Global prevalence and genotype distribution of hepatitis C virus infection in 2015 : A modelling study

Publisher Copyright: © 2017 Elsevier LtdBackground The 69th World Health Assembly approved the Global Health Sector Strategy to eliminate hepatitis C virus (HCV) infection by 2030, which can become a reality with the recent launch of direct acting antiviral therapies. Reliable disease burden estimates are required for national strategies. This analysis estimates the global prevalence of viraemic HCV at the end of 2015, an update of—and expansion on—the 2014 analysis, which reported 80 million (95% CI 64–103) viraemic infections in 2013. Methods We developed country-level disease burden models following a systematic review of HCV prevalence (number of studies, n=6754) and genotype (n=11 342) studies published after 2013. A Delphi process was used to gain country expert consensus and validate inputs. Published estimates alone were used for countries where expert panel meetings could not be scheduled. Global prevalence was estimated using regional averages for countries without data. Findings Models were built for 100 countries, 59 of which were approved by country experts, with the remaining 41 estimated using published data alone. The remaining countries had insufficient data to create a model. The global prevalence of viraemic HCV is estimated to be 1·0% (95% uncertainty interval 0·8–1·1) in 2015, corresponding to 71·1 million (62·5–79·4) viraemic infections. Genotypes 1 and 3 were the most common cause of infections (44% and 25%, respectively). Interpretation The global estimate of viraemic infections is lower than previous estimates, largely due to more recent (lower) prevalence estimates in Africa. Additionally, increased mortality due to liver-related causes and an ageing population may have contributed to a reduction in infections. Funding John C Martin Foundation.publishersversionPeer reviewe

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Odanacatib for the treatment of postmenopausal osteoporosis. results of the LOFT multicentre, randomised, double-blind, placebo-controlled trial and LOFT extension study

Background: Odanacatib, a cathepsin K inhibitor, reduces bone resorption while maintaining bone formation. Previous work has shown that odanacatib increases bone mineral density in postmenopausal women with low bone mass. We aimed to investigate the efficacy and safety of odanacatib to reduce fracture risk in postmenopausal women with osteoporosis. Methods: The Long-term Odanacatib Fracture Trial (LOFT) was a multicentre, randomised, double-blind, placebo-controlled, event-driven study at 388 outpatient clinics in 40 countries. Eligible participants were women aged at least 65 years who were postmenopausal for 5 years or more, with a femoral neck or total hip bone mineral density T-score between −2·5 and −4·0 if no previous radiographic vertebral fracture, or between −1·5 and −4·0 with a previous vertebral fracture. Women with a previous hip fracture, more than one vertebral fracture, or a T-score of less than −4·0 at the total hip or femoral neck were not eligible unless they were unable or unwilling to use approved osteoporosis treatment. Participants were randomly assigned (1:1) to either oral odanacatib (50 mg once per week) or matching placebo. Randomisation was done using an interactive voice recognition system after stratification for previous radiographic vertebral fracture, and treatment was masked to study participants, investigators and their staff, and sponsor personnel. If the study completed before 5 years of double-blind treatment, consenting participants could enrol in a double-blind extension study (LOFT Extension), continuing their original treatment assignment for up to 5 years from randomisation. Primary endpoints were incidence of vertebral fractures as assessed using radiographs collected at baseline, 6 and 12 months, yearly, and at final study visit in participants for whom evaluable radiograph images were available at baseline and at least one other timepoint, and hip and non-vertebral fractures adjudicated as being a result of osteoporosis as assessed by clinical history and radiograph. Safety was assessed in participants who received at least one dose of study drug. The adjudicated cardiovascular safety endpoints were a composite of cardiovascular death, myocardial infarction, or stroke, and new-onset atrial fibrillation or flutter. Individual cardiovascular endpoints and death were also assessed. LOFT and LOFT Extension are registered with ClinicalTrials.gov (number NCT00529373) and the European Clinical Trials Database (EudraCT number 2007-002693-66). Findings: Between Sept 14, 2007, and Nov 17, 2009, we randomly assigned 16 071 evaluable patients to treatment: 8043 to odanacatib and 8028 to placebo. After