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Background and aims: We investigated the clinical impact of the newly defined metabolic-associated fatty liver disease (MAFLD) in patients undergoing hepatectomy for HCC (MAFLD-HCC) comparing the characteristics and outcomes of patients with MAFLD-HCC to viral- and alcoholic-related HCC (HCV-HCC, HBV-HCC, A-HCC). Methods: A retrospective analysis of patients included in the He.RC.O.Le.S. Group registry was performed. The characteristics, short- and long-term outcomes of 1315 patients included were compared according to the study group before and after an exact propensity score match (PSM). Results: Among the whole study population, 264 (20.1%) had MAFLD-HCC, 205 (15.6%) had HBV-HCC, 671 (51.0%) had HCV-HCC and 175 (13.3%) had A-HCC. MAFLD-HCC patients had higher BMI (p < 0.001), Charlson Comorbidities Index (p < 0.001), size of tumour (p < 0.001), and presence of cirrhosis (p < 0.001). After PSM, the 90-day mortality and severe morbidity rates were 5.9% and 7.1% in MAFLD-HCC, 2.3% and 7.1% in HBV-HCC, 3.5% and 11.7% in HCV-HCC, and 1.2% and 8.2% in A-HCC (p = 0.061 and p = 0.447, respectively). The 5-year OS and RFS rates were 54.4% and 37.1% in MAFLD-HCC, 64.9% and 32.2% in HBV-HCC, 53.4% and 24.7% in HCV-HCC and 62.0% and 37.8% in A-HCC (p = 0.345 and p = 0.389, respectively). Cirrhosis, multiple tumours, size and satellitosis seems to be the independent predictors of OS. Conclusion: Hepatectomy for MAFLD-HCC seems to have a higher but acceptable operative risk. However, long-term outcomes seems to be related to clinical and pathological factors rather than aetiological risk factors.

BackgroundLittle is known about peripherally inserted central catheter (PICC) use, appropriateness and device outcomes in Brazil.MethodsWe conducted an observational, prospective, cohort study spanning 16 Brazilian hospitals from October 2018 to August 2020. Patients ≥18 years receiving a PICC were included. PICC placement variables were abstracted from medical records. PICC-related major (deep vein thrombosis (DVT), central line-associated bloodstream infection (CLABSI) and catheter occlusion) and minor complications were collected. Appropriateness was evaluated using the Michigan Appropriateness Guide for Intravenous Catheters (MAGIC). Devices were considered inappropriate if they were in place for <5 days, were multi-lumen, and/or were placed in patients with a creatinine >2.0 mg/dL. PICCs considered appropriate met none of these criteria. Mixed-effects logistic regression models adjusting for patient-level and hospital-level characteristics assessed the association between appropriateness and major complications.ResultsData from 12 725 PICCs were included. Mean patient age was 66.4±19 years and 51.0% were female. The most common indications for PICCs were intravenous antibiotics (81.1%) and difficult access (62.7%). Most PICCs (72.2%) were placed under ultrasound guidance. The prevalence of complications was low: CLABSI (0.9%); catheter-related DVT (1.0%) and reversible occlusion (2.5%). Of the 12 725 devices included, a total of 7935 (62.3%) PICCs were inappropriate according to MAGIC. With respect to individual metrics for appropriateness, 17.0% were placed for <5 days, 60.8% were multi-lumen and 11.3% were in patients with creatinine >2.0 mg/dL. After adjusting for patient and hospital-level characteristics, multi-lumen PICCs considered inappropriate were associated with greater odds of major complications (OR 2.54, 95% CI 1.61 to 4.02).ConclusionsUse of PICCs in Brazilian hospitals appears to be safe and comparable with North America. However, opportunities to improve appropriateness remain. Future studies examining barriers and facilitators to improving device use in Brazil would be welcomed.

Background: Lung ultrasound (LUS) showed a promising role in the diagnosis and monitoring of patients hospitalized for novel coronavirus disease (COVID-19). However, no data are available on its role in elderly patients. Aims: The aim of this study was to evaluate the diagnostic and prognostic role of LUS in elderly patients hospitalized for severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) pneumonia. Methods: Consecutive elderly patients (age >65 years) hospitalized for COVID-19 were enrolled. Demographics, laboratory, comorbidity, and the clinical features of the patients were collected. All patients underwent LUS on admission to the ward. LUS characteristics have been analyzed. Uni- and multivariate analyses to evaluate predictors for in-hospital death were performed. Results: Thirty-seven hospitalized elderly patients (19 men) with a diagnosis of SARS-CoV-2 infection were consecutively enrolled. The median age was 82 years (interquartile range 74.5–93.5). Ultrasound alterations were found in all patients enrolled; inhomogeneous interstitial syndrome with spared areas (91.9%) and pleural alterations (100%) were the most frequent findings. At univariate analysis, LUS score (hazard ratio [HR] 1.168, 95% CI 1.049–1.301) and pleural effusions (HR 3.995, 95% CI 1.056–15.110) were associated with in-hospital death. At multivariate analysis, only LUS score (HR 1.168, 95% CI 1.049–1.301) was independelty associated with in-hospital death. The LUS score’s best cutoff for distinguishing patients experiencing in-hospital death was 17 (at multivariate analysis LUS score ≥17, HR 4.827, 95% CI 1.452–16.040). In-hospital death was significantly different according to the LUS score cutoff of 17 (p = 0.0046). Conclusion: LUS could play a role in the diagnosis and prognosis in elderly patients hospitalized for SARS-CoV-2 infection.

Disturbances of conscious awareness, or self-disorders, are a defining feature of schizophrenia. These include symptoms such as delusions of control, i.e. the belief that one’s actions are controlled by an external agent. Models of self-disorders point at altered neural mechanisms of source monitoring, i.e. the ability of the brain to discriminate self-generated stimuli from those driven by the environment. However, evidence supporting this putative relationship is currently lacking. We performed electroencephalography (EEG) during self-paced, brisk right fist closures in ten (M = 9; F = 1) patients with Early-Course Schizophrenia (ECSCZ) and age and gender-matched healthy volunteers. We measured the Readiness Potential (RP), i.e. an EEG feature preceding self-generated movements, and movement-related EEG spectral changes. Self-disorders in ECSCZ were assessed with the Examination of Anomalous Self-Experience (EASE). Patients showed a markedly reduced RP and altered post-movement Event-Related Synchronization (ERS) in the beta frequency band (14–24 Hz) compared to healthy controls. Importantly, smaller RP and weaker ERS were associated with higher EASE scores in ECSCZ. Our data suggest that disturbances of neural correlates preceding and following self-initiated movements may reflect the severity of self-disorders in patients suffering from ECSCZ. These findings point towards deficits in basic mechanisms of sensorimotor integration as a substrate for self-disorders.

Objective: To compare different stereotactic body techniques—intensity-modulated radiotherapy with photons and protons, applied to radiotherapy of prostatic cancer—with simultaneous integrated boost (SIB) on the dominant intraprostatic lesion (DIL). Methods: Ten patients were selected for this planning study. Dosimetric results were compared between volumetric modulated arc therapy, intensity-modulated radiation therapy (IMRT), and intensity-modulated proton therapy both with two (IMPT 2F) and five fields (IMPT 5F) planning while applying the prescription schemes of 7.25 Gy/fraction to the prostate gland and 7.5 Gy/fraction to the DIL in 5 fractions. Results: Comparison of the coverages of the planning target volumes showed that small differences exist. The IMPT-2F-5F techniques allowed higher doses in the targets; conformal indexes resulted similar; homogeneity was better in the photon techniques (2%–5%). Regarding the organs at risk, all the techniques were able to maintain the dose well below the prescribed constraints: in the rectum, the IMPT-2F-5F and IMRT were more efficient in lowering the intermediate doses; in the bladder, the median dose was significantly better in the case of IMPT (2F–5F). In the urethra, the best sparing was achieved only by IMPT-5F. Conclusions: Stereotactic radiotherapy with SIB for localized prostate cancer is feasible with all the investigated techniques. Concerning IMPT, the two-beam technique does not seem to have a greater advantage compared to the standard techniques; the 5-beam technique seems more promising also accounting for the range uncertainty.

Objective Markers of seizure recurrence are needed to personalize antiseizure medication (ASM) therapy. In the clinical practice, EEG features are considered to be related to the risk of seizure recurrence for genetic generalized epilepsies (GGE). However, to our knowledge, there are no studies analyzing systematically specific EEG features as indices of ASM efficacy in GGE. In this study, we aimed at identifying EEG indicators of ASM responsiveness in Juvenile Myoclonic Epilepsy (JME), which, among GGE, is characterized by specific electroclinical features. Methods We compared the features of prolonged ambulatory EEG (paEEG, 22 h of recording) of JME patients experiencing seizure recurrence within a year (“cases”) after EEG recording, with those of patients with sustained seizure freedom for at least 1 year after EEG (“controls”). We included only EEG recordings of patients who had maintained the same ASM regimen (dosage and type) throughout the whole time period from the EEG recording up to the outcome events (which was seizure recurrence for the “cases”, or 1‐year seizure freedom for “controls”). As predictors, we evaluated the total number, frequency, mean and maximum duration of epileptiform discharges (EDs) and spike density (i.e. total EDs duration/artifact‐free EEG duration) recorded during the paEEG. The same indexes were assessed also in standard EEG (stEEG), including activation methods. Results Both the maximum length and the mean duration of EDs recorded during paEEG significantly differed between cases and controls; when combined in a binary logistic regression model, the maximum length of EDs emerged as the only valid predictor. A cut‐off of EDs duration of 2.68 seconds discriminated between cases and controls with a 100% specificity and a 93% sensitivity. The same indexes collected during stEEG lacked both specificity and sensitivity. Significance The occurrence of prolonged EDs in EEG recording might represent an indicator of antiepileptic drug failure in JME patients.

