Harm reduction and abstinence-based models for treatment of substance use disorders during the COVID-19 pandemic : a global perspective

M.F. is an employee of the US Federal Government and is supported by National Institutes of Health (NIH) intramural funding (ZIA-DA000635 and ZIA-AA000218), outside of this research.The COVID-19 pandemic has significantly affected treatment services for people with substance use disorders (SUDs). Based on the perspectives of service providers from eight countries, we discuss the impact of the pandemic on SUD treatment services. Although many countries quickly adapted in provision of harm reduction services by changes in policy and service delivery, some went into a forced abstinence-based strategy. Similarly, disruption of abstinence-based approaches such as therapeutic communities has been reported. Global awareness is crucial for responsible management of SUDs during the pandemic, and the development of international health policy guidelines is an urgent need in this area.Publisher PDFPeer reviewe

Functional Characterization of Mitochondrial Uncoupling Protein 2 by EPR Studies

Uncoupling protein1 (UCP1) in brown adipose tissue was discovered earlier as the main uncoupling source of respiration. We describe the basic facts and a modest contribution of our group to the area of research on mitochondrial uncoupling proteins. After defining the terms uncoupling, leak, proton-mediated uncoupling, we discuss the assumption that due to its low abundance, uncoupling protein 2 (UCP2) can provide only mild uncoupling, i.e. can decrease the proton motive force by several mV only. A fatty acid cycling mechanism is described as a plausible explanation for the protonophoretic function of all uncoupling proteins together with our experiments supporting it. A speculation for the phylogenesis of all uncoupling proteins can be deduced by estimated UCP2 content in several tissues, and details of its activation are explained on the basis of our experiments. In the present study a solubilization and refolding method for UCP2 from inclusion bodies was developed and characterized. As it was known and also demonstrated from previous experiments on UCP1 that fatty acids are substrates, we used the same procedure to study the function of UCP2. Utilizing spin-labelled fatty acids (SLFA) for our experiments we demonstrated the binding of fatty acids to UCP2, and the competition of other natural fatty acids like oleic acid, palmitic acid, arachidonic acid and eicosatrienoic acid to the preformed complex emphasizes the presence of a fatty acid binding site for mitochondrial UCP2. The findings were observed by EPR spectroscopy where the highly immobilized spectra with presence of spin-labelled fatty acid eventually end up as free spin label spectra with a particular concentration of the natural fatty acid added to the UCP2 bound with spin-labelled fatty acid. This fits in significantly with the earlier findings of UCP1 and also leads to assumption of functional explanation about the physiological relevance between the uncoupling proteins functions. The present study, in which representative and sensitive parameters for EPR spectroscopy were established, at the same time describes the concentration effects of fatty acids upon the protein bound with spin-labelled fatty acids which are much of importance in comparison to physiological levels, being in the micromolar range (µM) as compared with milli molar (mM) as for UCP1 previously. In appropriate examples, different fatty acids are used and compared with competitors like alkylsulfonates also emphasizing the function of the protein. And the studies with the effect of nucleotides inhibition demonstrate that there exists a putative binding site for fatty acids. Much significance lies in demonstration with the spin-labelled-ATP studies where competition of ATP to the protein bound to spin-labelled ATP explains about the inhibition effect of nucleotides on the UCP2. So the present study applies different methods for the functional characterization of UCP2. The studies of natural fatty acids and alkylsulfonates with UCP2 bound to spin-labelled fatty acid, and study of nucleotide inhibition on UCP2 are closely related and give the much awaited answer