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BACKGROUND: Immediate initiation of antiretroviral therapy (ART) regardless of CD4 cell count reduces risk for AIDS and non-AIDS-related events in asymptomatic, HIV-positive persons and is the standard of care. However, most HIV-positive persons initiate ART when their CD4 count decreases below 500 × 10 9 cells/L. Consequences of delayed ART on risk for non-AIDS-defining and AIDS-defining cancer, one of the most common reasons for death in HIV, are unclear. OBJECTIVE: To estimate the long-term risk difference for cancer with the immediate ART strategy.DESIGN: Multinational prospective cohort study.SETTING: The D:A:D (Data collection on Adverse events of anti-HIV Drugs) study, which included HIV-positive persons from Europe, Australia, and the United States.PARTICIPANTS: 8318 HIV-positive persons with at least 1 measurement each of CD4 cell count and viral load while ART-naive (study period, 2006 to 2016).MEASUREMENTS: The parametric g-formula was used, with adjustment for baseline and time-dependent confounders (CD4 cell count and viral load), to assess the 10-year risk for non-AIDS-defining and AIDS-defining cancer of immediate versus deferred (at CD4 counts RESULTS: During 64 021 person-years of follow-up, 231 cases of non-AIDS-defining cancer and 272 of AIDS-defining cancer occurred among HIV-positive persons with a median age of 36 years (interquartile range, 29 to 43 years). With immediate ART, the 10-year risk for non-AIDS-defining cancer was 2.97% (95% CI, 2.37% to 3.50%) and that for AIDS-defining cancer was 2.50% (CI, 2.37% to 3.38%). Compared with immediate ART initiation, the 10-year absolute risk differences when deferring ART to CD4 counts less than 500 × 10 9 cells/L and less than 350 × 10 9 cells/L were 0.12 percentage point (CI, -0.01 to 0.26 percentage point) and 0.29 percentage point (CI, -0.03 to 0.73 percentage point), respectively, for non-AIDS-defining cancer and 0.32 percentage point (CI, 0.21 to 0.44 percentage point) and 1.00 percentage point (CI, 0.67 to 1.44 percentage points), respectively, for AIDS-defining cancer. LIMITATION: Potential residual confounding due to observational study design.CONCLUSION: In this young cohort, effects of immediate ART on 10-year risk for cancer were small, and further supportive data are needed for non-AIDS-defining cancer.PRIMARY FUNDING SOURCE: Highly Active Antiretroviral Therapy Oversight Committee.

Exposure to both chronic and acute stressors can disrupt functional connectivity (FC) of the default mode network (DMN), salience network (SN), and central executive network (CEN), increasing risk for negative health outcomes. During adolescence, these stress-sensitive triple networks undergo critical neuromaturation that is altered by chronic exposure to general forms of trauma or victimization. However, no work has directly examined how acute stress affects triple network FC in adolescents or whether polyvictimization-exposure to multiple categories/subtypes of victimization-influences adolescent triple network neural acute stress response.This functional magnetic resonance imaging study examined seed-to-voxel FC of the DMN, SN, and CEN during the Montreal Imaging Stress Task. Complete data from 73 participants aged 9 to 16 years (31 female) are reported.During acute stress, FC was increased between DMN and CEN regions and decreased between the SN and the DMN and CEN. Greater polyvictimization was associated with reduced FC during acute stress exposure between the DMN seed and a cluster containing the left insula of the SN.These results indicate that acute stress exposure alters FC between the DMN, SN, and CEN in adolescents. In addition, FC changes during stress between the DMN and SN are further moderated by polyvictimization exposure.

Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease 2019 (COVID-19) continues to have a devastating impact across the globe. However, little is known about the disease course in patients with autoimmune hepatitis (AIH). Methods Data for patients with AIH and SARS-CoV-2 infection were combined from three international reporting registries and outcomes were compared to those with chronic liver disease of other aetiology (non-AIH CLD) and to patients without liver disease (non-CLD). Results Between 25th March and 24th October 2020, data were collected for 932 patients with CLD and SARS-CoV-2 infection including 70 with autoimmune hepatitis (AIH). Fifty-eight (83%) of AIH patients were taking one or more immunosuppressive drug. There were no differences in rates of major outcomes between AIH and non-AIH CLD including hospitalization (76% vs 85%; p= 0.06), ICU admission (29% vs. 23%; p=0.240), and death (23% vs. 20%; p=0.643). Factors associated with death within the AIH cohort included age (OR 2.16/10 years; 1.07–3.81), Child-Turcotte-Pugh (CTP) class B (OR 42.48; 4.40–409.53), and CTP-C cirrhosis (OR 69.30; 2.83–1694.50), but not use of immunosuppression. Propensity score matched (PSM) analysis comparing AIH with non-AIH CLD demonstrated no increased risk adverse outcomes including death (+3.2%; -9.2%–15.7%). PSM analysis of AIH versus non-CLD patients (n=769) demonstrated increased risk of hospitalization with AIH (+18.4%; 5.6–31.2%), but equivalent risk of all other outcomes including death (+3.2%; -9.1%–15.6%). Conclusion AIH patients were not at increased risk of adverse outcomes despite immunosuppressive treatment compared to other causes of CLD and to matched cases without liver disease., Graphical abstract, Highlights • This is the largest cohort of patients with autoimmune hepatitis and laboratory proven SARS-COV-2 infection reported to date. • There were no differences in rates of major adverse COVID-19 outcomes including hospitalization, intensive care unit (ICU) admission, and death between AIH patients and those with other aetiologies of liver disease. • When compared to patients without liver disease in propensity score matched analysis, patients with AIH had higher rates of hospitalization but no increased risk of ICU admission or death despite potential reporting of AIH cases with more severe baseline liver disease. • Independent risk factors for death in AIH patients were age and baseline liver disease severity, but not the use of immunosuppression., Lay summary: Little is known about the outcomes of COVID-19 in patients with autoimmune hepatitis (AIH), a rare chronic inflammatory liver disease. This study combines data from three large registries to describe the course of COVID-19 in this patient group. We show that AIH patients do not appear to have an increased risk of death from COVID-19 compared to patients with other forms of liver disease and compared to patients without liver disease, despite the use of medications which suppress the immune system.

Purpose Reduced exposure to echinocandins has been reported in specific patient populations, such as critically ill patients; however, fixed dosing strategies are still employed. The present review examines the accumulated evidence supporting echinocandin therapeutic drug monitoring (TDM) and summarizes available assays and sampling strategies. Methods A literature search was conducted using PubMed® in December 2020, with search terms such as echinocandins, anidulafungin, caspofungin, micafungin, or rezafungin with pharmacology, pharmacokinetics, pharmacodynamics, drug-drug interactions, therapeutic drug monitoring, resistance, drug susceptibility testing, toxicity, adverse drug reactions, bioanalysis, chromatography, and mass spectrometry. Data on pharmacokinetic/pharmacodynamic (PK/PD) outcome markers, drug resistance, PK variability, drug-drug interactions, assays, and TDM sampling strategies were summarized. Results Echinocandins demonstrate drug exposure-efficacy relationships, and maximum concentration/minimal inhibitory concentration ratio (Cmax/MIC) and area under the concentration-time curve/MIC ratio (AUC/MIC) are proposed PK/PD markers for clinical response. The relationship between drug exposure and toxicity remains poorly clarified. TDM could be valuable in patients at risk of low drug exposure, such as those with critical illness and/or obesity. TDM of echinocandins may also be useful in patients with moderate liver impairment, drug-drug interactions, hypoalbuminemia, and those undergoing extracorporeal membrane oxygenation, as these conditions are associated with altered exposure to caspofungin and/or micafungin. Assays are available to measure anidulafungin, micafungin, and caspofungin concentrations. A limited-sampling strategy for anidulafungin has been reported. Conclusion Echinocandin TDM should be considered in patients at known risk of suboptimal drug exposure. However, for implementing TDM, clinical validation of PK/PD targets is needed.

