Showing papers by "Universidad del Desarrollo published in 2019"

Epacadostat plus pembrolizumab versus placebo plus pembrolizumab in patients with unresectable or metastatic melanoma (ECHO-301/KEYNOTE-252): a phase 3, randomised, double-blind study

Abstract: Summary Background Immunotherapy combination treatments can improve patient outcomes. Epacadostat, an IDO1 selective inhibitor, and pembrolizumab, a PD-1 inhibitor, showed promising antitumour activity in the phase 1–2 ECHO-202/KEYNOTE-037 study in advanced melanoma. In this trial, we aimed to compare progression-free survival and overall survival in patients with unresectable stage III or IV melanoma receiving epacadostat plus pembrolizumab versus placebo plus pembrolizumab. Methods In this international, randomised, placebo-controlled, double-blind, parallel-group, phase 3 trial, eligible participants were aged 18 years or older, with unresectable stage III or IV melanoma previously untreated with PD-1 or PD-L1 checkpoint inhibitors, an ECOG performance status of 0 or 1, and had a known BRAFV600 mutant status or consented to BRAFV600 mutation testing during screening. Patients were stratified by PD-L1 expression and BRAFV600 mutation status and randomly assigned (1:1) through a central interactive voice and integrated web response system to receive epacadostat 100 mg orally twice daily plus pembrolizumab 200 mg intravenously every 3 weeks or placebo plus pembrolizumab for up to 2 years. We used block randomisation with a block size of four in each stratum. Primary endpoints were progression-free survival and overall survival in the intention-to-treat population. The safety analysis population included randomly assigned patients who received at least one dose of study treatment. The study was stopped after the second interim analysis; follow-up for safety is ongoing. This study is registered with ClinicalTrials.gov , number NCT02752074 . Findings Between June 21, 2016, and Aug 7, 2017, 928 patients were screened and 706 patients were randomly assigned to receive epacadostat plus pembrolizumab (n=354) or placebo plus pembrolizumab (n=352). Median follow-up was 12·4 months (IQR 10·3–14·5). No significant differences were found between the treatment groups for progression-free survival (median 4·7 months, 95% CI 2·9–6·8, for epacadostat plus pembrolizumab vs 4·9 months, 2·9–6·8, for placebo plus pembrolizumab; hazard ratio [HR] 1·00, 95% CI 0·83–1·21; one-sided p=0·52) or overall survival (median not reached in either group; epacadostat plus pembrolizumab vs placebo plus pembrolizumab: HR 1·13, 0·86–1·49; one-sided p=0·81). The most common grade 3 or worse treatment-related adverse event was lipase increase, which occurred in 14 (4%) of 353 patients receiving epacadostat plus pembrolizumab and 11 (3%) of 352 patients receiving placebo plus pembrolizumab. Treatment-related serious adverse events were reported in 37 (10%) of 353 patients receiving epacadostat plus pembrolizumab and 32 (9%) of 352 patients receiving placebo plus pembrolizumab. There were no treatment-related deaths in either treatment group. Interpretation Epacadostat 100 mg twice daily plus pembrolizumab did not improve progression-free survival or overall survival compared with placebo plus pembrolizumab in patients with unresectable or metastatic melanoma. The usefulness of IDO1 inhibition as a strategy to enhance anti-PD-1 therapy activity in cancer remains uncertain. Funding Incyte Corporation, in collaboration with Merck Sharp & Dohme.

The Global State of the Genetic Counseling Profession.

Abstract: The profession of genetic counseling (also called genetic counselling in many countries) began nearly 50 years ago in the United States, and has grown internationally in the past 30 years. While there have been many papers describing the profession of genetic counseling in individual countries or regions, data remains incomplete and has been published in diverse journals with limited access. As a result of the 2016 Transnational Alliance of Genetic Counseling (TAGC) conference in Barcelona, Spain, and the 2017 World Congress of Genetic Counselling in the UK, we endeavor to describe as fully as possible the global state of genetic counseling as a profession. We estimate that in 2018 there are nearly 7000 genetic counselors with the profession established or developing in no less than 28 countries.

