Genetic causes of Parkinson’s disease in the Maltese : a study of selected mutations in LRRK2, MTHFR, QDPR and SPR

The samples and data used in this study were collected as part of the 5th framework (FP5) EU funded Geoparkinson study, project number QLK4‐CT‐ 1999‐01133. The Maltese arm of this group included Prof Christian Scerri, Dr Joseph Borg, Dr Karen Cassar, Ms Wilma Cassar, Ms Ruth Galdies, Dr Norbert Vella, Dr Vicky Mifsud, Dr Josanne Aquilina and Dr Galea Debono.Background: Mutations in Leucine-rich repeat kinase 2 NM_198578 (LRRK2 c.6055G>A (p.G2019S), LRRK2 c.4321C>G (p.R1441G)) and alpha-synuclein NM_000345 (SNCA c.209G>A (p.A53T)) genes causing Parkinson's disease (PD) are common in Mediterranean populations. Variants in the Quinoid Dihydropteridine Reductase NM_000320 (QDPR c.68G>A (p.G23D)), Sepiapterin Reductase NM_003124 (SPR c.596-2A>G) and Methylenetetrahydrofolate Reductase NM_005957 (MTHFR c.677C>T and c.1298A>C) genes are frequent in Malta and potential candidates for PD. Methods: 178 cases and 402 control samples from Malta collected as part of the Geoparkinson project were genotyped for MTHFR polymorphisms, QDPR and SPR mutations. Only PD and parkinsonism cases were tested for SNCA and LRRK2 mutations. Results: LRRK2 c.4321C>G and SNCA c.209G>A were not detected. The LRRK2 c.6055G>A mutation was found in 3.1 % of Maltese PD cases. The QDPR mutation was found in both cases and controls and did not increase risk for PD. The SPR mutation was found in controls only. The odds ratios for MTHFR polymorphisms were not elevated. Conclusions: The LRRK2 c.6055G>A is a cause of PD in the Maltese, whilst QDPR c.68G>A, SPR c.596-2A>G and MTHFR c.677C>T and c.1298A>C are not important determinants of PD.The samples and data used in this study were collected as part of the 5th framework (FP5) EU funded Geoparkinson study, project number QLK4‐CT‐ 1999‐01133. This work was supported by research grants of SBW and RF from the University of Malta. The funders played no other part in the research or its interpretation.peer-reviewe

CYP2C19 genetic polymorphisms in Maltese patients on clopidogrel therapy

Introduction and Aims: The prevalence of CYP2C19 genetic polymorphisms in the Maltese population is not reported. The aims were to determine CYP2C19 *2 and *17 allele frequencies and CYP2C19 genotype distribution in a cohort of Maltese patients on clopidogrel and to compare observed frequencies of the CYP2C19 *2 allele and *2/*2 genotype to other populations bordering the Mediterranean Sea. Methods: Genotyping for the CYP2C19 *2 and *17 alleles in Maltese patients on clopidogrel was performed using TaqMan® drug metabolism assays. The frequency of both alleles and six genotypes (*1/*1, *1/*2, *2/*2, *1/*17, *17/*17, *2/*17) were determined. Observed frequencies of the CYP2C19 *2 allele and *2/*2 genotype were compared to fourteen populations bordering the Mediterranean Sea (p>0.05 indicated similar prevalence) Results: Frequencies of the CYP2C19 *2 and *17 alleles in the 244 patients genotyped were 12.3% and 15.4% respectively. CYP2C19 genotype distribution was: *1/*1 (52.1%), *1/*17 (22.5%), *1/*2 (18.0%), 2/*17 (6.6%), *17/*17 (0.8%) and *2/*2 (0). Prevalence of the *2 allele in the Maltese cohort was similar to all fourteen populations bordering the Mediterranean Sea, while prevalence of *2/*2 was similar to Egyptian, Moroccan, Southern French, Slovenian, Turkish and Tunisian populations (p>0.05). Conclusions: This study provides an indication of the prevalence of CYP2C19 polymorphisms in Maltese patients. The high percentage of patients with CYP2C19 IM or UM phenotype demonstrates that CYP2C19 genotyping could aid clinicians to individualise treatment with clopidogrel and other drugs metabolised by the CYP2C19 enzyme.peer-reviewe

CYP2C19*2 allele carrier status and coronary in-stent restenosis : is there an association?