Massive weight loss (MWL) has a positive impact on the comorbidities associated with obesity but leaves patients with ongoing body issues due to skin excess. Almost all patients present some degree of breast ptosis and breast volume deficiency, which can be addressed with different techniques including autologous flaps.A literature search was conducted by using PubMed, Google Scholar, and Cochrane databases. Patient's characteristics, type of bariatric surgery, amount of weight loss, flap size and design, simultaneous breast and extra-breast procedures were analyzed. Aesthetic and patient-reported outcomes, postoperative complications, revision rate, and donor site morbidity were also registered.Twelve articles fulfilled inclusion criteria, and 79 patients were included, for a total of 157 flaps. Different flap designs and flap combinations were described; those originating from lateral chest wall area were the most commonly used. Simultaneous breast procedures were reported in 72 patients. Simultaneous extra-breast body contouring (BC) procedure was performed in 40 cases. The overall complication rate was 9.55% and a total of ten revisionary procedures were performed. Satisfaction of the patients was globally quite high.Advantages of the use of autologous tissue in breast reshaping after MWL is the avoidance of implant-related complications and the simultaneous improvement of the silhouette. The complication rate resulted in acceptable, aesthetic, and patient-reported outcomes resulted to be encouraging, even if there was a lack of standardization in the evaluation. A comparative randomized study to confront the use of autologous flaps combined with mastopexy versus the use of implants combined with mastopexy can be useful to confirm the promising results.This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Several redox modifications have been described during viral infection, including influenza virus infection, but little is known about glutathionylation and this respiratory virus. Glutathionylation is a reversible, post-translational modification, in which protein cysteine forms transient disulfides with glutathione (GSH), catalyzed by cellular oxidoreductases and in particular by glutaredoxin (Grx). We show here that (i) influenza virus infection induces protein glutathionylation, including that of viral proteins such as hemagglutinin (HA); (ii) Grx1-mediated deglutathionylation is important for the viral life cycle, as its inhibition, either with an inhibitor of its enzymatic activity or by siRNA, decreases viral replication. Overall these data contribute to the characterization of the complex picture of redox regulation of the influenza virus replication cycle and could help to identify new targets to control respiratory viral infection.

AIM This study investigates the pharmacokinetic/pharmacodynamic (PK/PD) target attainment of linezolid in patients infected with multidrug-resistant (MDR) tuberculosis (TB). METHODS A pharmacometric model was developed including 244 timed linezolid concentration samples from 39 patients employing NONMEM 7.4. The probability of target attainment (PTA, PK/PD target: unbound (f) area-under-the-concentration-time-curve (AUC)/minimal inhibitory concentration (MIC) of 119) as well as a region-specific cumulative fraction of response (CFR) were estimated for different dosing regimens. RESULTS A one-compartment model with linear elimination with a clearance (CL) of 7.69 L/h (interindividual variability 34.1%), a volume of distribution (Vd) of 45.2 L and an absorption constant (KA) of 0.679 h-1 (interoccasion variability 143.7%) allometric scaled by weight best described the PK of linezolid. The PTA at an MIC of 0.5 mg/L was 55% or 97% if patients receiving 300 or 600 mg twice daily, respectively. CFRs varied greatly among populations and geographic regions. A desirable global CFR of ≥90% was achieved if linezolid was administered at a dose of 600 mg twice daily but not at a dose of 300 mg twice daily. CONCLUSION This study showed that a dose of 300 mg twice daily of linezolid might not be sufficient to treat MDR-TB patients from a PK/PD perspective. Thus, it might be recommendable to start with a higher dose of 600 mg twice daily to ensure PK/PD target attainment. Hereby, therapeutic drug monitoring and MIC determination should be performed to control PK/PD target attainment as linezolid shows high variability in its PK in the TB population.

BACKGROUND: Circadian rhythm disturbances are frequently implicated in psychosis. Indeed, research has suggested several avenues by which circadian rhythms may play a mechanistic role as well as contribute to clinical outcomes. Despite its potential role as a risk factor, little is known about circadian rhythm disruption among individuals at clinical high risk (CHR) for psychosis, clinical correlates, or specificity to the psychosis risk syndrome. METHODS: Eighty-four CHR, 74 individuals with depressive disorders (DD), and 101 non-psychiatric controls (NPC) participated in structured clinical interviews and provided self-reports of chronotype preference. Clinical (positive, negative, anxious, and depressive symptoms) and social functioning outcomes were self-reported and/or clinician-rated. Analyses of covariance controlling for demographics examined group differences in chronotype preference, and partial Pearson correlations evaluated associations with clinical/functional outcomes. RESULTS: Group differences were observed (F(11, 246)=8.05, p

Advanced age represents one of the major risk factors for Parkinson's Disease. Recent biomedical studies posit a role for microRNAs, also known to be remodelled during ageing. However, the relationship between microRNA remodelling and ageing in Parkinson's Disease, has not been fully elucidated. Therefore, the aim of the present study is to unravel the relevance of microRNAs as biomarkers of Parkinson's Disease within the ageing framework. We employed Next Generation Sequencing to profile serum microRNAs from samples informative for Parkinson's Disease (recently diagnosed, drug-naïve) and healthy ageing (centenarians) plus healthy controls, age-matched with Parkinson's Disease patients. Potential microRNA candidates markers, emerging from the combination of differential expression and network analyses, were further validated in an independent cohort including both drug-naïve and advanced Parkinson's Disease patients, and healthy siblings of Parkinson's Disease patients at higher genetic risk for developing the disease. While we did not find evidences of microRNAs co-regulated in Parkinson's Disease and ageing, we report that hsa-miR-144-3p is consistently down-regulated in early Parkinson's Disease patients. Moreover, interestingly, functional analysis revealed that hsa-miR-144-3p is involved in the regulation of coagulation, a process known to be altered in Parkinson's Disease. Our results consistently show the down-regulation of hsa-mir144-3p in early Parkinson's Disease, robustly confirmed across a variety of analytical and experimental analyses. These promising results ask for further research to unveil the functional details of the involvement of hsa-mir144-3p in Parkinson's Disease., This work was supported by the Horizon 2020 Framework Programme (Grant number 634821, PROPAG-AGING).

Objective Registry data show that Cushing's syndrome (CS) and adrenal insufficiency (AI) increase mortality rates associated with infectious diseases. Little information is available on susceptibility to milder forms of infections, especially those not requiring hospitalization. This study aimed to investigate infectious diseases in patients with glucocorticoid disorders through the development of a specific tool. Methods We developed and administered the InfeCtions in pAtients with endocRinOpathies (ICARO) questionnaire, addressing infectious events over a 12-month observation period, to 1017 outpatients referred to 4 University Hospitals. The ICARO questionnaire showed good test–retest reliability. The odds of infection (OR (95% CI)) were estimated after adjustment for confounders and collated into the ICARO score, reflecting the frequency and duration of infections. Results In total, 780 patients met the inclusion criteria: 43 with CS, 32 with adrenal incidentaloma and mild autonomous cortisol secretion (MACS), and 135 with AI, plus 570 controls. Compared to controls, CS was associated with higher odds of urinary tract infections (UTIs) (5.1 (2.3–9.9)), mycoses (4.4 (2.1–8.8)), and flu (2.9 (1.4–5.8)). Patients with adrenal incidentaloma and MACS also showed an increased risk of UTIs (3.7 (1.7–8.0)) and flu (3.2 (1.5–6.9)). Post-dexamethasone cortisol levels correlated with the ICARO score in patients with CS. AI was associated with higher odds of UTIs (2.5 (1.6–3.9)), mycoses (2.3 (1.4–3.8)), and gastrointestinal infections (2.2 (1.5–3.3)), independently of any glucocorticoid replacement dose. Conclusions The ICARO tool revealed a high prevalence of self-reported infections in patients with glucocorticoid disorders. ICARO is the first of its kind questionnaire, which could be a valuable tool for monitoring infections in various clinical settings.

