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Chronic lymphedema causes psychophysical sequelae jeopardizing quality of life (QoL) of breast cancer (BC) survivors, and lack of effective therapies represents a major challenge for healthcare professionals. Structured adapted physical activity (APA) may represent an effective strategy to attenuate cancer treatment-related impairments and improve QoL. Here, we describe the effects of a specific APA intervention based on a novel multiperspective methodology in counteracting lymphedema-related morphofunctional alterations and improving QoL of BC survivors.BC survivors with chronic moderate/severe lymphedema attending the Cancer Rehabilitation Center in Florence were assessed before and after 8-week APA. The protocol consisted of both APA specialist-supervised and self-leaded sessions using a tailor-designed proprioceptive board. Body mass index, bioimpedance parameters, indirect upper limb volume measurement, and ultrasonography were performed. Wrist flexion/extension and hand strength functional tests were also executed. QoL, depression/anxiety and pain intensity were evaluated by ULL27, HADS, distress thermometer and NRS questionnaires, respectively.Although bioimpedance, ultrasound and volumetric measures remained mostly unchanged, wrist mobility, pain perception, depression, and QoL were all significantly ameliorated after APA.Our findings suggest that a multidisciplinary treatment approach involving APA professionals should be employed in the management of BC-related lymphedema to improve patient psychophysical outcomes and QoL.

Despite the development of new targeted and immune therapies, the prognosis of metastatic melanoma remains bleak. Therefore, it is critical to better understand the mechanisms controlling advanced melanoma to develop more effective treatment regimens. Hedgehog/GLI (HH/GLI) signaling inhibitors targeting the central pathway transducer Smoothened (SMO) have shown to be clinical efficacious in skin cancer; however, several mechanisms of non-canonical HH/GLI pathway activation limit their efficacy. Here, we identify a novel SOX2-BRD4 transcriptional complex driving the expression of GLI1, the final effector of the HH/GLI pathway, providing a novel mechanism of non-canonical SMO-independent activation of HH/GLI signaling in melanoma. Consistently, we find a positive correlation between the expression of GLI1 and SOX2 in human melanoma samples and cell lines. Further, we show that combined targeting of canonical HH/GLI pathway with the SMO inhibitor MRT-92 and of the SOX2-BRD4 complex using a potent Proteolysis Targeted Chimeras (PROTACs)-derived BRD4 degrader (MZ1), yields a synergistic anti-proliferative effect in melanoma cells independently of their BRAF, NRAS, and NF1 mutational status, with complete abrogation of GLI1 expression. Combination of MRT-92 and MZ1 strongly potentiates the antitumor effect of either drug as single agents in an orthotopic melanoma model. Together, our data provide evidence of a novel mechanism of non-canonical activation of GLI1 by the SOX2-BRD4 transcriptional complex, and describe the efficacy of a new combinatorial treatment for a subset of melanomas with an active SOX2-BRD4-GLI1 axis.

Background Diastasis recti is an abdominal wall defect that occurs frequently in women during pregnancy. Patients with diastasis can experience lower back pain, uro-gynecological symptoms, and discomfort at the level of the defect. Diastasis recti is diagnosed when the inter-rectus distance is > 2 cm. Several techniques, including both minimally invasive and open access surgical treatment, are available. Abdominoplasty with plication of the anterior rectus sheath is the most commonly used, with the major limitation of requiring a wide skin incision. The new technique we propose is a modification of Costa’s technique that combines Rives–Stoppa principles and minimally invasive access using a surgical stapler to plicate the posterior sheaths of the recti abdominis. Methods It is a fully laparoscopic technique. The pneumoperitoneum is induced from a sovrapubic trocar, placed using an open access technique. The posterior rectus sheath is dissected from the rectus muscle using a blunt dissector to create a virtual cavity. The posterior sheets of the recti muscles are plicated using an endo-stapler. A mesh is then placed in the retromuscular space on top of the posterior sheet without any fixation. Using a clinical questionnaire, we analyzed the outcomes in 74 patients who underwent minimally invasive repair for diastasis of the rectus abdominis sheath. Results Seventy-four patients (9 men and 65 women) were treated using this technique. Follow-up was started two months after surgery. All procedures were conducted successfully. There were no major complications or readmissions. No postoperative infections were reported. There were two recurrences after six months. There was a significant reduction in symptoms. Conclusions This new method is feasible and has achieved promising results, even though a longer follow-up is needed to objectively assess this technique.

The worldwide spread of SARS-CoV-2 has been responsible for an infectious pandemic, with repercussions on socio-economic aspects and on the physical and mental health of the general population. The present systematic review aimed to evaluate the data belonging to the European framework, analyzing the population by age group. Original articles and reviews on the state of mental health of the general European population have been researched starting from 2021. Initially, a total of 1764 studies were found, among which a total of 75 were selected. Youth were the age group most affected by pandemic consequences on mental health, with emotional and behavioral alterations observed from a third to more than a half of children and adolescents examined. Among both adolescents and adults, the female gender had a higher prevalence of psychopathological symptoms. The main risk factors were poor social support, economic difficulties, and, in particular, unemployment or job changes. Additional individual risk factors were the perception of loneliness, the presence of pre-pandemic mental illness/distress, and some personality traits, such as neuroticism, impulsiveness, and the use of maladaptive coping strategies. Unexpectedly, the elderly maintained good resilience towards change, even if a stress factor was represented by the feeling of loneliness and poor social contact. As regards suicidal behaviors, among adolescents, there was an increase in attempts of 25%, with a greater risk for the female gender. This risk increased also among adults, in association with symptoms of anxiety and depression, and poor socio-environmental conditions. In conclusion, some population groups were found to be at greater risk of psychological burden during pandemic waves, thus representing priority targets for socio-health interventions.

Purpose Clinical trials have demonstrated the favorable efficacy/safety profile of pasireotide in patients with Cushing’s disease (CD). We report interim long-term results of an ongoing real-world evidence study of subcutaneous pasireotide in patients with CD. Methods Adults with CD receiving pasireotide, initiated before (prior-use) or at study entry (new-use), were monitored for ≤ 3 years during a multicenter observational study (http://clinicaltrials.gov identifier NCT02310269). Primary objective was to assess long-term safety of pasireotide alone or with other CD therapies. Results At the time of this interim analysis, 127 patients had received pasireotide (new-use, n = 31; prior-use, n = 96). Eight patients had completed the 3-year observation period, 53 were ongoing, and 66 had discontinued. Among 31 new-use and 92 prior-use patients with ≥ 1 safety assessment, respectively: 24 (77%) and 37 (40%) had drug-related adverse events (AEs); 7 (23%) and 10 (11%) had serious drug-related AEs. Most common drug-related AEs were nausea (14%), hyperglycemia (11%) and diarrhea (11%); these were more frequently reported in new users and mostly of mild-to-moderate severity. 14 (45%) new-use and 15 (16%) prior-use patients experienced hyperglycemia-related AEs. Mean urinary free cortisol (mUFC) was within normal range at baseline and months 1, 12 and 24, respectively, in: 1/16 (6%), 9/18 (50%), 1/3 (33%) and 0/0 new users; 28/43 (65%), 15/27 (56%), 27/33 (82%) and 12/19 (63%) prior users. Conclusions Pasireotide is well tolerated and provides sustained reductions in mUFC during real-world treatment of CD. The lower rate of hyperglycemia-related AEs in prior users suggests that hyperglycemia tends not to deteriorate if effectively managed soon after onset. Clinical Trial Registration Number: NCT02310269.

