搜索结果：Open medicine (Warsaw, Poland)

BACKGROUND: Disorders affecting the nervous system are diverse and include neurodevelopmental disorders, late-life neurodegeneration, and newly emergent conditions, such as cognitive impairment following COVID-19. Previous publications from the Global Burden of Disease, Injuries, and Risk Factor Study estimated the burden of 15 neurological conditions in 2015 and 2016, but these analyses did not include neurodevelopmental disorders, as defined by the International Classification of Diseases (ICD)-11, or a subset of cases of congenital, neonatal, and infectious conditions that cause neurological damage. Here, we estimate nervous system health loss caused by 37 unique conditions and their associated risk factors globally, regionally, and nationally from 1990 to 2021. METHODS: We estimated mortality, prevalence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs), with corresponding 95% uncertainty intervals (UIs), by age and sex in 204 countries and territories, from 1990 to 2021. We included morbidity and deaths due to neurological conditions, for which health loss is directly due to damage to the CNS or peripheral nervous system. We also isolated neurological health loss from conditions for which nervous system morbidity is a consequence, but not the primary feature, including a subset of congenital conditions (ie, chromosomal anomalies and congenital birth defects), neonatal conditions (ie, jaundice, preterm birth, and sepsis), infectious diseases (ie, COVID-19, cystic echinococcosis, malaria, syphilis, and Zika virus disease), and diabetic neuropathy. By conducting a sequela-level analysis of the health outcomes for these conditions, only cases where nervous system damage occurred were included, and YLDs were recalculated to isolate the non-fatal burden directly attributable to nervous system health loss. A comorbidity correction was used to calculate total prevalence of all conditions that affect the nervous system combined. FINDINGS: Globally, the 37 conditions affecting the nervous system were collectively ranked as the leading group cause of DALYs in 2021 (443 million, 95% UI 378-521), affecting 3·40 billion (3·20-3·62) individuals (43·1%, 40·5-45·9 of the global population); global DALY counts attributed to these conditions increased by 18·2% (8·7-26·7) between 1990 and 2021. Age-standardised rates of deaths per 100 000 people attributed to these conditions decreased from 1990 to 2021 by 33·6% (27·6-38·8), and age-standardised rates of DALYs attributed to these conditions decreased by 27·0% (21·5-32·4). Age-standardised prevalence was almost stable, with a change of 1·5% (0·7-2·4). The ten conditions with the highest age-standardised DALYs in 2021 were stroke, neonatal encephalopathy, migraine, Alzheimer's disease and other dementias, diabetic neuropathy, meningitis, epilepsy, neurological complications due to preterm birth, autism spectrum disorder, and nervous system cancer. INTERPRETATION: As the leading cause of overall disease burden in the world, with increasing global DALY counts, effective prevention, treatment, and rehabilitation strategies for disorders affecting the nervous system are needed. FUNDING: Bill & Melinda Gates Foundation.