Background & aims Survivorship is a well-established concept in the cancer care continuum with a focus on disease recurrence, quality of life, and minimizing competing risks for mortality; however, this has not been well studied in liver transplantation (LT). We aimed to investigate what survivorship means to LT patients and identify motivations and coping strategies for overcoming challenges after LT. Approach & results Twenty in-depth home interviews were conducted among adults 3 to 6 months after LT. Interviews were conducted by trained qualitative research experts, coded and analyzed using an inductive approach. A majority of LT recipients (75%) identified themselves as survivors. Integral to the definition of survivorship was overcoming hardship (including experiences on the waitlist) and the unique experience of being given a "second chance" at life. Motivations to survive included: 1) honoring a new chance at life (55%), 2) family (40%), 3) spirituality/faith (30%), and 4) fear of rejection (15%). LT recipients and caregivers identified multiple strategies to cope with post-LT challenges including relying on a large network of community, spiritual, and virtual support. These findings informed a conceptual model of LT survivorship based on socioecological theory, which identified the following variables influencing survivorship: 1) pre-transplant experiences, 2) individual attributes and challenges, 3) interpersonal relationships with caregivers and other social support, 4) community relationships, and, 5) largescale factors including neighborhood and financial issues. Conclusions LT recipients identify themselves as survivors, and post-LT identities were greatly influenced by pre-LT experiences. These perspectives informed an in depth conceptual model of survivorship after transplantation. We identified sources of motivation and coping strategies used in LT recovery that could be targets of survivorship interventions aimed at improving post-LT outcomes.

Purpose Pursuing active aging and maintaining the quality of life (QoL) is essential, particularly in older people living in residential care facilities (RCFs). We evaluated physical activity (PA) as an intervention to improve the QoL in this population, trying to hypothesize future perspectives in this field. Methods A systematic search was performed on Pubmed. Only randomized control trials or quasi-experimental control group trials were considered. Results Results showed that a high-frequency PA can be effective in older people, allowing them to improve their functional mobility, autonomy, anxiety level, balance, and social interactions. Moreover, a moderate-intensity PA showed the most interesting results, improving all the QoL-related aspects considered. Conclusion Results highlight the beneficial effects of multidisciplinary intervention strategies in increasing QoL and QoL-related aspects of RCFs older residents, contemplating PA as the main instrument. However, structured PA is necessary to fully understand which protocol could be the most effective.

Purpose “Non thyroidal illness syndrome” (NTIS) or “euthyroid sick syndrome” (ESS) is a possible biochemical finding in euthyroid patients with severe diseases. It is characterized by a reduction of serum T3 (fT3), sometimes followed by reduction of serum T4 (fT4). The relationship between thyroid hormones levels and mortality is well known and different studies showed a direct association between NTIS and mortality. The sudden spread of the 2019 novel coronavirus (SARS-CoV 2) infection (COVID-19) and its high mortality become a world healthcare problem. Our aim in this paper was to investigate if patients affected by COVID-19 presented NTIS and the relationship between thyroid function and severity of this infection. Methods We evaluated the thyroid function in two different groups of consecutive patients affected by COVID-19 with respect to a control group of euthyroid patients. Group A included patients hospitalized for COVID-19 pneumonia while patients requiring intensive care unit (ICU) for acute respiratory syndrome formed the group B. Group C identified the control group of euthyroid patients. Results Patients from group A and group B showed a statistically significant reduction in fT3 and TSH compared to group C. In group B, compared to group A, a further statistically significant reduction of fT3 and TSH was found. Conclusions COVID-19 in-patients can present NTIS. FT3 and TSH serum levels are lower in patients with more severe symptoms.

Purpose Triple-negative breast cancer (TNBC) represents a subtype of breast cancer which lacks the expression of oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER2): TNBC accounts for approximately 20% of newly diagnosed breast cancers and is associated with younger age at diagnosis, greater recurrence risk and shorter survival time. Therapeutic options are very scarce. Aim of the present analysis is to provide further insights into the clinical activity of metronomic chemotherapy (mCHT), in a real-life setting. Methods We used data included in the VICTOR-6 study for the present analysis. VICTOR-6 is an Italian multicentre retrospective cohort study, which collected data of metastatic breast cancer (MBC) patients who have received mCHT between 2011 and 2016. Amongst the 584 patients included in the study, 97 were triple negative. In 40.2% of the TNBC patients, mCHT was the first chemotherapy treatment, whereas 32.9% had received 2 or more lines of treatment for the metastatic disease. 45.4% out of 97 TNBC patients received a vinorelbine (VRL)-based regimen, which resulted in the most used type of mCHT, followed by cyclophosphamide (CTX)-based regimens (30.9%) and capecitabine (CAPE)-based combinations (22.7%). Results Overall response rate (ORR) and disease control rate (DCR) were 17.5% and 64.9%, respectively. Median progression free survival (PFS) and overall survival (OS) were 6.0 months (95% CI: 4.9–7.2) and 12.1 months (95% CI: 9.6–16.7). Median PFS was 6.9 months for CAPE-based regimens (95% CI: 5.0–18.4), 6.1 months (95% CI: 4.0–8.9) for CTX-based and 5.3 months (95% CI: 4.1–9.5) for VRL-based ones. Median OS was 18.2 months (95% CI: 9.1-NE) for CAPE-based regimens and 11.8 months for VRL- (95% CI: 9.3–16.7 and CTX-based ones (95%CI: 8.7–52.8). Tumour response, PFS and OS decreased proportionally in later lines. Conclusion This analysis represents the largest series of TNBC patients treated with mCHT in a real-life setting and provides further insights into the advantages of using this strategy even in this poor prognosis subpopulation.

Recently, the use of antiretroviral drug tenofovir disoproxil fumarate (TDF) is increased, thanks to the new co-formulation with doravirine, the availability of booster-free regimens, and its advantageous lipid-lowering effect. The aim of our study was to identify genetic markers that contribute to assess the risk of TDF-related renal toxicity. We have retrospectively investigated, in 179 HIV positive patients treated with TDF, the association between the main variants in ABCC2, ABCC4, and ABCC10 genes and four safety endpoints, three clinically relevant as renal outcomes and a higher tenofovir plasma concentration. In patients with an annual eGFR decline >5 mL/min/1.73 m2 a difference in genotype frequencies was observed for ABCC10 c.1875 + 526 G>A (3 subjects AA vs. 44 GG + GA, p = 0.045). In patients with an eGFR decrement >25%, plus a decline in GFR category and TDF discontinuation, a difference was observed for ABCC4 c.*38T>G (35 subjects TG + GG vs. 18 TT, p = 0.052). At univariate analysis OR was 1.39 [(95% CI 1.00-1.96) p = 0.054] and at multivariate analysis OR was 1.49 [(95% CI 1.00-2.22) p = 0.049]. The stronger associations were found between the tenofovir accumulation and ABCC4 c.*38T>G and c.3348G>A: the percentage of these patients was higher in the TG + GG (p = 0.011) and in the AA (p = 0.004) genotype, respectively. The logistic regression analysis confirmed these significant relationships. No significant association was observed in patients with eGFR < 60 mL/min/1.73m2 and with the studied ABCC2 polymorphisms. Our results show a major role for a combined determination of ABCC4/ABCC10 variants as an indicator of tenofovir toxicity in the clinical practice.