Context Patients with amiodarone-induced thyrotoxicosis (AIT) and severely reduced left ventricular ejection fraction (LVEF) have a high mortality rate that may be reduced by total thyroidectomy. Whether in this subset of patients thyroidectomy should be performed early during thyrotoxicosis or later after restoration of euthyroidism has not yet been settled. Objectives Mortality rates, including peritreatment mortality and 5-year cardiovascular mortality, and predictors of death, evaluated by Cox regression analysis. Methods Retrospective cohort study of 64 consecutive patients with AIT selected for total thyroidectomy from 1997 to 2019. Four groups of patients were identified according to serum thyroid hormone concentrations and LVEF: Group 1 (thyrotoxic, LVEF Results Among patients with low LVEF (Groups 1 and 3), mortality was higher in patients undergoing thyroidectomy after restoration of euthyroidism (Group 3) than in those submitted to surgery when still thyrotoxic (Group 1): peritreatment mortality rates were 40% versus 0%, respectively (P = .048), whereas 5-year cardiovascular mortality rates were 53.3% versus 12.3%, respectively (P = .081). Exposure to thyrotoxicosis was longer in Group 3 than in Group 1 (112 days, interquartile range [IQR] 82.5-140, vs 76 days, IQR 24.8-88.5, P = .021). Survival did not differ in patients with LVEF ≥40% submitted to thyroidectomy irrespective of being thyrotoxic (Group 2) or euthyroid (Group 4): in this setting, peritreatment mortality rates were 6.3% versus 4% (P = .741) and 5-year cardiovascular mortality rates were 12.5% and 20% (P = .685), respectively. Age (hazard ratio [HR] 1.104, P = .029) and duration of exposure to thyrotoxicosis (HR 1.004, P = .039), but not presurgical serum thyroid hormone concentrations (P = .577 for free thyroxine, P = .217 for free triiodothyronine), were independent predictors of death. Conclusions A prolonged exposure to thyrotoxicosis resulted in increased mortality in patients with reduced LVEF, which may be reduced by early thyroidectomy.

Traumatic brain injury (TBI) during birth constitutes one of the most relevant causes of mortality and morbidity in newborns worldwide. Although improvements in obstetrical management and better indications for caesarean section have led to a consistent decrease in the incidence of perinatal mechanical injury, vacuum extraction is still associated with a high complications rate leading to several forensic issues in the evaluation of healthcare professional management.Vacuum-associated lesions may be topographically distinguished as extracranial or intracranial injuries. In order to achieve a correct assessment, diagnostic procedure should include post-mortem computed tomography and magnetic resonance imaging, autopsy examination, brain sampling and histological/immunohistochemical examination.Post-mortem imaging represents a valid aid to guarantee preliminary evidence and direct subsequent investigations. An appropriate autopsy sampling must include several areas of cortex and underlying white matter; moreover, any visceral hemorrhages or other lesions should be sampled for the histological and immunohistochemical assessment of vitality and timing.This study aimed to promote a validated step-by-step procedure to be adopted in order to standardize and to make easier the post-mortem framing and timing of vacuum-associated pediatric brain injuries.

Falls may lead to hip fractures, which have a detrimental effect on the prognosis of patients as well as a considerable impact on healthcare expenditures. Since a secondary hip fracture (SHF) may lead to even higher costs than primary fractures, the development of innovative services is crucial to limit falls and curb costs in high-risk patients. An early economic evaluation assessed which patients with a second hip fracture could benefit most from an exoskeleton preventing falls and whether its development is feasible.The life-course of hip fractured patients presenting with dementia or cardiovascular diseases was simulated using a Markov model relying on the United Kingdom administrative data and complemented by published literature. A group of experts provided the exoskeleton parameters. Secondary analyses included a threshold analysis to identify the exoskeleton requirements (e.g. minimum impact of the exoskeleton on patients' quality of life) leading to a reimbursable incremental cost-effectiveness ratio. Similarly, the uncertainty around these requirements was modelled by varying their standard errors and represented alongside population Expected Value of Perfect Information (EVPI).Our base-case found the exoskeleton cost-effective when providing a statistically significant reduction in SHF risk. The secondary analyses identified 286 cost-effective combinations of the exoskeleton requirements. The uncertainty around these requirements was explored producing further 22,880 scenarios, which showed that this significant reduction in SHF risk was not necessary to support the exoskeleton adoption in clinical practice. Conversely, a significant improvement in women quality of life was crucial to obtain an acceptable population EVPI regardless of the cost of the exoskeleton.Our study identified the exoskeleton requisites to be cost-effective and the value of future research. Decision-makers could use our analyses to assess not only whether the exoskeleton could be cost-effective but also how much further research and development of the exoskeleton is worth to be pursued.

Although lithium is widely used in current practice to treat bipolar disorder (BD) and treatment-resistant major depressive disorder (MDD) among older adults, little is known about its efficacy and tolerability in this population, which is generally excluded from randomized clinical trials. The objective of this study was to evaluate the efficacy and tolerability of long-term use of lithium among older adults with BD and MDD.Data from the Cohort of individuals with Schizophrenia and mood disorders Aged 55 years or more (CSA) were used. Two groups of patients with BD and MDD were compared: those who were currently receiving lithium versus those who were not. The effects of lithium on psychiatric (i.e., depressive symptoms severity, perceived clinical severity, rates of psychiatric admissions in the past-year), geriatric (overall and cognitive functioning) and physical outcomes (i.e., rates of non-psychiatric medical comorbidities and general hospital admissions in the past-year) were evaluated. All analyses were adjusted for age, sex, duration of disorder, diagnosis, smoking status, alcohol use, and use of antipsychotics, antiepileptics or antidepressants.Among the 281 older participants with BD or MDD, 15.7% were taking lithium for a mean duration of 12.5(SD = 11.6) years. Lithium use was associated with lower intensity of depressive symptoms, reduced perceived clinical global severity and lower benzodiazepine use (all p 0.05), without being linked to greater rates of medical comorbidities, except for hypothyroidism.Data were cross-sectional and data on lifetime history of psychotropic medications was not assessed.Our results suggest that long-term lithium use may be efficient and relatively well-tolerated in older adults with BD or treatment-resistant MDD.

Polypharmacy increases the risk of potentially inappropriate prescribing. STOPP&START criteria identify a group of drugs representing inappropriate medication and a group of drugs representing potential prescribing omissions. To evaluate the appropriateness of prescription of antiplatelet and anticoagulant drugs in a sample of patients admitted to an internal medicine ward and their impact on three different outcomes: length of hospitalization, intra-hospital death, and risk of re-admission in the hospital. We analyzed a cohort of 485 inpatients followed for 1 year after discharge from the hospital. The study sample had a mean age of 70.4 ± 17.6 years, and 48.9% were female. Clinical indication for antiplatelet was not appropriate in 41.2% of the subjects. Anticoagulant therapy was not appropriate in 22.8% of the subjects: there was incorrect clinical indication in 5/33 and inappropriate dosing in 28/33. START criteria for antiplatelet drug, but neither STOPP criteria for antiplatelet nor for anticoagulant was positively associated with the length of hospitalization (t = 3.08, p

ObjectivesWe aimed to assess the expression of the CCL24 chemokine in systemic sclerosis (SSc) and to evaluate the possible pathogenic implications of the CCL24/CCR3 axis using both in vitro and in vivo models. We further investigated the efficacy of an anti-CCL24 monoclonal antibody (mAb), CM-101, in inhibiting cell activation as well as dermal and pulmonary inflammation and fibrosis in experimental animal models.MethodsWe used ELISA and fluorescence immunohistochemistry to determine CCL24 levels in serum and CCL24/CCR3 expression in skin biopsies of SSc patients. Skin fibroblasts and endothelial cells treated with CCL24 or SSc serum with or without CM-101 were used to follow cell activation and differentiation. Prevention and treatment in vivo bleomycin (BLM)-induced models were used to evaluate experimental dermal and pulmonary fibrosis progression following treatment with the CM-101 mAb.ResultsCCL24 circulating levels were significantly elevated in SSc patients. CCL24/CCR3 expression was strongly increased in SSc skin. Blockade of CCL24 with CM-101 significantly reduced the activation of dermal fibroblasts and their transition to myofibroblasts induced by SSc serum. CM-101 was also able to significantly inhibit endothelial cell activation induced by CCL24. In BLM-induced experimental animal models, CM-101 profoundly inhibited both dermal and pulmonary fibrosis and inflammation.ConclusionsCCL24 plays an important role in pathological processes of skin and lung inflammation and fibrosis. Inhibition of CCL24 by CM-101 mAb can be potentially beneficial for therapeutic use in SSc patients.

Telocytes have recently emerged as unique interstitial cells defined by their extremely long, thin and moniliform prolongations termed telopodes. Despite growing evidence that these cells consistently reside in the stromal compartment of various organs from human beings, studies dealing with telocytes in structures of the oral cavity are scarce. Hence, the present morphologic study was undertaken to explore for the first time the presence and specific localization of telocytes within tissues of the normal human tongue, a complex muscular organ whose main functions include taste, speech, and food manipulation in the oral cavity. Telocytes were initially identified by CD34 immunostaining and confirmed by CD34/PDGFRα double immunofluorescence and transmission electron microscopy. CD34+/PDGFRα+ telocytes were organized in interstitial meshworks either in the tongue lamina propria or in the underlying striated muscle. Lingual telocytes were immunonegative for CD31, c-kit and α-SMA. Telopodes were finely distributed throughout the stromal space and concentrated beneath the lingual epithelium and around CD31+ vessels, skeletal muscle bundles/fibers, and intramuscular nerves and ganglia. They also enveloped salivary gland units outside the α-SMA+ myoepithelial cells and delimited lymphoid aggregates. These findings establish telocytes as a previously overlooked interstitial cell population worth investigating further in the setting of human tongue pathophysiology.

