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Introduction Sleep disruptions are frequently observed in individuals with bipolar disorder and have been linked to various unfavorable consequences, such as an elevated risk of relapse and lower quality of life. Nonetheless, the impact of sociodemographic factors on the development and progression of these disruptions remains largely unexplored. Gaining insight into the relationship between sleep disruptions and sociodemographic factors is essential for designing effective interventions and enhancing clinical outcomes for individuals affected by bipolar disorder Objectives The objective of this study is to examine the association between sleep disorders in patients with bipolar disorder II (BDII) and sociodemographic characteristics. Methods This is a cross-sectional, descriptive, and analytical study that was conducted over a one-month period from October 1 to October 31, 2022, with patients attending the follow-up unit of the mental health department at Nabeul Hospital ,Tunisia.The study employed a questionnaire as a tool for data collection, and participants provided voluntary and informed consent before responding. The protection of participant confidentiality and anonymity was carefully observed during all stages of the study. Results In this study, we enrolled patients who satisfied the following eligibility criteria: age range of 18 to 60 years, a confirmed diagnosis of type II bipolar disorder based on DSM V criteria, and psychiatric stability as demonstrated by no hospitalization within the preceding 6-month period. Our study included a sample of 40 male patients diagnosed with type II bipolar disorder. The participants had a mean age of 36 ± 13.2 years, and the majority were unmarried and living with their families or alone. Over two-thirds of the participants had attained a university level of education, while a large proportion of the patients, specifically 80%, reported being regular smokers. The results of the study revealed that the mean global score on the Pittsburgh Sleep Quality Index (PSQI) was 7.28 ± 3.35, indicating an overall low quality of sleep. The majority of the participants, that is 65% (26), had poor sleep quality scores (> 5), while 45% (18) reported experiencing poor sleep (PSQI ≥ 8). Our analyses further demonstrated that there was a significant association between tobacco consumption and PSQI scores (p=0.003). Additionally, we found that participants who were above 40 years old had a higher likelihood of experiencing sleep disturbances (p=0.0017). Conclusions According to the findings of our study, it appears that patients diagnosed with type II bipolar disorder may experience impaired sleep quality, which can be influenced by age and tobacco consumption. These results underscore the need for a holistic approach to patient care that addresses both the biological and sociodemographic factors that can impact sleep in this population. Disclosure of Interest None Declared

Introduction Sleep disturbances and suicidal behaviors are common among patients with type II bipolar disorder ( BDII), but the relationship between the two is unclear. Investigating this connection is important to identify interventions that can improve the quality of life and reduce the risk of suicide in this population. Objectives Our study’s objective is to examine the association between sleep disorders and suicidal behavior in patients with type II bipolar disorder (BDII). Methods In order to comprehensively investigate the association between sleep disturbances and suicidal behaviors among individuals diagnosed with type II bipolar disorder (TBII), we conducted a cross-sectional, descriptive, and analytical study over a duration of one month, specifically from the 1st to the 31st of October 2022. Our research was conducted within the follow-up unit of the mental health department at Nabeul Hospital, Tunisia, with the aim of capturing a diverse range of participants representative of the population of interest. To ensure the integrity and accuracy of our findings, we meticulously selected participants who met specific eligibility criteria. This included individuals aged between 18 and 60 years, who had a confirmed diagnosis of type II bipolar disorder according to the criteria outlined in the Diagnostic and Statistical Manual of Mental Disorders (DSM V). Furthermore, we sought to include participants who were psychiatrically stable, meaning they had not required hospitalization in the six months preceding the study. The Pittsburgh Sleep Quality Index (PSQI) was used to evaluate the participants’ sleep quality over a one-month period, while the Suicidal Behavior Questionnaire-Revised (SBQ-R) was used to assess suicidal behavior.The data was gathered through a questionnaire that prioritized ethical concerns, including obtaining informed consent from participants and maintaining confidentiality and anonymity throughout the study. Results In this study, we enrolled 40 male patients with a mean age of 36 ± 13.2 years and evaluated their sleep quality and suicidal behaviors. The results showed that the participants had a mean PSQI score of 7.28 ± 3.35, indicating that the overall sleep quality was not optimal. Specifically, 65% of the participants had poor sleep quality (> 5), and 45% reported poor sleep(PSQI ≥ 8) . The mean SBQ-R score was 10.3 ± 3.6, indicating a moderate level of suicidal behavior. Interestingly, we found a statistically significant correlation between PSQI and SBQ-R subscales, particularly with regard to suicidal thoughts (p=0.003) and suicide attempts (p=0.002). Conclusions Our study found a strong link between sleep problems and suicidal behavior in people with type II bipolar disorder. This highlights the need to address sleep issues to reduce suicide risk in these patients. Disclosure of Interest None Declared