to the question of functional similarities between UCP1 and UCP2. This supports the discussion of many groups which predict the functional similarity between these two proteins based upon sequence homology. Also many attempts have been reported in literature to explain the physiological functional relevance where by this present study can also be added to as we now suppose from the present conclusions of our experiments.Entkoppler-Protein 1 (uncoupling protein 1, UCP1) wurde bereits früher als Hauptursache der Atmungs-Entkopplung in braunem Fettgewebe entdeckt. Wir beschreiben hier die grundlegenden Tatsachen sowie unseren Beitrag zur Erforschung der mitochondrialen Entkoppler-Proteine. Nach einer Definition der Begriffe Entkopplung, Leck (leak) und Protonen-vermittelte Entkopplung, diskutieren wir die Annahme, dass Entkoppler-Protein 2 (UCP2) auf Grund seines geringeren Vorkommens nur schwache entkoppelnde Wirkung zeigen, d. h. die protonmotorische Kraft nur um wenige mV senken kann. Ein Fettsäure-Austausch-Mechanismus wird als plausible Erklärung für die Protonentransport-Funktion aller Entkoppler-Proteine beschrieben, der durch unsere Ergebnisse unterstützt wird. Eine Spekulation über die Phylogenese aller Entkoppler-Proteine kann durch Abschätzung des UCP2-Gehalts in verschiedenen Geweben abgeleitet werden, und Einzelheiten der Aktivierung können auf Grund unserer Experimente erklärt werden. In der vorliegenden Arbeit wurde eine Solubilisierungs- und Rückfaltungsmethode für UCP2 aus inclusion bodies entwickelt und charakterisiert. Da aus früheren Experimenten mit UCP1 bekannt war, dass Fettsäuren als Substrate fungieren, benutzten wir beim Studium der Funktion von UCP2 dieselbe Vorgehensweise wie dort. Unter Verwendung von spinmarkierten (spin-label-, SL-)Fettsäuren für unsere Experimente demonstrierten wir die Bindung von Fettsäuren an UCP2, und die Konkurrenzreaktion natürlicher Fettsäuren wie Ölsäure, Palmitinsäure, Arachidonsäure und Icosatriensäure am vorgeformten Komplex unterstreicht das Vorhandensein einer Fettsäure-Bindungstasche bei mitochondrialem UCP2. Die Beobachtungen wurden mit Hilfe von EPR-Spektroskopie gemacht, wobei zunächst bei Zugabe von SL-Fettsäure zu UCP2 Spektren erhalten werden, die für hohe Immobilisierung typisch sind, die aber bei Zugabe bestimmter Konzentrationen natürlicher Fettsäuren in die Spektren der freien SL-Fettsäure übergehen. Dies passt bedeutsamerweise zu den früheren Ergebnissen mit UCP1 und führt auch zu einer Annahme über die physiologische Relevanz der Funktionen der Entkoppler-Proteine. Die vorliegende Studie, in der repräsentative und sinnvolle Parameter für die EPR-Spektroskopie erarbeitet wurden, beschreibt zugleich Konzentrationseffekte von Fettsäuren auf den Komplex von Protein und SL-Fettsäure, die auch im Hinblick auf physiologische Konzentrationen durchaus Bedeutung haben, da sie im mikromolaren Bereich auftreten im Gegensatz zum millimolaren zuvor bei UCP1. Eine geeignete Auswahl verschiedener Fettsäuren wurde als Kompetitoren benutzt und in dieser Eigenschaft mit Alkylsulfonaten verglichen, wodurch ebenfalls die Funktion des Proteins deutlich gemacht wurde. Untersuchungen des Effekts der Inhibierung durch Nucleotide zeigen ebenfalls die Existenz der fraglichen Fettsäure-Bindungstasche. Große Bedeutung liegt in der Demonstration der Verdrängung von SL-ATP durch ATP aus dem Komplex mit dem Protein, wodurch der inhibitorische Effekt von Nucleotiden auf UCP2 erklärt wird. Hierzu werden in der vorliegenden Arbeit verschiedene Methoden zur funktionellen Charakterisierung von UCP1 angewandt. Die Untersuchungen natürlicher Fettsäuren und Alkylsulfonate mit UCP2 im Komplex mit spinmarkierter Fettsäure und die Untersuchung der Nucleotid-Inhibition von UCP2 hängen eng zusammen und geben die lang erwartete Antwort auf die Frage nach funktionellen Ähnlichkeiten bei UCP1 und UCP2. Dies stellt die Diskussionen vieler Gruppen auf eine neue Grundlage, die die funktionelle Ähnlichkeit beider Proteine auf Basis der Sequenzhomologie vorhersagen. Es gab auch viele Versuche in der Literatur, die physiologische Relevanz aufzuklären, wozu durch diese Untersuchungen, nach unseren gegenwärtigen Experimenten zu schließen, ebenfalls ein Beitrag geleistet werden kann