Myasthenia gravis (MG) is a neuromuscular autoimmune disease characterized by prevalence in young women (3:1). Several mechanisms proposed as explanations for gender bias, including skewed X chromosome inactivation (XCI) and dosage or sex hormones, are often involved in the development of autoimmunity. The skewed XCI pattern can lead to an unbalanced expression of some X-linked genes, as observed in several autoimmune disorders characterized by female predominance. No data are yet available regarding XCI and MG. We hypothesize that the preferential XCI pattern may contribute to the female bias observed in the onset of MG, especially among younger women. XCI analysis was performed on blood samples of 284 women between the ages of 20 and 82. XCI was tested using the Human Androgen Receptor Assay (HUMARA). XCI patterns were classified as random (XCI < 75%) and preferential (XCI ≥ 75%). In 121 informative patients, the frequency of skewed XCI patterns was 47%, significantly higher than in healthy controls (17%; p ≤ 0.00001). Interestingly, the phenomenon was observed mainly in younger patients (

Cerebrospinal fluid (CSF) amino acid (AA) levels and CSF/plasma AA ratios in Alzheimer Disease (AD) in relation to nutritional state are not known. Methods: In 30 fasting patients with AD (46% males, 74.4 ± 8.2 years; 3.4 ± 3.2 years from diagnosis) and nine control (CTRL) matched subjects, CSF and venous blood samples were drawn for AA measurements. Patients were stratified according to nutritional state (Mini Nutritional Assessment, MNA, scores). Results: Total CSF/plasma AA ratios were lower in the AD subpopulations than in NON-AD (p < 0.003 to 0.017. In combined malnourished (16.7%; MNA < 17) and at risk for malnutrition (36.6%, MNA 17–24) groups (CG), compared to CTRL, all essential amino acids (EAAs) and 30% of non-EAAs were lower (p < 0.018 to 0.0001), whereas in normo-nourished ADs (46.7%, MNA > 24) the CSF levels of 10% of EAAs and 25% of NON-EAAs were decreased (p < 0.05 to 0.00021). CG compared to normo-nourished ADs, had lower CSF aspartic acid, glutamic acid and Branched-Chain AA levels (all, p < 0.05 to 0.003). CSF/plasma AA ratios were

OBJECTIVE: The aim of this study was to evaluate correlation between centers' volume and incidence of failure to rescue (FTR) following liver resection for hepatocellular carcinoma (HCC). SUMMARY BACKGROUND DATA: FTR, defined as the probability of postoperative death among patients with major complication, has been proposed to assess quality of care during hospitalization. Perioperative management is challenging in cirrhotic patients and the ability to recognize and treat a complication may be fundamental to rescue patients from the risk of death. METHODS: Patients undergoing liver resection for HCC between 2008 and 2018 in 18 Centers enrolled in the He.Rc.O.Le.S. Italian register. Early results included major complications (Clavien ≥3), 90-day mortality, and FTR and were analyzed according to center's volume. RESULTS: Among 1935 included patients, major complication rate was 9.4% (8.6%, 12.3%, and 7.0% for low-, intermediate- and high-volume centers, respectively, P = 0.001). Ninety-day mortality rate was 2.6% (3.7%, 4.2% and 0.9% for low-, intermediate- and high-volume centers, respectively, P < 0.001). FTR was significantly higher at low- and intermediate-volume centers (28.6% and 26.5%, respectively) than at high-volume centers (6.1%, P = 0.002). Independent predictors for major complications were American Society of Anesthesiologists (ASA) >2, portal hypertension, intraoperative blood transfusions, and center's volume. Independent predictors for 90-day mortality were ASA >2, Child-Pugh score B, BCLC stage B-C, and center's volume. Center's volume and BCLC stage were strongly associated with FTR. CONCLUSIONS: Risk of major complications and mortality was related with comorbidities, cirrhosis severity, and complexity of surgery. These factors were not correlated with FTR. Center's volume was the only independent predictor related with severe complications, mortality, and FTR.

Liver surgery is the first line treatment for hepatocarcinoma. Hepatocarcinoma Recurrence on the Liver Study (HERCOLES) Group was established in 2018 with the goal to create a network of Italian centres sharing data and promoting scientific research on hepatocellular carcinoma (HCC) in the surgical field. This is the first national report that analyses the trends in surgical and oncological outcomes. Register data were collected by 22 Italian centres between 2008 and 2018. One hundred sixty-four variables were collected, regarding liver functional status, tumour burden, radiological, intraoperative and perioperative data, histological features and oncological follow-up. 2381 Patients were enrolled. Median age was 70 (IQR 63-75) years old. Cirrhosis was present in 1491 patients (62.6%), and Child-A were 89.9% of cases. HCC was staged as BCLC0-A in almost 50% of cases, while BCLC B and C were 20.7% and 17.9% respectively. Major liver resections were 481 (20.2%), and laparoscopy was employed in 753 (31.6%) cases. Severe complications occurred only in 5%. Postoperative ascites was recorded in 10.5% of patients, while posthepatectomy liver failure was observed in 4.9%. Ninety-day mortality was 2.5%. At 5years, overall survival was 66.1% and disease-free survival was 40.9%. Recurrence was intrahepatic in 74.6% of cases. Redo-surgery and thermoablation for recurrence were performed up to 32% of cases. This is the most updated Italian report of the national experience in surgical treatment for HCC. This dataset is consistently allowing the participating centres in creating multicentric analysis which are already running with a very large sample size and strong power. Liver surgery is the first line treatment for hepatocarcinoma. Hepatocarcinoma Recurrence on the Liver Study (HERCOLES) Group was established in 2018 with the goal to create a network of Italian centres sharing data and promoting scientific research on hepatocellular carcinoma (HCC) in the surgical field. This is the first national report that analyses the trends in surgical and oncological outcomes. Register data were collected by 22 Italian centres between 2008 and 2018. One hundred sixty-four variables were collected, regarding liver functional status, tumour burden, radiological, intraoperative and perioperative data, histological features and oncological follow-up. 2381 Patients were enrolled. Median age was 70 (IQR 63–75) years old. Cirrhosis was present in 1491 patients (62.6%), and Child-A were 89.9% of cases. HCC was staged as BCLC0-A in almost 50% of cases, while BCLC B and C were 20.7% and 17.9% respectively. Major liver resections were 481 (20.2%), and laparoscopy was employed in 753 (31.6%) cases. Severe complications occurred only in 5%. Postoperative ascites was recorded in 10.5% of patients, while posthepatectomy liver failure was observed in 4.9%. Ninety-day mortality was 2.5%. At 5years, overall survival was 66.1% and disease-free survival was 40.9%. Recurrence was intrahepatic in 74.6% of cases. Redo-surgery and thermoablation for recurrence were performed up to 32% of cases. This is the most updated Italian report of the national experience in surgical treatment for HCC. This dataset is consistently allowing the participating centres in creating multicentric analysis which are already running with a very large sample size and strong power.

Background This multi-institutional retrospective real life study was conducted in 22 Italian Oncology Centers and evaluated the role of Axitinib in second line treatment in not selected mRCC patients. Methods 148 mRCC patients were evaluated. According to Heng score 15.5%, 60.1% and 24.4% of patients were at poor risk, intermediate and favorable risk, respectively. Results PFS, OS, DCR and ORR were 7.14 months, 15.5 months, 70.6% and 16.6%, respectively. The duration of prior sunitinib treatment correlated with a longer significant mPFS, 8.8 vs 6.3 months, respectively. Axitinib therapy was safe, without grade 4 adverse events. The most frequent toxicities of all grades were: fatigue (50%), hypertension (26%), and hypothyroidism (18%). G3 blood pressure elevation significantly correlated with longer mPFS and mOS compared to G1-G2 or no toxicity. Dose titration (DT) to 7 mg and 10 mg bid was feasible in 24% with no statistically significant differences in mPFS and mOS. The sunitinib-axitinib sequence was safe and effective, the mOS was 41.15 months. At multivariate analysis, gender, DCR to axitinib and to previous sunitinib correlated significantly with PFS; whereas DCR to axitinib, nephrectomy and Heng score independently affected overall survival. Conclusions Axitinib was effective and safe in a not selected real life mRCC population. Trial registration INT – Napoli – 11/16 oss. Registered 20 April 2016. http://www.istitutotumori.na.it

Background Thymoma‐associated myasthenia gravis (TAMG) is one of the subtypes of myasthenia gravis with autoantibodies against the acetylcholine receptor (AChR‐Ab). We analyzed the clinical features of our cohort of TAMG patients and the changes in AChR‐Ab titer before and after thymectomy in order to identify factors predicting thymoma relapses. Methods We retrospectively assessed: age of MG onset, MG clinical status according to MGFA (Myasthenia Gravis Foundation of America), epoch of thymectomy, post‐thymectomy status, oncological features and surgical approach. AChR‐Ab dosages were measured both before and after thymectomy. Linear regression models were applied to identify clinical determinants of AChR‐Ab titers and the Cox regression model was fitted to estimate the factors associated with the risk of thymoma recurrence. Results The study sample included 239 MG patients, 27 of whom experienced one or more recurrences (median follow‐up time: 4.8 years). The AChR‐Ab titers decreased after first thymectomy (P, In our paper, we retrospectively analyzed the changes in antiacetylcholine receptor antibody (AChR‐Ab) titer before and after thymectomy and the clinical features of thymoma‐associated myasthenia gravis (TAMG) patients in order to identify clinical and serological predictors of thymoma recurrence. Our study emphasizes the importance of a multidisciplinary approach among Neurologists, Oncologists and Thoracic Surgeons, and identifies subgroups of MG patients with high risk of thymoma recurrence who therefore need a more accurate follow‐up.

