Very low serum IGF-1 levels are associated with vertebral fractures in adult males with beta-thalassemia major.

PURPOSE: Patients with beta-thalassemia major (BTM) often develop several endocrine disorders due to chronic iron overload. They are also prone to osteoporosis and vertebral fractures. Plasmatic insulin-like growth factor-1 (IGF-1) levels are often low in subjects with BTM, which origin is multifactorial. The aim of this study was to evaluate a possible relationship between serum IGF-1 levels and the presence of osteoporosis and/or vertebral fractures. METHODS: We retrospectively evaluated the occurrence of vertebral fractures in 30 adult male patients affected by BTM (mean age 43.3 ± 7.9 years) with low serum IGF-1 (median value 52.4 ng/ml, 38.5-83.4). Only 6 of them (20.0%) were diagnosed with GH deficiency (GHD) after GHRH/arginine stimulation test, while 23 (76.7%) had osteoporosis and 12 (40.0%) had known vertebral fractures. All patients except one also showed at least one endocrine disorder. RESULTS: Serum IGF-1 was significantly lower in BTM patients with vertebral fractures compared to patients without vertebral fractures (U = 41.0, p = 0.005) while it was not significantly different between patients with low bone mass compared to patients without low bone mass. The diagnosis of GHD was significantly associated with lower serum IGF-1 (p = 0.001) and vertebral fractures (p = 0.002) but not with low bone mass. After ROC analysis, we found that very low IGF-1 (≤ 50.0 ng/dl) was associated with vertebral fractures (sensitivity 83.3%, specificity 75.0%) and was also predictive of GHD (sensitivity 75.0%, specificity 100.0%). CONCLUSION: Our study shows that, in male patients with BTM, serum IGF-1 ≤ 50.0 ng/dl is a marker of vertebral fractures and it is predictive of a diagnosis of GHD.

Temporal trends in the clinical presentation of Graves' orbitopathy: a single-center retrospective study.

PURPOSE: Graves' ophthalmopathy (GO) is an autoimmune disease that affects orbital soft tissues and represents the most common extrathyroidal manifestation of Graves' disease (GD). The European Group of Graves' Ophthalmopathy (EUGOGO) has attempted to shed light on the European epidemiological picture of GO, suggesting that GO in newly diagnosed patients in recent years has a trend towards a less severe clinical presentation. There are no studies that focus this issue on the population of our area; we aimed to evaluate the trend of GO clinical presentation in our outpatient clinic through an observation period of 10 years. METHODS: We compared 55 consecutive patients, 11 males (F) and 44 females (M), who came to our observation from January 2005 to December 2006 [Group 1 (G1)], with 56 patients, 15 males, and 41 females, who were referred to us from 2015 to 2016 [Group 2 (G2)]. We studied the following putative predictors of GO presentation and severity: thyroid function, smoking, diabetes, hypercholesterolemia, time from GO diagnosis to referral to our thyroid centre (TGOD), sex and age. RESULTS: GO severity was significantly reduced in G2 vs. G1 (p = 0.04). TGOD ≥ 3 months was related to clinical characteristics of GO (severity and Clinical Activity Score ≥ 4) and was an independent predictor of GO severity (p = 0.01). The other variables evaluated had no independent effects. CONCLUSIONS: We found that GO severity at presentation was significantly reduced over a ten-year observation period (2005-2006 vs. 2015-2016) in GO patients referred to our tertiary thyroid centre. TGOD ≥ 3 months was an independent predictor of GO severity.

Experimental characterization of gaseous ion beams produced with the advanced ion source for hadrontherapy (AISHa) at 18 GHz.

The Advanced Ion Source for Hadrontherapy (AISHa) is an electron cyclotron resonance ion source operating at 18 GHz, developed at the Istituto Nazionale di Fisica Nucleare-Laboratori Nazionali del Sud, with the aim of producing high intensity and low emittance highly charged ion beams for hadrontherapy purposes. Moreover, thanks to its unique peculiarities, AISHa is a suitable choice for industrial and scientific applications. In the framework of the INSpIRIT and IRPT projects, in collaboration with the Centro Nazionale di Adroterapia Oncologica, new candidates for cancer treatment are being developed. In particular, the paper presents the results of the commissioning of four ion beams of interest for hadrontherapy: H+, C4+, He2+, and O6+. Their charge state distribution in the best experimental conditions, their emittance, and brightness will be critically discussed, along with the role of ion source tuning and space charge effects in beam transport. Perspectives for further developments will also be presented.