Background and objective: The CYP2C19*2 allele is associated with reduced clopidogrel bioactivation, increasing the risk of complications after percutaneous coronary intervention (PCI), particularly stent thrombosis. Recently published data suggests that CYP2C19*2 allele carriers have a higher risk for in-stent restenosis (ISR) after endovascular treatment. Very few studies have investigated the relationship between CYP2C19*2 and coronary ISR, with no significant association reported. The objective of this study was to assess the relationship between CYP2C19*2 allele carrier status and coronary ISR. Methods: Patients with previous PCI with stenting and who were scheduled for elective PCI after coronary angiogram were recruited from the cardiac catheterization suite over a 12-month period. The angiography report of each patient was perused to identify patients requiring PCI due to ISR. For patients with angiography-confirmed ISR, date of previous PCI to the restenosed stent was noted. CYP2C19*2 genotyping was undertaken using a TaqMan® Drug Metabolism assay. The association between CYP2C19*2 allele carrier status and incidence of coronary ISR within 1 year was assessed using Fisher’s exact test (p < 0.05 significance) and by calculating the odds ratio (OR) with a 95% confidence interval (CI). Results: Of the 82 patients with previous PCI, 29 (35.4%) had angiography-confirmed ISR (12 carriers, 17 noncarriers of CYP2C19*2). In 13 (44.8%) of these patients, the restenosed stent was deployed within 1 year and the patients were on clopidogrel therapy at the time of repeat PCI (8 carriers, 5 non-carriers of CYP2C19*2). The association between CYP2C19*2 allele carrier status and ISR within 1 year was not statistically significant (Fisher’s exact p = 0.067; OR: 4.80, 95% CI: 0.98–23.54, p = 0.053). Conclusions: Despite a higher proportion of CYP2C19*2 allele carriers exhibiting ISR within 1 year compared to non-carriers, the association was not statistically significant. This result may be attributed to the small sample size, and larger prospective studies are recommended to further assess this association.peer-reviewe

The distribution and prevalence of HPV genotype in Maltese women diagnosed with CIN 3 and cervical cancer

Introduction: The Human papilloma virus (HPV) is the causative agent of cervical carcinoma in women. There is a global variation of HPV genotypes that are highly carcinogenic. The aim of this study was to estimate the prevalence and type - specific distribution of HPV genotype in Maltese patients who were previously diagnosed with cervical intraepithelial neoplasia 3 (CIN 3) or cervical carcinoma.peer-reviewe

Repositioning of the global epicentre of non-optimal cholesterol

High blood cholesterol is typically considered a feature of wealthy western countries(1,2). However, dietary and behavioural determinants of blood cholesterol are changing rapidly throughout the world(3) and countries are using lipid-lowering medications at varying rates. These changes can have distinct effects on the levels of high-density lipoprotein (HDL) cholesterol and non-HDL cholesterol, which have different effects on human health(4,5). However, the trends of HDL and non-HDL cholesterol levels over time have not been previously reported in a global analysis. Here we pooled 1,127 population-based studies that measured blood lipids in 102.6 million individuals aged 18 years and older to estimate trends from 1980 to 2018 in mean total, non-HDL and HDL cholesterol levels for 200 countries. Globally, there was little change in total or non-HDL cholesterol from 1980 to 2018. This was a net effect of increases in low- and middle-income countries, especially in east and southeast Asia, and decreases in high-income western countries, especially those in northwestern Europe, and in central and eastern Europe. As a result, countries with the highest level of non-HDL cholesterol-which is a marker of cardiovascular riskchanged from those in western Europe such as Belgium, Finland, Greenland, Iceland, Norway, Sweden, Switzerland and Malta in 1980 to those in Asia and the Pacific, such as Tokelau, Malaysia, The Philippines and Thailand. In 2017, high non-HDL cholesterol was responsible for an estimated 3.9 million (95% credible interval 3.7 million-4.2 million) worldwide deaths, half of which occurred in east, southeast and south Asia. The global repositioning of lipid-related risk, with non-optimal cholesterol shifting from a distinct feature of high-income countries in northwestern Europe, north America and Australasia to one that affects countries in east and southeast Asia and Oceania should motivate the use of population-based policies and personal interventions to improve nutrition and enhance access to treatment throughout the world.Peer reviewe

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Height and body-mass index trajectories of school-aged children and adolescents from 1985 to 2019 in 200 countries and territories: a pooled analysis of 2181 population-based studies with 65 million participants

