Multiplexed high-throughput immune cell imaging in patients with high-risk triple negative early breast cancer: Analysis from the International Breast Cancer Study Group (IBCSG) Trial 22-00.

BACKGROUND: Triple-negative breast cancer (TNBC) is the most aggressive breast cancer (BC) subtype, with dismal prognosis and limited option in advanced settings, yet stromal tumor infiltrating lymphocytes (sTILs) in this subtype has a predictive role. PATIENTS AND METHODS: The International Breast Cancer Study Group (IBCSG) Trial 22-00 is a randomized phase III clinical trial testing the efficacy of low-dose metronomic oral Cyclophosphamide-Methotrexate (CM) maintenance following standard adjuvant chemotherapy treatment for early-stage hormone receptor-negative breast cancer patients. A case-cohort sampling was used. We characterized immune cells infiltrates in patients with TNBC by 6 plex immunofluorescence (IF) staining for CD4, FOXP3, CD3, cytokeratine and CD8 RESULTS: We confirmed that high immune CD3+ T cells as well as stromal and intra-epithelial Tregs (CD4+Foxp3+ T cells) infiltrates were associated with a better Distant Recurrence-Free Interval (DRFI), especially in LN+ patient, regardless of the treatment. More importantly, we showed that the spatial distribution of immune cells at baseline is crucial, as CM maintenance was detrimental for T cells excluded LN+ TNBC patients. CONCLUSIONS: immune spatial classification on immune cells infiltrates seems crucial and could help patients' selection in clinical trial and greatly improve responses to specific therapies.

Radioimmunotherapy versus autologous hematopoietic stem cell transplantation in relapsed/refractory follicular lymphoma: a Fondazione Italiana Linfomi multicenter, randomized, phase III trial.

BACKGROUND: Optimal consolidation for young patilents with relapsed/refractory (R/R) follicular lymphoma (FL) remains uncertain in the rituximab era, with an unclear benefit of autologous stem cell transplantation (ASCT). The multicenter, randomized, phase III FLAZ12 (NCT01827605) trial compared anti-CD20 radioimmunotherapy (RIT) with ASCT as consolidation after chemoimmunotherapy, both followed by rituximab maintenance. PATIENTS AND METHODS: Patients (age 18-65 years) with R/R FL and without significant comorbidities were enrolled and treated with three courses of conventional, investigator-chosen chemoimmunotherapies. Those experiencing at least a partial response were randomized 1 : 1 to ASCT or RIT before CD34+ collection, and all received postconsolidation rituximab maintenance. Progression-free survival (PFS) was the primary endpoint. The target sample size was 210 (105/group). RESULTS: Between August 2012 and September 2019, of 164 screened patients, 159 were enrolled [median age 57 (interquartile range 49-62) years, 55% male, 57% stage IV, 20% bulky disease]. The study was closed prematurely because of low accrual. Data were analyzed on 8 June 2023, on an intention-to-treat basis, with a 77-month median follow-up from enrollment. Of the 141 patients (89%), 70 were randomized to ASCT and 71 to RIT. The estimated 3-year PFS in both groups was 62% (hazard ratio 1.11, 95% confidence interval 0.69-1.80, P = 0.6662). The 3-year overall survival also was similar between the two groups. Rates of grade ≥3 hematological toxicity were 94% with ASCT versus 46% with RIT (P < 0.001), and grade ≥3 neutropenia occurred in 94% versus 41%, respectively (P < 0.001). Second cancers occurred in nine patients after ASCT and three after radioimmunotherapy (P = 0.189). CONCLUSIONS: Even if prematurely discontinued, our study did not demonstrate the superiority of ASCT versus RIT. ASCT was more toxic and demanding for patients and health services. Both strategies yielded similar, favorable long-term outcomes, suggesting that consolidation programs milder than ASCT require further investigation in R/R FL.

Investigating the relationship between autistic traits and symptoms and Catatonia Spectrum.