Background Pisa syndrome (PS) is a clinical condition frequently associated with Parkinson's disease (PD). It is characterized by a trunk lateral flexion higher than 10 degrees and reversible when lying. One pathophysiological hypothesis is the altered verticality perception, due to a somatosensory impairment. Osteopathic Manipulative Treatment (OMT) manages fascial-system alterations, linked to somatic dysfunctions. Fascial system showed to be implicated in proprioceptive sensibility. Objective The aim of the study was to assess OMT efficacy on postural control in PD-PS patients by stabilometry. Methods In this single-blinded trial we studied 24 PD-PS patients, 12 of whom were randomly assigned to receive a multidisciplinary physical therapy protocol (MIRT) and sham OMT, while the other 12 received four OMT plus MIRT, for one month. The primary endpoint was the eye closed sway area assessment after the intervention. Evaluation of trunk lateral flexion (TLF) with DIERS formetrics was also performed. Results At one month, the sway area of the OMT group significantly decreased compared to placebo (mean delta OMT - 326.00±491.24 mm2, p = 0.01). In the experimental group TLF showed a mean inclination reduction of 3.33 degrees after treatment (p = 0.044, mean d = 0.54). Moreover, a significant positive association between delta ECSA and delta TLF was observed (p = 0.04, r = 0.46). Discussion Among PD-PS patients, MIRT plus OMT showed preliminary evidence of postural control and TLF improvement, compared to the control group.

Summary Background The Butantan Institute has manufactured a lyophilised tetravalent live-attenuated dengue vaccine Butantan-DV, which is analogous to the US National Institutes of Health (NIH) TV003 admixture. We aimed to assess the safety and immunogenicity of Butantan-DV. Methods We did a two-step, double-blind, randomised placebo-controlled phase 2 trial at two clinical sites in Sao Paulo, Brazil. We recruited healthy volunteers aged 18–59 years; pregnant women, individuals with a history of neurological, heart, lung, liver or kidney disease, diabetes, cancer, or autoimmune diseases, and individuals with HIV or hepatitis C were excluded. Step A was designed as a small bridge-study between Butantan-DV and TV003 in DENV-naive participants. In step A, we planned to randomly assign 50 dengue virus (DENV)-naive individuals to receive two doses of Butantan-DV, TV003, or placebo, given 6 months apart. In step B, we planned to randomly assign 250 participants (DENV-naive and DENV-exposed) to receive one dose of Butantan-DV or placebo. Participants were randomly assigned, by computer-generated block randomisation (block sizes of five); participants in step A were randomly assigned (2:2:1) to receive Butantan-DV, TV003, or placebo and participants in step B were randomly assigned (4:1) to receive Butantan-DV or placebo. Participants and study staff were unaware of treatment allocation. The primary safety outcome was the frequency of solicited and unsolicited local and systemic adverse reactions within 21 days of the first vaccination, analysed by intention to treat. The primary immunogenicity outcome was seroconversion rates of the DENV-1-4 serotypes measured 91 days after the first vaccination, analysed in the per-protocol population, which included all participants in step A, and all participants included in step B who completed all study visits with serology sample collection. This trial is registered with ClinicalTrials.gov , NCT01696422 . Findings Between Nov 5, 2013, and Sept 21, 2015, 300 individuals were enrolled and randomly assigned: 155 (52%) DENV-naive participants and 145 (48%) DENV-exposed participants. Of the 155 DENV-naive participants, 97 (63%) received Butantan-DV, 17 (11%) received TV003, and 41 (27%) received placebo. Of the 145 DENV-exposed participants, 113 (78%) received Butantan-DV, three (2%) received TV003, and 29 (20%) received placebo. Butantan-DV and TV003 were both immunogenic, well-tolerated, and no serious adverse reactions were observed. In step A, rash was the most frequent adverse event (16 [845] of 19 participants in the Butantan-DV group and 13 [76%] of 17 participants in the TV003 group). Viraemia was similar between the Butantan-DV and TV003 groups. Of the 85 DENV-naive participants in the Butantan-DV group who attended all visits for sample collection for seroconversion analysis and thus were included in the per-protocol analysis population, 74 (87%) achieved seroconversion to DENV-1, 78 (92%) to DENV-2, 65 (76%) to DENV-3, and 76 (89%) to DENV-4. Of the 101 DENV-exposed participants in the Butantan-DV group who attended all visits for sample collection for seroconversion analysis, 82 (81%) achieved seroconversion to DENV-1, 79 (78%) to DENV-2, 83 (82%) to DENV-3, and 78 (77%) to DENV-4. Interpretation Butantan-DV and TV003 were safe and induced robust, balanced neutralising antibody responses against the four DENV serotypes. Efficacy evaluation of the Butantan-DV vaccine is ongoing. Funding Intramural Research Program US NIH National Institute of Allergy and Infectious Diseases, Brazilian National Bank for Economic and Social Development, Fundacao de Amparo a Pesquisa do Estado de Sao Paulo, and Fundacao Butantan.

Among patients with vasodilatory shock, gene expression scores may identify different immune states. We aimed to test whether such scores are robust in identifying patients' immune state and predicting response to hydrocortisone treatment in vasodilatory shock.We selected genes to generate continuous scores to define previously established subclasses of sepsis. We used these scores to identify a patient's immune state. We evaluated the potential for these states to assess the differential effect of hydrocortisone in two randomized clinical trials of hydrocortisone versus placebo in vasodilatory shock.We initially identified genes associated with immune-adaptive, immune-innate, immune-coagulant functions. From these genes, 15 were most relevant to generate expression scores related to each of the functions. These scores were used to identify patients as immune-adaptive prevalent (IA-P) and immune-innate prevalent (IN-P). In IA-P patients, hydrocortisone therapy increased 28-day mortality in both trials (43.3% vs 14.7%, P = 0.028) and (57.1% vs 0.0%, P = 0.99). In IN-P patients, this effect was numerically reversed.Gene expression scores identified the immune state of vasodilatory shock patients, one of which (IA-P) identified those who may be harmed by hydrocortisone. Gene expression scores may help advance the field of personalized medicine.

Although the prevalence of mental disorders in prisoners is known to be higher than in the general population, less is known about the antipsychotic (AP) prescribing rate in jail. The aim of this research was to investigate prevalence and appropriateness of AP prescription in an Italian prison to expand our understanding on this crucial area of clinical-forensic practice.A cross-sectional (census day) design was used among male adults in the Parma Penitentiary Institutes (PPI). Sociodemographic, clinical and prescription data were collected from the PPI electronic clinical database management system. The AP prescribing appropriateness was examined in accordance with the therapeutic indications included in the Italian National Formulary. A descriptive statistical analysis was performed.A total of 98 (14.1%) of 696 PPI prisoners were taking AP medications. Moreover, 90 (91.8%) of the 98 PPI participants were also taking other psychotropic medications concurrently. Quetiapine and olanzapine were the most common prescribed APs. Antipsychotic medications were most likely to be prescribed for off-label indications (74.4%). Less than one fifth of all AP prescriptions were for psychotic disorders.Antipsychotic medications are widely used in prison, often together with other psychotropic drugs. Considering their common adverse effects, it is crucial to longitudinally monitor their potential risk of metabolic, cardiovascular, and extrapyramidal symptoms and signs, as well as their early risk of mortality. Given the high prevalence of AP off-label prescription, the rationale for AP prescribing should be clearly documented and regularly reviewed within the prison by mental health professionals.

Background: Cholesterol has a pivotal role in human physiology, exerting both structural and functional activity. However, higher blood cholesterol levels, especially low-density lipoprotein cholesterol (LDL-C), are a major cardiovascular risk factor. Therefore, special attention has been given to the effect of dietary factors in influencing LDL-C blood levels. In particular, much research has focused on dairy products, since they are a main component of different dietary patterns worldwide. A large body of evidence did not support the hypothesis that dairy products significantly increase circulating LDL-C, but no definitive data are available. Hence, we aimed to assess the relationships among LDL-C, habitual dairy food intake and anthropometric variables in a cohort representative of the general population in a Mediterranean area. Methods: We evaluated 802 healthy adults included in the ABCD_2 (Alimentazione, Benessere Cardiovascolare e Diabete) study (ISRCTN15840340), a longitudinal observational single-center study of a cohort representative of the general population of Palermo, Sicily. The habitual intake of dairy products was assessed with a validated food frequency questionnaire, and LDL-C serum levels and several anthropometric parameters were measured. Results: The group with high LDL-C serum concentrations (≥130 vs. &lt, 130 mg/dL) exhibited higher age, body mass index (BMI), waist-to-hip ratio (WHR), body fat percentage, systolic and diastolic blood pressure, carotid intima-media thickness and glycated hemoglobin. The habitual diet was not different between the groups in terms of macronutrient, cholesterol, egg and dairy food intake, with the exception of the weekly number of portions of milk (higher in the low LDL-C group vs. the high LDL-C group) and ricotta cheese (higher in the high LDL-C group vs. the LDL-C group). No significant correlation was found between LDL-C blood levels and the habitual intake of dairy products or the dietary intake of cholesterol and fats. The multivariate regression analyses (R2 = 0.94) showed that LDL-C blood levels were significantly associated with the habitual intake of milk (p &lt, 0.005) and ricotta cheese (p &lt, 0.001) and with BMI (p &lt, 0.001). Conclusion: Our study reported that total dairy food consumption was not correlated with LDL-C blood levels. However, multivariate analyses showed an inverse association between serum LDL-C and milk intake as well as a positive association between ricotta cheese intake and LDL-C concentrations. More studies are needed to better characterize the relationship between dairy products and circulating LDL-C.

