Community-based management of arterial hypertension and cardiovascular risk factors by lay village health workers for people with controlled and uncontrolled blood pressure in rural Lesotho: joint protocol for two cluster-randomized trials within the ComBaCaL cohort study (ComBaCaL aHT Twic 1 and ComBaCaL aHT TwiC 2).
Humans
Hypertension
/ drug therapy
Community Health Workers
Lesotho
Antihypertensive Agents
/ therapeutic use
Heart Disease Risk Factors
Blood Pressure
/ drug effects
Randomized Controlled Trials as Topic
Female
Male
Community Health Services
Treatment Outcome
Adult
Middle Aged
Cardiovascular Diseases
/ prevention & control
Africa
Arterial hypertension
Clinical decision support system
Community health worker
Community-based care
Lesotho
Non-communicable diseases
Trials within cohort
Village Health Workers
Journal
Trials
ISSN: 1745-6215
Titre abrégé: Trials
Pays: England
ID NLM: 101263253
Informations de publication
Date de publication:
06 Jun 2024
06 Jun 2024
Historique:
received:
26
01
2024
accepted:
03
06
2024
medline:
7
6
2024
pubmed:
7
6
2024
entrez:
6
6
2024
Statut:
epublish
Résumé
Arterial hypertension (aHT) is a major cause for premature morbidity and mortality. Control rates remain poor, especially in low- and middle-income countries. Task-shifting to lay village health workers (VHWs) and the use of digital clinical decision support systems may help to overcome the current aHT care cascade gaps. However, evidence on the effectiveness of comprehensive VHW-led aHT care models, in which VHWs provide antihypertensive drug treatment and manage cardiovascular risk factors is scarce. Using the trials within the cohort (TwiCs) design, we are assessing the effectiveness of VHW-led aHT and cardiovascular risk management in two 1:1 cluster-randomized trials nested within the Community-Based chronic disease Care Lesotho (ComBaCaL) cohort study (NCT05596773). The ComBaCaL cohort study is maintained by trained VHWs and includes the consenting inhabitants of 103 randomly selected villages in rural Lesotho. After community-based aHT screening, adult, non-pregnant ComBaCaL cohort participants with uncontrolled aHT (blood pressure (BP) ≥ 140/90 mmHg) are enrolled in the aHT TwiC 1 and those with controlled aHT (BP < 140/90 mmHg) in the aHT TwiC 2. In intervention villages, VHWs offer lifestyle counseling, basic guideline-directed antihypertensive, lipid-lowering, and antiplatelet treatment supported by a tablet-based decision support application to eligible participants. In control villages, participants are referred to a health facility for therapeutic management. The primary endpoint for both TwiCs is the proportion of participants with controlled BP levels (< 140/90 mmHg) 12 months after enrolment. We hypothesize that the intervention is superior regarding BP control rates in participants with uncontrolled BP (aHT TwiC 1) and non-inferior in participants with controlled BP at baseline (aHT TwiC 2). The TwiCs were launched on September 08, 2023. On May 20, 2024, 697 and 750 participants were enrolled in TwiC 1 and TwiC 2. To our knowledge, these TwiCs are the first trials to assess task-shifting of aHT care to VHWs at the community level, including the prescription of basic antihypertensive, lipid-lowering, and antiplatelet medication in Africa. The ComBaCaL cohort and nested TwiCs are operating within the routine VHW program and countries with similar community health worker programs may benefit from the findings. ClinicalTrials.gov NCT05684055. Registered on January 04, 2023.
Sections du résumé
BACKGROUND
BACKGROUND
Arterial hypertension (aHT) is a major cause for premature morbidity and mortality. Control rates remain poor, especially in low- and middle-income countries. Task-shifting to lay village health workers (VHWs) and the use of digital clinical decision support systems may help to overcome the current aHT care cascade gaps. However, evidence on the effectiveness of comprehensive VHW-led aHT care models, in which VHWs provide antihypertensive drug treatment and manage cardiovascular risk factors is scarce.
