Tawam Hospital

BACKGROUND: Hypophosphatasia results from mutations in the gene for the tissue-nonspecific isozyme of alkaline phosphatase (TNSALP). Inorganic pyrophosphate accumulates extracellularly, leading to rickets or osteomalacia. Severely affected babies often die from respiratory insufficiency due to progressive chest deformity or have persistent bone disease. There is no approved medical therapy. ENB-0040 is a bone-targeted, recombinant human TNSALP that prevents the manifestations of hypophosphatasia in Tnsalp knockout mice. METHODS: We enrolled infants and young children with life-threatening or debilitating perinatal or infantile hypophosphatasia in a multinational, open-label study of treatment with ENB-0040. The primary objective was the healing of rickets, as assessed by means of radiographic scales. Motor and cognitive development, respiratory function, and safety were evaluated, as well as the pharmacokinetics and pharmacodynamics of ENB-0040. RESULTS: Of the 11 patients recruited, 10 completed 6 months of therapy; 9 completed 1 year. Healing of rickets at 6 months in 9 patients was accompanied by improvement in developmental milestones and pulmonary function. Elevated plasma levels of the TNSALP substrates inorganic pyrophosphate and pyridoxal 5'-phosphate diminished. Increases in serum parathyroid hormone accompanied skeletal healing, often necessitating dietary calcium supplementation. There was no evidence of hypocalcemia, ectopic calcification, or definite drug-related serious adverse events. Low titers of anti-ENB-0040 antibodies developed in four patients, with no evident clinical, biochemical, or autoimmune abnormalities at 48 weeks of treatment. CONCLUSIONS: ENB-0040, an enzyme-replacement therapy, was associated with improved findings on skeletal radiographs and improved pulmonary and physical function in infants and young children with life-threatening hypophosphatasia. (Funded by Enobia Pharma and Shriners Hospitals for Children; ClinicalTrials.gov number, NCT00744042.).

OBJECTIVE: To evaluate the effects of therapeutic heparin compared with prophylactic heparin among moderately ill patients with covid-19 admitted to hospital wards. DESIGN: Randomised controlled, adaptive, open label clinical trial. SETTING: 28 hospitals in Brazil, Canada, Ireland, Saudi Arabia, United Arab Emirates, and US. PARTICIPANTS: 465 adults admitted to hospital wards with covid-19 and increased D-dimer levels were recruited between 29 May 2020 and 12 April 2021 and were randomly assigned to therapeutic dose heparin (n=228) or prophylactic dose heparin (n=237). INTERVENTIONS: Therapeutic dose or prophylactic dose heparin (low molecular weight or unfractionated heparin), to be continued until hospital discharge, day 28, or death. MAIN OUTCOME MEASURES: The primary outcome was a composite of death, invasive mechanical ventilation, non-invasive mechanical ventilation, or admission to an intensive care unit, assessed up to 28 days. The secondary outcomes included all cause death, the composite of all cause death or any mechanical ventilation, and venous thromboembolism. Safety outcomes included major bleeding. Outcomes were blindly adjudicated. RESULTS: . At 28 days, the primary composite outcome had occurred in 37/228 patients (16.2%) assigned to therapeutic heparin and 52/237 (21.9%) assigned to prophylactic heparin (odds ratio 0.69, 95% confidence interval 0.43 to 1.10; P=0.12). Deaths occurred in four patients (1.8%) assigned to therapeutic heparin and 18 patients (7.6%) assigned to prophylactic heparin (0.22, 0.07 to 0.65; P=0.006). The composite of all cause death or any mechanical ventilation occurred in 23 patients (10.1%) assigned to therapeutic heparin and 38 (16.0%) assigned to prophylactic heparin (0.59, 0.34 to 1.02; P=0.06). Venous thromboembolism occurred in two patients (0.9%) assigned to therapeutic heparin and six (2.5%) assigned to prophylactic heparin (0.34, 0.07 to 1.71; P=0.19). Major bleeding occurred in two patients (0.9%) assigned to therapeutic heparin and four (1.7%) assigned to prophylactic heparin (0.52, 0.09 to 2.85; P=0.69). CONCLUSIONS: In moderately ill patients with covid-19 and increased D-dimer levels admitted to hospital wards, therapeutic heparin was not significantly associated with a reduction in the primary outcome but the odds of death at 28 days was decreased. The risk of major bleeding appeared low in this trial. TRIAL REGISTRATION: ClinicalTrials.gov NCT04362085.