Necessity or opportunity? the effects of State fragility and economic development on entrepreneurial efforts

Abstract: This paper studies the effects of state fragility and economic development on necessity and opportunity-based individual entrepreneurial efforts. We contribute to the literature on the contextual determinants of entrepreneurship by examining multilevel data on 956,925 individuals from 51 countries for the period of 2005–2013. We show that state fragility has a positive effect on necessity-based entrepreneurial efforts while hindering opportunity-based efforts. Our findings illustrate that the level of economic development moderates the relationship between state fragility and necessity-driven entrepreneurial efforts reducing the likelihood of the latter. We discuss the implications for theory and for proentrepreneurship policy.

Priorities to reduce the burden of stroke in Latin American countries

Abstract: Summary The large and increasing burden of stroke in Latin American countries, and the need to meet the UN and WHO requirements for reducing the burden from non-communicable disorders (including stroke), brought together stroke experts and representatives of the Ministries of Health of 13 Latin American countries for the 1st Latin American Stroke Ministerial meeting in Gramado, Brazil, to discuss the problem and identify ways of cooperating to reduce the burden of stroke in the region. Discussions were focused on the regional and country-specific activities associated with stroke prevention and treatment, including public stroke awareness, prevention strategies, delivery and organisation of care, clinical practice gaps, and unmet needs. The meeting culminated with the adoption of the special Gramado Declaration, signed by all Ministerial officials who attended the meeting. With agreed priorities for stroke prevention, treatment, and research, an opportunity now exists to translate this Declaration into an action plan to reduce the burden of stroke.

Expression and clinical significance of PD-L1, B7-H3, B7-H4 and TILs in human small cell lung Cancer (SCLC)

Abstract: Small cell lung cancer (SCLC) accounts for 10–15% of all lung malignancies and its prognosis is dismal. Although early studies have shown promising clinical activity of immune checkpoint blockers, the immune composition and expression of potentially actionable immunostimulatory targets in this malignancy are poorly understood. Using multiplexed quantitative immunofluorescence (QIF), we measured the levels of 3 different B7 family ligands PD-L1, B7-H3, B7-H4 and major tumor infiltrating lymphocyte (TIL) subsets in 90 SCLC samples represented in tissue microarray format. Associations between the marker levels, clinicopathological variables and survival were studied. PD-L1 protein was detected in 7.3%, B7-H3 in 64.9% and B7-H4 in 2.6% of SCLC cases. The markers showed limited co-expression and were not associated with the level of TILs, age, gender and stage. Elevated B7-H4 was associated with shorter 5-year overall survival. The levels of CD3+, CD8+ and CD20+ TILs and the ratio of total/effector T-cells were significantly lower in SCLC than in non-small cell lung cancer. High levels of CD3+, but not CD8+ or CD20+ TILs were significantly associated with longer survival. Taken together, our study indicate variable expression and clinical role of B7-family ligands in SCLC with predominant expression of the candidate target B7-H3 and the presence of a limited cytotoxic anti-tumor immune response. These results support the evaluation of B7-H3 blockers and/or pro-inflammatory therapies in SCLC.

