[1] SUNG H, FERLAY J, SIEGEL R L, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries
[J]. CA: A Cancer Journal for Clinicians, 2021, 71(3): 209-49.

[2] LIVER E A F T S O T. EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma
[J]. J Hepatol, 2018, 69(1): 182-236.

[3] REDDY S K, STEEL J L, CHEN H W, et al. Outcomes of curative treatment for hepatocellular cancer in nonalcoholic steatohepatitis versus hepatitis C and alcoholic liver disease
[J]. Hepatology, 2012, 55(6): 1809-19.

[4] RUMGAY H, ARNOLD M, FERLAY J, et al. Global burden of primary liver cancer in 2020 and predictions to 2040
[J]. J Hepatol, 2022, 77(6): 1598-606.

[5] HOLMES J A, RUTLEDGE S M, CHUNG R T. Direct-acting antiviral treatment for hepatitis C
[J]. Lancet (London, England), 2019, 393(10179): 1392-4.

[6] FOSTER G R, IRVING W L, CHEUNG M C, et al. Impact of direct acting antiviral therapy in patients with chronic hepatitis C and decompensated cirrhosis
[J]. J Hepatol, 2016, 64(6): 1224-31.

[7] CONTI F, BUONFIGLIOLI F, SCUTERI A, et al. Early occurrence and recurrence of hepatocellular carcinoma in HCV-related cirrhosis treated with direct-acting antivirals
[J]. Journal of Hepatology, 2016, 65(4): 727-33.

[8] SARAIYA N, YOPP A C, RICH N E, et al. Systematic review with meta-analysis: recurrence of hepatocellular carcinoma following direct-acting antiviral therapy
[J]. Alimentary pharmacology & therapeutics, 2018, 48(2): 127-37.

[9] FRAZZONI L, SIKANDAR U, METELLI F, et al. Hepatocellular Carcinoma Recurrence after Hepatitis C Virus Therapy with Direct-Acting Antivirals. A Systematic Review and Meta-Analysis
[J]. Journal of clinical medicine, 2021, 10(8).

[10] GA WELLS B S, D O'CONNELL, J PETERSON, V WELCH, M LOSOS, P TUGWELL，. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses
[Z]. 2023

[11] FRIEDRICH J O, ADHIKARI N K, BEYENE J. Inclusion of zero total event trials in meta-analyses maintains analytic consistency and incorporates all available data
[J]. BMC medical research methodology, 2007, 7: 5.

[12] LIN L, CHU H. Quantifying publication bias in meta-analysis
[J]. Biometrics, 2018, 74(3): 785-94.

[13] Lack of evidence of an effect of direct-acting antivirals on the recurrence of hepatocellular carcinoma: Data from three ANRS cohorts
[J]. J Hepatol, 2016, 65(4): 734-40.

[14] REIG M, MARIñO Z, PERELLó C, et al. Unexpected high rate of early tumor recurrence in patients with HCV-related HCC undergoing interferon-free therapy
[J]. J Hepatol, 2016, 65(4): 719-26.

[15] BIELEN R, MORENO C, VAN VLIERBERGHE H, et al. The risk of early occurrence and recurrence of hepatocellular carcinoma in hepatitis C-infected patients treated with direct-acting antivirals with and without pegylated interferon: A Belgian experience
[J]. J Viral Hepat, 2017, 24(11): 976-81.

[16] CABIBBO G, PETTA S, CALVARUSO V, et al. Is early recurrence of hepatocellular carcinoma in HCV cirrhotic patients affected by treatment with direct-acting antivirals? A prospective multicentre study
[J]. Alimentary pharmacology & therapeutics, 2017, 46(7): 688-95.

[17] IDA H, HAGIWARA S, KONO M, et al. Hepatocellular Carcinoma after Achievement of Sustained Viral Response with Daclatasvir and Asunaprevir in Patients with Chronic Hepatitis C Virus Infection
[J]. Digestive Diseases, 2017, 35(6): 565-73.

[18] IKEDA K, KAWAMURA Y, KOBAYASHI M, et al. Direct-Acting Antivirals Decreased Tumor Recurrence After Initial Treatment of Hepatitis C Virus-Related Hepatocellular Carcinoma
[J]. Digestive Diseases and Sciences, 2017, 62(10): 2932-42.