METHODS
METHODS
Using the trials within the cohort (TwiCs) design, we are assessing the effectiveness of VHW-led aHT and cardiovascular risk management in two 1:1 cluster-randomized trials nested within the Community-Based chronic disease Care Lesotho (ComBaCaL) cohort study (NCT05596773). The ComBaCaL cohort study is maintained by trained VHWs and includes the consenting inhabitants of 103 randomly selected villages in rural Lesotho. After community-based aHT screening, adult, non-pregnant ComBaCaL cohort participants with uncontrolled aHT (blood pressure (BP) ≥ 140/90 mmHg) are enrolled in the aHT TwiC 1 and those with controlled aHT (BP < 140/90 mmHg) in the aHT TwiC 2. In intervention villages, VHWs offer lifestyle counseling, basic guideline-directed antihypertensive, lipid-lowering, and antiplatelet treatment supported by a tablet-based decision support application to eligible participants. In control villages, participants are referred to a health facility for therapeutic management. The primary endpoint for both TwiCs is the proportion of participants with controlled BP levels (< 140/90 mmHg) 12 months after enrolment. We hypothesize that the intervention is superior regarding BP control rates in participants with uncontrolled BP (aHT TwiC 1) and non-inferior in participants with controlled BP at baseline (aHT TwiC 2).
DISCUSSION
CONCLUSIONS
The TwiCs were launched on September 08, 2023. On May 20, 2024, 697 and 750 participants were enrolled in TwiC 1 and TwiC 2. To our knowledge, these TwiCs are the first trials to assess task-shifting of aHT care to VHWs at the community level, including the prescription of basic antihypertensive, lipid-lowering, and antiplatelet medication in Africa. The ComBaCaL cohort and nested TwiCs are operating within the routine VHW program and countries with similar community health worker programs may benefit from the findings.
TRIAL REGISTRATION
BACKGROUND
ClinicalTrials.gov NCT05684055. Registered on January 04, 2023.
Identifiants
pubmed: 38845045
doi: 10.1186/s13063-024-08226-2
pii: 10.1186/s13063-024-08226-2
doi:
Substances chimiques
Antihypertensive Agents
0
Banques de données
ClinicalTrials.gov
['NCT05684055']
Types de publication
Journal Article
Clinical Trial Protocol
Langues
eng
Sous-ensembles de citation
IM
Pagination
365Subventions
Organisme : Direktion für Entwicklung und Zusammenarbeit
ID : 7F-10345.01.01
Organisme : World Diabetes Foundation
ID : WDF20-1778
Organisme : Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
ID : 323530_207035
Informations de copyright
© 2024. The Author(s).
Références
Murray CJL, Aravkin AY, Zheng P, Abbafati C, Abbas KM, Abbasi-Kangevari M, et al. Global burden of 87 risk factors in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. The Lancet. 2020;396(10258):1223–49.
doi: 10.1016/S0140-6736(20)30752-2
The Global Cardiovascular Risk Consortium, Magnussen C, Ojeda FM, Leong DP, Alegre-Diaz J, Amouyel P, et al. Global Effect of Modifiable Risk Factors on Cardiovascular Disease and Mortality. N Engl J Med. 2023;389(14):1273–85.
Roth GA, Mensah GA, Johnson CO, Addolorato G, Ammirati E, Baddour LM, et al. Global Burden of Cardiovascular Diseases and Risk Factors, 1990–2019: Update From the GBD 2019 Study. J Am Coll Cardiol. 2020;76(25):2982–3021.
pubmed: 33309175
pmcid: 7755038
doi: 10.1016/j.jacc.2020.11.010
Gouda HN, Charlson F, Sorsdahl K, Ahmadzada S, Ferrari AJ, Erskine H, et al. Burden of non-communicable diseases in sub-Saharan Africa, 1990–2017: results from the Global Burden of Disease Study 2017. Lancet Glob Health. 2019;7(10):e1375–87.
pubmed: 31537368
doi: 10.1016/S2214-109X(19)30374-2
Zhou B, Carrillo-Larco RM, Danaei G, Riley LM, Paciorek CJ, Stevens GA, et al. Worldwide trends in hypertension prevalence and progress in treatment and control from 1990 to 2019: a pooled analysis of 1201 population-representative studies with 104 million participants. The Lancet. 2021;398(10304):957–80.
doi: 10.1016/S0140-6736(21)01330-1
Geldsetzer P, Manne-Goehler J, Marcus ME, Ebert C, Zhumadilov Z, Wesseh CS, et al. The state of hypertension care in 44 low-income and middle-income countries: a cross-sectional study of nationally representative individual-level data from 1·1 million adults. The Lancet. 2019;394(10199):652–62.
doi: 10.1016/S0140-6736(19)30955-9
Lamloum D, Fassio F, Osetinsky B, Tediosi F. Care Cascades for Hypertension in Low-Income Settings: A Systematic Review and Meta-Analysis. Int J Public Health. 2023;12(68):1606428.
doi: 10.3389/ijph.2023.1606428
World Health Organization. Global report on hypertension: the race against a silent killer. Geneva; 2023.