Background IgG4 is associated with two emerging groups of rare diseases: 1) IgG4 autoimmune diseases (IgG4-AID) and 2) IgG4-related diseases (IgG4-RLD). Anti-neuronal IgG4-AID include MuSK myasthenia gravis, LGI1- and Caspr2-encephalitis and autoimmune nodo-/paranodopathies (CNTN1/Caspr1 or NF155 antibodies). IgG4-RLD is a multiorgan disease hallmarked by tissue-destructive fibrotic lesions with lymphocyte and IgG4 plasma cell infiltrates and increased serum IgG4 concentrations. It is unclear whether IgG4-AID and IgG4-RLD share relevant clinical and immunopathological features. Methods We collected and analyzed clinical, serological, and histopathological data in 50 patients with anti-neuronal IgG4-AID and 19 patients with IgG4-RLD. Results A significantly higher proportion of IgG4-RLD patients had serum IgG4 elevation when compared to IgG4-AID patients (52.63% vs. 16%, p = .004). Moreover, those IgG4-AID patients with elevated IgG4 did not meet the diagnostic criteria of IgG4-RLD, and their autoantibody titers did not correlate with their serum IgG4 concentrations. In addition, patients with IgG4-RLD were negative for anti-neuronal/neuromuscular autoantibodies and among these patients, men showed a significantly higher propensity for IgG4 elevation, when compared to women (p = .005). Last, a kidney biopsy from a patient with autoimmune paranodopathy due to CNTN1/Caspr1-complex IgG4 autoantibodies and concomitant nephrotic syndrome did not show fibrosis or IgG4+ plasma cells, which are diagnostic hallmarks of IgG4-RLD. Conclusion Our observations suggest that anti-neuronal IgG4-AID and IgG4-RLD are most likely distinct disease entities.

Introduction Patients with cancer are presumed a frail group at high risk of contracting coronavirus disease (COVID-19), and vaccination represents a cornerstone in addressing the COVID-19 pandemic. However, data on COVID-19 vaccination in cancer patients are fragmentary and poor. Methods An observational study was conducted to evaluate the seropositivity rate and safety of a two-dose regimen of the BNT162b2 or messenger RNA-1273 vaccine in adult patients with solid cancer undergoing active anticancer treatment or whose treatment had been terminated within 6 months of the start of the study. The control group was composed of healthy volunteers. Serum samples were evaluated for SARS-COV-2 antibodies before vaccinations and 2–6 weeks after the administration of the second vaccine dose. Primary end-point: seropositivity rate. Secondary end-points: safety, factors influencing seroconversion, IgG titers of patients versus healthy volunteers, COVID-19 infection. Results Between 20th March 2021 and 12th June 2021, 293 consecutive patients with cancer-solid tumours underwent a program of COVID-19 vaccinations; of these, 2 patients refused vaccination, 13 patients did not receive the second dose of the vaccine because of cancer progression, and 21 patients had COVID-19 antibodies at baseline and were excluded. The 257 evaluable patients had a median age of 65 years (range 28–86), 66.15% with metastatic disease. Primary end-point: seropositivity rate in patients was 75.88% versus 100% in the control group. Secondary end-points: no Grade 3–4 side-effects, no COVID-19 infections were reported. Patients median IgG titer was significantly lower than in the control group; male sex and active anticancer therapy influenced negative seroconversion. BNT162b2 or messenger RNA-1273 vaccines were immunogenic in cancer patients, showing good safety profile.

Background: Immune activation is a significant contributor to HIV pathogenesis and disease progression. In virally-suppressed individuals on ART, low-level immune activation has been linked to several non-infectious comorbid diseases. However, studies have not been systematically performed in sub-Saharan Africa and thus the impact of demographics, ART and regional endemic co-infections on immune activation is not known. We therefore comprehensively evaluated in a large multinational African cohort markers for immune activation and its distribution in various settings. Methods: 2747 specimens from 2240 people living with HIV (PLWH) and 477 without HIV from the observational African Cohort Study (AFRICOS) were analyzed for 13 immune parameters. Samples were collected along with medical history, sociodemographic and comorbidity data at 12 HIV clinics across 5 programs in Uganda, Kenya, Tanzania and Nigeria. Data were analyzed with univariate and multivariate methods such as random forests and principal component analysis. Findings: Immune activation was markedly different between PLWH with detectable viral loads, and individuals without HIV across sites. Among viremic PLWH, we found that all immune parameters were significantly correlated with viral load except for IFN-α. The overall inflammatory profile was distinct between men and women living with HIV, in individuals off ART and with HIV viremia. We observed stronger differences in the immune activation profile with increasing viremia. Using machine learning methods, we found that geographic differences contributed to unique inflammatory profiles. We also found that among PLWH, age and the presence of infectious and/or noninfectious comorbidities showed distinct inflammatory patterns, and biomarkers may be used to predict the presence of some comorbidities. Interpretation: Our findings show that chronic immune activation in HIV-1 infection is influenced by HIV viral load, sex, age, region and ART use. These predictors, as well as associations among some biomarkers and coinfections, influence biomarkers associated with noncommunicable diseases. Funding: This work was supported by the President's Emergency Plan for AIDS Relief via a cooperative agreement between the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., and the U.S. Department of Defense [W81XWH-11-2-0174, W81XWH-18-2-0040]. The investigators have adhered to the policies for protection of human subjects as prescribed in AR 70–25. This article was prepared while Michael A. Eller was employed at Henry M. Jackson Foundation for the Advancement of Military Medicine for the U.S. Military HIV Research Program. The views expressed are those of the authors and should not be construed to represent the positions of the US Army or the Department of Defense. The opinions expressed in this article are the author's own, and do not reflect the view of the National Institutes of Health, the U.S. Department of Health and Human Services, or the U.S. government. CA extern

Routine Outcome Monitoring (ROM) is still poorly implemented in the routine forensic psychiatric practice. As reliable ROM instruments are lacking, the aims of this research was to assess the psychometric properties of the Parma Scale (Pr-Scale) and its sensitivity to measure scores' longitudinal changes.Interrater and test-retest reliability, internal consistency and concurrent validity were investigated in offenders with mental disorder. Scores' longitudinal changeability was examined after a 3-month period using the Wilcoxon test for repeated measure.Sixty male adult patients were recruited in this study. Our findings showed good to excellent interrater and test-retest reliability, concurrent validity and internal consistency for the Pr-Scale. Pr-Scale scores also display a moderate to large changeability over time.Our results support the clinical use of the Pr-Scale in forensic psychiatric settings as reliable ROM instrument.

Dry eye disease (DED) is a multifactorial disease of the ocular surface system whose chore mechanisms are tear film instability, inflammation, tear hyperosmolarity and epithelial damage. In recent years, novel therapies specifically targeting inflammation and oxidative stress are being investigated and used in this field. Therefore, an increasing body of evidence supporting the possible role of different micronutrients and nutraceutical products for the treatment of ocular surface diseases is now available. In the present review, we analyzed in detail the effects on ocular surface of omega-3 fatty acids, vitamins A, B12, C, D, selenium, curcumin and flavonoids. Among these, the efficacy of omega-3 fatty acid supplementation in ameliorating DED signs and symptoms is supported by robust scientific evidence. Further long-term clinical trials are warranted to confirm the safety and efficacy of the supplementation of the other micronutrients and nutraceuticals.

Funder: Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Brazilian Federal Agency for the Support and Evaluation of Graduate Education); doi: https://doi.org/10.13039/501100002322, Funder: Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Reproductive compatibility usually decreases according to increasing genetic difference and the time of divergence between species. However, the amount of modification required to influence hybridization may vary in different species. Thus, it is extremely important to conduct studies that seek to understand what and how variables influence the reproductive isolation of species. We have explored a system involving two species of subterranean rodents that present morphological, karyotypic, and evolutionary history differences and are capable of generating hybrids. To gain insight into the karyotype organization of genus Ctenomys, we examined the chromosome evolution by classical and molecular cytogenetics of both parental species and hybrids. Furthermore, we have used different approaches to analyze the differences between the parental species and the hybrids, and determined the origin of the hybrids. The results of our work demonstrate unequivocally that some species that present extensive differences in chromosome organization, phenotype, evolutionary history, sperm morphology and genetic, which are usually associated with reproductive isolation, can generate natural hybrids. The results also demonstrate that females of both species are able to generate hybrids with males of the other species. In addition, the chromosome-specific probes prepared from Ctenomys flamarioni provide an invaluable tool for comparative cytogenetics in closely related species.

