Fostamatinib effectiveness and safety for immune thrombocytopenia in clinical practice.

ABSTRACT: Fostamatinib, a recently approved Syk inhibitor used in adult primary immune thrombocytopenia (ITP), has been shown to be safe and effective in this disorder. However, clinical trial results may not be similarly reproduced in clinical practice. Here, 138 patients with ITP (both primary and secondary) from 42 Spanish centers who had been treated with fostamatinib were evaluated prospectively and retrospectively. The median age of our cohort (55.8% women) was 66 years (interquartile range [IQR], 56-80). The median time since ITP diagnosis at fostamatinib initiation was 51 months (IQR, 10-166). The median number of therapies before fostamatinib initiation was 4 (IQR, 2-5), including eltrombopag (76.1%), romiplostim (57.2%), and IV immunoglobulins (44.2%). Fifty-eight patients (42.0%) had signs/symptoms of bleeding in the month before treatment initiation. Seventy-nine percent of patients responded to fostamatinib with 53.6% complete responses (platelet count > 100 × 109/L). Eighty-three patients (60.1%) received fostamatinib monotherapy, achieving a high response rate (85.4%). The proportion of time in response during the 27-month period examined was 83.3%. The median time to platelet response was 11 days (IQR, 7-21). Sixty-seven patients (48.5%) experienced adverse events, mainly grade 1 to 2; the commonest of which were diarrhea (n = 28) and hypertension (n = 21). One patient had deep venous thrombosis, and one patient developed acute myocardial infarction. Fostamatinib was shown to be effective with good safety profile in patients with primary and secondary ITP across a wide age spectrum in this real-world study.

Autoimmune hemolytic anemia during pregnancy and puerperium: an international multicenter experience.

Relapsing or occurring de novo autoimmune hemolytic anemia (AIHA) during pregnancy or puerperium is a poorly described condition. Here, we report 45 pregnancies in 33 women evaluated at 12 centers from 1997 to 2022. Among the 20 women diagnosed with AIHA before pregnancy, 10 had a relapse. An additional 13 patients developed de novo AIHA during gestation/puerperium (2 patients had AIHA relapse during a second pregnancy). Among 24 hemolytic events, anemia was uniformly severe (median Hb, 6.4 g/dL; range, 3.1-8.7) and required treatment in all cases (96% steroids ± intravenous immunoglobulin, IVIG, 58% transfusions). Response was achieved in all patients and was complete in 65% of the cases. Antithrombotic prophylaxis was administered to 8 patients (33%). After delivery, rituximab was administered to 4 patients, and cyclosporine was added to 1 patient. The rate of maternal complications, including premature rupture of membranes, placental detachment, and preeclampsia, was 15%. Early miscarriages occurred in 13% of the pregnancies. Fetal adverse events (22% of cases) included respiratory distress, fetal growth restriction, preterm birth, AIHA of the newborn, and 2 perinatal deaths. In conclusion, the occurrence of AIHA does not preclude the ability to carry out a healthy pregnancy, provided close monitoring, prompt therapy, and awareness of potential maternal and fetal complications.

Tumoral periprostatic adipose tissue exovesicles-derived miR-20a-5p regulates prostate cancer cell proliferation and inflammation through the RORA gene.

BACKGROUND: From the first steps of prostate cancer (PCa) initiation, tumours are in contact with the most-proximal adipose tissue called periprostatic adipose tissue (PPAT). Extracellular vesicles are important carriers of non-coding RNA such as miRNAs that are crucial for cellular communication. The secretion of extracellular vesicles by PPAT may play a key role in the interactions between adipocytes and tumour. Analysing the PPAT exovesicles (EVs) derived-miRNA content can be of great relevance for understanding tumour progression and aggressiveness. METHODS: A total of 24 samples of human PPAT and 17 samples of perivesical adipose tissue (PVAT) were used. EVs were characterized by western blot and transmission electron microscopy (TEM), and uptake by PCa cells was verified by confocal microscopy. PPAT and PVAT explants were cultured overnight, EVs were isolated, and miRNA content expression profile was analysed. Pathway and functional enrichment analyses were performed seeking potential miRNA targets. In vitro functional studies were evaluated using PCa cells lines, miRNA inhibitors and target gene silencers. RESULTS: Western blot and TEM revealed the characteristics of EVs derived from PPAT (PPAT-EVs) samples. The EVs were up taken and found in the cytoplasm of PCa cells. Nine miRNAs were differentially expressed between PPAT and PVAT samples. The RORA gene (RAR Related Orphan Receptor A) was identified as a common target of 9 miRNA-regulated pathways. In vitro functional analysis revealed that the RORA gene was regulated by PPAT-EVs-derived miRNAs and was found to be implicated in cell proliferation and inflammation. CONCLUSION: Tumour periprostatic adipose tissue is linked to PCa tumour aggressiveness and could be envisaged for new therapeutic strategies.

