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Introduction Differential diagnosis between dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) is crucial for an adequate patients' management but might be challenging. We investigated with advanced MRI techniques gray (GM) and white matter (WM) damage in DLB patients compared to those with AD. Methods 24 DLB patients, 26 age- and disease severity-matched AD patients, and 20 age and sex-matched controls performed clinical and neuropsychological assessment, and brain structural and diffusion-tensor MRI. We measured GM atrophy using voxel-based morphometry, WM hyperintensities (WMH) using a local thresholding segmentation technique, and normal-appearing WM (NAWM) damage using tract-based spatial statistic. Results DLB and AD patients exhibited mild-to-moderate-stage dementia. Compared to controls, GM damage was diffuse in AD, while limited to bilateral thalamus and temporal regions in DLB. Compared to DLB, AD patients exhibited GM atrophy in bilateral fronto-temporal and occipital regions. DLB and AD patients showed higher WMH load than controls, with no differences among each other. WMH in DLB were diffuse with relative prevalence in posterior parietal-occipital regions. Compared to controls, both DLB and AD patients showed reduced microstructural integrity of the main supratentorial and infratentorial NAWM tracts. AD patients exhibited greater posterior NAWM damage than DLB. Conclusions DLB showed prominent WM degeneration compared to the limited GM atrophy, while in AD both tissue compartments were severely involved. In DLB, NAWM microstructural degeneration was independent of WMH, thus revealing two possible underlying processes. Different pathophysiological mechanisms are likely to drive GM and WM damage distribution in DLB and AD.

Objective. To analyze the potential role of colchicine monotherapy in patients with tumor necrosis factor receptor associated periodic syndrome (TRAPS) in terms of control of clinical and laboratory manifestations. Methods. Patients with TRAPS treated with colchicine monotherapy were retrospectively enrolled; demographic, clinical and therapeutic data were collected and statistically analysed after having clustered patients according to different times at disease onset, penetrance of mutations, dosage of colchicine, and different disease manifestations. Results. 24 patients (14 males; 15 with pediatric disease onset) treated with colchicine monotherapy were enrolled. Colchicine resulted in a complete response in 3 (12.5%) cases, partial response in 14 (58.3%) patients, and lack of response in 7 (29.2%) patients. There were not significant differences in colchicine response between pediatric and adult disease onset (p=0.42), between low- and high-penetrance mutations (p=0.62), and according to different dosages (p=0.66). No significant differences were identified in the frequency of specific disease manifestations between patients experiencing any response to colchicine and patients with lack of response. Conclusions. Colchicine monotherapy is useful in a low percentage of TRAPS patients; nevertheless, it could be attempted in patients with milder phenotypes and at a lower risk of developing reactive amyloidosis.

Background Alzheimer's Disease is characterized by a heterogeneous course. Predicting a fast rather than a slow decline over time is crucial to both provide a reliable prognosis and elaborate stricter enrolment criteria in clinical trials. Here we searched for independent predictors of cognitive decline rate to assess the risk of fast disease progression already at baseline. Methods 53 subjects with an "in-vivo biomarker confirmed" diagnosis of Alzheimer's Disease were included. Neuropsychological assessment, plasma neurofilaments (NfL) concentrations and, in a subsample of 23 patients, Brain Magnetic Resonance Imaging were available. Patients were labelled FAST or SLOW depending on the Mini Mental State Test (MMSE) points lost per year (FAST if more than 3 points). We adopted single logistic regression models to search for independent predictors of FAST progression. Results At baseline no differences were found between FAST and SLOW subgroups in demographics, MMSE scores, vascular burden and Medial Temporal Lobe (MTL) atrophy measurements. Higher plasma NfL concentrations and worse scores at Semantic Verbal Fluency (SVF) and Clock Drawing Test (CDT) were independent predictors of FAST decline, after controlling for age, education, sex and baseline disease severity stage. The regression model combining all the predictors correctly classified 80% of patients overall. The risk of FAST decline was 81.2% if all the three predictors were abnormal (i.e., SVF ≤ 21.5; CDT ≤ 5.5; NfL ≥ 22.19). Conclusions An easily applicable algorithm including plasma neurofilament measurement and two neuropsychological tests worldwide adopted in clinical practice (SVF and CDT), may allow the clinicians to reliably stratify AD patients depending on the risk of fast cognitive decline.

Summary Background Through a comprehensive analysis of Italy's estimates from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017, we aimed to understand the patterns of health loss and response of the health-care system, and offer evidence-based policy indications in light of the demographic transition and government health spending in the country. Methods Estimates for Italy were extracted from GBD 2017. Data on Italy are presented for 1990 and 2017, on prevalence, causes of death, years of life lost, years lived with disability, disability-adjusted life-years (DALYs), life expectancy at birth and at age 65 years, healthy life expectancy, and Healthcare Access and Quality (HAQ) Index. We compared the estimates for Italy with those of 15 other western European countries. Findings The quality of the universal health system and healthy behaviours contribute to favourable overall health, even in comparison with other western European countries. In 2017, life expectancy and HAQ Index score in Italy were among the highest globally, with life expectancy at birth reaching 85·3 years for females and 80·8 for males in 2017, ranking Italy eighth globally for females and sixth for males, and an HAQ Index score of 94·9 in 2016 compared with 81·54 in 1990, keeping Italy ranked as ninth globally. Between 1990 and 2017 age-standardised death rates for cardiovascular diseases decreased by 53·7% (95% uncertainty interval −56·1 to −51·4), for neoplasms decreased by 28·2% (−32·3 to −24·6), and for transport injuries decreased by 62·1% (−64·6 to −59·2). However, population ageing is causing an increase in the burden of specific diseases, such as Alzheimer's disease and other dementias (DALYs increased by 77·9% [68·4 to 87·2]) and pancreatic (DALYs increased by 39·7% [28·4 to 51·7]) and uterine cancers (DALYs increased by 164·7% [129·7 to 202·5]). Behavioural risk factors, which are potentially modifiable, still have a strong effect, particularly on cardiovascular diseases and neoplasms. For instance, in 2017, 44 400 (41 200 to 47 800) cancer deaths were attributed to smoking, 12 000 (9600 to 14 800) to alcohol use, and 9500 (5400 to 14 200) to high body-mass index, while 47 000 (31 100 to 65 700) deaths due to cardiovascular diseases could be attributed to high LDL cholesterol, 28 700 (19 700 to 38 500) to diets low in whole grains, and 15 900 (8500 to 24 900) to low physical activity. Interpretation Italy provides an interesting example of the results that can be achieved by a mix of relatively healthy lifestyles and a universal health system. Two main issues require attention, population ageing and gradual decrease of public health financing, which both pose several challenges to the future of Italy's health status. Our findings should be useful to Italy's policy makers and health system experts elsewhere. Funding Bill & Melinda Gates Foundation.

Background and Purpose: Clinical trials on stroke prevention in patients with atrial fibrillation have consistently shown clinical benefit from either warfarin or non–vitamin K antagonist oral anticoagulants (NOACs). NOAC-treated patients have consistently reported to be at lower risk for intracerebral hemorrhage (ICH) than warfarin-treated patients. The aims of this prospective, multicenter, multinational, unmatched, case-control study were (1) to investigate for risk factors that could predict ICH occurring in patients with atrial fibrillation during NOAC treatment and (2) to evaluate the role of CHA 2 DS 2 -VASc and HAS-BLED scores in the same setting. Methods: Cases were consecutive patients with atrial fibrillation who had ICH during NOAC treatment. Controls were consecutive patients with atrial fibrillation who did not have ICH during NOAC treatment. As within the CHA 2 DS 2 -VASc and HAS-BLED scores there are some risk factors in common, several multivariable logistic regression models were performed to identify independent prespecified predictors for ICH events. Results: Four hundred nineteen cases (mean age, 78.8±8.1 years) and 1526 controls (mean age, 76.0±10.3 years) were included in the study. From the different models performed, independent predictors of ICH were increasing age, concomitant use of antiplatelet agents, active malignancy, high risk of fall, hyperlipidemia, low clearance of creatinine, peripheral artery disease, and white matter changes. Low doses of NOACs (given according to label or not) and congestive heart failure were inversely associated with the risk of ICH. HAS-BLED and CHA 2 DS 2 -VASc scores performed poorly in predicting ICH with areas under the curves of 0.496 (95% CI, 0.468–0.525) and 0.530 (95% CI, 0.500–0.560), respectively. Conclusions: Several risk factors were associated to ICH in patients treated with NOACs for stroke prevention but not HAS-BLED and CHA 2 DS 2 -VASc scores.