a median follow-up of 36·5 months (IQR 34·43–40·15) 4297 women assigned to odanacatib and 3960 assigned to placebo enrolled in LOFT Extension (total median follow-up 47·6 months, IQR 35·45–60·06). In LOFT, cumulative incidence of primary outcomes for odanacatib versus placebo were: radiographic vertebral fractures 3·7% (251/6770) versus 7·8% (542/6910), hazard ratio (HR) 0·46, 95% CI 0·40–0·53; hip fractures 0·8% (65/8043) versus 1·6% (125/8028), 0·53, 0·39–0·71; non-vertebral fractures 5·1% (412/8043) versus 6·7% (541/8028), 0·77, 0·68–0·87; all p&lt;0·0001. Combined results from LOFT plus LOFT Extension for cumulative incidence of primary outcomes for odanacatib versus placebo were: radiographic vertebral fractures 4·9% (341/6909) versus 9·6% (675/7011), HR 0·48, 95% CI 0·42–0·55; hip fractures 1·1% (86/8043) versus 2·0% (162/8028), 0·52, 0·40–0·67; non-vertebral fractures 6·4% (512/8043) versus 8·4% (675/8028), 0·74, 0·66–0·83; all p&lt;0·0001. In LOFT, the composite cardiovascular endpoint of cardiovascular death, myocardial infarction, or stroke occurred in 273 (3·4%) of 8043 patients in the odanacatib group versus 245 (3·1%) of 8028 in the placebo group (HR 1·12, 95% CI 0·95–1·34; p=0·18). New-onset atrial fibrillation or flutter occurred in 112 (1·4%) of 8043 patients in the odanacatib group versus 96 (1·2%) of 8028 in the placebo group (HR 1·18, 0·90–1·55; p=0·24). Odanacatib was associated with an increased risk of stroke (1·7% [136/8043] vs 1·3% [104/8028], HR 1·32, 1·02–1·70; p=0·034), but not myocardial infarction (0·7% [60/8043] vs 0·9% [74/8028], HR 0·82, 0·58–1·15; p=0·26). The HR for all-cause mortality was 1·13 (5·0% [401/8043] vs 4·4% [356/8028], 0·98–1·30; p=0·10). When data from LOFT Extension were included, the composite of cardiovascular death, myocardial infarction, or stroke occurred in significantly more patients in the odanacatib group than in the placebo group (401 [5·0%] of 8043 vs 343 [4·3%] of 8028, HR 1·17, 1·02–1·36; p=0·029, as did stroke (2·3% [187/8043] vs 1·7% [137/8028], HR 1·37, 1·10–1·71; p=0·0051). Interpretation: Odanacatib reduced the risk of fracture, but was associated with an increased risk of cardiovascular events, specifically stroke, in postmenopausal women with osteoporosis. Based on the overall balance between benefit and risk, the study's sponsor decided that they would no longer pursue development of odanacatib for treatment of osteoporosis. Funding: Merck Sharp &amp; Dohme Corp, a subsidiary of Merck &amp; Co, Inc, Kenilworth, NJ, USA

Correction to: Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study (Intensive Care Medicine, (2021), 47, 2, (160-169), 10.1007/s00134-020-06234-9)

1832The original version of this article unfortunately contained a mistake. The members of the ESICM Trials Group Collaborators were not shown in the article but only in the ESM. The full list of collaborators is shown below. The original article has been corrected.openopenLabeau S.O.; Afonso E.; Benbenishty J.; Blackwood B.; Boulanger C.; Brett S.J.; Calvino-Gunther S.; Chaboyer W.; Coyer F.; Deschepper M.; Francois G.; Honore P.M.; Jankovic R.; Khanna A.K.; Llaurado-Serra M.; Lin F.; Rose L.; Rubulotta F.; Saager L.; Williams G.; Blot S.I.; Muzha D.; Ribas A.M.; Lipovesty F.; Loudet C.; Eller P.; Mostafa N.; Honore P.M.; Telleria V.M.; Smajic J.; Nogueira P.C.; Nafees K.M.K.; Hentchoya R.; Soledad J.; Cardenas Y.; Reyes A.G.; Sustic A.; Mpouzika M.; Vymazal T.; Jensen H.I.; Aguirre-Bermeo H.; Maddison L.; Valta M.; Bloos F.; Adipa F.E.; Koulouras V.; Enamorado J.; Agoston Z.; Birgisdottir H.; Gupta A.; Gurjar M.; Kilapong B.; Hashemian S.M.; Martin-Loeches I.; Cortegiani A.; Fletcher K.; Hayashi Y.; Waweru-Siika W.; Abidi K.; Lee S.-M.; Hadri B.; Dolgusevs M.; Abillama F.F.; Jovaisa T.; Thix C.; Elhadi M.; Nor B.M.; Ratnam S.; Mazlan M.Z.; Maiyalagan S.; Sanchez-Hurtado L.; Belii A.; Naranpurev M.; Gautam P.; De lange D.; Parke R.; Ilesanmi R.E.; Shosholcheva M.; Petosic A.; Lind R.; Ffarcsi M.H.; Bogarin J.; Hernandez A.M.; Mikaszewska-Sokolewicz M.; Sousa B.; Tomescu D.; Sandesc D.; Twagirumugabe T.; Gusarov V.; Ebaid M.; Slobodianiuk G.; Martonova A.; Knafelj R.; Mer M.; Maseda E.; Panka B.; Schefold J.C.; Joelsson-Alm E.; Trongtrakul K.; Merritt-Charles L.; Besbes L.O.; Dikmen Y.; Zgrzheblovska L.; Fielding M.; von der Osten I.; Muzha D.; Greca A.; Cani A.; Xhindi N.; Hyska G.; Ribas A.M.; Pinto S.; Alves P.; Esposito R.; Valgolio E.; Minope J.T.S.; Abdala A.; Ayala M.; Bravo S.; Bantar A.; Delgado P.; Badariotti G.; Lipovestky F.; Diaz A.; Saul P.; Setten M.; Aucapina A.; Acosta Y.; Gonzalez V.; Camputaro L.; Baccaro F.; Villa R.; Diaz A.; Mastantuono M.; Dean E.; Rostello O.F.; Brizuela P.; Bartoli J.R.; Guereschi M.; Quiroga C.; Putruele S.; Villegas P.; Curilen V.; Fernandez R.; Nocheretti M.G.; Escalante