Existing animal and human research support the causal role of stress in the emergence of anhedonia, and in turn, the influence of anhedonia in social functioning. However, this model has not been tested in relation to psychosis-risk; this literature gap is notable given that both anhedonia and declining social functioning represent key markers of risk of developing a psychotic disorder such as schizophrenia. The current research tested the evidence for this model using structural equation modeling in 240 individuals selected based on a range of psychosis-risk symptomatology from the general community. Results supported this model in comparison with alternative models, and additionally emphasized the direct role of perceived stress in social functioning outcomes. Findings suggest the clinical relevance of targeting early perceptions of stress in individuals meeting psychosis-risk self-report criteria in an effort to prevent subsequent anhedonia and declines in social functioning.

Contemporary models of psychosis suggest that a continuum of severity of psychotic symptoms exists, with subthreshold psychotic experiences (PEs) potentially reflecting some genetic and environmental risk factors shared with clinical psychosis. Thus, identifying abnormalities in brain activity that manifest across this continuum can shed new light on the pathophysiology of psychosis. Here, we investigated the moment-to-moment engagement of brain networks (“states”) in individuals with schizophrenia (SCZ) and PEs and identified features of these states that are associated with psychosis-spectrum symptoms. Transient brain states were defined by clustering “single snapshots” of blood oxygen level-dependent images, based on spatial similarity of the images. We found that individuals with SCZ (n = 35) demonstrated reduced recruitment of three brain states compared to demographically matched healthy controls (n = 35). Of these three illness-related states, one specific state, involving primarily the visual and salience networks, also occurred at a lower rate in individuals with persistent PEs (n = 22), compared to demographically matched healthy youth (n = 22). Moreover, the occurrence rate of this marker brain state was negatively correlated with the severity of PEs (r = −0.26, p = 0.003, n = 130). In contrast, the spatial map of this state appeared to be unaffected in the SCZ or PE groups. Thus, reduced engagement of a brain state involving the visual and salience networks was demonstrated across the psychosis continuum, suggesting that early disruptions of perceptual and affective function may underlie some of the core symptoms of the illness.

The desire to obtain social rewards (e.g. positive feedback) features prominently in our lives and relationships, and is relevant to understanding psychopathology – where behavior is often impaired. Investigating social rewards within the psychosis-spectrum offers an especially useful opportunity, given the high rates of impaired social functioning and social isolation. The goal of this study was to investigate hedonic experience associated with social reward processing as a potential biomarker for psychosis risk. This study used a task-based functional magnetic resonance imaging (fMRI) paradigm in adolescents at clinical high-risk for the development of psychosis (CHR, n = 19) and healthy unaffected peers (healthy controls – HC, n = 20). Regional activation and connectivity of the ventromedial prefrontal cortex and ventral striatum were examined in response to receiving positive social feedback relative to an ambiguous feedback condition. Expectations of impaired hedonic processes in CHR youth were generally not supported, as there were no group differences in neural response or task-based connectivity. Although interesting relationships were found linking neural reward response and connectivity with social, anticipatory, and consummatory anhedonia in the CHR group, results are difficult to interpret in light of task limitations. We discuss potential implications for future study designs that seek to investigate social reward processing as a biomarker for psychosis risk.

Background Healthcare workers (HCWs) are commonly infected by SARS-CoV-2 and represent one of the most vulnerable groups. Adequate prevention strategies are necessary to guarantee HCWs’ safety, as well as to prevent dissemination of the infection among patients. Aims To describe a case series of SARS-CoV-2-positive HCWs in a large public healthcare organization in Milan (Italy) during the most devastating weeks of the epidemic and analyse the sources, symptoms and duration of SARS-CoV-2 infection. Methods This study included 172 SARS-CoV-2-positive HCWs who were infected between the 25th of February and the 7th of April 2020. A nasopharyngeal swab (NPS) and RT-PCR were used to indicate. Results Initially, the most common sources of infection were other positive HCWs (49%). Medical doctors and nursing assistants were most frequently infected, with infection rates of 53/1000 and 50/1000, respectively. COVID-19 departments were less affected than internal medicine, surgery, intensive care, or emergency room. The most commonly reported symptom was mild cough, while loss of smell (anosmia) and loss of taste (ageusia) were reported as moderate and severe by 30–40% of HCWs. The time necessary for 50% of workers to recover from the infection was 23 days, while it took 41 days for 95% of HCWs to become virus-free. Conclusions HCWs are commonly infected due to close contacts with other positive HCWs, and non-COVID departments were most affected. Most HCWs were asymptomatic or subclinical but contact tracing and testing of asymptomatic HCWs help identify and isolate infected workers.

Objectiveprimary empty sella (PES) represents a frequent finding, but data on hormonal alterations are heterogeneous, and its natural history is still unclear. Our aim was to evaluate the pituitary function of patients with PES over a long follow-up.Designmulticenter retrospective cohort study enrolling patients referred between 1984-2020 to five Pituitary Units, with neuroradiological confirmed PES and a complete hormonal assessment.Methodswe analyzed hormonal (including basal and dynamic evaluations), clinical and neuroradiological data collected at diagnosis and at the last visit (at least 6 months of follow-up).Resultswe recruited 402 patients (females=63%, mean age=51.5 ± 16 years) with PES (partial, total, undefined in 66%, 13% and 21%, respectively). Hypopituitarism was present in 40.5% (hypogonadism=20.4%, hypoadrenalism=14.7%, growth hormone deficiency=14.7%, hypothyroidism=10.2%, diabetes insipidus=1.5%; multiple deficiencies=11.4%) and hypeprolactinemia in 6.5%. Interestingly, hormonal alterations were diagnosed in 29% of incidental PES. Hypopituitarism was associated with male sex (p=0.02), suspected endocrinopathy (pp=0.003) and not with age, BMI, number of pregnancies and neuroradiological grade. A longitudinal assessment was possible in 166/402 (median follow-up=58 months). In 5/166 (3%), new deficiencies occurred, whereas 14/166 (8.4%) showed a hormonal recovery. A progression from partial to total PES, which was found in 6/98 patients assessed with a second imaging, was the only parameter significantly related to the hormonal deterioration (p=0.006).Conclusionsthis is the largest cohort of patients with PES reported. Hypopituitarism is frequent (40%) but hormonal deterioration seems uncommon (3%). Patients need to be carefully evaluated at diagnosis, even if PES is incidentally discovered.

We present a deep proteogenomic profiling study of 87 lung adenocarcinoma (LUAD) tumors from the United States, integrating whole-genome sequencing, transcriptome sequencing, proteomics and phosphoproteomics by mass spectrometry, and reverse-phase protein arrays. We identify three subtypes from somatic genome signature analysis, including a transition-high subtype enriched with never smokers, a transversion-high subtype enriched with current smokers, and a structurally altered subtype enriched with former smokers, TP53 alterations, and genome-wide structural alterations. We show that within-tumor correlations of RNA and protein expression associate with tumor purity and immune cell profiles. We detect and independently validate expression signatures of RNA and protein that predict patient survival. Additionally, among co-measured genes, we found that protein expression is more often associated with patient survival than RNA. Finally, integrative analysis characterizes three expression subtypes with divergent mutations, proteomic regulatory networks, and therapeutic vulnerabilities. This proteogenomic characterization provides a foundation for molecularly informed medicine in LUAD.