Real-life clinical practice in Spain in the setting of new drug availability for ITP treatment. A Delphi-based Spanish expert panel consensus.

Immune thrombocytopenia (ITP) is a common autoimmune hematological disorder. Despite this, diagnosis is still challenging due to clinical heterogeneity and the lack of a specific diagnostic test. New findings in the pathology and the availability of new drugs have led to the development of different guidelines worldwide. In the present study, the Delphi methodology has been used to get a consensus on the management of adult patients with ITP in Spain and to help in decision-making. The Delphi questionnaire has been designed by a scientific ad hoc committee and has been divided into 13 topics, with a total of 127 items, covering the maximum possible scenarios for the management of ITP. As a result of the study, a total consensus of 81% has been reached. It is concluded that this Delphi consensus provides practical recommendations on topics related to diagnosis and management of ITP patients to help doctors to improve outcomes. Some aspects remain unclear, without consensus among the experts. Thus, more advances are needed to optimize ITP management.

What is the context? Immune thrombocytopenia (ITP) is a hematologic autoimmune disease characterized by accelerated destruction and inadequate production of platelets mediated by autoantibodies (platelet count <100 × 10⁹ /L).Despite being a common condition, its heterogeneous clinical course makes its diagnosis and management still a challenge.In recent years, new molecules with different mechanisms of action have emerged for the treatment of ITP.Due to the increasing information about the pathology and its therapies, several international guidelines have recently been established to provide recommendations for the management and treatment of ITP.There are still many patient scenarios and disease aspects which are not addressed in the guidelines.What is new? Our Spanish ITP Expert Group has developed a Delphi consensus study to provide recommendations and promote standardization of the management of adult patients with ITP in Spain.The scientific committee defined 127 statements for consensus, corresponding to 13 chapters: (i) Diagnosis of ITP, (ii) First-line treatment, (iii) Second-line treatment, (iv) Treatment of refractory patients, (v) Follow-up, (vi) Emergency and surgery, (vii) ITP in the elderly, (viii) ITP in pregnancy, (ix) Anticoagulation and antiplatelet, (x) Secondary ITP, (xi) Quality of life, (xii) Discontinuation of TPO-RA, and (xiii) ITP and Covid.The total number of agreed statements achieved was 103, giving a final percentage of consensus in the Delphi questionnaire of 81%.What is the impact? This Delphi consensus provides recommendations based on real clinical practice data, regarding the diagnosis, treatment, and management of patients and scenarios in ITP to assist clinicians in addressing this disease and achieving optimal outcomes for the patient.

Latent trajectories of recent and delayed memory and their predictors: evidence from SHARE.

OBJECTIVES: Cognitive decline is common in the old age, but some evidence suggests it may already occur during adulthood. Previous studies have linked age, gender, educational attainment, depression, physical activity, and social engagement to better cognitive performance over time. However, most studies have used global measures of cognition, which could mask subtle changes in specific cognitive domains. The aim of this study is to examine trajectories of recent and delayed memory recall from a variable-centered perspective, in order to elucidate the impact of age, gender, educational attainment, depression, physical activity, and social engagement on recent and delayed memory both at initial time and across a 10-year period. DESIGN AND PARTICIPANTS: The sample was formed by 56,616 adults and older adults that participated in waves 4 to 8 of the Survey of Health, Aging and Retirement in Europe (SHARE). ANALYSES: We used latent growth modeling to establish latent recent and delayed memory trajectories, and then tested the effects of the aforementioned covariates on the latent intercept and slopes. RESULTS: Results showed that both recent and delayed recall display a quadratic trajectory of decline. All covariates significantly explained initial levels of immediate and delayed recall, but only a few had statistically significant effects on the slope terms. CONCLUSIONS: We discuss differences between present results and those previously reported in studies using a person-centered approach. This study provides evidence of memory decline during adulthood and old adulthood. Further, results provide support for the neural compensation reserve theory.

