatis Elementary Body (EB) suspension. Then, different unknown C. trachomatis EB suspensions were quantified and the chlamydial susceptibility testing to erythromycin was performed, using the DFA as comparison. Our results showed a very high concordance between these two assays, as evidenced by the enumeration of chlamydial IFUs as well as the determination of erythromycin Minimum Inhibitory Concentration (MIC). In conclusion, the ICW assay may be a promising candidate as an accurate and accessible methodology for C. trachomatis antimicrobial susceptibility testing.

Several studies have shown that, in spite of the fact that motor symptoms manifest late in the course of Alzheimer's disease (AD), neuropathological progression in the motor cortex parallels that in other brain areas generally considered more specific targets of the neurodegenerative process. It has been suggested that motor cortex excitability is enhanced in AD from the early stages, and that this is related to disease's severity and progression. To investigate the neurophysiological hallmarks of motor cortex functionality in early AD we combined transcranial magnetic stimulation (TMS) with electroencephalography (EEG). We demonstrated that in mild AD the sensorimotor system is hyperexcitable, despite the lack of clinically evident motor manifestations. This phenomenon causes a stronger response to stimulation in a specific time window, possibly due to locally acting reinforcing circuits, while network activity and connectivity is reduced. These changes could be interpreted as a compensatory mechanism allowing for the preservation of sensorimotor programming and execution over a long period of time, regardless of the disease's progression. Hum Brain Mapp 37:2083-2096, 2016. © 2016 Wiley Periodicals, Inc.

Introduction Pegvisomant (PEG) in monotherapy or combined with somatostatin analogs (SSAs) is used to control acromegaly, improving metabolism. However, the metabolic changes induced by PEG have not been systematically reviewed. Objective To address the following questions: does PEG or the combination of PEG and SSAs affect fasting plasma glucose (FPG), glycosylated Hb (HbA1c), glucose load (2-hour oral glucose tolerance test), insulin levels [fasting plasma insulin (FPI)], homeostatic model assessment of insulin resistance (HOMA-I), homeostatic model assessment of β-cell function, lipid profile, or body mass index? Are the effects disease-related or drug-related? Data sources Indexed databases up to January 2019. Study selection Prospective interventional trials reporting glycometabolic outcomes under PEG or PEG plus SSAs for a minimum of 6 months. Data extraction Three reviewers screened eligible publications (7248), three others extracted the outcomes, and all assessed the risk of biases. Data synthesis Thirteen studies were included in the PEG and 5 in the PEG plus SSAs analysis (overall 550 subjects). PEG significantly decreased FPG [effect size (ES) -0.80 mmol/L (95% CI, -1.06 to -0.55); P = 0.000], HbA1c [ES -0.43% (95% CI, -0.56 to -0.31); P = 0.000], FPI [ES -5.31 mU/L (95% CI, -10.23 to -0.39); P = 0.034], and HOMA-I [ES -0.61 (95% CI, -1.17 to -0.04); P = 0.034]. Effects on FPG and FPI were not correlated to IGF-1 changes. The addition of PEG to SSAs mitigated the effects of SSAs on metabolism, producing an overall neutral effect. Conclusions Independently of disease control, PEG in monotherapy or combined with SSAs seems to improve glucose metabolism, reducing FPG, HbA1c, FPI, and HOMA-I.