[19] KANWAL F, KRAMER J, ASCH S M, et al. Risk of Hepatocellular Cancer in HCV Patients Treated With Direct-Acting Antiviral Agents
[J]. Gastroenterology, 2017, 153(4): 996-1005.e1.

[20] KOBAYASHI M, SUZUKI F, FUJIYAMA S, et al. Sustained virologic response by direct antiviral agents reduces the incidence of hepatocellular carcinoma in patients with HCV infection
[J]. J Med Virol, 2017, 89(3): 476-83.

[21] NAGAOKI Y, IMAMURA M, AIKATA H, et al. The risks of hepatocellular carcinoma development after HCV eradication are similar between patients treated with peg-interferon plus ribavirin and direct-acting antiviral therapy
[J]. PLoS ONE, 2017, 12(8).

[22] OGATA F, KOBAYASHI M, AKUTA N, et al. Outcome of All-Oral Direct-Acting Antiviral Regimens on the Rate of Development of Hepatocellular Carcinoma in Patients with Hepatitis C Virus Genotype 1-Related Chronic Liver Disease
[J]. Oncology (Switzerland), 2017, 93(2): 92-8.

[23] RAVI S, AXLEY P, JONES D, et al. Unusually High Rates of Hepatocellular Carcinoma After Treatment With Direct-Acting Antiviral Therapy for Hepatitis C Related Cirrhosis
[J]. Gastroenterology, 2017, 152(4): 911-2.

[24] VIRLOGEUX V, PRADAT P, HARTIG-LAVIE K, et al. Direct-acting antiviral therapy decreases hepatocellular carcinoma recurrence rate in cirrhotic patients with chronic hepatitis C
[J]. Liver International, 2017, 37(8): 1122-7.

[25] CALVARUSO V, CABIBBO G, CACCIOLA I, et al. Incidence of Hepatocellular Carcinoma in Patients With HCV-Associated Cirrhosis Treated With Direct-Acting Antiviral Agents
[J]. Gastroenterology, 2018, 155(2): 411-21.e4.

[26] EL KASSAS M, FUNK A L, SALAHELDIN M, et al. Increased recurrence rates of hepatocellular carcinoma after DAA therapy in a hepatitis C-infected Egyptian cohort: A comparative analysis
[J]. Journal of Viral Hepatitis, 2018, 25(6): 623-30.

[27] FLISIAK R, JANCZEWSKA E, ŁUCEJKO M, et al. Durability of virologic response, risk of de novo hepatocellular carcinoma, liver function and stiffness 2 years after treatment with ombitasvir/paritaprevir/ritonavir ±dasabuvir±ribavirin in the AMBER, real-world experience study
[J]. J Viral Hepat, 2018, 25(11): 1298-305.

[28] HASSANY M, ELSHARKAWY A, MAGED A, et al. Hepatitis C virus treatment by direct-acting antivirals in successfully treated hepatocellular carcinoma and possible mutual impact
[J]. European Journal of Gastroenterology and Hepatology, 2018, 30(8): 876-81.

[29] KUFTINEC G, LOEHFELM T, CORWIN M, et al. De novo hepatocellular carcinoma occurrence in hepatitis C cirrhotics treated with direct-acting antiviral agents
[J]. Hepatic Oncology, 2018, 5(1).

[30] MASETTI C, LIONETTI R, LUPO M, et al. Lack of reduction in serum alpha-fetoprotein during treatment with direct antiviral agents predicts hepatocellular carcinoma development in a large cohort of patients with hepatitis C virus-related cirrhosis
[J]. J Viral Hepat, 2018, 25(12): 1493-500.

[31] OGAWA E, FURUSYO N, NOMURA H, et al. Short-term risk of hepatocellular carcinoma after hepatitis C virus eradication following direct-acting anti-viral treatment
[J]. Alimentary pharmacology & therapeutics, 2018, 47(1): 104-13.

[32] OOKA Y, MIHO K, SHUNTARO O, et al. Prediction of the very early occurrence of HCC right after DAA therapy for HCV infection
[J]. Hepatology International, 2018, 12(6): 523-30.