BACKGROUND: In recent years, numerous studies have highlighted the overlap between autism spectrum disorder (ASD) and catatonia, both from a clinical and pathophysiological perspective. This study aimed to investigate the relationship between the autism spectrum (autistic traits and ASD signs, symptoms, and behavioral manifestation) and Catatonia Spectrum (CS). METHODS: A total sample of 376 subjects was distributed in four diagnostic groups. Subjects were assessed with the Structured Clinical Interview for DSM-5, Research Version, the Adult Autism Subthreshold Spectrum (AdAS Spectrum), and CS. In the statistical analyses, the total sample was also divided into three groups according to the degree of autism severity, based on the AdAS Spectrum total score. RESULTS: A statistically significant positive correlation was found between AdAS Spectrum and CS total score within the total sample, the gender subgroups, and the diagnostic categories. The AdAS Spectrum domains found to be significantly and strongly correlated with the total CS score were hyper-hypo reactivity to sensory input, verbal communication, nonverbal communication, restricted interests and rumination, and inflexibility and adherence to routine. The three groups of different autistic severity were found to be distributed across all diagnostic groups and the CS score increased significantly from the group without autistic traits to the group with ASD. CONCLUSIONS: Our study reports a strong correlation between autism spectrum and CS.

Long-term benefit of lurbinectedin as palliative chemotherapy in progressive malignant pleural mesothelioma (MPM): final efficacy and translational data of the SAKK 17/16 study.

BACKGROUND: The SAKK 17/16 study showed promising efficacy data with lurbinectedin as second- or third-line palliative therapy in malignant pleural mesothelioma. Here, we evaluated long-term outcome and analyzed the impact of lurbinectedin monotherapy on the tumor microenvironment at the cellular and molecular level to predict outcomes. MATERIAL AND METHODS: Forty-two patients were treated with lurbinectedin in this single-arm study. Twenty-nine samples were available at baseline, and seven additional matched samples at day one of cycle two of treatment. Survival curves and rates between groups were compared using the log-rank test and Kaplan-Meier method. Statistical significance was set at P value <0.05. RESULTS: Updated median overall survival (OS) was slightly increased to 11.5 months [95% confidence interval (CI) 8.8-13.8 months]. Thirty-six patients (85%) had died. The OS rate at 12 and 18 months was 47% (95% CI 32.1% to 61.6%) and 31% (95% CI 17.8% to 45.0%), respectively. Median progression-free survival was 4.1 months (95% CI 2.6-5.5 months). No new safety signals were observed. Patients with lower frequencies of regulatory T cells, as well as lower tumor-associated macrophages (TAMs) at baseline, had a better OS. Comparing matched biopsies, a decrease of M2 macrophages was observed in five out of seven patients after exposure to lurbinectedin, and two out of four patients showed increased CD8+ T-cell infiltrates in tumor. DISCUSSION: Lurbinectedin continues to be active in patients with progressing malignant pleural mesothelioma. According to our very small sample size, we hypothesize that baseline TAMs and regulatory T cells are associated with survival. Lurbinectedin seems to inhibit conversion of TAMs to M2 phenotype in humans.

Neutropenia and survival outcomes in metastatic colorectal cancer patients treated with trifluridine/tipiracil in the RECOURSE and J003 trials.