R.G.; Loudet C.I.; Fernandez S.; Gonzalez A.L.; Alvarez G.A.; Iglesias F.; Chaparro S.; Zakalik G.; Pagella G.; Baini M.; Campos P.A.; Sabbag I.; Schmukler A.; Fonseca I.P.; Alvarez G.M.; Ramirez M.; Tapia F.; Bascary C.A.; del Valle Gimenez G.; Bertoletti F.P.; Milioto E.; Bonsignore P.J.M.; Fernandez M.A.; Smith J.; Chimunda T.; Thompson L.; Maguire T.; Watts S.; Mitchell M.; Powell M.; Lye I.; Parsons L.; Baker N.; Reynolds C.; Thompson A.; Masters K.; Sosnowski K.; Morrison L.; Leslie G.D.; Lakshmanan R.; Tabah A.; Brown W.; McDowell-Skaines S.; McLucas A.; Smith C.; Tallot M.; Jones S.; Barakat-Johnson M.; Leong T.; Butcher R.; Martin K.; Douschan P.; von Lewinski D.; Eller P.; Schmutz R.; Kolussi U.; Salman F.; Ateya Z.; Mostafa N.; De Decker K.; Van Regenmortel N.; Jans A.; Wijnands P.; Coremans S.; De Bels D.; Depuydt T.; Paillet C.; Jacquet L.-M.; Swinnen W.; Hannes F.; Mergeay M.; Van de Velde S.; Allaert S.; Hoste P.; Borin C.; Balon S.; Fraipont V.; Biston P.; De Schryver N.; Dugernier T.; Van Cotthem I.; Telleria V.M.; Smajic J.; de Almeida A.O.; Jorge S.A.; Becker D.; Schmidt R.C.; Oliveira E.; Ramalho A.; Mazocoli E.; Fioretti A.; Barros E.; Serpa L.; Bianchini S.; Campanili T.; Pantaleao T.; Garcia P.C.; Ronchini A.L.V.; Santos R.; Nafees K.M.K.; Manap N.B.A.; Hentchoya R.; Bagshaw S.; Carney D.; Bagshaw S.; Davidow J.; Bagshaw S.; Rokosh E.; Bagshaw S.; Laizner A.M.; Smith S.; McQuirter M.; Kampayana B.S.; Favre R.; Sills M.; Laizner A.M.; Dallaire J.; Laizner A.M.; Becker C.; Microys S.; Bowes B.; Lajeunesse J.; Ghosh R.; Baptiste-Savoie J.; Raizman R.; Bagshaw S.; Suen G.; Taghavi N.; Smith O.; Fielding C.; Canales J.; Molina P.; Chaparro J.; Sepulveda M.I.; Zamorano M.J.F.; Rocha P.; Villanueva X.; Araya P.; Dayan M.; Avalos F.; Li X.; Liu Y.; Li X.; Chen X.; Jiang Z.; Yang J.; Chen J.; Yang L.; Wang K.; Gao J.; Fang X.; Zhao R.; Xia X.; Liu H.; Li J.; Wang H.; Meng G.; Di Y.; Wang D.; Zhao R.H.; Hu L.P.; Fang X.; Peipei X.; Jiao Q.F.; Wang H.Y.; Xia C.J.; Liu Y.; Ye M.; Wan Y.; Wang W.; Ding Y.; Ren A.; Gao Y.; Li Q.; Du G.; Yang J.; Shen Y.; Ding Y.; Li N.; Yuan C.; Li J.; Tan L.; Lin Q.; Guo H.; Yan H.; Xu X.; Zhang W.; Liang J.; Zhang L.; Tian E.; Zhao Q.; InSu L.; Dong J.; Gu Y.; Liu Y.; Zhao L.; Wang W.; Qiao H.; Tuo L.; Lv M.; Zhu J.Y.; Zhu J.F.; Wei Y.; Liu M.; He Y.; Cheng J.; Liu J.; Jia N.; Wei D.; Li Q.; Wu X.; Duan H.; Lin D.; Liang Q.; Luo X.; Xiong Y.; Huang R.F.; Fu J.; Zan T.; Ye M.; Shi Z.; Long Y.; Lei Y.; Liu X.; Yumei C.; Wang L.L.; Zhang Y.; Xu Y.; Cheng; Zhijuan W.; Sun C.; Song J.H.; Wang Y.; Liu X.M.; Liu Y.; Yuan Y.; Huang Q.; Yang F.; Wu Y.; Luo X.; Bai X.; Zheng H.; Song M.; Sun Y.; Li Z.S.; Luo F.; Liu M.; Li L.C.; Li X.; Zhang G.; Xiao L.; Yu T.; Gao G.; Wei W.; Wang F.; Han T.; Li T.; Zeng Q.; Zeng J.M.; Long Y.; Pan F.; Wang J.; He G.; Chen H.; Zhang F.; Chao Y.; Chunhua G.; Yao X.; Bai D.; Liu L.; Xu X.; Wang Y.; Liang X.; Zhang N.; Li X.; Zhang A.; Chen X.; Hu X.C.; Zhang H.; Wang R.X.; Tak P.S.; Ho S.W.; Jiang Q.X.; Ding X.; Hong L.; Miao L.; Feng Z.; Huang L.P.; Wu J.; Wang Y.; Guo J.; Zhang B.; Ma C.; Han Y.; Liu C.; Ding M.; Luan L.; Zheng J.; Lv S.; Jiang S.; Cao W.; Xue X.; Li J.; Liu G.; Wang J.; Wei X.; Zhang W.; Jiang Y.; Yao Z.; Gao L.; Li J.; Zhao W.; Jiang M.; Hao J.; Zhang J.; Song C.; Chen F.; Wang S.; Hu L.; Cao D.; Liu Y.; Wan J.; Wang X.; Shao H.; Zhang Z.; Cui X.; Liu J.; Zhao L.; Li X.; Fan L.; Zhang L.; Yu M.; Li B.; Li C.; Liu L.; Liu X.L.; Chen W.; Li Y.; Zhigang Z.; Yuchen W.; Mu C.; Zhu G.; Yang F.; Bo Q.; Li L.; Chen M.; Jiang J.H.; Yin H.; Pang X.; Gong Y.Y.; Yang S.; Yan X.; Zheng X.; Lei D.H.; Lei L.; Guo Y.; Liu L.; Yu J.; Sun W.; Bi A.P.; Li W.; Wu Y.; Li J.; Ni D.; Li X.; Liu Y.; Wu Z.; Song B.; Chen J.; Fei Q.; Xiaoyan Y.; Ran Q.; Xixi L.; Jiao X.; Ji H.; Zhiping S.; Hong M.; Jianhong M.; Hao Y.; Yin L.; Wang Y.; Hui C.; Ju W.; Xia X.; Huo Y.; Wang Y.; Chen L.; Yan Y.; Zhao Q.; Chen H.; Bao G.; Cao Y.; Hong L.; Zhang H.; Zhang Y.; Xu L.; Guixiang J.; Li Y.; Zhao H.M.; Huang X.; Dai Z.; Jian Y.; Zhang H.; Tian Z.; Cao Z.Q.; Li M.; Liu Y.; Ouyang F.; Ma F.; Jin W.; Ge L.; Wu S.F.; Li J.; Yuan W.; Chen T.; Shi G.; Chen Z.; Liu K.; Lin X.; Yuemen L.; Lijuan S.; Tian X.F.; Wang S.; Feng Z.X.; Liu X.Z.; Dong Y.; Zhang J.; Bocui N.; Jiang Z.X.; Yang J.; Wang G.X.; Zhao Y.; Wu X.; Yang Q.; Hu R.L.; Li X.Q.; Yu Z.J.; Yao Y.; Deng X.; Xiao Y.; Xie Y.; Yang Y.; Yang H.; Zhou Y.; Li Z.; Xiao M.; Yang Y.X.; Tian Y.; Gama L.M.S.; Hernandez J.S.; Cardenas Y.; Caicedo N.; Marin J.; Ochoa M.