Social participation, loneliness, and physical inactivity over time: evidence from SHARE.

OBJECTIVES: We aimed to explore the reciprocal effects of social participation, loneliness, and physical inactivity over a period of 6 years in a representative sample of European adults over 50 years old. DESIGN: A longitudinal study with a six-year follow-up period was conducted. SETTING: Four waves of the Survey of Health, Ageing and Retirement in Europe project were used. PARTICIPANTS: This study includes 64,887 participants from Europe and Israel, who were aged 50 or older at the first time. MEASUREMENTS: The relationship between participation in social activities, loneliness and physical inactivity was analyzed, controlling for age, gender, and disability. A series of cross-lagged panel models (CLPMs) were applied to analyze the relationships among these variables. RESULTS: A CLPM with equal autoregressive cross-lagged effects across waves was the best fit to the data (χ2 = 7137.8, CFI = .972, RMSEA = .049, SRMR = .036). The autoregressive effects for the three variables showed high stability across waves, and all the cross-lagged effects in the model were statistically significant. Social activity and physical inactivity maintained a strong negative cross-lagged effect, while their cross-lagged effects on loneliness were comparatively smaller. Social activity had a positive cross-lagged effect on loneliness, while physical inactivity had a negative cross-lagged effect on loneliness. CONCLUSIONS: These findings highlight the importance of promoting physical activity and social participation and addressing loneliness through targeted interventions in older adults.

Early immunomodulation in immune thrombocytopenia-A report of the ICIS meeting in Lenzerheide, Switzerland 2022.

The only way to prevent immune thrombocytopenia (ITP) from becoming refractory would be to restore tolerance to platelets at an early phase of the disease. Numerous immune alterations probably accumulate in chronic ITP; thus, the chances of cure decrease significantly with time. Currently, sustained remission off treatment (SROT) is a clinical definition describing patients who can discontinue their ITP treatment without risk and maintain a state of remission. Different treatment strategies are presently being evaluated with the goal of attaining SROT, mostly combining drugs targeting the innate and/or the adaptive immune system, the inflammation state, so as increasing the platelet load. In this sense, thrombopoietin receptor agonists (TPO-RAs) have shown promising results if used as upfront treatment. TPO-RAs seem to exhibit immunomodulation and immune tolerance properties, increasing not only the platelet antigen mass but also increasing the transforming growth factor-ß concentration, and stimulating regulatory T and B lymphocytes. However, more immunological studies are needed to establish accurate molecular alterations in ITP that are potentially reversed with treatments.

In silico analysis of prognostic and diagnostic significance of target genes from prostate cancer cell lines derived exomicroRNAs.