BACKGROUND: The phase II J003 (N = 169) and phase III RECOURSE (N = 800) trials demonstrated a significant improvement in survival with trifluridine (FTD)/tipiracil (TPI) versus placebo in patients with refractory metastatic colorectal cancer. This post hoc analysis investigated pharmacokinetic data of FTD/TPI exposure and pharmacodynamic markers, such as chemotherapy-induced neutropenia (CIN) and clinical outcomes. PATIENTS AND METHODS: A total of 210 patients from RECOURSE were enrolled in this substudy. A limited sampling approach was used, with three pharmacokinetic samples drawn on day 12 of cycle 1. Patients were categorized as being above or below the median area under the plasma concentration-time curve (AUC) for FTD and TPI. We conducted a post hoc analysis using the entire RECOURSE population to determine the correlations between CIN and clinical outcome. We then carried out a similar analysis on the J003 trial to validate the results. RESULTS: In the RECOURSE subset, patients in the high FTD AUC group had a significantly increased CIN risk. Analyses of the entire population demonstrated that FTD/TPI-treated patients with CIN of any grade in cycles 1 and 2 had significantly longer median overall survival (OS) and progression-free survival (PFS) than patients who did not develop CIN and patients in the placebo group. Patients who required an FTD/TPI treatment delay had increased OS and PFS versus those in the placebo group and those who did not develop CIN. Similar results were obtained in the J003 cohort. CONCLUSIONS: In RECOURSE, patients with higher FTD drug exposure had an increased CIN risk. FTD/TPI-treated patients who developed CIN had improved OS and PFS versus those in the placebo group and those who did not develop CIN. Similar findings were reported in the J003 cohort, thus validating the RECOURSE results. The occurrence of CIN may be a useful predictor of treatment outcomes for FTD/TPI-treated patients. CLINICALTRIALS. GOV IDENTIFIER: NCT01607957 (RECOURSE). JAPAN PHARMACEUTICAL INFORMATION CENTER NUMBER: JapicCTI-090880 (J003).

A phase III trial comparing oral S-1/cisplatin and intravenous 5-fluorouracil/cisplatin in patients with untreated diffuse gastric cancer.

BACKGROUND: The effect of histology-based treatment regimen on diffuse gastric adenocarcinoma has not been evaluated in clinical trials. This international phase III trial evaluated the efficacy and safety of S-1 (a contemporary oral fluoropyrimidine)/cisplatin versus 5-fluorouracil (5-FU)/cisplatin in chemotherapy-naïve patients with diffuse-type adenocarcinoma involving the gastroesophageal junction or stomach. PATIENTS AND METHODS: Eligibility criteria included untreated, measurable, advanced diffuse adenocarcinoma confirmed by central pathology and performance status of 0-1. Patients were randomized (2 : 1) to receive S-1/cisplatin or 5-FU/cisplatin. Primary end point was overall survival (OS), and secondary end points were progression-free survival, time to treatment failure, overall response rate, and safety. A multivariable analysis was also carried out. RESULTS: Overall, 361 patients were randomized (S-1/cisplatin, n = 239; 5-FU/cisplatin, n = 122); half (51%) were men, and median age was 56.0 years. In each group, median number of treatment cycles per patient was 4 (range, S-1/cisplatin: 1-20; 5-FU/cisplatin: 1-30), and dose intensity was >95%. OS was not different in the two groups {median OS with S-1/cisplatin, 7.5 [95% confidence interval (CI): 6.7, 9.3]; 5-FU/cisplatin, 6.6 [95% CI: 5.7, 8.1] months; hazard ratio, 0.99 [95% CI: 0.76, 1.28]; P = 0.9312}. Overall response rate was significantly higher in the S-1/cisplatin than 5-FU/cisplatin group (34.7% versus 19.8%; P = 0.01), but progression-free survival and time to treatment failure were not different. Safety was similar between the 2 groups; however, fewer patients treated with S-1/cisplatin than 5-FU/cisplatin had ≥1 grade 3/4 treatment-emergent adverse event or ≥1 adverse event resulting in treatment discontinuation. One treatment-related death occurred in each group. Slow accrual led to early termination. CONCLUSIONS: These data suggest that S-1/cisplatin and 5-FU/cisplatin are similar in efficacy and safety in untreated patients with advanced diffuse adenocarcinoma of the gastroesophageal junction or stomach. The primary end point was not met. CLINICALTRIAL.GOV REGISTRATION NUMBER: NCT01285557.

Synthesis and biological evaluation in vitro and in mammalian cells of new heteroaryl carboxyamides as HIV-protease inhibitors.

