Improving the quality of care and patient safety in oncology, the contribution of simulation-based training: A scoping review.

Objective: Simulation-based training (SBT) is an effective educational method widely used in many clinical settings, including oncology. This study aimed to undertake a scoping review of research related to SBT in oncology to provide a comprehensive understanding of the role of SBT in enhancing the skills of healthcare professionals and thereby improving the quality of care and patient safety in oncology. Methods: We conducted a scoping review to map published studies in Medline, Scopus, and Web of Science databases. Peer-reviewed articles about data on the role of SBT in improving and enhancing the skills of healthcare professionals in oncology published in English and French from 2012 to 2022 were retrieved. Two researchers screened, extracted, and analyzed all identified studies independently. Results: Of the 1,013 publications identified in the initial phase, 29 studies were included in the analysis. Twenty-five of these studies focused on non-technical skills, such as decision-making, communication, teamwork, and cognitive abilities. Thirteen studies focused on technical skills. The results of all included studies showed significant improvement in the skills of oncology healthcare professionals through SBT programs. Fourteen studies subjectively assessed the role of this educational tool, while nine objectively evaluated it. Six studies used a combined subjective and objective evaluation method. Conclusions: SBT is a very effective tool for improving the skills of healthcare professionals in oncology. Supporting and promoting SBT is essential to providing high-quality care and ensuring patient safety in all areas of health care.

Persistent organic pollutant exposure as a risk factor of gestational diabetes mellitus: A systematic review and meta-analysis.

BACKGROUND: Findings related to the association between persistent organic pollutants (POPs) and gestational diabetes mellitus (GDM) are inconclusive. OBJECTIVES: To estimate the strength of the association between POP exposure and GDM in a systematic review with meta-analysis. SEARCH STRATEGY: MEDLINE, Scopus and Web of Science were searched until July 2023. SELECTION CRITERIA: Cohort and case-control studies analysing the association between POPs and GDM. DATA COLLECTION AND ANALYSIS: We assessed the risk of bias using the Quality in Prognosis Studies scale (QUIPS). Standardised mean differences were pooled using random-effect models. MAIN RESULTS: Sixteen articles including 12 216 participants were selected. The risk of bias was high in four articles (25%), moderate in 11 (68.75%) and low in one (6.25%). Small mean difference between GDM cases and controls was observed for PFHpA (0.26, 95% confidence interval [CI] 0.1-0.35, I2 = 0.0%), PCB180 (0.37, 95% CI 0.19-0.56; I2 = 25.3%), BDE47 (0.23, 95% CI 0.0-0.45, I2 = 0%), BDE99 (0.36, 95% CI 0.14-0.59; I2 = 0%), BDE100 (0.42, 95% CI 0.19-0.64; I2 = 0%) and HCB (0.22, 95% CI 0.01-0.42, I2 = 39.6%). No considerable difference was observed for the rest of POPs. CONCLUSION: Small mean differences between GDM cases and controls were observed for some POPs. However, evidence shows mostly moderate quality and results were heterogeneous. Improved research methodology is needed to assess POPs and GDM risk.

Replacement of watching television with physical activity and the change in gestational diabetes mellitus risk: A case-control study.

OBJECTIVE: To evaluate the effect of replacing 1 h/week of watching television with 1 h/week of light to moderate (LMPA) or vigorous physical activity (VPA) before and during pregnancy on the risk of gestational diabetes mellitus (GDM). METHODS: A case-control study was conducted in pregnant women. Physical activity and television watching before and during pregnancy were assessed using the Paffenbarger Physical Activity Questionnaire. Each type of activity was classified according to intensity (metabolic equivalent of task; MET): less than 6 METs is LMPA, 6 METs or more is VPA. The duration of physical activity and watching television was calculated, and logistic regression models were used to estimate adjusted odds ratios (aOR) and 95% confidence intervals for their association with GDM risk. The isotemporal substitution model was used to calculate the effect of replacing 1 h/week of watching television with the same duration of physical activity. RESULTS: The GDM cases (n = 290) spent less time performing VPA than controls without GDM (n = 1175) and more time watching television during pregnancy (P < 0.05). During pregnancy, the risk of GDM increased for each hour of watching television (aOR = 1.02; 95% confidence interval 1.00-1.03). Women who spent more time watching television during pregnancy were likely to develop GDM (aOR>14 h/week vs. 0-6 h/week = 2.03; 95% confidence interval 1.35-3.08). Replacing 1 h/week of watching television with 1 h/week of VPA during pregnancy could decrease the chance of developing GDM (aOR = 0.66; 95% confidence interval 0.43-1.00). CONCLUSIONS: A simple change of 1 h/week of watching television for 1 h/week of VPA in pregnant women may reduce the risk of GDM considerably.