[33] ROMANO A, ANGELI P, PIOVESAN S, et al. Newly diagnosed hepatocellular carcinoma in patients with advanced hepatitis C treated with DAAs: A prospective population study
[J]. Journal of Hepatology, 2018, 69(2): 345-52.

[34] SINGER A W, REDDY K R, TELEP L E, et al. Direct-acting antiviral treatment for hepatitis C virus infection and risk of incident liver cancer: a retrospective cohort study
[J]. Alimentary Pharmacology and Therapeutics, 2018, 47(9): 1278-87.

[35] AKUTA N, SUZUKI F, SEZAKI H, et al. Complex association of virus- and host-related factors with hepatocellular carcinoma rate following hepatitis C virus clearance
[J]. Journal of Clinical Microbiology, 2019, 57(1).

[36] AZIZ B, NAZAR T, AKHLAQ S. The frequency of occurrence of hepatocellular carcinoma after direct antiviral therapy in hepatitis c virus patients
[J]. Pakistan Journal of Medical Sciences, 2019, 35(1): 101-5.

[37] CARRAT F, FONTAINE H, DORIVAL C, et al. Clinical outcomes in patients with chronic hepatitis C after direct-acting antiviral treatment: a prospective cohort study
[J]. Lancet (London, England), 2019, 393(10179): 1453-64.

[38] DEGASPERI E, D'AMBROSIO R, IAVARONE M, et al. Factors Associated With Increased Risk of De Novo or Recurrent Hepatocellular Carcinoma in Patients With Cirrhosis Treated With Direct-Acting Antivirals for HCV Infection
[J]. Clinical Gastroenterology and Hepatology, 2019, 17(6): 1183-91.e7.

[39] IDE T, KOGA H, NAKANO M, et al. Direct-acting antiviral agents do not increase the incidence of hepatocellular carcinoma development: a prospective, multicenter study
[J]. Hepatol Int, 2019, 13(3): 293-301.

[40] IDILMAN R, DEMIR M, ALADAG M, et al. Low recurrence rate of hepatocellular carcinoma following ledipasvir and sofosbuvir treatment in a real-world chronic hepatitis C patients cohort
[J]. J Viral Hepat, 2019, 26(6): 666-74.

[41] KOGISO T, SAGAWA T, KODAMA K, et al. Hepatocellular carcinoma after direct-acting antiviral drug treatment in patients with hepatitis C virus
[J]. JGH Open, 2019, 3(1): 52-60.

[42] LASHEN S A, SHAMSEYA M M, MADKOUR M A. Hepatocellular Carcinoma Occurrence/Recurrence after Direct-Acting Antivirals for Hepatitis C in Egyptian Cohort: Single-Center Experience
[J]. Dig Dis, 2019, 37(6): 488-97.

[43] MUN E J, GREEN P, BERRY K, et al. No difference between direct-acting antivirals for hepatitis C in hepatocellular carcinoma risk
[J]. European Journal of Gastroenterology and Hepatology, 2019, 31(1): 47-52.

[44] NAGAOKI Y, IMAMURA M, NISHIDA Y, et al. The impact of interferon-free direct-acting antivirals on clinical outcome after curative treatment for hepatitis C virus-associated hepatocellular carcinoma: Comparison with interferon-based therapy
[J]. J Med Virol, 2019, 91(4): 650-8.

[45] NAKANO M, KOGA H, IDE T, et al. Predictors of hepatocellular carcinoma recurrence associated with the use of direct-acting antiviral agent therapy for hepatitis C virus after curative treatment: A prospective multicenter cohort study
[J]. Cancer Med, 2019, 8(5): 2646-53.

[46] NISHIBATAKE KINOSHITA M, MINAMI T, TATEISHI R, et al. Impact of direct-acting antivirals on early recurrence of HCV-related HCC: Comparison with interferon-based therapy
[J]. Journal of Hepatology, 2019, 70(1): 78-86.

[47] PIñERO F, MENDIZABAL M, RIDRUEJO E, et al. Treatment with direct-acting antivirals for HCV decreases but does not eliminate the risk of hepatocellular carcinoma
[J]. Liver international : official journal of the International Association for the Study of the Liver, 2019, 39(6): 1033-43.