Functional Characterization of Mitochondrial Uncoupling Protein 2 by EPR Studies

Uncoupling protein1 (UCP1) in brown adipose tissue was discovered earlier as the main uncoupling source of respiration. We describe the basic facts and a modest contribution of our group to the area of research on mitochondrial uncoupling proteins. After defining the terms uncoupling, leak, proton-mediated uncoupling, we discuss the assumption that due to its low abundance, uncoupling protein 2 (UCP2) can provide only mild uncoupling, i.e. can decrease the proton motive force by several mV only. A fatty acid cycling mechanism is described as a plausible explanation for the protonophoretic function of all uncoupling proteins together with our experiments supporting it. A speculation for the phylogenesis of all uncoupling proteins can be deduced by estimated UCP2 content in several tissues, and details of its activation are explained on the basis of our experiments. In the present study a solubilization and refolding method for UCP2 from inclusion bodies was developed and characterized. As it was known and also demonstrated from previous experiments on UCP1 that fatty acids are substrates, we used the same procedure to study the function of UCP2. Utilizing spin-labelled fatty acids (SLFA) for our experiments we demonstrated the binding of fatty acids to UCP2, and the competition of other natural fatty acids like oleic acid, palmitic acid, arachidonic acid and eicosatrienoic acid to the preformed complex emphasizes the presence of a fatty acid binding site for mitochondrial UCP2. The findings were observed by EPR spectroscopy where the highly immobilized spectra with presence of spin-labelled fatty acid eventually end up as free spin label spectra with a particular concentration of the natural fatty acid added to the UCP2 bound with spin-labelled fatty acid. This fits in significantly with the earlier findings of UCP1 and also leads to assumption of functional explanation about the physiological relevance between the uncoupling proteins functions. The present study, in which representative and sensitive parameters for EPR spectroscopy were established, at the same time describes the concentration effects of fatty acids upon the protein bound with spin-labelled fatty acids which are much of importance in comparison to physiological levels, being in the micromolar range (µM) as compared with milli molar (mM) as for UCP1 previously. In appropriate examples, different fatty acids are used and compared with competitors like alkylsulfonates also emphasizing the function of the protein. And the studies with the effect of nucleotides inhibition demonstrate that there exists a putative binding site for fatty acids. Much significance lies in demonstration with the spin-labelled-ATP studies where competition of ATP to the protein bound to spin-labelled ATP explains about the inhibition effect of nucleotides on the UCP2. So the present study applies different methods for the functional characterization of UCP2. The studies of natural fatty acids and alkylsulfonates with UCP2 bound to spin-labelled fatty acid, and study of nucleotide inhibition on UCP2 are closely related and give the much awaited answer to the question of functional similarities between UCP1 and UCP2. This supports the discussion of many groups which predict the functional similarity between these two proteins based upon sequence homology. Also many attempts have been reported in literature to explain the physiological functional relevance where by this present study can also be added to as we now suppose from the present conclusions of our experiments.Entkoppler-Protein 1 (uncoupling protein 1, UCP1) wurde bereits früher als Hauptursache der