Introduction The COVID-19 pandemic represents a stressful event for humanity. The spread of this disease mainly affects health professionals and interests them closely. Objectives Identify the impact of the COVID-19 pandemic on the mental health of healthcare personnels and associated factors exposing them to increased psychological fragility. Methods The current article is a narrative review of the existing literature. A search on electronic database like PubMed was undertaken using the search terms “coronavirus mental health healthcare workers”. 20 articles were included in this review. Results Studies revealed that health care workers have prensented considerable psychiatric symptoms such as anxiety, depression, PTSD, stress, insomnia, somatization, mental and physical exhaustion, addiction and obssessive compulsive symptoms. The prevalence of these symptoms varies from study to another with almost a more notable prevalence of anxiety and depressive symptoms. The following factors that predispose to developing mental distress were noted: being a frontline health worker, having direct contact with infected patients, working in a city with a high infection rate, female sex, isolation, being a suspected case, stigmatization, change of organization, lack of materials, lack of information, lack of communication, lack of support, fear of contamination or of contaminating loved ones, having an organic pathology. Conclusions This notable impact of the pandemic on the mental health of healthcare workers alerts us as colleagues and civil society to the ultimate need for an urgent adequate and up-to-date intervention to alleviate this distress.

Introduction Several studies have mentioned the link between psychotrauma and psychosis. A direct causal link remains to be discussed. Objectives Evaluate the link between sexual abuse and psychosis. Methods We report the case of a male patient who developed schizophrenia following sodomy rape. We performed a literature review based on a PubMed search with the following keywords: “rape sodomy psychosis”. Results Mr. M., 26 years old, with a personal psychiatric history of chronic psychosis evolving for 10 years, consulted us for follow-up of his schizophrenia. When he was 16, the patient was raped by sodomy by a 40-year-old man under stabbing threat. After this incident, the patient did not verbalize this trauma, he isolated himself, became irritable and aggressive and has had olfactory hallucinations. The symptomatology worsened until the age of 24 when the patient presented a delusional syndrome with a theme of persecution, mysticism, bewitchment by a mechanism of interpretation and visual hallucinations. Then,he was hospitalized in psychiatry for psychomotor instability, verbal hetero-aggression. He had been diagnosed with schizophrenia evolving over 9 years. Treatment with an antipsychotic: risperidone and valproic acid was started. The evolution was quickly favorable but the patient currently presents blunted affect, a sexual disinterest and a strong desire for revenge from his rapist. Treatment adjustment and psychotherapy would be considered. Conclusions The onset of subsequent rape psychosis and the persistence of symptoms related to the trauma are arguments in favor of a direct causal link between sexual abuse and schizophrenia. Disclosure No significant relationships.

Introduction Clozapine is the drug of choice for patients with an unsatisfactory response to classic antipsychotic treatment. Little is known about the involvement of clozapine in the development of parotid disease. Objectives Identify the clinical characteristics of Clozapine-induced parotitis through a case and literature review. Methods We report the case of a patient with a refractory schizoaffective disorder, bipolar type and who developed recurrent parotitis while taking clozapine. We conducted a literature review based on a PubMed search of articles published on this subject with the following keywords: ‘parotitis clozapine’. Results Miss W., 34 years old, suffers from a severe schizoaffective disorder that has been diagnosed for several years. She has received various psychotropic medications. She suffered from frequent relapses that required recurrent hospital admissions. One year ago, a diagnosis of treatment-resistant schizoaffective disorder was made. The decision to introduce clozapine, associated with mood stabilizer treatment, was made on the basis of her treatment refractory symptoms. She experienced considerable sialorrhea after beginning clozapine treatment. Miss W. developed bilateral recurrent swelling over both temporal-mandibular areas after 6 months of treatment. It often appears after eating and lasts from 4 to 6 hours. There was no change in white blood cell count and she was afebrile. An otolaryngologist was consulted and a diagnosis of clozapine-induced parotitis was suggested. A spasmolytic and an anticholinergic treatment were prescribed and clozapine was continued. Conclusions This iatrogenic effect of clozapine must be recognized by clinicians in order to be better prevented.