Summary Background Conventional treatment of patients with adrenal insufficiency involves administration of glucocorticoids multiple times a day and has been associated with weight gain and metabolic impairment. The optimal glucocorticoid replacement therapy for these patients is highly debated because of the scarcity of evidence from randomised trials. We aimed to establish whether the timing and pharmacokinetics of glucocorticoid replacement therapy affect the metabolism and immune system of patients with adrenal insufficiency. Methods We did a single-blind randomised controlled trial at two reference university hospitals in Italy. Eligible patients (aged 18–80 years) with adrenal insufficiency were on conventional glucocorticoid therapy and had been stable for at least 3 months before enrolment. Patients were randomly assigned (1:1) with a computer-generated random sequence stratified by type of adrenal insufficiency and BMI to continue conventional glucocorticoid therapy (standard treatment group) or to switch to an equivalent dose of once-daily, modified-release oral hydrocortisone (switch treatment group). Outcome assessors were masked to treatment allocation. The primary outcome was bodyweight change from baseline to 24 weeks. Secondary outcomes included immune cell profiles, susceptibility to infections, and quality of life. Efficacy analyses included all patients who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov, NCT02277587. Findings Between March 1, 2014, and June 30, 2016, 89 patients with adrenal insufficiency were randomly assigned to continue standard glucocorticoid therapy (n=43) or to switch to once-daily, modified-release hydrocortisone (n=46). At 24 weeks, bodyweight reduction was superior in patients in the once-daily hydrocortisone group compared with those in the standard treatment group (–2·1 kg [95% CI −4·0 to −0·3] vs 1·9 kg [–0·1 to 3·9]; treatment difference −4·0 kg, 95% CI −6·9 to −1·1; p=0·008). Additionally, patients in the once-daily hydrocortisone group had more normal immune cell profiles, reduced susceptibility to infections, and improved quality of life compared with the standard glucocorticoid therapy group. We observed no difference in frequency or severity of adverse events between the two intervention groups, although a lower cumulative number of recurrent upper respiratory tract infections was observed with once-daily hydrocortisone than with standard treatment (17 vs 38; p=0·016). Most adverse events were mild; three serious adverse events occurred in each group, of which one adverse advent (arthritis) in the switch treatment group could be considered drug related. Interpretation Patients with adrenal insufficiency on conventional glucocorticoid replacement therapy multiple times a day exhibit a pro-inflammatory state and weakened immune defence. Restoration of a more physiological circadian glucocorticoid rhythm by switching to a once-daily, modified-release regimen reduces bodyweight, normalises the immune cell profile, reduces recurrent infections, and improves the quality of life of patients with adrenal insufficiency. Funding Italian Ministry of University and Research.

The aim of this study was to identify the impact of comorbidities on outcomes of patients with vegetative state (VS) or minimally conscious state (MCS). All patients in VS or MCS consecutively admitted to two postacute care units within a 1-year period were evaluated at baseline and at 6 months through the Coma Recovery Scale-Revised Version and the Disability Rating Scale (DRS). Comorbidities were also recorded for each patient along the same period. Six-month outcomes included death, full recovery of consciousness, and functional improvement. One hundred and thirty-nine patients (88 male and 51 female; median age, 59 years) were included. Ninety-seven patients were in VS (70%) and 42 in MCS (30%). At 6 months, 33 patients were dead (24%), 39 had a full recovery of consciousness (28%), and 67 remained in VS or MCS (48%). According to DRS scores, 40% of patients (n=55) showed a functional improvement in the level of disability. One hundred and thirty patients (94%) showed at least one comorbidity. Severity of comorbidities (hazard ratio [HR]=2.8; 95% confidence interval [CI], 1.71-4.68; p0.001) and the presence of ischemic or organic heart diseases (HR=2.6; 95% CI, 1.21-5.43; p=0.014) were the strongest predictors of death, together with increasing age (HR=1.0; 95% CI, 1.0-1.06; p=0.033). Respiratory diseases and arrhythmias without organic heart diseases were negative predictors of full recovery of consciousness (odds ratio [OR]=0.3; 95% CI, 0.12-0.7; p=0.006; OR=0.2; 95% CI, 0.07-0.43; p0.001) and functional improvement (OR=0.4; 95% CI, 0.15-0.85, p=0.020; OR=0.2; 95% CI, 0.08-0.45; p0.001). Our data show that comorbidities are common in these patients and some of them influence recovery of consciousness and outcomes.