-E.; Gomez M.; Rojas-Suarez J.; Gonzalez J.; Reyes A.J.G.; Chapeta E.; Orozco E.; Filipovic-Grcic I.; Vukovic A.; Pecenkovic S.; Suput A.; Sustic A.; Zivanovic-Posilovic G.; Bozena A.; Udiljak N.; Milic M.; Radivojevic R.C.; Mihaljevic S.; Matas M.; Tonkovic D.; Culjak H.; Herceg I.; Pavlisa G.; Dobric M.; Beker T.; Adam V.N.; Goranovic T.; Markoulias C.; Mathaios M.; Mylordou M.; Achilleos E.; Kleanthous P.; Kotanidi V.; Foka M.; Charalabous I.; Alexandrou A.; Georgiou M.; Patsalos A.; Zepoy S.; Constantinou C.; Piza P.; Vymazal T.; Wiborg E.; Bruhn L.; Kaasby K.; Pedersen K.R.; Mikkelsen S.; Collet M.; Langvad A.; Andresen H.; Fischer S.; Kjaergard I.E.; Jepsen B.; Husted B.; Bestle M.; Kodal A.M.; Hansen T.C.B.; Pedersen A.S.B.; Thomsen T.D.; Hoegenhaven A.; From M.; Frandsen T.M.; Henning G.; Hansen A.; Jensen H.I.; Bliksted I.A.; Tamayo L.M.; Mogrovejo P.; Aguirre-Bermeo H.; Palaez C.; Tutillo D.R.M.; Hurtado C.V.; Garcia M.F.; Alvarez D.; Guerrero F.; Vasquez A.; Kutimets M.; Tamme K.; Maddison L.; Anvelt E.; Dlamini-Sserumaga L.; Lofqvist C.; Lusenius V.; Kauppi O.; Sakki J.-K.; Tervo-Heikkinen T.; Kesti U.; Merilainen M.; Karjula E.; Peltomaa M.; Palmu A.; Ahtiala M.; Valta M.A.; Mentec H.; Plantefeve G.; Besch G.; Pili-Floury S.; Ledochowski S.; Deserts M.D.; Giacardi C.; Daubin C.; Massard A.; Le Guen Y.; Blanc A.; Mandaroux S.; Gunther S.C.; Avogadro P.; Radavidson A.; Turc J.; Jochmans S.; Quintard H.; Boyer L.; Bruel C.; Philippart F.; Montravers P.; Atchade E.; Flessel N.; Chinardet B.; Soulisse L.; Pillard C.; Ngo D.; Bongiorno B.; Heitzler N.; Souppart V.; Gautheret N.; Timsit J.-F.; Essardy F.; Fartoukh M.; Mehay D.; Etourneau F.; Farkas J.-C.; Beuret P.; Preda G.; De Montmollin E.; Castelain V.; Jaschinski U.; Rothenfusser M.; Kindgen-Milles D.; Dimski T.; Fiedler C.; Heinicke T.; Meybohm P.; Schulze T.; Bota M.; Pelz S.; Odenthal T.; Christ M.; Bloos F.; Bosl K.; Chovas A.; Stehr S.; Simon P.; Grotheer S.; Schuppel S.; Schaller S.; Albrecht L.; Stubner A.; Graeser S.; Kolbe N.; Lausch M.; Diers A.; Guenther U.; Riessen R.; Roller M.; Osei I.P.; Kusi-Appiah A.-C.; Yakubu Y.H.; Guadi-Gosh B.; Dragoumanis C.; Christofis C.; Kazakos N.; Bastani S.; Martinos C.; Bekos V.; Papanikolaou M.; Papavasilopoulou T.; Efthymiou A.; Chantziara V.; Kyriakoudi A.; Kakaras N.; Diakaki C.; Flevari A.; Nikolaou C.; Katerina K.; Avramopoulou L.; Tsikritsaki K.; Gkiokas G.; Pantiora E.; Katsenos C.; Patsiou E.-C.; Alexandropoulou P.; Koutsodimitropoulos I.; Farmakis E.; Nestora K.; Chatzis M.; Kondili E.; Soundoulounaki S.; Mousafiri O.; Lepida D.; Liarmakopoulou A.; Koulouras V.; Papathanakos G.; Oikonomou M.; Ioannides P.; Papadopoulos D.; Staikos I.; Stafylaraki M.; Raitsiou B.; Mandis K.; Ravani I.; Kourelea S.; Efthimiou A.; Thoma G.; Bakas A.; Psarulis K.; Anisoglou S.; Papageorgiou E.; Michailidou E.; Tholioti T.; Lavrentieva A.; Sourla E.; Spyropoulou A.; Pantelas N.; Stalika K.M.M.; Georgakas I.; Karathanou A.; Tsikriki S.; Dimoula A.; Kanakaki S.; Vakalos A.; Pagioulas K.; Enamorado J.E.; Nardai G.; Hawchar F.; Blondal A.; Rygvadottir B.; Jonasdottir R.J.; Birgisdottir H.; Shah B.; Kaushik S.; Tripathy S.; Singh M.; Agarwal S.; Gupta M.; Ahmad M.; Mangal K.; Bhargava V.; Kushare V.; Jha S.; Bhakhtiani L.; Gupta A.; Kamal M.; Gurjar M.; Baronia A.; Kilapong B.; Susanti A.; Lestari M.I.; Zulkifli Z.; Baskoro W.; Zand F.; Zarei F.; Mahmoodpoor A.; Heidari F.; Jafaraghaee F.; O'Shea A.; O'Shea F.; O'Donnell C.; Craig G.; Fitzpatrick G.; Dunne L.; Hastings J.; Marsh B.; Cody C.; Campbell E.; Doyle D.; Pacturanan M.; Sheehan C.; Carey A.; Carter C.; Mulvey R.; Finn D.O.C.R.; Motherway C.; Walsh A.; Kehoe J.; Delossantos S.; Lalor J.; O'Nuallain S.; Behan H.; McPherson S.; Corcoran A.; Gordon P.; Rooney G.; Levy D.; Azencot M.; Gurevich V.; Lavy A.; Bendelari V.; Marconi R.; Barone A.; Gatti C.; Giampaoletti A.; Borgognoni C.; Ghioldi D.M.; Raimondo A.; Castiglione G.; Bruno A.V.; Rubulotta G.; Mo A.; Corso A.; Girianni S.; Bruni A.; Garofalo E.; Maggiore S.M.; Di Risio A.; Calamai I.; Spina R.; Spadaro S.; Volta C.A.; Cotoia A.; Mirabella L.; Maulicino L.; Abregal G.; Donvito M.; D'Ambrosio P.; Binda F.; Adamina I.; Galazzi A.; Negro A.; Vaschetto R.; Capuzzi F.; Boschetto M.; Stivanello L.; Bonaccorso L.; Megna C.; Cortegiani A.; Iozzo P.; Rizzo A.; Scire G.; Taibi M.R.; Tranello F.P.; Manzo A.; Traina L.; Pastore B.; Quaini A.; Giusti G.D.; Montaldi G.; Piergentili F.; Mancini F.; Casaioli S.; Uccelli F.; Guarracino F.; Onelli A.; Di Gravio V.; Cossu M.; Matrona O.; Rocco M.; Alampi D.; Dellafiore F.; Ranalli F.; Bossolasco M.; Brizio E.; Migliorino P.; Cortellazi P.; Rosati M.; D'Ambrosio F.; Quagliotto C.; Roman-Pognuz E.; Peratoner A.; De Rosa S.; Martin M.A.; De Sanctis F.; Ciorba P.; Fletcher K.; Toppin P.; Harding-Goldson H.; Taito S.; Shime N.; Yamamoto R.; Kanda F.; Hirao A.; Egi M.; Noguchi A.; Hashimoto S.; Aya U.; Sakuramoto H.; Ohuchi A.; Kataoka J.; Maruyama K.; Nakayama I.; Nishime Y.; Fujimoto K.; Takahashi K.; Tsujimoto M.; Shimizu M.; Waweru-Siika W.; Tole E.; Correia M.C.; Kim J.H.; Park S.; Kim K.C.; Baek J.; Bae J.