Efforts to improve pain education and knowledge about prescription opioid misuse and opioid/substance use disorder in undergraduate medical education continue to be inadequate. To advance educational practices and address training needs to counter the opioid epidemic, we created a longitudinal pain and addiction curriculum that includes three patient vignettes in which the patient requests an early refill of opioid medication. The goal was to introduce students to the potential impact of personal biases on health care delivery and medical decision-making with patients who have pain and/or substance use disorders.Three clinical vignettes were presented to early matriculating medical students (MS 1s) using a progressive case disclosure approach in the format of a PowerPoint presentation with embedded audio interactions and follow-up audience response system questions. The same vignettes were converted into OSCEs for early clinical clerkship students (MS 3s).A total of 180 MS 1s participated in the case presentations, and 124 MS 3s participated in the OSCE session. There was a significant difference between students' level of comfort and individual patient requests for early prescription refills in both student cohorts. MS 1s were significantly more likely to provide the early refill to the elderly female patient compared to the two middle-age male patients, whereas a majority of MS 3s wanted more information.This module can be presented to medical students who have little clinical exposure and to health care trainees at other levels of clinical exposure.

Retention of first-time donors is pivotal for blood collection centers. The present study built on research showing the importance of donor identity among regular donors and sought to compare the effectiveness of various communication strategies on return rate.Postal letters were sent to a large sample of first-time whole blood donors (N = 1219) a few weeks following their first donation. Four versions of this letter were differently constructed in a way to boost the acquisition of donor identity (i.e., by including information about their ABO and Rh(D) blood group, emphasizing the salience of donor identity, offering a keyring with personalized information, or specifying the percentage of those sharing the same ABO and Rh(D) blood group). One version with no identity-related information served as a control condition. Participants' subsequent blood donations were tracked for 5-22 months after receiving the letter.Survival analysis showed that the return rate was significantly higher among those who had received information about the percentage of the country's population with the same ABO and Rh(D) blood group (in comparison with the four other versions). There was no significant effect on the blood type rarity.Blood collection centers could orient the strategy employed to communicate with first-time donors to improve donors' retention. Arousing a sense of social identification with others with the same blood type may reveal a promising avenue.

Dysregulations in autonomic and endocrine stress responses are linked to the emergence of psychopathology in adolescence. However, most studies fail to consider the interplay between these systems giving rise to conflicting findings and a gap in understanding adolescent stress response regulation. A multisystem framework-investigation of parasympathetic (PNS), sympathetic (SNS), and hypothalamic pituitary adrenal (HPA) axis components and their coordination-is necessary to understand individual differences in stress response coordination which contribute to stress vulnerabilities. As the first investigation to comprehensively evaluate these three systems in adolescence, the current study employed the Trier Social Stress Test in 72 typically developing adolescents (mean age = 13) to address how PNS, SNS, and HPA stress responses are coordinated in adolescence. Hypotheses tested key predictions of the Adaptive Calibration Model (ACM) of stress response coordination. PNS and SNS responses were assessed via heart rate variability (HRV) and salivary alpha amylase (sAA) respectively. HPA responses were indexed by salivary cortisol. Analyses utilized piecewise growth curve modeling to investigate these aims. Supporting the ACM theory, there was significant hierarchical coordination between the systems such that those with low HRV had higher sAA and cortisol reactivity and those with high HRV had low-to-moderate sAA and cortisol responsivity. Our novel results reveal the necessity of studying multisystem dynamics in an integrative fashion to uncover the true mechanisms of stress response and regulation during development. Additionally, our findings support the existence of characteristic stress response profiles as predicted by the ACM model.

Purpose: Pancreatic neuroendocrine neoplasms (PNENs) are a group of clinically rare and heterogeneous tumors of the pancreas. Currently there are no studies investigating the gender difference in PNEN susceptibility. Thus, the purpose of this study was aimed at examining how gender shapes risk factors, clinicopathological features, and comorbidities in PNENs. Methods: The study design consisted of an Italian multicenter, retrospective study. The study included all consecutive patients with PNENs followed at the participating centers. Two hundred and twenty-nine patients (105 males,124 females, age 54 ± 0.98 years) with PNENs were enrolled at the participating centers. The clinicopathological features (age, gender, BMI, histology, tumor size, tumor grade, distant metastasis, hormonal function, and diagnostic circumstances), comorbidities (cardiovascular diseases (CVD), pancreatitis, type 2 diabetes (T2DM), and potential risk factors (smoking and drinking) were included in the analysis. Results: Females were slightly prevalent (54.15%). PNENs were diagnosed at younger age in females compared to males (p = 0.04). The prevalence of CVD was significantly higher in males than in females (p = 0.006). In the female group, the presence of T2DM was significantly associated with higher tumor grade (p = 0.04) and metastatic disease (p = 0.02). The proportion of smokers and alcohol drinkers was significantly higher in the male group (p < 0.001). No significant gender differences were detected regarding the other parameters included in the analysis. Conclusions: This study has identified gender differences of PNENs in terms of age at diagnosis, associated comorbidities, and potential risk factors. A gender-tailored approach could become a potential strategy to better understand the natural history of PNENs and improve the effectiveness of PNENs clinical management.

Fatal Familial Insomnia (FFI) is a hereditary prion disease caused by a mutation at codon 178 of the prion-protein gene leading to a D178N substitution in the protein determining severe and selective atrophy of mediodorsal and anteroventral thalamic nuclei. FFI is characterized by physiological sleep loss, which polygraphically appears to be a slow wave sleep loss, autonomic and motor hyperactivation with peculiar episodes of oneiric stupor. Alteration of autonomic functions is a great burden for FFI patients consisting in sympathetic overactivation, dysregulation of its physiological responses and disruption of circadian rhythms. The cardiovascular system is the most frequently and severely affected confirming the increased sympathetic drive with preserved parasympathetic responses. Sleep loss, autonomic and motor hyperactivation define Agrypnia Excitata (AE), which is not exclusive to FFI, but it has been canonically described also in Morvan Syndrome and Delirium Tremens. These three conditions present different pathophysiological mechanisms but share the same thalamo-limbic impairment of which AE is one of the possible clinical presentations. FFI, and consequently also AE, is a model for the investigation of the essential role of the thalamus in the organization of body homeostasis, integrating both sleep and autonomic function control.

According to the drug label, linezolid dosage adjustments are not needed in geriatric patients. Nevertheless, clinical evidence suggests that elderly patients may benefit from the use of reduced linezolid doses to limit drug overexposure. Here, we aimed to describe the results of the last 5 years of therapeutic drug monitoring of linezolid in our institution with a special focus on elderly patients.Linezolid therapeutic drug monitoring requests collected between January 2016 and June 2020 were considered. Linezolid trough concentrations were considered both as a continuous variable and as a categorical variable, clustering data according to the therapeutic range proposed by available literature (2, 2-8, and8 mg/L, respectively). Patients' age and sex were considered as categorical variables. Comparisons of linezolid trough concentrations between groups of patients stratified according to age were performed using an analysis of variance; comparisons in the frequency distributions were performed using the chi-squared test.From 2016 to 2020, we collected 3250 linezolid TDM requests. A highly significant, progressive increment in the linezolid trough concentrations was observed moving from patients aged50 years (5.8 ± 5.6 mg/L) to those aged90 years (16.6 ± 10.0 mg/L), with an overall increment of 30% per decade of age. Nearly 30%, 50%, and 65% of patients aged65 years, 65-80 years, and80 years, respectively, had supra-therapeutic linezolid trough concentrations at the first therapeutic drug monitoring assessment. This trend did not change significantly moving from 2016 to 2020.Elderly patients given linezolid at the conventional 600-mg twice-daily dose might be at a high risk of being overexposed to treatment, eventually increasing their risk to experience drug-related hematological toxicity. Reduced linezolid dosing schemes should be potentially considered in elderly patients at a low risk of treatment failure, ideally guided by therapeutic drug monitoring.