Objective Verifying the validity and feasibility of the WOQ-19 as a useful tool in routine clinical practice and in management of patients. Methods 532 consecutive Parkinson's disease (PD) patients were recruited from 6 different neurological outpatient units, specialized in movement disorders, of central Italy. Inclusion criteria were diagnosis of PD and any current pharmacological treatment of PD while exclusion criteria were evident cognitive or depressive impairment, infusion with dopamine agonists or Duodopa, or Deep Brain Stimulation therapy. Patients were asked to complete the Italian version of WOQ-19 before the neurological visit. A medical form for the collection of demographic and clinical data of patients and for the evaluation of comprehensibility and usability the WOQ-19 was filled by the neurologist during the visit. Results Our data confirmed that WOQ-19 was able to identify WO in 69% of patients, a percentage similar to the recently reported in the Italian WOQ-19 validation study. Motor symptoms were more frequent than non-motor symptoms (80% vs. 20%). Patients who experienced WO had a higher age of PD onset, more severe disease, longer disease duration and were more likely to be female. Conclusions The WOQ-19 was understandable for the patient, easily administered and suitable for routine outpatient use. It could be also particularly useful in clinical practice in the early identification of non-motor symptoms, often under reported by patients and revealed only with clinical support.

Aim To examine whether the results at 4 years of age of the developmental questionnaire QS4-G can predict the outcome of cognitive, neuropsychological and academic abilities 4–6 years later. The QS4-G is a validated parental questionnaire designed for the screening and surveillance of the neuropsychological and behavioural developmental status of 4-year-olds (93 questions). Methods Longitudinal prospective study on a subsample of the QS4-G validation original sample was conducted. According to previous results, the sample was divided into two groups: ‘at risk’ and ‘not at risk’. Sensitivity, specificity, accuracy and likelihood ratios were assessed and referred to outcomes. Results Thirty-five children were classified as ‘not at risk’ and 16 as ‘at risk’. There were significant associations between past QS4-G score and cognitive, neuropsychological and academic abilities 4–6 years later. With the same cut-off identified at the first cross-sectional study, sensitivity and specificity for difficulties in cognitive development were 90% and 83% while in the neuropsychological abilities 62% and 90%, respectively. A lower predictive validity was found for difficulties in academic abilities (sensitivity 43%, specificity 86%). QS4-G specific area scores showed significant correlations with related academic tests at follow-up (rho range: 0.404–0.565, P < 0.005). Conclusions QS4-G shows good predictive validity for cognitive development and neuropsychological abilities. The risk of false negatives for academic abilities can be reduced by analysing the specific area results of QS4-G, which show good correlations with related tests at follow-up.

Cerebral vasomotor reactivity (CVR) is reduced in patients with diabetes mellitus (DM), and glucose variability (GV) might be responsible for cerebrovascular damage.Studying patients with insulin resistance without DM, we explored the role of GV in impairing CVR.We studied 18 metabolic syndrome (MS) patients without DM, 9 controls (C), and 26 patients with DM.Groups were compared in terms of CVR, GV, and 24-hour blood pressure. To evaluate the impact of acute hyperglycemia on CVR, a hyperglycemic clamp was performed in MS patients and controls.Baseline CVR was reduced in DM vs C and MS (C vs DM = 20.2, 95% CI = 3.5-36.9, P = .014; and MS vs DM = 22.2, 95% CI = 8.6-35.8, P = .001), but similar between MS and C (MS vs C = 2.0, 95% CI = -14.7 to 18.7, P = .643). During acute hyperglycemia, CVR fell in MS and C to values comparable to DM. GV progressively increased from C to MS to DM. In MS, CVR at 120 minutes and GV displayed a negative correlation (r = -0.48, P = .043), which did not change after controlling for mean 24-hour systolic and diastolic blood pressure. In MS, the CVR reduction was significantly correlated to GV (r = 0.55, P = .02).GV is increased in patients with MS but without DM and is the major predictor of CVR reduction induced by acute hyperglycemia, possibly representing the earliest cause of cerebrovascular damage in DM.