[48] PREDA C M, BAICUS C, SANDRA I, et al. Recurrence rate of hepatocellular carcinoma in patients with treated hepatocellular carcinoma and hepatitis C virus-associated cirrhosis after ombitasvir/paritaprevir/ritonavir +dasabuvir +ribavirin therapy
[J]. United European Gastroenterol J, 2019, 7(5): 699-708.

[49] RINALDI L, PERRELLA A, GUARINO M, et al. Incidence and risk factors of early HCC occurrence in HCV patients treated with direct acting antivirals: a prospective multicentre study
[J]. Journal of translational medicine, 2019, 17(1): 292.

[50] SINGAL A G, RICH N E, MEHTA N, et al. Direct-Acting Antiviral Therapy Not Associated With Recurrence of Hepatocellular Carcinoma in a Multicenter North American Cohort Study
[J]. Gastroenterology, 2019, 156(6): 1683-92.e1.

[51] WATANABE T, TOKUMOTO Y, JOKO K, et al. Predictors of hepatocellular carcinoma occurrence after direct-acting antiviral therapy in patients with hepatitis C virus infection
[J]. Hepatology Research, 2019, 49(2): 136-46.

[52] ZOU W Y, CHOI K, KRAMER J R, et al. Risk of Hepatocellular Cancer Recurrence in Hepatitis C Virus+ Patients Treated with Direct-Acting Antiviral Agents
[J]. Digestive Diseases and Sciences, 2019, 64(11): 3328-36.

[53] ABE K, WAKABAYASHI H, NAKAYAMA H, et al. Factors associated with hepatocellular carcinoma occurrence after HCV eradication in patients without cirrhosis or with compensated cirrhosis
[J]. PLoS ONE, 2020, 15(12 December).

[54] BUONOMO A R, SCOTTO R, COPPOLA C, et al. Direct acting antivirals treatment for hepatitis C virus infection does not increase the incidence of de novo hepatocellular carcinoma occurrence: Results from an Italian real-life cohort (LINA cohort)
[J]. Medicine, 2020, 99(6): e18948.

[55] CHAN P P Y, LEVY M T, SHACKEL N, et al. Hepatocellular carcinoma incidence post direct-acting antivirals in hepatitis C-related advanced fibrosis/cirrhosis patients in Australia
[J]. Hepatobiliary and Pancreatic Diseases International, 2020, 19(6): 541-6.

[56] GUARINO M, DI COSTANZO G G, BRUZZESE D, et al. Incidence of HCC recurrence after DAA treatment for HCV in a multicentre Italian cohort study
[J]. Liver Cancer International, 2020, 1(1): 12-24.

[57] HASSANY S M, HASSAN W, ABO-ALAM H, et al. Direct-acting antiviral drugs and occurrence of hepatocellular carcinoma: Unjust or oppressed
[J]. Infection and Drug Resistance, 2020, 13: 1873-80.

[58] KANWAL F, KRAMER J R, ASCH S M, et al. Long-Term Risk of Hepatocellular Carcinoma in HCV Patients Treated With Direct Acting Antiviral Agents
[J]. Hepatology, 2020, 71(1): 44-55.

[59] KUO Y H, WANG J H, CHANG K C, et al. The influence of direct-acting antivirals in hepatitis C virus related hepatocellular carcinoma after curative treatment
[J]. Investigational New Drugs, 2020, 38(1): 202-10.

[60] LIN W C, LIN Y S, CHANG C W, et al. Impact of direct-acting antiviral therapy for hepatitis C-related hepatocellular carcinoma
[J]. PLoS One, 2020, 15(5): e0233212.

[61] MIUMA S, MIYAMOTO J, TAURA N, et al. Influence of interferon-free direct-acting antiviral therapy on primary hepatocellular carcinoma recurrence: A landmark time analysis and time-dependent extended cox proportional hazards model analysis
[J]. Internal Medicine, 2020, 59(7): 901-7.

[62] SANGIOVANNI A, ALIMENTI E, GATTAI R, et al. Undefined/non-malignant hepatic nodules are associated with early occurrence of HCC in DAA-treated patients with HCV-related cirrhosis
[J]. J Hepatol, 2020, 73(3): 593-602.