Risk factors and predisposing conditions for urinary tract infection

Abstract: Understanding individual and population-specific risk factors associated with recurrent urinary tract infections (UTIs) can help physicians tailor prophylactic strategies. Frequent intercourse, vulvovaginal atrophy, change of the local bacterial flora, history of UTIs during premenopause or in childhood, family history, and a nonsecretor blood type are substantiated risk factors for recurrent uncomplicated UTIs. This is a narrative review based on relevant literature according to the experience and expertise of the authors. Asymptomatic bacteriuria is generally benign; however, during pregnancy it is more common and is associated with an increased likelihood of symptomatic infection, which may harm the mother or fetus. Screening of pregnant women and appropriate treatment with antimicrobials must be balanced with the potential for adverse treatment-related outcomes; appropriate prophylaxis should be considered where possible. High-quality data are currently lacking on risks related to asymptomatic bacteriuria in pregnancy and further data in this hard-to-study population should be a primary concern for researchers. Incomplete voiding represents the primary risk factor for UTIs associated with conditions such as urinary incontinence and prolapse. Correcting the presence of residual urine remains the most effective prophylaxis in these populations. Bladder function alters throughout life; however, changes in function may be particularly profound in clinical populations at high risk of UTIs. Patients with neurogenic bladder will also likely have other evolving medical issues which increase the risk of UTIs, such as repeated catheterization and increasing residual urine volume. More aggressive antimicrobial prophylactic strategies may be appropriate in these patients. Again, the paucity of data on prophylaxis in these high-risk patients requires the attention of the research community.

The universal decay of collective memory and attention

Abstract: Collective memory and attention are sustained by two channels: oral communication (communicative memory) and the physical recording of information (cultural memory). Here, we use data on the citation of academic articles and patents, and on the online attention received by songs, movies and biographies, to describe the temporal decay of the attention received by cultural products. We show that, once we isolate the temporal dimension of the decay, the attention received by cultural products decays following a universal biexponential function. We explain this universality by proposing a mathematical model based on communicative and cultural memory, which fits the data better than previously proposed log-normal and exponential models. Our results reveal that biographies remain in our communicative memory the longest (20–30 years) and music the shortest (about 5.6 years). These findings show that the average attention received by cultural products decays following a universal biexponential function. The attention received by cultural products—including scientific papers, patents, songs, movies and biographies—decays following a biexponential function, suggesting that collective memory follows a universal pattern.

Sex differences in treatment and outcome after stroke: Pooled analysis including 19,000 participants

Abstract: Objective To explore the sex differences in outcomes and management after stroke using a large sample with high-quality international trial data. Methods Individual participant data were obtained from 5 acute stroke randomized controlled trials. Data were obtained on demographics, medication use, in-hospital treatment, and functional outcome. Study-specific crude and adjusted models were used to estimate sex differences in outcomes and management, and then pooled using random-effects meta-analysis. Results There were 19,652 participants, of whom 7,721 (40%) were women. After multivariable adjustments, women with ischemic stroke had higher survival at 3–6 months (odds ratio [OR] 0.82, 95% confidence interval [CI] 0.70–0.97), higher likelihood of disability (OR 1.20, 95% CI 1.06–1.36), and worse quality of life (weighted mean difference −0.07, 95% CI −0.09 to 0.04). For management, women were more likely to be admitted to an acute stroke unit (OR 1.17, 95% CI 1.01–1.34), but less likely to be intubated (OR 0.58, 95% CI 0.36–0.93), treated for fever (OR 0.82, 95% CI 0.70–0.95), or admitted to an intensive care unit (OR 0.83, 95% CI 0.74–0.93). For preadmission medications, women had higher odds of being prescribed antihypertensive agents (OR 1.22, 95% CI 1.13–1.31) and lower odds of being prescribed antiplatelets (OR 0.86, 95% CI 0.79–0.93), glucose-lowering agents (OR 0.86, 95% CI 0.78–0.94), or lipid-lowering agents (OR 0.85, 95% CI 0.77–0.94). Conclusions This analysis suggests that women who had ischemic stroke had better survival but were also more disabled and had poorer quality of life. Variations in hospital and out-of-hospital management may partly explain the disparities.