Atezolizumab plus bevacizumab versus lenvatinib or sorafenib in non-viral unresectable hepatocellular carcinoma: an international propensity score matching analysis.

BACKGROUND: A growing body of evidence suggests that non-viral hepatocellular carcinoma (HCC) might benefit less from immunotherapy. MATERIALS AND METHODS: We carried out a retrospective analysis of prospectively collected data from consecutive patients with non-viral advanced HCC, treated with atezolizumab plus bevacizumab, lenvatinib, or sorafenib, in 36 centers in 4 countries (Italy, Japan, Republic of Korea, and UK). The primary endpoint was overall survival (OS) with atezolizumab plus bevacizumab versus lenvatinib. Secondary endpoints were progression-free survival (PFS) with atezolizumab plus bevacizumab versus lenvatinib, and OS and PFS with atezolizumab plus bevacizumab versus sorafenib. For the primary and secondary endpoints, we carried out the analysis on the whole population first, and then we divided the cohort into two groups: non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) population and non-NAFLD/NASH population. RESULTS: One hundred and ninety patients received atezolizumab plus bevacizumab, 569 patients received lenvatinib, and 210 patients received sorafenib. In the whole population, multivariate analysis showed that treatment with lenvatinib was associated with a longer OS [hazard ratio (HR) 0.65; 95% confidence interval (CI) 0.44-0.95; P = 0.0268] and PFS (HR 0.67; 95% CI 0.51-0.86; P = 0.002) compared to atezolizumab plus bevacizumab. In the NAFLD/NASH population, multivariate analysis confirmed that lenvatinib treatment was associated with a longer OS (HR 0.46; 95% CI 0.26-0.84; P = 0.0110) and PFS (HR 0.55; 95% CI 0.38-0.82; P = 0.031) compared to atezolizumab plus bevacizumab. In the subgroup of non-NAFLD/NASH patients, no difference in OS or PFS was observed between patients treated with lenvatinib and those treated with atezolizumab plus bevacizumab. All these results were confirmed following propensity score matching analysis. By comparing patients receiving atezolizumab plus bevacizumab versus sorafenib, no statistically significant difference in survival was observed. CONCLUSIONS: The present analysis conducted on a large number of advanced non-viral HCC patients showed for the first time that treatment with lenvatinib is associated with a significant survival benefit compared to atezolizumab plus bevacizumab, in particular in patients with NAFLD/NASH-related HCC.

Identification of lenvatinib prognostic index via recursive partitioning analysis in advanced hepatocellular carcinoma.

BACKGROUND: After the advent of new treatment options for advanced hepatocellular carcinoma (HCC), the identification of prognostic factors is crucial for the selection of the most appropriate therapy for each patient. PATIENTS AND METHODS: With the aim to fill this gap, we applied recursive partitioning analysis (RPA) to a cohort of 404 patients treated with lenvatinib. RESULTS: The application of RPA resulted in a classification based on five variables that originated a new prognostic score, the lenvatinib prognostic index (LEP) index, identifying three groups: low risk [patients with prognostic nutritional index (PNI) >43.3 and previous trans-arterial chemoembolization (TACE)]; medium risk [patients with PNI >43.3 but without previous TACE and patients with PNI <43.3, albumin-bilirubin (ALBI) grade 1 and Barcelona Clinic Liver Cancer stage B (BCLC-B)]; high risk [patients with PNI <43.3 and ALBI grade 2 and patients with PNI <43.3, albumin-bilirubin (ALBI) grade 1 and Barcelona Clinic Liver Cancer stage C (BCLC-C)]. Median overall survival was 29.8 months [95% confidence interval (CI) 22.8-29.8 months] in low risk patients (n = 128), 17.0 months (95% CI 15.0-24.0 months) in medium risk (n = 162) and 8.9 months (95% CI 8.0-10.7 months) in high risk (n = 114); low risk hazard ratio (HR) 1 (reference group), medium risk HR 1.95 (95% CI 1.38-2.74), high risk HR 4.84 (95% CI 3.16-7.43); P < 0.0001. The LEP index was validated in a cohort of 127 Italian patients treated with lenvatinib. While the same classification did not show a prognostic value in a cohort of 311 patients treated with sorafenib, we also show a possible predictive role in favor of lenvatinib in the low risk group. CONCLUSIONS: LEP index is a promising, easy-to-use tool that may be used to stratify patients undergoing systemic treatment of advanced HCC.