Purpose: To evaluate the improvement in electrical synchrony and left ventricle (LV) hemodynamics provided by combining the dynamic atrioventricular delay (AVD) of SyncAVTM CRT and the multiple LV pacing sites of MultiPoint pacing (MPP). Methods: Patients with LBBB and QRS duration (QRSd) > 140 ms implanted with a CRT-D or CRT-P device and quadripolar LV lead were enrolled in this prospective study. During a post-implant follow-up visit, QRSd was measured from 12-lead surface electrograms by experts blinded to pacing configurations. QRSd reduction relative to intrinsic rhythm was evaluated during biventricular pacing (BiV) and MPP for two AVDs: nominal (140/110 ms paced/sensed) and SyncAV (patient-optimized SyncAV offset [10–60 ms] minimizing QRSd). Echocardiography particle imaging velocimetry (Echo-PIV) analysis was performed for each configuration. The resulting hemodynamic force LV flow angle (φ) was analyzed, which ranges from 0o (predominantly base-apex forces) to 90o (predominantly transverse forces). Higher angles indicate more energy dissipation at lateral walls due to transverse flow; lower angles indicate healthier flow aligned with the longitudinal base-apex path of the pressure gradient. Results: Twelve patients (58% male, 17% ischemic, 32±7% ejection fraction, 165 ± 18 ms intrinsic QRSd) completed QRSd and Echo-PIV assessment. Relative to intrinsic rhythm, BiV and MPP with nominal AVD reduced QRSd by 10 ± 9% and 12 ± 9%, respectively. BiV+SyncAV and MPP+SyncAV further reduced QRSd by 19 ± 8%, (p < 0.05 vs. BiV with nominal AVD) and 23 ± 9% (p < 0.05 vs BiV+SyncAV), respectively. Echo-PIV showed similar sequential hemodynamic improvements. LV flow angular orientation during intrinsic activation (46 ± 3o) reduced with BiV+SyncAV (37 ± 4o, p < 0.05 vs intrinsic) and further with MPP+SyncAV (34 ± 4o, p < 0.05 vs BiV+SyncAV). Conclusion: These results suggest that SyncAV may improve electrical synchrony and influence LV flow patterns in patients suffering from heart failure compared to conventional CRT with a fixed AVD, with further improvement observed by combining with MPP.

The objective of this study is to describe the possible prognostic impact of smoking habit on adult-onset Still’s disease (AOSD) patients, by the assessment of clinical characteristics, life-threatening complications occurrence, and mortality in smokers than non-smokers. A multicentre retrospective study of prospectively followed-up AOSD patients included in Gruppo Italiano di Ricerca in Reumatologia Clinica e Sperimentale (GIRRCS) cohort was conducted. Out of 185 AOSD assessed patients, 45 smokers were identified. These showed a higher frequency of pericarditis (35.5% vs 16.4%, p = 0.011), pleuritis (33.3% vs 14.3%, p = 0.008), and abdominal pain (17.7% vs 6.4%, p = 0.035). Furthermore, smokers showed higher values of systemic score (6.4 ± 2.2 vs 5.4 ± 1.8, p = 0.004), an increased rate of macrophage activation syndrome (MAS) (28.9% vs 6.4%, p < 0.0001) and of parenchymal lung disease (17.7% vs 12.6%, p = 0.035). Although not significant, these patients more frequently experienced a poor prognosis (13.3% vs 4.3%, p = 0.074). Smoking habit predicted MAS occurrence in both univariate (HR: 5.98, 95% CI: 2.45–14.57, p < 0.0001) and multivariate regression models (HR: 6.21, 95% CI: 2.46–15.70, p < 0.0001). Smokers had a significant higher risk of parenchymal lung disease in both univariate (HR: 3.97, 95% CI: 1.43–11.02, p = 0.008) and multivariate regression models (HR: 3.90, 95% CI: 1.36–11.23, p = 0.012). Smoking habit also increased the risk of mortality in univariate regression model (HR: 4.25, 95% CI: 1.33–13.55, p = 0.015). Smoking habit resulted to be a negative prognostic factor on AOSD patients. Smokers were characterised by a higher frequency of serositis and higher values of systemic score. Additionally, these patients were more frequently burdened by MAS and parenchymal lung disease associated with a poor prognosis.Key points•Smoking habit resulted to be a negative prognostic factor on AOSD.•Smokers were characterised by an increased frequency of serositis and higher values of systemic score.•Cigarette exposure was associated with MAS and parenchymal lung disease in AOSD.

The McCluskey index has been used as a tool to predict massive bleeding (6 red blood cells units) during orthotropic liver transplantation. The objective of this study is to verify its efficacy at our institution.Between May 1998 and December 2017, we performed 1216 orthotropic liver transplantations, of which 1016 had sufficient data registered with respect to hemoderivative transfusion. We divided these patients into groups based on the original study of McCluskey. This study was approved by the ethical committee of our Institution and was performed in accordance with the Declaration of Helsinki.The mean Model for End-Stage Liver Disease score in the 4 groups was 7.5 (range, 7-8) for low risk; 13 (range, 3-32) for medium risk, 17 (range, 8-41) for high risk, and 25 (range, 11-36) for very high risk (P.001). No significant differences were observed regarding body mass index or hospital stay. No differences have been found in the number of suboptimal donors among the groups. With respect to hemoderivative transfusions, we observed the following for red blood cells: 7 (range, 6-8) units for low risk; 5.5 (range, 0-74) for medium risk; 7 (range, 0-73) for high risk, and 12 (range, 5-30) for very high risk (P.001) and transfusion of plasma: 12 (range, 10-15) units for low risk; 11 (range, 0-89) for medium risk; 14 (range, 0-76) for high risk, and 13 (range, 3-30) for very high risk (P = .001).The McCluskey index is a good indicator of the risk of hemorrhage and hence the necessity of transfusion.

La depresión infantojuvenil es una entidad clínica reconocida que produce alteraciones estructurales y funcionales a nivel neuroendocrino. Los factores de riesgo incluyen antecedentes de síntomas depresivos en los padres, desestructuración familiar, acontecimientos estresantes crónicos, abuso físico, emocional o sexual. Estas alteraciones se asocian a problemas de memoria, lenguaje, regulación emocional y hormonal. Durante la niñez los síntomas depresivos tienden a coexistir con síntomas somáticos debido a que, frecuentemente, los pacientes tienen dificultad para expresar sus emociones, por lo que estos síntomas son motivo de consulta médica. En el presente reporte, se presenta el caso de una adolescente con depresión asociada a galactorrea, pero con prolactina en rangos normales. La galactorrea podría presentarse con hiperprolactinemia, pero también puede ser euprolactinémica aun cuando asociada a eventos estresantes crónicos.

Introduction Intraoperative bleeding during liver transplantation has been correlated with a higher risk of morbidity and mortality and decrease in patient and graft survival. Materials and Methods Between January 2006 and December 2016 we performed 783 orthotopic liver transplants. After applying exclusion criteria, we found liver grafts from donors after circulatory death (DCD, group A) were used in 69 patients and liver grafts from donors after brain death (group B) were used in 265 patients. Results No difference was found in terms of sex, body mass index, Model for End-Stage Liver Disease score, indication for transplantation, intensive care unit stay, and Child-Pugh score. The mean transfusion of hemoderivates was as follows: red blood cell 9 (0-28) units in group A vs 6 (0-20) units in group B (P = .004) and fresh frozen plasma 10 (0-29) units in group A vs 9.5 (0-23) in group B (P = .000). The only 2 factors related to massive blood transfusion (>6 units of red blood cell) were uncontrolled DCD condition (odds ratio = 2.38; 95% confidence interval, 1.32-4.31; P = .004), and higher Model for End-Stage Liver Disease score (odds ratio = 2.63; 95% confidence interval, 1.53-4.55; P = .001). Survival at 1, 3, and 5 years was 81.3%, 70.2%, and 68.9% in group A vs 89%, 83.7%, and 78% in group B (P = .070). Conclusion The use of liver grafts from DCDs is associated with increased necessity of transfusion of hemoderivates in comparison with the use of liver grafts from donors after brain death.

Objective Hashimoto’s thyroiditis is known to cluster with other systemic autoimmune disorders. Rheumatic manifestations, such as a seronegative non-erosive polyarthritis have been described. The aim of this study was to evaluate the characteristics and the prevalence of rheumatic features in thyroiditis patients, and to ascertain whether the association with systemic autoimmune disorders improved the arthritis manifestations. Methods In total, 180 thyroiditis patients were enrolled. Major clinical and demographic characteristics have been recorded. Patients underwent a rheumatological clinical assessment and extra-articular manifestations allowing for a differential diagnosis with systemic autoimmune diseases and spondyloarthropathy. Presence of systemic autoimmune diseases was recorded. Results A total of 8.33% of thyroiditis patients shown a peripheral inflammatory arthritis (P = 0.002). Female gender (P = 0.042) and thyroid peroxidase (TPOAbs) positivity (P = 0.001) were more frequent. In total, 37 patients had systemic autoimmune diseases (P = 0.0003). A significant high prevalence of coeliac disease and Addison disease was found (P = 0.034 and P = 0.049, respectively). In patients with coeliac disease, the articular manifestations were more frequent (21.21%) (P = 0.001) and the risk to develop joint involvement was 2.96. Conclusion Although we found an articular involvement in about one-third of thyroiditis patients, the prevalence of inflammatory arthropathy was only 8.33%. The prevalence of other coexisting autoimmune disorders was 34.26% with a significant prevalence of coeliac disease (7.41%). Thyroiditis patients with coeliac disease have an articular involvement more frequently than those without. In these patients, we have found a high risk of developing arthritis than patients with only thyroiditis, suggesting cumulative autoimmune effects in the developing articular involvement.

