In vitro effect of nematophagous fungus Duddingtoniaflagrans on gastro-intestinal strongyles of sheep

Желудачно-цревне стонгилиде представљају један од најважнијих фактора који негативно утичу на здравље, добробит и економичност производње свих категорија оваца које се узгајају на пашњацима. Контрола паразитског гастроентеритиса (ПГЕ) се најчешће спроводи применом антихелминтика. Међутим, интензивна примена је довела до развоја резистенције код свих класа лекова, и представља значајан проблем на глобалном нивоу. Примена нематофагних гљива у редукцији броја ларвица на пашњаку, посебно врсте Duddingtonia flagrans, је једна од мера у оквиру интегрисане контроле паразита оваца. Гљива се даје овцама без обзира на ниво паразитизма, а ефекат је дозно-завистан. Према недавним подацима из литературе, редукција се чак смањује када однос између броја хламидоспора и јаја паразита (ХПГ:ЈПГ) у измету није оптималан. Циљ истраживања је утврђивање врста желудачно-цревних стонгилида и њиховог значаја на једној фарми оваца; провера ефикасности ивермектина који се најчешће користи у контроли ПГЕ на имању и провера хипотезе да се најбољи ефекат гљиве in vitro постиже формирањем доза заснованом на оптималном односу ХПГ:ЈПГ. Овце су клинички прегледане да се утврде симптоми ПГЕ. Паразитолошка испитивања и идентификација стронгилида су урађени стандардним копролошким техникама и прегледом одраслих облика из органа дигестивног тракта. Интензитет инвазије је процењен на основу налаза броја јаја и резултата копрокултуре. Способност FAMACHA© дијаграма да дијагностикује клиничку анемију је упоређена утврђивањем корелације са вредностима хематокрита. Ефикасност ивермектина против стронгилида и рода Nematodirus је испитана посебно, применом стандардног теста редукције јаја (FECRT). Нематофагна активност изолата D. flagrans MUCL 9827 је испитивана кроз интеракцију инфективних ларвица стронгилида са културом засејаном на 2% гладни агар. Утврђивање ХПГ:ЈПГ односа у којем D. flagrans MUCL 9827 доводи до оптималне редукције ларвица је урађено помоћу теста копрокултуре за дванаест природно заражених оваца, при чему је свака животиња посебна експериментална јединица. Испитане су четири дозе хламидоспора (0:1 (контрола); 2:1; 5:1; 10:1; 20:1), а за сваку дозу (однос) је урађено по 3 понављања. Код оваца на испитиваном имању паразитира 11 врста желудачно-цревних стронгилида: - у сиришту: Haemonchus contortus, Teladorsagia circumcinta и Trichostrongylus axei; - у танком цреву: Trichostrongylus colubriformis, Nematodirus spathiger, Nematodirus filicollis, Nematodirus abnormalis и Strongyloides papillosus; - у дебелом цреву: Chabertia ovina, Oesophagostomum venulosum и Trichuris discolor Доминантна врста током целе године је H. contortus, у просеку чини 72,3% популације а највиши ниво достиже у летњим месецима. Род Trichostrongylus је други по значају уз заступљеност од 17,6% и преовлађује у јесењим месецима. Клинички симптоми и патоанатомски налаз одговарају ПГЕ (Trichostrongylidosis et strongylosis ventriculi et intestini ovium). Интензитет инвазије је висок односно умерен за 31,7% и 28,4% прегледаних животиња, тим редом, што значи да је потребно је применити дехелминтизацију у 60,1% инвадираних оваца. Помоћу FAMACHA© дијаграма нису успешно идентификоване овце које су имале клиничку анемију због негативне корелације са вредностима хематокрита (rho=- 0,2446, р=0,0541). Након теста редукције јаја (FECRT), установљено је да ефикасност ивермектина стронгилида износи око 80% (у распону од 67-99%). У односу на генеричку ефикасност, најмање је осетљив род Trichostrongylus (ПР(%)=33-80), резистенција коју додатно треба испитати постоји код T. circumcinta (ПР(%)=93; 95% ИП: 83-97), а сумња на резистенцију је установљена код H. contortus (ПР(%)=97; 95% ИП: 89-99). Резистенција постоји и код рода Nematodirus, где је редукција јаја била 74% (95% ИП: 38-89). У in vitro условима, D. flagrans MUCL 9827 развија замке и хвата инфективне ларвица, што је утврђено на 2% гладном агару, али само у једној култури. D. flagrans MUCL 9827 је у тесту копрокултуре постигла дозно-зависну редукцију ларвица желудачно-цревних стронгилида оваца у распону од 11,31-29,02%, али та редукција није била значајна у односу на контролу (р=0,827). Проценат смањења броја ларвица за ХПГ:ЈПГ однос 10:1 је био 4% мањи у односу на ХПГ:ЈПГ однос 20:1, а забележена је и боља активност против ИВМ резистентних ларвица и најмањи број култура без икакве редукције. Забележени клинички симптоми, употпуњени копролошким, патоанатомским и налазом интензитета инвазије потврђују да ПГЕ има значајан утицај на здравље, добробит и производне параметре оваца. Терапија ивермектином није довољно ефикасна у контроли стронгилида оваца на имању због присуства резистенције. Испитивани изолат гљиве испољава биолошки ефекат in vitro. Одређено је да је у датим условима теста копрокултуре оптимални ХПГ:ЈПГ однос 10:1. На основу резултата у in vitro условима, изолат D. flagrans MUCL 9827 није погодан за биолошку контролу желудачно-цревних стронгилида оваца.