Abstract Background Anxiety disorders comprise some of the most common mental health conditions. This study examined the global and regional burden of anxiety disorders over the last three decades. The study was designed to help accurately target preventative and management efforts by highlighting trends and high-risk groups. Epidemiological data relating to anxiety disorders from the latest Global Burden of Disease dataset were analyzed to determine the prevalence, incidence, and disability adjusted life years (DALYs) rates from 1990 to 2019 for 204 countries and regions. Results An estimated 4.05% of the global population has an anxiety disorder, translating to 301 million people. The number of persons affected has increased by more than 55% from 1990 to 2019. Anxiety disorder metrics show a continuous increase in prevalence, incidence, and DALY rates. Portugal has the highest prevalence (8,671 cases per 100,000), followed by Brazil, Iran, and New Zealand. The prevalence is higher in high-income regions. Women are 1.66 times more likely to be affected by anxiety disorders than men. Age-standardized rates have remained stable, indicating the possible stability of risk factors. Conclusions The prevalence of anxiety disorders has been rising over the last three decades. The prevalence of anxiety appears to increase with socioeconomic development, a higher dependent older population, and urbanization. Future research on this topic could include the development of more accurate cross-cultural metrics to assess anxiety and its correlates, as well as population-based studies to assess trends in anxiety over time.

INTRODUCTION: Diabetes self-management education is a cornerstone of diabetes care. However, many diabetics in the United Arab Emirates (UAE) lack sufficient knowledge about their disease due to illiteracy. Thus, before considering any possible intervention it was imperative to assess present knowledge, attitudes, and practices of patients towards the management of diabetes. METHODS: A random sample of 575 DM patients was selected from diabetes outpatient's clinics of Tawam and Al-Ain hospitals in Al-Ain city (UAE) during 2006-2007, and their knowledge attitude and practice assessed using a questionnaire modified from the Michigan Diabetes Research Training Center instrument. RESULTS: Thirty-one percent of patients had poor knowledge of diabetes. Seventy-two had negative attitudes towards having the disease and 57% had HbA(1c) levels reflecting poor glycemic control. Only seventeen percent reported having adequate blood sugar control, while 10% admitted non-compliance with their medications. Knowledge, practice and attitude scores were all statistically significantly positively, but rather weakly, associated, but none of these scores was significantly correlated with HbA(1c). CONCLUSIONS: The study showed low levels of diabetes awareness but positive attitudes towards the importance of DM care and satisfactory diabetes practices in the UAE. Programs to increase patients' awareness about DM are essential for all diabetics in the UAE in order to improve their understanding, compliance and management and, thereby, their ability to cope with the disease.

This is the first completed prospective randomized clinical efficacy trial of antifungals in the treatment of invasive aspergillosis (IA) and the first to compare the clinical efficacy of two dosages of liposomal amphotericin B (L-AmB) for IA in neutropenic patients with cancer or those undergoing bone marrow transplantation. Eighty-seven of 120 patients were eligible and evaluable. Clinical responses were documented for 26 (64%) of 41 patients receiving 1 mg/(kg.d) (L-AmB-1) and 22 (48%) of 46 receiving 4 mg/(kg.d) (L-AmB-4). Radiologic response rates were similar: 24 (58%) of the L-AmB-1 recipients and 24(52%) of the L-AmB-4 recipients. The six-month survival rates were 43% (L-AmB-1) and 37% (L-AmB-4). These differences were not significant. The numbers of deaths directly due to IA at 6 months were similar: 9 (22%) of 41 L-AmB-1 recipients and 9 (20%) of 46 L-AmB-4 recipients. No other variable independently influenced survival, apart from central nervous system IA. L-AmB is effective in treating approximately 50%-60% of patients who have IA. A 1-mg/(kg.d) dosage is as effective as a 4-mg/(kg.d) dosage, and no advantages to use of the higher, more expensive, dosage has been observed.