Shining a Light on Prostate Cancer: Photodynamic Therapy and Combination Approaches.

Prostate cancer is a major health concern worldwide, and current treatments, such as surgery, radiation therapy, and chemotherapy, are associated with significant side effects and limitations. Photodynamic therapy (PDT) is a promising alternative that has the potential to provide a minimally invasive and highly targeted approach to treating prostate cancer. PDT involves the use of photosensitizers (PSs) that are activated by light to produce reactive oxygen species (ROS), which can induce tumor cell death. There are two main types of PSs: synthetic and natural. Synthetic PSs are classified into four generations based on their structural and photophysical properties, while natural PSs are derived from plant and bacterial sources. Combining PDT with other therapies, such as photothermal therapy (PTT), photoimmunotherapy (PIT), and chemotherapy (CT), is also being explored as a way to improve its efficacy. This review provides an overview of conventional treatments for prostate cancer, the underlying principles of PDT, and the different types of PSs used in PDT as well as ongoing clinical studies. It also discusses the various forms of combination therapy being explored in the context of PDT for prostate cancer, as well as the challenges and opportunities associated with this approach. Overall, PDT has the potential to provide a more effective and less invasive treatment option for prostate cancer, and ongoing research is aimed at improving its selectivity and efficacy in clinical settings.

Health-related quality of life during three trimesters of pregnancy in Morocco: cross-sectional pilot study.

Background: Pregnancy is universally considered a normal physiological process. However, it has a considerable impact on the quality of mothers' lives. This study piloted the use of the generic EuroQoL-5 Dimensions-5 Levels (EQ-5D-5L) descriptive system and the EuroQol Visual Analogue Scale (EQ-VAS) questionnaire, to assess the health-related quality of life (HRQoL) during pregnancy and its associated factors. Methods: In this cross-sectional pilot study carried out from August to December 2019 we assessed the HRQoL and its associated factors among Moroccan pregnant women who received prenatal care at Settat's health centers. The collected data from 270 pregnant women were compared to a dataset of 289 non-pregnant women using the EQ-5D-5L instrument and socioeconomic and obstetrical questionnaires. A multiple linear regression model was used to identify associated factors. The HRQoL comparison was made using the improved RIDIT approach, which allows estimating the Absolute Risk Increase (ARI) of problems related to mobility, usual activities, and self-care and the ARI of pain/discomfort and anxiety/depression (i.e. an ARI = 10% in mobility means that pregnancy increases problems in this health dimension by 10%). Findings: A total of 559 women were included in our study. Our results showed that the HRQoL in pregnant women was significantly lower than in non-pregnant women (EQ-5D index score = 0.71 ± 0.24 vs 0.79 ± 0.29; p < 0.0001). Similarly, the pregnancy reduced the EQ-VAS score (mean difference = -7.8 ± 17.21; p < 0.0001). The pregnancy increased the problems in mobility (ARI = 9.7% [1.7-17.6], p = 0.02), in self-care (ARI = 8% [2-14], p = 0.01), and in usual activities (ARI = 27.3% [18.9-35.7], p < 0.0001). Also, the pregnancy increased pain/discomfort (ARI = 26.5% [18-35.1], p < 0.0001) and anxiety/depression (ARI = 12% [3.2-20.9], p = 0.0112). The rural pregnant women had the worst HRQoL (EQ-5D index score = 0.57) compared to their urban peers (EQ-5D index score = 0.77). Likewise, women in the third trimester and nulliparous had the worst HRQoL (EQ-5D index score = 0.64 and 0.84 respectively). Interpretation: The results highlighted that place of residence, parity, and gestational age are strongly associated with pregnant's HRQoL. The five EQ-5D-5L dimensions were affected during pregnancy. Consequently, there is a need to develop specific programs to monitor the HRQoL during pregnancy in order to ensure better maternal health care. Funding: This study was funded by University Hassan First's own fund [grant number FP/01/2018].