BACKGROUND: Cancer-secreted exovesicles are important for cell-to-cell communication by altering cancer-related signalling pathways. Exovesicles-derived miRNAs (exomiRNAs)-target genes can be useful for diagnostic and prognostic purposes. METHODS: ExomiRNA from prostate cancer (PCa) cells (PC-3 and LNCaP) were quantified by qRT-PCR and compared to the healthy cell line RWPE-1 by using miRNome PCR 752 miRNAs Panel. MiRNet database was used to predict exomiRNA-target genes. ExomiRNA-target genes pathway functional enrichment was performed by using Reactome database and Enrichr platform. Protein-protein interaction analysis was carried out by using the STRING database. RNA target-gene sequencing data from The Cancer Genome Atlas Prostate Adenocarcinoma (TCGA-PRAD) database was screened out in 465 PCa patients for candidate gene expression in prostate tumour (PT) tissue and non-pathologic prostate (N-PP) tissue. Signature gene candidates were statistically analysed for diagnosis and prognosis usefulness. RESULTS: A total of 36 exomiRNAs were found downregulated when comparing PCa cells vs a healthy cell line; and when comparing PC-3 vs LNCaP, 14 miRNAs were found downregulated and 52 upregulated. Reactome pathway database revealed altered pathways and genes related to miRNA biosynthesis, miRNA-mediated gene silencing (TNRC6B and AGO1), and cell proliferation (CDK6), among others. Results showed that TNRC6B gene expression was up-regulated in PT tissue compared to N-PP (n = 52 paired samples) and could be useful for diagnostic purposes. Likewise, gene expression levels of CDK6, TNRC6B, and AGO1 were down-regulated in high-risk PT (n = 293) compared to low-risk PCa tissue counterparts (n = 172). When gene expression levels of CDK6, TNRC6B, and AGO1 were tested as a prognostic panel, the results showed that these improve the prognostic power of classical biomarkers. CONCLUSION: ExomiRNAs-targets genes, TNRC6B, CDK6, and AGO1, showed a deregulated expression profile in PCa tissue and could be useful for PCa diagnosis and prognosis.

Exploring developmental trajectories throughout adolescence of children with autism spectrum disorder without intellectual disability.

Characterizing the developmental trajectories of children with autism spectrum disorder (ASD) throughout adolescence and across different domains of functioning offers opportunities to improve long-term outcomes. This prospective study explored, for the first time, the evolution of children with ASD-without intellectual disability (ID) in terms of socio-adaptative skills, learning behaviors, executive functioning (EF), and internalizing/externalizing problems, compared to typically developing (TD) peers. Forty-five children with ASD-without ID and 37 matched TD children (aged 7-11) were assessed at baseline and after 5 years. Parents and teachers completed measures on theory of mind (ToM), socialization, daily living skills, learning style, EF, and emotional/behavioural difficulties at both time points. On all the domains assessed, the ASD group performed significantly worse than the TD group, both in childhood and adolescence. Specific changes were noted between baseline and follow-up assessment on adaptive skills, prosocial behavior, emotional control, inhibit, working memory and monitoring. Group membership (ASD/TD) was influenced by peer relationships and inhibit EF variables. These findings have implications for clinical and school settings.

European Delphi panel to build consensus on tapering and discontinuing thrombopoietin receptor agonists in immune thrombocytopenia.

To establish pan-European consensus on tapering and discontinuing thrombopoietin receptor agonists (TPO-RAs) in patients with immune thrombocytopenia (ITP), we applied a three-step Delphi technique consisting of a one-to-one interview round and two online survey rounds. Three healthcare professionals (HCPs) from Italy, Spain, and the United Kingdom formed the Steering Committee (SC), which advised on study design, panelist selection, and survey development. A literature review also informed the development of the consensus statements. Likert scales were used to collect quantitative data on panelists' level of agreement. Twelve hematologists representing nine European countries assessed 121 statements spanning three categories: (1) patient selection; (2) tapering and discontinuation strategies; (3) post-discontinuation management. Consensus was reached on approximately half of the statements in each category (32.2%; 44.6%; 66%). Panelists agreed on patients' main selection criteria, patients' involvement in decision-making, tapering strategies, and follow-up criteria. Areas not reaching consensus were risk factors and predictors of successful discontinuation, monitoring intervals, and rates of successful discontinuation or relapse. This lack of consensus signals knowledge and practice gaps among European countries and suggests the need for the development of clinical practice guidelines that outline a pan-European, evidence-based approach to tapering and discontinuing TPO-RAs.

