PRAJA is overexpressed in glioblastoma and contributes to neural precursor development

PRAJA, a RING-H2 E3 ligase, is abundantly expressed in brain tissues such as the cerebellum and frontal cortex, amongst others, and more specifically in neural progenitor cells as well as in multiple cancers that include glioblastomas. However, the specific role that Praja plays in neural development and gliomas remains unclear. In this investigation, we performed bioinformatic analyses to examine Praja1 and Praja2 expression across 29 cancer types, and observed raised levels of Praja1 and Praja2 in gliomas with an inverse relationship between Praja1 and apoptotic genes and Praja substrates such as Smad3. We analyzed the role of Praja in the developing brain through loss of function studies, using morpholinos targeting Praja1 in embryonic zebrafish, and observed that Praja1 is expressed prominently in regions enriched with neural precursor cell subtypes. Antisense Praja morpholinos resulted in multiple embryonic defects including delayed neural development likely through increased apoptosis. Further studies revealed high levels of Cdk1 with loss of Praja1 in TGF-β or insulin treated cells, supporting the link between Praja1 and cell cycle regulation. In summary, these studies underscore Praja\u27s role in mammalian brain development and Praja1 deregulation may lead to gliomas possibly through the regulation of cell cycle and/or apoptosis

Current state of knowledge of basic life support in health professionals of the largest city in Pakistan: A cross-sectional study

Background: Basic Life Support (BLS) is the recognition of sudden cardiac arrest and activation of the emergency response system, followed by resuscitation, and rapid defibrillation. According to WHO, Pakistan has one of the highest mortality rates from accidental deaths therefore assessment and comparison of BLS knowledge in health professionals is crucial. We thereby aim to assess and compare the knowledge of BLS in doctors, dentists and nurses. Methods: A multi-centric cross-sectional survey was conducted in Karachi at different institutions belonging to the private as well as government sector from January to March 2018. We used a structured questionnaire which was adapted from pretested questionnaires that have been used previously in similar studies. Descriptive statistics were analyzed using SPSS v22.0, where adequate knowledge was taken as a score of at least 50%. P \u3c 0.05 was considered as significant. Logistic regression was used to identify the factors affecting the knowledge regarding BLS in health care professionals. Results: The responders consisted of 140 doctors, nurses and dentists each. Only one individual (dentist) received a full score of 100%. In total, 58.3% of the population had inadequate knowledge. Average scores of doctors, dentists and nurses were 53.5, 43.3 and 38.4% respectively. Doctors, participants with prior training in BLS and those with 6 to 10 years after graduation were found to be a significant predictor of adequate knowledge, on multivariate analysis. Conclusion: Even though knowledge of BLS in doctors is better than that of dentists and nurses, overall knowledge of health care professionals is extremely poor. Present study highlights the need for a structured training of BLS for health care workers

Salt consumption awareness in Portugal: comparison between the ECOS surveys of 2014 and 2018

O consumo excessivo de sal aumenta o risco de doenças crónicas, pelo que a sensibilização da população é uma medida recomendada pela Organização Mundial de Saúde (OMS) e pela Direção-Geral da Saúde (DGS) para a diminuição do seu consumo. O objetivo deste estudo foi estimar a prevalência relativa à preocupação com o consumo de sal, em 2014 e 2018 em Portugal, avaliar a sua evolução e caracterizar o perfil sociodemográfico dos participantes que manifestaram preocupação com o consumo de sal nos dois anos em análise. Os dados foram recolhidos no âmbito do inquérito telefónico ECOS (Em Casa Observamos Saúde) para esses anos. Em 2014, 77% dos inquiridos referiram ter preocupação quanto ao consumo de sal face a 75% em 2018. Em ambos os anos, as mulheres revelaram uma maior preocupação quanto ao consumo de sal, comparativamente ao sexo masculino, embora essa diferença fosse mais evidente em 2014. Adicionalmente, verificou-se que a preocupação com o consumo de sal aumenta com a idade, sendo o grupo etário com mais de 65 anos o que registou uma maior preocupação relativamente ao consumo do sal, nos dois anos em análise. Não se observaram diferenças estatisticamente significativas entre os níveis de escolaridade ou as regiões.Excessive salt consumption increases the risk of chronic diseases. Thus raising awareness is a measure to reduce its consumption, recommended by the World Health Organization (WHO) and the Portuguese Directorate General of Health. The aim of this study was to estimate the prevalence of individuals who reported awareness regarding their salt consumption in 2014 and 2018, and to investigate its distribution among several sociodemographic characteristics. Data was collected by means of a national representative panel telephonic survey, ECOS. In 2014, 77% of respondents reported watching or reducing salt consumption, compared to 75% in 2018, but this difference between years was not significant. In both years, women were more aware of salt intake than men, although this difference was more significant in 2014. Additionally, awareness regarding salt consumption increased with age, with the age group over 65 years old being the most aware, in the two years under analysis. No statistically significant differences were found among the different educational level groups, or regions.info:eu-repo/semantics/publishedVersio

The Karachi intracranial stenosis study (KISS) Protocol: an urban multicenter case-control investigation reporting the clinical, radiologic and biochemical associations of intracranial stenosis in Pakistan.