Lifestyle Habits Determinants of Health-Related Quality of Life in Moroccan College Students.

The transition to university is a critical period during which considerable life changes arise. Useful national data to design tailored interventions aimed at promoting health-related quality of life (HRQoL) among Moroccan students are lacking. The present study is aimed at filling this gap by investigating the levels and associated factors of HRQoL among a national sample of Moroccan university students. HRQoL was assessed using the EQ-5D-5L instrument. Data from 2759 university students were collected in a large, cross-sectional, web-based survey. All statistical analyses were conducted using the R software. The EQ-5D-5L findings showed that the majority of students rated level 1 (no problems) and level 2 (slight problems) for the "Mobility", "Self-Care", "Usual Activities", and "Pain/Discomfort" HRQoL dimensions. However, the "Anxiety/Depression" dimension was the exception; more than half (57.1%) of the students were slightly to extremely anxious or depressed. The levels of lifestyle habits were of concern among participants of this study. With respect to sedentary behaviors and physical activity, we found that approximately 80% of participants spent ≥2 h/day on different screen-based sedentary behaviors, and 60% were physically inactive. Lifestyle habits that were found to be associated with HRQoL are sleeping time, physical activity, leisure, hygiene, household activities, homework, and social media time. The multiple regression model explained 93% of the EQ-VAS score variance. The findings could be of great importance for researchers and policymakers interested in promoting health of university students.

Modern drug self-medication and associated factors among pregnant women at Settat city, Morocco.

Purpose: The consumption of drugs during pregnancy without medical advice constitutes a risk for the mother and the fetus. It is a public health problem. This study aimed to assess self-medication practices among pregnant women, the most used medicines, and factors associated with this practice. Methods: A cross-sectional study was conducted using a structured questionnaire on pregnant women who were attending Settat health centers. A simple random sampling technique was used to select the study participants. Descriptive and inferential statistics were computed using the SPSS version 19. Results: Among 364 pregnant women, 118 (32%) practiced self-medication in modern medicine. Paracetamol was the most used medication, and nausea and vomiting were the most frequent symptoms reported by self-medicated pregnant women. Multivariate logistic regression analysis showed that women over 30 years old were four-fold more likely to practice self-medication than the other groups [AOR: 4.19; 95% CI (1.80-9.77)]. Similarly, unemployed women [AOR: 3.93; 95% CI (0.80-19.23)], those in third trimester [AOR: 2.63; 95% CI (1.29-5.36)], multiparous [AOR: 6.03; 95% CI (3.12-11.65)], without chronic illness [AOR: 2.84; 95% CI (1.26-6.41)], without therapeutic treatment [AOR: 10.1; 95% CI (2.81-37.03)] and who have attended ANC at least once, were more likely to practice self-medication than the other groups. Conclusion: The prevalence of modern drug self-medication among pregnant women in Morocco is classified as lower. Health professionals can exert positive pressure through education and information provided during ANC about OTC medications to significantly reduce the rate of self-medication.

Post-COVID-19 mental health and its associated factors at 3-months after discharge: A case-control study.

Background: Mental health disorders are among the most significant sequelae of the COVID-19 pandemic. Therefore, the aim of this study is to investigate the mental health status and associated risk factors of Moroccan COVID-19 survivors 3 months after hospital discharge. Methods: A case-control study was conducted from September 2021 to February 2022 on 824 participants. 213 were COVID-19 survivors and 611 were control group. Data were collected ether through an online anonymous survey. Anxiety and depression disorders were assessed using Hospital Anxiety and Depression Scale (HADS). Results: The average age of all participants was 55.17 ±â€¯16.44. Our findings highlighted higher prevalence of mental health disorders including anxiety and depression in COVID-19 survivors at 3 months after hospital discharge (HADS-A = 12.84; HADS-D = 10.91) compared to control group (HADS-A = 9.90; HADS-D = 8.27) (p < 0.001). Older patients, suffering from type 2 diabetes and kidney diseases, admitted to ICU, who stayed a long duration in the hospital, who had severe and longer duration of symptoms and who used Chloroquine, had higher levels of anxiety and depression after discharge. Conclusions: The present investigation highlights the need to develop a post-COVID-19 rehabilitation programs that can better manage the post COVID-19 impact and restore a good mental health for COVID-19 survivors. Also, to create preventative strategies to limit mental health disorders in COVID-19 survivors.