Aims An exhaustive and updated estimation of cardiovascular disease burden and vascular risk factors is still lacking in European countries. This study aims to fill this gap assessing the global Italian cardiovascular disease burden and its changes from 1990 to 2017 and comparing the Italian situation with European countries. Methods All accessible data sources from the 2017 Global Burden of Disease study were used to estimate the cardiovascular disease prevalence, mortality and disability-adjusted life years and cardiovascular disease attributable risk factors burden in Italy from 1990 to 2017. Furthermore, we compared the cardiovascular disease burden within the 28 European Union countries. Results Since 1990, we observed a significant decrease of cardiovascular disease burden, particularly in the age-standardised prevalence (–12.7%), mortality rate (–53.8%), and disability-adjusted life years rate (–55.5%). Similar improvements were observed in the majority of European countries. However, we found an increase in all-ages prevalence of cardiovascular diseases from 5.75 m to 7.49 m Italian residents. Cardiovascular diseases still remain the first cause of death (34.8% of total mortality). More than 80% of the cardiovascular disease burden could be attributed to known modifiable risk factors such as high systolic blood pressure, dietary risks, high low density lipoprotein cholesterol, and impaired kidney function. Conclusions Our study shows a decline in cardiovascular mortality and disability-adjusted life years, which reflects the success in reducing disability, premature death and early incidence of cardiovascular diseases. However, the burden of cardiovascular diseases is still high. An approach that includes the cooperation and coordination of all stakeholders of the Italian National Health System is required to further reduce this burden.

Introduction: Biologic disease-modifying antirheumatic drugs (bDMARDs) play a pivotal role in the treatment of psoriatic arthritis (PsA). Despite this, their discontinuation due to inefficacy or adverse events is often observed. The aims of this study are to describe retention rates and treatment trends of anti-TNFα, anti-IL17, and anti-IL12/23R agents in patients with PsA and to identify factors associated with bDMARDs discontinuation in a real-world clinical setting. Methods: A retrospective cohort study based on the analysis of the three Italian prescription cohorts of patients with PsA has been performed. Survival analysis was performed using Kaplan-Meier curves and Cox proportional-hazards model. Results: During the follow up, which lasted 25.5 (12–60) months, 68 patients discontinued a bDMARD: 13 for primary failure, 12 for secondary failure, 15 for adverse events, 5 for remission, 12 because of lost at follow-up, and 11 for other causes. Cox proportional-hazards demonstrated that a shorter disease duration (HR 0.994991, 95% CI 0.9910336–0.9989647, p = 0.014) and first-line bDMARD (HR 0.5090986, 95% CI 0.3073519–0.8432722, p = 0.009) have a protective role on bDMARD retention rate, while the multivariable analysis failed in demonstrating an independent protective role of male sex on drug retention rate (p = 0.083). No significant differences in retention rate have been found regarding biologic drugs, combination therapy or monotherapy, and class of bDMARD (anti-TNFα or anti-pIL12/23R and anti-IL-17). Conclusions: This study shows that a shorter disease duration and treatment with a first-line bDMARD are predictors of bDMARDs retention rate, further highlighting the importance of early diagnosis of PsA.Key Points• No significant difference in retention among patients treated with anti-IL17A, anti-IL12/23R, and anti-TNFα agents has been demonstrated.• A shorter disease duration and first-line bDMARD treatment are associated with persistence in biologic treatment.

Cardiac amyloidosis is an infiltrative disorder caused by transthyretin or immunoglobulin free light-chain deposition, which determines clinical disease with similar phenotype but different time course, prognosis and therapy. Multimodality imaging is the cornerstone for disease diagnosis and management. Multimodality imaging has revolutionized the approach to the disease favoring its awareness and simplifying its diagnosis, especially in ATTR cardiac amyloidosis. This describes the different imaging tools, from the traditional to the more novel ones, and highlights the different approach in each different setting (prognosis, subtyping, prognosis, monitoring disease progression, and response to therapy).

Pancreas transplantation (PT) is considered as the only treatment that can convert a diabetic patient in a euglucemic state without the use of insulin or oral antidiabetic drugs. From 1996 to the end of 2016, more than 50,000 PT were performed in USA, and in Spain were performed 1.730 PT during the last 10 years. In this review we will perform an update of PT considering the introduction of several advances in the last years, adding our accumulated experience from the beginning of our program in the year 1995. The first PT was carried out in the Hospital of the University of Minnesota, and from that date several significant improvements have been introduced along the time due to advances in surgical technique in pancreas donors and recipients, perioperative management of patients, and introduction of more potent immunosuppressors able to reduce the rejection rate under 20%. Although PT is a therapy associated with a higher morbidity (pancreas graft thrombosis, systemic and intraabdominal infections, anastomotic leakages, etc.), currently most of the PT teams have obtained a rate of 93% of patient survival at 3-years, and between 78% and 83% of graft survival at 3-years. Additionally, the normal pancreas graft function is associated with an improvement of quality of life and most of complications related to diabetes, without the necessity to treat with antidiabetics drugs or insulin.

INTRODUCTION Rehabilitating a severely atrophic maxilla is a complex procedure. In case of severe resorption, zygomatic implants are indicated and loading of the implants at the end of the surgery is desirable. We present a new method by means of guided surgery for the placement of zygomatic implants, using specially designed metal templates that should be supported by bone. METHODS The treatment planning for completely guided prosthetic rehabilitation of the maxilla with zygomatic implants was digitally performed. A radiographic template was designed for the prosthetic treatment planning. A surgical template was used to replicate the digitally planned steps in vivo. RESULTS The procedure ended with the positioning of a custom-made temporary prosthesis. This method can reduce the surgery duration, simplify the procedure, and optimize the outcome. It requires equal cooperation among technicians, prosthodontists, and surgeons. Nineteen out of twenty patients included in the study presented successful implants and prosthesis at the moment of analysis. CONCLUSIONS The present approach addressed the needs for zygomatic-implant surgery. The surgical and prosthetic plan, position, emergence, the shape of the implants, the position of the temporary prosthesis, the inter-arch relationships, and surgical templates were designed in a completely virtual environment and performed by the surgeon on stereolithographic models beforehand. Consequently, the surgical procedure was considerably simplified.

Background Opioids have been linked to worse oncologic outcomes in surgical patients. Studies in certain cancer types have identified associations between survival and intra-tumoural opioid receptor gene alterations, but no study has investigated whether the tumour genome interacts with opioid exposure to affect survival. We sought to determine whether intraoperative opioid exposure is associated with recurrence-specific survival and overall survival in early-stage lung adenocarcinoma, and whether selected tumour genomics are associated with this relationship. Associations between ketamine and dexmedetomidine and outcomes were also studied. Methods Surgical patients (N=740) with pathological stage I–III lung adenocarcinoma and next-generation sequencing data were retrospectively reviewed from a prospectively maintained database. Results On multivariable analysis, ketamine administration was protective for recurrence-specific survival (hazard ratio = 0.44, 95% confidence interval 0.24–0.80; P=0.007), compared with no adjunct. Higher intraoperative oral morphine milligram equivalents were significantly associated with worse overall survival (hazard ratio=1.09/10 morphine milligram equivalents, 95% confidence interval 1.02–1.17; P=0.010). Significant interaction effects were found between morphine milligram equivalents and fraction genome altered and morphine milligram equivalents and CDKN2A, such that higher fraction genome altered or CDKN2A alterations were associated with worse overall survival at higher morphine milligram equivalents (P=0.044 and P=0.052, respectively). In contrast, alterations in the Wnt (P=0.029) and Hippo (P=0.040) oncogenic pathways were associated with improved recurrence-specific survival at higher morphine milligram equivalents, compared with unaltered pathways. Conclusions Intraoperative opioid exposure is associated with worse overall survival, whereas ketamine exposure is associated with improved recurrence-specific survival in patients with early-stage lung adenocarcinoma. This is the first study to investigate tumour-specific genomic interactions with intraoperative opioid administration to modify survival associations.

While next-generation sequencing (NGS) is used to guide therapy in patients with metastatic lung adenocarcinoma (LUAD), use of NGS to determine pathologic LN metastasis prior to surgery has not been assessed. To bridge this knowledge gap, we performed NGS using MSK-IMPACT in 426 treatment-naive patients with clinical N2-negative LUAD. A multivariable logistic regression model that considered preoperative clinical and genomic variables was constructed. Most patients had cN0 disease (85%) with pN0, pN1, and pN2 rates of 80%, 11%, and 9%, respectively. Genes altered at higher rates in pN-positive than in pN-negative tumors were STK11 (p = 0.024), SMARCA4 (p = 0.006), and SMAD4 (p = 0.011). Fraction of genome altered (p = 0.037), copy number amplifications (p = 0.001), and whole-genome doubling (p = 0.028) were higher in pN-positive tumors. Multivariable analysis revealed solid tumor morphology, tumor SUVmax, clinical stage, SMARCA4 and SMAD4 alterations were independently associated with pathologic LN metastasis. Incorporation of clinical and tumor genomic features can identify patients at risk of pathologic LN metastasis; this may guide therapy decisions before surgical resection.