Background: Intracranial stenosis is the most common cause of stroke among Asians. It has a poor prognosis with a high rate of recurrence. No effective medical or surgical treatment modality has been developed for the treatment of stroke due to intracranial stenosis. We aim to identify risk factors and biomarkers for intracranial stenosis and to develop techniques such as use of transcranial doppler to help diagnose intracranial stenosis in a cost-effective manner. Methods/Design: The Karachi Intracranial Stenosis Study (KISS) is a prospective, observational, case-control study to describe the clinical features and determine the risk factors of patients with stroke due to intracranial stenosis and compare them to those with stroke due to other etiologies as well as to unaffected individuals. We plan to recruit 200 patients with stroke due to intracranial stenosis and two control groups each of 150 matched individuals. The first set of controls will include patients with ischemic stroke that is due to other atherosclerotic mechanisms specifically lacunar and cardioembolic strokes. The second group will consist of stroke free individuals. Standardized interviews will be conducted to determine demographic, medical, social, and behavioral variables along with baseline medications. Mandatory procedures for inclusion in the study are clinical confirmation of stroke by a healthcare professional within 72 hours of onset, 12 lead electrocardiogram, and neuroimaging. In addition, lipid profile, serum glucose, creatinine and HbA1C will be measured in all participants. Ancillary tests will include carotid ultrasound, transcranial doppler and magnetic resonance or computed tomography angiogram to rule out concurrent carotid disease. Echocardiogram and other additional investigations will be performed at these centers at the discretion of the regional physicians. Discussion: The results of this study will help inform locally relevant clinical guidelines and effective public health and individual interventions

A Pan-cancer analysis reveals high-frequency genetic alterations in mediators of signaling by the tgf-β superfamily

We present an integromic analysis of gene alterations that modulate transforming growth factor β (TGF-β)-Smad-mediated signaling in 9,125 tumor samples across 33 cancer types in The Cancer Genome Atlas (TCGA). Focusing on genes that encode mediators and regulators of TGF-β signaling, we found at least one genomic alteration (mutation, homozygous deletion, or amplification) in 39% of samples, with highest frequencies in gastrointestinal cancers. We identified mutation hotspots in genes that encode TGF-β ligands (BMP5), receptors (TGFBR2, AVCR2A, and BMPR2), and Smads (SMAD2 and SMAD4). Alterations in the TGF-β superfamily correlated positively with expression of metastasis-associated genes and with decreased survival. Correlation analyses showed the contributions of mutation, amplification, deletion, DNA methylation, and miRNA expression to transcriptional activity of TGF-β signaling in each cancer type. This study provides a broad molecular perspective relevant for future functional and therapeutic studies of the diverse cancer pathways mediated by the TGF-β superfamily

The Pakistan risk of myocardial infarction study: A resource for the study of genetic, lifestyle and other determinants of myocardial infarction in south Asia

The burden of coronary heart disease (CHD) is increasing at a greater rate in South Asia than in any other region globally, but there is little direct evidence about its determinants. The Pakistan Risk of Myocardial Infarction Study (PROMIS) is an epidemiological resource to enable reliable study of genetic, lifestyle and other determinants of CHD in South Asia. By March 2009, PROMIS had recruited over 5,000 cases of first-ever confirmed acute myocardial infarction (MI) and over 5,000 matched controls aged 30-80 years. For each participant, information has been recorded on demographic factors, lifestyle, medical and family history, anthropometry, and a 12-lead electrocardiogram. A range of biological samples has been collected and stored, including DNA, plasma, serum and whole blood. During its next stage, the study aims to expand recruitment to achieve a total of about 20,000 cases and about 20,000 controls, and, in subsets of participants, to enrich the resource by collection of monocytes, establishment of lymphoblastoid cell lines, and by resurveying participants. Measurements in progress include profiling of candidate biochemical factors, assay of 45,000 variants in 2,100 candidate genes, and a genomewide association scan of over 650,000 genetic markers. We have established a large epidemiological resource for CHD in South Asia. In parallel with its further expansion and enrichment, the PROMIS resource will be systematically harvested to help identify and evaluate genetic and other determinants of MI in South Asia. Findings from this study should advance scientific understanding and inform regionally appropriate disease prevention and control strategies

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570