Magnitude and determinants of excess total, age-specific and sex-specific all-cause mortality in 24 countries worldwide during 2020 and 2021: results on the impact of the COVID-19 pandemic from the C-MOR project.

INTRODUCTION: To examine the impact of the COVID-19 pandemic on mortality, we estimated excess all-cause mortality in 24 countries for 2020 and 2021, overall and stratified by sex and age. METHODS: Total, age-specific and sex-specific weekly all-cause mortality was collected for 2015-2021 and excess mortality for 2020 and 2021 was calculated by comparing weekly 2020 and 2021 age-standardised mortality rates against expected mortality, estimated based on historical data (2015-2019), accounting for seasonality, and long-term and short-term trends. Age-specific weekly excess mortality was similarly calculated using crude mortality rates. The association of country and pandemic-related variables with excess mortality was investigated using simple and multilevel regression models. RESULTS: Excess cumulative mortality for both 2020 and 2021 was found in Austria, Brazil, Belgium, Cyprus, England and Wales, Estonia, France, Georgia, Greece, Israel, Italy, Kazakhstan, Mauritius, Northern Ireland, Norway, Peru, Poland, Slovenia, Spain, Sweden, Ukraine, and the USA. Australia and Denmark experienced excess mortality only in 2021. Mauritius demonstrated a statistically significant decrease in all-cause mortality during both years. Weekly incidence of COVID-19 was significantly positively associated with excess mortality for both years, but the positive association was attenuated in 2021 as percentage of the population fully vaccinated increased. Stringency index of control measures was positively and negatively associated with excess mortality in 2020 and 2021, respectively. CONCLUSION: This study provides evidence of substantial excess mortality in most countries investigated during the first 2 years of the pandemic and suggests that COVID-19 incidence, stringency of control measures and vaccination rates interacted in determining the magnitude of excess mortality.

An Increased Risk for Ischemic Stroke in the Short-Term Period following COVID-19 Infection: A Nationwide Population-Based Study.

INTRODUCTION: The association disclosed between coronavirus disease 2019 (COVID-19) infection and ischemic stroke (IS) raises concern. The exact risk periods, which were not consistent between studies, require further investigation. METHODS: We linked two national databases: the COVID-19 database and the Israeli National Stroke Registry. The self-controlled case series method was used to estimate the association between COVID-19 infection and a first IS. The study population included all Israeli residents who had both a first IS event and a first COVID-19 diagnosis during 2020. The date of the PCR test served to define the day of exposure, and the 28 days following it were categorized into three risk periods: days 1-7, 8-14, and 15-28. A relative incidence (RI) with a 95% confidence interval (95% CI) was calculated based on the incidence rate of events in a post-exposure period, compared to the incidence rate in a control period. RESULTS: From January 1, 2020, to December 31, 2020, 308,015 Israelis aged 18+ were diagnosed with COVID-19 and 9,535 were diagnosed with a first IS. Linking the two databases, 555 persons had both diagnoses during 2020. The mean age of the study population was 71.5 ± 13.7, 55.1% were males, 77.8% had hypertension, 73.7% had hyperlipidemia, 51.9% had diabetes, and 28.5% had ischemic heart disease. Comparing the risk period and the control period, we found a very similar distribution of the cardiovascular risk factors. The risk for an acute IS was 3.3-fold higher in the first week following COVID-19 diagnosis, compared with a control period (RI = 3.3; 95% CI: 2.3-4.6). The RI among males (RI = 4.5; 95% CI: 2.9-6.8) was 2.2-fold higher compared to females. The increased risk did not last beyond the first week following exposure. CONCLUSION: Physicians should be aware of the elevated risk for IS among patients experiencing COVID-19, particularly among men with high burden of cardiovascular risk factors.

A Short Profile of Hypnotherapy Licensure in Israel.

In Israel, only physicians, dentists, and psychologists who complete an accredited licensing process may practice hypnosis. This study examines the characteristics of hypnotherapists compared to nonhypnotherapists in the same discipline. All hypnotherapists in Israel were compared to nonhypnotherapist health professionals. There are more subspecialists among hypnotists, and the most common specialties were psychiatry, pediatric dentistry, and clinical psychology. These findings imply self-sorting of hypnotists as a result of the regulation in Israel. Licensure of hypnotherapists could be useful in other countries by comprehensive follow-up of all licensed hypnotists and by improving public and health professional perceptions of the field and its relevance to clinical practice.

Membrane-delimited proteolytic regulation of opioid receptors.

Prolonged exposure of opioid receptors to agonists leads to their regulation by the classical process of clathrin-dependent internalization, followed by their intracellular degradation (down regulation). We have previously shown that the opioid agonist etorphine induced an additional process of down regulation of mu-opioid receptors (MOR) that occurred in intact MOR-transfected HEK-293 cells, as well as in isolated membranes. In the present study we show that etorphine similarly down regulated rat kappa-opioid receptors (KORs), which do not undergo the classical process of internalization and down regulation. This process was resistant to inhibitors of clathrin-coated pit formation (hypertonic sucrose, mono-dansyl-cadaverine) and was mainly mediated by membranous serine- and amino-peptidases. We further show that various opioid ligands, besides etorphine, induced down regulation of either KOR or MOR in isolated membranes. The ability of the various opioid ligands to induce membrane-delimited KOR or MOR down regulation did not correlate to their classical pharmacological profile, suggesting functional selectivity of the effect. Levorphanol, but not its stereoisomer dextrophan, induced membrane-delimited down regulation of both KOR and MOR, indicating that stereoselective binding to the receptor was necessary to initiate the process. Our findings that this proteolytic regulation of opioid receptors occurs not only in isolated membranes but also in intact cells and that it occurs even when the receptors are resistant to the conventional process of down regulation indicate its possible physiological role in the regulation of opioid activity.

Agonist-specific down regulation of mu-opioid receptors: Different cellular pathways are activated by different opioid agonists.

Opioid agonists are known to induce down regulation of opioid receptors through the classical pathway that involves phosphorylation, clathrin-dependent endocytosis and lysosomal/endosomal degradation of the internalized receptors. As expected, exposure of mu-opioid receptor (MOR)-transfected HEK-293 cells to either DAMGO (a specific mu-opioid agonist) or etorphine (a wide spectrum opioid agonist) resulted in down regulation of the receptors that was blocked by the kinase inhibitor staurosporine, by hypertonic sucrose and by the lysosomal and proteasomal inhibitors chloroquine and lactacystin. High concentration of etorphine, but not of DAMGO, induced an additional process of down regulation that was resistant to staurosporine, to hypertonic sucrose and to chloroquine-lactacystin. Etorphine, but not DAMGO, also induced down regulation of mu-opioid receptors in isolated membranes of HEK cells. This membrane-delimited down regulation was blocked by selective inhibitors of protease enzymes, suggesting the involvement of membranous serine- and amino-peptidases. This membranous down regulation of opioid receptors was dependent on the concentration of etorphine and was blocked by the opioid antagonist naloxone. Etorphine induced similar down regulation in membranes of HEK-293 cells transfected with delta-opioid receptors (DOR) as well in membranes of cells that endogenously express opioid receptors. This agonist-specific membrane-delimited regulatory process appears to be physiologically relevant and should be taken into account when studying long term effects of opioid drugs.