Background The aim of this study is to evaluate risk factors for infection as well as infection rates after open reduction and internal fixation for distal tibia fractures with a distal tibia locking plate and/or isolated screws. Methods This is a retrospective and descriptive study based on 55 patients treated in our Major Trauma Centre from January 2009 to December 2016. All patients were classified by age, sex, open or closed fracture, injury mechanism, comorbidities, fixation and time from injury to surgery. 22 extraarticular fractures AO/OTA 43-A and 33 intraarticular (14 cases 43-B and 19 43-C) were recorded. High energy trauma was related in 27 patients, while open fractures were observed in 10 patients. Splint until surgery was applied routinely while temporary external fixation (EF) was performed in 21 patients (7 extraarticular and 14 intraarticular). Patients were treated by 5 different consultant surgeons performing isolated screws (SC) in 20% of the surgeries, antero-medial locking distal tibia plate (AM) and anterolateral (AL) were used in 47% and 33% of the patients respectively. After assessing normality and homogeneity of the subgroups, statistical contrast tests were performed. Results Infection rate was 31.5%, mainly caused by S. aureus. We obtained a statistically significant correlation between greater age and infection rate. In the same way, a positive statistical trend between infection and AL plating was found. The use of EF followed by ORIF was not observed as a risk factor for infection compared with splint followed by internal fixation, however, the group of patients in which a splint was used, a positive relationship was found between the infection rate and shorter time until the definitive fixation. No statistically significant associations were found between extra/intraarticular fracture pattern, use of corticosteroids or open fractures and infection rate. Conclusion Greater age was a predisposing factor for infection. The use of external fixation before definitive ORIF seems to be a safe procedure regarding risk infection, and if an external fixation is not used, we recommend longer waiting time until definitive ORIF. Screw fixation or antero-medial plates, if allowed by fracture pattern, can be an option to avoid infection.

Resumen Introduccion Existe controversia respecto a la tecnica ideal de reconstruccion pancreatico-yeyunal posreseccion duodeno-pancreatica. La tutorizacion externa del Wirsung se ha considerado por muchos autores como una tecnica con menor incidencia de fistulas y morbimortalidad. Analizamos nuestra experiencia con esta tecnica. Pacientes y metodos Analisis retrospectivo de la morbimortalidad, de una serie de 80 pacientes consecutivos intervenidos, durante 6,5 anos, por tumores pancreaticos cefalicos o periampulares realizando reseccion y pancreatico-yeyunostomia con tutorizacion externa del Wirsung. Resultados La edad media de los pacientes fue 68,3 ± 9 anos y la tasa de resecabilidad del 78%. La consistencia del pancreas era blanda en 51,2% de pacientes y dura en 48,8%. Se preservo el piloro en 43,8%. El tumor mas frecuente fue el adenocarcinoma (68,8%) y se consiguio un R0 en 70%. La fistula bioquimica se presento en 11,2%, la fistula pancreatica grado B en 12,5% y la C en 2,5%, mientras que la tasa de reintervencion abdominal fue del 10%. La mediana de estancia hospitalaria fue de 16 dias y la mortalidad postoperatoria y a 90 dias fue del 2,5%. La tasa de retraso del vaciamiento gastrico fue del 36,3%, diabetes de novo del 12,5% e insuficiencia exocrina del 30%. La supervivencia a uno, tres y cinco anos fue 80,2, 53,6 y 19,2%. Conclusiones Aunque nuestras tasas de morbimortalidad con la tutorizacion externa del Wirsung son bajas, coincidiendo con series mas amplias recientemente publicadas, se precisa un analisis comparativo con otras tecnicas reconstructivas, con mas casos, para elegir la mejor opcion despues de una duodenopancreatectomia cefalica.

Background: Family caregivers of patients with dementia are at high risk of stress and burden, and quarantine due to the coronavirus disease 2019 (COVID-19) pandemic may have increased the risk of psychological disturbances in this population. The current study was carried out during the national lockdown declared in March 2020 by the Italian government as a containment measure of the first wave of the coronavirus pandemic and is the first nationwide survey on the impact of COVID-19 lockdown on the mental health of dementia informal caregivers.Methods: Eighty-seven dementia centers evenly distributed on the Italian territory enrolled 4,710 caregiver–patient pairs. Caregivers underwent a telephone interview assessing classical symptoms of caregiver stress and concern for the consequences of COVID-19 infection on patient’s health. We calculated prevalence of symptoms and regressed them on various potential stress risk factors: caregivers’ sociodemographic characteristics and lifestyle, patients’ clinical features, and lockdown-related elements, like discontinuity in medical care.Results: Approximately 90% of caregivers reported at least one symptom of stress, and nearly 30% reported four or more symptoms. The most prevalent symptoms were concern for consequences of COVID-19 on patient’s health (75%) and anxiety (46%). The main risk factors for stress were identified as a conflicting relationship with the patient and discontinuity in assistance, but caregiver’s female sex, younger age, lower education, and cohabitation with the patient also had an impact. Availability of help from institutions or private individuals showed a protective effect against sense of abandonment but a detrimental effect on concern about the risk for the patient to contract COVID-19. The only protective factor was mild dementia severity, which was associated with a lower risk of feeling isolated and abandoned; type of dementia, on the other hand, did not affect stress risk.Conclusion: Our results demonstrate the large prevalence of stress in family caregivers of patients with dementia during the COVID-19 pandemic and have identified both caregivers and situations at a higher risk of stress, which should be taken into account in the planning of interventions in support of quarantined families and patients.

International audience; Autoimmune diseases (AIDs) share similar serological, clinical, and radiological findings, but, behind these common features, there are different pathogenic mechanisms, immune cells dysfunctions, and targeted organs. In this context, multiple lines of evidence suggest the application of precision medicine principles to AIDs to reduce the treatment failure. Precision medicine refers to the tailoring of therapeutic strategies to the individual characteristics of each patient, thus it could be a new approach for management of AIDS which considers individual variability in genes, environmental exposure, and lifestyle. Precision medicine would also assist physicians in choosing the right treatment, the best timing of administration, consequently trying to maximize drug efficacy, and, possibly, reducing adverse events. In this work, the growing body of evidence is summarized regarding the predictive factors for drug response in patients with AIDs, applying the precision medicine principles to provide high-quality evidence for therapeutic opportunities in improving the management of these patients.

Background and ObjectivesTo assess cortical, subcortical, and cerebellar gray matter (GM) atrophy using MRI in patients with disorders of the frontotemporal lobar degeneration (FTLD) spectrum with known genetic mutations.MethodsSixty-six patients carrying FTLD-related mutations were enrolled, including 44 with pure motor neuron disease (MND) and 22 with frontotemporal dementia (FTD). Sixty-one patients with sporadic FTLD (sFTLD) matched for age, sex, and disease severity with genetic FTLD (gFTLD) were also included, as well as 52 healthy controls. A whole-brain voxel-based morphometry (VBM) analysis was performed. GM volumes of subcortical and cerebellar structures were obtained.ResultsCompared with controls, GM atrophy on VBM was greater and more diffuse in genetic FTD, followed by sporadic FTD and genetic MND cases, whereas patients with sporadic MND (sMND) showed focal motor cortical atrophy. Patients carrying C9orf72 and GRN mutations showed the most widespread cortical volume loss, in contrast with GM sparing in SOD1 and TARDBP. Globally, patients with gFTLD showed greater atrophy of parietal cortices and thalami compared with sFTLD. In volumetric analysis, patients with gFTLD showed volume loss compared with sFTLD in the caudate nuclei and thalami, in particular comparing C9-MND with sMND cases. In the cerebellum, patients with gFTLD showed greater atrophy of the right lobule VIIb than sFTLD. Thalamic volumes of patients with gFTLD with a C9orf72 mutation showed an inverse correlation with Frontal Behavioral Inventory scores.DiscussionMeasures of deep GM and cerebellar structural involvement may be useful markers of gFTLD, particularly C9orf72-related disorders, regardless of the clinical presentation within the FTLD spectrum.

Objectives To stratify adult-onset Still’s disease (AOSD) patients in distinct clinical subsets to be differently managed, by using a multi-dimensional characterization. Methods AOSD patients were evaluated by using a hierarchical unsupervised cluster analysis comprising age, laboratory markers systemic score and outcomes. The squared Euclidean distances between each pair of patients were calculated and put into a distance matrix, which served as the input clustering algorithm. Derived clusters were descriptively analysed for any possible difference. Results Four AOSD patients clusters were identified. Disease onset in cluster 1 was characterized by fever (100%), skin rash (92%) and arthritis (83%), with the highest ferritin levels [mean (S.D.) 14 724 (6837) ng/ml]. In cluster 2, the onset was characterized by fever (100%), arthritis (100%) and liver involvement (90%), together with the highest CRP levels [288.10 (46.01) mg/l]. The patients in cluster 3 presented with fever (100%), myalgia (96%) and sore throat (92%). The highest systemic score values [8.88 (1.70)] and the highest mortality rate (54.2%) defined cluster 3. Fever (100%) and arthritis (90%) were the symptoms at the onset in cluster 4, which was characterized by the lowest ferritin and CRP levels [1457 (1298) ng/ml and 54.98 (48.67) mg/l, respectively]. Conclusion Four distinct phenotypic subgroups in AOSD could be suggested, possibly associated with different genetic background and pathogenic mechanisms. Our results could provide the basis for a precision medicine approach in AOSD in an attempt to find a clinical and laboratory multidimensional stratification and characterization, which would drive a tailored therapeutic approach in these patients.