Consensus paper on postural dysfunction: recommendations for prevention, diagnosis and therapy.

Good fundamentals of posture and balance are essential for the efficient performance of both simple daily tasks and more complex movement patterns. In particular, postural balance is the ability to keep the body in equilibrium and to regain balance after the shift of body segments: postural control mechanisms of integration of the visual, vestibular and foot afferential channels contribute to this. This document provides recommendations based on scientific evidence, clinical practice, and consensus between experts concerning the prevention, diagnosis, and treatment of postural dysfunction at the three stages of life as the developmental age, adult age, and old age > 65 years and follows the "National Guidelines on Classification and Measuring of Posture and its Dysfunctions" per the Italian Ministry of Health (December 2017). The paper answers four main questions: i) "Which measures can be adopted to prevent postural dysfunctions?" ii) "What can we do in order to make a correct diagnosis of postural dysfunction?" iii) "What are the correct treatment programs for postural dysfunctions?" iv) Which professional competencies and experiences are useful for preventing, diagnosing and treating postural dysfunctions? By the Consensus of the Experts and the scientific evidence, emerge that the approach to postural dysfunctions requires a multidisciplinary and interdisciplinary team. Furthermore, rehabilitation treatment interventions must be specific to the age groups that have been indicated, to consider the integration of the main systems and subsystems of postural control that change with age.

Negative impacts of COVID-19 lockdown on mental health service access and follow-up adherence for immigrants and individuals in socio-economic difficulties.

OBJECTIVES: Lockdown measures in response to the coronavirus disease 2019 (COVID-19) pandemic can have serious mental health effects on the population, especially in vulnerable groups, such as those living in poor socio-economic conditions, those who are homeless, migrant workers and asylum seekers/refugees. In addition, these vulnerable groups frequently have greater difficulty accessing health services and in treatment adherence. The aim of this study is to estimate the impact of the COVID-19-related lockdown on service utilisation and follow-up adherence in an Italian mental health outpatient service for migrants and individuals in socio-economic difficulties. STUDY DESIGN: The design of this study is a retrospective cross-sectional study. METHODS: All patients who visited the mental health outpatient service in the months of February and March in the years 2017-2020 were included in the study. To compare service utilisation before and after the lockdown, the number of patients who visited the mental health outpatient service for psychiatric interview were recorded. Follow-up adherence was calculated as the percentage of patients who visited in February and subsequently attended a follow-up visit in March of the same year. RESULTS: The number of patients who visited the outpatient service between February 2017 and February 2020 was continuously increasing. In March 2020, fewer patients visited the service for psychiatric interview, in line with the introduction of lockdown measures. In addition, the number of the patients who visited in February 2020 and returned for their follow-up visits in March 2020 declined from approximately 30% over the same months in 2017-2019 to 17.53% in March 2020. CONCLUSIONS: The lockdown-related reduction in numbers of patients accessing the mental health service makes it difficult to help vulnerable populations during a period of time in which their mental health needs are expected to increase. Moreover, the reduction seen in follow-up compliance increases the risk of treatment discontinuation and possible relapse. Proactive alternative strategies need to be developed to reach these vulnerable populations.

Eculizumab treatment in patients with COVID-19: preliminary results from real life ASL Napoli 2 Nord experience.