Stem cell exosomes inhibit angiogenesis and tumor growth of oral squamous cell carcinoma

Abstract: Recently, exosomes secreted by menstrual mesenchymal stem cells have been identified as inhibitory agents of tumor angiogenesis and modulators of the tumor cell secretome in prostate and breast cancer. However, their direct effect on endothelial cells and paracrine mediators have not yet been investigated. Using a carrier-based cell culture system to test the scalability for exosome production, we showed that different types of endothelial cells present specific kinetics for exosomes internalization. Exosome-treatment of endothelial cells increased cytotoxicity and reduced VEGF secretion and angiogenesis in a dose-dependent manner. Using the hamster buccal pouch carcinoma as a preclinical model for human oral squamous cell carcinoma, we demonstrated a significant antitumor effect of intra-tumoral injection of exosomes associated with a loss of tumor vasculature. These results address up-scaling of exosome production, a relevant issue for their clinical application, and also assess menstrual stem cell exosomes as potential anti-angiogenic agents for the treatment of neoplastic conditions.

Comparative study of the neural differentiation capacity of mesenchymal stromal cells from different tissue sources: An approach for their use in neural regeneration therapies.

Abstract: Mesenchymal stem cells (MSCs) can trans/differentiate to neural precursors and/or mature neurons and promote neuroprotection and neurogenesis. The above could greatly benefit neurodegenerative disorders as well as in the treatment of post-traumatic and hereditary diseases of the central nervous system (CNS). In order to attain an ideal source of adult MSCs for the treatment of CNS diseases, adipose tissue, bone marrow, skin and umbilical cord derived MSCs were isolated and studied to explore differences with regard to neural differentiation capacity. In this study, we demonstrated that MSCs from several tissues can differentiate into neuron-like cells and differentially express progenitors and mature neural markers. Adipose tissue MSCs exhibited significantly higher expression of neural markers and had a faster proliferation rate. Our results suggest that adipose tissue MSCs are the best candidates for the use in neurological diseases.

Effectiveness of Technology Transfer Policies and Legislation in Fostering Entrepreneurial Innovations across Continents: An overview

Abstract: The purpose of this article and the special issue is to improve our understanding of the theoretical, managerial, and policy implications of the effectiveness of technology transfer policies on entrepreneurial innovation. We accomplish this objective by examining the relationship between entrepreneurship, innovation and public policies in the 186 papers published from 1970 to 2019. Our analysis begins by clarifying the definition of entrepreneurial innovations and outlining the published research per context. We then present the seven papers that contribute to this special issue. We conclude by outlining an agenda for additional research on this topic.

Near-Apneic Ventilation Decreases Lung Injury and Fibroproliferation in an Acute Respiratory Distress Syndrome Model with Extracorporeal Membrane Oxygenation

Abstract: Rationale: There is wide variability in mechanical ventilation settings during extracorporeal membrane oxygenation (ECMO) in patients with acute respiratory distress syndrome. Although lung rest is...

Rural entrepreneurship in place: an integrated framework

Abstract: Agglomeration-oriented theories have grown significantly in the past decade in the explanation and promotion of entrepreneurship. Theoretical frameworks and normative models such as entrepr...

Entrepreneurship and attention deficit/hyperactivity disorder: a large-scale study involving the clinical condition of ADHD

Abstract: A growing conversation has emerged linking ostensibly dark or pathological individual-level characteristics to entrepreneurship. Attention deficit/hyperactivity disorder (ADHD) is among the most central and emblematic. Recent studies have made great strides—articulating the theoretical relevance of ADHD-type behavior in entrepreneurship and suggesting a positive link consistent with narratives in the popular press. However, quantitative studies have yet to empirically examine ADHD in line with its theoretical roots and definition—as a clinical disorder. The present paper contributes by providing a theoretically–empirically aligned test of the connection between the condition of ADHD and entrepreneurial intention and action. Based on a large-scale data collection effort (N = 9869) and cross-sectional methodology, the results find a positive connection between clinical ADHD and entrepreneurial intentions as well as entrepreneurial action. This grounds prior research on ADHD and entrepreneurship, indicating that individuals with ADHD are indeed more likely to not just espouse entrepreneurial intentions, but also to initiate business venturing. Considering the design, it suggests a self-selection toward entrepreneurship in individuals with ADHD (before potentially being a choice of last resort).