IntroductionPrevious studies showed that quarantine for pandemic diseases is associated with several psychological and medical effects. The consequences of quarantine for COVID-19 pandemic in patients with dementia are unknown. We investigated the clinical changes in patients with Alzheimer’s disease and other dementias, and evaluated caregivers’ distress during COVID-19 quarantine.MethodsThe study involved 87 Italian Dementia Centers. Patients with Alzheimer’s Disease (AD), Dementia with Lewy Bodies (DLB), Frontotemporal Dementia (FTD), and Vascular Dementia (VD) were eligible for the study. Family caregivers of patients with dementia were interviewed by phone in April 2020, 45 days after quarantine declaration. Main outcomes were patients’ changes in cognitive, behavioral, and motor symptoms. Secondary outcomes were effects on caregivers’ psychological features.Results4913 patients (2934 females, 1979 males) fulfilled the inclusion criteria. Caregivers reported a worsening in cognitive functions in 55.1% of patients, mainly in subjects with DLB and AD. Aggravation of behavioral symptoms was observed in 51.9% of patients. In logistic regression analysis, previous physical independence was associated with both cognitive and behavioral worsening (odds ratio 1.85 [95% CI 1.42–2.39], 1.84 [95% CI 1.43–2.38], respectively). On the contrary, pandemic awareness was a protective factor for the worsening of cognitive and behavioral symptoms (odds ratio 0.74 [95% CI 0.65–0.85]; and 0.72 [95% CI 0.63–0.82], respectively). Approximately 25.9% of patients showed the onset of new behavioral symptoms. A worsening in motor function was reported by 36.7% of patients. Finally, caregivers reported a high increase in anxiety, depression, and distress.ConclusionOur study shows that quarantine for COVID-19 is associated with an acute worsening of clinical symptoms in patients with dementia as well as increase of caregivers’ burden. Our findings emphasize the importance to implement new strategies to mitigate the effects of quarantine in patients with dementia.

Background: The Covid-19 pandemic may have a deleterious impact on patients with autoimmune systemic diseases (ASD) due to their deep immune-system alterations. Objective: This study aims to investigate the prevalence of symptomatic Covid-19 and its correlations with both organ involvement and ongoing treatments in a large series of Italian ASD patients during the first wave of pandemic. Methods: Our multicenter telephone 6-week survey included 3,029 unselected ASD patients enrolled at 36 tertiary referral centers of northern, central, and southern Italian macro-areas with different diffusion of the pandemic. Symptomatic SARS-CoV-2 infection was classified as definite Covid-19 (presence of symptoms plus positive oral/nasopharyngeal swabs) or highly suspected Covid-19 (highly suggestive symptoms, in the absence of a swab testing). Results: A significantly higher prevalence of definite plus highly suspected Covid-19 compared to the Italian general population was detected in the whole ASD series (p=.000), as well as in patients from the three macro-areas (p=.000 in all). Statistically higher prevalence of Covid-19 was also found in connective tissue diseases compared to chronic arthritis subgroup (p=.000) and in ASD patients with pre-existing interstitial lung involvement (p=.000). Patients treated with either conventional disease-modifying anti-rheumatic drugs (DMARDs) and/or biological DMARDs showed a significantly lower prevalence of Covid-19 (p=.000 in both). Finally, scleroderma patients undergoing low-dose aspirin showed a significantly lower rate of Covid-19 compared to those without (p=0.003). Conclusion: The higher prevalence of Covid-19 in ASD patients, along with the significant correlations with important clinical features and therapeutic regimens, suggests the need to develop targeted prevention/management strategies during the current pandemic wave.

Background To report a case of acute exudative polymorphous paraneoplastic vitelliform maculopathy in a patient with a history of choroidal melanoma, with metastases to the pancreas, liver, and central nervous system. Case presentation A 63-year-old patient, with a history of enucleation of the right eye due to choroidal melanoma, complained of progressive visual loss during a follow-up visit. Fundoscopic examination revealed multiple small areas of serous retinal detachment scattered throughout the posterior pole and ancillary tests confirmed the diagnosis of acute exudative polymorphous paraneoplastic vitelliform maculopathy (AEPPVM). Screening for systemic metastases showed pancreatic, hepatic, and central nervous system involvement. Conclusions We describe a rare case of acute exudative polymorphous paraneoplastic vitelliform maculopathy, which should be considered in patients with or without a history of melanoma, who have vitelliform retinal detachments. Nevertheless, no previous reviews of literature have shown a correlation between AEPPVM and pancreatic metastasis.

BACKGROUND Outcomes after thoracic metastasectomy in patients with testicular germ cell tumors (GCTs) who received first-line chemotherapy alone versus salvage chemotherapy remain unexplored. METHODS We conducted a retrospective review of patients who underwent thoracic metastasectomy for residual GCT between 1997 and 2019 at a single tertiary center. Factors associated with progression-free survival (PFS) and overall survival (OS) were assessed using multivariable Cox regression. RESULTS Of 251 patients, 191 received only first-line chemotherapy (76%) and 60 received salvage chemotherapy (24%). Median follow-up was 3.45 years (interquartile range, 1-7.93 years). Among first-line patients without teratoma in the primary tumor, with necrosis in the retroperitoneal nodes and normalized or decreasing serum tumor markers, 17 of 20 had intrathoracic necrosis (85%). Among first-line and salvage patients, respectively, 5-year OS was 93% (95% confidence interval [CI], 89%-98%) versus 63% (95% CI, 51%-78%; P < .001), and 5-year PFS was 69% (95% CI, 62%-77%) versus 40% (95% CI, 29%-56%; P < .001). On multivariable analysis, multiple lung lesions (hazard ratio [HR] = 3.01; 95% CI, 1.50-6.05; P = .002) and brain metastasis (HR = 4.51; 95% CI, 2.34-8.73; P < .001) at diagnosis, salvage chemotherapy (HR = 1.85; 95% CI, 1.10-3.13; P = .021), teratoma (HR = 2.68; 95% CI, 1.50-4.78; P = .001), and viable malignancy (HR = 4.34; 95% CI, 2.44-7.71; P < .001) were associated with worse PFS. CONCLUSIONS Although GCT patients treated with salvage chemotherapy followed by thoracic metastasectomy have more aggressive disease and poorer PFS, they can achieve encouraging OS. Our findings highlight the integral role of aggressive thoracic metastasectomy in the treatment of GCT patients with residual thoracic disease after first line-only or salvage chemotherapy.

Background: Neurological conditions are highly prevalent and disabling, in particular in the elderly. The Italian population has witnessed sharp ageing and we can thus expect a rising trend in the incidence, prevalence and disability of these conditions. Methods: We relied on the Global Burden of Disease 2019 study to extract Italian data on incidence, prevalence and years lived with a disability (YLDs) referred to a broad set of neurological disorders including, brain and nervous system cancers, stroke, encephalitis, meningitis, tetanus, traumatic brain injury, and spinal cord injury. We assessed changes between 1990 and 2019 in counts and age-standardized rates. Results: The most prevalent conditions were tension-type headache, migraine, and dementias, whereas the most disabling were migraine, dementias and traumatic brain injury. YLDs associated with neurological conditions increased by 22.5%, but decreased by 2.3% in age-standardized rates. The overall increase in prevalence and YLDs counts was stronger for non-communicable diseases with onset in old age compared to young to adult-age onset ones. The same trends were in the opposite direction when age-standardized rates were taken into account. Conclusions: The increase in YLDs associated with neurological conditions is mostly due to population ageing and growth: nevertheless, lived disability and, as a consequence, impact on health systems has increased. Actions are needed to improve outcome and mitigate disability associated with neurological conditions, spanning among diagnosis, treatment, care pathways and workplace interventions.

Purpose: KRAS G12C is the most common KRAS mutation in primary lung adenocarcinoma. Phase I clinical trials have demonstrated encouraging clinical activity of KRASG12C inhibitors in the metastatic setting. We investigated disease-free survival (DFS) and tumor genomic features in patients with surgically resected KRASG12C-mutant lung adenocarcinoma. Experimental Design: Patients who underwent resection of stage I–III lung adenocarcinoma and next-generation sequencing (NGS) were evaluated. Exclusion criteria were receipt of induction therapy, incomplete resection, and low-quality NGS. Mutations were classified as KRAS wild-type (KRASwt), G12C (KRASG12C), or non-G12C (KRASother). DFS was compared between groups using the log-rank test; factors associated with DFS were assessed using Cox regression. Mutual exclusivity and cooccurrence, tumor clonality, and mutational signatures were assessed. Results: In total, 604 patients were included: 374 KRASwt (62%), 95 KRASG12C (16%), and 135 KRASother (22%). Three-year DFS was not different between KRAS-mutant and KRASwt tumors. However, 3-year DFS was worse in patients with KRASG12C than KRASother tumors (log-rank P = 0.029). KRASG12C tumors had more lymphovascular invasion (51% vs. 37%; P = 0.032) and higher tumor mutation burden [median (interquartile range), 7.0 (5.3–10.8) vs. 6.1 (3.5–9.7); P = 0.021], compared with KRASother tumors. KRASG12C mutation was independently associated with worse DFS on multivariable analysis. Our DFS findings were externally validated in an independent The Cancer Genome Atlas cohort. Conclusions: KRAS G12C mutations are associated with worse DFS after complete resection of stage I–III lung adenocarcinoma. These tumors harbor more aggressive clinicopathologic and genomic features than other KRAS-mutant tumors. We identified a high-risk group for whom KRASG12C inhibitors may be investigated to improve survival.