Želudačno-crevne stongilide predstavljaju jedan od najvažnijih faktora koji negativno utiču na zdravlje, dobrobit i ekonomičnost proizvodnje svih kategorija ovaca koje se uzgajaju na pašnjacima. Kontrola parazitskog gastroenteritisa (PGE) se najčešće sprovodi primenom antihelmintika. Međutim, intenzivna primena je dovela do razvoja rezistencije kod svih klasa lekova, i predstavlja značajan problem na globalnom nivou. Primena nematofagnih gljiva u redukciji broja larvica na pašnjaku, posebno vrste Duddingtonia flagrans, je jedna od mera u okviru integrisane kontrole parazita ovaca. Gljiva se daje ovcama bez obzira na nivo parazitizma, a efekat je dozno-zavistan. Prema nedavnim podacima iz literature, redukcija se čak smanjuje kada odnos između broja hlamidospora i jaja parazita (HPG:JPG) u izmetu nije optimalan. Cilj istraživanja je utvrđivanje vrsta želudačno-crevnih stongilida i njihovog značaja na jednoj farmi ovaca; provera efikasnosti ivermektina koji se najčešće koristi u kontroli PGE na imanju i provera hipoteze da se najbolji efekat gljive in vitro postiže formiranjem doza zasnovanom na optimalnom odnosu HPG:JPG. Ovce su klinički pregledane da se utvrde simptomi PGE. Parazitološka ispitivanja i identifikacija strongilida su urađeni standardnim koprološkim tehnikama i pregledom odraslih oblika iz organa digestivnog trakta. Intenzitet invazije je procenjen na osnovu nalaza broja jaja i rezultata koprokulture. Sposobnost FAMACHA© dijagrama da dijagnostikuje kliničku anemiju je upoređena utvrđivanjem korelacije sa vrednostima hematokrita. Efikasnost ivermektina protiv strongilida i roda Nematodirus je ispitana posebno, primenom standardnog testa redukcije jaja (FECRT). Nematofagna aktivnost izolata D. flagrans MUCL 9827 je ispitivana kroz interakciju infektivnih larvica strongilida sa kulturom zasejanom na 2% gladni agar. Utvrđivanje HPG:JPG odnosa u kojem D. flagrans MUCL 9827 dovodi do optimalne redukcije larvica je urađeno pomoću testa koprokulture za dvanaest prirodno zaraženih ovaca, pri čemu je svaka životinja posebna eksperimentalna jedinica. Ispitane su četiri doze hlamidospora (0:1 (kontrola); 2:1; 5:1; 10:1; 20:1), a za svaku dozu (odnos) je urađeno po 3 ponavljanja. Kod ovaca na ispitivanom imanju parazitira 11 vrsta želudačno-crevnih strongilida: - u sirištu: Haemonchus contortus, Teladorsagia circumcinta i Trichostrongylus axei; - u tankom crevu: Trichostrongylus colubriformis, Nematodirus spathiger, Nematodirus filicollis, Nematodirus abnormalis i Strongyloides papillosus; - u debelom crevu: Chabertia ovina, Oesophagostomum venulosum i Trichuris discolor Dominantna vrsta tokom cele godine je H. contortus, u proseku čini 72,3% populacije a najviši nivo dostiže u letnjim mesecima. Rod Trichostrongylus je drugi po značaju uz zastupljenost od 17,6% i preovlađuje u jesenjim mesecima. Klinički simptomi i patoanatomski nalaz odgovaraju PGE (Trichostrongylidosis et strongylosis ventriculi et intestini ovium). Intenzitet invazije je visok odnosno umeren za 31,7% i 28,4% pregledanih životinja, tim redom, što znači da je potrebno je primeniti dehelmintizaciju u 60,1% invadiranih ovaca. Pomoću FAMACHA© dijagrama nisu uspešno identifikovane ovce koje su imale kliničku anemiju zbog negativne korelacije sa vrednostima hematokrita (rho=- 0,2446, r=0,0541). Nakon testa redukcije jaja (FECRT), ustanovljeno je da efikasnost ivermektina strongilida iznosi oko 80% (u rasponu od 67-99%). U odnosu na generičku efikasnost, najmanje je osetljiv rod Trichostrongylus (PR(%)=33-80), rezistencija koju dodatno treba ispitati postoji kod T. circumcinta (PR(%)=93; 95% IP: 83-97), a sumnja na rezistenciju je ustanovljena kod H. contortus (PR(%)=97; 95% IP: 89-99). Rezistencija postoji i kod roda Nematodirus, gde je redukcija jaja bila 74% (95% IP: 38-89). U in vitro uslovima, D. flagrans MUCL 9827 razvija zamke i hvata infektivne larvica, što je utvrđeno na 2% gladnom agaru, ali samo u jednoj kulturi. D. flagrans MUCL 9827 je u testu koprokulture postigla dozno-zavisnu redukciju larvica želudačno-crevnih strongilida ovaca u rasponu od 11,31-29,02%, ali ta redukcija nije bila značajna u odnosu na kontrolu (r=0,827). Procenat smanjenja broja larvica za HPG:JPG odnos 10:1 je bio 4% manji u odnosu na HPG:JPG odnos 20:1, a zabeležena je i bolja aktivnost protiv IVM rezistentnih larvica i najmanji broj kultura bez ikakve redukcije. Zabeleženi klinički simptomi, upotpunjeni koprološkim, patoanatomskim i nalazom intenziteta invazije potvrđuju da PGE ima značajan uticaj na zdravlje, dobrobit i proizvodne parametre ovaca. Terapija ivermektinom nije dovoljno efikasna u kontroli strongilida ovaca na imanju zbog prisustva rezistencije. Ispitivani izolat gljive ispoljava biološki efekat in vitro. Određeno je da je u datim uslovima testa koprokulture optimalni HPG:JPG odnos 10:1. Na osnovu rezultata u in vitro uslovima, izolat D. flagrans MUCL 9827 nije pogodan za biološku kontrolu želudačno-crevnih strongilida ovaca.Gastrointestinal strongyles represent one of the main factors which have negative impact on health, welfare and economics of production of all grazing sheep categories. The usual control measures of parasitic gastroenteritis (PGE) involve the use of anthelmintics. However, intensive exploitation