Contribution of the Unfolded Protein Response (UPR) to the Pathogenesis of Proteasome-Associated Autoinflammatory Syndromes (PRAAS).

Abstract: Type I interferonopathies cover a phenotypically heterogeneous group of rare genetic diseases including the recently described proteasome-associated autoinflammatory syndromes (PRAAS). By definition, PRAAS are caused by inherited and/or de novo loss-of-function mutations in genes encoding proteasome subunits such as PSMB8, PSMB9, PSMB7, PSMA3, or proteasome assembly factors including POMP and PSMG2, respectively. Disruption of any of these subunits results in perturbed intracellular protein homeostasis including accumulation of ubiquitinated proteins which is accompanied by a type I interferon (IFN) signature. The observation that, similarly to pathogens, proteasome dysfunctions are potent type I IFN inducers is quite unexpected and, up to now, the underlying molecular mechanisms of this process remain largely unknown. One promising candidate for triggering type I IFN under sterile conditions is the unfolded protein response (UPR) which is typically initiated in response to an accumulation of unfolded and/or misfolded proteins in the endoplasmic reticulum (ER) (also referred to as ER stress). The recent observation that the UPR is engaged in subjects carrying POMP mutations strongly suggests its possible implication in the cause-and-effect relationship between proteasome impairment and interferonopathy onset. The purpose of this present review is therefore to discuss the possible role of the UPR in the pathogenesis of PRAAS. We will particularly focus on pathways initiated by the four ER-membrane proteins ATF6, PERK, IRE1-α, and TCF11/Nrf1 which undergo activation under proteasome inhibition. An overview of the current understanding of the mechanisms and potential cross-talk between the UPR and inflammatory signaling casacades is provided to convey a more integrated picture of the pathophysiology of PRAAS and shed light on potential biomarkers and therapeutic targets.

Dopamine receptor D3 signalling in astrocytes promotes neuroinflammation

Abstract: Neuroinflammation constitutes a pathogenic process leading to neurodegeneration in several disorders, including Alzheimer’s disease, Parkinson’s disease (PD) and sepsis. Despite microglial cells being the central players in neuroinflammation, astrocytes play a key regulatory role in this process. Our previous results indicated that pharmacologic-antagonism or genetic deficiency of dopamine receptor D3 (DRD3) attenuated neuroinflammation and neurodegeneration in two mouse models of PD. Here, we studied how DRD3-signalling affects the dynamic of activation of microglia and astrocyte in the context of systemic inflammation. Neuroinflammation was induced by intraperitoneal administration of LPS. The effect of genetic DRD3-deficiency or pharmacologic DRD3-antagonism in the functional phenotype of astrocytes and microglia was determined by immunohistochemistry and flow cytometry at different time-points. Our results show that DRD3 was expressed in astrocytes, but not in microglial cells. DRD3 deficiency resulted in unresponsiveness of astrocytes and in attenuated microglial activation upon systemic inflammation. Furthermore, similar alterations in the functional phenotypes of glial cells were observed by DRD3 antagonism and genetic deficiency of DRD3 upon LPS challenge. Mechanistic analyses show that DRD3 deficiency resulted in exacerbated expression of the anti-inflammatory protein Fizz1 in glial cells both in vitro and in vivo. These results suggest that DRD3 signalling regulates the dynamic of the acquisition of pro-inflammatory and anti-inflammatory features by astrocytes and microglia, finally favouring microglial activation and promoting neuroinflammation.

Using principles of authentic assessment to redesign written examinations and tests

Abstract: Tests and examinations are widely used internationally. Despite their pervasiveness, they tend to measure lower order thinking skills in a decontextualized manner at a time when the literature frequently argues for the benefits of a richer, authentic approach to assessment. The focus of this paper is to improve authenticity in test assessment methods through promoting realism, cognitive challenge and evaluative judgement during the planning, administering and following up of assessment tasks. The article builds on a systematic literature review, in which the main principles of authentic assessment were outlined. In this paper, we posit how these principles can be implemented through the three chronological phases of the assessment process: before, during and after the act of assessment.