[63] SHIHA G, MOUSA N, SOLIMAN R, et al. Incidence of HCC in chronic hepatitis C patients with advanced hepatic fibrosis who achieved SVR following DAAs: A prospective study
[J]. J Viral Hepat, 2020, 27(7): 671-9.

[64] TANAKA S, SHINKAWA H, TAMORI A, et al. Surgical outcomes for hepatocellular carcinoma detected after hepatitis C virus eradiation by direct-acting antivirals
[J]. Journal of Surgical Oncology, 2020, 122(8): 1543-52.

[65] TANI J, MORISHITA A, SAKAMOTO T, et al. Simple scoring system for prediction of hepatocellular carcinoma occurrence after hepatitis C virus eradication by direct–acting antiviral treatment: All Kagawa liver disease group study
[J]. Oncology Letters, 2020, 19(3): 2205-12.

[66] TAYYAB G U N, RASOOL S, NASIR B, et al. Hepatocellular carcinoma occurs frequently and early after treatment in HCV genotype 3 infected persons treated with DAA regimens
[J]. BMC Gastroenterology, 2020, 20(1).

[67] AHN Y H, LEE H, KIM D Y, et al. Independent risk factors for hepatocellular carcinoma recurrence after direct-acting antiviral therapy in patients with chronic hepatitis C
[J]. Gut and Liver, 2021, 15(3): 410-9.

[68] CHI C T, CHEN C Y, SU C W, et al. Direct-acting antivirals for patients with chronic hepatitis C and hepatocellular carcinoma in Taiwan
[J]. Journal of microbiology, immunology, and infection = Wei mian yu gan ran za zhi, 2021, 54(3): 385-95.

[69] HAMOIR C, HORSMANS Y, STäRKEL P, et al. Risk of hepatocellular carcinoma and fibrosis evolution in hepatitis c patients with severe fibrosis or cirrhosis treated with direct acting antiviral agents
[J]. Acta Gastro-Enterologica Belgica, 2021, 84(1): 25-32.

[70] KARBEYAZ F, KISSLING S, JAKLIN P J, et al. Rates of hepatocellular carcinoma after start of treatment for chronic hepatitis c remain high with direct acting antivirals: Analysis from a swiss liver transplant center
[J]. Journal of Hepatocellular Carcinoma, 2021, 8: 565-74.

[71] MINAMI T, TATEISHI R, FUJIWARA N, et al. Impact of Obesity and Heavy Alcohol Consumption on Hepatocellular Carcinoma Development after HCV Eradication with Antivirals
[J]. Liver Cancer, 2021, 10(4): 309-19.

[72] MUZICA C M, STANCIU C, CIJEVSCHI-PRELIPCEAN C, et al. Long-term risk of hepatocellular carcinoma following direct-acting antiviral therapy in compensated liver cirrhosis induced by hepatitis c virus infection
[J]. Hepatitis Monthly, 2021, 21(6).

[73] OCHI H, HIRAOKA A, HIROOKA M, et al. Direct-acting antivirals improve survival and recurrence rates after treatment of hepatocellular carcinoma within the Milan criteria
[J]. J Gastroenterol, 2021, 56(1): 90-100.

[74] RIDZIAUSKAS M, ZABLOCKIENĖ B, JANČORIENĖ L, et al. Assessment of Liver Stiffness Regression and Hepatocellular Carcinoma Risk in Chronic Hepatitis C Patients after Treatment with Direct-Acting Antiviral Drugs
[J]. Medicina (Kaunas, Lithuania), 2021, 57(3).

[75] SáNCHEZ-AZOFRA M, FERNáNDEZ I, GARCíA-BUEY M L, et al. Hepatocellular carcinoma risk in hepatitis C stage-3 fibrosis after sustained virological response with direct-acting antivirals
[J]. Liver international: official journal of the International Association for the Study of the Liver, 2021, 41(12): 2885-91.

[76] TANI J, SENOH T, MORIYA A, et al. Long-term outcomes and evaluation of hepatocellular carcinoma recurrence after hepatitis c virus eradication by direct-acting antiviral treatment: All kagawa liver disease group (akldg) study
[J]. Cancers, 2021, 13(9).