-M.; Park S.Y.; Park T.S.; Lee H.B.; Park S.Y.; Park J.; Yeon-Joo L.; Young-Jae C.; Lee S.-M.; Jeon K.; Kim S.C.; Lee J.; Chee H.K.; Huh J.W.; Sim Y.S.; Kim J.; Chang Y.; Ahn J.-J.; Kang B.J.; Lee W.-Y.; Lee S.J.; Hadri B.; Baftiu N.; Krastins I.; Dolgusevs M.; Abillama F.F.; Stiban S.; Feghaly M.E.; Gharios E.; Merheb M.; Benlamin M.; Khaled A.; Belkhair W.A.; Tabib M.; Ashour F.; Elhadi A.; Tababa O.W.E.; Khaled T.; Alkhumsi S.I.R.; Alshrif A.I.; Aboufray A.A.; 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Villafuerte M.V.E.; Herrera M.O.G.; Belii A.; Naranpurev M.; Baasanjav B.; Hachimi A.; Elkhayari M.; Abidi K.; Dendane T.; Subedi N.B.; Pathak S.D.; Gautam P.; Manandhar M.; Van Gulik L.; Van Den Brink M.; Van Vliet P.; Gerretsen B.; Van Den Berg L.; De Haan M.; Tuinstra B.; Kuijpers P.; Reijntjens J.; Vermeijden J.W.; Rinket M.; Vanroest M.; Reidinga A.; Loef B.; Dieperink W.; Onrust M.; Dormans T.; Bormans L.; Koopmans M.; Gerritsen R.T.; Van Den Elst A.; Evers M.; Oiting O.; Wilting R.; Ramaker B.; van der Kuil M.; Fijen J.-W.; Haas L.; De Lange D.; Haringman J.; Newby L.; Parke R.; Gilder E.; Hacking D.; Dagooc R.; Song R.; Waibel H.; Dawn F.; Rapley J.; Chadwick L.; Chapman C.; Crone P.; Albrett J.; Marko P.; Goodson J.; Browne T.; Whitticase R.; Davidson C.; Judd H.; Owens D.; Onyeka T.; Ugwu I.; Ilesanmi R.; Adejumo P.O.; Owojuyigbe A.; Adenekan A.; Uba S.; Chime C.; Jibrin D.; Sankey B.J.; Adekola O.; Olanipekun S.; Olanipekun S.; Adekola O.; Shosolcheva M.; Gievski V.; Kartalov A.; Naumovski F.; Kuzmanovska B.; Trposak A.; Bogoevska-Miteva Z.; Rosalia R.; Olsen B.F.; Sjobo B.; Jensen K.D.; Sykehus D.; Johansen B.F.; Straede E.; Johansen E.; Finnstrom I.J.; Toellefsen A.; Ostenjo H.; Bjorgen H.; Bratsberg B.; Kristoffersen E.; Skorstad E.M.; Hansen S.; Vullum S.; Lunde G.A.; Arntsen W.; Lund M.; Akselsen G.R.; Monstad K.R.; Stenset A.; Haugom H.; Monsen B.; Hogvall L.; Trudvang S.; Galaaen B.; Malmin S.K.; Andersen M.H.; Hargott R.F.; Andersen Y.; Steffenak E.; Nyhus M.; Meland B.; Hashmi M.; Rivas N.; Maidana E.; de Jesus Ortiz A.; Cabral D.M.B.; Simi M.; Aponte C.; Rivas J.C.; Gill S.; Garcia A.; Alvarenga G.; Cespedes L.; Perez H.; Moreira M.L.; Canete F.; Gonzalez R.; Monges N.; Garcia A.; Coman M.; Pederzani M.; Franco N.; Aganon F.; Martinez R.; Noblezada-Uy D.; Ellazar C.G.; Cerezo F.D.; Hernandez A.M.; Palo J.E.; Aperocho C.A.J.; Isanan M.; Tubacka M.; Jasiewicz P.; Czuczwar M.; Borys M.; Gutysz-Wojnicka A.; Glinka L.; Gawda R.; Mikaszewska-Sokolewicz M.; Bilawicz J.; Cabrita P.; Vieira J.; Figueiredo M.F.; Pinheiro C.M.; Antunes N.; Pedro L.; Ferreira F.; Parente I.; Varela M.; Fernandes F.; Martins C.; Viveiros A.; Cavaco R.; Rita C.S.; Dias S.; Feranandes A.M.; Silva P.; Nunes C.; Cabral J.; Sousa B.; Pires F.; Ferreira H.; Santos J.; Pinto V.M.V.; Bispo B.M.; Ferreira A.; Molinos E.; Lafuente E.; Gregorio R.; Costa H.; Lima A.; Ferreira S.; Seromenho V.; Luis E.; Valerio I.; Cesar H.; Tavares A.; Alsheikhly A.S.; Mahmood S.; Guran C.T.; Moise A.; Filipescu D.C.; Luchian M.; Tomescu D.; Popescu M.; Scutariu M.A.; Petrisor C.; Hagau N.; Grigoras I.; Patrichi T.; Gusarev V.; Pivkina A.; Kulakov V.; Ignatenko O.; Kovaleva J.; Zhivotneva T.; Zhedaeva M.; Matiushkov N.; Ershova O.; Egorova N.; Khoronenko V.; Baskakov D.; Sergeev D.; Piradov M.; Grishina L.; Magomedov M.; Zuev E.; Gorokhovatsky U.; Leonova A.; Fadeeva L.; Belskiy V.; Galishevskiy D.; Zubareva N.; Tribulev M.; Zueva O.; Kiselev A.; Kamenshchikov N.; Tokareva E.; Petrushin M.; Starchenko I.; Twagirumugabe T.; Nshimyumuremyi I.; Muhizi J.; Buregeya E.; Nzarora J.; Assiri A.; Ebaid M.S.; Almekhlafi G.; Mandourah Y.; Velickovic J.; Velickovic D.; Jovanovic B.; Hadzibegovic A.; Stefanovic B.; Misic V.; Bumbasirevic V.; Rajkovic M.; Stojanovic M.; Gavrilovic S.; Stanojevic M.; Martonova A.; Yaghi A.; Turcan A.; Firment P.; Slobodianiuk G.; Rabarova D.; Lancaricova D.; Vlaovic J.; Groznik M.; Lukic M.; Perme J.; Sostaric M.; Umek N.; Mirkovic T.; Dolenc S.; Knafelj R.; Fister M.; Zorko N.; Markota A.; Yeni N.P.; Jali P.; Schmollgruber S.; Syed M.R.; Parag N.; Wise R.; Galiana M.; Navarro J.A.; De Pablo A.M.; Albert P.; Martinez P.; Mendiara Y.; Garcia B.; Llinas A.A.; Riveiro M.; Gallart E.; Riera A.; Sanz M.; Salo S.; Lajara M.A.G.; Nieto M.V.; Garcia R.; Pena J.M.G.; Gorgolas M.C.; Isasi M.A.; Sierra R.; Gordo F.; Conejo I.; Salva-Costa V.; Garzon-Tovar C.; Lospitao S.; Gonzalez R.; Gutierrez P.; Girona M.; Adamuz J.; Olivares P.G.; de Ceballos J.P.G.; Tirado C.; De Wit I.; Polo A.B.C.; del Mar Diaz Salcedo M.; Ripolles-Melchor J.; Martinez-Hurtado E.; Alvarez J.D.; Arcas M.L.B.; Gonzalez J.I.T.; de la Ventana A.B.S.; Calleja P.L.