Immune thrombocytopenia (ITP) is a condition that may cause extensive bruising and excessive bleeding. Another sign is a pattern of small reddish-purple dots resembling a rash. ITP is treated with a class of medications known as thrombopoietin receptor agonists (TPO-RAs), which include eltrombopag, avatrombopag, and romiplostim. Sometimes the beneficial effects of the medication last even after the patient stops taking it, which means that some patients can be tapered off it. This paper presents the results of a Delphi panel­a method of research that gathers insights from experts­about tapering and discontinuing TPO-RAs. There were 12 physicians from nine European countries on the Delphi panel, all practicing hematologists with expertise in tapering and discontinuing TPO-RAs in patients with ITP. Panelists were presented with a total of 130 statements over three survey rounds. At the end of Round Three, 52 statements (40%) achieved consensus (response pattern of ≥80% "Agree"), and six statements (4.6%) achieved dissensus (response pattern of ≥80% "Disagree"). Consensus was achieved on the appropriateness of tapering the dose of the TPO-RA for two to three months prior to attempting discontinuation. The panel also reached consensus on considering tapering in a slower fashion (six to 12 months) for patients showing suboptimal response to TPO-RAs. More than half the survey's statements did not achieve consensus or dissensus. This signals that knowledge gaps exist and highlights the importance of conducting prospective, real-world evidence studies to identify best practices and develop pan-European guidelines for tapering and discontinuing TPO-RAs.

Deepening the understanding of the structural validity of the Tilburg Frailty Indicator.

BACKGROUND: Psychometric properties of the Tilburg Frailty Indicator (TFI) have shown low internal consistency for psychological and social domains, and evidence for its structure validity is controversial. Moreover, research on TFI is frequently limited to community dwellings. AIMS: To evaluate structural validity, reliability, and convergent and divergent validity of the Spanish version of the Tilburg Frailty Indicator (TFI) in both community-dwelling and institutionalized older people. MATERIALS AND METHODS: A cross-sectional study was conducted on Spanish older adults (n = 457) recruited from both community settings (n = 322) and nursing homes (n = 135). Participants completed the TFI and other frailty instruments: Fried's Frailty Phenotype, Edmonton Frailty Scale, FRAIL Scale, and Kihon Checklist (KCL). Confirmatory Factor Analysis (CFA), and reliability and validity coefficients were estimated. RESULTS AND DISCUSSION: Some items from physical and social domains showed low factor loadings (< 0.40). The three-factor CFA model showed better fit indices after depurating these items. Reliability estimates were good (CRI ≥ 0.70) for physical and psychological domains in the institutionalized sample, while in the community dwellings, only physical domain reliability was adequate. Convergent and divergent validity of physical and psychological domains was good, except for some alternative psychological measures highly correlating with the TFI physical component (KCL-depressive mood and Edmonton mood). However, the social domain showed low correlations with some social indicators. CONCLUSION: The findings of this study clarify some of the controversial validation results of the TFI structure and provide evidence to improve its use in psychometric terms. CLINICAL TRIAL REGISTRATION NUMBER: NCT03832608.

Does depression mediate the pain-frailty relationship? Latent variables approach.

Frailty is highly prevalent among older adults. This study aims to add evidence to the mediational role of depression in the pain-frailty relationship. Data came from a sample of 2578 Spanish older adults recruited from the Survey of Health, Aging, and Retirement in Europe (SHARE). A set of competing structural equation models were performed: (a) independent prediction, (b) full mediation, and (c) partial mediation. Results showed a better fit for the partial mediation model. This model was extended including covariates. The effects of pain and depression remained relevant in the final model, which explained 91% of the frailty variance. These findings support the relevance of the pain-depression dyad in frailty development. Although the pain shows a direct impact on frailty, this association is partially mediated by depression. The interplay of these conditions could be crucial for treatment effectiveness.

Correlates of musculoskeletal pain and kinesiophobia in older adults with heart failure: A structural equation model.

The study aimed to study the influence of musculoskeletal pain on kinesiophobia in patients with heart failure. This cross-sectional study recruited 107 heart failure patients aged 73.18±12.68 years (57% men) from an outpatient setting. Participants self-reported pain using the Musculoskeletal System Assessment Inventory and the Cornell Musculoskeletal Discomfort Questionnaire. Kinesiophobia was assessed with the Tampa Scale for Kinesiophobia-11. About 62% reported musculoskeletal pain, with knees (16.8%) and lower back (12.%) being the most painful locations. About 31% reported moderate levels and 24% indicated high levels of kinesiophobia. There were positive and significant associations between the indicators of pain and kinesiophobia. Results showed an adequate structural equation model fit to the data with musculoskeletal pain factors explaining 22.09% of the variance in kinesiophobia. Assessment of kinesiophobia in patients with heart failure with musculoskeletal pain is essential to improve self-care and overall quality of life.