Introduction: Serum thyrotropin (TSH) receptor antibodies (TRAbs) are occasionally found in patients with amiodarone-induced thyrotoxicosis (AIT), and usually point to a diagnosis of type 1 AIT (AI...

Alkaptonuria (AKU), a rare genetic disorder, is characterized by the accumulation of homogentisic acid (HGA) in organs due to a deficiency in functional levels of the enzyme homogentisate 1,2-dioxygenase (HGD), required for the breakdown of HGA, because of mutations in the HGD gene. Over time, HGA accumulation causes the formation of the ochronotic pigment, a dark deposit that leads to tissue degeneration and organ malfunction. Such behaviour can be observed also in vitro for HGA solutions or HGA-containing biofluids (e.g. urine from AKU patients) upon alkalinisation, although a comparison at the molecular level between the laboratory and the physiological conditions is lacking. Indeed, independently from the conditions, such process is usually explained with the formation of 1,4-benzoquinone acetic acid (BQA) as the product of HGA chemical oxidation, mostly based on structural similarity between HGA and hydroquinone that is known to be oxidized to the corresponding para-benzoquinone. To test such correlation, a comprehensive, comparative investigation on HGA and BQA chemical behaviours was carried out by a combined approach of spectroscopic techniques (UV spectrometry, Nuclear Magnetic Resonance, Electron Paramagnetic Resonance, Dynamic Light Scattering) under acid/base titration both in solution and in biofluids. New insights on the process leading from HGA to ochronotic pigment have been obtained, spotting out the central role of radical species as intermediates not reported so far. Such evidence opens the way for molecular investigation of HGA fate in cells and tissue aiming to find new targets for Alkaptonuria therapy.

BACKGROUND Disease phenotype and outcome of late-onset Crohn's disease are still poorly defined. METHODS In this Italian nationwide multicentre retrospective study, patients diagnosed ≥65 years (late-onset) were compared with young adult-onset with 16-39 years and adult-onset Crohn's disease 40-64 years. Data were collected for 3 years following diagnosis. RESULTS A total of 631 patients (late-onset 153, adult-onset 161, young adult-onset 317) were included. Colonic disease was more frequent in late-onset (P < 0005), stenosing behaviour was more frequent than in adult-onset (P < 0003), but fistulising disease was uncommon. Surgery rates were not different between the three age groups. Systemic steroids were prescribed more frequently in young adult-onset in the first year, but low bioavailability steroids were used more frequently in late-onset in the first 2 years after diagnosis (P < 0.036, P < 0.041, respectively). The use of immunomodulators and anti-TNF's even in patients with more complicated disease, that is, B2 or B3 behaviour (Montreal classification), remained significantly inferior (P < 0.0001) in late-onset compared to young adult-onset. Age at diagnosis, Charlson comorbidity index, and steroid used in the first year were negatively associated with the use of immunomodulators and biologics. Comorbidities, related medications and hospitalizations were more frequent in late-onset. Polypharmacy was present in 56% of elderly Crohn's disease patients. CONCLUSION Thirty-two percent of late-onset Crohn's disease presented with complicated disease behaviour. Despite a comparable use of steroids and surgery, immunomodulators and biologics were used in a small number of patients.

BACKGROUND We report a prospective, nationwide cohort evaluating the safety and effectiveness of CT-P13. METHODS A structured database was used to record serious adverse events (SAEs), clinical remission/response, inflammatory biomarkers (CRP and calprotectin), and endoscopic findings. RESULTS Eight hundred ten patients with inflammatory bowel disease (IBD) (452 Crohn's disease [CD]) were enrolled. Four hundred fifty-nine patients were naive to anti-TNFα (group A), 196 had a previous exposure (group B), and the remaining 155 were switched to CT-P13 (group C). All patients were included in the safety evaluation with a mean follow-up of 345 ± 215 days and a total number of 6501 infusions. One hundred fifty-four SAEs were reported (19%), leading to cessation of the biosimilar in 103 subjects (12.7%). Infusion reactions were 71, leading to cessation of the biosimilar in 53 subjects (6.5%), being significantly more frequent in patients pre-exposed to anti-TNFα (P = 0.017). The efficacy of therapy was calculated in 754 IBD patients, with a mean follow-up of 329 ± 202 days. Forty-eight patients had a primary failure (6.4%), and 188 (25.6%) lost response during follow-up. Six hundred twenty-eight (364 CD) and 360 IBD patients (222 CD) completed the follow-up at 6 and 12 months, respectively. At 12 months, patients without loss of response were 71%, 64%. and 82% in groups A, B, and C, respectively (log rank P = 0.01). Clinical/endoscopic scores and inflammatory biomarkers dropped significantly in CD and UC patients (P = 0.01 and P < 0.0001) compared with baseline. CONCLUSIONS In this large prospective cohort, no further signals of difference in safety and effectiveness of CT-P13 in IBD has been observed.

The finding of corpse parts poses several challenges for the forensic pathologist presenting implications for identification, diagnosis of death and determination of wounds vitality. Further interpretative difficulties in cases of cadaveric dismemberment derive from the scarcity of tanatochronological parameters useful to estimate the post-mortem interval (PMI) and the absence of uniform investigative protocols in the different centres of forensic pathology. The present study proposes an investigation protocol for the cadaveric dismemberment through the discussion of a case series. The study group consisted of cases in which the dismemberment was performed after the murder. For all cases, a study protocol based on crime scene investigation, post-mortem computed tomography (PMCT), autopsy, toxicological, histological, immunohistochemical and genetic investigations was implemented. In particular, the standardised use of radiographic study before the autopsy allows all to have information that can guide the forensic pathologist during the autopsy. The use of immunohistochemistry allows an assessment of the vitality of the lesions possibly involved in the determinism of death, as well as of the surfaces of dismemberment, representing a tool of considerable utility for forensic purposes. The genetic investigations allow the identification of the victims, while the toxicological ones highlight the possible abuse of substances. The implemented protocol presents a demonstrated usefulness in improving diagnostic accuracy in corpse dismemberment cases.

Purpose The aim of this study was to evaluate the microscopic structure of a human cornea 2 years after manual deep anterior lamellar keratoplasty (DALK) for keratoconus with a recipient residual stromal bed thickness of 100 μm, using light and transmission electron microscopy. Methods A human cornea treated with manual DALK for keratoconus 2 years before was removed during penetrating keratoplasty because of stromal opacity of unknown origin, involving about half of the sample. The transparent half of the specimen was processed for light and transmission electron microscopy. Results Light microscopy examination performed with different staining techniques (hematoxylin and eosin, Picrosirius red, and Masson trichrome) revealed a homogeneous stroma. No interface was detected. Electron microscopy confirmed these findings. Conclusions This study confirmed the available clinical and confocal studies that show progressive stromal remodeling after manual DALK. Two years after surgery, no posterior stromal interface was detected.

Headache is a common finding in the postpartum period, caused by a spectrum of different conditions. Most headaches in the postpartum period are self-limiting and benign in etiology, but there are some potentially serious causes to be considered. We disclose two cases of postpartum headache, initially considered as post-dural puncture headache (PDPH), that evolved into a harmful condition and showed that an expanded differential diagnosis for headache in the postpartum is mandatory, requiring a high level of attention from health professionals. In fact, a careful examination of the medical history, physical examination, and the recognition for the need for early neuroradiological imaging should increase diagnostic accuracy.