Background. Progressive increase of an aging population in Western countries will result in a growth of stroke prevalence. As many stroke survivors chronically show severe disability, increase in economic, social, and medical burden could be expected in the future. Objective and subjective measures of poststroke recovery are necessary to obtain predictive information, to improve the treatments, and to better allocate resources. Aim. To explore a measure of the temporal dimension of poststroke recovery, to search for predictive association with multiple clinical variables, and to improve tailoring of poststroke treatments. Method. In this observational monocentric cohort study, 176 poststroke inpatients at their first cerebrovascular event were consecutively enrolled. A novel measure based on the time needed to reach the main milestones of motor recovery was proposed. Moreover, two commonly used outcome measures, a measure of global functioning (Functional Independence Measure (FIM™)) and a measure of neurological poststroke deficit (Fugl-Meyer scale), were collected for the investigations of possible predictors. Results. The patients showed a substantial increase in Fugl-Meyer and FIM scores during the rehabilitative treatment. The acquisition of three milestones was significantly associated with female sex (autonomous standing), length of stay and Fugl-Meyer initial score (autonomous walking), and Fugl-Meyer initial score (functional arm). These findings provided quantitative data on motor milestone reacquisition in a sample of poststroke patients. It also demonstrated the value of the Fugl-Meyer score in predicting the acquisition of two motor milestones, relevant for daily life activities. Conclusion. Systematic recording of the timescale of poststroke recovery showed that motor milestone reacquisition happens, on average and when attainable, in less than 30 days in our sample of patients. The present study underscores the importance of the Fugl-Meyer score as a possible predictor for better improvement in reacquisition times of milestone functional recovery.

Background Symptomatic severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection incidence is higher in the elderly patients. Pre-existing geriatric conditions such as comorbidity and frailty seem related to worse hospital outcomes. Aims To assess the role of nutritional status as an independent prognostic factor for in-hospital death in elderly patients. Methods Consecutive elderly patients (age > 65 years) hospitalized for novel coronavirus disease (COVID-19) were enrolled. Demographics, laboratory and comorbidity data were collected. Nutritional status was evaluated using the Geriatric Nutritional Risk Index (GNRI). Uni- and multivariate Cox regression analyses to evaluate predictors for in-hospital death were performed. Results One hundred and nine hospitalized elderly patients (54 male) were consecutively enrolled. At univariate analysis, age (HR 1.045 [CI 1.008–1.082]), cognitive impairment (HR 1.949 [CI 1.045–3.364]), C-reactive protein (HR 1.004 [CI 1.011–1.078]), lactate dehydrogenases (HR 1.003 [CI 1.001–1.004]) and GNRI moderate–severe risk category (HR 8.571 [CI 1.096–67.031]) were risk factors for in-hospital death, while albumin (HR 0.809 [CI 0.822–0.964]), PaO2/FiO2 ratio (HR 0.996 [CI 0.993–0.999]) and body mass index (HR 0.875 [CI 0.782–0.979]) were protective factors. Kaplan–Meier survival curves showed a significative higher survival in patients without GNRI moderate or severe risk category (p = 0.0013). At multivariate analysis, PaO2/FiO2 ratio (HR 0.993 [CI 0.987–0.999], p = 0.046) and GNRI moderate–severe risk category (HR 9.285 [1.183–72.879], p = 0.034) were independently associated with in-hospital death. Conclusion Nutritional status assessed by GNRI is a significative predictor of survival in elderly patients hospitalized for COVID-19. The association between GNRI and PaO2/FiO2 ratio is a good prognostic model these patients.

Environmental enrichment may slow cognitive decay possibly acting through an improvement in vascular function. Aim of the study was to assess the effects of a 7-month cognitive, social, and physical training program on cognitive and vascular function in patients with mild cognitive impairment. In a single-center, randomized, parallel-group study, 113 patients (age, 65–89 years) were randomized to multidomain training (n=55) or usual care (n=58). All participants underwent neuropsychological tests and vascular evaluation, including brachial artery flow-mediated dilation, carotid–femoral pulse wave velocity, carotid distensibility, and assessment of circulating hematopoietic CD34+ and endothelial progenitor cells. At study entry, an age-matched control group (n=45) was also studied. Compared with controls, patients had at study entry a reduced flow-mediated dilation (2.97±2.14% versus 3.73±2.06%; P =0.03) and hyperemic stimulus (shear rate area under the curve, 19.1±15.7 versus 25.7±15.1×10 −3 ; P =0.009); only the latter remained significant after adjustment for confounders ( P =0.03). Training improved Alzheimer disease assessment scale cognitive (training, 14.0±4.8 to 13.1±5.5; nontraining, 12.1±3.9 to 13.2±4.8; P for interaction visit×training=0.02), flow-mediated dilation (2.82±2.19% to 3.40±1.81%, 3.05±2.08% to 2.24±1.59%; P =0.006; P =0.023 after adjustment for diameter and shear rate area under the curve), and circulating hematopoietic CD34 + cells and prevented the decline in carotid distensibility (18.4±5.3 to 20.0±6.6, 23.9±11.0 to 19.5±7.1 Pa −1 ; P =0.005). The only clinical predictor of improvement of cognitive function after training was established hypertension. There was no correlation between changes in measures of cognitive and vascular function. In conclusion, a multidomain training program slows cognitive decline, especially in hypertensive individuals. This effect is accompanied by improved systemic endothelial function, mobilization of progenitor CD34 + cells, and preserved carotid distensibility. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01725178.

BackgroundPersistent systemic inflammation leads to multidistrectual body dysfunctions. Attenuation of inflammation may improve patients’ functional and life prognoses. We hypothesized that essential amino acids (EAAs) given to elderly patients in rehabilitation after acute diseases may be associated with a reduced inflammatory state. Therefore, this retrospective study investigated whether the supplementation of EAAs – modulators of immune competence – was associated with a reduced inflammation rate in elderly patients.MethodsThe medical records of 282 patients admitted to the rehabilitation (rehab) institute after acute index events (surgery or medical diseases) (age: 81.18 ± 8.58 years; females: 67.9%) were analyzed.Results46 patients (16.3% of the entire population) had received EAA supplements (S), whereas the remaining 236 patients had not (N-S). Systemic inflammation (I) (serum C-reactive protein (CRP) > 0.5 mg/dL) was present in 67.4% of the I-S group and 57.2% of the I-N-S group. During rehab, the I-S group (but not the I-N-S group) showed a reduction in CRP levels ( p = 0.03) and an increase in circulating lymphocytes ( p = 0.035), immune cells of the adaptive immune system. C-reactive protein levels remained virtually unchanged in non-inflamed patients who received supplements but increased in non-inflamed patients who did not receive supplements ( p = 0.05). Stratified for developed infections, CRP levels reduced in S patients ( p = 0.008) but did not in N-S patients.ConclusionEAA supplementation was associated with reduced inflammation in both inflamed and infected patients. In addition, EAA supplementation was associated with increased circulating lymphocytes in inflamed patients.

Background Complement is likely to have a role in refractory generalised myasthenia gravis, but no approved therapies specifically target this system. Results from a phase 2 study suggested that eculizumab, a terminal complement inhibitor, produced clinically meaningful improvements in patients with anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis. We further assessed the efficacy and safety of eculizumab in this patient population in a phase 3 trial. Methods We did a phase 3, randomised, double-blind, placebo-controlled, multicentre study (REGAIN) in 76 hospitals and specialised clinics in 17 countries across North America, Latin America, Europe, and Asia. Eligible patients were aged at least 18 years, with a Myasthenia Gravis-Activities of Daily Living (MG-ADL) score of 6 or more, Myasthenia Gravis Foundation of America (MGFA) class II-IV disease, vaccination against Neisseria meningitides, and previous treatment with at least two immunosuppressive therapies or one immunosuppressive therapy and chronic intravenous immunoglobulin or plasma exchange for 12 months without symptom control. Patients with a history of thymoma or thymic neoplasms, thymectomy within 12 months before screening, or use of intravenous immunoglobulin or plasma exchange within 4 weeks before randomisation, or rituximab within 6 months before screening, were excluded. We randomly assigned participants (1:1) to either intravenous eculizumab or intravenous matched placebo for 26 weeks. Dosing for eculizumab was 900 mg on day 1 and at weeks 1, 2, and 3; 1200 mg at week 4; and 1200 mg given every second week thereafter as maintenance dosing. Randomisation was done centrally with an interactive voice or web-response system with patients stratified to one of four groups based on MGFA disease classification. Where possible, patients were maintained on existing myasthenia gravis therapies and rescue medication was allowed at the study physician's discretion. Patients, investigators, staff, and outcome assessors were masked to treatment assignment. The primary efficacy endpoint was the change from baseline to week 26 in MG-ADL total score measured by worst-rank ANCOVA. The efficacy population set was defined as all patients randomly assigned to treatment groups who received at least one dose of study drug, had a valid baseline MG-ADL assessment, and at least one post-baseline MG-ADL assessment. The safety analyses included all randomly assigned patients who received eculizumab or placebo. This trial is registered with ClinicalTrials.gov, number NCT01997229. Findings Between April 30, 2014, and Feb 19, 2016, we randomly assigned and treated 125 patients, 62 with eculizumab and 63 with placebo. The primary analysis showed no significant difference between eculizumab and placebo (least-squares mean rank 56·6 [SEM 4·5] vs 68·3 [4·5]; rank-based treatment difference -11·7, 95% CI -24·3 to 0·96; p=0·0698). No deaths or cases of meningococcal infection occurred during the study. The most common adverse events in both groups were headache and upper respiratory tract infection (ten [16%] for both events in the eculizumab group and 12 [19%] for both in the placebo group). Myasthenia gravis exacerbations were reported by six (10%) patients in the eculizumab group and 15 (24%) in the placebo group. Six (10%) patients in the eculizumab group and 12 (19%) in the placebo group required rescue therapy. Interpretation The change in the MG-ADL score was not statistically significant between eculizumab and placebo, as measured by the worst-rank analysis. Eculizumab was well tolerated. The use of a worst-rank analytical approach proved to be an important limitation of this study since the secondary and sensitivity analyses results were inconsistent with the primary endpoint result; further research into the role of complement is needed. Funding Alexion Pharmaceuticals.