The clinical significance of molecular detection of respiratory viruses in bronchoalveolar lavage (BAL) samples is poorly defined. We performed an observational retrospective study including all patients who underwent a BAL procedure in our institution, regardless of the reason for bronchoscopy, from January 2015-December 2018. Respiratory viruses were detected by real-time polymerase chain reaction with a commercial multiplex panel, and a cell culture was performed to detect cytomegalovirus and herpes simplex virus. Positive results were correlated with clinical symptoms and patients' characteristics. Of 540 BAL samples analysed, 113 (20.9%) were positive for any respiratory virus. Viral detection was significantly associated with respiratory symptoms (83.2% vs 68.9%, P=.004) and radiological infiltrates (67.3% vs 52.2%, P=.006). The most frequent viruses detected were rhinovirus (42/113, 37.2%), influenza virus (20/113, 17.7%) and parainfluenza virus (PIV) (16/113, 14.2%). Respiratory pathogens codetections were found in 51/113 (45.1%) BAL samples, including more than one virus (16/51, 31.4%), fungi (8/51, 15.7%, and bacteria (9/51, 17.6%). Viral detection was significantly higher in immunocompromised patients (26.5% vs 16.9%; P=.022). PIV and human metapneumovirus were mostly observed in lung (50.0%, 8/16) and haemopoietic transplant recipients (25%, 2/8), respectively, with clinical repercussions. Our data underline that molecular diagnosis allows identification of viral agents as the aetiology of respiratory infections; however, the high frequency of co-detections hinders identification of the agent responsible for the current respiratory symptomatology. Immunocompromised patients are the target population in whom to investigate the presence of respiratory viruses in their BAL samples. This article is protected by copyright. All rights reserved.

[EN] Trial Design: An interventional, phase 4, single group assignment, without masking (open label), preventive clinical trial was carried out in health workers with biological risk in their tasks, who have been filed as non-responders to conventional vaccination against Hepatitis B. Methods: 67 health workers with biological risk in their tasks, who have been filed as non-responders to conventional vaccination against Hepatitis B, were enrolled in the Clinical Trial. All participants were from 18 years up to 64 years old. Inclusion Criteria: NHS workers -including university students doing their internships in health centres dependent on the National Health System (inclusion of students is regulated and limited by specific instructions on labour prevention in each autonomous community)- classified as non-responders. The criteria defining them as non-responders to the conventional hepatitis B vaccine is anti HBsAb titers < 10 mUI/ml following the application of six doses of conventional vaccine at 20 lg doses (two complete guidelines). The objective of this study was to provide Health workersstaff with an additional protection tool against hepatitis B infection, and to evaluate the efficacy of the adjuvanted vaccine in healthy non-responders to conventional hepatitis B vaccine. The primary outcome was the measurement of antibody antiHBs before the first Fendrix dose and a month after the administration of each dose. Other outcome was collection of adverse effects during administration and all those that could be related to the vaccine and that occur within 30 days after each dose. In this study, only one group was assigned. There was no randomization or masking. Results: The participants were recruited between April 13, 2018 and October 31, 2019. 67 participants were enrolled in the Clinical Trial and included the analyses. The primary immunisation consists of 4 separate 0.5 ml doses of Fendrix , administered at the following schedule: 1 month, 2 months and 6 months from the date of the first dose. Once the positivity was reached in any of the doses, the participant finished the study and was not given the following doses. 68.66% (46 out 67) had a positive response to first dose of Fendrix. 57.14% (12 out 21) had a positive response to second dose of Fendrix . 22.22% (2 out 9) had a positive response to third dose of Fendrix and 42.96% (3 out 7) had a positive response to last dose of Fendrix. Overall, 94.02% (64 out 67) of participants had a positive response to Fendrix . No serious adverse event occurred. Conclusions: The use of Fendrix , is a viable vaccine alternative for NHS workers classified as ‘‘nonresponders”. Revaccination of healthy non-responders with Fendrix, resulted in very high proportions of responders without adverse events. Trial registration: The trial was registered in the Spanish National Trial Register (REEC), ClinicalTrials.gov and inclusion has been stopped (identifier NCT03410953; EudraCT-number 2016-004991-23). Funding: GRS 1360/A/16: Call for aid for the financing of research projects in biomedicine, health management and socio-health care to be developed in the centres of the Regional Health Management of Autonomous Community of Castile-Leon. In addition, this work has been supported by the Spanish Platform for Clinical Research and Clinical Trials, SCReN (Spanish Clinical Research Network), funded by the Subdirectorate General for Research Evaluation and Promotion of the Carlos III Health Institute (ISCIII), through the project PT13/0002/0039 and project PT17/0017/0023 integrated in the State Plan for R&D&I 2013–2016 and co-financed by and the European Regional Development Fund (ERDF).

ObjectiveTo describe frequency and clinical characteristics of MAYV infection in Piura, as well as the association of this pathogen with DENV.ResultsA total of 86/496 (17.3%) cases of MAYV were detected, of which 54 were MAYV mono-infection and 32 were co-infection with DENV, accounting for 10.9% and 6.4%, respectively. When evaluating monoinfection by MAYV the main groups were 18–39 and 40–59 years old, with 25.9% and 20.4% respectively. Co-infections were more common in the age group 18–39 and those > 60 years old, with 34.4% and 21.9%, respectively. The most frequent clinical presentation were headaches (94.4%, 51/54) followed by arthralgias (77.8%, 42/54). During the 8-month study period the most cases were identified in the months of May (29.1%) and June (50.0%).

INTRODUCTION: The purpose of the study is to genomically characterize the biology and related therapeutic opportunities of prognostically important predominant histological subtypes in lung adenocarcinoma (LUAD). METHODS: We identified 604 patients with stage I-III LUAD who underwent complete resection and targeted next-generation sequencing using the MSK-IMPACT platform. Tumors were classified according to predominant histologic subtype and grouped by architectural grade (lepidic [LEP], acinar or papillary [ACI/PAP], and micropapillary or solid [MIP/SOL]). Associations between clinicopathologic factors, genomic features, mutational signatures, and recurrence were examined within subtypes and, when appropriate, quantified using competing-risks regression, with adjustment for pathologic stage and extent of resection. RESULTS: MIP/SOL tumors had higher tumor mutational burden (p

Background This ongoing follow-up study evaluated the persistence of efficacy and immune responses for 6 additional years in adults vaccinated with the glycoprotein E (gE)-based adjuvanted recombinant zoster vaccine (RZV) at age ≥50 years in 2 pivotal efficacy trials (ZOE-50 and ZOE-70). The present interim analysis was performed after ≥2 additional years of follow-up (between 5.1 and 7.1 years [mean] post-vaccination) and includes partial data for year (Y) 8 post-vaccination. Methods Annual assessments were performed for efficacy against herpes zoster (HZ) from Y6 post-vaccination and for anti-gE antibody concentrations and gE-specific CD4[2+] T-cell (expressing ≥2 of 4 assessed activation markers) frequencies from Y5 post-vaccination. Results Of 7413 participants enrolled for the long-term efficacy assessment, 7277 (mean age at vaccination, 67.2 years), 813, and 108 were included in the cohorts evaluating efficacy, humoral immune responses, and cell-mediated immune responses, respectively. Efficacy of RZV against HZ through this interim analysis was 84.0% (95% confidence interval [CI], 75.9–89.8) from the start of this follow-up study and 90.9% (95% CI, 88.2–93.2) from vaccination in ZOE-50/70. Annual vaccine efficacy estimates were >84% for each year since vaccination and remained stable through this interim analysis. Anti-gE antibody geometric mean concentrations and median frequencies of gE-specific CD4[2+] T cells reached a plateau at approximately 6-fold above pre-vaccination levels. Conclusions Efficacy against HZ and immune responses to RZV remained high, suggesting that the clinical benefit of RZV in older adults is sustained for at least 7 years post-vaccination. Clinical Trials Registration. NCT02723773.

Background Adult-onset Still’s disease (AOSD) is a systemic inflammatory disorder of unknown aetiology usually affecting young adults. Interestingly, recent evidence from the juvenile counterpart of AOSD suggested the emergent high fatality rate of lung disease (LD) in these patients. In this work, we aimed to characterise LD in AOSD, to identify associated clinical features and predictive factors, and to describe long-term outcomes of the disease comparing patients with LD and those without. Methods A retrospective assessment of prospectively followed patients, from January 2001 to December 2019, was provided to describe the rate of LD in AOSD, associated clinical features and predictive factors, and long-term outcomes. Patients with AOSD, who were included in Gruppo Italiano di Ricerca in Reumatologia Clinica e Sperimentale (GIRRCS) cohort, were assessed. Results Out of 147 patients included in GIRRCS cohort, 18 (12.25%) patients were reported to be affected by LD, at the time of diagnosis of AOSD, who were characterised by older age, a higher prevalence of myalgia, of lymph node involvement, of pleuritis, and abdominal pain. Furthermore, patients with LD showed higher values of systemic score and ferritin. Among those clinical variables, older age and systemic score were also independently predictors of LD. Chest CT scans were also obtained, and the most common finding was the peripheral consolidations in 8 (44.4%) patients. Finally, a higher mortality rate, of 38.9%, was registered in patients with LD than others, since it was associated with a significant decreased survival rate. Conclusions The presence of LD could suggest an emergent cause of mortality in AOSD, as observed in juvenile counterpart recognising a further marker of severity and poor prognosis to be careful evaluated. Patients with LD were also characterised by some clinical features, higher values of systemic score and ferritin than the others, identifying a subset of patients mostly burdened by systemic signs and symptoms. Although specific designed future studies are needed to fully elucidate the significance of LD in AOSD, a more accurate evaluation and management of this feature could improve the long-term outcomes of these patients.