Cognitive and behavioral profiles in children with autism spectrum disorder with and without Attention-Deficit/hyperactivity disorder.

BACKGROUND: Understanding the developmental trajectories of children with autism spectrum disorder (ASD) with and without comorbid ADHD is relevant to tailor care plans. This prospective study assessed, for the first time, cognitive, emotional, behavioral, and learning outcomes in adolescence of children with ASD-ADHD and in those with ASD+ADHD in childhood. Possible predictors of severity of ASD core symptoms in adolescence were also evaluated. METHODS: Forty-five adolescents without intellectual disability, 26 diagnosed in childhood with ASD-ADHD and 19 with ASD+ADHD, were evaluated at baseline (mean age: 8.6 ± 1.3) and at 5-year follow-up (mean age: 12.9 ± 0.9). Parents and teachers completed questionnaires on executive functions, theory of mind (ToM), emotional/behavioral difficulties (EBD), and learning style at both time points.. RESULTS: Overall different developmental trajectories for the two groups were found. In general, deficits in metacognition processes, ToM skills, EBD, and learning abilities were more pronounced in the ASD+ group. Over time, the ASD+ADHD group, but not the ASD-ADHD, tended to improve in EBD and metacognition but their level of development continued to be lower compared with ASD+ADHD. EBD in childhood were significant predictors of autism core symptoms of adolescents. CONCLUSIONS: Our findings highlight the importance of an early identification of comorbid ADHD symptoms in ASD to offer treatment strategies based on specific developmental trajectories.

Sustained Remission Off-Treatment (SROT) of TPO-RAs: The Burgos Ten-Step Eltrombopag Tapering Scheme.

Background and Objectives: TPO-RAs (romiplostim/eltrombopag/avatrombopag) have broadly demonstrated high efficacy rates (59-88%), durable responses (up to three years) and a satisfactory safety profile in clinical trials. The effect of TPO-RAs is classically considered to be transient because platelet numbers usually dropped rapidly to baseline unless therapy was maintained. However, several groups have reported the possibility of successfully discontinuing TPO-RAs in some patients without further need for concomitant treatments. This concept is usually referred as sustained remission off-treatment (SROT). Materials and Methods: Unfortunately, we still lack predictors of the response to discontinuation even after the numerous biological, clinical and in vitro studies performed to study this phenomenon. The frequency of successful discontinuation is matter of controversy, although a percentage in the range of 25-40% may probably be considered a consensus. Here, we describe all major routine clinical practice studies and reviews that report the current position on this topic and compare them with our own results in Burgos. Results: We report our Burgos ten-step eltrombopag tapering scheme with which we have achieved an elevated percentage rate of success (70.3%) in discontinuing treatment. Conclusions: We hope this protocol may help successfully taper and discontinue TPO-RAs in daily clinical practice.

Current Concepts in the Diagnosis and Management of Adult Primary Immune Thrombocytopenia: Our Personal View.

Primary immune thrombocytopenia (ITP) is an acquired blood disorder that causes a reduction in circulating platelets with the potential for bleeding. The incidence of ITP is slightly higher in adults and affects more women than men until 60 years, when males are more affected. Despite advances in basic science, primary ITP remains a diagnosis of exclusion. The disease is heterogeneous in its clinical behavior and response to treatment. This reflects the complex underlying pathophysiology, which remains ill-understood. Platelet destruction plays a role in thrombocytopenia, but underproduction is also a major contributing factor. Active ITP is a proinflammatory autoimmune disease involving abnormalities within the T and B regulatory cell compartments, along with several other immunological abnormalities. Over the last several years, there has been a shift from using immunosuppressive therapies for ITP towards approved treatments, such as thrombopoietin receptor agonists. The recent COVID-19 pandemic has hastened this management shift, with thrombopoietin receptor agonists becoming the predominant second-line treatment. A greater understanding of the underlying mechanisms has led to the development of several targeted therapies, some of which have been approved, with others still undergoing clinical development. Here we outline our view of the disease, including our opinion about the major diagnostic and therapeutic challenges. We also discuss our management of adult ITP and our placement of the various available therapies.