Introduction Lorazepam is a benzodiazepine derivative that is globally used for the therapy of anxiety and insomnia. Objectives The objective of our work was to show that Lorazepam can be a cause of unexpected liver injury even though it is a rare entity. Methods We reported the case of a patient who had a Drug-Induced Liver Injury (DILI) under Lorazepam. We performed a literature review based on a PubMed search with the following keywords: “Lorazepam,DILI”. Results A 20 year-old-Tunisian woman was hospitalized in the psychiatry department of the hospital of Nabeul in Tunisia for a brief psychotic episode.She had a DILI under Olanzapine, Chlorpromazine and Lorazepam, which conducted us to interrupt her treatments except for the Lorazepam(5mg/day). The hepatic tests went back to normal even under Lorazepam. Few days later, the liver enzymes increased again to reach very high levels. Extensive workup was negative for other causes of liver injury, including viral hepatitis A, B, C and E.; capillary electrophoresis of serum proteins was normal; Exhaustive immunological tests were performed searching for auto immune hepatitis(anti-smooth muscle antibodies, anti-LKM1, anti-LC1, anti-SLA/LP) primary biliary cholangitis(anti-mitochondrial antibodies, anti-GP210, anti-sp100) and other antibodies like antinuclear antibodies were negative. Liver biopsy showed polymorphic inflammatory infiltrate including some eosinophilic polynuclear cells and rare vaguely epitheloid macrophages, with necrotico-inflammatory foci in the lobules, all of which were consistent with DILI. Lorazepam was discontinued and within 10 days her liver enzymes decreased and completely normalized. Conclusions Lorazepam, with an unknown action mechanism, can be a cause of DILI. Disclosure No significant relationships.

The economic performance of petroleum products transport companies is dependent on the reliability of their equipment. Ruptures of the weld joints of petroleum products carriage pipelines have major consequences at the human, environmental and economic levels. Weld joints are potential sites of dangerous cracks. The management of reliability of weld joints in pipelines is useful to integrate the quality planning and risks throughout their life cycle and to systematically track their characteristics all along their life cycles. The use in situ of inspection results from non-destructive control techniques is an essential component of evaluation and control of reliability of pipes in their function. It requires calculation methods and tools to assist in the decision-making in support of inspection and repair campaigns. It is in this context that the present study was conducted, which is a contribution to the efforts of methodological assessment of the reliability of petroleum products transport pipelines.

The growing oil demand requires the construction of new pipes of large diameters, to carry large quantities of oil and natural gas to consumers. This has led industrialists to manufacture high resistance steel tubes. On the other hand to increase the capacity of pipelines, it is necessary to increase the operating pressure. Ensuring high reliability of pressure pipes requires a significant increase in pipe wall thickness, and the development of high-quality rolled steels. In this context the choice of pipes for the construction of the oil transporting pipelines require a reliability approach, showing explicitly the dependency between increase in the pipe wall thickness and the pipelines reliability improvement. This issue is the subject of the current study, which is dedicated to the formulation and analysis of the problem, where by the methods of structures reliability and mathematical statistics, one determines quantitative indices of reliability of pipes which are used in comparing different variants in order to select the best solution. Such an approach allows specifying, at the projection and construction stages, the requirements of proper working of hydrocarbons transport pipelines.

Problems of hydrocarbons transporting pipelines aging and rehabilitation are currently a major concern for operators of such installations. Rehabilitating and insuring hydrocarbons transporting pipelines, require interventions, such as the renovation of existing lines, the replacement of some pipelines with new ones, in order to meet the growing demand of consumers and improve the supply reliability. In this context, a decision to repair or replace a section of pipe must combine both a technical analysis of failures and sound economic analysis of the choice of possible interventions, which is the purpose of this study, dedicated to research and policy determination of repair and replacement of aged pipe sections, taking into account the factors mentioned above, and based on significant feedback.