Summary Background Comparable global data on health and nutrition of school-aged children and adolescents are scarce. We aimed to estimate age trajectories and time trends in mean height and mean body-mass index (BMI), which measures weight gain beyond what is expected from height gain, for school-aged children and adolescents. Methods For this pooled analysis, we used a database of cardiometabolic risk factors collated by the Non-Communicable Disease Risk Factor Collaboration. We applied a Bayesian hierarchical model to estimate trends from 1985 to 2019 in mean height and mean BMI in 1-year age groups for ages 5–19 years. The model allowed for non-linear changes over time in mean height and mean BMI and for non-linear changes with age of children and adolescents, including periods of rapid growth during adolescence. Findings We pooled data from 2181 population-based studies, with measurements of height and weight in 65 million participants in 200 countries and territories. In 2019, we estimated a difference of 20 cm or higher in mean height of 19-year-old adolescents between countries with the tallest populations (the Netherlands, Montenegro, Estonia, and Bosnia and Herzegovina for boys; and the Netherlands, Montenegro, Denmark, and Iceland for girls) and those with the shortest populations (Timor-Leste, Laos, Solomon Islands, and Papua New Guinea for boys; and Guatemala, Bangladesh, Nepal, and Timor-Leste for girls). In the same year, the difference between the highest mean BMI (in Pacific island countries, Kuwait, Bahrain, The Bahamas, Chile, the USA, and New Zealand for both boys and girls and in South Africa for girls) and lowest mean BMI (in India, Bangladesh, Timor-Leste, Ethiopia, and Chad for boys and girls; and in Japan and Romania for girls) was approximately 9–10 kg/m2. In some countries, children aged 5 years started with healthier height or BMI than the global median and, in some cases, as healthy as the best performing countries, but they became progressively less healthy compared with their comparators as they grew older by not growing as tall (eg, boys in Austria and Barbados, and girls in Belgium and Puerto Rico) or gaining too much weight for their height (eg, girls and boys in Kuwait, Bahrain, Fiji, Jamaica, and Mexico; and girls in South Africa and New Zealand). In other countries, growing children overtook the height of their comparators (eg, Latvia, Czech Republic, Morocco, and Iran) or curbed their weight gain (eg, Italy, France, and Croatia) in late childhood and adolescence. When changes in both height and BMI were considered, girls in South Korea, Vietnam, Saudi Arabia, Turkey, and some central Asian countries (eg, Armenia and Azerbaijan), and boys in central and western Europe (eg, Portugal, Denmark, Poland, and Montenegro) had the healthiest changes in anthropometric status over the past 3·5 decades because, compared with children and adolescents in other countries, they had a much larger gain in height than they did in BMI. The unhealthiest changes—gaining too little height, too much weight for their height compared with children in other countries, or both—occurred in many countries in sub-Saharan Africa, New Zealand, and the USA for boys and girls; in Malaysia and some Pacific island nations for boys; and in Mexico for girls. Interpretation The height and BMI trajectories over age and time of school-aged children and adolescents are highly variable across countries, which indicates heterogeneous nutritional quality and lifelong health advantages and risks

Rising rural body-mass index is the main driver of the global obesity epidemic in adults

Body-mass index (BMI) has increased steadily in most countries in parallel with a rise in the proportion of the population who live in cities(.)(1,2) This has led to a widely reported view that urbanization is one of the most important drivers of the global rise in obesity(3-6). Here we use 2,009 population-based studies, with measurements of height and weight in more than 112 million adults, to report national, regional and global trends in mean BMI segregated by place of residence (a rural or urban area) from 1985 to 2017. We show that, contrary to the dominant paradigm, more than 55% of the global rise in mean BMI from 1985 to 2017-and more than 80% in some low- and middle-income regions-was due to increases in BMI in rural areas. This large contribution stems from the fact that, with the exception of women in sub-Saharan Africa, BMI is increasing at the same rate or faster in rural areas than in cities in low- and middle-income regions. These trends have in turn resulted in a closing-and in some countries reversal-of the gap in BMI between urban and rural areas in low- and middle-income countries, especially for women. In high-income and industrialized countries, we noted a persistently higher rural BMI, especially for women. There is an urgent need for an integrated approach to rural nutrition that enhances financial and physical access to healthy foods, to avoid replacing the rural undernutrition disadvantage in poor countries with a more general malnutrition disadvantage that entails excessive consumption of low-quality calories.Peer reviewe

Seasonal and inter-seasonal RSV activity in the European Region during the COVID-19 pandemic from autumn 2020 to summer 2022

© 2023 The Authors. Influenza and Other Respiratory Viruses published by John Wiley & Sons Ltd.Background: The emergence of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in early 2020 and subsequent implementation of public health and social measures (PHSM) disrupted the epidemiology of respiratory viruses. This work describes the epidemiology of respiratory syncytial virus (RSV) observed during two winter seasons (weeks 40–20) and inter-seasonal periods (weeks 21–39) during the pandemic between October 2020 and September 2022. Methods: Using data submitted to The European Surveillance System (TESSy) by countries or territories in the World Health Organization (WHO) European Region between weeks 40/2020 and 39/2022, we aggregated country-specific weekly RSV counts of sentinel, non-sentinel and Severe Acute Respiratory Infection (SARI) surveillance specimens and calculated percentage positivity. Results for both 2020/21 and 2021/22 seasons and inter-seasons were compared with pre-pandemic 2016/17 to 2019/20 seasons and inter-seasons. Results: Although more specimens were tested than in pre-COVID-19 pandemic seasons, very few RSV detections were reported during the 2020/21 season in all surveillance systems. During the 2021 inter-season, a gradual increase in detections was observed in all systems. In 2021/22, all systems saw early peaks of RSV infection, and during the 2022 inter-seasonal period, patterns of detections were closer to those seen before the COVID-19 pandemic. Conclusion: RSV surveillance continued throughout the COVID-19 pandemic, with an initial reduction in transmission, followed by very high and out-of-season RSV circulation (summer 2021) and then an early start of the 2021/22 season. As of the 2022/23 season, RSV circulation had not yet normalised.Peer reviewe