Atmungs-Entkopplung in braunem Fettgewebe entdeckt. Wir beschreiben hier die grundlegenden Tatsachen sowie unseren Beitrag zur Erforschung der mitochondrialen Entkoppler-Proteine. Nach einer Definition der Begriffe Entkopplung, Leck (leak) und Protonen-vermittelte Entkopplung, diskutieren wir die Annahme, dass Entkoppler-Protein 2 (UCP2) auf Grund seines geringeren Vorkommens nur schwache entkoppelnde Wirkung zeigen, d. h. die protonmotorische Kraft nur um wenige mV senken kann. Ein Fettsäure-Austausch-Mechanismus wird als plausible Erklärung für die Protonentransport-Funktion aller Entkoppler-Proteine beschrieben, der durch unsere Ergebnisse unterstützt wird. Eine Spekulation über die Phylogenese aller Entkoppler-Proteine kann durch Abschätzung des UCP2-Gehalts in verschiedenen Geweben abgeleitet werden, und Einzelheiten der Aktivierung können auf Grund unserer Experimente erklärt werden. In der vorliegenden Arbeit wurde eine Solubilisierungs- und Rückfaltungsmethode für UCP2 aus inclusion bodies entwickelt und charakterisiert. Da aus früheren Experimenten mit UCP1 bekannt war, dass Fettsäuren als Substrate fungieren, benutzten wir beim Studium der Funktion von UCP2 dieselbe Vorgehensweise wie dort. Unter Verwendung von spinmarkierten (spin-label-, SL-)Fettsäuren für unsere Experimente demonstrierten wir die Bindung von Fettsäuren an UCP2, und die Konkurrenzreaktion natürlicher Fettsäuren wie Ölsäure, Palmitinsäure, Arachidonsäure und Icosatriensäure am vorgeformten Komplex unterstreicht das Vorhandensein einer Fettsäure-Bindungstasche bei mitochondrialem UCP2. Die Beobachtungen wurden mit Hilfe von EPR-Spektroskopie gemacht, wobei zunächst bei Zugabe von SL-Fettsäure zu UCP2 Spektren erhalten werden, die für hohe Immobilisierung typisch sind, die aber bei Zugabe bestimmter Konzentrationen natürlicher Fettsäuren in die Spektren der freien SL-Fettsäure übergehen. Dies passt bedeutsamerweise zu den früheren Ergebnissen mit UCP1 und führt auch zu einer Annahme über die physiologische Relevanz der Funktionen der Entkoppler-Proteine. Die vorliegende Studie, in der repräsentative und sinnvolle Parameter für die EPR-Spektroskopie erarbeitet wurden, beschreibt zugleich Konzentrationseffekte von Fettsäuren auf den Komplex von Protein und SL-Fettsäure, die auch im Hinblick auf physiologische Konzentrationen durchaus Bedeutung haben, da sie im mikromolaren Bereich auftreten im Gegensatz zum millimolaren zuvor bei UCP1. Eine geeignete Auswahl verschiedener Fettsäuren wurde als Kompetitoren benutzt und in dieser Eigenschaft mit Alkylsulfonaten verglichen, wodurch ebenfalls die Funktion des Proteins deutlich gemacht wurde. Untersuchungen des Effekts der Inhibierung durch Nucleotide zeigen ebenfalls die Existenz der fraglichen Fettsäure-Bindungstasche. Große Bedeutung liegt in der Demonstration der Verdrängung von SL-ATP durch ATP aus dem Komplex mit dem Protein, wodurch der inhibitorische Effekt von Nucleotiden auf UCP2 erklärt wird. Hierzu werden in der vorliegenden Arbeit verschiedene Methoden zur funktionellen Charakterisierung von UCP1 angewandt. Die Untersuchungen natürlicher Fettsäuren und Alkylsulfonate mit UCP2 im Komplex mit spinmarkierter Fettsäure und die Untersuchung der Nucleotid-Inhibition von UCP2 hängen eng zusammen und geben die lang erwartete Antwort auf die Frage nach funktionellen Ähnlichkeiten bei UCP1 und UCP2. Dies stellt die Diskussionen vieler Gruppen auf eine neue Grundlage, die die funktionelle Ähnlichkeit beider Proteine auf Basis der Sequenzhomologie vorhersagen. Es gab auch viele Versuche in der Literatur, die physiologische Relevanz aufzuklären, wozu durch diese Untersuchungen, nach unseren gegenwärtigen Experimenten zu schließen, ebenfalls ein Beitrag geleistet werden kann