Background Falls may lead to hip fractures, which have a detrimental effect on the prognosis of patients as well as a considerable impact on healthcare expenditures. Since a secondary hip fracture (SHF) may lead to even higher costs than primary fractures, the development of innovative services is crucial to limit falls and curb costs in high-risk patients. An early economic evaluation assessed which patients with a second hip fracture could benefit most from an exoskeleton preventing falls and whether its development is feasible. Methods The life-course of hip fractured patients presenting with dementia or cardiovascular diseases was simulated using a Markov model relying on the United Kingdom administrative data and complemented by published literature. A group of experts provided the exoskeleton parameters. Secondary analyses included a threshold analysis to identify the exoskeleton requirements (e.g. minimum impact of the exoskeleton on patients’ quality of life) leading to a reimbursable incremental cost-effectiveness ratio. Similarly, the uncertainty around these requirements was modelled by varying their standard errors and represented alongside population Expected Value of Perfect Information (EVPI). Results Our base-case found the exoskeleton cost-effective when providing a statistically significant reduction in SHF risk. The secondary analyses identified 286 cost-effective combinations of the exoskeleton requirements. The uncertainty around these requirements was explored producing further 22,880 scenarios, which showed that this significant reduction in SHF risk was not necessary to support the exoskeleton adoption in clinical practice. Conversely, a significant improvement in women quality of life was crucial to obtain an acceptable population EVPI regardless of the cost of the exoskeleton. Conclusions Our study identified the exoskeleton requisites to be cost-effective and the value of future research. Decision-makers could use our analyses to assess not only whether the exoskeleton could be cost-effective but also how much further research and development of the exoskeleton is worth to be pursued.

Objectives SSc is an autoimmune disease characterized by peripheral vasculopathy and skin and internal organ fibrosis. Accumulating evidence underlines a close association between a metabolic reprogramming of activated fibroblasts and fibrosis. This prompted us to determine the metabolism of SSc dermal fibroblasts and the effect on the vasculopathy characterizing the disease. Methods A Seahorse XF96 Extracellular Flux Analyzer was used to evaluate SSc fibroblast metabolism. In vitro invasion and capillary morphogenesis assays were used to determine the angiogenic ability of endothelial cells (ECs). Immunofluorescence, flow cytometry and real-time PCR techniques provided evidence of the molecular mechanism behind the impaired vascularization that characterizes SSc patients. Results SSc fibroblasts, compared with controls, showed a boosted glycolytic metabolism with increased lactic acid release and subsequent extracellular acidification that in turn was found to impair EC invasion and organization in capillary-like networks without altering cell viability. A molecular link between extracellular acidosis and endothelial dysfunction was identified as acidic ECs upregulated MMP-12, which cleaves and inactivates urokinase-type plasminogen activator receptor, impairing angiogenesis in SSc. Moreover, the acidic environment was found to induce the loss of endothelial markers and the acquisition of mesenchymal-like features in ECs, thus promoting the endothelial-to-mesenchymal transition process that contributes to both capillary rarefaction and tissue fibrosis in SSc. Conclusion This study showed the relationship of the metabolic reprogramming of SSc dermal fibroblasts, extracellular acidosis and endothelial dysfunction that may contribute to the impairment and loss of peripheral capillary networks in SSc disease.

Background: Growing evidence indicates that physical/sporting activities may improve the health outcomes and quality of life (QoL) of breast cancer (BC) survivors. Since recent reports have suggested that sailing can improve the psychophysical well-being and QoL of people with disabilities, this pilot study evaluated the effectiveness of a tailored sailing experience on the QoL and psychological distress (PD) of BC survivors. Methods: A group of 19 breast cancer survivors, who were attending the Cancer Rehabilitation Center in Florence, were invited to participate in a sailing school and completed a survey based on a structured online questionnaire assessing QoL and PD both on departure (baseline) and one week after returning (follow-up). The survey comprised a first part (i.e., sociodemographic characteristics and the practice of physical/sporting activities at baseline; sailing experience satisfaction at follow-up) and a second part (i.e., Short Form-12 (SF-12), State/Trait-Anxiety Inventory form Y (STAI-Y), distress thermometer questionnaires). A paired Student’s t-test was used to compare the baseline versus follow-up QoL and PD scores. Results: A statistically significant improvement in SF-12 mental component scores and a reduction in both STAI-Y state/trait components and distress thermometer scores were found after the sailing experience. Conclusions: We conclude that sailing practice could be a feasible intervention to increase the psychophysical well-being of BC survivors.

Background The aim of our retrospective study is to compare the efficacy and indications of transanal endoscopic microsurgery (TEM), endoscopic submucosal dissection (ESD), and endoscopic full-thickness resection device (FTRD) with Over-The-Scope Clip (OTSC®) System for en-bloc resection of rectal lesions. Methods This study collected 76 cases of rectal neoplasms from a single hospital institution. Primary endpoints were complete en-bloc resection, intraprocedural adverse events, R0 en-bloc resection and an early discharge of the patient. Secondary endpoints included procedure-related adverse events. Results Mean tumor sizes were statistically significant smaller among patients treated with FTRD rather than TEM and ESD. TEO and FTRD treated patients experienced a higher en-bloc resection rate, with a shorter procedure time and hospital stay. No significant difference concerning the R0 resection was found. TEO and FTRD recorded lower perforation rates as compared to ESD, whereas no difference emerged concerning the bleeding rate and the post-polypectomy syndrome rate. Conclusions Our study showed that each technique has specific features, so that each one offers advantages and disadvantages. Nevertheless, all of them ensure high en-bloc resection rates, whereas no difference exists for R0 resection rate. TEO provides the possibility to remove low rectal large lesions as compared to ESD and FTRD.

Since gastroduodenal FTRD system is commercially available, several data have been reported in Literature concerning duodenal full-thickness resections, whereas few cases of gastric full-thickness resections has been described. In this case series We report three patients treated with this innovative tool for resecting lesions of the gastric wall. The indications ranged notably: a neuroendocrine tumor in a difficult to treat environment in the first case, a recurrent adenocarcinoma in a poorly surgical candidate patient in the second case and a pre-pyloric lesion for the third patient. In the third patient, a complete pyloric stenosis due to the clip deployment occurred. Clinical success rate was 100%. Even if current Literature is still poor of articles dealing with gastric full-thickness resection device based on over-the-scope-clip system. Our case series show how this novel tool might be take into consideration for whenever both surgery and standard endoscopic resection techniques are poorly feasible.

Objective A standardization of minor salivary gland (MSG) histopathology in primary Sjogren's syndrome (pSS) has been recently proposed. Although there is strong agreement that germinal center (GC)-like structures should be routinely identified, due to their prognostic value, a consensus regarding the best protocol is still lacking. Aim of this study was to compare the performance of different histological techniques and operators to identify GC-like structures in pSS MSGs. MSG biopsies from 50 pSS patients were studied. Methods Three blinded operators (one pathologist and two rheumatologists with different years of experience in pSS MSG assessment) assessed 50 MSGs of which one slide was stained with haematoxylin and eosin (H&E) and consecutive slides were processed to investigate CD3/CD20, CD21 and Bcl-6 expression. Results By assessing 225 foci, the best agreement was between H&E-stained sections evaluated by the rheumatologist with more years of experience in pSS MSG assessment and CD3/CD20 segregation. In the foci with CD21 positivity, the agreement further increased. Bcl-6- foci could display a GC, detected with other staining, but not vice versa. Conclusion GC assessment on H&E-stained sections should be performed with caution, being operator-dependent. The combination of H&E with CD3/CD20 and CD21 staining should be recommended as it is reliable, feasible, able to overcome the bias of operator experience and easily transferrable into routine practice.

The standard corneal collagen cross-linking (CXL), that includes the removal of corneal epithelium to permit adequate penetration of riboflavin in the stroma, is an established procedure to halting keratoconus progression. However, as epithelial removal may cause postoperative pain and an increased risk of corneal infection, new therapeutic approaches have been proposed. Iontophoresis is a recently developed non-invasive technique which provides the use of electrical current during CXL to enhance transepithelial penetration of riboflavin into the corneal stroma. Here, we describe for the first time the morphological changes of the corneal stromal compartment in a patient with keratoconus who underwent in vivo iontophoresis-assisted CXL (ionto-CXL) before full-thickness corneal transplantation. Immunohistochemistry for type I collagen and CD34 was performed to investigate the stromal distribution of collagen fibers and keratocytes, respectively. The histology of ionto-CXL-treated keratoconic cornea, collected 6 months after the intervention, was compared with that of healthy corneas and either untreated or standard CXL-treated keratoconic corneas. An attempt to restore a normal stromal architecture was observed in the ionto-CXL-treated cornea compared with untreated keratoconic corneas. In particular, the ionto-CXL-treated cornea showed a parallel distribution of type I collagen fibers, although fiber interweaving appeared less organized than in healthy corneas and standard CXL-treated keratoconic corneas. Moreover, the distribution of CD34-positive keratocytes was improved in keratoconic corneas following ionto-CXL treatment, though a scattered CD34 immunoreactivity was still noticeable in the subepithelial stroma. This study provides histological evidence that ionto-CXL may represent a non-invasive alternative in the management of progressive keratoconus in adults.