How the COVID-19 Pandemic and its Consequences Affect the Presence of and Search for Meaning of Life: A Longitudinal Study.

The presence of meaning in life (PML) and the search for meaning in life (SML) are crucial when facing difficult times. Although several theoretical frameworks have tried to explain the dynamics of meaning in life during adversity, empirical evidence about interactions among both constructs using longitudinal designs is scarce. This study examined the trajectories of both PML and SML during the COVID-19 lockdown period in Spain. In total, 220 adults fulfilled an online survey during two periods: a strict and a relaxed lockdown period. Latent growth models showed that both PML and SML declined slightly during the strict lockdown, but they reached a plateau during the relaxed lockdown. Results also showed that age and having a partner predicted higher PML and lower SML at baseline, whereas being male predicted higher scores on PML. PML and SML were negatively associated at baseline, higher SML at baseline was related to a steeper decreasing PML slope during the strict lockdown, and the PML and SML slopes in the relaxed lockdown period were negatively related. This study contributes to better understanding longitudinal fluctuations of meaning in life in situations of adversity.

The lipidomic profile of the tumoral periprostatic adipose tissue reveals alterations in tumor cell's metabolic crosstalk.

BACKGROUND: Periprostatic adipose tissue (PPAT) plays a role in prostate cancer (PCa) progression. PPAT lipidomic composition study may allow us to understand the tumor metabolic microenvironment and provide new stratification factors. METHODS: We used ultra-high-performance liquid chromatography-mass spectrometry-based non-targeted lipidomics to profile lipids in the PPAT of 40 patients with PCa (n = 20 with low-risk and n = 20 high-risk). Partial least squares-discriminant analysis (PLS-DA) and variable importance in projection (VIP) analysis were used to identify the most relevant features of PPAT between low- and high-risk PCa, and metabolite set enrichment analysis was used to detect disrupted metabolic pathways. Metabolic crosstalk between PPAT and PCa cell lines (PC-3 and LNCaP) was studied using ex vivo experiments. Lipid uptake and lipid accumulation were measured. Lipid metabolic-related genes (SREBP1, FASN, ACACA, LIPE, PPARG, CD36, PNPLA2, FABP4, CPT1A, FATP5, ADIPOQ), inflammatory markers (IL-6, IL-1B, TNFα), and tumor-related markers (ESRRA, MMP-9, TWIST1) were measured by RT-qPCR. RESULTS: Significant differences in the content of 67 lipid species were identified in PPAT samples between high- and low-risk PCa. PLS-DA and VIP analyses revealed a discriminating lipidomic panel between low- and high-risk PCa, suggesting the occurrence of disordered lipid metabolism in patients related to PCa aggressiveness. Functional analysis revealed that alterations in fatty acid biosynthesis, linoleic acid metabolism, and ß-oxidation of very long-chain fatty acids had the greatest impact in the PPAT lipidome. Gene analyses of PPAT samples demonstrated that the expression of genes associated with de novo fatty acid synthesis such as FASN and ACACA were significantly lower in PPAT from high-risk PCa than in low-risk counterparts. This was accompanied by the overexpression of inflammatory markers (IL-6, IL-1B, and TNFα). Co-culture of PPAT explants with PCa cell lines revealed a reduced gene expression of lipid metabolic-related genes (CD36, FASN, PPARG, and CPT1A), contrary to that observed in co-cultured PCa cell lines. This was followed by an increase in lipid uptake and lipid accumulation in PCa cells. Tumor-related genes were increased in co-cultured PCa cell lines. CONCLUSIONS: Disturbances in PPAT lipid metabolism of patients with high-risk PCa are associated with tumor cell metabolic changes.