This study examines the frequency of consanguineous marriage and the coefficient of inbreeding in the United Arab Emirates (UAE). The study was conducted in Al Ain and Dubai cities between October 1994 and March 1995. A sample of 2033 married UAE females aged 15 years and over participated. The degree of consanguinity between each female and her spouse, and the degree of consanguinity between their parents were recorded. The rate of consanguinity in the present generation was high (50.5%) with a coefficient of inbreeding of 0.0222. The commonest type of consanguineous marriage was between first cousins (26.2%). Double first cousin marriages were common (3.5%) compared to other populations. The consanguinity rate in the UAE has increased from 39% to 50.5% in one generation. The level of consanguinity was higher in Al Ain (54.2%) than in Dubai (40%).

UNLABELLED: In tumor response monitoring studies with (18)F-FDG PET, maximum standardized uptake value (SUV(max)) is commonly applied as a quantitative metric. Although it has several advantages due to its simplicity of determination, concerns about the influence of image noise on single-pixel SUV(max) persist. In this study, we measured aspects of bias and reproducibility associated with SUV(max) and the closely related peak SUV (SUV(peak)) using real patient data to provide a realistic noise context. METHODS: List-mode 3-dimensional PET data were acquired for 15 min over a single bed position in twenty (18)F-FDG oncology patients. For each patient, data were sorted so as to form 2 sets of images: respiration-gated images such that each image had statistical quality comparable to a 3 min/bed position scan, and 5 statistically independent (ungated) images of different durations (1, 2, 3, 4, and 5 min). Tumor SUV(max) and SUV(peak) (12-mm-diameter spheric region of interest positioned so as to maximize the enclosed average) were analyzed in terms of reproducibility and bias. The component of reproducibility due to statistical noise (independent of physiologic and other variables) was measured using paired SUVs from 2 comparable respiration-gated images. Bias was measured as a function of scan duration. RESULTS: Replicate tumor SUV measurements had a within-patient SD of 5.6% ± 0.9% for SUV(max) and 2.5% ± 0.4% for SUV(peak). SUV(max) had average positive biases of 30%, 18%, 12%, 4%, and 5% for the 1-, 2-, 3-, 4-, and 5-min images, respectively. SUV(peak) was also biased but to a lesser extent: 11%, 8%, 5%, 1%, and 4% for the 1-, 2-, 3-, 4-, and 5-min images, respectively. CONCLUSION: The advantages of SUV(max) are best exploited when PET images have a high statistical quality. For images with noise properties typically associated with clinical whole-body studies, SUV(peak) provides a slightly more robust alternative for assessing the most metabolically active region of tumor.

We aimed to assess global trends in Human Immunodeficiency Virus (HIV)/Acquired Immune Deficiency Syndrome (AIDS) and evaluate progress toward eradication since the inception of the pandemic. Data were extracted from the Global Burden of Disease 2019 update and the UNAIDS Data 2019. The datasets included annual figures from 1990 to 2019 for HIV/AIDS in 204 countries and all world regions. We analyzed rates and trends for prevalence, incidence, mortality and disability adjusted life years. Analysis of age and gender distribution in different regions was used to assess demographic changes. Forecasting was used to estimate disease burden up to 2040. Although many countries have witnessed a decrease in the incidence, for Russia, Ukraine, Portugal, Brazil, Spain and the United States, the rates of new cases are rising since 2010. This trend is present even in age-standardized analysis, indicating a rise in excess of population growth. Over 0.5% of the world's population is infected. About 5000 new infections occur daily, of which 500 are children. Mortality rates are falling globally; currently at 11 deaths per 100,000 population, forecasted to decrease to 8.5 deaths by 2040. Prevalence continues to increase, with South Africa, Nigeria, Mozambique, India, Kenya and the United States having the highest burden. The total number as well as the rates of new HIV infections are rising every year in Europe, South America, North America and other regions over the last decade. Maternal-to-child transmission continues at high rates despite effective preventive regimens. There is an urgent need to develop programs to curb the rising incidence of HIV.