Frequency of the Types of Alopecia at Twenty-Two Specialist Hair Clinics: A Multicenter Study.

Abstract: Background The frequency of different types of alopecia is not clearly reported in recent studies. Objective To analyze the frequency of the types of alopecia in patients consulting at specialist hair clinics (SHC) and to assess for global variations. Methods Multicenter retrospective study including data from patients evaluated at referral SHC in Europe, America, Africa and Australia. Results A total of 2,835 patients (72.7% females and 27.3% males) with 3,133 diagnoses of alopecia were included (73% were non-cicatricial and 27% were cicatricial alopecias). In all, 57 different types of alopecia were characterized. The most frequent type was androgenetic alopecia (AGA) (37.7%), followed by alopecia areata (AA) (18.2%), telogen effluvium (TE) (11.3%), frontal fibrosing alopecia (FFA) (10.8%), lichen planopilaris (LPP) (7.6%), folliculitis decalvans (FD) (2.8%), discoid lupus (1.9%) and fibrosing alopecia in a pattern distribution (FAPD) (1.8%). There was a male predominance in patients with acne keloidalis nuchae, dissecting cellulitis and FD, and female predominance in traction alopecia, central centrifugal cicatricial alopecia, FFA, TE, FAPD and LPP. Conclusion AGA followed by AA and TE were the most frequent cause of non-cicatricial alopecia, while FFA was the most frequent cause of cicatricial alopecia in all studied geographical areas.

R&D transfer, policy and innovative ambitious entrepreneurship: evidence from Latin American countries

Abstract: In this article, we explore the effectiveness of government intervention, R&D, and pro-innovation mechanisms in the likelihood of being an innovative entrepreneur with high ambitions of growing, in the particular context of Latin America and the Caribbean. We use a longitudinal approach, with a multilevel mixed-effects logistic regression procedure. The data comes mainly from the Global Entrepreneurship Monitor and the Global Competitiveness Index. The sample covers 14 countries from Latin America and the Caribbean between 2006 and 2015. The results provide empirical insights about firm and individual characteristics that explain the likelihood of being an innovative and ambitious entrepreneur. We also find that effective and narrowed policies in addition to an innovation-driven environment, also increases innovative-ambitious entrepreneurs. The paper includes implications for policy makers that want to enhance local entrepreneurial framework conditions.

Systems Analysis of the 22q11.2 Microdeletion Syndrome Converges on a Mitochondrial Interactome Necessary for Synapse Function and Behavior.

Abstract: Neurodevelopmental disorders offer insight into synaptic mechanisms. To unbiasedly uncover these mechanisms, we studied the 22q11.2 syndrome, a recurrent copy number variant, which is the highest schizophrenia genetic risk factor. We quantified the proteomes of 22q11.2 mutant human fibroblasts from both sexes and mouse brains carrying a 22q11.2-like defect, Df(16)A+/- Molecular ontologies defined mitochondrial compartments and pathways as some of top ranked categories. In particular, we identified perturbations in the SLC25A1-SLC25A4 mitochondrial transporter interactome as associated with the 22q11.2 genetic defect. Expression of SLC25A1-SLC25A4 interactome components was affected in neuronal cells from schizophrenia patients. Furthermore, hemideficiency of the Drosophila SLC25A1 or SLC25A4 orthologues, dSLC25A1-sea and dSLC25A4-sesB, affected synapse morphology, neurotransmission, plasticity, and sleep patterns. Our findings indicate that synapses are sensitive to partial loss of function of mitochondrial solute transporters. We propose that mitoproteomes regulate synapse development and function in normal and pathological conditions in a cell-specific manner.SIGNIFICANCE STATEMENT We address the central question of how to comprehensively define molecular mechanisms of the most prevalent and penetrant microdeletion associated with neurodevelopmental disorders, the 22q11.2 microdeletion syndrome. This complex mutation reduces gene dosage of ∼63 genes in humans. We describe a disruption of the mitoproteome in 22q11.2 patients and brains of a 22q11.2 mouse model. In particular, we identify a network of inner mitochondrial membrane transporters as a hub required for synapse function. Our findings suggest that mitochondrial composition and function modulate the risk of neurodevelopmental disorders, such as schizophrenia.