of this approach has led to the development of resistance in all classes of drugs, which represents a significant problem globally. Reduction in larval numbers on the pastures using nematophagous fungi, particularly Duddingtonia flagrans, represents one of the promising measures of the integrated sheep parasite control. The fungus is administered to sheep regardless of parasite burden and the effect is dose-dependent. According to the recent literature data, reduction could even be decreased if the ratio between the number of chlamydospores and parasite eggs (CPG:EPG) in the feces is not optimal. The aim of this research was identification of the gastrointestinal strongyle species, and investigation of their impact on a particular sheep farm; determination of the efficacy of ivermectin which was the most frequently used drug for the control of PGE on the property and to check the hypothesis that the best effect of fungal treatment in vivo is achieved if dosage is based on the optimal CPG:EPG ratio. Sheep were clinically examined for the symptoms of PGE. Parasitological investigation and identification of strongyles were performed combining the standard coprological techniques and examination of the adult worms, collected from the gastrointestinal system of sheep. Evaluation of the intensity of the parasitic invasion was performed by combining the faecal egg counts and the results of coprocultures. Ability of FAMACHA© diagrams to diagnose clinical anemia was determined based on the correlation with the haematocrit values. The efficacy of ivermectin against strongyles and Nematodirus spp. was examined separately, using standard faecal egg count reduction test (FECRT). Nematophagous activity of D. flagrans isolate MUCL 9827 was examined through interaction of infective strongyle larvae with fungal culture grown on 2% water agar (WA). To determine CPG:EPG ratio at which larval reduction by D. flagrans MUCL 9827 is optimal, the coproculture assay was performed for 12 naturally infected sheep. Each animal was separate experimental unit. Four doses of chlamydospores were tested (0:1 (control); 2:1; 5:1; 10:1; 20:1), each at three repetitions. Eleven species of gastro-intestinal strongyles were found to parasitise sheep on the farm: - in the abomasum: Haemonchus contortus, Teladorsagia circumcinta and Trichostrongylus axei; - in the small intestine: Trichostrongylus colubriformis, Nematodirus spathiger, Nematodirus filicollis, Nematodirus abnormalis and Strongyloides papillosus; - in the large intestine: Chabertia ovina, Oesophagostomum venulosum and Trichuris discolor. The dominant species throughout the year was H. contortus, with 72.3% of average population which reaches the highest level in the summer months. Trichostrongylus is the second most important genus, comprising 17,6% of parasite population and reaching maximum levels during the autumn. Clinical symptoms and post-mortem findings corresponded to PGE (Trichostrongylidosis et strongylosis ventriculi et intestini ovium). Intensity of the invasion was high and medium in 31,7% and 28,4% of the examined animals, respectively, which means that 60,1% of sheep need anthelmintic treatement. Identification of sheep with clinical anemia using the FAMACHA© diagram was unsuccessful due to negative correlation with the haematocrit levels (rho=-0,2446, р=0,0541). According to FECRT, the efficacy of ivermectin against the strongyles was approximately 80% (with the range of 67-99%). Genus based efficacy calculations showed that the least sensitive was Trichostrongylus spp. (PR (%) = 33- 80), resistance which requires further examination was found in T. circumcinta (PR (%) = 93; 95% CIs: 83-97) and that resistance was suspected in H. contortus (PR (%) = 97; 95% CIs: 89- 99). Resistance was also observed in Nematodirus spp. with egg reduction level of 74% (95% CIs: 38-89)). D. flagrans MUCL 9827 showed trap development and subsequent trapping of infective larvae at tested in vitro conditions on 2% WA, but only in one plate. Dose dependent larval reduction in range of 11,31-29,02% was recorded after coproculture assay with D. flagrans MUCL 9827. However, this reduction was not considered significant, compared to the control (р=0,827). The percenage of larval reduction was 4% lower for 10:1 CPG:EPG ratio compared to 20:1 CPG:EPG ratio. Better activity against ivermectin-resistant larvae and the smallest number of cultures without any reduction was also observed for 10:1 ratio. The recorded clinical symptoms, with coprological, post-mortem and infection level findings, confirm that the PGE has a significant impact on the health, welfare and production parameters of sheep. Due to resistance, ivermectin therapy is not effective enough in sheep strongyle control on the examined farm. The tested isolate of D. flagrans exhibits biological effect, in vitro. It was determined that, in the given circumstances of the coproculture assay, the optimal CPG:EPG ratio is 10:1. Based on the results of the in vitro study, isolate D. flagrans MUCL 9827 is not considered suitable for biological control of gastrointestinal strongyles of the sheep