UNLABELLED: Saffron has been proposed as a promising candidate for cancer chemoprevention. The purpose of this investigation was to investigate the chemopreventive action and the possible mechanisms of saffron against diethylnitrosamine (DEN)-induced liver cancer in rats. Administration of saffron at doses of 75, 150, and 300 mg/kg/day was started 2 weeks prior to the DEN injection and was continued for 22 weeks. Saffron significantly reduced the DEN-induced increase in the number and the incidence of hepatic dyschromatic nodules. Saffron also decreased the number and the area of placental glutathione S-transferase-positive foci in livers of DEN-treated rats. Furthermore, saffron counteracted DEN-induced oxidative stress in rats as assessed by restoration of superoxide dismutase, catalase, and glutathione-S-transferase levels and diminishing of myeloperoxidase activity, malondialdehyde and protein carbonyl formation in liver. The results of immunohistochemical staining of rat liver showed that saffron inhibited the DEN-mediated elevations in numbers of cells positive for Ki-67, cyclooxygenase 2, inducible nitric oxide synthase, nuclear factor-kappa B p-65, and phosphorylated tumor necrosis factor receptor. Saffron also blocked the depletion in the number of cells positive for TUNEL (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling) and M30 CytoDeath in liver tissues of DEN-treated rats. In vitro experiments carried out using HepG2 cells also confirmed these findings and showed inhibition of nuclear factor-kappa B activation, increased cleavage of caspase-3, as well as DNA damage and cell cycle arrest upon saffron treatment. CONCLUSION: This study provides evidence that saffron exerts a significant chemopreventive effect against liver cancer through inhibition of cell proliferation and induction of apoptosis. This report also shows some evidence that saffron protects rat liver from cancer via modulating oxidative damage and suppressing inflammatory response.

Mitochondria are found in all nucleated human cells and perform various essential functions, including the generation of cellular energy. Mitochondria are under dual genome control. Only a small fraction of their proteins are encoded by mitochondrial DNA (mtDNA), whereas more than 99% of them are encoded by nuclear DNA (nDNA). Mutations in mtDNA or mitochondria-related nDNA genes result in mitochondrial dysfunction leading to insufficient energy production required to meet the needs for various organs, particularly those with high energy requirements, including the central nervous system, skeletal and cardiac muscles, kidneys, liver, and endocrine system. Because cardiac muscles are one of the high energy demanding tissues, cardiac involvement occurs in mitochondrial diseases with cardiomyopathies being one of the most frequent cardiac manifestations found in these disorders. Cardiomyopathy is estimated to occur in 20-40% of children with mitochondrial diseases. Mitochondrial cardiomyopathies can vary in severity from asymptomatic status to severe manifestations including heart failure, arrhythmias, and sudden cardiac death. Hypertrophic cardiomyopathy is the most common type; however, mitochondrial cardiomyopathies might also present as dilated, restrictive, left ventricular non-compaction, and histiocytoid cardiomyopathies. Cardiomyopathies are frequent manifestations of mitochondrial diseases associated with defects in electron transport chain complexes subunits and their assembly factors, mitochondrial transfer RNAs, ribosomal RNAs, ribosomal proteins, translation factors, mtDNA maintenance, and coenzyme Q10 synthesis. Other mitochondrial diseases with cardiomyopathies include Barth syndrome, Sengers syndrome, TMEM70-related mitochondrial complex V deficiency, and Friedreich ataxia.