A point mutation (P56S) in the gene-encoding vesicle-associated membrane-protein-associated protein B (VAPB) leads to an autosomal-dominant form of amyotrophic lateral sclerosis (ALS), classified as ALS-8. The mutant VAPB is characterized by ER-associated aggregates that lead to a complete reorganization of ER structures. Growing evidences suggest VAPB involvement in ALS pathomechanisms. In fact, numerous studies demonstrated VAPB alteration also in sporadic ALS (sALS) and showed the presence of its aggregates when others ALS-related gene are mutant. Recently, the identification of new biomarkers in peripheral blood mononuclear cells (PBMCs) has been proposed as a good noninvasive option for studying ALS. Here, we evaluated VAPB as a possible ALS pathologic marker analyzing PBMCs of sALS patients. Immunofluorescence analysis (IFA) showed a peculiar pattern of VAPB aggregates in sALS, not evident in healthy control (HC) subjects and in Parkinson&rsquo, s disease (PD) PBMCs. This specific pattern led us to suppose that VAPB could be misfolded in sALS. The data indirectly confirmed by flow cytometry assay (FCA) showed a reduction of VAPB fluorescent signals in sALS. However, our observations were not associated with the presence of a genetic mutation or altered gene expression of VAPB. Our study brings further evidences of the VAPB role in ALS as a diagnostic biomarker.

Context It is not known whether total thyroidectomy is more favorable than medical therapy for patients with amiodarone-induced thyrotoxicosis (AIT). Objective To compare total thyroidectomy with medical therapy on survival and cardiac function in AIT patients. Methods Observational longitudinal cohort study involving 207 AIT patients that had received total thyroidectomy (surgery group, n = 51) or medical therapy (medical therapy group, n = 156) over a 20-year period. AIT types and left ventricular ejection fraction (LVEF) classes were determined at diagnosis of AIT. Cardiac and thyroid function were reevaluated during the study period. Survival was estimated using the Kaplan-Meier method. Results Overall mortality and cardiac-specific mortality at 10 and 5 years, respectively, were lower in the surgery group than in the medical therapy group (P = 0.04 and P = 0.01, respectively). The lower mortality rate of the surgery group was due to patients with moderate to severely compromised LVEF (P = 0.005 vs medical therapy group). In contrast, mortality of patients with normal or mildly reduced LVEF did not differ between the 2 groups (P = 0.281 and P = 0.135, respectively). Death of patients with moderate to severe LV systolic dysfunction in the medical therapy group occurred after 82 days (interquartile range, 56–99), a period longer than that necessary to restore euthyroidism in the surgery group (26 days; interquartile range, 15–95; P = 0.038). Risk factors for mortality were age (hazard ratio [HR] = 1.036) and LVEF (HR = 0.964), whereas total thyroidectomy was shown to be a protective factor (HR = 0.210). LVEF increased in both groups after restoration of euthyroidism, above all in the most compromised patients in the surgery group. Conclusions Total thyroidectomy could be considered the therapeutic choice for AIT patients with severe systolic dysfunction, whereas it is not superior to medical therapy in those with normal or mildly reduced LVEF.

Type 2 amiodarone-induced thyrotoxicosis (AIT2) is a form of drug-induced destructive thyroiditis, usually treated with oral glucocorticoids (oGCs). Our objective was to investigate the short-term effects of intravenous glucocorticoids (ivGCs) on serum thyroid hormone concentrations in patients with AIT2. Exploratory study of three naive AIT2 patients treated with iv methylprednisolone (two pulses of 400 mg with no interpulse oGCs), followed by oGCs, matched 1:3 with AIT2 patients treated with oGCs alone. Changes in serum thyroid hormone concentrations were evaluated in the short-term period (24 h and 7 days) and after a cumulative dosage of 400 and 800 mg equivalents of methylprednisolone; in addition, healing time and duration of exposure to GCs were calculated. During the first 24 h of treatment, serum FT4 concentrations increased in ivGCs patients, and decreased in oGCs patients (+ 3.3% vs − 10.7%, respectively, p = 0.025). After 7 days, serum FT4 and FT3 concentrations decreased significantly in both groups, with no statistical difference between them (p = 0.439 for FT4 and p = 0.071 for FT3), even though the cumulative GCs dose was higher in ivGCs than in oGCs patients (800 mg vs 280 mg, p = 0.008). Furthermore, the iv administration of single 400 mg pulses of methylprednisolone resulted in a less significant decrease in serum thyroid hormone concentrations when compared to equivalent GCs doses fractionated in several consecutive days (p = 0.021 for FT4 and p = 0.052 for FT3). There were no significant differences in the healing time (p = 0.239) and duration of exposure to GCs (p = 0.099). High-dose ivGCs therapy does not offer advantages over standard oGCs therapy in the rapid, short-term control of AIT2.

Little is known about the respective effects of depression and cognitive impairment on quality of life among older adults with schizophrenia spectrum disorder.We used data from the Cohort of individuals with Schizophrenia Aged 55-years or more (CSA) study, a large multicenter sample of older adults with schizophrenia or schizoaffective disorder (N = 353). Quality of life (QoL), depression and cognitive impairment were assessed using the Quality of Life Scale (QLS), the Center of Epidemiologic Studies Depression scale and the Mini-Mental State Examination, respectively. We used structural equation modeling to examine the shared and specific effects of depression and cognitive impairment on QoL, while adjusting for sociodemographic characteristics, general medical conditions, psychotropic medications and the duration of the disorder.Depression and cognitive impairment were positively associated (r = 0.24, p 0.01) and both independently and negatively impacted on QoL (standardized β = -0.41 and β = -0.32, both p 0.01) and on each QLS quality-of-life domains, except for depression on instrumental role and cognitive impairment on interpersonal relations in the sensitivity analyses excluding respondents with any missing data. Effects of depression and cognitive impairment on QoL were not due to specific depressive symptoms or specific cognitive domains, but rather mediated through two broad dimensions representing the shared effects across all depressive symptoms and all cognitive deficits, respectively.Because of the cross-sectional design of this study, measures of association do not imply causal associations.Mechanisms underlying these two broad dimensions should be considered as important potential targets to improve quality of life of this vulnerable population.

Objectives SSc is a chronic autoimmune disease characterized by inflammation of the skin and multiple internal organs. Articular involvement is one of the main features of SSc, and typical hallmarks of SpA have been found in SSc patients. The aim of the present study was to estimate the prevalence of entheseal and synovio-entheseal complex (SEC) alterations in a cohort of SSc patients. Methods One hundred SSc patients and 25 healthy subjects were included in this cross-sectional study. The enthesis sites of lateral epicondylar common extensor tendons (CET) and the enthesis of the Glasgow Ultrasound Enthesis Scoring System were evaluated. SEC involvement was evaluated only at CET enthesis. Results In SSc, the Glasgow Ultrasound Enthesis Scoring System score was significantly higher (median 4.0, interquartile range 2.0–7.0) than in controls (median 1.0, interquartile range 0.0–3.0) (P < 0.0001). CET enthesis of SSc patients showed more frequent US B-mode alterations than that of controls (χ2 = 11.47, P = 0.0007 for size; χ2 = 13.79, P = 0.0002 for cortical irregularity, χ2 = 5.24, P = 0.022 for calcification/enthesophytes). Power Doppler US signal at CET enthesis was significantly more frequent in SSc patients than in healthy controls (χ2 = 9.11, P = 0.0025), as was the concomitant SEC involvement (χ2 = 8.52, P = 0.0035). Conclusion These data show that SSc patients frequently present US features of enthesopathy. Moreover, CET enthesopathy was correlated with SEC inflammation, suggesting that entheseal inflammation in SSc may share the same micro-anatomical targets as found in SpA.

Background: Late-onset UC represents an important issue for the near future, but its outcomes and relative therapeutic strategies are yet poorly studied. Aim: To better define the natural history of late-onset ulcerative colitis. Methods: In a multicenter retrospective study, we investigated the disease presentation and course in the first 3 years in 1091 UC patients divided into 3 age-groups: diagnosis >65 years, 40-64 years, and

The "born to read" initiative entails a dialogic reading to children in poor socio-economical conditions aimed at fostering cognitive and relational skills. Reading is professionally delivered by experts to promote psycho-social development of children and their parents. In this study the project was extended to include children positive at early screening for hearing impairment. A total of 26 children were included and 14 parents were taught to read aloud and emphatically. Reading session were delivered for at least 10 minutes at least 3 times/week, usually at bedtime, for one year. The Griffiths scale were applied to explore the expressive and receptive language skills (Scale C) and eye and hand coordination (Scale D), as measures of linguistic and neurocognitive skills. Program sustainability and reactions by the parents were also investigated. All 14 families successfully received the training, becoming capable of reading aloud and emphatically and provided reading sessions for the entire duration of the study. Children receiving the intervention performed slightly better than controls and those who were exposed to increased number of sessions, performed even better although the differences with controls were not significant. Parents enjoyed reading to their children. They expressed satisfaction and gratitude for being able to play an active and productive role in children rehabilitation. The results of this pilot study suggest that the born to read initiative may be considered in adjunct to medical and psychological interventions to enhance the benefits of early screening of hearing function.