Spatial, temporal, and demographic patterns in prevalence of chewing tobacco use in 204 countries and territories, 1990�2019: a systematic analysis from the Global Burden of Disease Study 2019

Background: Chewing tobacco and other types of smokeless tobacco use have had less attention from the global health community than smoked tobacco use. However, the practice is popular in many parts of the world and has been linked to several adverse health outcomes. Understanding trends in prevalence with age, over time, and by location and sex is important for policy setting and in relation to monitoring and assessing commitment to the WHO Framework Convention on Tobacco Control. Methods: We estimated prevalence of chewing tobacco use as part of the Global Burden of Diseases, Injuries, and Risk Factors Study 2019 using a modelling strategy that used information on multiple types of smokeless tobacco products. We generated a time series of prevalence of chewing tobacco use among individuals aged 15 years and older from 1990 to 2019 in 204 countries and territories, including age-sex specific estimates. We also compared these trends to those of smoked tobacco over the same time period. Findings: In 2019, 273·9 million (95 uncertainty interval 258·5 to 290·9) people aged 15 years and older used chewing tobacco, and the global age-standardised prevalence of chewing tobacco use was 4·72 (4·46 to 5·01). 228·2 million (213·6 to 244·7; 83·29 82·15 to 84·42) chewing tobacco users lived in the south Asia region. Prevalence among young people aged 15�19 years was over 10% in seven locations in 2019. Although global age-standardised prevalence of smoking tobacco use decreased significantly between 1990 and 2019 (annualised rate of change: �1·21% �1·26 to �1·16), similar progress was not observed for chewing tobacco (0·46% 0·13 to 0·79). Among the 12 highest prevalence countries (Bangladesh, Bhutan, Cambodia, India, Madagascar, Marshall Islands, Myanmar, Nepal, Pakistan, Palau, Sri Lanka, and Yemen), only Yemen had a significant decrease in the prevalence of chewing tobacco use, which was among males between 1990 and 2019 (�0·94% �1·72 to �0·14), compared with nine of 12 countries that had significant decreases in the prevalence of smoking tobacco. Among females, none of these 12 countries had significant decreases in prevalence of chewing tobacco use, whereas seven of 12 countries had a significant decrease in the prevalence of tobacco smoking use for the period. Interpretation: Chewing tobacco remains a substantial public health problem in several regions of the world, and predominantly in south Asia. We found little change in the prevalence of chewing tobacco use between 1990 and 2019, and that control efforts have had much larger effects on the prevalence of smoking tobacco use than on chewing tobacco use in some countries. Mitigating the health effects of chewing tobacco requires stronger regulations and policies that specifically target use of chewing tobacco, especially in countries with high prevalence. Funding: Bloomberg Philanthropies and the Bill & Melinda Gates Foundation. © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licens

Spatial, temporal, and demographic patterns in prevalence of smoking tobacco use and attributable disease burden in 204 countries and territories, 1990�2019: a systematic analysis from the Global Burden of Disease Study 2019

Background: Ending the global tobacco epidemic is a defining challenge in global health. Timely and comprehensive estimates of the prevalence of smoking tobacco use and attributable disease burden are needed to guide tobacco control efforts nationally and globally. Methods: We estimated the prevalence of smoking tobacco use and attributable disease burden for 204 countries and territories, by age and sex, from 1990 to 2019 as part of the Global Burden of Diseases, Injuries, and Risk Factors Study. We modelled multiple smoking-related indicators from 3625 nationally representative surveys. We completed systematic reviews and did Bayesian meta-regressions for 36 causally linked health outcomes to estimate non-linear dose-response risk curves for current and former smokers. We used a direct estimation approach to estimate attributable burden, providing more comprehensive estimates of the health effects of smoking than previously available. Findings: Globally in 2019, 1·14 billion (95 uncertainty interval 1·13�1·16) individuals were current smokers, who consumed 7·41 trillion (7·11�7·74) cigarette-equivalents of tobacco in 2019. Although prevalence of smoking had decreased significantly since 1990 among both males (27·5 26·5�28·5 reduction) and females (37·7% 35·4�39·9 reduction) aged 15 years and older, population growth has led to a significant increase in the total number of smokers from 0·99 billion (0·98�1·00) in 1990. Globally in 2019, smoking tobacco use accounted for 7·69 million (7·16�8·20) deaths and 200 million (185�214) disability-adjusted life-years, and was the leading risk factor for death among males (20·2% 19·3�21·1 of male deaths). 6·68 million 86·9% of 7·69 million deaths attributable to smoking tobacco use were among current smokers. Interpretation: In the absence of intervention, the annual toll of 7·69 million deaths and 200 million disability-adjusted life-years attributable to smoking will increase over the coming decades. Substantial progress in reducing the prevalence of smoking tobacco use has been observed in countries from all regions and at all stages of development, but a large implementation gap remains for tobacco control. Countries have a clear and urgent opportunity to pass strong, evidence-based policies to accelerate reductions in the prevalence of smoking and reap massive health benefits for their citizens. Funding: Bloomberg Philanthropies and the Bill & Melinda Gates Foundation. © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licens