Introduction...509 Notes on some of the most exceptional investigators...513 Fermentation by yeast extracts...517 The rôle of phosphates in fermentation...518 The discovery of NAD and NADP...524 The formation of glycerol in fermentation...525 Recognition of an identical glycolyticpathway in yeasts, animals and plants...529 Elucidating some enzymes of alcoholic fermentation...531 Conclusion...536 References...537 Scientists do not solve problems because they possess a magic wand … but because they have studied a problem for a long time … (Feyerabend, 1975 [67] p. 302). Probably most species of yeasts can ferment sugar to ethanol 239. They are famous for this ability, especially on an industrial scale, and this is why research on fermentation by yeasts has had extensive financial support. The second and third articles in this series1 describe how, in the nineteenth century, Louis Pasteur2 carried out extensive physiological studies of fermentation by intact living yeast cells and later, in 1897, Eduard Buchner 31, 32 achieved fermentation by cell-free extracts, making it practicable to study the biochemistry of fermentation in vitro 19, 20. The present review records how the metabolic pathway of alcoholic fermentation was gradually revealed (summarized chronologically in Table 1). During the twentieth century, this research was central for generating major advances in biochemistry, with massive economic applications. … the initiation of fermentation does not require so complicated an apparatus as the living cell. The agent responsible for the fermenting activity of the extracted juice is a dissolved substance, no doubt a protein; this will be called zymase.3 This is the catabolic pathway5 by means of which D-glucose is broken down to pyruvate to produce two moles of ATP6 per mole of glucose (Figures 1 and 2). In alcoholic fermentation, yeasts convert the pyruvate to ethanol and carbon dioxide and this whole process gives the yeasts chemical energy which is stored in the phosphate bonds of ATP 139. ATP was discovered in 1929 in animal tissues by Karl Lohmann 142 and also simultaneously by Cyrus Fiske7 and Yellapragada Subbarow8 71. However, its rôle as a phosphate donor in the formation of hexose phosphates and its importance in many other enzymic reactions was not then recognized. The glycolytic pathway. Each reaction of the pathway is given a letter for reference in the text. Note: Because one molecule of D-fructose 1,6-bisphosphate yields two molecules of glyceraldehyde 3-phosphate (D, E), thereafter there are two molecules of each catabolite for each molecule of D-glucose phosphorylated Path of carbon atoms in the conversion of glucose to ethanol and carbon dioxide. Each carbon atom of a glucose molecule is numbered to show its fate during fermentation It is interesting to speculate on how enzymology might have developed if the simple experiment to prepare a cell-free yeast extract and to prove the enzymic nature of fermentation (for which the relatively modest equipment needed was then available) had been carried out as an immediate sequel to the work of Cagniard-Latour, Schwann and Kützing. The eventual upsurge of enzymology could have occurred at least 50 years earlier … (224 p. 254). Enzymes are neither proteins, nor carbohydrates, nor do they belong to any of the known large groups of complex organic compounds.9 If, as many workers believe, the enzymes are all proteins, it is certainly remarkable that the majority of the successful attempts to purify them have led to the obtaining of substances which are at least predominantly non-proteins, although the original material from which they were derived consisted largely of protein (90 pp. 174–175). The only regrettable point in Pasteur's work on fermentation is that he did not explore Traube's suggestion of enzyme action in the yeast cells, nor did he visualize the possibility of extracting fermentation enzymes, even though an ever-increasing number of cell-free enzyme actions were being reported. Pasteur's chemical training and experimental skill would have given a high chance of success to such experiments (224 p. 253). The catabolism of pyruvate to ethanol by yeasts, or to lactic acid by muscle By 1940, the complete pathway of glycolysis had been elicited, largely by a few remarkable biochemists, of whom five were of Jewish origin, as was an astonishing number of other outstanding twentieth century biochemists. Six were Nobel prizewinners. In the 1930s and 1940s, a number of such notable scientists and their colleagues became victims of political turbulence and social upheaval, and so were forced into exile. Several were refugees from the German Nazi government of the 1930s 53 and contributed enormously to the advances of biochemistry in the countries where they settled, particularly Britain and America (which were at war with Germany in the 1940s until 1945). The following are brief notes on the lives of some outstanding biochemists who elucidated the glycolytic pathway. Carl Ferdinand Cori (1896–1984) was born in Prague (then within the Austro-Hungarian Empire), spent much of his youth in Trieste, and studied medicine in Budapest and Prague. He married Gerty Radnitz (see below). When working in the University of Graz in 1922, he decided to emigrate to the USA, partly because of the poverty in Austria at that time (an effect of the Treaty of Versailles) and partly, as his wife was Jewish, because of local anti-semitism (it was required to prove 'Aryan' descent to be employed at the university). On invitation, he went to work in Buffalo, New York, moving to Washington University medical school in 1931. Carl and Gerty Cori jointly received the Nobel Prize for Physiology or Medicine in 1947. Like many others, Carl was a dedicated experimenter and felt strongly about administrative work. He wrote '… Faustus considers suicide … [but survives] by making a pact with the devil, who promises him power … a similar crisis exists when a scientist begins to play with the idea of going into administration' (46 p. 1) 41, 192, 209. Gerty Theresa Cori (née Radnitz) (1896–1957), like her husband Carl, was born in Prague, where she too studied medicine. She emigrated to the USA with Carl, with whom she worked closely thereafter. Gerty Cori was only the third woman to receive a Nobel prize in science, the others being Marie Curie and Irène Joliot-Curie 75, 193. Gustav Embden (1874–1933), studied medicine at the universities of Freiburg-im-Breisgau, Munich and Strasbourg, later working with Paul Ehrlich at Frankfurt. Embden became professor and, in 1925, rector of Bonn University. Working with muscle, he made his very significant contributions to research on glycolysis 47, 226. Harden's outstanding qualities as an investigator were clarity of mind, precision of observation, and a capacity to analyse dispassionately the results of an experiment and define their significance. He mistrusted the use of his imagination beyond a few paces in advance of the facts. Had he exercised less restraint, he might have gone further; as it was he had little to withdraw 113. Arthur Harden. © The Nobel Foundation, reproduced by permission Otto Fritz Meyerhof (1884–1951) (Figure 5) qualified in medicine at Heidelberg, having written a thesis on a psychiatric subject, and was actively interested in philosophy for much of his life. In 1918 Meyerhof chose muscle for experimental work, because it then seemed the most convenient and promising material to study the connexions between chemical changes, heat production and mechanical work 176. He was at the Kaiser Wilhelm Institute for Experimental Therapy and Biochemistry, Berlin14 from 1924–1929, when he became head of the department of physiology at the Kaiser Wilhelm Institute for Medical Research in Heidelberg. With the Nazis in power Meyerhof, being Jewish, had to leave Germany and so worked in Paris from 1938 to 1940. Then, when the Germans occupied Paris, he fled to the USA, becoming professor at the University of Pennsylvania. He was welcomed there, having shared the 1922 Nobel Prize in physiology or medicine with A. V. Hill 77, 202. Otto Fritz Meyerhof. © The Nobel Foundation, reproduced by permission Carl Neuberg (1877–1956) (Figure 6), although one of the main founders of modern biochemistry, had a less illustrious scientific career than that of Meyerhof. In 1906, he started the Biochemische Zeitschrift and edited 278 volumes over the next 30 years. He became director of the Kaiser Wilhelm Institute for Experimental Therapy and Biochemistry, Berlin, in 1925 and it is said that his laboratory generated about 900 publications (78 p. 272); but, as he was Jewish, the Nazi regime forced him to leave the Institute and he emigrated to The Netherlands, to Palestine and, finally to the USA in 1940. Like many others, his career reflected the political upheavals of his time 65, 84, 140, 189, 191. Carl Neuberg. Photograph reproduced by kind permission of Archiv zur Geschichte der Max-Planck-Gesellschaft, Berlin–Dahlem Jacob Karol Parnas (sometimes called Yakub Oskarovich Parnas) (1884–1949) also had a life much affected by the political geography of the twentieth century. He was born in a part of the Austro-Hungarian Empire, near the border of what was then Russian Poland, but is now the Ukraine. He, too, was of Jewish descent, his native town, Tarnopol, having about 30 000 inhabitants, half of whom were Jews 3. Parnas held professorships in Strasbourg (1913), then a part of Germany, now in France; in Warsaw (1916–1919), which was then in Russia, but now Poland; and in Lwów (1920–1941), then in Poland, but now Lviv in the Ukraine. From 1943, he was head of the Biological and Medical Chemistry Institute in Moscow 125 (227 pp. 434–435). Hans Karl August Simon von Euler-Chelpin (1873–1964), who published as H. von Euler, was, like Harden, a polymath of great versatility. He studied painting at the Munich Academy and then physics in Berlin under Max Planck and organic chemistry under Emil Fischer. Later, von Euler worked in Göttingen with Walther Nernst, also in Stockholm with Svante Arrhenius and, back in Berlin, with Jacobus van't Hoff. Although born a German, he became a Swedish citizen in 1902 and was professor of chemistry at Stockholm from 1906; yet von Euler served in the German armed forces in World War I and later, evidently unmoved by Hitlerism, as a German diplomat during World War II. In 1929, he shared the Nobel prize in chemistry with Harden for work on fermentation. His son, Ulf von Euler, also became a Nobel prize-winner, in medicine or physiology 115, 188. Otto Heinrich Warburg (1883–1970) (Figure 7), one of the greatest of all biochemists, took a doctorate under Emil Fischer in Berlin. He was in the Prussian army in World War I but spent most of his working life at the Kaiser Wilhelm Institute for Cell Physiology, Berlin. As well as an enormous output of over 500 publications, mostly on cell metabolism, on which subject he made major contributions, Warburg was responsible for significant advances in biochemical methodology. The Warburg manometer, developed for measuring rates of gas exchange in the 1920s, became standard equipment in biochemical laboratories from the 1930s to the 1960s. The gas phase in the manometer vessel (Figure 8) was achieved by constant shaking of the vessels in a temperature-controlled water bath 246. Warburg was also responsible for valuable developments in spectrophotometry and received the Nobel prize for physiology or medicine in 1931. Otto Heinrich Warburg. Photograph reproduced by kind permission of Archiv zur Geschichte der Max-Planck-Gesellschaft, Berlin–Dahlem The Warburg manometer. The U-tube (T) of narrow bore is calibrated in millimetres. The bottom of the tube is attached to a rubber reservoir (R) and the screw clamp squeezes the reservoir and thereby adjusts the level of the liquid in the tube. The left arm of the tube is open at the top; the right arm has a side arm (S) to which a glass vessel can be attached by means of a ground joint. At the top of the right arm is a tap, by which the vessel can be closed or opened. The manometer is mounted on a board which can be attached to a shaking apparatus. Reproduced by permission from Krebs (1981 127) … I learned that a scientist must have the courage to attack the great unsolved problems of his time, and solutions usually have to be forced by carrying out innumerable experiments without much critical hesitation (248 p. 1). Despite his Jewish ancestry, Warburg was not persecuted by the Nazis, as he was protected by Reichsmarschall Göring (Goering), who ruled that Warburg was to be unharmed as he was only one-quarter Jewish.15 Much of Warburg's research was on cancer, which was a source of great anxiety to the leading Nazis 126, 127. After Buchner's success with fermentation by cell-free yeast extracts in the first years of the twentieth century, it was deemed necessary to find out how, if at all, such fermentation differed from that by intact living cells. Using brewing yeasts, three kinds of cell-free preparation that ferment sugars were used quite widely: (i) Buchner's 'zymase', described in the third of the present articles 20, was made by grinding the yeast mixed with quartz sand and kieselguhr; (ii) in 1900 Robert Albert16 prepared 'Zymin' by repeatedly treating yeast with acetone 1, 2; (iii) a product was obtained by macerating dried yeast 131; this preparation was called Lebedew17 juice, for example by Maurice Ingram18 117 and by Friedrich Nord19 and Sidney Weiss20 190, while Joseph Fruton21 refers to 'juice of Lebedev' (80 p. 295). The term 'zymase' was sometimes used for Buchner's whole yeast extract 38 and sometimes for the 'enzyme' present in yeast extract and responsible for converting sugar to ethanol and carbon dioxide. Haldane used the word 'myozymase' for 'the glycolytic enzyme complex of muscle' (90 p. 133). A fourth technique for obtaining active cell-free extracts of yeasts, although perhaps not much used, was developed in 1913 by Henry Dixon22 and William Atkins23, who extracted 'zymase' from brewery yeast by freezing the yeast in liquid air 54. In 1911, Harden reported that living yeast (intact cells) ferments glucose 'forty times as quickly' as yeast juice (94 p. 27). He had improved on the method of Allan Macfadyen24 and his colleagues at the Jenner Institute in London, who had already estimated the carbon dioxide evolved in yeast fermentation by passing the gas through sodium hydroxide and titrating 149. Harden was subsequently able to make more frequent measurements of fermentation with an azotometer (or 'nitrometer') 221 (Figure 9); this equipment enabled him to take readings of carbon dioxide production about every 4 min. Harden's use of a Schiff's azotometer 221 connected to a fermentation flask. The medium is first saturated with carbon dioxide; the volume of gas evolved can then be measured. The level of mercury in the reservoir is kept constant by a syphon overflow so that no change of pressure in the flask occurs. For each reading, the fermenting mixture must be shaken vigorously in order to avoid supersaturation with carbon dioxide. Reproduced by permission from Harden, Thompson and Young (1910 [100]) … the confusion in the literature as to the quantitative relations of lactic acid in muscle was wholly due to faulty technique …. When the muscle is disintegrated as a preliminary to extraction for analytical purposes, the existing equilibrium is entirely upset (112 p. 361). Many workers studied the rôle of phosphates in glycolysis during the first half of the twentieth century. Their research not only uncovered the course and nature of alcoholic fermentation by yeasts and of lactic acid production by muscles; it was also the key to understanding other metabolic processes, including the energy-transforming machinery of living cells. In 1870, the extremely distinguished German chemist, Adolf von Baeyer,27 offered a wild speculation 15 that the intermediate stages of ethanolic and lactic acid fermentations involved the successive removal and addition of water (Figure 10). Thirty-one years later, an of for the glycolytic pathway was made by who from (then part of In that phosphates fermentation p. and Buchner this p. published in 1870, of intermediate stages of ethanolic fermentation from glucose the successive removal and addition of water to its and from removal of water and of in the of the carbon The in lactic acid fermentation to acid and in alcoholic fermentation to der der … 15 p. The that yeast is able to effect the fermentation of a relatively part of the sugar has usually been to the action of a enzyme of the It was of to study the effect of to the mixture of yeast and … was the of a of attempts to a similar effect by in the course of which a and of was used … (94 p. The two to which the in fermentation by the addition of juice were were the of phosphates in the and the in yeast juice of a or the of which is for fermentation (94 p. … the of carbon dioxide and which would have been in the of phosphate by a to the phosphate in the or (94 p. … solutions of sodium or phosphate … or a mixture of with the were … the liquid being to the was saturated with carbon dioxide at the of the and the volume of carbon dioxide by the addition of acid was … The of carbon dioxide evolved each addition is the and is … to the phosphate (see and pp. by Harden and Young in the action of phosphate on the fermentation of glucose by yeast The mixture water glucose at A no phosphate and successive of of sodium phosphate or From of … It that the of phosphate is for the alcoholic fermentation of glucose by the reaction which being the The is then of phosphate exists which a of fermentation. of beyond this the of fermentation p. 1,6-bisphosphate In an to their Harden and Young from the by acid in and by enzyme action in its chemical was not until by and at the Institute As as Harden made a which subsequently is remarkable that the is not or by living p. there are now known to be no in the of (i) yeasts sugar and (ii) glycolytic do not from the metabolic in Harden and Robert D-glucose from fermenting yeast juice years later, Neuberg discovered hexose D-fructose by D-fructose 1,6-bisphosphate and this was subsequently in fermenting yeast juice developed by the in the 1920s, made it to the of phosphates in the By and obtained D-glucose as is the of the intermediate of some one of the hexose it to at the to it into with some of the … The production of of the with an of formation of and it that this be but a part of the intermediate product which has the Meyerhof and … by his for many years an to a of the of p. of bonds in glycolysis Krebs and in Warburg and and studied the activity of at Warburg had developed the use of cells and for measuring enzyme activity and discovered that have a studies enabled Warburg and his colleagues to the nature of the of ATP in the With the they could show that glyceraldehyde 3-phosphate was certainly the in the Fritz first to the bonds of ATP in 139. This is not the needed to a between two but of bonds much This energy is used in in active and in Harden and Young made that glucose fermentation on the of a material in their yeast extracts pp. Their was a first understanding the rôle of for enzymic This was a major in … the experiment was made of carrying out the fermentation in the of with the that about to per more sugar was than in the of the … This … was the of … attempts to a similar effect … in the course of which a and of was used … to produce a very in the (94 p. A between research on glycolysis in yeast and in muscle was reported in two of 1918 He had in and other animal the which had been in alcoholic fermentation. In he the to be necessary for as well as metabolism, by yeast and A number of years the of Harden and were into and In the was to have two one of which Meyerhof and Lohmann as ATP The other was by von Euler and his colleagues and by Warburg and and was to be a of and with two phosphate groups Warburg and that its be and for the of a which they had from yeast extract in (see Table Warburg and the active part the as in Because Warburg that von Euler and were on the with their from he did not like idea of going to Stockholm for He finally but going to if the word in p. The of the industrial production of glycerol from yeast fermentation is a remarkable example of how studies in this and industrial can This example of was to great use by Germany in World War when the for glycerol for making the the which from the a century had of glycerol to be when yeast ferments sugar to ethanol and carbon dioxide. In 1913 and workers Buchner and of sugar by yeast juice and and reported the formation of acid during alcoholic fermentation. When Otto and acid to be by yeast to ethanol and carbon and that pyruvate might be an intermediate in ethanolic fermentation, colleagues to leave the study of the rôle of acid in sugar fermentation for his to have been many others, went on to on the part by pyruvate in fermentation. between and Neuberg and his colleagues finally (i) pyruvate is during hexose (ii) the pyruvate is to and carbon dioxide; and (iii) is to by to fermenting and so an addition with they that hexose is broken down to which are of is the of which down to acid and the of the is the only that can be made is the formation of of the fermentation pathway by which glycerol is of the fermentation pathway by The German chemical in Berlin, where and the process in Germany in and the process to By this in Germany during World War at least of glycerol were every and used to make for The was about of the sugar p. … during the the German army was interested in the experiments and results work from the of the time and the that the of glycerol to the would be because of the … for some time have been with the between catabolism in yeast and catabolism of in for the fermentation published in pp. Meyerhof that lactic acid was from or by muscle extracts if yeast were He used the word for this which he obtained by ethanolic of Then, in Warburg and from yeast an enzyme from which von Euler and later obtained two 1, with ATP and the of hexose or to and Much lactic acid was the mixture had been for and and to muscle The study of phosphate in muscle extracts a into the of the of fermentation, because the to this formation of are entirely identical in the of alcoholic fermentation and lactic acid production … between the glycolytic of muscle and the of yeast are revealed by the similar action of chemical substances on the two For Harden that strongly fermentation in extracts of yeast on of of the … From and other must that with phosphate is the of the alcoholic fermentation and the formation of lactic acid and, that the is most the next in the … be the in there is a