BackgroundCystic fibrosis (CF) is a disorder affecting the respiratory, digestive, reproductive systems and sweat glands. This lethal hereditary disease has known or suspected links to the dysbiosis gut microbiota. High-throughput meta-omics-based approaches may assist in unveiling this complex network of symbiosis modifications.ObjectivesThe aim of this study was to provide a predictive and functional model of the gut microbiota enterophenotype of pediatric patients affected by CF under clinical stability.MethodsThirty-one fecal samples were collected from CF patients and healthy children (HC) (age range, 1-6 years) and analysed using targeted-metagenomics and metabolomics to characterize the ecology and metabolism of CF-linked gut microbiota. The multidimensional data were low fused and processed by chemometric classification analysis.ResultsThe fused metagenomics and metabolomics based gut microbiota profile was characterized by a high abundance of Propionibacterium, Staphylococcus and Clostridiaceae, including Clostridium difficile, and a low abundance of Eggerthella, Eubacterium, Ruminococcus, Dorea, Faecalibacterium prausnitzii, and Lachnospiraceae, associated with overexpression of 4-aminobutyrate (GABA), choline, ethanol, propylbutyrate, and pyridine and low levels of sarcosine, 4-methylphenol, uracil, glucose, acetate, phenol, benzaldehyde, and methylacetate. The CF gut microbiota pattern revealed an enterophenotype intrinsically linked to disease, regardless of age, and with dysbiosis uninduced by reduced pancreatic function and only partially related to oral antibiotic administration or lung colonization/infection.ConclusionsAll together, the results obtained suggest that the gut microbiota enterophenotypes of CF, together with endogenous and bacterial CF biomarkers, are direct expression of functional alterations at the intestinal level. Hence, it's possible to infer that CFTR impairment causes the gut ecosystem imbalance.This new understanding of CF host-gut microbiota interactions may be helpful to rationalize novel clinical interventions to improve the affected children's nutritional status and intestinal function.

Objective.To investigate whether patients with a very early diagnosis of systemic sclerosis (VEDOSS) may already present circulating markers and in vitro signs of microvascular dysfunction.Methods.Serum samples were obtained from 55 patients with systemic sclerosis (SSc), 25 patients with VEDOSS, and 55 matched healthy controls (HC). Serum levels of pan-vascular endothelial growth factor (VEGF) and soluble neuropilin-1 (sNRP-1) were measured by ELISA. Human dermal microvascular endothelial cells (H-MVEC) were cultured and stimulated with SSc, VEDOSS, and HC sera. Protein expression of NRP-1 was analyzed by Western blotting, cell proliferation by 5′-bromodeoxyuridine assay, migration capacity by wound-healing assay, and capillary-like tube formation by Matrigel assay.Results.Serum levels of pan-VEGF were increased in patients with VEDOSS and SSc versus HC (p = 0.05 and p = 0.003, respectively). Serum levels of sNRP-1 were significantly reduced in patients with VEDOSS and SSc compared with controls (p = 0.012 and p = 0.027, respectively). NRP-1 expression was decreased in H-MVEC stimulated with VEDOSS sera (p < 0.001 vs HC). Proliferation was reduced in H-MVEC stimulated either with VEDOSS or SSc sera in comparison with HC sera (p = 0.015 and p = 0.043, respectively). Wound healing was compromised in H-MVEC stimulated with VEDOSS and SSc sera versus HC sera (p < 0.01 for both). Capillarogenesis was decreased in H-MVEC stimulated with VEDOSS sera (p < 0.01) and SSc sera (p < 0.001) compared with cells stimulated with HC sera.Conclusion.Similar to patients with SSc, patients with VEDOSS already present biological signs of endothelial dysfunction. Our data demonstrate that VEDOSS sera significantly modify endothelial cell behavior and impair the angiogenic potential of the microvascular system.

Background and aim We aimed to evaluate the outcome of patients with acute severe ulcerative colitis previously exposed to immunosuppressive (IMS) therapy. Methods We retrospectively collected data from 86 consecutive patients from 2008. Early outcome was evaluated as response to steroids, rescue therapy, and colectomy rate, whereas colectomy free-survival was determined along the follow-up. Results The overall response rates to steroids and rescue therapy was 33.7% and 90.5%, respectively, while early colectomy rate was 22.1%. Patients previously treated with IMS (n = 47) showed a trend towards lower response to steroids (25.5% vs 43.6%; p = 0.10), and a high-risk of early colectomy (29.8% vs 12.8%; p = 0.07), but a similar response to rescue therapy (87.5% vs 94.4%, p = 0.62) when compared with IMS-naive patients (n = 39). The overall cumulative probability to avoid the surgery was 67.5% and 56.6% at 12 and 60 months, respectively, regardless of previous exposure to IMS (p = 0.30). At multivariate analysis the risk of early colectomy was increased by previous IMS (OR 5.16, p = 0.017), anaemia (OR 4.26, p = 0.02), and diagnosis above 40 years (OR 5.31, p = 0.011). Conclusions Patients previously treated with IMS showed a non-significant trend towards a worse response with steroid therapy, a satisfactory response rate to rescue therapy, and a similar probability of avoiding colectomy during the follow-up vs IMS-naive patients.

BACKGROUND The disease course and colectomy rate of ulcerative colitis (UC) vary largely in population-based and referral center cohorts. We retrospectively evaluated our cohort to determine the disease course and risk factors for colectomy. METHODS A cohort of 1723 ulcerative colitis patients (986 males; mean age, 34.8 ± 15.4 yrs) were identified and followed since 1960s for a mean of 11 ± 9 years (range, 1-49 yrs). RESULTS The disease extension was classified as E1, E2, and E3 on diagnosis at 19.7%, 54.2%, and 26.1% of patients, respectively. At the final follow-up, the disease extension increased in 20% of the cases. Extraintestinal manifestations (EIMs) were reported by 11% of the patients, whereas systemic corticosteroids (CS), IM or anti-TNFα agents were used by 68.6%, 20.4%, and 6.4% of patients, respectively. The crude colectomy rate was 7% (120 pts), with a 1.2% rate (n = 21) at 1 year from diagnosis (95% CI, 0.7-1.7) and a Kaplan-Meyer estimation of up to 18.2% after 30 years of follow-up. The 1-year colectomy rate showed no significant difference through the decades, whereas the 5-year and 10-year absolute value of colectomy was halved in the last 2 decades compared with the period from 1960 to 1990 (P = 0.01), with a general trend of a reduced colectomy rate at survival curves (P = 0.056). CONCLUSIONS The colectomy rate was low in our cohort and further reduced in the last 2 decades. However, despite the availability of anti-TNFα agents, no further significant reduction of colectomies was observed in the last decade.

Novel devices based on the emission of near-infrared electromagnetic radiation (NIR) have been developed to minimize venous puncture failures. These instruments produce an “augmented reality” image, in which subcutaneous veins are depicted on a LCD display. We compared the new technique with standard venipuncture in a population of elderly patients. Patients admitted in Intensive Care Unit were randomized to standard or to NIR assisted procedure. In the 103 enrolled patients (age 74 ± 12 years; standard venipuncture—N = 56; NIR—N = 47), no differences were found in procedure length, number of attempts, and referred pain. With NIR there was a lower incidence of hematomas and fewer anxiety and depressive symptoms. The use of the novel NIR-based device is safer and more psychologically tolerable, and it is not associated to an increase of procedure length or number of attempts.