Objective Meta-analyses show that nonbound ceruloplasmin (non-Cp) copper (also known as free or labile copper) in serum is higher in patients with Alzheimer disease (AD). It differentiates subjects with mild cognitive impairment (MCI) from healthy controls. However, a longitudinal study on an MCI cohort has not yet been performed to assess the accuracy of non-Cp copper for the prediction of conversion from MCI to AD during a long-term follow-up. Methods The study included 42 MCI converters and 99 stable MCI subjects. We assessed levels of copper, ceruloplasmin, non-Cp copper, iron, transferrin, ferritin, and APOE genotype. A multiple Cox regression analysis—with age, sex, baseline Mini-Mental State Examination, APOE4, iron, non-Cp copper, transferrin, ferritin, hypercholesterolemia, and hypertension as covariates—was applied to predict the conversion from MCI to AD. Results Among the evaluated parameters, the only significant predictor of conversion to AD was non-Cp copper (hazard ratio = 1.23, 95% confidence interval = 1.03–1.47, p = 0.022); for each additional micromole per liter unit (μmol/l) of non-Cp copper, the hazard increased by ∼20%. Subjects with non-Cp copper levels >1.6μmol/l had a hazard conversion rate (50% of conversion in 4 years) that was ∼3× higher than those with values ≤1.6μmol/l (

Background Current efforts to improve clinical effectiveness and utility of repetitive transcranial magnetic stimulation (rTMS) in the treatment of major depression (MD) include theta burst stimulation (TBS), a patterned form of rTMS. Here, we investigated the efficacy of bilateral TBS to the dorsolateral prefrontal cortex (dlPFC) in patients with MD in additon to ongoing medication and psychotherapy. Methods In this randomized-controlled trial, thirty-two patients with MD were treated for six weeks (thirty sessions) with either successively intermittent, activity enhancing TBS (iTBS) to the left and continuous, inhibiting TBS (cTBS) to the right dlPFC or with bilateral sham stimulation. Primary outcome measure was the proportion of treatment response defined as a Montgomery–Asberg Depression Rating Scale (MADRS)≤50% compared to baseline. Secondary outcomes comprised response and remission rates of the Hamilton Depression Rating Scale (HAMD) and the Beck Depression Inventory (BDI). Results A larger number of responders were found in the cTBS (n=9) compared to the sham-stimulation (n=4) group (odds ratio: 3.86; Wald χ2=3.9, p=0.048). On secondary endpoint analysis, patient-reported outcome as assessed by the BDI, pointed towards a higher rate of remitters in the cTBS (n=6) than in the sham (n=1) group (odds ratio: 9; Wald χ2=3.5, p=0.061). Limitations With regard to the pilot character of the study and the small sample size, the results have to be considered as preliminary. Conclusions These findings provide first evidence that six weeks treatment of MDD with iTBS to the left and cTBS to the right dlPFC for six weeks is safe, feasible and superior to sham stimulation applied add-on to pharmacological and psychotherapeutic treatment.

Background: Neuromodulation techniques, i.e. repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), can modify cerebral hemodynamics. High frequency rTMS appeared to decrease cerebral vasomotor reactivity (VMR), while there is still poor evidence about the effect of low frequency (LF) rTMS on cerebral blood flow (CBF) and VMR. Hypothesis: The present study aimed to test if LF rTMS decreases CBF and increases cerebral VMR. Monolateral or bilateral hemispheric involvement and duration of the effect were considered. A possible role of autonomic nervous system in CBF and VMR modulation was also investigated. Methods: Twenty-four right-handed healthy subjects underwent randomly real (12) or sham (12) 20-min 1-Hz rTMS on left primary motor cortex. Mean flow velocity and VMR of middle cerebral arteries were evaluated by means of transcranial Doppler before (T0), after 10 min (T1) and after 2 (T2), 5 (T3) and 24 h (T4) from rTMS. Heart rate variability (HRV) was studied within the same timing interval, assessing low frequency/high frequency (LF/HF) ratio as index of autonomic balance. Results: After real rTMS compared with sham stimulation, MFV decreased bilaterally at T1 (F = 3.240, P = .030) while VMR increased bilaterally (F = 5.116, P = .002) for at least 5 h (T3). LF/HF ratio decreased early after real rTMS (F = 2.881, P = .040). Conclusion: 1-Hz rTMS may induce a bilateral long-lasting increase of VMR, while its effect on MFV is short-lasting. Moreover, HRV changes induced by rTMS suggest a possible autonomic nervous system modulation.