OBJECTIVE: SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2)-related pneumonia, referred to as COVID-19 (Coronavirus Disease 19), is a public health emergency as it carries high morbidity, mortality, and has no approved specific pharmacological treatments. In this case series, we aimed to report preliminary data obtained with anti-complement C5 therapy with eculizumab in COVID-19 patients admitted to intensive care unit (ICU) of ASL Napoli 2 Nord. PATIENTS AND METHODS: This is a case series of patients with a confirmed diagnosis of SARS-CoV2 infection and severe pneumonia or ARDS who were treated with up to 4 infusions of eculizumab as an off-label agent. Patients were also treated with anticoagulant therapy with Enoxaparin 4000 IU/day via subcutaneous injection, antiviral therapy with Lopinavir 800 mg/day + Ritonavir 200 mg/day, hydroxychloroquine 400 mg/day, ceftriaxone 2 g/day IV, vitamine C 6 g/day for 4 days, and were on Non-Invasive Ventilation (NIV). RESULTS: We treated four COVID-19 patients admitted to the intensive care unit because of severe pneumonia or ARDS. All patients successfully recovered after treatment with eculizumab. Eculizumab induced a drop in inflammatory markers. Mean C Reactive Protein levels dropped from 14.6 mg/dl to 3.5 mg/dl and the mean duration of the disease was 12.8 days. CONCLUSIONS: Eculizumab has the potential to be a key player in treatment of severe cases of COVID-19. Our results support eculizumab use as an off-label treatment of COVID-19, pending confirmation from the ongoing SOLID-C19 trial.

Genetic profiling using plasma-derived cell-free DNA in therapy-naïve hepatocellular carcinoma patients: a pilot study.

Background: Hepatocellular carcinomas (HCCs) are not routinely biopsied, resulting in a lack of tumor materials for molecular profiling. Here we sought to determine whether plasma-derived cell-free DNA (cfDNA) captures the genetic alterations of HCC in patients who have not undergone systemic therapy. Patients and methods: Frozen biopsies from the primary tumor and plasma were synchronously collected from 30 prospectively recruited, systemic treatment-naïve HCC patients. Deep sequencing of the DNA from the biopsies, plasma-derived cfDNA and matched germline was carried out using a panel targeting 46 coding and non-coding genes frequently altered in HCCs. Results: In 26/30 patients, at least one somatic mutation was detected in biopsy and/or cfDNA. Somatic mutations in HCC-associated genes were present in the cfDNA of 63% (19/30) of the patients and could be detected 'de novo' without prior knowledge of the mutations present in the biopsy in 27% (8/30) of the patients. Mutational load and the variant allele fraction of the mutations detected in the cfDNA positively correlated with tumor size and Edmondson grade. Crucially, among the seven patients in whom the largest tumor was ≥5 cm or was associated with metastasis, at least one mutation was detected 'de novo' in the cfDNA of 86% (6/7) of the cases. In these patients, cfDNA and tumor DNA captured 87% (80/92) and 95% (87/92) of the mutations, suggesting that cfDNA and tumor DNA captured similar proportions of somatic mutations. Conclusion: In patients with high disease burden, the use of cfDNA for genetic profiling when biopsy is unavailable may be feasible. Our results support further investigations into the clinical utility of cfDNA in a larger cohort of patients.

Distribution of IL28B Polymorphism in a Cohort of Italians and Immigrants with HCV Infection: Association with Viraemia, Stage of Fibrosis and Response to Treatment.

Aims of the study are to investigate, in a cohort of patients affected by HCV chronic hepatitis with genotypes 1 and 4, the prevalence of interleukin 28B (IL28B) genotypes, the possible association between IL28B polymorphism and severity of liver damage, the role of IL28B CC as a predictor of outcome. 365 patients with HCV infection were observed between 2013 and 2014. Demographic, virological, biochemical, and genetic characteristics of each patient were investigated. Liver fibrosis was assessed by transient elastometry. Mean age of the patients (72.9 % males, 27.1 % females) is 50 years. 91.5 % % of patients are Caucasian, 8.5 % African. In the patients with HCV1 and HCV4 a higher frequency of IL28B CT is observed with a prevalence of 52.1 and 61.8 % respectively. As regards ethnic group, African people have a prevalence of 35.5 % for CC, while Caucasians have a prevalence of 23.8 % for CC. In our cohort, IL28B polymorphism does not show significant differences among ethnic groups and in HCV1 and HCV4 genotypes. As described in literature, IL28B CC genotype is confirmed as predictor of sustained virological response in both Caucasians and Africans. A significant correlation between liver fibrosis and IL28B polymorphism emerges.