Summary Background Among asymptomatic patients with severe carotid artery stenosis but no recent stroke or transient cerebral ischaemia, either carotid artery stenting (CAS) or carotid endarterectomy (CEA) can restore patency and reduce long-term stroke risks. However, from recent national registry data, each option causes about 1% procedural risk of disabling stroke or death. Comparison of their long-term protective effects requires large-scale randomised evidence. Methods ACST-2 is an international multicentre randomised trial of CAS versus CEA among asymptomatic patients with severe stenosis thought to require intervention, interpreted with all other relevant trials. Patients were eligible if they had severe unilateral or bilateral carotid artery stenosis and both doctor and patient agreed that a carotid procedure should be undertaken, but they were substantially uncertain which one to choose. Patients were randomly allocated to CAS or CEA and followed up at 1 month and then annually, for a mean 5 years. Procedural events were those within 30 days of the intervention. Intention-to-treat analyses are provided. Analyses including procedural hazards use tabular methods. Analyses and meta-analyses of non-procedural strokes use Kaplan-Meier and log-rank methods. The trial is registered with the ISRCTN registry, ISRCTN21144362. Findings Between Jan 15, 2008, and Dec 31, 2020, 3625 patients in 130 centres were randomly allocated, 1811 to CAS and 1814 to CEA, with good compliance, good medical therapy and a mean 5 years of follow-up. Overall, 1% had disabling stroke or death procedurally (15 allocated to CAS and 18 to CEA) and 2% had non-disabling procedural stroke (48 allocated to CAS and 29 to CEA). Kaplan-Meier estimates of 5-year non-procedural stroke were 2·5% in each group for fatal or disabling stroke, and 5·3% with CAS versus 4·5% with CEA for any stroke (rate ratio [RR] 1·16, 95% CI 0·86–1·57; p=0·33). Combining RRs for any non-procedural stroke in all CAS versus CEA trials, the RR was similar in symptomatic and asymptomatic patients (overall RR 1·11, 95% CI 0·91–1·32; p=0·21). Interpretation Serious complications are similarly uncommon after competent CAS and CEA, and the long-term effects of these two carotid artery procedures on fatal or disabling stroke are comparable. Funding UK Medical Research Council and Health Technology Assessment Programme.

Adult onset Still's disease (AOSD) is a rare systemic autoinflammatory disease, characterised by fever, arthritis, and skin rash, and joint involvement is one of its clinical manifestations. The aims of this work were to assess joint involvement, to describe main patterns of involvement, and associated clinical characteristics. In this work, we aimed at assessing the joint involvement in AOSD by using MRI, to describe main patterns and associated clinical characteristics. In addition, we aimed at assessing the global transcriptomic profile of synovial tissues in AOSD to elucidate possible pathogenic pathways involved. We also evaluated the global transcriptomic profile of synovial tissues to elucidate possible pathogenic pathways involved in the disease. Thus, AOSD patients, who underwent to MRI exam on joints, were assessed to describe patterns of joint involvement and associated clinical characteristics. Some synovial tissues were collected for RNA-sequencing purposes. The most common MRI finding was the presence of synovitis on 60.5%, mainly in peripheral affected joints, with low to intermediate signal intensity on T1-weighted images and intermediate to high signal intensity on T2-fat-saturated weighted and STIR images. Bone oedema and MRI-bone erosions were reported on 34.9% and 25.6% MRI exams, respectively. Patients with MRI-bone erosions showed a higher prevalence of splenomegaly, a more frequent chronic disease course, lower levels of erythrocyte sedimentation rate, and ferritin. In AOSD synovial tissues, a hyper-expression of interleukin (IL)-1, IL-6, and TNF pathways was shown together with ferritin genes. In conclusion, in AOSD patients, the most common MRI-finding was the presence of synovitis, characterised by intermediate to high signal intensity on T2-fat-saturated weighted and STIR images. MRI-bone erosions and bone oedema were also observed. In AOSD synovial tissues, IL-1, IL-6, and TNF pathways together with ferritin genes resulted to be hyper-expressed.

Anna Rago,1 Enrica Pezzullo,1 Marco Malvezzi Caracciolo d’Aquino,1 Gabriella Scognamiglio,1 Valentina Maria Caso,2 Francesco Martone,3 Emilio Attena,4 Valentina Parisi,5 Antonio D’Onofrio,4 Paolo Golino,1 Gerardo Nigro,1 Vincenzo Russo1 1Department of Cardiology, Monaldi Hospital, Naples, Italy; 2Department of Medical Translational Sciences, University of the Study of Campania “Luigi Vanvitelli”, Naples, Italy; 3Clinical Biochemistry Unit, Monaldi Hospital, Naples, Italy; 4Departmental Unit of Electrophysiology, Monaldi Hospital, Naples, Italy; 5Department of Translational Medical Sciences, University of Naples Federico II, Naples, ItalyCorrespondence: Vincenzo RussoDepartment of Medical Transalational Sciences, University of Campania - Monaldi Hospital, Via Leonardo Bianchi, Naples, 80131, ItalyFax +39-0817587482Email v.p.russo@libero.itAim: The aim of the present study was to assess the safety and effectiveness of non-vitamin K antagonist oral anticoagulants (NOACs) versus vitamin K antagonists (VKAs) in atrial fibrillation (AF) patients undergoing electrical cardioversion (EC).Methods: A propensity score-matched analysis was performed in order to identify two homogeneous groups including AF patients on NOACs and VKAs treatment scheduled for EC. The primary safety endpoint was major bleeding. The composite of stroke, transient ischemic attack (TIA) and systemic embolism (SE) was the primary effectiveness endpoint. The discontinuation rate of anticoagulant therapy was assessed.Results: A total of 495 AF patients on NOACs therapy and scheduled for EC were compared to 495 VKAs recipients. No statistically significant differences in the incidence of both major bleeding (1.01% versus 1.4%; P= 0.5) and thromboembolic events (0.6% versus 0.8%; P= 0.7) were observed during a mean follow-up of 15 ± 3 months. The discontinuation rate of NOACs was significantly lower compared to VKAs (1.6% versus 3.6%, P=0.04).Conclusion: We showed a safe and effective clinical profile of NOACs among AF patients scheduled for electrical cardioversion in real-life setting. Patients on NOACs therapy showed a lower discontinuation rate compared to those on VKAs.Keywords: atrial fibrillation, electrical cardioversion, transesophageal echocardiogram, non-vitamin K antagonist oral anticoagulants, discontinuation rate, vitamin K antagonists

A growing body of evidence suggests the usability of biologic disease-modifying anti-rheumatic drugs (bDMARDs) in treating adult-onset Still's disease (AOSD). In a multicentre "real-life" cohort, the physicians' prescribing motivations and patients' predictive characteristics of being treated with bDMARDs were assessed. Patients with AOSD, who were included in GIRRCS (Gruppo Italiano di Ricerca in Reumatologia Clinica e Sperimentale) cohort and treated with bDMARDs, were retrospectively assessed. Relevant data were collected by a review of clinical charts. Forty-four patients treated with bDMARDs were analysed, with slight male preponderance (52.3%) and a mean age of 39.3 ± 15.2years. All patients were treated with corticosteroids (CCSs) (38.6% with low dosage) and 93.2% were treated with synthetic DMARDs (sDMARDs). Regarding the effectiveness of the first-line bDMARD, 65.6% of patients experienced a complete remission, defined as complete disappearance of both systemic and joint symptoms and normalisation of laboratory evidence of disease. The physicians' prescribing motivations for bDMARDs were inadequate response to CCSs and/or sDMARDs, CCS-sparing effect and occurrence of macrophage activation syndrome (MAS). Analysing patients' characteristics, chronic disease course (OR 3.09; 95%CI 1.22-7.80, p = 0.017), defined as disease with persistent symptoms, was predictive of being treated with bDMARDs, whereas age (OR 0.97, 95%CI 0.93-0.99, p = 0.048) was negatively associated, suggesting younger age as a further predictive factor. Patients with AOSD were treated with bDMARDs for inadequate response to CCSs and/or sDMARDs, CCS-sparing effect and MAS occurrence. Younger age and chronic disease course were patients' predictive characteristics of being treated with bDMARDs.