Background and objective: Patient selection criteria and experimental interventions of randomized controlled trials may not reflect how things work in practice. The aim of this study was to describe the characteristics of chronic obstructive pulmonary disease (COPD) patients undergoing an inpatient pulmonary rehabilitation program (PRP) and the correlates of success. Methods: Retrospective database review of 975 consecutive patients transferred from acute care hospitals after an acute exacerbation (group A: 14.6%) or admitted from home (group B: 75.4%), from 2010 to 2017. Patients were also divided according to the associated registered main diagnosis: COPD (group 1: 30.6%); COPD and respiratory failure (group 2: 51.7%); COPD and obstructive sleep apnea (group 3: 17.6%). Baseline correlates of post-PRP changes in six minute walking test (6MWT) were also evaluated. Results: Global Initiative for Chronic Obstructive Lung Disease stages 3 and 4 were the most commonly represented in group 2 (p = 0.0001). Comorbidity Index of all patients was 3.9 ± 1.8. The overall in-hospital mortality rate was 1.3% (5.6% vs 0.6%, in groups A and B, respectively; p = 0.0001). Hypertension, cardiac diseases and obesity were observed in 65.2, 52.2 and 29.6% of patients, respectively. Post-PRP 6MWT increased in all groups. Age, male gender, airway obstruction and baseline 6MWT were correlated with a post-PRP 30 meter increase in 6MWT. Conclusion: Confirming data of literature, this real-life study shows the characteristics of COPD patients undergoing an inpatient PRP with significant improvement in exercise capacity, independent of whether in stable state or after a recent exacerbation or of the associated main diagnosis. Keywords: Exercise training, COPD, Comorbidities, Exercise capacity, Respiratory failure, OSAS

Objective: Despite the fact that the ear is the site to monitor arterial oxygen saturation by pulse oximetry (SpO2) closest to carotid chemoreceptors, sleep studies almost invariably use finger probes. This study aimed to assess the timing and morphological differences between SpO2 signals at the ear and finger during Cheyne-Stokes respiration (CSR) in heart failure (HF) patients. Methods: We studied 21 HF patients with CSR during a 40-min in-laboratory resting recording. SpO2 was recorded by: (1) two identical bedside pulse-oximeters with an ear (SpO2_Ear) and a finger probe (SpO2_Finger), and (2) a standard polysomnograph with a finger probe (SpO2_PSG). We estimated the delays between signals and, for each signal, computed the mean and minimum SpO2, the magnitude of cyclic desaturations and the overall time spent with SpO2 Results: The SpO2_Finger signal was significantly delayed [bias: 12.7 s (95% limits of agreement: 2.2, 23.0 s)] and slightly but not significantly downward-shifted with respect to SpO2_Ear. SpO2_PSG was almost synchronous with SpO2_Finger; however, a further significant downward shift was observed relative to the latter. In particular, minimum SpO2_PSG was significantly lower [-2.1% (- 4.8, 0.6%)], and desaturations and T90% were significantly higher than SpO2_Finger [1.2% (-1.3, 3.7%), and 13.9% (-12.3, 40.0%), respectively]. Conclusion: During CSR in HF patients, the marked delay between SpO2_Ear and SpO2_Finger makes the interpretation of the timing relationship between peripheral chemoreceptor stimulation and ventilatory events rather difficult. The observed discrepancies between SpO2_PSG and SpO2_Finger, which may be due to differences in the processing of raw SpO2 signals, call for a standardization of processing algorithms.

An important aspect of the perceived quality of vocal music is the degree to which the vocalist sings in tune. Although most listeners seem sensitive to vocal mistuning, little is known about the development of this perceptual ability or how it differs between listeners. Motivated by a lack of suitable preexisting measures, we introduce in this article an adaptive and ecologically valid test of mistuning perception ability. The stimulus material consisted of short excerpts (6 to 12 s in length) from pop music performances (obtained from MedleyDB; Bittner et al., 2014) for which the vocal track was pitch-shifted relative to the instrumental tracks. In a first experiment, 333 listeners were tested on a two-alternative forced choice task that tested discrimination between a pitch-shifted and an unaltered version of the same audio clip. Explanatory item response modeling was then used to calibrate an adaptive version of the test. A subsequent validation experiment applied this adaptive test to 66 participants with a broad range of musical expertise, producing evidence of the test’s reliability, convergent validity, and divergent validity. The test is ready to be deployed as an experimental tool and should make an important contribution to our understanding of the human ability to judge mistuning. Electronic supplementary material The online version of this article (10.3758/s13428-019-01225-1) contains supplementary material, which is available to authorized users.

Background Obstructive sleep apnea (OSA) is often associated with clinical, psychological and neuropsychological comorbidities such as Mild Cognitive Impairment (MCI). This study evaluated changes in clinical, psychosocial, Health Related Quality of Life (HRQoL) and neuropsychological profile in OSA subjects after ventilatory therapy, making comparison with normative data. The aim of the study was to verify the suitability of the HRQoL and neuropsychological screening tests in detecting variations in OSA subjects. Methods At baseline, 32 OSA subjects underwent the following assessment: EuroQol (EQ-5D-3L) and EQ VAS, Hospital Anxiety and Depression Scale (HADS), Montreal Cognitive Assessment (MoCA) and Frontal Assessment Battery (FAB). After the ventilatory titration, 31 OSA subjects repeated the EQ VAS, MoCA and FAB assessment. Results The analyzed subjects (77% male, 58.97±10.06 years old and 47.34±26.67 AHI [ev*hr-1]) showed low emotive distress, a lower perception of HRQoL than normative data and 35.48% of them exhibited executive deficits, too. MCI was detected in 3.2% and 48.4% of subjects after normative Italian and international correction, respectively. Subsequently the ventilatory therapy and the rehabilitative interdisciplinary treatment, subjects improved in EQ VAS (68.23±18.73 vs. 87.13±10.80, P=0.0001), FAB scores (15,30±2.03 vs. 16,65±1,40, P=0.007) and MoCA memory subtest scores (2.16±1.34 vs. 3.06±1.63, P=0.008). Conclusions Ventilatory therapy provided during a rehabilitative and interdisciplinary program increased subjects' HRQoL, executive functions and verbal memory.

Vocalizations including laughter, cries, moans, or screams constitute a potent source of information about the affective states of others. It is typically conjectured that the higher the intensity of the expressed emotion, the better the classification of affective information. However, attempts to map the relation between affective intensity and inferred meaning are controversial. Based on a newly developed stimulus database of carefully validated non-speech expressions ranging across the entire intensity spectrum from low to peak, we show that the intuition is false. Based on three experiments (N = 90), we demonstrate that intensity in fact has a paradoxical role. Participants were asked to rate and classify the authenticity, intensity and emotion, as well as valence and arousal of the wide range of vocalizations. Listeners are clearly able to infer expressed intensity and arousal; in contrast, and surprisingly, emotion category and valence have a perceptual sweet spot: moderate and strong emotions are clearly categorized, but peak emotions are maximally ambiguous. This finding, which converges with related observations from visual experiments, raises interesting theoretical challenges for the emotion communication literature.

OBJECTIVES: To investigate the association among hypertension, tinnitus, and sensorineural hearing loss and evaluate the influence of other covariates on this association. METHODS: Baseline data (2008-2010) from the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) were analyzed. Altogether, 900 participants were evaluated. The baseline assessment consisted of a 7-hour examination to obtain clinical and laboratory variables. Hearing was measured using pure-tone audiometry. RESULTS: Overall, 33.3% of the participants had hypertension. Participants with hypertension were more likely to be older, male, and diabetic compared to those without hypertension. The prevalence of tinnitus was higher among hypertensive participants and the odds ratio for tinnitus was higher in participants with hypertension than in those without hypertension. However, the difference was not significant after adjusting for age. Audiometric results at 250-8,000 Hz were worse in participants with hypertension than in those without hypertension in the crude analysis; however, the differences were not significant after adjustment for age, sex, diagnosis of diabetes, and exposure to noise. No significant difference was observed in hearing thresholds among participants having hypertension for

Temporal asymmetry is a peculiar aspect of heart period (HP) variability (HPV). HPV asymmetry (HPVA) is reduced with aging and pathology, but its origin is not fully elucidated. Given the impact of respiration on HPV resulting in the respiratory sinus arrhythmia (RSA) and the asymmetric shape of the respiratory pattern, a possible link between HPVA and RSA might be expected. In this study we tested the hypothesis that HPVA is significantly associated with RSA and asymmetry of the respiratory rhythm. We studied 42 middle-aged healthy (H) subjects, and 56 chronic heart failure (CHF) patients of whom 26 assigned to the New York Heart Association (NYHA) class II (CHF-II) and 30 to NYHA class III (CHF-III). Electrocardiogram and lung volume were monitored for 8 minutes during spontaneous breathing (SB) and controlled breathing (CB) at 15 breaths/minute. The ratio of inspiratory (INSP) to expiratory (EXP) phases, namely the I/E ratio, and RSA were calculated. HPVA was estimated as the percentage of negative HP variations, traditionally measured via the Porta’s index (PI). Departures of PI from 50% indicated HPVA and its significance was tested via surrogate data. We found that RSA increased during CB and I/E ratio was smaller than 1 in all groups and experimental conditions. In H subjects the PI was about 50% during SB and it increased significantly during CB. In both CHF-II and CHF-III groups the PI was about 50% during SB and remained unmodified during CB. The PI was uncorrelated with RSA and I/E ratio regardless of the experimental condition and group. Pooling together data of different experimental conditions did not affect conclusions. Therefore, we conclude that the HPVA cannot be explained by RSA and/or I/E ratio, thus representing a peculiar feature of the cardiac control that can be aroused in middle-aged H individuals via CB.