[77] CAVIGLIA G P, TROSHINA G, SANTANIELLO U, et al. Long-Term Hepatocellular Carcinoma Development and Predictive Ability of Non-Invasive Scoring Systems in Patients with HCV-Related Cirrhosis Treated with Direct-Acting Antivirals
[J]. Cancers, 2022, 14(3).

[78] CHEN Y S, HUANG K H, WANG P M, et al. The Impact of Direct-Acting Antiviral Therapy on the Risk of Recurrence after Curative Resection in Patients with Hepatitis-C-Virus-Related Early Stage Hepatocellular Carcinoma
[J]. Medicina (Kaunas, Lithuania), 2022, 58(2).

[79] ELBAZ T, WAKED I, EL-AKEL W, et al. Impact of successful HCV treatment using direct acting antivirals on recurrence of well ablated hepatocellular carcinoma
[J]. Expert Review of Anti-Infective Therapy, 2022, 20(2): 307-14.

[80] KUROMATSU R, IDE T, OKAMURA S, et al. Hepatitis C Virus Elimination Using Direct Acting Antivirals after the Radical Cure of Hepatocellular Carcinoma Suppresses the Recurrence of the Cancer
[J]. Cancers, 2022, 14(9).

[81] OGAWA E, NAKAMUTA M, FURUSYO N, et al. Long-term assessment of recurrence of hepatocellular carcinoma in patients with chronic hepatitis C after viral cure by direct-acting antivirals
[J]. Journal of gastroenterology and hepatology, 2022, 37(1): 190-9.

[82] OGAWA E, NOMURA H, NAKAMUTA M, et al. Development of Hepatocellular Carcinoma in Patients Aged 75-84 Years with Chronic Hepatitis C Treated with Direct-Acting Antivirals
[J]. Journal of Infectious Diseases, 2022, 226(3): 431-40.

[83] SANTANA-SALGADO I, BAUTISTA-SANTOS A, MORENO-ALCáNTAR R. Risk factors for developing hepatocellular carcinoma in patients treated with direct-acting antivirals
[J]. Revista de Gastroenterologia de Mexico, 2022, 87(4): 455-61.

[84] TADA T, KUMADA T, MATONO T, et al. Characteristics of hepatocellular carcinoma in patients with hepatitis C virus who received direct-acting antiviral therapy and achieved sustained virological response: The impact of a hepatologist on surveillance
[J]. JGH Open, 2022, 6(7): 462-9.

[85] YOO H W, PARK J Y, KIM S G, et al. Regression of liver fibrosis and hepatocellular carcinoma development after HCV eradication with oral antiviral agents
[J]. Sci Rep, 2022, 12(1): 193.

[86] HONG H, CHOI W M, LEE D, et al. Prediction of Hepatocellular Carcinoma Development in Korean Patients after Hepatitis C Cure with Direct-Acting Antivirals
[J]. Gut and liver, 2023.

[87] LEAL C, STROGOFF-DE-MATOS J, THEODORO C, et al. Incidence and Risk Factors of Hepatocellular Carcinoma in Patients with Chronic Hepatitis C Treated with Direct-Acting Antivirals
[J]. Viruses, 2023, 15(1).

[88] Global prevalence and genotype distribution of hepatitis C virus infection in 2015: a modelling study
[J]. The lancet Gastroenterology & hepatology, 2017, 2(3): 161-76.

[89] VAN DER MEER A J, VELDT B J, FELD J J, et al. Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis
[J]. Jama, 2012, 308(24): 2584-93.

[90] BOURLIèRE M, BRONOWICKI J P, DE LEDINGHEN V, et al. Ledipasvir-sofosbuvir with or without ribavirin to treat patients with HCV genotype 1 infection and cirrhosis non-responsive to previous protease-inhibitor therapy: a randomised, double-blind, phase 2 trial (SIRIUS)
[J]. The Lancet Infectious diseases, 2015, 15(4): 397-404.

[91] LEROY V, ANGUS P, BRONOWICKI J P, et al. Daclatasvir, sofosbuvir, and ribavirin for hepatitis C virus genotype 3 and advanced liver disease: A randomized phase III study (ALLY-3+)
[J]. Hepatology, 2016, 63(5): 1430-41.

[92] POORDAD F, HEZODE C, TRINH R, et al. ABT-450/r-ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis
[J]. The New England journal of medicine, 2014, 370(21): 1973-82.