BACKGROUND: Estimates of demographic metrics are crucial to assess levels and trends of population health outcomes. The profound impact of the COVID-19 pandemic on populations worldwide has underscored the need for timely estimates to understand this unprecedented event within the context of long-term population health trends. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 provides new demographic estimates for 204 countries and territories and 811 additional subnational locations from 1950 to 2021, with a particular emphasis on changes in mortality and life expectancy that occurred during the 2020-21 COVID-19 pandemic period. METHODS: 22 223 data sources from vital registration, sample registration, surveys, censuses, and other sources were used to estimate mortality, with a subset of these sources used exclusively to estimate excess mortality due to the COVID-19 pandemic. 2026 data sources were used for population estimation. Additional sources were used to estimate migration; the effects of the HIV epidemic; and demographic discontinuities due to conflicts, famines, natural disasters, and pandemics, which are used as inputs for estimating mortality and population. Spatiotemporal Gaussian process regression (ST-GPR) was used to generate under-5 mortality rates, which synthesised 30 763 location-years of vital registration and sample registration data, 1365 surveys and censuses, and 80 other sources. ST-GPR was also used to estimate adult mortality (between ages 15 and 59 years) based on information from 31 642 location-years of vital registration and sample registration data, 355 surveys and censuses, and 24 other sources. Estimates of child and adult mortality rates were then used to generate life tables with a relational model life table system. For countries with large HIV epidemics, life tables were adjusted using independent estimates of HIV-specific mortality generated via an epidemiological analysis of HIV prevalence surveys, antenatal clinic serosurveillance, and other data sources. Excess mortality due to the COVID-19 pandemic in 2020 and 2021 was determined by subtracting observed all-cause mortality (adjusted for late registration and mortality anomalies) from the mortality expected in the absence of the pandemic. Expected mortality was calculated based on historical trends using an ensemble of models. In location-years where all-cause mortality data were unavailable, we estimated excess mortality rates using a regression model with covariates pertaining to the pandemic. Population size was computed using a Bayesian hierarchical cohort component model. Life expectancy was calculated using age-specific mortality rates and standard demographic methods. Uncertainty intervals (UIs) were calculated for every metric using the 25th and 975th ordered values from a 1000-draw posterior distribution. FINDINGS: Global all-cause mortality followed two distinct patterns over the study period: age-standardised mortality rates declined between 1950 and 2019 (a 62·8% [95% UI 60·5-65·1] decline), and increased during the COVID-19 pandemic period (2020-21; 5·1% [0·9-9·6] increase). In contrast with the overall reverse in mortality trends during the pandemic period, child mortality continued to decline, with 4·66 million (3·98-5·50) global deaths in children younger than 5 years in 2021 compared with 5·21 million (4·50-6·01) in 2019. An estimated 131 million (126-137) people died globally from all causes in 2020 and 2021 combined, of which 15·9 million (14·7-17·2) were due to the COVID-19 pandemic (measured by excess mortality, which includes deaths directly due to SARS-CoV-2 infection and those indirectly due to other social, economic, or behavioural changes associated with the pandemic). Excess mortality rates exceeded 150 deaths per 100 000 population during at least one year of the pandemic in 80 countries and territories, whereas 20 nations had a negative excess mortality rate in 2020 or 2021, indicating that all-cause mortality in these countries was lower during the pandemic than expected based on historical trends. Between 1950 and 2021, global life expectancy at birth increased by 22·7 years (20·8-24·8), from 49·0 years (46·7-51·3) to 71·7 years (70·9-72·5). Global life expectancy at birth declined by 1·6 years (1·0-2·2) between 2019 and 2021, reversing historical trends. An increase in life expectancy was only observed in 32 (15·7%) of 204 countries and territories between 2019 and 2021. The global population reached 7·89 billion (7·67-8·13) people in 2021, by which time 56 of 204 countries and territories had peaked and subsequently populations have declined. The largest proportion of population growth between 2020 and 2021 was in sub-Saharan Africa (39·5% [28·4-52·7]) and south Asia (26·3% [9·0-44·7]). From 2000 to 2021, the ratio of the population aged 65 years and older to the population aged younger than 15 years increased in 188 (92·2%) of 204 nations. INTERPRETATION: Global adult mortality rates markedly increased during the COVID-19 pandemic in 2020 and 2021, reversing past decreasing trends, while child mortality rates continued to decline, albeit more slowly than in earlier years. Although COVID-19 had a substantial impact on many demographic indicators during the first 2 years of the pandemic, overall global health progress over the 72 years evaluated has been profound, with considerable improvements in mortality and life expectancy. Additionally, we observed a deceleration of global population growth since 2017, despite steady or increasing growth in lower-income countries, combined with a continued global shift of population age structures towards older ages. These demographic changes will likely present future challenges to health systems, economies, and societies. The comprehensive demographic estimates reported here will enable researchers, policy makers, health practitioners, and other key stakeholders to better understand and address the profound changes that have occurred in the global health landscape following the first 2 years of the COVID-19 pandemic, and longer-term trends beyond the pandemic. FUNDING: Bill & Melinda Gates Foundation.