-A.; Alvarez R.G.; Zamora P.S.; Guerrero A.O.; Cosano R.; Perez-Vacas J.; Campos-Perez M.; Barreiro E.M.; Sanchez L.C.; Diaz M.G.; Jimenez R.; Del Rio Cabajo L.; Muriel D.S.; Alonso H.F.; Fernandez A.W.; Pinan I.S.; Albaiceta G.M.; Fernandez M.C.I.; Abos F.J.S.; Monedero P.; Chueca R.M.; Aguirre L.G.; Manosa S.C.; Luque C.P.; Calpe N.; Losilla M.R.; Fores M.T.; Farre O.; Fernandez O.; del Rosario Villar Redondo M.; Arteta Arteta D.S.; Sanchez M.A.H.; Espinosa C.P.; Reyes L.M.; Domenech L.C.; Guillen C.V.; Alvarez J.T.; del Cotillo M.; Barrueco-Francioni J.E.; Conde B.B.; Blanco M.P.S.; Blasco M.L.; Clement A.I.; Hurtado C.; Sanz L.C.; Perez-Torres D.; Prol-Silva E.; Pereira J.; Gonzalez I.A.; Cano A.E.; Nunez C.R.; Fernadez I.L.; Fernandez A.A.M.; Del Bosque Diez R.; Hilario B.; Zalba-Etayo B.; Pascual-Bielsa A.; Panka B.; Banwarie P.; Nahar D.; van Axel A.; Boedjawan N.N.; Jansson E.B.; Malvemyr A.-S.; Johansson L.; Sandberg U.; Tingsvik C.; Mattsson G.; Lof G.; Spangfors M.; Ringdal M.; Geijer S.; Orvelius L.; Hylen M.; Lagerhall C.; Joelsson-Alm E.; Akerman E.; Hellkvist V.H.; Mickelsson U.; Akerman E.; Wahlbom E.; Larsson I.-M.; Wallin E.; Boroli F.; Ory S.; Jong M.L.; Dullenkopf A.; Lang M.; Fleury Y.; Maus M.; Ben-Hamouda N.; Fishman A.; Hsu M.Y.; Chang S.C.; Trongtratul K.; Sawawiboon C.; Morakul S.; Khwannimit B.; Merritt-Charles L.; Singh K.; Ventour D.; Figaro-Barclay D.; Sankar-Maharaj S.; Mebazaa M.S.; Kamoun S.; Elatrous S.; Besbes L.; Abroug F.; Naija W.; Elhechmi Y.Z.; Sellami W.; Hajjej Z.; Merhabene T.; Talik I.; Kuscu O.O.; Dilek O.; Zerman A.; Dal H.C.; Turan S.; Aydemir S.; Yilmaz H.; Calili D.K.; Izdes S.; Cengiz M.; Gumus A.; Tasdemir B.; Kagnici A.; Ay M.; Ay S.A.; Caliskan G.; Akbas T.; Balbay A.O.; Efe S.; Inal V.; Elay G.; Karabacak P.; Ozserezli B.; Senturk E.; Demirkiran O.; Bozbay S.; Dikmen Y.; Erdogan E.; Akker M.; Peker N.; Ozgultekin A.; Serin S.O.; Turan C.; Karaoren G.; Goksu S.; Karakurt S.; Arikan H.; Gul F.; Cinel I.; Kara I.; Undar H.N.; Bayraktar Y.S.; Celik J.B.; Tokur M.E.; Aydin D.T.; Yildiz I.; Ozcan B.; Erdivanli B.; Erdivanli B.; Ozcan B.; Eroglu A.; Akdag D.; Unlu N.; Fielding M.; Dungca A.; Ali A.; Thankamma B.; Reyes P.E.; John S.; Rajendran A.; Ahmad F.K.E.; Smiley K.A.; Hojden S.; Miller M.T.; Das Sasidharan Nair V.; Antonio M.G.S.; Qawasmeh K.A.; Shawish S.A.; Twiggs H.; Rosado I.; Babych V.; Morren F.; Young C.; Vaughan-Jones N.; Harris S.; Burns K.; Georgiev C.; Shayamano R.; Kerslake I.; Creber P.; Vochin A.; O'Brien C.; Caddell P.; Hagan S.; Hughes M.; Torlinski T.; Sherwin J.; Kannan S.; Markham A.; Lebon R.; Cupitt J.; Cranshaw J.; White N.; Marriott V.; Milner W.; Groba C.B.; Azoia J.; Polgarova P.; George S.; Kapoor R.; Lynch C.; Fox N.; Cranmer K.; Fox N.; Llewellym T.; Matthews K.; Maltby L.; Ibao J.; Boulton K.; Jarman R.; Baxter K.; Raj A.S.; Moghal A.; White J.; Barrowcliffe S.; Pulletz M.; Ganeshalingam V.; Baruah R.; Baker H.; Woods J.; Ei P.P.; Ogbeide V.; Hayden P.; Matthews K.; Hughes J.; Balasubramanian M.; Salberg A.; Saha R.; Holmquist D.; Young C.; Derbyshire C.; Smith N.; Stones E.; Ademokun J.; Popescu M.; Legorburo M.S.; North S.; Brett C.; Jaundoo H.; Craig J.; Whiteley S.; Howcroft C.; Wilby L.; Delve P.; Shaw D.; Williams K.; Welters I.D.; McMullen J.; Brett S.; Flores L.; Trueman-Dawkins T.; Templeton M.; Adams J.; Smith C.; Prowle J.; Byers H.; McDonnell A.; Rose B.O.; Reece-Anthony R.; Mendes L.; Vizcaychipi M.; Bull R.; Lacaden G.; Santiago E.; Delgado C.C.; Farnell-Ward S.; Thorpe E.; Somerville J.; Williams A.; Cummings D.; Derrick H.; Brumwell S.; Randell C.; McCann N.; Aves E.; Berry G.; Szakmany T.; Gunter U.; Pulak P.; Sarkar N.; Wright K.; Gomes V.; Jones J.; Palfrey R.; Camsooksai J.; Lewis A.; Eneas A.; Tridente A.; Barr L.; Jovaisa T.; Thomas B.; Parkin E.; Horner D.; Frey C.; Bench S.; Baumber R.; Broadhurst P.; Jackson M.; Williams L.; Clark M.; Paddle J.; Bean S.; Buckley S.; Palfreeman C.; Liu S.; Allison N.; Attwood B.; Parsons P.; Houghton V.; Turner S.J.; Higgins D.; Bielskute E.; Horrigan N.; Jacob R.; Habgood K.; Zaki A.; Collins A.; Lord J.; Ramiro C.; Kubisz-Pudelko A.; Kotze M.; Williams H.; Iovenko I.; Tsarev A.; Zgrzheblovska L.; Briva A.; Mendez G.; Napolitano L.; Teig M.; Lee J.; Rodriguez G.E.; Ben-Jacob T.; Potestio C.; Eng T.; Mahanes D.; Khanna A.; Duggal A.;

Global change in hepatitis C virus prevalence and cascade of care between 2015 and 2020: a modelling study