The aim of the present study was to define the frequency of organ-specific and non-organ-specific autoantibodies in a cohort of Latent Autoimmune Diabetes in Adults (LADA) patients and to test whether multiple antibodies positivity could be a predictor of early insulin dependence.We enrolled 210 LADA and 210 type 2 diabetes mellitus (T2D) patients. In all subjects anti-islet antigen-2 (IA-2Ab), anti-thyroperoxidase (TPOAb), anti-zinc transporter 8 (ZnT8Ab), anti-nuclear (ANA), anti-parietal cell (APCA), anti-smooth muscle (ASMA), anti-mitochondrial (AMA), anti-liver kidney microsomes (LKM), and anti-reticulin (ARA) circulating antibodies were assessed.The frequency of TPOAb, ZnT8Ab, APCA, and IA-2Ab positivity was, respectively, detected in 40.0%, 32.4%, 24.7%, and 9.5% of LADA patients, whereas their frequency was significantly lower in T2D patients (11.4%, 1.9%, 9.5%, and 0.0%, respectively, p0.001). The frequency of ANA was the same in both groups whereas the frequency of ASMA, ARA, AMA, and LKM was very low (range 0.0-3.3%). The presence of TPOAb associated with ZnT8Ab, IA-2Ab, or APCA allows one to predict the progression of disease with a high specificity but low sensibility.LADA patients show an increased frequency of organ- and non-organ-specific antibodies. Consequently, a screening is worthwhile in these patients. The simultaneous presence of TPOAb with ZnT8, IA-2Ab, or APCA may help differentiate clinical phenotypes and predict faster insulin dependence in LADA patients.

Prices for newer analogue insulin products have increased. Lower-cost human insulin may be effective for many patients with type 2 diabetes.To evaluate the association between implementation of a health plan-based intervention of switching patients from analogue to human insulin and glycemic control.A retrospective cohort study using population-level interrupted times series analysis of members participating in a Medicare Advantage and prescription drug plan operating in 4 US states. Participants were prescribed insulin between January 1, 2014, and December 31, 2016 (median follow-up, 729 days). The intervention began in February 2015 and was expanded to the entire health plan system by June 2015.Implementation of a health plan program to switch patients from analogue to human insulin.The primary outcome was the change in mean hemoglobin A1c (HbA1c) levels estimated over three 12-month periods: preintervention (baseline) in 2014, intervention in 2015, and postintervention in 2016. Secondary outcomes included rates of serious hypoglycemia or hyperglycemia using ICD-9-CM and ICD-10-CM diagnostic codes.Over 3 years, 14 635 members (mean [SD] age: 72.5 [9.8] years; 51% women; 93% with type 2 diabetes) filled 221 866 insulin prescriptions. The mean HbA1c was 8.46% (95% CI, 8.40%-8.52%) at baseline and decreased at a rate of -0.02% (95% CI, -0.03% to -0.01%; P .001) per month before the intervention. There was an association between the start of the intervention and an overall HbA1c level increase of 0.14% (95% CI, 0.05%-0.23%; P = .003) and slope change of 0.02% (95% CI, 0.01%-0.03%; P .001). After the completion of the intervention, there were no significant differences in changes in the level (0.08% [95% CI, -0.01% to 0.17%]) or slope (0.001% [95% CI, -0.008% to 0.010%]) of mean HbA1c compared with the intervention period (P = .09 and P = 0.81, respectively). For serious hypoglycemic events, there was no significant association between the start of the intervention and a level (2.66/1000 person-years [95% CI, -3.82 to 9.13]; P = .41) or slope change (-0.66/1000 person-years [95% CI, -1.59 to 0.27]; P = .16). The level (1.64/1000 person-years [95% CI, -4.83 to 8.11]; P = .61) and slope (-0.23/1000 person-years [95% CI, -1.17 to 0.70]; P = .61) changes in the postintervention period were not significantly different compared with the intervention period. The baseline rate of serious hyperglycemia was 22.33 per 1000 person-years (95% CI, 12.70-31.97). For the rate of serious hyperglycemic events, there was no significant association between the start of the intervention and a level (4.23/1000 person-years [95% CI, -8.62 to 17.08]; P = .51) or slope (-0.51/1000 person-years [95% CI, -2.37 to 1.34]; P = .58) change.Among Medicare beneficiaries with type 2 diabetes, implementation of a health plan program that involved switching patients from analogue to human insulin was associated with a small increase in population-level HbA1c.

Objective The study aimed to evaluate the long-term efficacy and safety of vedolizumab in a real-life cohort of patients with inflammatory bowel diseases enrolled at a tertiary referral center. Methods Data were retrospectively collected from August 2016 to November 2018. The primary outcomes were clinical response and remission at 14, 24, and 52 weeks, and steroid-free remission rate (SFRR) at 52 weeks. Endoscopic response and remission rates at 52 weeks were the secondary outcomes. Results Altogether 49 patients (22 with ulcerating colitis [UC] and 27 with Crohn's Disease [CD]) were enrolled. The clinical response rate gradually dropped from 85% and 50% in CD and UC, respectively, at week 14 to 59% and 25% at week 52, with significantly a higher response in CD at week 14. The endoscopic response at week 52 was 55% in CD and 25% in UC (P = 0.21). CD group had a higher SFRR than UC group (41% vs 20%) at 52 weeks, although the difference was not statistically significant. Similar clinical and endoscopic rates were observed in biologic-naive and -experienced patients. We reported no discontinuation due to adverse drug reactions, and only mild to moderate events. Conclusions In our cohort the clinical response in the induction phase was similar to those of registered trials, despite surprising better results for CD. During the maintenance phase we observed an higher drop out than in the reported literatures. Of note, its good safety profile makes vedolizumab a reliable choice in patients with contraindications to anti-tumor necrosis factor agents.

Italian baseball played by visually impaired and blind athletes is an adapted team sport which maintains the peculiar fast-moving features of this popular sport. It is also a mixed team game played together with sighted subjects. Here, we performed a national survey aimed at assessing the differences in psychological well-being (PWB) and quality of life (QoL) between visually impaired baseball players from Italian teams and non-players using a structured online questionnaire. Forty-three visually impaired baseball players and thirty-four visually impaired sedentary individuals completed a structured self-report survey including the validated 18-item Italian versions of the PWB (PWB-18) scale and the Short Form-12 (SF-12) questionnaire to assess the QoL. PWB-18 and SF-12 reference data from the Italian normally sighted population were also employed for comparison with the visually impaired baseball player group. Visually impaired baseball players reported better scores in all dimensions of the PWB-18 scale and significant higher scores in both physical and mental QoL evaluated by SF-12 than the non-player group. In addition, PWB-18 scale findings revealed significant differences between visually impaired baseball players and the reference normally sighted population consisting in lower scores for autonomy, environmental mastery, positive relations with others and purpose in life dimensions. Conversely, the mean scores for PWB-18 personal growth and self-acceptance dimensions were not significantly different between the two groups. The SF-12 questionnaire results demonstrated a significantly higher physical score in visually impaired players compared with the reference population. Instead, the SF-12 mental score of visually impaired athletes tended to be lower, though this difference was not statistically significant. Collectively, our findings suggest that the practice of Italian baseball may have a positive impact on PWB and QoL of visually impaired individuals.

The severity of psychopathology has a strong negative impact on quality of life (QoL) among older adults with schizophrenia spectrum disorder. However, because these subjects generally experience multiple psychiatric symptoms, it remains unclear whether decreased QoL in this population is due to specific symptoms (e.g., hallucinations), specific dimensions of psychopathology (e.g., negative symptoms), a general psychopathology dimension representing the shared effect across all psychiatric symptoms, or a combination of these explanations. Data were derived from the Cohort of individuals with Schizophrenia Aged 55 years or more (CSA) study, a large (N = 353) multicenter sample of older adults with schizophrenia spectrum disorder recruited from French public-sector psychiatric departments. We used structural equation modeling to examine the shared and specific effects of psychiatric symptoms on QoL, while adjusting for sociodemographic characteristics, general medical conditions, global cognitive functioning and psychotropic medications. Psychiatric symptoms and QoL were assessed face-to-face by psychiatrists using the Brief Psychiatric Rating Scale (BPRS) and the Quality of Life Scale (QLS). Among older adults with schizophrenia spectrum disorder, effects of psychiatric symptoms on QoL were exerted mostly through a general psychopathology dimension (β = − 0.43, p

One of the best indicators of adrenal gland dysfunction is the level of free cortisol measured in the 24-h urine (UFC) which faithfully reflects the level of biologically active serum cortisol not subjected to circadian variations. Liquid chromatography coupled with tandem mass spectrometry (LC–MS–MS) is a sensitive, accurate and precise method recently available in routine laboratories that could remedy interference problems of immunoassays. In this study, a literature reference range for UFC measured by LC–MS–MS was verified, and UFC values measured by LC–MS–MS and immunoassay were compared. Immunometric UFC measurement was performed by ACCESS CORTISOL assay without preliminary extraction, using Beckman Coulter UniCel DxI 600 highly automated platform. Liquid chromatography–tandem mass spectrometry UFC measurement was performed by a home-made validated method using cortisol-D4 as internal standard with preliminary deproteinization of urinary samples by centrifugal filter and injection on reverse-phase column. Cortisol was analyzed in positive ion mode with an ESI interface. The reference interval from literature (11–70 μg/day) was confirmed by results obtained for healthy study group. Comparison study of the two methods highlighted a constant and proportional systematic error with a general tendency to overestimate results for the in-use method. In conclusion, the direct immunometric method overestimates UFC results with respect to liquid chromatography–tandem mass spectrometry which represents the reference method. The literature reference range 11–70 μg/day was confirmed and can be adopted by our lab that will shift all UFC tests performed in routine to the mass spectrometry-based method, satisfying clinicians’ request.