Anna Byszewska,1 Joanna Konopińska,2 Aleksandra Kinga Kicińska,1 Zofia Mariak,2 Marek Rękas1 1Department of Ophthalmology, Military Institute of Medicine, Warsaw 04-141, Poland; 2Department of Ophthalmology, Medical University of Białystok, Białystok 15-276, PolandCorrespondence: Anna ByszewskaDepartment of Ophthalmology, Military Institute of Medicine, Ul. Szaserów 128, Warsaw 04-141, PolandTel +48-500-285-890Email ania.byszewska@gmail.comAbstract: Canaloplasty is a surgical procedure that has undergone a number of developments since its introduction in 2005. Many thousands of canaloplasties have been performed around the world since then and is, by definition, a blebless procedure. It does not necessitate the use of any antifibrotic agents and results in safe and effective IOP reductions in patients with open-angle glaucoma (OAG) with minimal complications and no bleb-related adverse events. When considering the surgical management of patients with early and medium stages of the disease, canaloplasty can be considered as a first line option. This paper will overview the theoretical effectiveness of canal surgery, the fundamental aspects of aqueous outflow resistance with particular emphasis on the role of the trabecular meshwork, Schlemm’s canal, and the collector channels, and the methods available for the clinical evaluation of the outflow pathways in relation to the ocular anatomy. Further, the paper will detail the surgical technique itself and how this has developed over time together with the clinical aspects that should be accounted for when selecting patients for this surgery.Keywords: glaucoma, aqueous outflow, canaloplasty, minicanaloplasty, canaloplasty ab interno, ABiC, schlemm’s canal, canaloplasty modification, canaloplasty patients selection, iTrack, canaloplasty qualification

BACKGROUND: Diabetes is one of the leading causes of death and disability worldwide, and affects people regardless of country, age group, or sex. Using the most recent evidentiary and analytical framework from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD), we produced location-specific, age-specific, and sex-specific estimates of diabetes prevalence and burden from 1990 to 2021, the proportion of type 1 and type 2 diabetes in 2021, the proportion of the type 2 diabetes burden attributable to selected risk factors, and projections of diabetes prevalence through 2050. METHODS: Estimates of diabetes prevalence and burden were computed in 204 countries and territories, across 25 age groups, for males and females separately and combined; these estimates comprised lost years of healthy life, measured in disability-adjusted life-years (DALYs; defined as the sum of years of life lost [YLLs] and years lived with disability [YLDs]). We used the Cause of Death Ensemble model (CODEm) approach to estimate deaths due to diabetes, incorporating 25 666 location-years of data from vital registration and verbal autopsy reports in separate total (including both type 1 and type 2 diabetes) and type-specific models. Other forms of diabetes, including gestational and monogenic diabetes, were not explicitly modelled. Total and type 1 diabetes prevalence was estimated by use of a Bayesian meta-regression modelling tool, DisMod-MR 2.1, to analyse 1527 location-years of data from the scientific literature, survey microdata, and insurance claims; type 2 diabetes estimates were computed by subtracting type 1 diabetes from total estimates. Mortality and prevalence estimates, along with standard life expectancy and disability weights, were used to calculate YLLs, YLDs, and DALYs. When appropriate, we extrapolated estimates to a hypothetical population with a standardised age structure to allow comparison in populations with different age structures. We used the comparative risk assessment framework to estimate the risk-attributable type 2 diabetes burden for 16 risk factors falling under risk categories including environmental and occupational factors, tobacco use, high alcohol use, high body-mass index (BMI), dietary factors, and low physical activity. Using a regression framework, we forecast type 1 and type 2 diabetes prevalence through 2050 with Socio-demographic Index (SDI) and high BMI as predictors, respectively. FINDINGS: In 2021, there were 529 million (95% uncertainty interval [UI] 500-564) people living with diabetes worldwide, and the global age-standardised total diabetes prevalence was 6·1% (5·8-6·5). At the super-region level, the highest age-standardised rates were observed in north Africa and the Middle East (9·3% [8·7-9·9]) and, at the regional level, in Oceania (12·3% [11·5-13·0]). Nationally, Qatar had the world's highest age-specific prevalence of diabetes, at 76·1% (73·1-79·5) in individuals aged 75-79 years. Total diabetes prevalence-especially among older adults-primarily reflects type 2 diabetes, which in 2021 accounted for 96·0% (95·1-96·8) of diabetes cases and 95·4% (94·9-95·9) of diabetes DALYs worldwide. In 2021, 52·2% (25·5-71·8) of global type 2 diabetes DALYs were attributable to high BMI. The contribution of high BMI to type 2 diabetes DALYs rose by 24·3% (18·5-30·4) worldwide between 1990 and 2021. By 2050, more than 1·31 billion (1·22-1·39) people are projected to have diabetes, with expected age-standardised total diabetes prevalence rates greater than 10% in two super-regions: 16·8% (16·1-17·6) in north Africa and the Middle East and 11·3% (10·8-11·9) in Latin America and Caribbean. By 2050, 89 (43·6%) of 204 countries and territories will have an age-standardised rate greater than 10%. INTERPRETATION: Diabetes remains a substantial public health issue. Type 2 diabetes, which makes up the bulk of diabetes cases, is largely preventable and, in some cases, potentially reversible if identified and managed early in the disease course. However, all evidence indicates that diabetes prevalence is increasing worldwide, primarily due to a rise in obesity caused by multiple factors. Preventing and controlling type 2 diabetes remains an ongoing challenge. It is essential to better understand disparities in risk factor profiles and diabetes burden across populations, to inform strategies to successfully control diabetes risk factors within the context of multiple and complex drivers. FUNDING: Bill & Melinda Gates Foundation.

Early diagnosis and appropriate treatment of rejection are crucial in preventing irreversible damage to the transplanted organ. Currently, noninvasive diagnostic methods for the detection of the rejection lack specificity and cannot be relied on (1). Consequently, a histopathologic biopsy of the pancreas is the method of choice in diagnosing rejection. The most common technique is the ultrasonographically guided approach (2). The complication rate of this procedure is estimated to be between 2.8% and 13% (most common complications include hyperamylasemia, bleeding, acute pancreatitis and infection) (3–6). The diagnostic yield for percutaneous ultrasound-guided biopsies is estimated to be 78% to 96%, depending on operator experience and type of needle used (3, 4, 6). Failure is usually because of lack of an ultrasonographic window or obtaining inadequate tissue. If pancreas tissue cannot be obtained, patients have traditionally undergone a percutaneous computed tomography scan–guided, laparoscopic, or open biopsy. An alternative means of tissue diagnosis might be endosonography (endoscopic ultrasound [EUS])-guided transduodenal biopsy. This method enables the visualization of the gastrointestinal tract, as well as neighboring structures. It is currently used primarily in imaging of the pancreas, biliary tree, lymph nodes, and vessels. Endoscopic ultrasound is also used for guiding biopsies of the native pancreas, with a relatively low complication rate of 1.6% to 3.6% (7, 8). To the best of our knowledge, there have been no reports on the use of EUS to obtain pancreas biopsies in pancreas transplant recipients. We performed EUS-guided pancreas biopsy in a 32-year-old woman with a history of type 1 diabetes mellitus (diagnosed at age 4) and end-stage renal disease treated by hemodialysis, who underwent simultaneous pancreas and kidney transplantation. Arterial reconstruction was performed between the donor superior mesenteric and splenic arteries, using a donor iliac artery or Y-graft. The pancreas allograft was placed in a head-up configuration with anastomoses constructed between the donor portal vein and recipient infrarenal inferior vena cava, and the donor Y-graft and the recipient right common iliac artery. The pancreas graft was placed in a head-up configuration. After revascularization, enteric drainage was executed using the duodenoduodenostomy technique (9, 10). The immunosuppressive regimen included thymoglobulin for induction and mycophenolate mofetil, tacrolimus, and steroids for maintenance treatment. The postoperative course was complicated by delayed pancreas function and fluid collection. An open biopsy of the pancreas transplant was performed during relaparotomy for postoperative fluid collection. Moderate acute cell-mediated allograft rejection (grade II) was diagnosed, and pulse steroids were started, resulting in improvement of glycemic control (normoglycemia was achieved). Despite the treatment, the increase in serum amylase and lipase activity persisted. An endoscopic biopsy of the donor duodenum has been performed on the patient as a surrogate marker for pancreas allograft rejection but was unremarkable (11, 12). Percutaneous ultrasound-guided or computed tomography–guided biopsy was deemed not technically possible because of interposed bowel, and therefore an EUS-guided biopsy was performed (the patient was reluctant to undergo an open or laparoscopic biopsy). The procedure was performed under propofol sedation, using a Pentax UTK-3870 (Pentax Europe GmbH, Hamburg, Germany) echoendoscope with a Hitachi Avius HI Vision (Hitachi Medical Corp., Tokyo, Japan) ultrasound system. The pancreas graft was sampled by means of the transplanted duodenum (Fig. 1) using a 22G EchoTip ProCore needle (Cook Ireland Ltd., Limerick, Ireland), which is an aspiration needle with a core trap. Within the pancreas, nine quick back-and-forth jabbing movements of the needle were performed (13). The biopsy yielded adequate pancreas allograft tissue fragment (Fig. 2). Histologic examination revealed no signs of inflammation or C4d deposits within the capillaries. No complications were observed after the biopsy. Amylase and lipase serum activity levels remained stably elevated. The patient was discharged the following day and is doing well at 8 months follow-up.FIGURE 1: With EUS imaging guidance, a 22-gauge biopsy needle is advanced into the pancreas allograft. EUS, endoscopic ultrasound.FIGURE 2: Photomicrograph of a pancreas biopsy specimen.It has to be mentioned that the concept of transduodenal pancreas biopsy is not new, and the technique was used in the 1990s when most pancreases were bladder-drained (14, 15). At that time 14-gauge to 16-gauge core-cut needles were used for cystoscopic transduodenal biopsies and 18-gauge core-biopsy needles for percutaneous biopsies, and even then, cystoscopic transduodenal biopsies resulted in lower rate of major complications (15). The transduodenal technique is a more “invasive” alternative to a percutaneous biopsy (although 22G or 19G needle is used (13) as compared to 18G needle for percutaneous approach) and may be attempted when an adequate ultrasound window for percutaneous biopsy is difficult or impossible to find. It is, however, less invasive than laparoscopic and open techniques. It has to be also stressed that the use of EUS to obtain a transduodenal pancreas biopsy was possible in this case only because exocrine drainage was obtained through duodenoduodenostomy. In conclusion, in pancreatic graft recipients with drainage of exocrine secretions of the pancreatic graft in the recipient duodenum, it is possible to obtain an EUS-guided transduodenal biopsy of the transplanted pancreas. Marta Serwańska-Świętek 1 Małgorzata Degowska2 Konrad Patena1 Agnieszka Perkowska3 Marek Durlik4,5 Grażyna Rydzewska2,5 Andrzej Rydzewski1,5 1 Department of Internal Medicine Nephrology and Transplantation Medicine Central Clinical Hospital of the Ministry of Interior, Warsaw, Poland 2 Department of Internal Medicine and Gastroenterology Central Clinical Hospital of the Ministry of Interior Warsaw, Poland 3 Transplantation Institute Medical University of Warsaw Warsaw, Poland 4 Department of Gastrointestinal and Transplantation Surgery Central Clinical Hospital of the Ministry of Interior Warsaw, Poland 5 Department of Surgical Research and Transplantology Mossakowski Medical Research Centre Warsaw, Poland