The immunosuppressive treatment of immune-mediated thrombotic thrombocytopenic purpura (iTTP) in patients with intolerance or refractoriness to the B-cell depleting monoclonal antibody rituximab remains debated. Daratumumab, a plasma cell-directed monoclonal antibody targeting CD38, represents a therapeutic option, but data are scarce. The French Thrombotic Microangiopathies Reference Center conducted a nationwide survey on iTTP patients treated with daratumumab. Nine episodes from seven patients were identified. Treatment was administered for A Disintegrin And Metalloproteinase with ThromboSpondin-1 motifs, 13th member (ADAMTS13) relapses while patients were otherwise in clinical response (N = 8), or during the acute phase of the disease following rituximab intolerance (N = 1). Patients have received a median of three previous therapeutic lines. ADAMTS13 activity improved in eight cases following daratumumab administration, including three cases where ADAMTS13 normalized. ADAMTS13 relapses occurred in three patients; in two cases, retreatment with daratumumab was successful. Median ADAMTS13 relapse-free survival was not reached; 12-month ADAMTS13 relapse-free survival was 56%. Daratumumab-related adverse events occurred in five cases and were non-severe infusion-related reactions in all cases. These results suggest that daratumumab may be an effective treatment option for iTTP patients with intolerance or refractoriness to rituximab., (© 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Prior studies have suggested that immune thrombotic thrombocytopenic purpura (iTTP) may display seasonal variation; however, methodologic limitations and sample sizes have diminished the ability to perform a rigorous assessment. This 5-year retrospective study assessed the epidemiology of iTTP and determined whether it displays a seasonal pattern. Patients with both initial and relapsed iTTP (defined as a disintegrin and metalloprotease with thrombospondin type motifs 13 activity <10%) from 24 tertiary centers in Australia, Canada, France, Greece, Italy, Spain, and the US were included. Seasons were defined as: Northern Hemisphere-winter (December-February); spring (March-May); summer (June-August); autumn (September-November) and Southern Hemisphere-winter (June-August); spring (September-November); summer (December-February); autumn (March-May). Additional outcomes included the mean temperature in months with and without an iTTP episode at each site. A total of 583 patients experienced 719 iTTP episodes. The observed proportion of iTTP episodes during the winter was significantly greater than expected if equally distributed across seasons (28.5%, 205/719, 25.3%-31.9%; p = .03). Distance from the equator and mean temperature deviation both positively correlated with the proportion of iTTP episodes during winter. Acute iTTP episodes were associated with the winter season and colder temperatures, with a second peak during summer. Occurrence during winter was most pronounced at sites further from the equator and/or with greater annual temperature deviations. Understanding the etiologies underlying seasonal patterns of disease may assist in discovery and development of future preventative therapies and inform models for resource utilization., (© 2024 The Author(s). American Journal of Hematology published by Wiley Periodicals LLC.)

Objectives: The association between immune-mediated thrombotic thrombocytopenic purpura (iTTP) and Sjögren disease (SjD) has been poorly investigated. This study presents the first retrospective cohort of iTTP-SjD aiming to identify risk factors for iTTP occurrence in SjD patients and examine their clinical course., Methods: Patients with iTTP-SjD were identified within the French TTP Registry based on American College of Rheumatology/European League Against Rheumatism 2016 criteria. A comparative analysis was conducted with two control groups comprising primary SjD (pSjD) patients from the French ASSESS cohort and idiopathic iTTP patients from the French TTP Registry. Demographic, clinical and biological data were retrospectively collected., Results: Thirty iTTP-SjD patients were included and compared with 65 pSjD and 45 idiopathic iTTP patients. The majority of iTTP-SjD patients (n=18) were diagnosed with SjD at the time of iTTP diagnosis. In comparison with the pSjD cohort, iTTP-SjD patients were diagnosed with SjD at a younger age (p=0.039) and showed a higher prevalence of anti-SjS-related antigen A antibody positivity and xerostomia (p=0.015, p=0.035, respectively). EULAR Sjogren's Syndrome Disease Activity Index showed similar activity levels between the two groups. iTTP-SjD patients were treated with plasma exchange (n=28), corticosteroids, rituximab (n=19) and caplacizumab (n=3). In comparison with the idiopathic iTTP cohort, mortality rates (log-rank tests, p=0.228), biological and clinical iTTP relapses (multivariate analysis, p=0.181) were comparable and short-term outcomes (survival at day 30, relapse) were favourable., Conclusion: iTTP can be a rare complication in patients with SjD. Further studies involving larger cohorts and long-term follow-up are warranted to confirm these findings and to explore the efficacy of immunomodulators and caplacizumab in iTTP-SjD patients., Competing Interests: Competing interests: GN received speaker fees from Novartis, Amgen, Galapagos and BMS. AV is a member of the French advisory boards for Sanofi and Takeda and received speaker fees from Sanofi, Octapharma, LFB-Biomédicaments and Takeda. XM received fees from BMS, Galapagos, GSK, Novartis and Pfizer. PC is a member of advisory boards and received speaker fees from Sanofi, Alexion, Octapharma and Takeda. IB received speaker fees from Galapagos. BSJ received speaker fees from Sanofi, Takeda and LFB-Biomédicaments. JL, LG and RB declare no conflicts of interest., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The COVID-19 pandemic related to SARS-CoV-2 virus was responsible for global pandemic. The severe form of the disease was linked to excessive activation of immune pathways together with a systemic cytokine storm response and thrombotic venous or arterial complications. Factors predicting severe outcomes including venous and/or pulmonary thrombosis (VT) and death were identified, but the prognostic role of their combination was not addressed extensively., Objectives: We investigated the role of prognostic factors from the coagulation or inflammatory pathways to better understand the outcome of the disease., Methods: For this, we prospectively studied 167 SARS-CoV-2-positive patients from admission in intensive care units (ICU) or emergency departments from four academic hospitals over a 14-month period. Besides standard biology, we assessed serum concentrations of inflammatory markers, coagulation factors and peripheral blood cells immunophenotyping., Results: Thirty-nine patients (23.3%) developed VT and 30 patients (18%) died. By univariate analysis, C-reactive protein (CRP) level > 150 mg/L, interleukin-6 (IL-6) ≥ 20 pg/mL, D-dimers > 1,500 μg/L, ADAMTS13 activity ≤ 50%, Von., Conclusion: A combination of coagulation and inflammatory markers can refine the prognostication of severe outcome in COVID-19, and could be useful for the initial evaluation of other types of viral infection., Competing Interests: PC was member of the Clinical Advisory Board for Alexion, Sanofi, Takeda, and Janssen. AV had participated to Advisory boards for Sanofi. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhu, Bouzid, Travert, Géri, Cohen, Picod, Heming, Rottman, Joly-Laffargue, Veyradier, Capron and Coppo.)