Aims Recent studies have identified neuroretinal abnormalities in persons affected by diabetes mellitus, before the onset of microvascular alterations. However, the role of glycemic variability (GV) on early retinal neurodegeneration is still not clarified. Methods To explore the relationship between glycemic control and neuroretinal characteristics, 37 persons with Type 1 diabetes mellitus (Type 1 DM) divided into two groups with no signs (noRD) and with mild non-proliferative diabetic retinopathy (NPDR) compared to 13 healthy control participants (C) were recruited. All persons underwent an optical coherence tomography with automatic segmentation of all neuroretinal layers. Measurements of mean of nasal (N)/temporal (T)/superior (S)/inferior (I) macular quadrants for individual layer were also calculated. Metabolic control was evaluated by glycated hemoglobin (HbA1c), and indexes of GV were calculated from continuous glucose monitoring. Results The difference among the three groups in terms of RNFL thickness was significantly dependent on quadrant (F(6;132) = 2.315; p = 0.037). This interaction was due to a specific difference in RNFL-N thickness, where both Type 1 DM groups showed a similar reduction versus C (−3.9 for noDR and −4.9 for NPDR), without any relevant difference between them (−1.0). Inner nuclear layer (INL) was increased in all quadrants in the two Type 1 DM groups compared to C (mean difference = 7.73; 95% CI: 0.32–15.14, p = 0.043; mean difference = 7.74; 95% CI: 0.33–15.15, p = 0.043, respectively). A negative correlation between RNFL-N and low blood glucose index (r = −0.382, p = 0.034) and positive correlation between INL and continuous overall net glycemic action −1, −2, −4 h (r = 0.40, p = 0.025; r = 0.39, p = 0.031; r = 0.41, p = 0.021, respectively) were observed in Type 1 DM patients. The triglycerides were positively and significantly correlated to INL (r = 0.48, p = 0.011), in Type 1 DM subjects. GV and triglycerides resulted both independent predictors of increased INL thickness. No correlation was found with HbA1c. Conclusions Early structural damage of neuroretina in persons with Type 1 DM patients is related to glucose fluctuations. GV should be addressed, even in the presence of a good metabolic control.

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BACKGROUND AND PURPOSE An effort to define and validate a Harmonized Protocol for standard hippocampal segmentation is being carried out. We wished to estimate the effect of magnetic resonance image (MRI) spatial orientation on manual hippocampal segmentations to define optimal standard orientation of MRIs for hippocampal volumetry. METHODS Three expert tracers segmented twice the hippocampi of 10 ADNI subjects on MRI slices oriented perpendicular to the anterior-posterior commissure (AC-PC) line and the long hippocampal axes plane, following internationally harmonized landmarks. We computed intra and interrater reliability figures for total volumes and similarity coefficients. RESULTS Total volume reliability was similar for both orientations. Similarity coefficients were significantly higher for the AC-PC orientation (exact P = 0.002). DISCUSSION These data show that AC-PC orientation is slightly more reliable for manual segmentations, possibly due to better visualization of the cerebrospinal fluid spaces separating hippocampal head and amygdala. A Delphi panel of experts has used these data to decide on the optimal orientation for a Harmonized Protocol for hippocampal segmentation.

Revised diagnostic criteria for Alzheimer disease (AD) acknowledge a key role of imaging biomarkers for early diagnosis. Diagnostic accuracy depends on which marker (i.e., amyloid imaging, ¹⁸F-fluorodeoxyglucose [FDG]-PET, SPECT, MRI) as well as how it is measured ("metric": visual, manual, semiautomated, or automated segmentation/computation). We evaluated diagnostic accuracy of marker vs metric in separating AD from healthy and prognostic accuracy to predict progression in mild cognitive impairment. The outcome measure was positive (negative) likelihood ratio, LR+ (LR-), defined as the ratio between the probability of positive (negative) test outcome in patients and the probability of positive (negative) test outcome in healthy controls. Diagnostic LR+ of markers was between 4.4 and 9.4 and LR- between 0.25 and 0.08, whereas prognostic LR+ and LR- were between 1.7 and 7.5, and 0.50 and 0.11, respectively. Within metrics, LRs varied up to 100-fold: LR+ from approximately 1 to 100; LR- from approximately 1.00 to 0.01. Markers accounted for 11% and 18% of diagnostic and prognostic variance of LR+ and 16% and 24% of LR-. Across all markers, metrics accounted for an equal or larger amount of variance than markers: 13% and 62% of diagnostic and prognostic variance of LR+, and 29% and 18% of LR-. Within markers, the largest proportion of diagnostic LR+ and LR- variability was within ¹⁸F-FDG-PET and MRI metrics, respectively. Diagnostic and prognostic accuracy of imaging AD biomarkers is at least as dependent on how the biomarker is measured as on the biomarker itself. Standard operating procedures are key to biomarker use in the clinical routine and drug trials.