BACKGROUND: Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis, which are typically transmitted via respiratory droplets, are leading causes of invasive diseases, including bacteraemic pneumonia and meningitis, and of secondary infections subsequent to post-viral respiratory disease. The aim of this study was to investigate the incidence of invasive disease due to these pathogens during the early months of the COVID-19 pandemic. METHODS: In this prospective analysis of surveillance data, laboratories in 26 countries and territories across six continents submitted data on cases of invasive disease due to S pneumoniae, H influenzae, and N meningitidis from Jan 1, 2018, to May, 31, 2020, as part of the Invasive Respiratory Infection Surveillance (IRIS) Initiative. Numbers of weekly cases in 2020 were compared with corresponding data for 2018 and 2019. Data for invasive disease due to Streptococcus agalactiae, a non-respiratory pathogen, were collected from nine laboratories for comparison. The stringency of COVID-19 containment measures was quantified using the Oxford COVID-19 Government Response Tracker. Changes in population movements were assessed using Google COVID-19 Community Mobility Reports. Interrupted time-series modelling quantified changes in the incidence of invasive disease due to S pneumoniae, H influenzae, and N meningitidis in 2020 relative to when containment measures were imposed. FINDINGS: 27 laboratories from 26 countries and territories submitted data to the IRIS Initiative for S pneumoniae (62 837 total cases), 24 laboratories from 24 countries submitted data for H influenzae (7796 total cases), and 21 laboratories from 21 countries submitted data for N meningitidis (5877 total cases). All countries and territories had experienced a significant and sustained reduction in invasive diseases due to S pneumoniae, H influenzae, and N meningitidis in early 2020 (Jan 1 to May 31, 2020), coinciding with the introduction of COVID-19 containment measures in each country. By contrast, no significant changes in the incidence of invasive S agalactiae infections were observed. Similar trends were observed across most countries and territories despite differing stringency in COVID-19 control policies. The incidence of reported S pneumoniae infections decreased by 68% at 4 weeks (incidence rate ratio 0·32 [95% CI 0·27-0·37]) and 82% at 8 weeks (0·18 [0·14-0·23]) following the week in which significant changes in population movements were recorded. INTERPRETATION: The introduction of COVID-19 containment policies and public information campaigns likely reduced transmission of S pneumoniae, H influenzae, and N meningitidis, leading to a significant reduction in life-threatening invasive diseases in many countries worldwide. FUNDING: Wellcome Trust (UK), Robert Koch Institute (Germany), Federal Ministry of Health (Germany), Pfizer, Merck, Health Protection Surveillance Centre (Ireland), SpID-Net project (Ireland), European Centre for Disease Prevention and Control (European Union), Horizon 2020 (European Commission), Ministry of Health (Poland), National Programme of Antibiotic Protection (Poland), Ministry of Science and Higher Education (Poland), Agencia de Salut Pública de Catalunya (Spain), Sant Joan de Deu Foundation (Spain), Knut and Alice Wallenberg Foundation (Sweden), Swedish Research Council (Sweden), Region Stockholm (Sweden), Federal Office of Public Health of Switzerland (Switzerland), and French Public Health Agency (France).

BACKGROUND: Mortality statistics are fundamental to public health decision making. Mortality varies by time and location, and its measurement is affected by well known biases that have been exacerbated during the COVID-19 pandemic. This paper aims to estimate excess mortality from the COVID-19 pandemic in 191 countries and territories, and 252 subnational units for selected countries, from Jan 1, 2020, to Dec 31, 2021. METHODS: All-cause mortality reports were collected for 74 countries and territories and 266 subnational locations (including 31 locations in low-income and middle-income countries) that had reported either weekly or monthly deaths from all causes during the pandemic in 2020 and 2021, and for up to 11 year previously. In addition, we obtained excess mortality data for 12 states in India. Excess mortality over time was calculated as observed mortality, after excluding data from periods affected by late registration and anomalies such as heat waves, minus expected mortality. Six models were used to estimate expected mortality; final estimates of expected mortality were based on an ensemble of these models. Ensemble weights were based on root mean squared errors derived from an out-of-sample predictive validity test. As mortality records are incomplete worldwide, we built a statistical model that predicted the excess mortality rate for locations and periods where all-cause mortality data were not available. We used least absolute shrinkage and selection operator (LASSO) regression as a variable selection mechanism and selected 15 covariates, including both covariates pertaining to the COVID-19 pandemic, such as seroprevalence, and to background population health metrics, such as the Healthcare Access and Quality Index, with direction of effects on excess mortality concordant with a meta-analysis by the US Centers for Disease Control and Prevention. With the selected best model, we ran a prediction process using 100 draws for each covariate and 100 draws of estimated coefficients and residuals, estimated from the regressions run at the draw level using draw-level input data on both excess mortality and covariates. Mean values and 95% uncertainty intervals were then generated at national, regional, and global levels. Out-of-sample predictive validity testing was done on the basis of our final model specification. FINDINGS: Although reported COVID-19 deaths between Jan 1, 2020, and Dec 31, 2021, totalled 5·94 million worldwide, we estimate that 18·2 million (95% uncertainty interval 17·1-19·6) people died worldwide because of the COVID-19 pandemic (as measured by excess mortality) over that period. The global all-age rate of excess mortality due to the COVID-19 pandemic was 120·3 deaths (113·1-129·3) per 100 000 of the population, and excess mortality rate exceeded 300 deaths per 100 000 of the population in 21 countries. The number of excess deaths due to COVID-19 was largest in the regions of south Asia, north Africa and the Middle East, and eastern Europe. At the country level, the highest numbers of cumulative excess deaths due to COVID-19 were estimated in India (4·07 million [3·71-4·36]), the USA (1·13 million [1·08-1·18]), Russia (1·07 million [1·06-1·08]), Mexico (798 000 [741 000-867 000]), Brazil (792 000 [730 000-847 000]), Indonesia (736 000 [594 000-955 000]), and Pakistan (664 000 [498 000-847 000]). Among these countries, the excess mortality rate was highest in Russia (374·6 deaths [369·7-378·4] per 100 000) and Mexico (325·1 [301·6-353·3] per 100 000), and was similar in Brazil (186·9 [172·2-199·8] per 100 000) and the USA (179·3 [170·7-187·5] per 100 000). INTERPRETATION: The full impact of the pandemic has been much greater than what is indicated by reported deaths due to COVID-19 alone. Strengthening death registration systems around the world, long understood to be crucial to global public health strategy, is necessary for improved monitoring of this pandemic and future pandemics. In addition, further research is warranted to help distinguish the proportion of excess mortality that was directly caused by SARS-CoV-2 infection and the changes in causes of death as an indirect consequence of the pandemic. FUNDING: Bill & Melinda Gates Foundation, J Stanton, T Gillespie, and J and E Nordstrom.