New heteroaryl HIV-protease inhibitors bearing a carboxyamide spacer were synthesized in few steps and high yield, from commercially available homochiral epoxides. Different substitution patterns were introduced onto a given isopropanoyl-sulfonamide core modifying the type of heteroarene and the central core, with the presence of either H or benzyl group. Their in vitro inhibition activity against recombinant protease showed a general beneficial effect of carboxyamide moiety, the IC50 values ranging between 1 and 15nM. In particular benzofuryl derivatives showed IC50 values among the best for such structurally simple inhibitors. Docking analysis allowed to identify the favorable situation of such benzofuryl derivatives in terms of number of interactions in the active site, supporting the experimental results on activity. The inhibition activity of such molecules has been also evaluated in HEK293 cells expressing the protease fused to green fluorescent protein, by western blotting analysis, fluorescence microscopy and cytofluorimetry.

Abnormal brain oscillations persist after recovery from bipolar depression.

When directly perturbed in healthy subjects, premotor cortical areas generate electrical oscillations in the beta range (20-40Hz). In schizophrenia, major depressive disorder and bipolar disorder (BD), these oscillations are markedly reduced, in terms of amplitude and frequency. However, it still remains unclear whether these abnormalities can be modulated over time, or if they can be still observed after treatment. Here, we employed transcranial magnetic stimulation (TMS) combined with EEG to assess the frontal oscillatory activity in eighteen BD patients before/after antidepressant treatments (sleep deprivation and light therapy), relative to nine healthy controls. In order to detect dominant frequencies, event related spectral perturbations (ERSP) were computed for each TMS/EEG session in all participants, using wavelet decomposition. The natural frequency at which the cortical circuit oscillates was calculated as the frequency value with the largest power across 300ms post-stimulus time interval. Severity of depression markedly decreased after treatment with 12 patients achieving response and nine patients achieving remission. TMS/EEG resulted in a significant activation of the beta/gamma band response (21-50Hz) in healthy controls. In patients, the main frequencies of premotor EEG responses to TMS did not significantly change before/after treatment and were always significantly lower than those of controls (11-27Hz) and comparable in patients achieving remission and in those not responding to treatment. These results suggest that the reduction of natural frequencies is a trait marker of BD, independent from the clinical status of the patients. The present findings shed light on the neurobiological underpinning of severe psychiatric disorders and demonstrate that TMS/EEG represents a unique tool to develop biomarkers in psychiatry.

Catechol-O-methyltransferase Val(108/158)Met polymorphism affects fronto-limbic connectivity during emotional processing in bipolar disorder.

Catechol-O-methyltransferase (COMT) inactivates catecholamines, Val/Val genotype was associated to an increased amygdala (Amy) response to negative stimuli and can influence the symptoms severity and the outcome of bipolar disorder, probably mediated by the COMT polymorphism (rs4680) interaction between cortical and subcortical dopaminergic neurotransmission. The aim of this study is to explore how rs4680 and implicit emotional processing of negative emotional stimuli could interact in affecting the Amy connectivity in bipolar depression. Forty-five BD patients (34 Met carriers vs. 11 Val/Val) underwent fMRI scanning during implicit processing of fearful and angry faces. We explore the effect of rs4680 on the strength of functional connectivity from the amygdalae to whole brain. Val/Val and Met carriers significantly differed for the connectivity between Amy and dorsolateral prefrontal cortex (DLPFC) and supramarginal gyrus. Val/Val patients showed a significant positive connectivity for all of these areas, where Met carriers presented a significant negative one for the connection between DLPFC and Amy. Our findings reveal a COMT genotype-dependent difference in corticolimbic connectivity during affective regulation, possibly identifying a neurobiological underpinning of clinical and prognostic outcome of BD. Specifically, a worse antidepressant recovery and clinical outcome previously detected in Val/Val patients could be associated to a specific increased sensitivity to negative emotional stimuli.