Purpose Motor evoked potentials (MEPs) elicited by a train of consecutive, individual transcranial magnetic stimuli demonstrate fluctuations in amplitude with respect to time when recorded from a relaxed muscle. The influence of time-varying, instantaneous modifications of the electroencephalography (EEG) properties immediately preceding the transcranial magnetic stimulation (TMS) has rarely been explored. The aim of this study was to investigate the influence of the pre-TMS motor cortex and related areas EEG profile on time variants of the MEPs amplitude. Method MRI-navigated TMS and multichannel TMS-compatible EEG devices were used. For each experimental subject, post-hoc analysis of the MEPs amplitude that was based on the 50th percentile of the MEPs amplitude distribution provided two subgroups corresponding to “high” (large amplitude) and “low” (small amplitude). The pre-stimulus EEG characteristics (coherence and spectral profile) from the motor cortex and related areas were analyzed separately for the “high” and “low” MEPs and were then compared. Results On the stimulated hemisphere, EEG coupling was observed more often in the high compared to the low MEP trials. Moreover, a paradigmatic pattern in which TMS was able to lead to significantly larger MEPs was found when the EEG of the stimulated motor cortex was coupled in the beta 2 band with the ipsilateral prefrontal cortex and in the delta band with the bilateral centro-parietal-occipital cortices. Conclusion This data provide evidence for a statistically significant influence of time-varying and spatially patterned synchronization of EEG rhythms in determining cortical excitability, namely motor cortex excitability in response to TMS. Hum Brain Mapp 35:1969–1980, 2014. © 2013 Wiley Periodicals, Inc.

Gaps in regulations pertaining to the collection and storage of biological materials in a biobank, at least in the European context, have made the writing of local guidelines essential from an ethical point of view. Nevertheless, until recently, the elaboration of local guidelines for the collection, use and storage of biological materials in a biobank has been the exception in Italy and all European countries. In this context, it is of value to know the policies, even if they are unwritten, of local ethics committees (ECs) engaged in the evaluation of research protocols involving biobanks and biological materials. This paper presents the results of a survey carried out among local Italian ECs (229) to document their attitudes and policies regarding the management of the ethical issues related to biobanks and the use of biological materials. A questionnaire was developed to investigate the areas regarded as critical from an ethical–legal point of view: informed consent and information to the subjects; protection of confidentiality; communication of research results; access/transfer of biological materials and related data; ownership of samples and data and intellectual property rights; and subjects' remuneration and benefit sharing. Twenty-six ECs from the Italian Institutes for Research and Care (62%) and 26 other ECs (14%) participated in the survey.

The effect of carotid artery stenting (CAS) on cognitive function is still debated. Cerebral microembolism, detectable by post-procedural diffusion-weighted imaging (DWI) lesions, has been suggested to predispose to cognitive decline. Our study aimed at evaluating the effect of CAS on cognitive profile focusing on the potential role of cerebral microembolic lesions, taking into consideration the impact of factors potentially influencing cognitive status (demographic features, vascular risk profile, neuropsychological evaluation at baseline and magnetic resonance (MR) markers of brain structural damage). Thirty-seven patients with severe carotid artery stenosis were enrolled. Neurological assessment, neuropsychological evaluation and brain MR were performed the day before CAS (E0). Brain MR with DWI was repeated the day after CAS (E1), while neuropsychological evaluation was done after a 14-month median period (E2). Volumes of both white matter hyperintensities and whole brain were estimated at E0 on axial MR FLAIR and T1w-SE sequences, respectively. Unadjusted ANOVA analysis showed a significant CAS*DWI interaction for MMSE (F=7.154(32), p=.012). After adjusting for factors potentially influencing cognitive status CAS*DWI interaction was confirmed for MMSE (F=7.092(13), p=.020). Patients with DWI lesions showed a mean E2-E0 MMSE reduction of -3.1, while group without DWI lesions showed a mean E2-E0 MMSE of +1.1. Our study showed that peri-procedural brain microembolic load impacts negatively on cognitive functions, independently from the influence of patients-related variables.