We read with interest the recently published paper from McGonagle et al 1 analysing the role of interleukin (IL)-17A in axial spondyloarthritis and psoriatic arthritis (PsA). The meta-analysis and functional study provided by the authors highlighted the efficacy of IL-17A block by secukinumab in the treatment of PsA. However, there is no mention of the role of body mass index (BMI), if any, in influencing the clinical response to secukinumab, given the lack of published data. PsA is a chronic inflammatory arthritis burdened by a series of metabolic comorbidities. Among them, obesity is very common in PsA, with a prevalence of 27%, as confirmed by a recent Spanish work.2 Obesity in PsA has been associated with higher disease activity and a worse effectiveness of biologic treatment in PsA. This has been certainly proven for anti-tumour necrosis factor (TNF)-α as demonstrated by different studies reporting, in obese patients, a reduced treatment response and adherence. In particular, …

ObjectiveTo assess the predictive role of ferritin and C-reactive protein (CRP) on occurrence of macrophage activation syndrome (MAS) and mortality in patients with adult onset Still's disease (AOSD), a rare and severe disease, included in the multicentre Gruppo Italiano di Ricerca in Reumatologia Clinica e Sperimentale (GIRRCS) cohort.MethodsThe predictive role, at the time of diagnosis, of serum levels of ferritin and CRP on occurrence of MAS and mortality, was evaluated by logistic regression analyses and receiver-operating characteristic (ROC) curves were built to identify patients at high risk of MAS and mortality, respectively.ResultsIn assessed 147 patients with AOSD, levels of ferritin were predictive of MAS (OR: 1.971; P: 0.002; CI 95%: 1.280-3.035). The ROC curve showed that the best cut-off for ferritin was 1225 ng/ml in predicting MAS (sensitivity 88%; specificity 57%). Levels of CRP were predictive of mortality in these patients (OR: 2.155; P: 0.007; CI 95%: 1.228-3.783). The ROC curve showed that the best cut-off for CRP was 68.7 mg/L in predicting mortality (sensitivity 80%; specificity of 65%).ConclusionsWe reported the predictive role of ferritin and CRP on MAS and mortality, respectively, in a large cohort of patients with AOSD, identifying subsets at higher risk of poor prognosis. Considering that the analysis of CRP and ferritin is widely available, these results could be readily transferable into clinical practice, thus improving the management of patients with AOSD.

Background: In March 2020, the World Health Organization declared a global pandemic due to the novel coronavirus SARS-CoV-2 and several governments planned a national quarantine in order to control the virus spread. Acute psychological effects of quarantine in frail elderly subjects with special needs, such as patients with dementia, have been poorly investigated. The aim of this study was to assess modifications of neuropsychiatric symptoms during quarantine in patients with dementia and their caregivers. Methods: This is a sub-study of a multicenter nation-wide survey. A structured telephone interview was delivered to family caregivers of patients with diagnosis of Alzheimer disease (AD), dementia with Lewy bodies (DLB), frontotemporal dementia (FTD), and vascular dementia (VD), followed regularly at 87 Italian memory clinics. Variations in behavioral and psychological symptoms (BPSD) were collected after 1 month since quarantine declaration and associations with disease type, severity, gender, and caregiver’s stress burden were analyzed. Results: A total of 4,913 caregivers participated in the survey. Increased BPSD was reported in 59.6% of patients as worsening of preexisting symptoms (51.9%) or as new onset (26%), and requested drug modifications in 27.6% of these cases. Irritability, apathy, agitation, and anxiety were the most frequently reported worsening symptoms and sleep disorder and irritability the most frequent new symptoms. Profile of BPSD varied according to dementia type, disease severity, and patients’ gender. Anxiety and depression were associated with a diagnosis of AD (OR 1.35, CI: 1.12–1.62), mild to moderate disease severity and female gender. DLB was significantly associated with a higher risk of worsening hallucinations (OR 5.29, CI 3.66–7.64) and sleep disorder (OR 1.69, CI 1.25–2.29), FTD with wandering (OR 1.62, CI 1.12–2.35), and change of appetite (OR 1.52, CI 1.03–2.25). Stress-related symptoms were experienced by two-thirds of caregivers and were associated with increased patients’ neuropsychiatric burden (p

Background There are still many pendent issues about the effective evaluation of cardiac resynchronization therapy impact on functional mitral regurgitation. In order to reduce the intrinsic difficulties of quantification of functional mitral regurgitation itself, an automatic quantification of real-time three-dimensional full-volume color Doppler transthoracic echocardiography was proposed as a new, rapid, and accurate method for the assessment of functional mitral regurgitation severity. Recent studies suggested that images of left ventricle flow by echo-particle imaging velocimetry could be a useful marker of synchrony. Echo-particle imaging velocimetry has shown that regional anomalies of synchrony/synergy of the left ventricle are related to the alteration, reduction, or suppression of the physiological intracavitary pressure gradients. Case summary We describe a case in which the two technologies are used in combination during acute echocardiographic optimization of left pacing vector in a 63-year-old man, Caucasian, who showed worsening heart failure symptoms a few days after an implant, and the effect of the device’s optimization at 6-month follow-up. Discussion The degree of realignment of hemodynamic forces, with quantitative analysis of the orientation of blood flow momentum (φ), can represent improvement of fluid dynamics synchrony of the left ventricle, and explain, with a new deterministic parameter, the effects of cardiac resynchronization therapy on functional mitral regurgitation. Real-time three-dimensional color flow Doppler quantification is feasible and accurate for measurement of mitral inflow, left ventricular outflow stroke volumes, and functional mitral regurgitation severity. Conclusion This clinical case offers an innovative and accurate approach for acute echocardiographic optimization of left pacing vector. It shows clinical utility of combined three-dimensional full-volume color Doppler transthoracic echocardiography/echo-particle imaging velocimetry assessment to increase response to cardiac resynchronization therapy, in terms of reduction of functional mitral regurgitation, improving fluid dynamics synchrony of the left ventricle. Electronic supplementary material The online version of this article (10.1186/s13256-019-2048-1) contains supplementary material, which is available to authorized users.

Psoriatic arthritis (PsA) is a chronic inflammatory arthritis that may be present in near 30% of patients affected by psoriasis (PsO), clinically characterized by inflammation of periarticular (e.g., enthesis) and articular structures. Recently, an autoimmune footprint of PsA pathogenesis has been demonstrated with the presence of autoantigens and related autoantibodies in PsA patients' sera. In this context, histological features of PsA synovitis supports the relevance of an autoimmune pathogenesis of the disease. Since there is no currently validated test for PsA, the analysis of PsA synovial tissue revealed pathognomonic characteristics of PsA that may support the clinician in the clinical practice. PsA synovitis is characterized by a sublining infiltrate with T and B cells, vascular proliferation and a relative thin lining layer of proliferating intimal synoviocytes. PsA synovial histopathology shows that ectopic lymphoid-neogenesis with an increase of IL-23 expression. These new pathogenetics features and the systemic nature of the disease raised the concept of a Systemic Psoriatic Disease (SysPsD), characterized by multiple extra-cutaneous and -articular manifestations, highlightening the great heterogeneity of this condition. SyPsD represents a heterogeneous chronic inflammatory condition with a wide spectrum of phenotypical manifestations. The purpose of this review is to describe the new pathogenetic mechanisms and the different clinical pictures of SysPsD, with the ultimate goal of improving the knowledge of this heterogeneous chronic inflammatory condition.

Objective: Adipokines have been considered in the pathogenesis of the inflammatory processes of psoriatic arthritis (PsA). The main aim of the current study is to investigate possible differences and correlations between adipokines and clinical expression in PsA patients with and without clinical evident psoriasis. Methods: Serum levels of TNF-?, IL-6, leptin, resistin, visfatin, and ghrelin were measured in 80 consecutive PsA patients, 42 PsA patients with clinically evident psoriasis (group 1) and 38 PsA patients sine psoriasis (group 2), fulfilling the CASPAR criteria. Results: Patients of the two groups were not significantly different for levels of TNF-?, IL-6, leptin, resistin, visfatin, and ghrelin. In the entire cohort, a positive association has been shown between leptin levels and female gender (? = 0.3, p = 0.001), BMI (? = 0.8, p < 0.0001), tender joint count (? = 0.23, p = 0.05), and patient pain-VAS score (? = 0.4, p = 0.049). In group 1, serum concentration of leptin was associated with female gender (? = 0.41, p < 0.0001) and BMI (? = 0.6, p = 0.012), whereas in group 2, a positive association was shown between leptin levels and BMI (? = 0.7, p = 0.003) and CRP (? = 0.35, p = 0.012). With regard to resistin, in the multivariate model, only the association between resistin and IL-6 was found (? = 0.33, p = 0.002). The association between resistin and IL-6 was confirmed in group 1 (? = 0.46, p = 0.004) but not in group 2. Conclusions: Until today, the present study represents the first investigating difference in the adipokine pattern between PsA patients with psoriasis and sine psoriasis. We report a strict interplay between leptin, female gender, BMI, and inflammatory activity in overall PsA patients. In PsA patients with clinical evident psoriasis, leptin was associated with female gender and BMI, and a close association between resistin and IL-6 was found. Further, a positive association between leptin levels and BMI and CRP was found in PsA sine psoriasis patients. Further studies are also advocated for clarifying the possible role of these adipokines as laboratory findings or as disease mediators in addressing the different phenotypes of the disease.Key PointsoLevels of TNF-?, IL-6, leptin, resistin, visfatin, and ghrelin did not differ between PsA patients with clinical evident psoriasis and PsA sine psoriasis.oThere is a strict interplay between leptin, female gender, BMI, and inflammatory activity in PsA.oThere is a close association between resistin and IL-6 in PsA patients with clinical evident psoriasis.