Brain-derived Neurotrophic Factor (BDNF) and gray matter volume in bipolar disorder.

INTRODUCTION: Bipolar Disorder (BD) is a severe psychiatric condition characterized by grey matter (GM) volumes reduction. Neurotrophic factors have been suggested to play a role in the neuroprogressive changes during the illness course. In particular peripheral brain-derived neurotrophic factor (BDNF) has been proposed as a potential biomarker related to disease activity and neuroprogression in BD. The aim of our study was to investigate if serum levels of BDNF are associated with GM volumes in BD patients and healthy controls (HC). METHODS: We studied 36 inpatients affected by a major depressive episode in course of BD type I and 17 HC. Analysis of variance was performed to investigate the effect of diagnosis on GM volumes in the whole brain. Threshold for significance was P<0.05, Family Wise Error (FWE) corrected for multiple comparisons. All the analyses were controlled for the effect of nuisance covariates known to influence GM volumes, such as age, gender and lithium treatment. RESULTS: BD patients showed significantly higher serum BDNF levels compared with HC. Reduced GM volumes in BD patients compared to HC were observed in several brain areas, encompassing the caudate head, superior temporal gyrus, insula, fusiform gyrus, parahippocampal gyrus, and anterior cingulate cortex. The interaction analysis between BDNF levels and diagnosis showed a significant effect in the middle frontal gyrus. HC reported higher BDNF levels associated with higher GM volumes, whereas no association between BDNF and GM volumes was observed in BD. DISCUSSION: Our study seems to suggest that although the production of BDNF is increased in BD possibly to prevent and repair neural damage, its effects could be hampered by underlying neuroinflammatory processes interfering with the neurodevelopmental role of BDNF.

Prevalencia de istmocele en el Hospital de San José de Bogotá, Colombia / Prevalence of isthmocele at the San José Hospital in Bogotá, Colombia

Objetivo: Describir la prevalencia de istmocele como hallazgo incidental en pacientes con antecedente de cesárea y síntomas clínicos asociados. Métodos: Estudio descriptivo de corte transversal, mediante muestreo no probabilístico por conveniencia, en pacientes con antecedente de cesárea, programadas para histeroscopia entre noviembre de 2014 y marzo de 2015, en el servicio de cirugía endoscópica ginecológica del Hospital San José de Bogotá, Colombia. Resultados: 42 pacientes fueron elegibles para el estudio por su antecedente de cesárea y todas fueron incluidas. La frecuencia de istmocele fue 83,3% en la histeroscopia, con similar localización en istmo y cérvix. La principal característica clínica presentada por las pacientes fue hemorragia uterina anormal (85,7%), mientras que la menos frecuente fue infertilidad (7,1%). En las pacientes con presencia de istmocele se observó una mayor prevalencia de dismenorrea (65,7% vs. 42,9%), antecedente de 2 o más cesáreas (60% vs. 42,9%) y cesárea de urgencia (54,3% vs. 28,6%) comparadas con el grupo de pacientes sin istmocele, en este último grupo se advirtió que el 100% de las pacientes no tenían antecedente de trabajo de parto previo. En mujeres con antecedente de cesárea y presencia de síntomas como sangrado uterino anormal, dismenorrea, dolor pélvico, infertilidad y dispareunia, la frecuencia de istmocele diagnosticado por histeroscopia fue mayor del 80%. Conclusión: El istmocele se debe a la cicatrización anómala uterina posterior a una cesárea, se requieren otros estudios para determinar no solo la prevalencia sino los factores protectores que reduzcan su incidencia para tener un impacto positivo en este tipo de pacientes.