Background Since the release of the first global hepatitis elimination targets in 2016, and until the COVID-19 pandemic started in early 2020, many countries and territories were making progress toward hepatitis C virus (HCV) elimination. This study aims to evaluate HCV burden in 2020, and forecast HCV burden by 2030 given current trends. Methods This analysis includes a literature review, Delphi process, and mathematical modelling to estimate HCV prevalence (viraemic infection, defined as HCV RNA-positive cases) and the cascade of care among people of all ages (age ≥0 years from birth) for the period between Jan 1, 2015, and Dec 31, 2030. Epidemiological data were collected from published sources and grey literature (including government reports and personal communications) and were validated among country and territory experts. A Markov model was used to forecast disease burden and cascade of care from 1950 to 2050 for countries and territories with data. Model outcomes were extracted from 2015 to 2030 to calculate population-weighted regional averages, which were used for countries or territories without data. Regional and global estimates of HCV prevalence, cascade of care, and disease burden were calculated based on 235 countries and territories. Findings Models were built for 110 countries or territories: 83 were approved by local experts and 27 were based on published data alone. Using data from these models, plus population-weighted regional averages for countries and territories without models (n=125), we estimated a global prevalence of viraemic HCV infection of 0·7% (95% UI 0·7–0·9), corresponding to 56·8 million (95% UI 55·2–67·8) infections, on Jan 1, 2020. This number represents a decrease of 6·8 million viraemic infections from a 2015 (beginning of year) prevalence estimate of 63·6 million (61·8–75·8) infections (0·9% [0·8–1·0] prevalence). By the end of 2020, an estimated 12·9 million (12·5–15·4) people were living with a diagnosed viraemic infection. In 2020, an estimated 641000 (623000–765000) patients initiated treatment. Interpretation At the beginning of 2020, there were an estimated 56·8 million viraemic HCV infections globally. Although this number represents a decrease from 2015, our forecasts suggest we are not currently on track to achieve global elimination targets by 2030. As countries recover from COVID-19, these findings can help refocus efforts aimed at HCV elimination

Global prevalence, treatment, and prevention of hepatitis B virus infection in 2016: a modelling study

Background: The 69th World Health Assembly approved the Global Health Sector Strategy to eliminate viral hepatitis by 2030. Although no virological cure exists for hepatitis B virus (HBV) infection, existing therapies to control viral replication and prophylaxis to minimise mother-to-child transmission make elimination of HBV feasible. We aimed to estimate the national, regional, and global prevalence of HBsAg in the general population and in the population aged 5 years in 2016, as well as coverage of prophylaxis, diagnosis, and treatment. Methods: In this modelling study, we used a Delphi process that included a literature review in PubMed and Embase, followed by interviews with experts, to quantify the historical epidemiology of HBV infection. We then used a dynamic HBV transmission and progression model to estimate the country-level and regional-level prevalence of HBsAg in 2016 and the effect of prophylaxis and treatment on disease burden. Findings: We developed models for 120 countries, 78 of which were populated with data approved by experts. Using these models, we estimated that the global prevalence of HBsAg in 2016 was 3·9% (95% uncertainty interval [UI] 3·4–4·6), corresponding to 291 992 000 (251 513 000–341 114 000) infections. Of these infections, around 29 million (10%) were diagnosed, and only 4·8 million (5%) of 94 million individuals eligible for treatment actually received antiviral therapy. Around 1·8 (1·6–2·2) million infections were in children aged 5 years, with a prevalence of 1·4% (1·2–1·6). We estimated that 87% of infants had received the three-dose HBV vaccination in the first year of life, 46% had received timely birth-dose vaccination, and 13% had received hepatitis B immunoglobulin along with the full vaccination regimen. Less than 1% of mothers with a high viral load had received antiviral therapy to reduce mother-to-child transmission. Interpretation: Our estimate of HBV prevalence in 2016 differs from previous studies, potentially because we took into account the effect of infant prophylaxis and early childhood vaccination, as well as changing prevalence over time. Although some regions are well on their way to meeting prophylaxis and prevalence targets, all regions must substantially scale-up access to diagnosis and treatment to meet the global targets. Funding: John C Martin Foundation

Odanacatib for the treatment of postmenopausal osteoporosis : Results of the LOFT multicentre, randomised, double-blind, placebo-controlled trial and LOFT Extension study