Long Time No Hear, Magnificent Wohlfahrtia! Morphological and Molecular Evidence of Almost Forgotten Flesh Fly in Serbia and Western Balkans

The “beautiful viviparous fly”, Wohlfahrtia magnifica, may have a magnificent appearance due to its striking morphology; however, it is a potentially deadly agent of obligate traumatic myiasis in humans and animals, with a serious impact on welfare and economics. The fly is found across the Palearctic realm, including the Western Balkan region, with reports from former Yugoslavian countries from the first half of the 20th century. In this paper, a recent case of wohlfahrtiosis recorded in Northern Serbia is evidenced using morphological and molecular techniques. Larvae were collected from two adult sheep with severe hoof myiasis and two young sheep with genital and interdigital myiasis. Morphological identification was performed for adults bred from the infested vulva and third-stage larvae (L3) collected from the hoof wounds, supported with barcoding sequences of the COI gene obtained from larval pairs from the hoof wounds of older and the genitalia of younger sheep. W. magnifica was identified according to the appearance of male fly terminalia and the morphology of L3, which was confirmed after the comparison of representative sequences of the COI gene (deposited in GenBank™ under accession numbers MT027108–MT027114) to those available in GenBank™. This finding represents the first reported case of wohlfahrtiosis in the Western Balkans in 80 years, highlighting the need to re-inform relevant stakeholders to achieve adequate disease control

Combating Anthelmintic Resistance in Ruminants: A Serbian Perspective

Heavy reliance on anthelmintics to control gastrointestinal nematodes (GIN) of grazing ruminants, led to the emergence of anthelmintic resistance (AR), a well known global problem to sustainable animal production, health and welfare. Ruminant producers in Serbia are seldomly aware of the serious losses that GIN can cause. Although resistance of Trichostrongylus spp. to ivermectin (IVM) was detected earlier in sheep, they rarely know about the existence of AR. To address the AR issue in a new manner, several Serbian researchers attended COMBAR training schools (TSs) and short term scientific missions (STSMs) in order to acquire new skills for improved diagnostics and control of GIN, such as the application of the Mini FLOTAC technique and the conduct of faecal egg count reduction tests (FECRTs) for monitoring anthelmintic efficacy. Using Mini FLOTAC, a set of small scale surveys was performed, to monitor GIN in grazing cattle (50 animals from 5 herds) and assess anthelmintic efficacy in sheep (11 farms tested for IVM, 3 farms tested for levamisole (LEV)) and goats (one farm tested for IVM, eprinomectin (EPR) and albendazole (ALB)). Results showed low levels of GIN infection in cattle (average 13 eggs per gram (epg), range 5-95 epg). In the goat farm, resistance to EPR and IVM was detected (percentage of egg reductions= 83 and 92%, respectively), while ALB retained full efficacy. Regarding sheep, AR to IVM was established in 8 farms (73%), with egg reductions ranging from 55 to 92%, while LEV showed full efficacy against GIN. An STSM supported the evaluation of essential oils from Serbian native plants against GIN using in vitro studies and showed promising results. Overall, COST Action COMBAR is contributing to sustainable parasite control in Serbia through training researchers in new research practices