Ideas and Opinions17 January 2017America, We Are Confused: The Updated U.S. Preventive Services Task Force Recommendation on Colorectal Cancer ScreeningMichael Bretthauer, MD, PhD, Michal F. Kaminski, MD, PhD, Cesare Hassan, MD, Mette Kalager, MD, PhD, Øyvind Holme, MD, PhD, Geir Hoff, MD, PhD, Magnus Løberg, MD, PhD, Jaroslaw Regula, MD, PhD, Antoni Castells, MD, PhD, and Hans-Olov Adami, MD, PhDMichael Bretthauer, MD, PhDFrom University of Oslo, Oslo University Hospital, and Cancer Registry of Norway, Oslo, Norway; Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland; Nuovo Regina Margherita Hospital, Rome, Italy; Sørlandet Hospital, Kristiansand, Norway; Telemark Hospital, Skien, Norway; Hospital Clínic, Barcelona, Spain; and Karolinska Institutet, Stockholm, Sweden., Michal F. Kaminski, MD, PhDFrom University of Oslo, Oslo University Hospital, and Cancer Registry of Norway, Oslo, Norway; Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland; Nuovo Regina Margherita Hospital, Rome, Italy; Sørlandet Hospital, Kristiansand, Norway; Telemark Hospital, Skien, Norway; Hospital Clínic, Barcelona, Spain; and Karolinska Institutet, Stockholm, Sweden., Cesare Hassan, MDFrom University of Oslo, Oslo University Hospital, and Cancer Registry of Norway, Oslo, Norway; Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland; Nuovo Regina Margherita Hospital, Rome, Italy; Sørlandet Hospital, Kristiansand, Norway; Telemark Hospital, Skien, Norway; Hospital Clínic, Barcelona, Spain; and Karolinska Institutet, Stockholm, Sweden., Mette Kalager, MD, PhDFrom University of Oslo, Oslo University Hospital, and Cancer Registry of Norway, Oslo, Norway; Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland; Nuovo Regina Margherita Hospital, Rome, Italy; Sørlandet Hospital, Kristiansand, Norway; Telemark Hospital, Skien, Norway; Hospital Clínic, Barcelona, Spain; and Karolinska Institutet, Stockholm, Sweden., Øyvind Holme, MD, PhDFrom University of Oslo, Oslo University Hospital, and Cancer Registry of Norway, Oslo, Norway; Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland; Nuovo Regina Margherita Hospital, Rome, Italy; Sørlandet Hospital, Kristiansand, Norway; Telemark Hospital, Skien, Norway; Hospital Clínic, Barcelona, Spain; and Karolinska Institutet, Stockholm, Sweden., Geir Hoff, MD, PhDFrom University of Oslo, Oslo University Hospital, and Cancer Registry of Norway, Oslo, Norway; Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland; Nuovo Regina Margherita Hospital, Rome, Italy; Sørlandet Hospital, Kristiansand, Norway; Telemark Hospital, Skien, Norway; Hospital Clínic, Barcelona, Spain; and Karolinska Institutet, Stockholm, Sweden., Magnus Løberg, MD, PhDFrom University of Oslo, Oslo University Hospital, and Cancer Registry of Norway, Oslo, Norway; Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland; Nuovo Regina Margherita Hospital, Rome, Italy; Sørlandet Hospital, Kristiansand, Norway; Telemark Hospital, Skien, Norway; Hospital Clínic, Barcelona, Spain; and Karolinska Institutet, Stockholm, Sweden., Jaroslaw Regula, MD, PhDFrom University of Oslo, Oslo University Hospital, and Cancer Registry of Norway, Oslo, Norway; Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland; Nuovo Regina Margherita Hospital, Rome, Italy; Sørlandet Hospital, Kristiansand, Norway; Telemark Hospital, Skien, Norway; Hospital Clínic, Barcelona, Spain; and Karolinska Institutet, Stockholm, Sweden., Antoni Castells, MD, PhDFrom University of Oslo, Oslo University Hospital, and Cancer Registry of Norway, Oslo, Norway; Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland; Nuovo Regina Margherita Hospital, Rome, Italy; Sørlandet Hospital, Kristiansand, Norway; Telemark Hospital, Skien, Norway; Hospital Clínic, Barcelona, Spain; and Karolinska Institutet, Stockholm, Sweden., and Hans-Olov Adami, MD, PhDFrom University of Oslo, Oslo University Hospital, and Cancer Registry of Norway, Oslo, Norway; Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland; Nuovo Regina Margherita Hospital, Rome, Italy; Sørlandet Hospital, Kristiansand, Norway; Telemark Hospital, Skien, Norway; Hospital Clínic, Barcelona, Spain; and Karolinska Institutet, Stockholm, Sweden.Author, Article, and Disclosure Informationhttps://doi.org/10.7326/M16-1805 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail We are surprised by the latest update of the recommendations for colorectal cancer screening from the U.S. Preventive Services Task Force (USPSTF) (1). Contrary to the principles of evidence-based medicine, the guidelines provided equally strong recommendations for tests with very different quality of evidence for benefits and harms.In recent years, most guideline makers have adopted transparent strategies to grade quality of evidence and strength of recommendations. Consequently, in the European Union colorectal cancer screening guidelines, we have graded the strength of recommendations for each screening strategy on the basis of the quality and trustworthiness of the supporting evidence (2). ...References1. Bibbins-Domingo K, Grossman DC, Curry SJ, Davidson KW, Epling JW, García FA, et al; US Preventive Services Task Force. Screening for colorectal cancer: US Preventive Services Task Force recommendation statement. JAMA. 2016;315:2564-75. [PMID: 27304597] doi:10.1001/jama.2016.5989 CrossrefMedlineGoogle Scholar2. Segnan N, Patnick J, von Karsa L, eds. European Commission. European Guidelines for Quality Assurance in Colorectal Cancer Screening and Diagnosis. 1st ed. Luxembourg: Publications Office of the European Union; 2010. doi:10.2772/15379 CrossrefGoogle Scholar3. Holme Ø, Løberg M, Kalager M, Bretthauer M, Hernán MA, Aas E, et al. Effect of flexible sigmoidoscopy screening on colorectal cancer incidence and mortality: a randomized clinical trial. JAMA. 2014;312:606-15. [PMID: 25117129] doi:10.1001/jama.2014.8266 CrossrefMedlineGoogle Scholar4. Kaminski MF, Kraszewska E, Rupinski M, Laskowska M, Wieszczy P, Regula J. Design of the Polish Colonoscopy Screening Program: a randomized health services study. Endoscopy. 2015;47:1144-50. [PMID: 26517847] doi:10.1055/s-0034-1392769 CrossrefMedlineGoogle Scholar5. Pitkäniemi J, Seppä K, Hakama M, Malminiemi O, Palva T, Vuoristo MS, et al. Effectiveness of screening for colorectal cancer with a faecal occult-blood test, in Finland. BMJ Open Gastroenterol. 2015;2:e000034. [PMID: 26462283] doi:10.1136/bmjgast-2015-000034 CrossrefMedlineGoogle Scholar6. Pilot Study of a National Screening Programme for Bowel Cancer in Norway [clinical trial]. Accessed at https://clinicaltrials.gov/ct2/show/NCT01538550 on 29 September 2016. Google Scholar7. Segnan N, Armaroli P, Bonelli L, Risio M, Sciallero S, Zappa M, et al; SCORE Working Group. Once-only sigmoidoscopy in colorectal cancer screening: follow-up findings of the Italian Randomized Controlled Trial—SCORE. J Natl Cancer Inst. 2011;103:1310-22. [PMID: 21852264] doi:10.1093/jnci/djr284 CrossrefMedlineGoogle Scholar8. Quintero E, Castells A, Bujanda L, Cubiella J, Salas D, Lanas Á, et al; COLONPREV Study Investigators. Colonoscopy versus fecal immunochemical testing in colorectal-cancer screening. N Engl J Med. 2012;366:697-706. [PMID: 22356323] doi:10.1056/NEJMoa1108895 CrossrefMedlineGoogle Scholar9. Bretthauer M, Kaminski MF, Løberg M, Zauber AG, Regula J, Kuipers EJ, et al; Nordic-European Initiative on Colorectal Cancer (NordICC) Study Group. Population-based colonoscopy screening for colorectal cancer: a randomized clinical trial. JAMA Intern Med. 2016;176:894-902. [PMID: 27214731] doi:10.1001/jamainternmed.2016.0960 CrossrefMedlineGoogle Scholar10. Colonoscopy and FIT as Colorectal Cancer Screening Test in the Average Risk Population [clinical trial]. Accessed at https://clinicaltrials.gov/ct2/show/NCT02078804 on 29 September 2016. Google Scholar Author, Article, and Disclosure InformationAffiliations: From University of Oslo, Oslo University Hospital, and Cancer Registry of Norway, Oslo, Norway; Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland; Nuovo Regina Margherita Hospital, Rome, Italy; Sørlandet Hospital, Kristiansand, Norway; Telemark Hospital, Skien, Norway; Hospital Clínic, Barcelona, Spain; and Karolinska Institutet, Stockholm, Sweden.Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M16-1805.Corresponding Author: Michael Bretthauer, MD, PhD, Institute of Health and Society, Departments of Health Management and Health Economics and Transplantation Medicine and KG Jebsen Center for Colorectal Cancer, University of Oslo, PO Box 1089 Blindern, Oslo 0316, Norway.Current Author Addresses: Drs. Bretthauer, Holme, Løberg, and Adami: Institute of Health and Society, Departments of Health Management and Health Economics and Transplantation Medicine and KG Jebsen Center for Colorectal Cancer, University of Oslo, PO Box 1089 Blindern, Oslo 0316, Norway.Drs. Kaminski and Regula: Department of Gastroenterological Oncology and Cancer Prevention, Maria Sklodowska-Curie Memorial Cancer Center, Roentgen Street 5, Warsaw 02-781, Poland.Dr. Hassan: Department of Gastroenterology, Nuovo Regina Margherita Hospital, Via Morosini 30, Rome 00153, Italy.Dr. Kalager: Institute of Health and Society, Departments of Health Management and Health Economics and Transplantation Medicine and KG Jebsen Center for Colorectal Cancer, University of Oslo, PO Box 1072 Blindern, Oslo 0316, Norway.Dr. Hoff: Department of Research, Telemark Hospital, Vindalskroken 17, Skien 3728, Norway.Dr. Castells: Institute of Digestive and Metabolic, Hospital Clínic, Villarroel 170, Barcelona 08036, Spain.Author Contributions: Conception and design: M. Bretthauer, M.F. Kaminski, M. Kalager, G. Hoff, H.O. Adami.Analysis and interpretation of the data: M. Bretthauer, M.F. Kaminski, M. Kalager, A. Castells, H.O. Adami.Drafting of the article: M. Bretthauer, A. Castells, H.O. Adami.Critical revision of the article for important intellectual content: M.F. Kaminski, C. Hassan, M. Kalager, Ø. Holme, G. Hoff, M. Løberg, J. Regula, A. Castells, H.O. Adami.Final approval of the article: M. Bretthauer, M.F. Kaminski, C. Hassan, M. Kalager, Ø. Holme, G. Hoff, M. Løberg, J. Regula, A. Castells, H.O. Adami.Collection and assembly of data: M. Bretthauer.This article was published at www.annals.org on 8 November 2016. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byWhat Constitutes Evidence? Colorectal Cancer Screening and the U.S. Preventive Services Task ForceFrailty as a Predictor of Colonoscopic Procedural Risk: Robust Associations from Fragile PatientsWhy "More Research Is Needed," Despite Overall Certainty: Women and Colorectal Cancer ScreeningKirsten Bibbins-Domingo, PhD, MD, MAS and John Inadomi, MDColon Cancer Screening among Patients Receiving Dialysis in the United States: Are We Choosing Wisely?The Best Laid Plans: Adaptation is an Essential Part of Going From Efficacy Research to Program ImplementationSigmoidoskopi og testing for blod i avføringen – en sammenlignende screeningstudie 17 January 2017Volume 166, Issue 2Page: 139-140KeywordsCancer screeningClinical trialsColorectal cancerColorectal cancer screeningDisclosureHealth economicsHematologic testsMortalityRandomized trialsTransplantation ePublished: 8 November 2016 Issue Published: 17 January 2017 Copyright & PermissionsCopyright © 2016 by American College of Physicians. 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<strong>Klimek Monika, Knap Joanna, Reda Mateusz, Masternak Marta. Physical activity in prevention and treatment of type 2 diabetes mellitus.</strong><strong> Journal of Education, Health and Sport. 2019;9(9):1175-1181. eISNN 2391-8306. DOI </strong><strong>http://dx.doi.org/10.5281/zenodo.3464935</strong> <strong>http://ojs.ukw.edu.pl/index.php/johs/article/view/7557</strong> <strong>The journal has had 5 points in Ministry of Science and Higher Education parametric evaluation. § 8. 2) and § 12. 1. 2) 22.02.2019.</strong> <strong>© The Authors 2019;</strong> <strong>This article is published with open access at Licensee Open Journal Systems of Kazimierz Wielki University in Bydgoszcz, Poland</strong> <strong>Open Access. This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author (s) and source are credited. This is an open access article licensed under the terms of the Creative Commons Attribution Non commercial license Share alike.</strong> <strong>(http://creativecommons.org/licenses/by-nc-sa/4.0/) which permits unrestricted, non commercial use, distribution and reproduction in any medium, provided the work is properly cited.</strong> <strong>The authors declare that there is no conflict of interests regarding the publication of this paper.</strong> <strong>Received: 10.09.2019. Revised: 30.09.2019. Accepted: 30.09.2019.</strong> <strong>Physical activity in prevention and treatment of type 2 diabetes mellitus</strong> <strong>Monika Klimek, Joanna Knap, Mateusz Reda, Marta Masternak</strong> Monika Klimek, klimkowa1@gmail.com, ORCID: 0000-0002-3849-4654 Doctoral program, Medical University of Lublin, Poland Joanna Knap, joanna.knap100@gmail.com, ORCID: 0000-0003-3157-8641 Doctoral program, Medical University of Lublin, Poland Postgraduate School of Molecular Medicine, Żwirki i Wigury 61 Street, 02-091 Warsaw, Poland Marta Masternak, podgorniakmarta@gmail.com, ORCID: 0000-0001-5947-7610 Doctoral program, Medical University of Lublin, Poland Mateusz Reda, mateusz.reda@gmail.com, ORCID: 0000-0003-1184-7787 Otolaryngology Head and Neck Department, Wyszynski Voivodship Specialist Hospital in Lublin, Poland <strong>Abstract</strong> Type 2 diabetes in more than 70% of cases is caused by overweight and obesity. In many cases, a proper diet and increased physical activity are effective in the prevention and treatment of insulin resistance and pre-diabetes, which usually prevents the development of the disease. However, the recommendations for physical activity in type 2 diabetics differ from those for healthy people. The paper presents an analysis of recommendations concerning physical activity in the prevention and treatment of type 2 diabetes. <strong>Key words: diabetes, obesity, insulin resistance, physical activity</strong>