Use of thrombopoietin receptor agonists for immune thrombocytopenia in pregnancy: results from a multicenter study.

Management of immune thrombocytopenia (ITP) during pregnancy can be challenging because treatment choices are limited. Thrombopoietin receptor agonists (Tpo-RAs), which likely cross the placenta, are not recommended during pregnancy. To better assess the safety and efficacy of off-label use of Tpo-RAs during pregnancy, a multicenter observational and retrospective study was conducted. Results from 15 pregnant women with ITP (pregnancies, n = 17; neonates, n = 18) treated with either eltrombopag (n = 8) or romiplostim (n = 7) during pregnancy, including 2 patients with secondary ITP, were analyzed. Median time of Tpo-RA exposure during pregnancy was 4.4 weeks (range, 1-39 weeks); the indication for starting Tpo-RAs was preparation for delivery in 10 (58%) of 17 pregnancies, whereas 4 had chronic refractory symptomatic ITP and 3 were receiving eltrombopag when pregnancy started. Regarding safety, neither thromboembolic events among mothers nor Tpo-RA-related fetal or neonatal complications were observed, except for 1 case of neonatal thrombocytosis. Response to Tpo-RAs was achieved in 77% of cases, mostly in combination with concomitant ITP therapy (70% of responders). On the basis of these preliminary findings, temporary off-label use of Tpo-RAs for severe and/or refractory ITP during pregnancy seems safe for both mother and neonate and is likely to be helpful, especially before delivery.

Effectiveness of a game-based educational strategy e-EDUCAGUIA for implementing antimicrobial clinical practice guidelines in family medicine residents in Spain: a randomized clinical trial by cluster.

BACKGROUND: Clinical practice guidelines (CPGs) have teaching potential for health professionals in training clinical reasoning and decision-making, although their use is limited. The objective was to evaluate the effectiveness of a game-based educational strategy e-EDUCAGUIA using simulated clinical scenarios to implement an antimicrobial therapy GPC compared to the usual dissemination strategies to improve the knowledge and skills on decision-making of family medicine residents. Additionally, adherence to e-EDUCAGUIA strategy was assessed. METHODS: A multicentre pragmatic cluster-randomized clinical trial was conducted involving seven Teaching Units (TUs) of family medicine in Spain. TUs were randomly allocated to implement an antimicrobial therapy guideline with e-EDUCAGUIA strategy ( intervention) or passive dissemination of the guideline (control). The primary outcome was the differences in means between groups in the score test evaluated knowledge and skills on decision-making at 1 month post intervention. Analysis was made by intention-to-treat and per-protocol analysis. Secondary outcomes were the differences in mean change intrasubject (from the baseline to the 1-month) in the test score, and educational game adherence and usability. Factors associated were analysed using general linear models. Standard errors were constructed using robust methods. RESULTS: Two hundred two family medicine residents participated (104 intervention group vs 98 control group). 100 medicine residents performed the post-test at 1 month (45 intervention group vs 55 control group), The between-group difference for the mean test score at 1 month was 11 ( 8.67 to 13.32) and between change intrasubject was 11,9 ( 95% CI 5,9 to 17,9). The effect sizes were 0.88 and 0.75 respectively. In multivariate analysis, for each additional evidence-based medicine training hour there was an increase of 0.28 points (95% CI 0.15-0.42) in primary outcome and in the change intrasubject each year of increase in age was associated with an improvement of 0.37 points and being a woman was associated with a 6.10-point reduction. 48 of the 104 subjects in the intervention group (46.2%, 95% CI: 36.5-55.8%) used the games during the month of the study. Only a greater number of evidence-based medicine training hours was associated with greater adherence to the educational game ( OR 1.11; CI 95% 1.02-1.21). CONCLUSIONS: The game-based educational strategy e-EDUCAGUIA shows positive effects on the knowledge and skills on decision making about antimicrobial therapy for clinical decision-making in family medicin residents in the short term, but the dropout was high and results should be interpreted with caution. Adherence to educational games in the absence of specific incentives is moderate. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02210442 . Registered 6 August 2014.