Increasing importance of anthelmintic resistance in European livestock: creation and meta-analysis of an open database

peer reviewedHelminth infections are ubiquitous in grazing ruminant production systems, and are responsible for significant costs and production losses. Anthelmintic Resistance (AR) in parasites is now widespread throughout Europe, although there are still gaps in our knowledge in some regions and countries. AR is a major threat to the sustainability of modern ruminant livestock production, resulting in reduced productivity, compromised animal health and welfare, and increased greenhouse gas emissions through increased parasitism and farm inputs. A better understanding of the extent of AR in Europe is needed to develop and advocate more sustainable parasite control approaches. A database of European published and unpublished AR research on gastrointestinal nematodes (GIN) and liver fluke (Fasciola hepatica) was collated by members of the European COST Action “COMBAR” (Combatting Anthelmintic Resistance in Ruminants), and combined with data from a previous systematic review of AR in GIN. A total of 197 publications on AR in GIN were available for analysis, representing 535 studies in 22 countries and spanning the period 1980–2020. Reports of AR were present throughout the European continent and some reports indicated high within-country prevalence. Heuristic sample size-weighted estimates of European AR prevalence over the whole study period, stratified by anthelmintic class, varied between 0 and 48%. Estimated regional (country) prevalence was highly heterogeneous, ranging between 0% and 100% depending on livestock sector and anthelmintic class, and generally increased with increasing research effort in a country. In the few countries with adequate longitudinal data, there was a tendency towards increasing AR over time for all anthelmintic classes in GIN: aggregated results in sheep and goats since 2010 reveal an average prevalence of resistance to benzimidazoles (BZ) of 86%, macrocyclic lactones except moxidectin (ML) 52%, levamisole (LEV) 48%, and moxidectin (MOX) 21%. All major GIN genera survived treatment in various studies. In cattle, prevalence of AR varied between anthelmintic classes from 0–100% (BZ and ML), 0–17% (LEV) and 0–73% (MOX), and both Cooperia and Ostertagia survived treatment. Suspected AR in F. hepatica was reported in 21 studies spanning 6 countries. For GIN and particularly F. hepatica, there was a bias towards preferential sampling of individual farms with suspected AR, and research effort was biased towards Western Europe and particularly the United Kingdom. Ongoing capture of future results in the live database, efforts to avoid bias in farm recruitment, more accurate tests for AR, and stronger appreciation of the importance of AR among the agricultural industry and policy makers, will support more sophisticated analyses of factors contributing to AR and effective strategies to slow its spread

Fifth European Dirofilaria and Angiostrongylus Days (FiEDAD) 2016

Peer reviewe

Mapping development and health effects of cooking with solid fuels in low-income and middle-income countries, 2000-18 : a geospatial modelling study

Background More than 3 billion people do not have access to clean energy and primarily use solid fuels to cook. Use of solid fuels generates household air pollution, which was associated with more than 2 million deaths in 2019. Although local patterns in cooking vary systematically, subnational trends in use of solid fuels have yet to be comprehensively analysed. We estimated the prevalence of solid-fuel use with high spatial resolution to explore subnational inequalities, assess local progress, and assess the effects on health in low-income and middle-income countries (LMICs) without universal access to clean fuels.Methods We did a geospatial modelling study to map the prevalence of solid-fuel use for cooking at a 5 km x 5 km resolution in 98 LMICs based on 2.1 million household observations of the primary cooking fuel used from 663 population-based household surveys over the years 2000 to 2018. We use observed temporal patterns to forecast household air pollution in 2030 and to assess the probability of attaining the Sustainable Development Goal (SDG) target indicator for clean cooking. We aligned our estimates of household air pollution to geospatial estimates of ambient air pollution to establish the risk transition occurring in LMICs. Finally, we quantified the effect of residual primary solid-fuel use for cooking on child health by doing a counterfactual risk assessment to estimate the proportion of deaths from lower respiratory tract infections in children younger than 5 years that could be associated with household air pollution.Findings Although primary reliance on solid-fuel use for cooking has declined globally, it remains widespread. 593 million people live in districts where the prevalence of solid-fuel use for cooking exceeds 95%. 66% of people in LMICs live in districts that are not on track to meet the SDG target for universal access to clean energy by 2030. Household air pollution continues to be a major contributor to particulate exposure in LMICs, and rising ambient air pollution is undermining potential gains from reductions in the prevalence of solid-fuel use for cooking in many countries. We estimated that, in 2018, 205000 (95% uncertainty interval 147000-257000) children younger than 5 years died from lower respiratory tract infections that could be attributed to household air pollution.Interpretation Efforts to accelerate the adoption of clean cooking fuels need to be substantially increased and recalibrated to account for subnational inequalities, because there are substantial opportunities to improve air quality and avert child mortality associated with household air pollution. Copyright (C) 2022 The Author(s). Published by Elsevier Ltd.Peer reviewe