BACKGROUND: Understanding the magnitude of cancer burden attributable to potentially modifiable risk factors is crucial for development of effective prevention and mitigation strategies. We analysed results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 to inform cancer control planning efforts globally. METHODS: The GBD 2019 comparative risk assessment framework was used to estimate cancer burden attributable to behavioural, environmental and occupational, and metabolic risk factors. A total of 82 risk-outcome pairs were included on the basis of the World Cancer Research Fund criteria. Estimated cancer deaths and disability-adjusted life-years (DALYs) in 2019 and change in these measures between 2010 and 2019 are presented. FINDINGS: Globally, in 2019, the risk factors included in this analysis accounted for 4·45 million (95% uncertainty interval 4·01-4·94) deaths and 105 million (95·0-116) DALYs for both sexes combined, representing 44·4% (41·3-48·4) of all cancer deaths and 42·0% (39·1-45·6) of all DALYs. There were 2·88 million (2·60-3·18) risk-attributable cancer deaths in males (50·6% [47·8-54·1] of all male cancer deaths) and 1·58 million (1·36-1·84) risk-attributable cancer deaths in females (36·3% [32·5-41·3] of all female cancer deaths). The leading risk factors at the most detailed level globally for risk-attributable cancer deaths and DALYs in 2019 for both sexes combined were smoking, followed by alcohol use and high BMI. Risk-attributable cancer burden varied by world region and Socio-demographic Index (SDI), with smoking, unsafe sex, and alcohol use being the three leading risk factors for risk-attributable cancer DALYs in low SDI locations in 2019, whereas DALYs in high SDI locations mirrored the top three global risk factor rankings. From 2010 to 2019, global risk-attributable cancer deaths increased by 20·4% (12·6-28·4) and DALYs by 16·8% (8·8-25·0), with the greatest percentage increase in metabolic risks (34·7% [27·9-42·8] and 33·3% [25·8-42·0]). INTERPRETATION: The leading risk factors contributing to global cancer burden in 2019 were behavioural, whereas metabolic risk factors saw the largest increases between 2010 and 2019. Reducing exposure to these modifiable risk factors would decrease cancer mortality and DALY rates worldwide, and policies should be tailored appropriately to local cancer risk factor burden. FUNDING: Bill & Melinda Gates Foundation.

Natural products and their structural analogues have historically made a major contribution to pharmacotherapy, especially for cancer and infectious diseases. Nevertheless, natural products also present challenges for drug discovery, such as technical barriers to screening, isolation, characterization and optimization, which contributed to a decline in their pursuit by the pharmaceutical industry from the 1990s onwards. In recent years, several technological and scientific developments - including improved analytical tools, genome mining and engineering strategies, and microbial culturing advances - are addressing such challenges and opening up new opportunities. Consequently, interest in natural products as drug leads is being revitalized, particularly for tackling antimicrobial resistance. Here, we summarize recent technological developments that are enabling natural product-based drug discovery, highlight selected applications and discuss key opportunities.