BACKGROUND: Breastfeeding is the preferred method of feeding for the infant. The present study aimed at investigating the different infant feeding practices and the influencing factors in the United Arab Emirates (UAE). METHODS: A convenient sample of 593 Emirati mothers who had infants up to 2 years of age was interviewed. The interviews included a detailed questionnaire and conducted in the Maternal and Child Health Centers (MCH) and Primary Health Centers (PHC) in three cities. RESULTS: Almost all the mothers in the study had initiated breastfeeding (98%). The mean duration of breastfeeding was 8.6 months. The initiation and duration of breastfeeding rates were influenced by mother's age (P<0.034)and education(P<0.01), parity(OR=2.13; P<0.001), rooming in(OR=21.70; P<0.001), nipple problem(P<0.010) and use of contraception(P<0.034). As for the feeding patterns, the results of the multiple logistic analyses revealed that rooming in (OR=4.48; P<0.001), feeding on demand (OR=2.29; P<0.005) and feeding more frequently at night (P<0.001) emerged as significant factors associated with exclusive or predominantly breastfeeding practices. Among the 593 infants in the study, 24.1% had complementary feeding, 25% of the infants were exclusively breastfed, and 49.4% were predominantly breastfed since birth. About 30% of the infants were given nonmilk fluids such as: Anis seed drink (Yansun), grippe water and tea before 3 months of age. The majority of the infants (83.5%) in the three areas received solid food before the age of 6 months. A variety of reasons were reported as perceived by mothers for terminating breastfeeding. The most common reasons were: new pregnancy (32.5%), insufficient milk supply (24.4%) and infant weaned itself (24.4%). CONCLUSIONS: In conclusion, infant and young child feeding practices in this study were suboptimal. There is a need for a national community-based breastfeeding intervention programme and for the promotion of exclusive breastfeeding as part of a primary public health strategy to decrease health risks and problems in the UAE.

OBJECTIVE: To determine the impact of the International Association of Diabetes and Pregnancy Study Group (IADPSG) criteria on 1) gestational diabetes mellitus (GDM) diagnosis compared with the American Diabetes Association (ADA) criteria and 2) the fasting plasma glucose (FPG) to predict GDM. RESEARCH DESIGN AND METHODS: In 10,283 pregnant women undergoing a 75-g oral glucose tolerance test (OGTT) for universal screening of GDM, two FPG thresholds (of the OGTT) were used to rule in and to rule out GDM. RESULTS: The IADPSG and ADA criteria identified GDM in 3,875 (37.7%) women and 1,328 (12.9%) women, respectively (P < 0.0005). FPG thresholds of >or=5.1 mmol/l ruled in GDM in 2,975 (28.9%) women with 100% specificity, while <4.4 mmol/l ruled out GDM in 2,228 (21.7%) women with 95.4% sensitivity. FPG independently could have avoided the OGTT in 5,203 (50.6%) women. CONCLUSIONS: The IADPSG criteria increased GDM prevalence nearly threefold. By circumventing a significant number of OGTTs, an initial FPG can greatly simplify the IADPSG diagnostic algorithm.

BACKGROUND: Vitamin D (vD) deficiency in pregnancy is a global health problem and the amount of vD supplementation to prevent vD deficiency is controversial. OBJECTIVE: The objective of the study was to determine effectiveness and safety of prenatal 2000 IU and 4000 IU/d compared with 400 IU/d vD3 supplementation in a randomized controlled trial in population in which vD deficiency is endemic. DESIGN/METHODS: Arab women were randomized at 12-16 weeks of gestation to 400, 2000, and 4000 IU/d vD3, which were continued to delivery. Serum 25-hydroxyvitamin D [25(OH)D] concentrations were measured during pregnancy and at delivery. The primary outcome was the maternal and cord blood 25(OH)D, and the secondary outcomes were the achievement of sufficient serum 25(OH)D of 32 ng/mL or greater (≥80 nmol/L) at delivery. SETTING: The locations were primary care and tertiary perinatal care centers. RESULTS: Of 192 enrolled, 162 (84%) continued to delivery. Mean serum 25(OH)D of 8.2 ng/mL (20.5 nmol/L) at enrollment was low. Mean serum 25(OH)D concentrations at delivery and in cord blood were significantly higher in the 2000 and 4000 IU than the 400 IU/d group (P < .001) and was highest in the 4000 IU/d group. The percent who achieved 25(OH)D greater than 32 ng/mL and greater than 20 ng/mL concentrations in mothers and infants was highest in 4000 IU/d group. Safety measurements were similar by group and no adverse event related to vD supplementation. CONCLUSIONS: Vitamin D supplementation of 2000 and 4000 IU/d appeared safe in pregnancy, and 4000 IU/d was most effective in optimizing serum 25(OH)D concentrations in mothers and their infants. These findings could apply to other populations in which vD deficiency is endemic.