Background: The immune form of thrombotic thrombocytopenic purpura (iTTP) and the hemolytic and uremic syndrome (HUS) are two major forms of thrombotic microangiopathy (TMA). Their treatment has been recently greatly improved. In this new era, both the prevalence and predictors of cerebral lesions occurring during the acute phase of these severe conditions remain poorly known., Aim: The prevalence and predictors of cerebral lesions appearing during the acute phase of iTTP and Shiga toxin-producing Escherichia coli-HUS or atypical HUS were evaluated in a prospective multicenter study., Methods: Univariate analysis was performed to report the main differences between patients with iTTP and those with HUS or between patients with acute cerebral lesions and the others. Multivariable logistic regression analysis was used to identify the potential predictors of these lesions., Results: Among 73 TMA cases (mean age 46.9 ± 16 years (range 21-87 years) with iTTP (n = 57) or HUS (n = 16), one-third presented with acute ischemic cerebral lesions on magnetic resonance imagery (MRI); two individuals also had hemorrhagic lesions. One in ten patients had acute ischemic lesions without any neurological symptom. The neurological manifestations did not differ between iTTP and HUS. In multivariable analysis, three factors predicted the occurrence of acute ischemic lesions on cerebral MRI: (1) the presence of old infarcts on cerebral MRI, (2) the level of blood pulse pressure, (3) the diagnosis of iTTP., Conclusion: At the acute phase of iTTP or HUS, both symptomatic and covert ischemic lesions are detected in one third of cases on MRI. Diagnosis of iTTP and the presence of old infarcts on MRI are associated with the occurrence of such acute lesions as well as increased blood pulse pressure, that may represent a potential target to further improve the therapeutic management of these conditions., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Introduction: Therapeutic vaccination based on synthetic long peptides (SLP ® ) containing both CD4+ and CD8+ T cell epitopes is a promising treatment strategy for chronic hepatitis B infection (cHBV)., Methods: We designed SLPs for three HBV proteins, HBcAg and the non-secreted proteins polymerase and X, and investigated their ability to induce T cell responses ex vivo . A set of 17 SLPs was constructed based on viral protein conservation, functionality, predicted and validated binders for prevalent human leukocyte antigen (HLA) supertypes, validated HLA I epitopes, and chemical producibility., Results: All 17 SLPs were capable of inducing interferon gamma (IFNɣ) production in samples from four or more donors that had resolved an HBV infection in the past (resolver). Further analysis of the best performing SLPs demonstrated activation of both CD8+ and CD4+ multi-functional T cells in one or more resolver and patient sample(s). When investigating which SLP could activate HBV-specific T cells, the responses could be traced back to different peptides for each patient or resolver., Discussion: This indicates that a large population of subjects with different HLA types can be covered by selecting a suitable mix of SLPs for therapeutic vaccine design. In conclusion, we designed a set of SLPs capable of inducing multifunctional CD8+ and CD4+ T cells ex vivo that create important components for a novel therapeutic vaccine to cure cHBV., Competing Interests: Author CM, WK, AW and KK were employed by the company ISA Pharmacuticals B.V. SB, DJ, MB, AW, WK and CM are listed as inventors on a patent application related to the work in this manuscript on novel long peptide antigens for treatment of hepatitis B related disease, filled by ISA Pharmaceuticals B.V. CM and WK have a stock appreciation right in the issued share capital of ISA Pharmaceuticals B.V. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declare that this study received funding from ISA Pharmaceuticals B.V. The funder had the following involvement in the study: study concept and design, analysis and interpretation of data, critical revision of the manuscript for important intellectual content, statistical analysis, obtained funding., (Copyright © 2023 Jansen, de Beijer, Luijten, Kwappenberg, Wiekmeijer, Kessler, Pieterman, Bouzid, Krebber, de Man, Melief and Buschow.)