Quality of Life During Pregnancy from 2011 to 2021: Systematic Review.

Purpose: Health-related quality of life (HRQoL) has emerged as a key concern in patient care. It has become one of the major objectives of clinical trials. Our study aims to describe the quality of life (QoL) during uncomplicated pregnancy and to assess its associated factors. Patients and Methods: The search of articles was carried out using the online database of PUBMED and Web of Science with a limit of time between 2011 and 2021. Data were retrieved by two independent reviewers. Results: 721 publications responding to keywords were identified, of which 73 articles on the topic were selected. The main countries that have published on this subject are Australia (n = 10) and China (n = 7). Twenty-three articles deal with QoL for pathological pregnancies. All the pathologies studied have a negative impact on the HRQoL of pregnant women, and its improvement depends on the type of treatment. Obesity, low back, and pelvic girdle pain, and hyperemesis gravidarum were the frequent pathologies during pregnancy. Socio-demographic characteristics related to improved well-being (favorable economic status, social support). Similarly, better sleep quality and moderate physical exercise were linked to an increased QoL. Physical and psychological factors were associated with a lower QoL. Conclusion: The HRQoL refers to patients' subjective evaluation of physical, mental, and social components of well-being. Optimizing the QoL during pregnancy necessitates a deeper understanding of their issues as well as counseling which provides support wherever needed.

Health-Related Quality of Life of Moroccan COVID-19 Survivors: A Case-Control Study.

Background: Research on COVID-19 has mostly focused on transmission, mortality and morbidity associated with the virus. However, less attention has been given to its impact on health-related quality of life (HRQoL) of patients with COVID-19. Therefore, this study aimed to determine the demographic and clinical risk factors associated with COVID-19 and evaluate its impact on the HRQoL of COVID-19 survivors. Methods: A case-control study was carried out between September 2021 and March 2022 on 1105 participants. A total of 354 were COVID-19 survivors and 751 were the control group. The HRQoL was assessed using both EQ-5D-5L and SF-6D generic instruments. Results: The average age of all participants was 56.17 ± 15.46. Older age, urban area, tobacco use, presence of chronic diseases especially type 1 diabetes, kidney and cardiovascular diseases were significantly associated with COVID-19. The COVID-19 survivors had significantly lower HRQoL (EQ-VAS = 50.89) compared to the control group (EQ-VAS = 63.36) (p-value < 0.0001). Pain/ discomfort and anxiety/depression were the most negatively affected by COVID-19 (p-value < 0.0001). Conclusions: The findings from this study could help healthcare professionals and policy makers to better understand the HRQoL sequelae among the COVID-19 survivors and contribute to develop tailored interventions.

Preventing Gestational Diabetes Mellitus by Improving Healthy Diet and/or Physical Activity during Pregnancy: An Umbrella Review.

Several epidemiological studies have analyzed the effects of lifestyle modification on reducing the risk of gestational diabetes mellitus (GDM); however, their results remain inconsistent. This umbrella review aims to evaluate the effects of diet and/or physical activity interventions during pregnancy on preventing GDM. Systematic reviews and meta-analysis of randomized clinical trials reporting preventive effects of diet and/or physical activity in reducing the incidence of GDM were included from PubMed, Web of Science, Scopus and Cochrane library. Two authors independently assessed the overlapping and quality of the 35 selected reviews using AMSTAR 2. The results, although variable, tend to defend the protective role of diet and physical activity interventions separately and independently of each other in the prevention of GDM. However, the results for the combined interventions show a possible protective effect; however, it is not entirely clear because most of the analyzed meta-analyses tend to approach 1, and heterogeneity cannot be ruled out. Establishing conclusions about the most efficient type of intervention and a dose-effect relationship was not feasible given the low quality of systematic reviews (83% low to critically low) and the variability in reporting interventions. Therefore, more studies with better quality and definition of the interventions are required. The protocol was previously registered in PROSPERO as CRD42021237895.

Simulation Based-Learning from Simple to Complicated Clinical Situations for Midwifery Students.