Objective: To describe the prevalence of isthmocele as an incidental finding in patients with a history of cesarean section and associated clinical symptoms. Methods: Descriptive cross-sectional study using nonprobabilistic sampling for convenience in patients with a history of cesarean section, scheduled for hysteroscopy between November 2014 and March 2015, in the gynecological endoscopic surgery service of the Hospital San José de Bogotá, Colombia. Results: 42 patients were eligible for the study because of their previous cesarean section and all were included. The frequency of isthmocele was 83.3% in hysteroscopy, with similar localization in the isthmus and cervix. The main clinical characteristic presented by the patients was abnormal uterine bleeding (85.7%), while the less common was infertility (7.1%). A higher prevalence of dysmenorrhea (65.7% vs. 42.9%) was observed in patients with isthmocele, a history of 2 or more cesareans (60% vs. 42.9%) and an emergency cesarean section (54, 3% vs. 28.6%) compared to the group of patients without isthmocele, in the latter group it was noted that 100% of the patients had no previous history of labor. In women with a history of cesarean section and presence of symptoms such as abnormal uterine bleeding, dysmenorrhea, pelvic pain, infertility and dyspareunia, the frequency of isthmocele diagnosed by hysteroscopy was greater than 80%. Conclusion: Isthmocele is due to abnormal uterine cicatrization after cesarean section, other studies are required to determine not only the prevalence but also the protective factors that reduce its incidence to have a positive impact on this kind of patients.

Nature of the placebo and nocebo effect in relation to functional neurologic disorders.

Placebos have long been considered a nuisance in clinical research, for they have always been used as comparators for the validation of new treatments. By contrast, today they represent an active field of research, and, due to the involvement of many mechanisms, the study of the placebo effect can actually be viewed as a melting pot of concepts and ideas for neuroscience. There is not a single placebo effect, but many, with different mechanisms across different medical conditions and therapeutic interventions. Expectation, anxiety, and reward are all involved, as well as a variety of learning phenomena and genetic variants. The most productive models to better understand the neurobiology of the placebo effect are pain and Parkinson's disease. In these medical conditions, several neurotransmitters have been identified, such as endogenous opioids, cholecystokinin, dopamine, as well as lipidic mediators, for example, endocannabinoids and prostaglandins. Since the placebo effect is basically a psychosocial context effect, these data indicate that different social stimuli, such as words and therapeutic rituals, may change the chemistry of the patient's brain, and these effects are similar to those induced by drugs.

Different contexts, different pains, different experiences.

Pain is an ambiguous perception: the same pain stimulation can be perceived differently in different contexts, producing different experiences, ranging from mild to unbearable pain. It can be even experienced as a rewarding sensation within the appropriate context. Overall, placebo and nocebo effects appear to be very good models to understand how the psychosocial context modulates the experience of pain. In this review, we examine the effects of different contexts on pain, with a specific focus on the neurobiological mechanisms. Positive and rewarding contexts inform the patients that an effective treatment is being delivered and are capable of producing pain relief through the activation of specific systems such as opioids, cannabinoids and dopamine. Conversely, a negative context can produce pain exacerbation and clinical worsening through the modulation of different systems, such as the activation of cholecystokinin and the deactivation of opioids and dopamine. In addition, when a therapy is delivered unbeknownst to the patient, its effects are reduced. A better understanding of the neurobiological underpinnings of the context-pain interaction is a challenge both for future pain research and for good clinical practice.

Herpes Virus Infections During Treatment With Etanercept in Juvenile Idiopathic Arthritis.

Incidence rates for varicella and herpes zoster were similar in patients with juvenile idiopathic arthritis receiving etanercept/methotrexate (n = 85, 184.9 patient-years [PY]) or methotrexate alone (n = 71, 199.4 PY); no complicated varicella or herpes zoster cases were reported; herpes labialis incidence was higher in patients receiving etanercept/methotrexate versus methotrexate alone (0.38 vs. 0.24 PY).

Prevalence of Diabetes Mellitus (DM) in a population of men affected by Erectile Dysfunction (ED).