Global age-sex-specific fertility, mortality, healthy life expectancy (HALE), and population estimates in 204 countries and territories, 1950-2019 : a comprehensive demographic analysis for the Global Burden of Disease Study 2019

Background: Accurate and up-to-date assessment of demographic metrics is crucial for understanding a wide range of social, economic, and public health issues that affect populations worldwide. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 produced updated and comprehensive demographic assessments of the key indicators of fertility, mortality, migration, and population for 204 countries and territories and selected subnational locations from 1950 to 2019. Methods: 8078 country-years of vital registration and sample registration data, 938 surveys, 349 censuses, and 238 other sources were identified and used to estimate age-specific fertility. Spatiotemporal Gaussian process regression (ST-GPR) was used to generate age-specific fertility rates for 5-year age groups between ages 15 and 49 years. With extensions to age groups 10–14 and 50–54 years, the total fertility rate (TFR) was then aggregated using the estimated age-specific fertility between ages 10 and 54 years. 7417 sources were used for under-5 mortality estimation and 7355 for adult mortality. ST-GPR was used to synthesise data sources after correction for known biases. Adult mortality was measured as the probability of death between ages 15 and 60 years based on vital registration, sample registration, and sibling histories, and was also estimated using ST-GPR. HIV-free life tables were then estimated using estimates of under-5 and adult mortality rates using a relational model life table system created for GBD, which closely tracks observed age-specific mortality rates from complete vital registration when available. Independent estimates of HIV-specific mortality generated by an epidemiological analysis of HIV prevalence surveys and antenatal clinic serosurveillance and other sources were incorporated into the estimates in countries with large epidemics. Annual and single-year age estimates of net migration and population for each country and territory were generated using a Bayesian hierarchical cohort component model that analysed estimated age-specific fertility and mortality rates along with 1250 censuses and 747 population registry years. We classified location-years into seven categories on the basis of the natural rate of increase in population (calculated by subtracting the crude death rate from the crude birth rate) and the net migration rate. We computed healthy life expectancy (HALE) using years lived with disability (YLDs) per capita, life tables, and standard demographic methods. Uncertainty was propagated throughout the demographic estimation process, including fertility, mortality, and population, with 1000 draw-level estimates produced for each metric. Findings: The global TFR decreased from 2·72 (95% uncertainty interval [UI] 2·66–2·79) in 2000 to 2·31 (2·17–2·46) in 2019. Global annual livebirths increased from 134·5 million (131·5–137·8) in 2000 to a peak of 139·6 million (133·0–146·9) in 2016. Global livebirths then declined to 135·3 million (127·2–144·1) in 2019. Of the 204 countries and territories included in this study, in 2019, 102 had a TFR lower than 2·1, which is considered a good approximation of replacement-level fertility. All countries in sub-Saharan Africa had TFRs above replacement level in 2019 and accounted for 27·1% (95% UI 26·4–27·8) of global livebirths. Global life expectancy at birth increased from 67·2 years (95% UI 66·8–67·6) in 2000 to 73·5 years (72·8–74·3) in 2019. The total number of deaths increased from 50·7 million (49·5–51·9) in 2000 to 56·5 million (53·7–59·2) in 2019. Under-5 deaths declined from 9·6 million (9·1–10·3) in 2000 to 5·0 million (4·3–6·0) in 2019. Global population increased by 25·7%, from 6·2 billion (6·0–6·3) in 2000 to 7·7 billion (7·5–8·0) in 2019. In 2019, 34 countries had negative natural rates of increase; in 17 of these, the population declined because immigration was not sufficient to counteract the negative rate of decline. Globally, HALE increased from 58·6 years (56·1–60·8) in 2000 to 63·5 years (60·8–66·1) in 2019. HALE increased in 202 of 204 countries and territories between 2000 and 2019

Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

Background: In an era of shifting global agendas and expanded emphasis on non-communicable diseases and injuries along with communicable diseases, sound evidence on trends by cause at the national level is essential. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) provides a systematic scientific assessment of published, publicly available, and contributed data on incidence, prevalence, and mortality for a mutually exclusive and collectively exhaustive list of diseases and injuries. Methods: GBD estimates incidence, prevalence, mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) due to 369 diseases and injuries, for two sexes, and for 204 countries and territories. Input data were extracted from censuses, household surveys, civil registration and vital statistics, disease registries, health service use, air pollution monitors, satellite imaging, disease notifications, and other sources. Cause-specific death rates and cause fractions were calculated using the Cause of Death Ensemble model and spatiotemporal Gaussian process regression. Cause-specific deaths were adjusted to match the total all-cause deaths calculated as part of the GBD population, fertility, and mortality estimates. Deaths were multiplied by standard life expectancy at each age to calculate YLLs. A Bayesian meta-regression modelling tool, DisMod-MR 2.1, was used to ensure consistency between incidence, prevalence, remission, excess mortality, and cause-specific mortality for most causes. Prevalence estimates were multiplied by disability weights for mutually exclusive sequelae of diseases and injuries to calculate YLDs. We considered results in the context of the Socio-demographic Index (SDI), a composite indicator of income per capita, years of schooling, and fertility rate in females younger than 25 years. Uncertainty intervals (UIs) were generated for every metric using the 25th and 975th ordered 1000 draw values of the posterior distribution. Findings: Global health has steadily improved over the past 30 years as measured by age-standardised DALY rates. After taking into account population growth and ageing, the absolute number of DALYs has remained stable. Since 2010, the pace of decline in global age-standardised DALY rates has accelerated in age groups younger than 50 years compared with the 1990–2010 time period, with the greatest annualised rate of decline occurring in the 0–9-year age group. Six infectious diseases were among the top ten causes of DALYs in children younger than 10 years in 2019: lower respiratory infections (ranked second), diarrhoeal diseases (third), malaria (fifth), meningitis (sixth), whooping cough (ninth), and sexually transmitted infections (which, in this age group, is fully accounted for by congenital syphilis; ranked tenth). In adolescents aged 10–24 years, three injury causes were among the top causes of DALYs: road injuries (ranked first), self-harm (third), and interpersonal violence (fifth). Five of the causes that were in the top ten for ages 10–24 years were also in the top ten in the 25–49-year age group: road injuries (ranked first), HIV/AIDS (second), low back pain (fourth), headache disorders (fifth), and depressive disorders (sixth). In 2019, ischaemic heart disease and stroke were the top-ranked causes of DALYs in both the 50–74-year and 75-years-and-older age groups. Since 1990, there has been a marked shift towards a greater proportion of burden due to YLDs from non-communicable diseases and injuries. In 2019, there were 11 countries where non-communicable disease and injury YLDs constituted more than half of all disease burden. Decreases in age-standardised DALY rates have accelerated over the past decade in countries at the lower end of the SDI range, while improvements have started to stagnate or even reverse in countries with higher SDI. Interpretation: As disability becomes an increasingly large component of disease burden and a larger component of health expenditure, greater research and developm nt investment is needed to identify new, more effective intervention strategies. With a rapidly ageing global population, the demands on health services to deal with disabling outcomes, which increase with age, will require policy makers to anticipate these changes. The mix of universal and more geographically specific influences on health reinforces the need for regular reporting on population health in detail and by underlying cause to help decision makers to identify success stories of disease control to emulate, as well as opportunities to improve. Funding: Bill & Melinda Gates Foundation. © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licens

Erratum: Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017

Interpretation: By quantifying levels and trends in exposures to risk factors and the resulting disease burden, this assessment offers insight into where past policy and programme efforts might have been successful and highlights current priorities for public health action. Decreases in behavioural, environmental, and occupational risks have largely offset the effects of population growth and ageing, in relation to trends in absolute burden. Conversely, the combination of increasing metabolic risks and population ageing will probably continue to drive the increasing trends in non-communicable diseases at the global level, which presents both a public health challenge and opportunity. We see considerable spatiotemporal heterogeneity in levels of risk exposure and risk-attributable burden. Although levels of development underlie some of this heterogeneity, O/E ratios show risks for which countries are overperforming or underperforming relative to their level of development. As such, these ratios provide a benchmarking tool to help to focus local decision making. Our findings reinforce the importance of both risk exposure monitoring and epidemiological research to assess causal connections between risks and health outcomes, and they highlight the usefulness of the GBD study in synthesising data to draw comprehensive and robust conclusions that help to inform good policy and strategic health planning

Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017

Background The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 comparative risk assessment (CRA) is a comprehensive approach to risk factor quantification that offers a useful tool for synthesising evidence on risks and risk–outcome associations. With each annual GBD study, we update the GBD CRA to incorporate improved methods, new risks and risk–outcome pairs, and new data on risk exposure levels and risk–outcome associations. Methods We used the CRA framework developed for previous iterations of GBD to estimate levels and trends in exposure, attributable deaths, and attributable disability-adjusted life-years (DALYs), by age group, sex, year, and location for 84 behavioural, environmental and occupational, and metabolic risks or groups of risks from 1990 to 2017. This study included 476 risk–outcome pairs that met the GBD study criteria for convincing or probable evidence of causation. We extracted relative risk and exposure estimates from 46 749 randomised controlled trials, cohort studies, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. Using the counterfactual scenario of theoretical minimum risk exposure level (TMREL), we estimated the portion of deaths and DALYs that could be attributed to a given risk. We explored the relationship between development and risk exposure by modelling the relationship between the Socio-demographic Index (SDI) and risk-weighted exposure prevalence and estimated expected levels of exposure and risk-attributable burden by SDI. Finally, we explored temporal changes in risk-attributable DALYs by decomposing those changes into six main component drivers of change as follows: (1) population growth; (2) changes in population age structures; (3) changes in exposure to environmental and occupational risks; (4) changes in exposure to behavioural risks; (5) changes in exposure to metabolic risks; and (6) changes due to all other factors, approximated as the risk-deleted death and DALY rates, where the risk-deleted rate is the rate that would be observed had we reduced the exposure levels to the TMREL for all risk factors included in GBD 2017. Findings In 2017, 34·1 million (95% uncertainty interval [UI] 33·3–35·0) deaths and 1·21 billion (1·14–1·28) DALYs were attributable to GBD risk factors. Globally, 61·0% (59·6–62·4) of deaths and 48·3% (46·3–50·2) of DALYs were attributed to the GBD 2017 risk factors. When ranked by risk-attributable DALYs, high systolic blood pressure (SBP) was the leading risk factor, accounting for 10·4 million (9·39–11·5) deaths and 218 million (198–237) DALYs, followed by smoking (7·10 million [6·83–7·37] deaths and 182 million [173–193] DALYs), high fasting plasma glucose (6·53 million [5·23–8·23] deaths and 171 million [144–201] DALYs), high body-mass index (BMI; 4·72 million [2·99–6·70] deaths and 148 million [98·6–202] DALYs), and short gestation for birthweight (1·43 million [1·36–1·51] deaths and 139 million [131–147] DALYs). In total, risk-attributable DALYs declined by 4·9% (3·3–6·5) between 2007 and 2017. In the absence of demographic changes (ie, population growth and ageing), changes in risk exposure and risk-deleted DALYs would have led to a 23·5% decline in DALYs during that period. Conversely, in the absence of changes in risk exposure and risk-deleted DALYs, demographic changes would have led to an 18·6% increase in DALYs during that period. The ratios of observed risk exposure levels to exposure levels expected based on SDI (O/E ratios) increased globally for unsafe drinking water and household air pollution between 1990 and 2017. This result suggests that development is occurring more rapidly than are changes in the underlying risk structure in a population. Conversely, nearly universal declines in O/E ratios for smoking and alcohol use indicate that, for a given SDI, exposure to these risks is declining. In 2017, the leading Level 4 risk factor for age-standardised DALY rates was high SBP in four super-regions: central Europe, eastern Europe, and central Asia; north Africa and Middle East; south Asia; and southeast Asia, east Asia, and Oceania. The leading risk factor in the high-income super-region was smoking, in Latin America and Caribbean was high BMI, and in sub-Saharan Africa was unsafe sex. O/E ratios for unsafe sex in sub-Saharan Africa were notably high, and those for alcohol use in north Africa and the Middle East were notably low. Interpretation By quantifying levels and trends in exposures to risk factors and the resulting disease burden, this assessment offers insight into where past policy and programme efforts might have been successful and highlights current priorities for public health action. Decreases in behavioural, environmental, and occupational risks have largely offset the effects of population growth and ageing, in relation to trends in absolute burden. Conversely, the combination of increasing metabolic risks and population ageing will probably continue to drive the increasing trends in non-communicable diseases at the global level, which presents both a public health challenge and opportunity. We see considerable spatiotemporal heterogeneity in levels of risk exposure and risk-attributable burden. Although levels of development underlie some of this heterogeneity, O/E ratios show risks for which countries are overperforming or underperforming relative to their level of development. As such, these ratios provide a benchmarking tool to help to focus local decision making. Our findings reinforce the importance of both risk exposure monitoring and epidemiological research to assess causal connections between risks and health outcomes, and they highlight the usefulness of the GBD study in synthesising data to draw comprehensive and robust conclusions that help to inform good policy and strategic health planning