PURPOSE: A health professional's learning curriculum should lead to the acquisition of technical and non-technical skills. This study aims at demonstrating the impact of simulation-based learning (SBL) experience on the learning of midwifery students. PATIENTS AND METHODS: Using an experimental design, the experimental group (n=14) received pretest, high fidelity simulation, then a post-test. Whereas the control group (n=14) received pretest, revision of the theoretical course instead of simulation, post-test 1, high fidelity simulation, then a post-test 2. The first scenario was about a normal childbirth when the midwifery students were in their 2nd year. And then the second one was about immediate postpartum hemorrhage when the students moved to their 3rd year. RESULTS: During the simulation sessions, the experimental group had a higher mean score in the post-test than the control group. This indicated that the simulation significantly (p<0.001) increased the students' knowledge. Also, for both eutocic and dystocic delivery simulation experiments, students obtained higher score in the second simulation sessions (19.69 and 19.4 for eutocic and dystocic, respectively) than in the first session (11.23 and 9.12 for eutocic and dystocic, respectively; p<0.0001). CONCLUSION: These findings confirm that SBL offers an opportunity for learners to be immersed in an environment that is closer to reality, thus improving learning in a safe environment.

An Excel program for calculating statistics presented in Marfak et al.'s article 'Improved RIDIT statistic approach provides more intuitive and informative interpretation of EQ-5D Data'.

The objective is to present and share an Excel program that we have developed to perform statistical analyses based on the Improved RIDIT approach of Marfak et al.'s article 'Improved RIDIT statistic approach provides more intuitive and informative interpretation of EQ-5D Data'.

Health-related quality of life and behavior-related lifestyle changes due to the COVID-19 home confinement: Dataset from a Moroccan sample.

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) virus initially appeared in Wuhan, Hubei Province, China has caused a novel coronavirus disease (COVID-19) [1]. The disease is rapidly spread around the world causing thousands of deaths and posing critical challenges for public health and clinical research in the world. The outbreak was declared by the World Health Organization (WHO) as a public health emergency of international concern. Nowadays, there are more than 18 millions of confirmed cases of coronavirus across the world with a total of 702,903 deaths [2]. In Morocco, there are 28,500 confirmed cases and 345 deaths. Forecasts for the cumulative number of confirmed, recovered, active and death cases were recently provided [3]. To manage the pandemic spread several countries adopted proactive and preventive measures including home confinement of the population. However, there is evidence that these measures, particularly home confinement, can cause unprecedented disruption in the well-being of the population. Being forced to stay at home and the daily activities' restrictions could impact the citizens' health-related quality of life (HRQoL) and behavior-related lifestyle. It has been reported that the COVID-19 pandemic has an impact on psychological behaviors [4], mental health [5] and anxiety/depression [6]. The Moroccan population was under home confinement from March 20, 2020. Assessing rapidly and simply the HRQoL during crisis such as the home confinement is a challenge of interest to provide speedy information to authorities which allow best management of damages yielding in crisis situation. The EQ-5D instrument is a generic questionnaire developed by the Euroqol group for measuring the HRQoL by combining five health dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) [7]. The EQ-5D instrument is translated into more than 300 languages and exhibit good reliability and validity in both patients and general population. Herein, we used the EQ-5D-5L instrument to assess for the first time the impact of the home confinement on the HRQoL. Also, we evaluated the changes in behaviors by asking some questions related to lifestyle before and during the home confinement. These data can help the Moroccan authorities and other countries to more understand the impact of this crisis on citizens and therefore to set up adequate protocols for managing the post-confinement or possible future crisis. We provided two datasets: (1) data we collected before confinement from a sample of 484 individuals describing their HRQoL [8] and (2) data we collected during the home confinement period from a sample of 537 individuals describing their HRQoL and behavior-related lifestyle.

The hidden Markov chain modelling of the COVID-19 spreading using Moroccan dataset.

The World Health Organization (WHO) declared in March 12, 2020 the COVID-19 disease as pandemic. In Morocco, the first local transmission case was detected in March 13. The number of confirmed cases has gradually increased to reach 15,194 on July 10, 2020. To predict the COVID-19 evolution, statistical and mathematical models such as generalized logistic growth model [1], exponential model [2], segmented Poisson model [3], Susceptible-Infected-Recovered derivative models [4] and ARIMA [5] have been proposed and used. Herein, we proposed the use of the Hidden Markov Chain, which is a statistical system modelling transitions from one state (confirmed cases, recovered, active or death) to another according to a transition probability matrix to forecast the evolution of COVID-19 in Morocco from March 14, to October 5, 2020. In our knowledge the Hidden Markov Chain was not yet applied to the COVID-19 spreading. Forecasts for the cumulative number of confirmed, recovered, active and death cases can help the Moroccan authorities to set up adequate protocols for managing the post-confinement due to COVID-19. We provided both the recorded and forecasted data matrices of the cumulative number of the confirmed, recovered and active cases through the range of the studied dates.