An overview of systematic reviews on mental health promotion, prevention, and treatment of common mental disorders for refugees, asylum seekers, and internally displaced persons

Abstract: Background Migrants who have been forced to leave their home, such as refugees, asylum seekers, and internally displaced persons (IDP), are likely to experience stressors which may lead to mental health problems. The efficacy of interventions for mental health promotion, prevention, and treatment may differ in this population. Objectives With this overview of systematic reviews, we will map the characteristics and methodological quality of existing systematic reviews and registered systematic review protocols on the promotion of mental health and prevention and treatment of common mental disorders among refugees, asylum seekers, and IDPs. The findings from this overview will be used to prioritise and inform future Cochrane reviews on the mental health of involuntary migrants. Methods We searched Ovid MEDLINE (1945 onwards), Ovid Embase (1974 onwards), Ovid PsycINFO, ProQuest PTSDpubs, Web of Science Core Collection, Cochrane Database of Systematic Reviews, NIHR Journals Library, CRD databases (archived), DoPHER, Epistemonikos, Health Evidence, 3ie International Initiative for Impact Evaluation, and PROSPERO, to identify systematic reviews of mental health interventions for involuntary migrants. We did not apply any restrictions on date, language, or publication status to the searches. We included systematic reviews or protocols for systematic reviews of interventions aimed at refugees, asylum seekers, and internally displaced persons. Interventions must have been aimed at mental health promotion (for example, classroom-based well-being interventions for children), prevention of mental health problems (for example, trauma-focussed Cognitive Behavioural Therapy to prevent post-traumatic stress disorder), or treatment of common mental disorders and symptoms (for example, narrative exposure therapy to treat symptoms of trauma). After screening abstracts and full-text manuscripts in duplicate, we extracted data on the characteristics of the reviews, the interventions examined in reviews, and the number of primary studies included in each review. Methodological quality of the included systematic reviews was assessed using AMSTAR 2. Main results The overview includes 23 systematic reviews and 15 registered systematic review protocols. Of the 23 published systematic reviews, meta-analyses were conducted in eight reviews. It was more common for the search strategy or inclusion criteria of the reviews to state that studies involving refugees were eligible for inclusion (23/23), than for asylum seekers (14/23) or IDPs (7/23) to be explicitly mentioned. In most reviews, study eligiblity was either not restricted by participant age (9/23), or restricted to adults (10/23). Reviews commonly reported on studies of diagnosis or symptoms of post-traumatic stress disorder or trauma (11/23) and were less likely to report on depression or anxiety (6/23). In 15 reviews the intervention of interest was focused on/ specific to psychological therapy. Across all 23 reviews, the interventions most commonly identified from primary studies were general Cognitive Behavioural Therapy, Narrative Exposure Therapy, and a range of different integrative and interpersonal therapies. Even though many reviews included studies of participants without a diagnosis of a mental health problem, they often assessed mental health treatments and did not usually distinguish between promotion, prevention, and treatment in the review aims. Together the 23 systematic reviews included 336 references, of which 175 were unique primary studies. Limitations to the methodological quality of reviews most commonly related to reporting of selection criteria (21/23), absence of a protocol (19/23), reporting of study design (20/23), search strategy (22/23), and funding sources of primary studies (19/23). Authors' conclusions Gaps exist in the evidence on mental health interventions for refugees, asylum seekers, and internally displaced persons. Most reviews do not specify that internally displaced persons are included in the selection criteria, even though they make up the majority of involuntary migrants worldwide. Reviews specific to mental health promotion and prevention of common mental disorders are missing, and there is more evidence available for adults or mixed populations than for children. The literature is focused on post-traumatic stress disorder and trauma-related symptoms, with less attention for depression and anxiety disorders. Better quality systematic reviews and better report of review design and methods would help those who may use these reviews to inform implementation of mental health interventions.