Studies attempting to deconstruct the heterogeneity of schizophrenia and the attenuated psychosis syndrome consistently find that negative symptoms are a core dimension that is distinct from other aspects of the illness (e.g., positive and disorganized symptoms). Negative symptoms are also highly predictive of poor community-based functional outcomes, suggesting they are a critical treatment target. Unfortunately, pharmacological and psychosocial treatments for negative symptoms have demonstrated limited effectiveness. To address this critical unmet therapeutic need, the NIMH sponsored a consensus development conference to delineate research priorities for the field and stimulate treatment development. A primary conclusion of this meeting was that next-generation negative symptom rating scales should be developed to address methodological and conceptual limitations of existing instruments. Although second-generation rating scales were developed for adults with schizophrenia, progress in this area has lagged behind for youth at clinical-high risk (CHR) for developing psychosis (i.e. those meeting criteria for a prodromal syndrome). Given that negative symptoms are highly predictive of the transition to diagnosable psychotic illness, enhancing our ability to detect negative symptoms in CHR youth is paramount. The current paper discusses conceptual and methodological limitations inherent to existing scales that assess negative symptoms in CHR youth. The theoretical and clinical implications of these limitations are evaluated. It is concluded that new scales specifically designed to assess negative symptoms in CHR youth are needed to accurately chart mental illness trajectories and determine when, where, and how to intervene. Recent efforts to develop next-generation measures designed specifically for CHR youth to meet this urgent need in the field are discussed. These new approaches offer significant progress for addressing issues inherent to earlier scales.

Summary Introduction To evaluate the aetiology of neonatal invasive diseases (positive cultures from blood or cerebrospinal fluid, CSF) due to bacteria other than coagulase-negative staphylococci in a large tertiary care centre and compare with results of surveillance cultures. Methods Retrospective analysis of microbiological data of children admitted in neonatal intensive care unit (NICU) of a large tertiary care centre from 2005 to 2018. Results 230 bacterial strains, 223 from blood and 7 from CSF, respectively, were detected as cause of invasive infections, while 152 were detected in surveillance cultures. Methicillin-susceptible Staphylococcus aureus (MSSA) was the most frequently isolated pathogen both in invasive infections (18%) and colonizations (23%) followed by Escherichia coli (16% on invasive disease and 20% of colonizations). Other common bacteria include Enterococcus faecalis and Streptococcus agalactiae for invasive disease and methicillin-resistant Staphylococcus aureus in colonizations. Invasive infection was due to a pathogen detected in surveillance cultures in 33% of cases. In more than 50% of invasive diseases the identified pathogen was not present in surveillance cultures. Conclusions The high percentage of invasive infections due to bacteria not previously identified in surveillance cultures raises doubts about the efficiency of this procedure and highlights the need to search for alternative infection sources. This finding and the high prevalence of invasive infections due to nosocomial pathogens such as Staphylococcus aureus could be the result of horizontal transmission between patients through the hands of health care professionals, emphasizing once again the importance of applying stringent hand hygiene procedures and isolation standards.

Exposure and clinical response to CNS drugs are largely variable. AGNP guidelines suggest therapy individualisation with therapeutic drug monitoring of plasma concentrations and pharmacogenetic testing. We present the retrospective analysis of the last 5 years' data collected in real life settings as indirect evidence of the applications of the AGNP guidelines in the routine clinical management of psychiatric patients requiring pharmacologic treatments.Plasma concentrations were quantified using a liquid chromatography/tandem mass spectrometry method. Genomic DNA was isolated using an automatic DNA extraction system. All genotypes were determined by Real-Time PCR.We collected a total of 4582 requests for TDM and 212 requests for pharmacogenetic analysis. A wide distribution in the trough concentrations was observed for most drugs indicating a high interpatient variability. Nearly 45% of the samples had trough levels below the minimum effective drug concentrations set by the AGNP guidelines; only 8% of the samples had high concentrations. For pharmacogenetics analysis, among antipsychotics, clozapine, haloperidol and aripiprazole were the most requested (78%); while for antidepressants SSRIs were the most frequently prescribed.These data suggest that physicians are becoming more confident with the laboratory pharmacologic tools to optimise treatments and/or that the pharmacological treatment of patients with psychiatric disorders is becoming more challenging. TDM and PGx might significantly contribute to the rational selection of the best drug and best dose in individual cases.

BACKGROUND Carbamazepine and oxcarbazepine are potent modulators of metabolic enzymes. Hence, potential drug-drug interactions (DDIs) may occur between these 2 drugs and antiretrovirals. Here, we aimed to assess the relevance of these drug-drug interactions in real-life clinical settings. METHODS Patients treated concomitantly with carbamazepine or oxcarbazepine and antiretrovirals for at least 3 months were considered. Data on therapeutic drug monitoring (TDM) of both antiepileptic and antiretrovirals as trough concentrations were collected. HIV-infected patients not concomitantly treated with antiepileptic drugs and who underwent TDM for antiretrovirals in the previous 2 years were considered as controls. RESULTS Eleven HIV-positive patients prescribed carbamazepine or oxcarbazepine were identified. All the TDM evaluations for carbamazepine and oxcarbazepine that resulted were within the therapeutic ranges. TDM results of darunavir measured in these patients were comparable with values usually measured in the control group. Conversely, the trough concentrations for atazanavir and dolutegravir demonstrated significantly lower values when compared with values usually measured in HIV-infected patients not treated with antiepileptic drugs (190 ± 91 versus 546 ± 380 ng/mL; -65%, P < 0.001; 191 ± 78 versus 1096 ± 510 ng/mL; -83%, P < 0.001, respectively). CONCLUSIONS Co-administration of carbamazepine or oxcarbazepine with atazanavir or dolutegravir should be avoided owing to the potential risk of virological failure; in case of these 2 drugs, the adoption of TDM is strongly advisable, eventually combining with increased antiretroviral doses.

Canonical immunoassays rely on highly sensitive and specific capturing of circulating biomarkers by interacting biomolecular baits. In this frame, bioprobe immobilization in spatially discrete three-dimensional (3D) spots onto analytical surfaces by hydrogel encapsulation was shown to provide relevant advantages over conventional two-dimensional (2D) platforms. Yet, the broad application of 3D systems is still hampered by hurdles in matching their straightforward fabrication with optimal functional properties. Herein, we report on a composite hydrogel obtained by combining a self-assembling peptide (namely, Q3 peptide) with low-temperature gelling agarose that is proved to have simple and robust application in the fabrication of microdroplet arrays, overcoming hurdles and limitations commonly associated with 3D hydrogel assays. We demonstrate the real-case scenario feasibility of our 3D system in the profiling of Covid-19 patients' serum IgG immunoreactivity, which showed remarkably improved signal-to-noise ratio over canonical assays in the 2D format and exquisite specificity. Overall, the new two-component hydrogel widens the perspectives of hydrogel-based arrays and represents a step forward towards their routine use in analytical practices.