In Europe and the United States, there is an increasing prevalence of the use of autologous blood products to facilitate healing in a variety of applications. Recently, we have learned more about specific growth factors, which play a crucial role in the healing process. With that knowledge there is abundant enthusiasm in the application of concentrated platelets, which release a supra-maximal quantity of these growth factors to stimulate recovery in non-healing injuries. For 20 years, the application of autologous PRP has been safely used and documented in many fields including; orthopedics, sports medicine, dentistry, ENT, neurosurgery, ophthalmology, urology, wound healing, cosmetic, cardiothoracic, and maxillofacial surgery. This article introduces the reader to PRP therapy and reviews the current literature on this emerging treatment modality. In summary, PRP provides a promising alternative to surgery by promoting safe and natural healing. However, there are few controlled trials, and mostly anecdotal or case reports. Additionally the sample sizes are frequently small, limiting the generalization of the findings. Recently, there is emerging literature on the beneficial effects of PRP for chronic non-healing tendon injuries including lateral epicondylitis and plantar fasciitis and cartilage degeneration (Mishra and Pavelko, The American Journal of Sports Medicine 10(10):1-5, 2006; Barrett and Erredge, Podiatry Today 17:37-42, 2004). However, as clinical use increases, more controlled studies are needed to further understand this treatment.

BACKGROUND: The BRAF inhibitors vemurafenib and dabrafenib have shown efficacy as monotherapies in patients with previously untreated metastatic melanoma with BRAF V600E or V600K mutations. Combining dabrafenib and the MEK inhibitor trametinib, as compared with dabrafenib alone, enhanced antitumor activity in this population of patients. METHODS: In this open-label, phase 3 trial, we randomly assigned 704 patients with metastatic melanoma with a BRAF V600 mutation to receive either a combination of dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) or vemurafenib (960 mg twice daily) orally as first-line therapy. The primary end point was overall survival. RESULTS: At the preplanned interim overall survival analysis, which was performed after 77% of the total number of expected events occurred, the overall survival rate at 12 months was 72% (95% confidence interval [CI], 67 to 77) in the combination-therapy group and 65% (95% CI, 59 to 70) in the vemurafenib group (hazard ratio for death in the combination-therapy group, 0.69; 95% CI, 0.53 to 0.89; P=0.005). The prespecified interim stopping boundary was crossed, and the study was stopped for efficacy in July 2014. Median progression-free survival was 11.4 months in the combination-therapy group and 7.3 months in the vemurafenib group (hazard ratio, 0.56; 95% CI, 0.46 to 0.69; P<0.001). The objective response rate was 64% in the combination-therapy group and 51% in the vemurafenib group (P<0.001). Rates of severe adverse events and study-drug discontinuations were similar in the two groups. Cutaneous squamous-cell carcinoma and keratoacanthoma occurred in 1% of patients in the combination-therapy group and 18% of those in the vemurafenib group. CONCLUSIONS: Dabrafenib plus trametinib, as compared with vemurafenib monotherapy, significantly improved overall survival in previously untreated patients with metastatic melanoma with BRAF V600E or V600K mutations, without increased overall toxicity. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT01597908.).

BACKGROUND: Suboptimal diet is an important preventable risk factor for non-communicable diseases (NCDs); however, its impact on the burden of NCDs has not been systematically evaluated. This study aimed to evaluate the consumption of major foods and nutrients across 195 countries and to quantify the impact of their suboptimal intake on NCD mortality and morbidity. METHODS: By use of a comparative risk assessment approach, we estimated the proportion of disease-specific burden attributable to each dietary risk factor (also referred to as population attributable fraction) among adults aged 25 years or older. The main inputs to this analysis included the intake of each dietary factor, the effect size of the dietary factor on disease endpoint, and the level of intake associated with the lowest risk of mortality. Then, by use of disease-specific population attributable fractions, mortality, and disability-adjusted life-years (DALYs), we calculated the number of deaths and DALYs attributable to diet for each disease outcome. FINDINGS: In 2017, 11 million (95% uncertainty interval [UI] 10-12) deaths and 255 million (234-274) DALYs were attributable to dietary risk factors. High intake of sodium (3 million [1-5] deaths and 70 million [34-118] DALYs), low intake of whole grains (3 million [2-4] deaths and 82 million [59-109] DALYs), and low intake of fruits (2 million [1-4] deaths and 65 million [41-92] DALYs) were the leading dietary risk factors for deaths and DALYs globally and in many countries. Dietary data were from mixed sources and were not available for all countries, increasing the statistical uncertainty of our estimates. INTERPRETATION: This study provides a comprehensive picture of the potential impact of suboptimal diet on NCD mortality and morbidity, highlighting the need for improving diet across nations. Our findings will inform implementation of evidence-based dietary interventions and provide a platform for evaluation of their impact on human health annually. FUNDING: Bill & Melinda Gates Foundation.

BACKGROUND: A recent meta-analysis raised concern regarding an increased risk of myocardial infarction and death from cardiovascular causes associated with rosiglitazone treatment of type 2 diabetes. METHODS: We conducted an unplanned interim analysis of a randomized, multicenter, open-label, noninferiority trial involving 4447 patients with type 2 diabetes who had inadequate glycemic control while receiving metformin or sulfonylurea, in which 2220 patients were assigned to receive add-on rosiglitazone (rosiglitazone group), and 2227 to receive a combination of metformin plus sulfonylurea (control group). The primary end point was hospitalization or death from cardiovascular causes. RESULTS: Because the mean follow-up was only 3.75 years, our interim analysis had limited statistical power to detect treatment differences. A total of 217 patients in the rosiglitazone group and 202 patients in the control group had the adjudicated primary end point (hazard ratio, 1.08; 95% confidence interval [CI], 0.89 to 1.31). After the inclusion of end points pending adjudication, the hazard ratio was 1.11 (95% CI, 0.93 to 1.32). There were no statistically significant differences between the rosiglitazone group and the control group regarding myocardial infarction and death from cardiovascular causes or any cause. There were more patients with heart failure in the rosiglitazone group than in the control group (hazard ratio, 2.15; 95% CI, 1.30 to 3.57). CONCLUSIONS: Our interim findings from this ongoing study were inconclusive regarding the effect of rosiglitazone on the overall risk of hospitalization or death from cardiovascular causes. There was no evidence of any increase in death from either cardiovascular causes or all causes. Rosiglitazone was associated with an increased risk of heart failure. The data were insufficient to determine whether the drug was associated with an increase in the risk of myocardial infarction. (ClinicalTrials.gov number, NCT00379769 [ClinicalTrials.gov].).

BACKGROUND: Enhancing tumor-specific T-cell immunity by inhibiting programmed death ligand 1 (PD-L1)-programmed death 1 (PD-1) signaling has shown promise in the treatment of extensive-stage small-cell lung cancer. Combining checkpoint inhibition with cytotoxic chemotherapy may have a synergistic effect and improve efficacy. METHODS: We conducted this double-blind, placebo-controlled, phase 3 trial to evaluate atezolizumab plus carboplatin and etoposide in patients with extensive-stage small-cell lung cancer who had not previously received treatment. Patients were randomly assigned in a 1:1 ratio to receive carboplatin and etoposide with either atezolizumab or placebo for four 21-day cycles (induction phase), followed by a maintenance phase during which they received either atezolizumab or placebo (according to the previous random assignment) until they had unacceptable toxic effects, disease progression according to Response Evaluation Criteria in Solid Tumors, version 1.1, or no additional clinical benefit. The two primary end points were investigator-assessed progression-free survival and overall survival in the intention-to-treat population. RESULTS: A total of 201 patients were randomly assigned to the atezolizumab group, and 202 patients to the placebo group. At a median follow-up of 13.9 months, the median overall survival was 12.3 months in the atezolizumab group and 10.3 months in the placebo group (hazard ratio for death, 0.70; 95% confidence interval [CI], 0.54 to 0.91; P=0.007). The median progression-free survival was 5.2 months and 4.3 months, respectively (hazard ratio for disease progression or death, 0.77; 95% CI, 0.62 to 0.96; P=0.02). The safety profile of atezolizumab plus carboplatin and etoposide was consistent with the previously reported safety profile of the individual agents, with no new findings observed. CONCLUSIONS: The addition of atezolizumab to chemotherapy in the first-line treatment of extensive-stage small-cell lung cancer resulted in significantly longer overall survival and progression-free survival than chemotherapy alone. (Funded by F. Hoffmann-La Roche/Genentech; IMpower133 ClinicalTrials.gov number, NCT02763579 .).

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Clinical outcome upon infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ranges from silent infection to lethal coronavirus disease 2019 (COVID-19). We have found an enrichment in rare variants predicted to be loss-of-function (LOF) at the 13 human loci known to govern Toll-like receptor 3 (TLR3)- and interferon regulatory factor 7 (IRF7)-dependent type I interferon (IFN) immunity to influenza virus in 659 patients with life-threatening COVID-19 pneumonia relative to 534 subjects with asymptomatic or benign infection. By testing these and other rare variants at these 13 loci, we experimentally defined LOF variants underlying autosomal-recessive or autosomal-dominant deficiencies in 23 patients (3.5%) 17 to 77 years of age. We show that human fibroblasts with mutations affecting this circuit are vulnerable to SARS-CoV-2. Inborn errors of TLR3- and IRF7-dependent type I IFN immunity can underlie life-threatening COVID-19 pneumonia in patients with no prior severe infection.