Medications, Deep Brain Stimulation, and Other Factors Influencing Impulse Control Disorders in Parkinson's Disease.

Abstract: Impulse control disorders (ICDs) in Parkinson's disease (PD) have a high cumulative incidence and negatively impact quality of life. ICDs are influenced by a complex interaction of multiple factors. Although it is now well-recognized that dopaminergic treatments and especially dopamine agonists underpin many ICDs, medications alone are not the sole cause. Susceptibility to ICD is increased in the setting of PD. While causality can be challenging to ascertain, a wide range of modifiable and non-modifiable risk factors have been linked to ICDs. Common characteristics of PD patients with ICDs have been consistently identified across many studies; for example, males with an early age of PD onset and dopamine agonist use have a higher risk of ICD. However, not all cases of ICDs in PD can be directly attributable to dopamine, and studies have concluded that additional factors such as genetics, smoking, and/or depression may be more predictive. Beyond dopamine, other ICD associations have been described but remain difficult to explain, including deep brain stimulation surgery, especially in the setting of a reduction in dopaminergic medication use. In this review, we will summarize the demographic, genetic, behavioral, and clinical contributions potentially influencing ICD onset in PD. These associations may inspire future preventative or therapeutic strategies.

Intranasal delivery of mesenchymal stem cell-derived exosomes reduces oxidative stress and markedly inhibits ethanol consumption and post-deprivation relapse drinking.

Abstract: Chronic ethanol consumption leads to brain oxidative stress and neuroinflammation, conditions known to potentiate and perpetuate each other. Several studies have shown that neuroinflammation results in increases in chronic ethanol consumption. Recent reports showed that the intra-cerebroventricular administration of mesenchymal stem cells to rats consuming alcohol chronically markedly inhibited oxidative-stress, abolished neuroinflammation and greatly reduced chronic alcohol intake and post deprivation relapse-like alcohol intake. However, the intra-cerebroventricular administration of living cells is not suitable as a treatment of a chronic condition. The present study aimed at inhibiting ethanol intake by the non-invasive intranasal administration of human mesenchymal stem cell products: exosomes, microvesicles (40 to 150 nm) with marked antioxidant activity extruded from mesenchymal stem cells. The exosome membrane can fuse with the plasma membrane of cells in different tissues, thus delivering their content intracellularly. The study showed that the weekly intranasal administration of mesenchymal stem cell-derived exosomes to rats consuming alcohol chronically (1) inhibited their ethanol intake by 84 percent and blunted the relapse-like 'binge' drinking that follows an alcohol deprivation period and ethanol re-access. (2) Intranasally administered exosomes were found in the brain within 24 hours; (3) fully reversed both alcohol-induced hippocampal oxidative-stress, evidenced by a lower ratio of oxidized to reduced glutathione, and neuroinflammation, shown by a reduced astrocyte activation and microglial density; and (4) increased glutamate transporter GLT1 expression in nucleus accumbens, counteracting the inhibition of glutamate transporter activity, reportedly depressed under oxidative-stress conditions. Possible translational implications are envisaged.

Factors predictive of serious infections over time in systemic lupus erythematosus patients: data from a multi-ethnic, multi-national, Latin American lupus cohort:

Abstract: AimThe aim of this study was to identify factors predictive of serious infections over time in patients with systemic lupus erythematosus (SLE).MethodsA multi-ethnic, multi-national Latin American ...