In systemic sclerosis (SSc), the main pathogenic scenario is represented by early endothelial cell injury and microvascular desertification culminating into skin and internal organ fibrosis.1 Growing evidence suggests that impaired vascular repair and neovascularisation could be related to failure of both angiogenesis and endothelial progenitor cell (EPC)-driven vasculogenesis.2 In SSc, the majority of studies are focused on the role of blood vessel dysfunction,1 2 while the involvement of the lymphatic microcirculation has attracted much less attention. Nevertheless, clinical and histological findings have shown that lesional SSc skin displays lymphatic circulatory abnormalities.3–5 These may be present since the earliest disease phases, when digital painless swelling (puffy fingers), due to the accumulation of protein-rich interstitial fluid (ie, oedema), is a clinical hallmark.3–5 Furthermore, in SSc reduced numbers of dermal microlymphatics have been correlated with development of digital ulcers (DU) and progression of cutaneous fibrosis.4 5 Postnatal lymphatic neovascularisation takes place through lymphangiogenesis (ie, the formation of novel lymphatic vessels from pre-existing ones) and lymphvasculogenesis. This last event stems from circulating bone marrow-derived lymphatic EPC (LEPC) that differentiate into mature endothelial cells expressing lymphatic-specific markers.6 On their surface, LEPC display CD34 and CD133, likewise their blood vascular counterpart (ie, EPC), but they …

Background:To present real-world evidence on the effects of switching from oral to long-acting injectable (LAI) antipsychotic maintenance treatment (AMT) in a sample of clinically stable patients with schizophrenia, with regard to subjective experience of treatment, attitude towards drug and quality of life.Methods:50 clinically stable adult schizophrenic outpatients were recruited. At the time of enrolment (T0), all patients were under a stabilized therapy with a single oral second-generation antipsychotic (SGA) and were switched to the equivalent maintenance regimen with the long-acting formulation of the same antipsychotic. 43 patients completed the 24-month prospective, longitudinal, open-label, observational study. Participants were assessed at baseline (T0), after 12 (T1) and 24 months (T2), using psychometric scales (PANSS, YMRS and MDRS) and patient-reported outcome measures (SWN-K, DAI-10 and SF-36).Results:The switch to LAI-AMT was associated with a significant clinical improvement at T1 and T2 compared to baseline (T0). All of the psychometric indexes, as well as patients’ subjective experience of treatment (SWN-K), and quality of life (SF-36) showed a significant improvement after one year of LAI-AMT, with stable results after two years. Patients’ attitude towards drug (DAI-10) increased throughout the follow-up period, with a further improvement during the second year.Conclusions:The switch to LAI-AMT may help to address the subjective core of an optimal recovery in stabilized schizophrenic patients. A sustained improvement in patients’ attitude towards drug may help to achieve patient’s compliance. The size of this study needs to be expanded to produce more solid and generalizable results.

ObjectiveIn systemic sclerosis (SSc), early microvascular injury is followed by impaired angiogenesis and peripheral capillary loss. Here, we investigated the possible contribution of the neurovascular guidance molecule Slit2 and its Roundabout (Robo) receptors to SSc-related endothelial cell dysfunction.MethodsCirculating Slit2 levels were measured in patients with SSc and healthy controls. Slit2, Robo1 and Robo4 expression was investigated in SSc and healthy skin biopsies and explanted dermal microvascular endothelial cells (MVECs). Slit2/Robo4 function in MVEC angiogenesis was studied by cell viability, wound healing and capillary-like tube formation assays.ResultsCirculating Slit2 was significantly increased in either SSc or patients with a very early diagnosis of SSc (VEDOSS) compared with controls. Interestingly, serum Slit2 levels were raised in patients with VEDOSS with nailfold videocapillaroscopy (NVC) abnormalities, while they were similar in VEDOSS with normal NVC and controls. In SSc, Slit2 and Robo4 expression was upregulated in clinically affected skin and explanted MVECs in respect to controls. The angiogenic performance of healthy MVECs was significantly reduced after challenge with recombinant human Slit2 or SSc sera. These inhibitory effects were significantly attenuated when SSc sera were preincubated with an anti-Slit2 blocking antibody. In vitro angiogenesis was severely compromised in SSc-MVECs and could be significantly ameliorated by Slit2 neutralisation or ROBO4 gene silencing. Slit2/Robo4 axis interfered with angiogenesis through the inhibition of Src kinase phosphorylation.ConclusionsIn SSc, increased circulating levels of Slit2 and activation of the Slit2/Robo4 antiangiogenic axis may contribute to peripheral microangiopathy since the very early phase of the disease.

Aberrant activation of the Hedgehog (HH) signaling is a critical driver in tumorigenesis. The Smoothened (SMO) receptor is one of the major upstream transducers of the HH pathway and a target for the development of anticancer agents. The SMO inhibitor Vismodegib (GDC-0449/Erivedge) has been approved for treatment of basal cell carcinoma. However, the emergence of resistance during Vismodegib treatment and the occurrence of numerous side effects limit its use. Our group has recently discovered and developed novel and potent SMO inhibitors based on acylguanidine or acylthiourea scaffolds. Here, we show that the two acylguanidine analogs, compound (1) and its novel fluoride derivative (2), strongly reduce growth and self-renewal of melanoma cells, inhibiting the level of the HH signaling target GLI1 in a dose-dependent manner. Both compounds induce apoptosis and DNA damage through the ATR/CHK1 axis. Mechanistically, they prevent G2 to M cell cycle transition, and induce signs of mitotic aberrations ultimately leading to mitotic catastrophe. In a melanoma xenograft mouse model, systemic treatment with 1 produced a remarkable inhibition of tumor growth without body weight loss in mice. Our data highlight a novel route for cell death induction by SMO inhibitors and support their use in therapeutic approaches for melanoma and, possibly, other types of cancer with active HH signaling.

ObjectiveAcromegalic patients have an increased risk of mortality. The objective of this study was to compare the effect of different therapies for acromegaly on mortality.Design and methodsThe mortality rate of 438 consecutive acromegalic patients was compared with that of the general population using the standardized mortality ratio (SMR); the effect of different therapies on survival was evaluated using Cox regression analysis.ResultsTwenty patients (4.5%) died between 1999 and 2009. Age- and sex-adjusted SMR was 0.70 (95% CI 0.43–1.08). The Cox regression analysis revealed that, in the whole population, both general risk factors (age and physical status) and specific factors for acromegaly (macroadenoma, hypopituitarism and uncontrolled disease) were associated with death. The most compromised patients at diagnosis had a higher mortality rate (P=0.001), which also occurred in patients with controlled acromegaly. Death occurred in 2.4% (adenomectomy), 2.6% (adenomectomy followed by somatostatin analogue (SSA) therapy) and 11.4% (SSA therapy as the primary therapy) of the patients. The risk of death was higher in patients receiving SSA therapy as the primary therapy (hazard ratio (HR) 5.52, 95% CI 1.06–28.77,P=0.043) than in all patients submitted to adenomectomy; however, a higher risk of death occurred only in diabetic patients treated with SSAs alone (HR 21.94, 95% CI 1.56–309.04,P=0.022). Radiotherapy was associated with an increased risk of mortality, which occurred in patients with the more locally advanced disease.ConclusionsTherapies for acromegaly and comorbidities have lowered the risk of mortality to the level of the general population; the effect of SSA therapy alone or that following pituitary adenomectomy was comparable to that of curative neurosurgery on survival in non-diabetic patients; on the contrary, SSA therapy as the primary therapy may be less effective than adenomectomy in reducing mortality rate in diabetic patients.