The growth hormone (GH)-insulin-like growth factor (IGF)-I axis is a key endocrine mechanism regulating linear growth in children. While paediatricians have a good knowledge of GH secretion and assessment, understanding and use of measurements of the components of the IGF system are less current in clinical practice. The physiological function of this axis is to increase the anabolic cellular processes of protein synthesis and mitosis, and reduction of apoptosis, with each being regulated in the appropriate target tissue. Measurement of serum IGF-I and IGF-binding protein (IGFBP)-3 concentrations can complement assessment of GH status in the investigation of short stature and contribute to prediction of growth response during GH therapy. IGF-I monitoring during GH therapy also informs the clinician about adherence and provides a safety reference to avoid over-dosing during long-term management.

Cancer is the second leading cause of death worldwide. Conventional therapies cause serious side effects and, at best, merely extend the patient's lifespan by a few years. Cancer control may therefore benefit from the potential that resides in alternative therapies. There is thus an increasing demand to utilize alternative concepts or approaches to the prevention of cancer. In this report, we show a potential protective effect of Fenugreek seeds against 7,12-dimethylbenz(alpha)anthracene (DMBA)-induced breast cancer in rats. At 200 mg/kg b.wt., Fenugreek seeds' extract significantly inhibited the DMBA-induced mammary hyperplasia and decreased its incidence. Epidemiological studies also implicate apoptosis as a mechanism that might mediate the Fenugreek's anti-breast cancer protective effects. To our knowledge, this is the first study that suggests significant chemopreventive effects of Fenugreek seeds against breast cancer.

The COVID-19 pandemic is one of the most serious global challenges to delivering affordable and equitable treatment to children with cancer we have witnessed in the last few decades. This Special Report aims to summarize general principles for continuing multidisciplinary care during the SARS-CoV-2 (COVID-19) pandemic. With contributions from the leadership of the International Society for Pediatric Oncology (SIOP), Children's Oncology Group (COG), St Jude Global program, and Childhood Cancer International, we have sought to provide a framework for healthcare teams caring for children with cancer during the pandemic. We anticipate the burden will fall particularly heavily on children, their families, and cancer services in low- and middle-income countries. Therefore, we have brought together the relevant clinical leads from SIOP Europe, COG, and SIOP-PODC (Pediatric Oncology in Developing Countries) to focus on the six most curable cancers that are part of the WHO Global Initiative in Childhood Cancer. We provide some practical advice for adapting diagnostic and treatment protocols for children with cancer during the pandemic, the measures taken to contain it (e.g., extreme social distancing), and how to prepare for the anticipated recovery period.

Detailed, country-specific epidemiological data are needed to characterize the burden of chronic hepatitis C virus (HCV) infection around the world. With new treatment options available, policy makers and public health officials must reconsider national strategies for infection control. In this study of 15 countries, published and unpublished data on HCV prevalence, viraemia, genotype, age and gender distribution, liver transplants and diagnosis and treatment rates were gathered from the literature and validated by expert consensus in each country. Viraemic prevalence in this study ranged from 0.2% in Iran and Lebanon to 4.2% in Pakistan. The largest viraemic populations were in Pakistan (7 001 000 cases) and Indonesia (3 187 000 cases). Injection drug use (IDU) and a historically unsafe blood supply were major risk factors in most countries. Diagnosis, treatment and liver transplant rates varied widely between countries. However, comparison across countries was difficult as the number of cases changes over time. Access to reliable data on measures such as these is critical for the development of future strategies to manage the disease burden.