Sleep-disordered breathing is highly prevalent in the elderly population. Obstructive sleep apnea (OSA) represents the most common sleep disorder among the adult and elderly population. Recently, OSA diagnosis has been associated with an increased risk of developing cognitive decline and dementia, including vascular dementia and Alzheimer's disease (AD). Subsequently, there have been studies on AD biomarkers investigating cerebrospinal fluid, blood, neuroimaging, and nuclear medicine biomarkers in patients with OSA. Furthermore, studies have attempted to assess the possible effects of continuous positive airway pressure (CPAP) treatment on the cognitive trajectory and AD biomarkers in patients with OSA. This review summarizes the findings of studies on each AD biomarker (cognitive, biofluid, neuroimaging, and nuclear medicine imaging) in patients with OSA, also accounting for the related effects of CPAP treatment. In addition, the hypothetical model connecting OSA to AD in a bi-directional interplay is analyzed. Finally, the sex-based differences in prevalence and clinical symptoms of OSA between men and women have been investigated in relation to AD risk. Further studies investigating AD biomarkers changes in patients with OSA and the effect of CPAP treatment should be auspicated in future for identifying strategies to prevent the development of AD.

ObjectiveThe role of diabetes as a predictor of mortality after stroke remains uncertain, and there are very few data for pre-diabetes. This study investigated the association of pre-diabetes and diabetes with 30-day and 1-year mortality after ischemic stroke (IS) and primary intracerebral hemorrhage (ICH).Research design and methodsBetween 2006 and 2013, 2076 patients with IS and 586 patients with ICH (median age 79) were admitted to hospital within 24 hours after stroke onset and were treated in a stroke unit, where they underwent measurement of glycated hemoglobin (HbA1c). Diabetes was retrospectively defined based on medical history, diagnosis during hospital stay or HbA1c ≥6.5% (48 mmol/mol). Pre-diabetes was defined as HbA1c of 5.7%–6.4% (39–47 mmol/mol). Stroke severity was measured using the National Institutes of Health Stroke Scale (NIHSS). HRs were used to test the association of pre-diabetes and diabetes with 30-day and 1-year mortality after stroke onset.ResultsAmong patients with IS, 830 had pre-diabetes and 632 had diabetes; 280 died within 30 days and the other 77 within 1 year. Among patients with ICH, 106 had pre-diabetes and 56 had diabetes; 150 died within 30 days and the other 92 within 1 year. In both stroke subtypes, pre-diabetes and diabetes were associated with higher 30-day mortality. In IS, however, the association was limited to patients with prestroke disability and very severe stroke. At NIHSS 25, HR was 1.58 (95% CI 1.07 to 2.35) for pre-diabetes and 1.67 (95% CI 1.14 to 2.46) for diabetes compared with normoglycemia. In ICH, the association was limited to women for pre-diabetes (HR 1.93, 95% CI 1.15 to 3.24) and to men for diabetes (HR 1.78, 95% CI 1.02 to 3.12). Prestroke glycemic status was unrelated to 1-year mortality.ConclusionsBoth pre-diabetes and diabetes predict short-term mortality after acute stroke, but the association varies depending on both prestroke and stroke-related characteristics. These findings may explain the heterogeneous results obtained by previous studies.

Vitamin B12, folate, and homocysteine are implicated in pivotal neurodegenerative mechanisms and partake in elders' mental decline. Findings on the association between vitamin-related biochemistry and cognitive abilities suggest that the structural and functional properties of the brain may represent an intermediate biomarker linking vitamin concentrations to cognition. Despite this, no previous study directly investigated whether vitamin B12, folate, and homocysteine levels are sufficient to explain individual neuropsychological profiles or, alternatively, whether the activity of brain regions modulated by these compounds better predicts cognition in elders. Here, we measured the relationship between vitamin blood concentrations, scores at seventeen neuropsychological tests, and brain activity of sixty-five elders spanning from normal to Mild Cognitive Impairment. We then evaluated whether task-related brain responses represent an intermediate phenotype, providing a better prediction of subjects' neuropsychological scores, as compared to the one obtained considering blood biochemistry only. We found that the hemodynamic activity of the right dorsal anterior cingulate cortex was positively associated (p value < 0 05 cluster corrected) with vitamin B12 concentrations, suggesting that elders with higher B12 levels had a more pronounced recruitment of this salience network region. Crucially, the activity of this area significantly predicted subjects' visual search and attention abilities (p value = 0 0023), whereas B12 levels per se failed to do so. Our results demonstrate that the relationship between blood biochemistry and elders' cognitive abilities is revealed when brain activity is included into the equation, thus highlighting the role of brain imaging as intermediate phenotype. Vitamin B12, folate, and homocysteine are implicated in pivotal neurodegenerative mechanisms and partake in elders' mental decline. Findings on the association between vitamin-related biochemistry and cognitive abilities suggest that the structural and functional properties of the brain may represent an intermediate biomarker linking vitamin concentrations to cognition. Despite this, no previous study directly investigated whether vitamin B12, folate, and homocysteine levels are sufficient to explain individual neuropsychological profiles or, alternatively, whether the activity of brain regions modulated by these compounds better predicts cognition in elders. Here, we measured the relationship between vitamin blood concentrations, scores at seventeen neuropsychological tests, and brain activity of sixty-five elders spanning from normal to Mild Cognitive Impairment. We then evaluated whether task-related brain responses represent an intermediate phenotype, providing a better prediction of subjects' neuropsychological scores, as compared to the one obtained considering blood biochemistry only. We found that the hemodynamic activity of the right dorsal anterior cingulate cortex was positively associated (p value < 0 05 cluster corrected) with vitamin B12 concentrations, suggesting that elders with higher B12 levels had a more pronounced recruitment of this salience network region. Crucially, the activity of this area significantly predicted subjects' visual search and attention abilities (p value = 0 0023), whereas B12 levels per se failed to do so. Our results demonstrate that the relationship between blood biochemistry and elders' cognitive abilities is revealed when brain activity is included into the equation, thus highlighting the role of brain imaging as intermediate phenotype.

To update the current knowledge concerning sleep complaints and breathing disorders in myotonic dystrophy type 2 (DM2) and to better understand if sleep and breathing symptoms may add a further clinical definition of DM2. Although DM2 has been poorly evaluated, the most relevant sleep disorders are sleep-disordered breathing (SDB) (37.5–66.7%) and restless legs syndrome (RLS) (50–60%). Excessive daytime somnolence (EDS) is not consistent with SDB, and a large percentage of patients with sleep complaints (58–69%) report pain. In addition, respiratory dysfunctions are reported in 6 to 15% of DM2 patients, albeit few data are available regarding pulmonary restriction, hypoventilation, and non-invasive ventilation (NIV). SDB, RLS, and pain may contribute to sleep fragmentation and EDS in DM2. In addition, few studies report hypoventilation and pulmonary restriction, although there are no studies at all on NIV, except for limited clinical experiences. These findings suggest performing a careful pulmonary examination and NIV when required. Furthermore, sleep studies and respiratory evaluation should be recommended if OSA or respiratory muscle dysfunctions are suspected. A large polysomnographic study should be performed to clarify the link between sleep disorders, pain, and sleep disruption in DM2.