Toxoplasmosis is a zoonotic disease, caused by the protozoan Toxoplasma gondii , affecting most warm-blooded animals. Assessing the seroprevalence of T. gondii in different animal species gives a good estimate of the global circulation of the parasite and the risk for human infections. However, the seroprevalence of T. gondii in dogs is not studied as much as other species, despite their close contact with wildlife and humans in rural or urban environments and evidence that dogs can also be a potential source for human contaminations. A commercial enzyme-inked immunosorbent assay (ELISA) kit to detect anti- T. gondii antibodies in sera of hunting dogs potentially naturally infected, was compared to the modified agglutination test (MAT), used as the reference method. The ELISA presented a sensitivity of 76.5% (CI 95%: 60.0-87.6) and a specificity of 87.7% (CI 95%: 76.7-93.9) and a substantial agreement with the MAT for the detection of canine anti- T. gondii antibodies. Both tests can therefore be used widely for epidemiology studies on T. gondii infections in dogs. With a mean seroprevalence of T. gondii infection in hunting dogs from northern Algeria of 36.8% (CI 95%: 34.9-38.7), this study also highlights the importance of T. gondii seroprevalence studies in companion animals to assess infectious risk for human populations.

Terminal T-cell exhaustion poses a significant barrier to effective anticancer immunotherapy efficacy, with current drugs aimed at reversing exhaustion being limited. Recent investigations into the molecular drivers of T-cell exhaustion have led to the identification of chronic IL2 receptor (IL2R)-STAT5 pathway signaling in mediating T-cell exhaustion. We targeted the key downstream IL2R-intermediate JAK 3 using a clinically relevant highly specific JAK3-inhibitor (JAK3i; PF-06651600) that potently inhibited STAT5-phosphorylation in vitro. Whereas pulsed high-dose JAK3i administration inhibited antitumor T-cell effector function, low-dose chronic JAK3i significantly improved T-cell responses and decreased tumor load in mouse models of solid cancer. Low-dose JAK3i combined with cellular and peptide vaccine strategies further decreased tumor load compared with both monotherapies alone. Collectively, these results identify JAK3 as a novel and promising target for combination immunotherapy., (©2022 American Association for Cancer Research.)

Background & Aims: Antigen-specific immunotherapy is a promising strategy to treat HBV infection and hepatocellular carcinoma (HCC). To facilitate killing of malignant and/or infected hepatocytes, it is vital to know which T cell targets are presented by human leucocyte antigen (HLA)-I complexes on patient-derived hepatocytes. Here, we aimed to reveal the hepatocyte-specific HLA-I peptidome with emphasis on peptides derived from HBV proteins and tumour-associated antigens (TAA) to guide development of antigen-specific immunotherapy., Methods: Primary human hepatocytes were isolated with high purity from (HBV-infected) non-tumour and HCC tissues using a newly designed perfusion-free procedure. Hepatocyte-derived HLA-bound peptides were identified by unbiased mass spectrometry (MS), after which source proteins were subjected to Gene Ontology and pathway analysis. HBV antigen and TAA-derived HLA peptides were searched for using targeted MS, and a selection of peptides was tested for immunogenicity., Results: Using unbiased data-dependent acquisition (DDA), we acquired a high-quality HLA-I peptidome of 2 × 10 5 peptides that contained 8 HBV-derived peptides and 14 peptides from 8 known HCC-associated TAA that were exclusive to tumours. Of these, 3 HBV- and 12 TAA-derived HLA peptides were detected by targeted MS in the sample they were originally identified in by DDA. Moreover, 2 HBV- and 2 TAA-derived HLA peptides were detected in samples in which no identification was made using unbiased MS. Finally, immunogenicity was demonstrated for 5 HBV-derived and 3 TAA-derived peptides., Conclusions: We present a first HLA-I immunopeptidome of isolated primary human hepatocytes, devoid of immune cells. Identified HBV-derived and TAA-derived peptides directly aid development of antigen-specific immunotherapy for chronic HBV infection and HCC. The described methodology can also be applied to personalise immunotherapeutic treatment of liver diseases in general., Lay Summary: Immunotherapy that aims to induce immune responses against a virus or tumour is a promising novel treatment option to treat chronic HBV infection and liver cancer. For the design of successful therapy, it is essential to know which fragments ( i.e. peptides) of virus-derived and tumour-specific proteins are presented to the T cells of the immune system by diseased liver cells and are thus good targets for immunotherapy. Here, we have isolated liver cells from patients who have chronic HBV infection and/or liver cancer, analysed what peptides are presented by these cells, and assessed which peptides are able to drive immune responses., Competing Interests: SIB collaborates with and receives co-funding from ISA Pharmaceuticals B.V., Leiden, the Netherlands. SIB and MTAdB are listed as inventors on a patent application filled by ISA Pharmaceuticals B.V. The authors declare no further conflicts of interest. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2022 The Author(s).)