Multiple sclerosis (MS) is a chronic neuroinflammatory condition of the central nervous system (CNS). It is a major cause of neurological disability in young adults, particularly women. What triggers the destruction of myelin sheaths covering nerve fibres is unknown. Both genetic and infectious agents have been implicated. Of the infectious agents, Epstein-Barr virus (EBV), a common herpesvirus, has the strongest epidemiological and serological evidence. However, the presence of EBV in the CNS and demonstration of the underlying mechanism(s) linking EBV to the pathogenesis of MS remain to be elucidated. We aimed at understanding the contribution of EBV infection in the pathology of MS. We examined 1055 specimens (440 DNA samples and 615 brain tissues) from 101 MS and 21 non-MS cases for the presence of EBV using PCR and EBER-in situ hybridization (EBER-ISH). EBV was detected by PCR and/or EBER-ISH in 91/101 (90%) of MS cases compared to only 5/21 (24%) of non-MS cases with other neuropathologies. None of the samples were PCR positive for other common herpesviruses (HSV-1, CMV, HHV-6). By quantitative PCR, EBV viral load in MS brain was mainly low to moderate in most cases. However, in 18/101 (18%) of MS cases, widespread but scattered presence of EBV infected cells was noted in the affected tissues by EBER-ISH. Immunohistochemical analysis of EBV gene expression in the 18 heavily infected cases, revealed that the EBV latent protein EBNA1, and to a lesser extent the early lytic protein BZLF1 were expressed. Furthermore, using double-staining we show for the first time that astrocytes and microglia, in addition to B-cells can also be infected. To the best of our knowledge, this is the most comprehensive study demonstrating that EBV is present and transcriptionally active in the brain of most cases of MS and supports a role for the virus in MS pathogenesis. Further studies are required to address the mechanism of EBV involvement in MS pathology.

Background: High expression of immune checkpoints in tumor microenvironment plays significant roles in inhibiting anti-tumor immunity, which is associated with poor prognosis and cancer progression. Major epigenetic modifications in both DNA and histone could be involved in upregulation of immune checkpoints in cancer. Methods: Expressions of different immune checkpoint genes and PD-L1 were assessed using qRT-PCR, and the underlying epigenetic modifications including CpG methylation and repressive histone abundance were determined using bisulfite sequencing, and histone 3 lysine 9 trimethylation (H3K9me3) and histone 3 lysine 27 trimethylation (H3K27me3) chromatin immunoprecipitation assays (ChIP), respectively. Results: We first assessed the expression level of six immune checkpoints/ligands and found that PD-1, CTLA-4, TIM-3, and LAG-3 were significantly upregulated in breast tumor tissues (TT), compared with breast normal tissues (NT). We investigated the epigenetic modifications beyond this upregulation in immune checkpoint genes. Interestingly, we found that CpG islands in the promoter regions of PD-1, CTLA-4, and TIM-3 were significantly hypomethylated in tumor compared with normal tissues. Additionally, CpG islands of PD-L1 promoter were completely demethylated (100%), LAG-3 were highly hypomethylated (80-90%), and TIGIT were poorly hypomethylated (20-30%), in both NT and TT. These demethylation findings are in accordance with the relative expression data that, out of all these genes, PD-L1 was highly expressed and completely demethylated and TIGIT was poorly expressed and hypermethylated in both NT and TT. Moreover, bindings of H3K9me3 and H3K27me3 were found to be reduced in the promoter loci of PD-1, CTLA-4, TIM-3, and LAG-3 in tumor tissues. Conclusion: Our data demonstrate that both DNA and histone modifications are involved in upregulation of PD-1, CTLA-4, TIM-3, and LAG-3 in breast tumor tissue and these epigenetic modifications could be useful as diagnostic/prognostic biomarkers and/or therapeutic targets in breast cancer.

Death rates due to COVID-19 pandemic vary considerably across regions and countries. Case Mortality Rates (CMR) per 100,000 population are more reliable than case-fatality rates per 100 test-positive cases, which are heavily dependent on the extent of viral case testing carried out in a country. We aimed to study the variations in CMR against population risk factors such as aging, underlying chronic diseases and social determinants such as poverty and overcrowding. Data on COVID-19 CMR in 93 countries was analyzed for associations with preexisting prevalence rates of eight diseases [asthma, lung cancer, Chronic Obstructive Pulmonary Disease (COPD), Alzheimer's Disease (AD), hypertension, ischemic heart disease, depression and diabetes], and six socio-demographic factors [Gross Domestic Product (GDP) per capita, unemployment, age over 65 years, urbanization, population density, and socio-demographic index]. These data were analyzed in three steps: correlation analysis, bivariate comparison of countries, and multivariate modelling. Bivariate analysis revealed that COVID-19 CMR were higher in countries that had high prevalence of population risk factors such as AD, lung cancer, asthma and COPD. On multivariate modeling however, AD, COPD, depression and higher GDP predicted increased death rates. Comorbid illnesses such as AD and lung diseases may be more influential than aging alone.