Cigarette smoke alters cell cycle and induces inflammation in lung fibroblasts.

BACKGROUND: Lung fibroblasts are crucial for the integrity of alveolar structure. Cigarette smoking, the major risk factor for chronic obstructive pulmonary disease, impairs the repair functions of lung fibroblasts. AIMS: The study simultaneously assessed for the first time cell cycle, p53, p21, p38, ERK 1/2 and IL-8. MAIN METHODS: Primary foetal lung fibroblasts (HFL-1) and primary lung fibroblasts from former (n = 5) and current (n = 5) smokers with/without cigarette smoke extracts (CSEs) and inhibitors of p38 and ERK1/2 were studied for cell cycle events and for marker expression by flow-cytometry, western-blot analysis and ELISA. KEY FINDINGS: CSE exposure did not induce caspase 3 cleavage or DNA laddering but reduced S phase, and increased G1 and G2/M in HFL-1. Furthermore CSE increased: p53 and p21 expression; p38 and ERK 1/2 pathway activation; and IL-8 release. Inhibitors of p38 and ERK 1/2 reversed the effects of CSE on cell cycle and on IL-8 release. ERK 1/2 inhibitor was able to reverse the effects of CSE on p21 expression. Primary lung fibroblasts from current smokers had higher ERK 1/2 activation in comparison to normal primary fibroblasts and higher percentage of cells in G1 phase and lower percentage of cells in S phase in comparison to former smoker fibroblasts. SIGNIFICANCE: Cigarette smoke may affect the reparative potential of lung fibroblasts altering the expression of p53 and p21 and the progression of the cell cycle to S phase. All these events are promoted by the activation of pro-inflammatory pathways.

Doppler-stabilized fiber link with 6 dB noise improvement below the classical limit.

It is known that temperature variations and acoustic noise affect ultrastable frequency dissemination along optical fiber. Active stabilization techniques are adopted to compensate for the fiber-induced phase noise. However, despite this compensation, the ultimate link performances are limited by the delay-unsuppressed noise that is related to the propagation delay of the light in the fiber. We demonstrate a post-processing approach which enables us to overcome this limit. We implement a subtraction algorithm between the optical signal delivered at the remote link end and the round-trip signal. In this way, a 6 dB improvement beyond the delay-unsuppressed noise is obtained. We confirm the prediction with experimental data obtained on a 47 km metropolitan fiber link and propose how to extend this method for frequency dissemination.

Platelet rich plasma in the treatment of bisphosphonate-related osteonecrosis of the jaw: personal experience and review of the literature.

Bisphosphonates (BPs) are a class of synthetic drugs commonly used to treat bone metastasis and various bone diseases that cause osseous fragility (such as osteoporosis). Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a common complication in patients who received BPs, especially intravenously. Recently, osteonecrosis of the jaw (ONJ) caused by chemotherapeutic not belonging to BPs drug class has been reported. For this reason, it has been proposed recently to rename BRONJ in antiresorptive agents related osteonecrosis of the jaw (ARONJ), to include a wider spectrum of drugs that may cause osteonecrosis of the jaw. The most debated topic about ARONJ/BRONJ is therapy. The most adequate procedure is far from being standardized and prevention seems to play a pivotal role. In our study, we considered 72 patients with BRONJ with nonsurgical therapy, surgical therapy, and surgical therapy with platelet rich plasma (PRP) gel to evaluate its therapeutic effect in promoting ONJ wounds healing. Good results showed by PRP in improving wound healing give away to case-control randomized studies that could give definitive evidence of its effectiveness.

Frequency transfer via a two-way optical phase comparison on a multiplexed fiber network.