Improving indoor air quality present in environments where people live is important to protect human health. This particularly applies to public transportation, where air quality may affect the health and safety of passengers, workers and staff. To provide better air quality, many buildings and transports are provided with heating, ventilation and air conditioning (HVAC) systems, which are always equipped with filters to retain the particulate present in the airflow, but they lack continuous air sanitization systems. In this study, a new UV-C LED and ionizer-based continuous sanitation air (CSA) system to be installed in a train HVAC was developed (international patent: N.PCT/IB2021/054194) and its sanitation efficacy against various microbial species (bacteria and fungi) was assessed. The device proved to be very effective at the microbial killing of aerodispersed microorganisms, both in its experimental configuration (ISO 15714:2019) and in a train setting. The installation of this CSA system on public transportation appears to be a promising solution to guarantee high microbiological air quality with a very low environmental impact due to its eco-friendly components.

Excessive fragmentary hypnic myoclonus, hypnic jerks, hypnagogic foot tremor, alternating leg muscle activation, and sleep-related cramps are less known sleep-related motor disorders (SRMDs). These manifestations are frequently missed or misinterpreted polygraphic findings that can be frequently confused with the more frequent SRMDs. These symptoms can present as isolated motor symptoms but can be also the cause of otherwise cryptogenic insomnias and somnolence. Expanding the knowledge on these isolated symptoms and defining their polygraphic and clinical features are essential for their identification. However, clear cut-offs to discern between the isolated phenomenon and the disorder are still to be found.

Patients with isolated rapid-eye-movement sleep behaviour disorder (RBD) are commonly regarded as being in the early stages of a progressive neurodegenerative disease involving alpha-synuclein pathology, such as Parkinson's disease, dementia with Lewy bodies, or multiple system atrophy. Abnormal alpha-synuclein deposition occurs early in the neurodegenerative process across the central and peripheral nervous systems and might precede the appearance of motor symptoms and cognitive decline by several decades. These findings provide the rationale to develop reliable biomarkers that can better predict conversion to clinically manifest alpha-synucleinopathies. In addition, biomarkers of disease progression will be essential to monitor treatment response once disease-modifying therapies become available, and biomarkers of disease subtype will be essential to enable prediction of which subtype of alpha-synucleinopathy patients with isolated RBD might develop.

Mutations in PRoline Rich Transmembrane protein 2 (PRRT2) cause pleiotropic syndromes including benign infantile epilepsy, paroxysmal kinesigenic dyskinesia, episodic ataxia, that share the paroxysmal character of the clinical manifestations. PRRT2 is a neuronal protein that plays multiple roles in the regulation of neuronal development, excitability, and neurotransmitter release. To better understand the physiopathology of these clinical phenotypes, we investigated PRRT2 interactome in mouse brain by a pulldown-based proteomic approach and identified α1 and α3 Na+/K+ ATPase (NKA) pumps as major PRRT2-binding proteins. We confirmed PRRT2 and NKA interaction by biochemical approaches and showed their colocalization at neuronal plasma membrane. The acute or constitutive inactivation of PRRT2 had a functional impact on NKA. While PRRT2-deficiency did not modify NKA expression and surface exposure, it caused an increased clustering of α3-NKA on the plasma membrane. Electrophysiological recordings showed that PRRT2-deficiency in primary neurons impaired NKA function during neuronal stimulation without affecting pump activity under resting conditions. Both phenotypes were fully normalized by re-expression of PRRT2 in PRRT2-deficient neurons. In addition, the NKA-dependent afterhyperpolarization that follows high-frequency firing was also reduced in PRRT2-silenced neurons. Taken together, these results demonstrate that PRRT2 is a physiological modulator of NKA function and suggest that an impaired NKA activity contributes to the hyperexcitability phenotype caused by PRRT2 deficiency.

We explored the efficacy and safety of lacosamide combined with inhibitors of fast-inactivated sodium channels or with other antiepileptic drugs, in patients with drug refractory focal epilepsy associated with intellectual or psychiatric disability.Observational study of lacosamide including the monitoring of lacosamide trough plasma levels and of electroencephalograms.We followed up 44 patients from the start of lacosamide therapy for up to 3 years, with a clinical, electroencephalogram (EEG), and pharmacological follow-up. Median patients' age was 32.7 years, median age at epilepsy onset was 3.5 years. Intellectual disability was severe in 55.4% of the cohort and drug refractoriness was diagnosed in 88.6% of patients, who had predominantly focal seizures (80%). The severity of their epilepsy was suggested by the use of combined therapies with non-sodium blockers and sodium blockers in 75% of patients. Lacosamide was added to previous therapies and up-titrated to a median of 300 mg/d. Lacosamide add-on led to simplification of the previous drug regimen with a dose reduction in 87.9% of users of sodium blockers and in 66.7% of users of non-sodium blockers, and to withdrawal of previously administered sodium blockers in 48.5% users and non-sodium blockers in 47.6% users. Lacosamide was prescribed at lower doses in the presence of oxcarbazepine (p = 0.029), lamotrigine (p = 0.015), and topiramate (p 0.001). Mean lacosamide plasma levels were 6.0 ± 2.4 mg/L; they were in linear correlation with the administered dose (RLacosamide add-on allowed dose reduction of previous therapies and reduced the frequency of seizures, showing good tolerability even at high doses, without exceeding reference plasma levels.

Video-polysomnography (v-PSG) is essential for diagnosing rapid eye movement (REM) sleep behavior disorder (RBD). Although there are current American Academy of Sleep Medicine standards to diagnose RBD, several aspects need to be addressed to achieve harmonization across sleep centers. Prodromal RBD is a stage in which symptoms and signs of evolving RBD are present, but do not yet meet established diagnostic criteria for RBD. However, the boundary between prodromal and definite RBD is still unclear. As a common effort of the Neurophysiology Working Group of the International RBD Study Group, this manuscript addresses the need for comprehensive and unambiguous v-PSG recommendations to diagnose RBD and identify prodromal RBD. These include: (1) standardized v-PSG technical settings; (2) specific considerations for REM sleep scoring; (3) harmonized methods for scoring REM sleep without atonia; (4) consistent methods to analyze video and audio recorded during v-PSGs and to classify movements and vocalizations; (5) clear v-PSG guidelines to diagnose RBD and identify prodromal RBD. Each section follows a common template: The current recommendations and methods are presented, their limitations are outlined, and new recommendations are described. Finally, future directions are presented. These v-PSG recommendations are intended for both practicing clinicians and researchers. Classification and quantification of motor events, RBD episodes, and vocalizations are however intended for research purposes only. These v-PSG guidelines will allow collection of homogeneous data, providing objective v-PSG measures and making future harmonized multicentric studies and clinical trials possible.

KRAS mutations are one of the most common oncogenic drivers in non-small cell lung cancer (NSCLC) and in lung adenocarcinomas in particular. Development of therapeutics targeting KRAS has been incredibly challenging, prompting indirect inhibition of downstream targets such as MEK and ERK. Such inhibitors, unfortunately, come with limited clinical efficacy, and therefore the demand for developing novel therapeutic strategies remains an urgent need for these patients. Exploring the influence of wild-type (WT) KRAS on druggable targets can uncover new vulnerabilities for the treatment of KRAS mutant lung adenocarcinomas. Using commercially available KRAS mutant lung adenocarcinoma cell lines, we explored the influence of WT KRAS on signaling networks and druggable targets. Expression and/or activation of 183 signaling proteins, most of which are targets of FDA-approved drugs, were captured by reverse-phase protein microarray (RPPA). Selected findings were validated on a cohort of 23 surgical biospecimens using the RPPA. Kinase-driven signatures associated with the presence of the KRAS WT allele were detected along the MAPK and AKT/mTOR signaling pathway and alterations of cell cycle regulators. FoxM1 emerged as a potential vulnerability of tumors retaining the KRAS WT allele both in cell lines and in the clinical samples. Our findings suggest that loss of WT KRAS impacts on signaling events and druggable targets in KRAS mutant lung adenocarcinomas.