Six-hundred twenty-one subjects with unilateral asymptomatic severe internal carotid artery (ICA) stenosis were prospectively evaluated with a median follow-up of 27 months (min = 6, max = 68). Vascular risk profile, plaque characteristic, stenosis progression, and common carotid artery intima-media thickness (IMT) were investigated in all patients. Outcome measures were occurrence of ischemic stroke ipsilateral to ICA stenosis and vascular death, while myocardial infarction, contralateral strokes, and transient ischemic attack were considered as competing events. A total of 99 subjects (15.9%) suffered from a vascular event. Among them, 39 were strokes ipsilateral to the stenosis (6.3%). Degree of stenosis, stenosis progression, and common carotid artery IMT resulted as independent predictive factors of ipsilateral stroke. Considering a stenosis of 60% to 70% as reference, a degree between 71% and 90% increased the risk by 2.45, while a degree between 91% and 99% increased the risk by 3.26. The progression of stenosis was a strong risk factor (hazard ratio = 4.32). Finally, the role of carotid IMT was confirmed as crucial additional measure, with an increased risk by 25% for each 0.1 mm IMT increase. Our data suggest that IMT, stenosis progression and severity should be considered as risk factors for cerebrovascular events in asymptomatic subjects with severe ICA stenosis.

Aim Restrictive lung dysfunction (RLD; defined as reduced forced vital capacity [FVC] in the presence of normal forced expiratory volume in 1 s [FEV1]/FVC ratio) is highly prevalent in the elderly, and is associated with diabetes, metabolic syndrome (MetS) and abdominal obesity. The aim of this study was to assess the relative contribution of diabetes, MetS and abdominal obesity in characterizing RLD in the elderly. Methods This was cross-sectional analysis of 192 consecutive, community-dwelling persons (mean age 70.8 ± 8 years). The participants were grouped according to the number of MetS components (i.e. 0, 1, 2, 3 or 4) and the presence of diabetes. According to the Adult Treatment Panel-III criteria, participants with three or four components were considered to be affected by MetS. Independent correlates of RLD and obstructive lung dysfunction (OLD; FEV1/FVC

Meta-analyses demonstrate copper involvement in Alzheimer's disease (AD), and the systemic ceruloplasmin status in relation to copper is an emerging issue. To deepen this matter, we evaluated levels of ceruloplasmin concentration, ceruloplasmin activity, ceruloplasmin specific activity (eCp/iCp), copper, non-ceruloplasmin copper iron, transferrin, the ceruloplasmin/transferrin ratio, and the APOE genotype in a sample of 84 AD patients and 58 healthy volunteers. From the univariate logistic analyses we found that ceruloplasmin concentration, eCp/iCp, copper, transferrin, the ceruloplas- min/transferrin ratio, and the APOE genotype were significantly associated with the probability of AD. In the multivariable logistic regression analysis, we selected the best subset of biological predictors by the forward stepwise procedure. The anal- ysis showed a decrease of the risk of having AD for eCp/iCp (p = 0.001) and an increase of this risk for non-ceruloplasmin copper (p = 0.008), age (p = 0.001), and APOE-4 allele (p < 0.001). The estimated model showed a good power in discrimi- nating AD patients from healthy controls (area under curve: 88%; sensitivity: 66%; specificity 93%). These data strength the breakdown of copper homeostasis and propose eCp/iCp as a reliable marker of ceruloplasmin status.