AIMS: A) to evaluate the prevalence of patients affected by Diabetes Mellitus (DM) in a population of men with Erectile Dysfunction (ED); B) to define the epidemiological, biochemical and therapeutic aspects. MATERIALS AND METHODS: N.934 subjects referred at our Andrology Unit for ED were studied. The diagnosis of ED was evaluated using the IIEF-5 questionnaire (Total score ≤21). RESULTS: The prevalence of subjects affected by DM in a population of men with ED was 19.5% (182/934). The age ranges were: ≥55 years (108/182; 59.3%); ≥40<55 years (70/182; 38.5%); <40 years (4/182; 2.2%). HbA1c mean value was 7.9% ± 0.8%. No significant differences were found in DM onset timing or in anti-diabetic treatment. In n.125/182 cases (68.7%) the ED onset followed the diagnosis of DM; in n.34/182 cases (18.7%) it appeared at the same time; and in n.23/182 cases (12.6%) appeared before DM diagnosis. ED TREATMENT: in n.18/182 subjects (9.9%) there was a concomitant hypotestosteronemia; these patients were treated only with testosterone replacement; this treatment was efficacious (IIEF-5 total score ≥22) in 8/18 subjects (44.4%). In n.146/182 subjects (80.2%) a treatment with PDE5-i was given. Of these 146 subjects, the therapy was given "on demand" to 108 subjects (efficacy in 50.9%; 55/108) and "once a day" to the remaining 38 subjects (efficacy 63.1%, 24/38) (p=0.428, n.s.). N.15/182 subjects (8.2%) were treated with intracavernous injections of Alprostadil (efficacy in 8/15, 53.3%). In n.3/182 subjects (1.6%) a penile prosthesis was implanted. CONCLUSIONS: DM is one of the most frequent organic causes of ED; there were many strategies to treat this symptom without interfering with the antidiabetic treatment. Finally, ED can be predictive of DM.

Neurology and psychiatry: waking up to opportunities of sleep. : State of the art and clinical/research priorities for the next decade.

In recent years, evidence has emerged for a bidirectional relationship between sleep and neurological and psychiatric disorders. First, sleep-wake disorders (SWDs) are very common and may be the first/main manifestation of underlying neurological and psychiatric disorders. Secondly, SWDs may represent an independent risk factor for neuropsychiatric morbidities. Thirdly, sleep-wake function (SWF) may influence the course and outcome of neurological and psychiatric disorders. This review summarizes the most important research and clinical findings in the fields of neuropsychiatric sleep and circadian research and medicine, and discusses the promise they bear for the next decade. The findings herein summarize discussions conducted in a workshop with 26 European experts in these fields, and formulate specific future priorities for clinical practice and translational research. More generally, the conclusion emerging from this workshop is the recognition of a tremendous opportunity offered by our knowledge of SWF and SWDs that has unfortunately not yet entered as an important key factor in clinical practice, particularly in Europe. Strengthening pre-graduate and postgraduate teaching, creating academic multidisciplinary sleep-wake centres and simplifying diagnostic approaches of SWDs coupled with targeted treatment strategies yield enormous clinical benefits for these diseases.

A MSFD complementary approach for the assessment of pressures, knowledge and data gaps in Southern European Seas: The PERSEUS experience.

PERSEUS project aims to identify the most relevant pressures exerted on the ecosystems of the Southern European Seas (SES), highlighting knowledge and data gaps that endanger the achievement of SES Good Environmental Status (GES) as mandated by the Marine Strategy Framework Directive (MSFD). A complementary approach has been adopted, by a meta-analysis of existing literature on pressure/impact/knowledge gaps summarized in tables related to the MSFD descriptors, discriminating open waters from coastal areas. A comparative assessment of the Initial Assessments (IAs) for five SES countries has been also independently performed. The comparison between meta-analysis results and IAs shows similarities for coastal areas only. Major knowledge gaps have been detected for the biodiversity, marine food web, marine litter and underwater noise descriptors. The meta-analysis also allowed the identification of additional research themes targeting research topics that are requested to the achievement of GES.