Improved RIDIT statistic approach provides more intuitive and informative interpretation of EQ-5D data.

BACKGROUND: EQ-5D is generic measure of health-related quality of life. Studies using EQ-5D generate ordinal data that are interpreted as categories ordered by severity. New analytic approaches taking into account the ordinal nature of the health dimension severity and leading to a better interpretation of EQ-5D data are needed to better elucidate differences in health-related quality of life. We propose utilizing the Improved RIDIT statistical method to analyze EQ-5D outcomes. METHODS: 556 Moroccan participants aged over 18 years representing four chronic diseases: back pain (n = 158), renal insufficiency (n = 56), diabetes (n = 82) or hypertension (n = 80) and healthy subjects (n = 180). All participants received the two EQ-5D versions. Two other published data sets were included. The first was extracted from a diabetic Spain study and the second was extracted from a clinical trial study. The Improved RIDIT analyses were carried out using an R statistic program we developed. RESULTS: Applying the Improved RIDIT on the EQ-5D data allowed estimating for the first time the ordinal odds, the Absolute Risk Reduction (ARR) or the Absolute Risk Increase (ARI) and the Number Needed to Treat. The ARI values estimated for Moroccan patients showed that (i) hypertension increased anxiety/depression by 66% and reduced mobility by 65%; (ii) back pain increased pain/discomfort by 69%; (iii) renal insufficiency impacts mobility (ARI = 57%, oddsordinal = 9.95) and usual activities (ARI = 44%, oddsordinal = 6.41) and (iv) diabetes acts only on anxiety/depression (ARI = 50%, oddsordinal = 4.8). Also, we demonstrated that the approach works well in clinical trials. CONCLUSIONS: Improved RIDIT provides more intuitive and informative interpretation of the EQ-5D data by (1) taking into account the level severity; estimating (2) the odds ordinal, (3) the ARR/ARI and the NNT; (4) analyzing the five dimensions of the EQ-5D separately, which gives clinical teams more precision in understanding the treatment/pathology impacts on the health status and completes the EQ-5D data analysis based on score utilities.

T/B ratio does not reflect levels of ZAP70 expression in clonal CLL B-cells due to ZAP70 overexpression in patient T-cells.

Flow cytometry is the reference technique for assessing ZAP70 expression, a marker of poor prognosis in CLL. One of the most common methods is to assess ZAP70 levels in CLL cells by calculating the ratio between ZAP70 mean fluorescence intensities (MFIs) in residual T-cells and CLL B-cells (ZAP70 T/B ratio). In this study, we developed a new method for ZAP70 labeling. Cells were labeled with a combination of anti ZAP70 phycoerythrin-conjugated SBZAP monoclonal antibody (mAb) and mAbs against CD45, CD19, and CD5. The latter three were used to specifically gate on different lymphocyte subsets. Staining was performed in absence (test) or in presence of excess unconjugated SBZAP mAb (isoclonic control). A so-called ZAP70 isoclonic ratio between SBZAP MFIs in the test and isoclonic control was calculated. A series of 32 patients with CLL and 10 normal controls were studied. Prediction of IGHV mutation status by ZAP70 isoclonic and T/B ratios was similar. By using the ZAP70 isoclonic ratio, we showed that ZAP70 expression was increased in T-cells from CLL patients. Nearly all cases with increased ZAP70 expression in CLL cells were associated with high ZAP70 expression in cognate T-cells. Therefore, the ZAP70 isoclonic ratio was more likely to closely reflect the biology of ZAP70 dysregulation rather than the T/B ratio. These results also explained why ZAP70 T/B ratios were artefactually close to normal in cells from CLL patients with high levels of ZAP70.

B7-H1, which represses EBV-immortalized B cell killing by autologous T and NK cells, is oppositely regulated by c-Myc and EBV latency III program at both mRNA and secretory lysosome levels.