We performed a two-way remote optical phase comparison on optical fiber. Two optical frequency signals were launched in opposite directions in an optical fiber and their phases were simultaneously measured at the other end. In this technique, the fiber noise is passively canceled, and we compared two optical frequencies at the ultimate 10(-21) stability level. The experiment was performed on a 47 km fiber that is part of the metropolitan network for Internet traffic. The technique relies on the synchronous measurement of the optical phases at the two ends of the link, which is here performed by digital electronics. This scheme offers some advantages with respect to active noise cancellation schemes, as the light travels only once in the fiber.

High-accuracy measurement of the blackbody radiation frequency shift of the ground-state hyperfine transition in 133Cs.

We report a high-accuracy direct measurement of the blackbody radiation shift of the 133Cs ground-state hyperfine transition. This frequency shift is one of the largest systematic frequency biases encountered in realizing the current definition of the International System of Units (SI) second. Uncertainty in the blackbody radiation frequency shift correction has led to its being the focus of intense theoretical effort by a variety of research groups. Our experimental measurement of the shift used three primary frequency standards operating at different temperatures. We achieved an uncertainty a factor of five smaller than the previous best direct measurement. These results tend to validate the claimed accuracy of the recently calculated values.

Prevalence of latent tuberculosis, syphilis, hepatitis B and C among asylum seekers in Malta.

BACKGROUND: In the last few years, Malta has witnessed increasing immigration flows from the Libyan coasts. Public health policies are focused on screening migrants for tuberculosis, whereas no systematic actions against STIs are implemented. The aim of this study is to define the epidemiological profile of asylum seekers in Malta as regards syphilis, hepatitis B, C and latent tuberculosis, thus supporting screening policies. METHODS: Five hundred migrants living in open centres were screened between December 2010 and June 2011. RESULTS: 83.2% of people was from Somalia, 81.2% males, average age 26.5 years. The tuberculin skin test (TST) was positive in 225 migrants (45%). Latent syphilis was diagnosed in 11 migrants, hepatitis C in 3 and 31 migrants were HBsAg positive. CONCLUSION: Systematic screening for asymptomatic migrants in Malta is not recommended for hepatitis C and syphilis, given the low prevalence observed. On the contrary, it should be considered for hepatitis B. TST could be indicated as the first step of a two step screening for migrants from countries with high TB incidence. Efficacy and cost-effectiveness could be achieved by further targeting screening to specific subgroups at higher risk of reactivation, such as people living with HIV and subjects affected by chronic diseases.

Epidemiological analysis on 2375 patients with TMJ disorders: basic statistical aspects.

The aim of this work was to present data from a large sample of patients with Temporo-Mandibular Disorders (TMD) in order to clarify some aspects of the development of pathological conditions that affect large parts of the population. This preliminary work put in relation, through an epidemiological evaluation, anamnestic and clinical data collected from a sample of 2375 patients affected by TMD. Personal data were provided by questionnaire (age, sex, status, etc.), while clinical data were collected following a specific medical chart compiled in accordance with international criteria for TMD. An analysis of these data clearly showed that there were large quantities of variables involved in these disorders and which occur with a wide variety possible of clinical signs. This complexity, in accordance with the current knowledge that it is not able to clarify the etiology of these disorders, makes intricate both diagnostic then therapeutic aspects. You would find in front of a multi-factorial systemic disease that, interfering with the individual bioavailability, exposes him to the possibility of perceiving noxious stimuli which otherwise would not able to reach the pain threshold. To support this hypothesis is the data founded in this report that showed how many patients suffered, at the same time, by muscle and spinal pain associated to headache, pain that occur with high frequency from the same side. The presence of these painful conditions tends to underestimate the dysfunctional problems even if they occur with greater clinical prevalence. Further research should be carried out to clarify these controversial issues.

Large-area fiber-optic gyroscope on a multiplexed fiber network.

We describe a fiber-optic gyroscope based on the Sagnac effect, realized on a multiplexed telecom fiber network. Our loop encloses an area of 20 km² and coexists with Internet data traffic. This Sagnac interferometer is capable of detecting signals that are larger than 10(-8) (rad/s)/√Hz, thus approaching ring laser gyroscopes without using a narrow-linewidth laser or sophisticated optics. The proposed gyroscope could be useful for seismic applications, opening new possibilities for this kind of optical fiber sensor.