The therapeutic landscape of thrombotic thrombocytopenic purpura (TTP) is rapidly changing with the recent availability of new targeted therapies. This progressive shift from empiricism to pathophysiology-based treatments reflects an intensive interaction between the continuous findings in the field of basic science and an efficient collaborative clinical research and represents a convincing example of the strength of translational medicine. Despite the rarity of TTP, national and international efforts could circumvent this limitation and shed light on the epidemiology, clinical presentation, prognosis, and long-term outcome of this disease. Importantly, they also provided high-quality results and practice changing studies for the benefit of patients. We report here the most recent therapeutic findings that allowed progressively improving the prognostic of TTP, both at the acute phase and through long-term outcome., Competing Interests: GB, SF and AP have no competing interest. AV is a member of the advisory board for Sanofi-Genzyme. PC is a member of the advisory board for Alexion, Octapharma, Shire, and Sanofi-Genzyme., (Thieme. All rights reserved.)

Immunopeptidomics is used to identify novel epitopes for (therapeutic) vaccination strategies in cancer and infectious disease. Various false discovery rates (FDRs) are applied in the field when converting liquid chromatography-tandem mass spectrometry (LC-MS/MS) spectra to peptides. Subsequently, large efforts have recently been made to rescue peptides of lower confidence. However, it remains unclear what the overall relation is between the FDR threshold and the percentage of obtained HLA-binders. We here directly evaluated the effect of varying FDR thresholds on the resulting immunopeptidomes of HLA-eluates from human cancer cell lines and primary hepatocyte isolates using HLA-binding algorithms. Additional peptides obtained using less stringent FDR-thresholds, although generally derived from poorer spectra, still contained a high amount of HLA-binders and confirmed recently developed tools that tap into this pool of otherwise ignored peptides. Most of these peptides were identified with improved confidence when cell input was increased, supporting the validity and potential of these identifications. Altogether, our data suggest that increasing the FDR threshold for peptide identification in conjunction with data filtering by HLA-binding prediction, is a valid and highly potent method to more efficient exhaustion of immunopeptidome datasets for epitope discovery and reveals the extent of peptides to be rescued by recently developed algorithms.

Trypanosoma evansi (T. evansi) is a flagellated parasite with worldwide distribution, mainly affecting camels, horses, dogs, buffaloes and wild animals. Trypanosomosis caused by T. evansi, known as surra, is a vector borne disease that affects the health and productivity of camels. The aim of our study was to assess the prevalence of trypanosomosis due to T. evansi in camels by the immune trypanolosis test and to identify associated risk factors. Our cross-sectional study was performed on 161 camels from Ghardaïa district, southern Algeria. A structured questionnaire was used to collect data on individual characteristics (age, gender and breed) husbandry management (herd size and activity of animals) and health conditions (history of abortion and clinical symptoms). The immune trypanolysis test revealed an overall seroprevalence of 9.3% (CI 95%, 5.9-14.9). Possible factors associated with T. evansi infection were analysed by univariate and multivariate logistic regression. The results showed that risk factors for camels were history of symptoms (P = 0.002, OR = 21.91, CI95% = 3.48-169.80), racing activities (P = 0.003, OR = 0.01, CI95% = 0.001-0.18) and small herd size (P = 0.013, OR = 8.22, CI95% = 1.64-49.75). In conclusion, this study showed that T. evansi is endemic in camels of Ghardaïa district. To reduce dissemination of the disease to non-endemic areas, it is recommended to minimise risk factors associated with the infection., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Survival of gastrointestinal cancer remains dismal, especially for metastasized disease. For various cancers, especially melanoma and lung cancer, immunotherapy has been proven to confer survival benefits, but results for gastrointestinal cancer have been disappointing. Hence, there is substantial interest in exploring the usefulness of adaptive immune system education with respect to anti-cancer responses though vaccination. Encouragingly, even fairly non-specific approaches to vaccination and immune system stimulation, involving for instance influenza vaccines, have shown promising results, eliciting hopes that selection of specific antigens for vaccination may prove useful for at least a subset of gastrointestinal cancers. It is widely recognized that immune recognition and initiation of responses are hampered by a lack of T cell help, or by suppressive cancer-associated factors. In this review we will discuss the hurdles that limit efficacy of conventional cancer therapeutic vaccination methods (e.g., peptide vaccines, dendritic cell vaccination). In addition, we will outline other forms of treatment (e.g., radiotherapy, chemotherapy, oncolytic viruses) that also cause the release of antigens through immunogenic tumor cell death and can thus be considered unconventional vaccination methods (i.e., in situ vaccination). Finally, we focus on the potential additive value that vaccination strategies may have for improving the effect immunotherapy. Overall, a picture will emerge that although the field has made substantial progress, successful immunotherapy through the combination with cancer antigen vaccination, including that for gastrointestinal cancers, is still in its infancy, prompting further intensification of the research effort in this respect.