EBV-immortalized B cells induce a complex immune response such that the virus persists as a clinically silent infection for the lifetime of the infected host. B7-H1, also called PD-L1, is a cosignaling molecule of the B7 family that can inhibit activated T cell effectors by interaction with its receptor PD-1. In this work, we have studied the dependence of B7-H1 on NF-κB and c-Myc, the two main transcription factors in EBV latency III proliferating B cells, on various lymphoblastoid and Burkitt lymphoma cell lines, some of them being inducible or not for the EBV latency III program and/or for c-Myc. We found that B7-H1 repressed killing of EBV-immortalized B cells by their autologous T and NK cells. At the mRNA level, NF-κB was a weak inducer whereas c-Myc was a strong repressor of B7-H1 expression, an effect mediated by STAT1 inhibition. At the protein level, B7-H1 molecules were stored in both degradative and unconventional secretory lysosomes. Surface membrane B7-H1 molecules were constitutively internalized and proteolyzed in lysosomes. The EBV latency III program increased the amounts of B7-H1-containing secretory lysosomes and their export to the surface membrane. By repressing actin polymerization, c-Myc blocked secretory lysosome migration and B7-H1 surface membrane export. In addition to B7-H1, various immunoregulatory molecules participating in the immunological synapse are stored in secretory lysosomes. By playing on actin polymerization, c-Myc could thus globally regulate the immunogenicity of transformed B cells, acting on export of secretory lysosomes to plasma membrane.

Thrombocytopenia resulting from mutations in filamin A can be expressed as an isolated syndrome.

Filaminopathies A caused by mutations in the X-linked FLNA gene are responsible for a wide spectrum of rare diseases including 2 main phenotypes, the X-linked dominant form of periventricular nodular heterotopia (FLNA-PVNH) and the otopalatodigital syndrome spectrum of disorders. In platelets, filamin A (FLNa) tethers the principal receptors ensuring the platelet-vessel wall interaction, glycoprotein Ibα and integrin αIIbß3, to the underlying cytoskeleton. Hemorrhage, coagulopathy, and thrombocytopenia are mentioned in several reports on patients with FLNA-PVNH. Abnormal platelet morphology in 2 patients with FLNA-PVNH prompted us to examine a third patient with similar platelet morphology previously diagnosed with immunologic thrombocytopenic purpura. Her enlarged platelets showed signs of FLNa degradation in Western blotting, and a heterozygous missense mutation in FLNA was detected. An irregular distribution of FLNa within the total platelet population was shown by confocal microscopy for all 3 patients. In vitro megakaryocyte cultures showed an abnormal differentiation, including an irregular distribution of FLNa with a frayed aspect, the presence of enlarged α-granules, and an abnormal fragmentation of the cytoplasm. Mutations in FLNA may represent an unrecognized cause of macrothrombocytopenia with an altered platelet production and a modified platelet-vessel wall interaction.

Abnormal VWF modifies megakaryocytopoiesis: studies of platelets and megakaryocyte cultures from patients with von Willebrand disease type 2B.

von Willebrand factor (VWF) is an essential mediator of platelet adhesion to the vessel wall, but little is known about its role in megakaryocytopoiesis. VWF and its platelet receptor, glycoprotein Ibalpha (GPIbalpha), are both expressed during megakaryocyte (MK) maturation. This study was designed to evaluate whether the enhanced VWF-GPIbalpha interactions typical of patients with von Willebrand disease type 2B (VWD2B) modify platelet production. Platelets from 9 patients with VWD2B with 7 different gain-of-function mutations were examined by electron microscopy (EM) and immunofluorescence labeling. For the patients with VWD2B, EM characteristically showed variable numbers of structurally abnormal giant platelets, sometimes in agglutinates. Cultures of MKs from controls performed with or without purified VWF confirmed a positive influence of VWF on platelet production with specific inhibition by an antibody blocking VWF binding to GPIbalpha. VWD2B MK cultures examined by EM showed a disorganized demarcation membrane system and abnormal granule distribution. They produced platelets with structural abnormalities typical of VWD2B. Confocal examination of MK revealed limited extension of pseudopods with few large proplatelets. These results confirm that megakaryocytopoiesis is modified by the enhanced VWF-GPIbalpha interactions. These data obtained for controls and patients with VWD2B suggest a novel regulatory role of VWF-GPIbalpha interactions in platelet production.