Background Odanacatib, a cathepsin K inhibitor, reduces bone resorption while maintaining bone formation. Previous work has shown that odanacatib increases bone mineral density in postmenopausal women with low bone mass. We aimed to investigate the efficacy and safety of odanacatib to reduce fracture risk in postmenopausal women with osteoporosis. Methods The Long-term Odanacatib Fracture Trial (LOFT) was a multicentre, randomised, double-blind, placebo-controlled, event-driven study at 388 outpatient clinics in 40 countries. Eligible participants were women aged at least 65 years who were postmenopausal for 5 years or more, with a femoral neck or total hip bone mineral density T-score between −2·5 and −4·0 if no previous radiographic vertebral fracture, or between −1·5 and −4·0 with a previous vertebral fracture. Women with a previous hip fracture, more than one vertebral fracture, or a T-score of less than −4·0 at the total hip or femoral neck were not eligible unless they were unable or unwilling to use approved osteoporosis treatment. Participants were randomly assigned (1:1) to either oral odanacatib (50 mg once per week) or matching placebo. Randomisation was done using an interactive voice recognition system after stratification for previous radiographic vertebral fracture, and treatment was masked to study participants, investigators and their staff, and sponsor personnel. If the study completed before 5 years of double-blind treatment, consenting participants could enrol in a double-blind extension study (LOFT Extension), continuing their original treatment assignment for up to 5 years from randomisation. Primary endpoints were incidence of vertebral fractures as assessed using radiographs collected at baseline, 6 and 12 months, yearly, and at final study visit in participants for whom evaluable radiograph images were available at baseline and at least one other timepoint, and hip and non-vertebral fractures adjudicated as being a result of osteoporosis as assessed by clinical history and radiograph. Safety was assessed in participants who received at least one dose of study drug. The adjudicated cardiovascular safety endpoints were a composite of cardiovascular death, myocardial infarction, or stroke, and new-onset atrial fibrillation or flutter. Individual cardiovascular endpoints and death were also assessed. LOFT and LOFT Extension are registered with ClinicalTrials.gov (number NCT00529373) and the European Clinical Trials Database (EudraCT number 2007-002693-66). Findings Between Sept 14, 2007, and Nov 17, 2009, we randomly assigned 16 071 evaluable patients to treatment: 8043 to odanacatib and 8028 to placebo. After a median follow-up of 36·5 months (IQR 34·43–40·15) 4297 women assigned to odanacatib and 3960 assigned to placebo enrolled in LOFT Extension (total median follow-up 47·6 months, IQR 35·45–60·06). In LOFT, cumulative incidence of primary outcomes for odanacatib versus placebo were: radiographic vertebral fractures 3·7% (251/6770) versus 7·8% (542/6910), hazard ratio (HR) 0·46, 95% CI 0·40–0·53; hip fractures 0·8% (65/8043) versus 1·6% (125/8028), 0·53, 0·39–0·71; non-vertebral fractures 5·1% (412/8043) versus 6·7% (541/8028), 0·77, 0·68–0·87; all p<0·0001. Combined results from LOFT plus LOFT Extension for cumulative incidence of primary outcomes for odanacatib versus placebo were: radiographic vertebral fractures 4·9% (341/6909) versus 9·6% (675/7011), HR 0·48, 95% CI 0·42–0·55; hip fractures 1·1% (86/8043) versus 2·0% (162/8028), 0·52, 0·40–0·67; non-vertebral fractures 6·4% (512/8043) versus 8·4% (675/8028), 0·74, 0·66–0·83; all p<0·0001. In LOFT, the composite cardiovascular endpoint of cardiovascular death, myocardial infarction, or stroke occurred in 273 (3·4%) of 8043 patients in the odanacatib group versus 245 (3·1%) of 8028 in the placebo group (HR 1·12, 95% CI 0·95–1·34; p=0·18). New-onset atrial fibrillation or flutter occurred in 112 (1·4%) of 8043 patients in the odanacatib group versus 96 (1·2%) of 8028 in the placebo group (HR 1·18, 0·90–1·55; p=0·24). Odanacatib was associated with an increased risk of stroke (1·7% [136/8043] vs 1·3% [104/8028], HR 1·32, 1·02–1·70; p=0·034), but not myocardial infarction (0·7% [60/8043] vs 0·9% [74/8028], HR 0·82, 0·58–1·15; p=0·26). The HR for all-cause mortality was 1·13 (5·0% [401/8043] vs 4·4% [356/8028], 0·98–1·30; p=0·10). When data from LOFT Extension were included, the composite of cardiovascular death, myocardial infarction, or stroke occurred in significantly more patients in the odanacatib group than in the placebo group (401 [5·0%] of 8043 vs 343 [4·3%] of 8028, HR 1·17, 1·02–1·36; p=0·029, as did stroke (2·3% [187/8043] vs 1·7% [137/8028], HR 1·37, 1·10–1·71; p=0·0051). Interpretation Odanacatib reduced the risk of fracture, but was associated with an increased risk of cardiovascular events, specifically stroke, in postmenopausal women with osteoporosis. Based on the overall balance between benefit and risk, the study's sponsor decided that they would no longer pursue development of odanacatib for treatment of osteoporosis