Global, regional, and national progress towards Sustainable Development Goal 3.2 for neonatal and child health: all-cause and cause-specific mortality findings from the Global Burden of Disease Study 2019

Background Sustainable Development Goal 3.2 has targeted elimination of preventable child mortality, reduction of neonatal death to less than 12 per 1000 livebirths, and reduction of death of children younger than 5 years to less than 25 per 1000 livebirths, for each country by 2030. To understand current rates, recent trends, and potential trajectories of child mortality for the next decade, we present the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 findings for all-cause mortality and cause-specific mortality in children younger than 5 years of age, with multiple scenarios for child mortality in 2030 that include the consideration of potential effects of COVID-19, and a novel framework for quantifying optimal child survival. Methods We completed all-cause mortality and cause-specific mortality analyses from 204 countries and territories for detailed age groups separately, with aggregated mortality probabilities per 1000 livebirths computed for neonatal mortality rate (NMR) and under-5 mortality rate (U5MR). Scenarios for 2030 represent different potential trajectories, notably including potential effects of the COVID-19 pandemic and the potential impact of improvements preferentially targeting neonatal survival. Optimal child survival metrics were developed by age, sex, and cause of death across all GBD location-years. The first metric is a global optimum and is based on the lowest observed mortality, and the second is a survival potential frontier that is based on stochastic frontier analysis of observed mortality and Healthcare Access and Quality Index. Findings Global U5MR decreased from 71·2 deaths per 1000 livebirths (95% uncertainty interval [UI] 68·3–74·0) in 2000 to 37·1 (33·2–41·7) in 2019 while global NMR correspondingly declined more slowly from 28·0 deaths per 1000 live births (26·8–29·5) in 2000 to 17·9 (16·3–19·8) in 2019. In 2019, 136 (67%) of 204 countries had a U5MR at or below the SDG 3.2 threshold and 133 (65%) had an NMR at or below the SDG 3.2 threshold, and the reference scenario suggests that by 2030, 154 (75%) of all countries could meet the U5MR targets, and 139 (68%) could meet the NMR targets. Deaths of children younger than 5 years totalled 9·65 million (95% UI 9·05–10·30) in 2000 and 5·05 million (4·27–6·02) in 2019, with the neonatal fraction of these deaths increasing from 39% (3·76 million [95% UI 3·53–4·02]) in 2000 to 48% (2·42 million; 2·06–2·86) in 2019. NMR and U5MR were generally higher in males than in females, although there was no statistically significant difference at the global level. Neonatal disorders remained the leading cause of death in children younger than 5 years in 2019, followed by lower respiratory infections, diarrhoeal diseases, congenital birth defects, and malaria. The global optimum analysis suggests NMR could be reduced to as low as 0·80 (95% UI 0·71–0·86) deaths per 1000 livebirths and U5MR to 1·44 (95% UI 1·27–1·58) deaths per 1000 livebirths, and in 2019, there were as many as 1·87 million (95% UI 1·35–2·58; 37% [95% UI 32–43]) of 5·05 million more deaths of children younger than 5 years than the survival potential frontier. Interpretation Global child mortality declined by almost half between 2000 and 2019, but progress remains slower in neonates and 65 (32%) of 204 countries, mostly in sub-Saharan Africa and south Asia, are not on track to meet either SDG 3.2 target by 2030. Focused improvements in perinatal and newborn care, continued and expanded delivery of essential interventions such as vaccination and infection prevention, an enhanced focus on equity, continued focus on poverty reduction and education, and investment in strengthening health systems across the development spectrum have the potential to substantially improve U5MR. Given the widespread effects of COVID-19, considerable effort will be required to maintain and accelerate progress