Mesenchymal stromal cells (MSC) are a promising therapy for immunological disorders. However, culture expanded MSC are large and get trapped in the capillary networks of the lungs after intravenous infusion, where they have a short survival time. Hypothetically, living cells are a risk for tumor formation. To reduce risks associated with MSC infusion and improve the distribution in the body, we generated membrane particles (MP) of MSC and MSC stimulated with IFN-γ (MPγ). Tracking analysis and electron microscopy indicated that the average size of MP was 120 nm, and they showed a round shape. MP exhibited ATPase, nucleotidase and esterase activity, indicating they are enzymatically active. MP and MPγ did not physically interact with T cells and had no effect on CD4 + and CD8 + T cells proliferation. However, MP and MPγ selectively bound to monocytes and decreased the frequency of pro-inflammatory CD14 + CD16 + monocytes by induction of selective apoptosis. MP and MPγ increased the percentage of CD90 positive monocytes, and MPγ but not MP increased the percentage of anti-inflammatory PD-L1 monocytes. MPγ increased mRNA expression of PD-L1 in monocytes. These data demonstrate that MP have immunomodulatory properties and have potential as a novel cell-free therapy for treatment of immunological disorders.

Introduction: Transcultural studies suggest that the social outcome of schizophrenia might be better in developing countries than in industrialized ones. This study aims to check this hypothesis and attempted to identify prognostic indicators of schizophrenia among Tunisian patients., Methods: This study included all the outpatients responding to DSM IV criteria of schizophrenia for at least five years, during the study period. The assessment tools were: an interview with the patients and their families, data from medical records and the Global Assessment of Functioning scale (GAF) applied for the premorbid period, at two years after onset, at five years, and during the interview (current assessment). The social outcome was assessed by marital and labour market status, social network, sexuality and the GAF score. The outcome was considered to be good, if the current GAF >60, intermediate if GAF was between 31 and 60 and severe if GAF

Clinical symptoms of bipolar disorders onset act as a prognostic risk-factor. Discrepancies of data are related with geographical or cultural conditions. Within a patient population of bipolar (ICD 10) in and out patients of a psychiatric department, manic or hypomanic disorders initiate the space disease in 33% of the cases theses features are similar within the western psychiatric population. In a maghrebian population this proportion reaches 50%. A percentage of 65% of bipolar 1 patients was found within our sample. Sex ratio is 1 for bipolar 1, when, for bipolar 2 disorders sex-ratio was superior to 1, in favor of females. Mean age of the first episode of the disease was younger for patients with a familial history of the disease.

Epidemiological research concerning the seasons of births of schizophrenics show for the greatest part that there's an excess of births in winter and in the beginning of spring. Research about the environmental theories of schizophrenia suggest that there would exist one or many seasonal environmental factors affecting the foetus and the neonate, and which would be likely to increase the risk of a subsequent development of schizophrenia. As no research concerning this subject have been published so far in Africa, the writers propose to study the distribution of births of a population of schizophrenics born in Tunisia in comparison to the general population and to compare it to a group of patients hospitalized because of major affective disorders. The results achieved show a significant decrease in the number of schizophrenics births during the third trimester and an excess of births during the month of october, the risk being greater in the case of disorganized schizophrenia. The greater risk for people born in october to develop subsequently schizophrenia is not found in the case of major affective disorders but it is found rather in the case of schizo-affective disorders. More over, we notice a decrease in the number of births during the month of July for the patients presenting major affective disorders and for those presenting schizo-affective disorders. Results seem to demonstrate that there would exist seasonal environmental factors specific to North Africa which are likely to affect the subsequent appearance of schizophrenic disorders. A particular interest should be given to viral infectious to enteroviruses which are responsible for summer diarrhea in Tunisia.(ABSTRACT TRUNCATED AT 250 WORDS)