Background Survivorship after liver transplantation (LT) is a novel concept providing a holistic view of the arduous recovery experienced after transplantation. We explored components of early survivorship including physical, emotional, and psychocological challenges to identify intervention targets for improving the recovery process of LT recipients and caregivers. Methods Twenty in-person interviews were conducted among adults 3-6 months post-LT. Trained qualitative research experts conducted interviews, coded, and analyzed transcripts to identify relevant themes and representative quotes. Results Early survivorship comprises overcoming: 1) physical challenges-the most-challenging experiences involving mobility, driving, dietary modifications, and medication adherence and 2) emotional and psychological challenges-including new health concerns, financial worries, body image/identity struggles, social isolation, dependency issues, and concerns about never returning to normal. Etiology of liver disease informed survivorship experiences including some patients with hepatocellular carcinoma expressing decisional regret or uncertainty in light of their post-LT experiences. Important topics were identified that framed LT recovery including setting expectations about waitlist experiences, hospital recovery, and ongoing medication requirements. Conclusion Early survivorship after LT within the first six months involves a wide array of physical, emotional and psychological challenges. Patients and caregivers identified what they wish they had known prior to transplant and strategies for recovery, which can inform targeted LT survivorship interventions.

BackgroundAlcohol consumption is a known risk factor for liver disease in HIV-infected populations. Therefore, knowledge of alcohol consumption behaviour and risk of disease progression associated with hazardous drinking are important in the overall management of HIV disease. We aimed at assessing the usefulness of routine data collected on alcohol consumption in predicting risk of severe liver disease (SLD) among people living with HIV (PLWHIV) with or without hepatitis C infection seen for routine clinical care in Italy.MethodsWe included PLWHIV from two observational cohorts in Italy (ICONA and HepaICONA). Alcohol consumption was assessed by physician interview and categorized according to the National Institute for Food and Nutrition Italian guidelines into four categories: abstainer; moderate; hazardous and unknown. SLD was defined as presence of FIB4 > 3.25 or a clinical diagnosis of liver disease or liver-related death. Cox regression analysis was used to evaluate the association between level of alcohol consumption at baseline and risk of SLD.ResultsAmong 9542 included PLWHIV the distribution of alcohol consumption categories was: abstainers 3422 (36%), moderate drinkers 2279 (23%), hazardous drinkers 637 (7%) and unknown 3204 (34%). Compared to moderate drinkers, hazardous drinking was associated with higher risk of SLD (adjusted hazard ratio, aHR = 1.45; 95% CI: 1.03–2.03). After additionally controlling for mode of HIV transmission, HCV infection and smoking, the association was attenuated (aHR = 1.32; 95% CI: 0.94–1.85). There was no evidence that the association was stronger when restricting to the HIV/HCV co-infected population.ConclusionsUsing a brief physician interview, we found evidence for an association between hazardous alcohol consumption and subsequent risk of SLD among PLWHIV, but this was not independent of HIV mode of transmission, HCV-infection and smoking. More efforts should be made to improve quality and validity of data on alcohol consumption in cohorts of HIV/HCV-infected individuals.

Advanced age is the major risk factor for idiopathic Parkinson's disease (PD), but to date the biological relationship between PD and ageing remains elusive. Here we describe the rationale and the design of the H2020 funded project "PROPAG-AGEING", whose aim is to characterize the contribution of the ageing process to PD development. We summarize current evidences that support the existence of a continuum between ageing and PD and justify the use of a Geroscience approach to study PD. We focus in particular on the role of inflammaging, the chronic, low-grade inflammation characteristic of elderly physiology, which can propagate and transmit both locally and systemically. We then describe PROPAG-AGEING design, which is based on the multi-omic characterization of peripheral samples from clinically characterized drug-naive and advanced PD, PD discordant twins, healthy controls and "super-controls", i.e. centenarians, who never showed clinical signs of motor disability, and their offspring. Omic results are then validated in a large number of samples, including in vitro models of dopaminergic neurons and healthy siblings of PD patients, who are at higher risk of developing PD, with the final aim of identifying the molecular perturbations that can deviate the trajectories of healthy ageing towards PD development.

Disorders of arousal (DoA) and sleep-related hypermotor epilepsy (SHE) are sleep-related events characterized by complex, often bizarre, and violent behaviors. DoA are involuntary motor manifestations of various complexities occurring during incomplete awakening from non-rapid eye movement sleep. SHE is a focal epilepsy characterized by stereotyped hyperkinetic or/and asymmetric tonic/dystonic seizures usually arising from non-rapid eye movement sleep. Even if many aspects regarding DoA and SHE have been clarified, the differential diagnosis remains challenging, because DoA and SHE share some semiologic features and genetic background. The clinical history, collected from the patient and his/her witness, represents the first and common milestone in the diagnosis. Validated questionnaires constitute suitable screening tools that could guide further analysis. The worldwide availability of homemade video recordings has increased the possibility of adding more objective information to the clinical history alone. The confirmed diagnosis relies on video-polysomnographic recording although it requires time, economic resources, and specific skills for the analysis. In this review we propose a simple diagnostic algorithm for the differential diagnosis between DoA and SHE in adults, based on the most updated knowledge, from the simpler tool to the most specific and tailored one.

The Coronavirus Disease 2019 (COVID-19) pandemic required a thorough re-organization of every sector of the healthcare system. Sleep laboratories need to renew protocols in order to guarantee the safety of patients and healthcare staff while providing exams. Polysomnography (PSG) examinations are essential for the diagnosis and treatment management of several sleep disorders, which may constitute a public or personal safety issue such as obstructive sleep apnea syndrome. Here we provide some practical advice on how to perform sleep studies after the COVID-19 outbreak based on our experience, the review of the existing literature and current national and international recommendations by Health Authorities. We believe that with appropriate precautions it is possible to guarantee a safe restart of PSG and other sleep studies.

ObjectivesTo evaluate the incidence and risk factors for liver enzyme elevations (LEE) in patients initiating first-line ART in the ICONA prospective observational cohort, between June 2009 and December 2017.Patients and methodsIn total, 6575 ART-naive patients were selected, initiating two NRTIs with the third drug being a boosted PI (n=2436; 37.0%), an NNRTI (n=2384; 36.3%) or an integrase strand transfer inhibitor (INSTI) (n=1755; 26.7%). HBV surface antigen and HCV RNA were detected in 3.9% and 5.8% of the study population. Inverse probability weighted Cox regression analysis was used to calculate the HRs, according to first-line regimen, for LEE, defined as ALT or AST increases of ≥2.5× upper limit of normal (ULN) for patients with normal baseline values or ≥2.5× baseline for patients with higher baseline values.ResultsOne hundred and eighty-three LEE occurred over 20722 patient-years of follow-up. After adjusting for the main confounders, the risk of LEE halved with INSTIs compared with NNRTIs (HR 0.46, 95% CI 0.25–0.86), with a significant reduction in the raltegravir group (HR 0.11, 95% CI 0.02–0.84 using the NNRTI class as reference). HRs for LEE were significantly higher in subjects with HBV or HCV coinfection, in patients with poorly controlled HIV infection and in those who acquired HIV through homosexual transmission.ConclusionsIn our study, INSTI use almost halved the risk of LEE compared with other regimens. This finding could be particularly important for choosing ART in patients with risk factors for liver toxicity such as HCV and HBV coinfections.