Objective: To report the safety and efficacy results of patients enrolled in the Italian Nivolumab Renal Cell Cancer Expanded Access Programme. Patients and Methods: Patients with metastatic renal cell cancer (mRCC) previously treated with agents targeting the vascular endothelial growth factor pathway were eligible to receive nivolumab 3 mg/kg once every 2 weeks. Patients included in the analysis had received ≥1 dose of nivolumab and were monitored for adverse events (AEs) using Common Terminology Criteria for Adverse Events (CTCAE) v.4.0. Results: A total of 389 patients were enrolled between July 2015 and April 2016, of whom 18% were aged ≥75 years, 6.7% had non-clear cell RCC, 49.6% had bone and 8.2% brain metastases, and 79% had received ≥2 previous lines of therapy. The most common any-grade treatment-related AEs were fatigue (13%) and rash (9%). Twenty-two patients (5.7%) discontinued treatment because of AEs. There were no treatment-related deaths. The objective response rate was 23.1%. At a median follow-up of 12 months, the median progression-free survival was 4.5 months (95% confidence interval 3.7–6.2) and the 12-month overall survival rate was 63%. Similar survival rates were reported among patients with non-clear-cell histology, elderly patients, those with bone and/or brain metastases, and those who had received prior first-line sunitinib or pazopanib, or prior everolimus. Conclusion: The safety and efficacy observed were consistent with those reported in the pivotal Checkmate 025 trial. Results in patients with non-clear-cell mRCC who were elderly, pretreated with everolimus, and had bone and/or brain metastases encourage the use of nivolumab in these categories of patients. © 2018 The Authors BJU International

Little is known about the role of lineage of strains of Clostridioides difficile (CD) on the clinical presentation of CD infection (CDI) in Latin America, especially regarding the treatment response. We conducted a multicenter, prospective study to investigate the predictive factors and treatment outcomes of CDI in hospitalized patients and to performed phenotypical and molecular characterization of CD strains. A total of 361 diarrheic patients at 5 hospitals from different regions of the country were enrolled. All stool samples were tested for glutamate dehydrogenase (GDH), toxins A and B, and toxin genes using a nucleic acid amplification test (NAAT). Specimens were cultured and susceptibility profile and whole-genome sequencing (WGS) were performed. CDI positivity was 15% (56/377). Predictive factors for CDI were prior use of meropenem (OR 4.09, 95% CI 2.097-7.095; p0.001), mucus in stools (OR 3.29; 95% CI 1.406-7.722; p=0.006) and neutrophil left-shift with20% of bands (OR 3.77; 95% IC 1.280-11.120; p=0.016). Overall mortality was 19%, with no deaths attributed to CDI. Oral metronidazole was used in 74% of cases, with 85% of cure and 14% of recurrence. A total of 35 CD isolates were recovered, all of them susceptible to metronidazole and vancomycin. The WGS revealed 17 different STs, six of which were novel. ST42 was the most common ST and hypervirulent strains were not found. Severe CDI were caused by ST42, ST5, ST8, ST48, ST33 and a novel ST667. The ermB gene was more frequently found in isolates of ST42 (p=0.004).

Background Cystic echinococcosis (CE) is a chronic, complex and neglected infection that may cause serious disease in humans. Given its peculiar epidemiologic and clinical features, collection of clinical data is challenging. Notification systems, when available, fail to record important clinical features, available data are mostly retrospectively collected and no prospectively enrolled uniform surveillance systems exist. The European Register of Cystic Echinococcosis database (ERCE) is the first systematic attempt to address these issues. Methods Here, we describe the demographics and clinical characteristics of 436 patients who accessed the CE clinic at the University of Pavia–San Matteo Hospital Foundation, in Pavia, Italy, from March 2012 to February 2020. Results Overall, 436 patients, consisting of 204 (46.8%) males and 232 (53.2%) females were enrolled; the mean age at enrollment was 50 (range 4–88) y. Of the 436 patients, 248 (56.9%) were born in Italy while 188 (43.1%) were foreign-born. In total, 638 CE cysts were counted, most of them in the CE4 (230; 36.1%) and CE3b (131; 20.5%) stages. Conclusions This is the largest cohort of CE patients with detailed clinical and demographic data published to date. We strongly encourage colleagues caring for CE patients in the European Union to join the ERCE.

It is still not known whether the oscillation in heart rate (HR) induced by sleep-disordered breathing (SDB) in patients with heart failure entails significant chronotropic effects. We hypothesised that since cyclical changes in ventilation and arterial blood gases during SDB affect HR through multiple and complexly interacting mechanisms characterised by large inter-subject variability, chronotropic effects may change from patient to patient. A total of 42 patients with moderate-to-severe chronic heart failure with systolic dysfunction underwent an in-hospital sleep study. Chronotropic effects of SDB were quantified by comparing the distribution of instantaneous HR during SDB with that during periods without SDB (noSDB) within the same night in each patient. Based on distribution changes from noSDB to SDB, 12, nine, 11, and 10 patients showed a significant tachycardic, bradycardic, tachycardic and bradycardic, and neither significant tachycardic nor significant bradycardic effect, respectively. Tachycardic and bradycardic effects were primarily due to an increase in the rate rather than in the magnitude of cyclical HR elevations and reductions, and were more prevalent and severe in patients with dominant obstructive and central events, respectively. The apnea-hypopnea index did not differ between groups. Conversely, the time spent with an oxygen saturation of

The identification of discrete dimensions underlining negative symptoms in First Episode Psychosis (FEP) may be useful in the treatment strategy for such severe symptomatology. Aim of this research was to investigate the negative symptom configuration in FEP patients and to compare the emerging factor solutions between individuals with and without Schizophrenia Spectrum Disorders (non-SSD vs SSD). Two-hundred-seventy-four participants (144 non-SSD and 130 SSD), aged 13-35 years, completed the Positive and Negative Syndrome Scale (PANSS) and the Global Assessment of Functioning (GAF). Confirmatory and exploratory factor analyses were then performed to examine PANSS negative symptom configuration in both SSD and non-SSD samples. In SSD, a 3-factor model solution (i.e. "Experiential Deficits", "Volition/Empathy Deficits" and "Motor/Affective Expression Deficits" domains) was identified. A different 2-factor configuration (with "Social/Communicative Withdrawal" and "Motor/Affective/Motivational Deficits" dimensions) was more appropriate in non-SSD. In conclusion, our results show differences in negative symptom factor models between non-SSD and SSD. Thus, a different specificity and significance of negative symptom solutions in FEP populations with diagnoses other than schizophrenia (compared to those with SSD) must be realistically considered.

Conflicting results about alterations of plasma amino acid (AA) levels are reported in subjects with Alzheimer&rsquo, s disease (AD). The current study aimed to provide more homogeneous AA profiles and correlations between AAs and cognitive tests. Venous plasma AAs were measured in 54 fasting patients with AD (37 males, 17 females, 74.63 &plusmn, 8.03 yrs, 3.2 &plusmn, 1.9 yrs from symptom onset). Seventeen matched subjects without neurodegenerative symptoms (NNDS) served as a control group (C-NNDS). Patients were tested for short-term verbal memory and attention capacity and stratified for nutritional state (Mini Nutritional Assessment, MNA). Compared to C-NNDS, patients exhibited lower plasma levels of aspartic acid and taurine (p &lt, 0.0001) and higher 3-methylhistidine (p &lt, 0.0001), which were independent of patients&rsquo, MNA. In comparison to normonourished AD, the patients at risk of and with malnutrition showed a tendency towards lower ratios of Essential AAs/Total AAs, Branched-chain AAs/Total AAs, and Branched-chain AAs/Essential AAs. Serine and histidine were positively correlated with verbal memory and attention capacity deficits, respectively. Total AAs negatively correlated with attention capacity deficits. Stratifying patients with AD for MNA may identify a dual pattern of altered AAs, one due to AD per se and the other linked to nutritional state. Significant correlations were observed between several AAs and cognitive tests.

Sacubitril/valsartan improved the prognosis of patients with heart failure with reduced ejection fraction in the PARADIGM-HF study. Recently, the TRANSITION and PIONEER-HF studies demonstrated the safety and efficacy of sacubitril/valsartan in patients hospitalized for acute decompensated heart failure, with treatment initiated after hemodynamic and clinical stabilization. In this case series study, we assessed the short-term effects of sacubitril/valsartan on exercise capacity, inflammation, and biomarkers in patients with acute decompensated heart failure. Patients admitted for acute decompensated heart failure to the Department of Internal Medicine of Telese Terme Hospital and Cardiovascular Department, University of Bari, from 9 March, 2017 to 9 June, 2018 were enrolled. Following hemodynamic stabilization, patients initiated sacubitril/valsartan 24/26 mg twice a day for 4 weeks, with up-titration to 49/51 mg twice a day based on tolerability after 1 week. Efficacy outcomes included the 6-min walking test, N-terminal pro-B-type natriuretic peptide, high-sensitivity C-reactive protein, and lymphocyte count. Safety outcomes included renal function, hyperkalemia, and symptomatic hypotension. In total, 40 patients completed the study and 27 (67.5%) patients were up-titrated. Compared with baseline, exercise capacity and relative lymphocyte count increased significantly after 4 weeks of treatment, while N-terminal pro-B-type natriuretic peptide and high-sensitivity C-reactive protein decreased significantly. N-terminal pro-B-type natriuretic peptide and relative lymphocyte count independently predicted the 6-min walking test distance (p = 0.021). No patients experienced any relevant side effects. Early initiation of sacubitril/valsartan in patients with heart failure with reduced ejection fraction after acute decompensated heart failure may be safe and effective in terms of functional capacity and biomarkers.

Aim: INVIDIa was a retrospective, multicenter study, exploring the clinical efficacy of influenza vaccine in 300 cancer patients undergoing immunotherapy. Overall survival (OS) was immature at the initial report. Methods: We reported the final OS analysis from the original study population and within subgroups. Results: Both at the univariate and multivariate analysis, the occurrence of influenza syndrome (IS) was significantly related to better OS in the overall population (OR: 0.53 [95% CI: 0.32–0.88]; p = 0.01). In the lung cancer subgroup, receiving flu vaccine and/or developing IS was related to better OS (p = 0.04). Within elderly patients, the flu vaccine was the main variable for the relative OS advantage (p = 0.05). Conclusion: Receiving the flu vaccine and/or developing IS was related to better OS within the INVIDIa population.