Kontis V, Cobb LK, Mathers CD, Frieden TR, Ezzati M, Danaei G. Three Public Health Interventions Could Save 94 Million Lives in 25 Years: Global Impact Assessment Analysis. Circulation. 2019;140(9):715–25.
pubmed: 31177824
pmcid: 6727958
doi: 10.1161/CIRCULATIONAHA.118.038160
Mbuthia GW, Magutah K, Pellowski J. Approaches and outcomes of community health worker’s interventions for hypertension management and control in low-income and middle-income countries: systematic review. BMJ Open. 2022;12(4): e053455.
pubmed: 35365519
pmcid: 8977767
doi: 10.1136/bmjopen-2021-053455
Jeet G, Thakur JS, Prinja S, Singh M. Community health workers for non-communicable diseases prevention and control in developing countries: Evidence and implications. PLoS ONE. 2017;12(7): e0180640.
pubmed: 28704405
pmcid: 5509237
doi: 10.1371/journal.pone.0180640
Khetan AK, Purushothaman R, Chami T, Hejjaji V, Madan Mohan SK, Josephson RA, et al. The Effectiveness of Community Health Workers for CVD Prevention in LMIC. Glob Heart. 2017;12(3):233-243.e6.
pubmed: 27993594
doi: 10.1016/j.gheart.2016.07.001
Anand TN, Joseph LM, Geetha AV, Prabhakaran D, Jeemon P. Task sharing with non-physician health-care workers for management of blood pressure in low-income and middle-income countries: a systematic review and meta-analysis. Lancet Glob Health. 2019;7(6):e761–71.
pubmed: 31097278
pmcid: 6527522
doi: 10.1016/S2214-109X(19)30077-4
Owoyemi A, Osuchukwu JI, Azubuike C, Ikpe RK, Nwachukwu BC, Akinde CB, et al. Digital Solutions for Community and Primary Health Workers: Lessons From Implementations in Africa. Front Digit Health. 2022;4: 876957.
pubmed: 35754461
pmcid: 9215204
doi: 10.3389/fdgth.2022.876957
Swartz A, LeFevre AE, Perera S, Kinney MV, George AS. Multiple pathways to scaling up and sustainability: an exploration of digital health solutions in South Africa. Glob Health. 2021;17(1):77.
doi: 10.1186/s12992-021-00716-1
Agarwal S, Glenton C, Tamrat T, Henschke N, Maayan N, Fønhus MS, et al. Decision-support tools via mobile devices to improve quality of care in primary healthcare settings. Cochrane Effective Practice and Organisation of Care Group, editor. Cochrane Database Syst Rev. 2021 Jul 27;2021(7). Available from: http://doi.wiley.com/ https://doi.org/10.1002/14651858.CD012944.pub2 [cited 2024 May 7]
Staehelin D, Dolata M, Peyer N, Gerber F, Schwabe G. Algorithmic Management for Community Health Worker in Sub-Saharan Africa: Curse or Blessing? In: Human-Computer Interaction – INTERACT 2023: 19th IFIP TC13 International Conference, York, UK, August 28 – September 1, 2023, Proceedings, Part III. Berlin, Heidelberg: Springer-Verlag; 2023. p. 94–114. Available from: https://doi.org/10.1007/978-3-031-42286-7_6
Benjamin IJ, Kreutz R, Olsen MH, Schutte AE, Lopez-Jaramillo P, Frieden TR, et al. Fixed-dose combination antihypertensive medications. The Lancet. 2019;394(10199):637–8.
doi: 10.1016/S0140-6736(19)31629-0
Bruyn E, Nguyen L, Schutte AE, Murphy A, Perel P, Webster R. Implementing Single-Pill Combination Therapy for Hypertension: A Scoping Review of Key Health System Requirements in 30 Low- and Middle-Income Countries. Glob Heart. 17(1):6.
Agarwal S, Perry HB, Long L, Labrique AB. Evidence on feasibility and effective use of mHealth strategies by frontline health workers in developing countries: systematic review. Trop Med Int Health. 2015;20(8):1003–14.
pubmed: 25881735
pmcid: 4692099
doi: 10.1111/tmi.12525
DiPette DJ, Skeete J, Ridley E, Campbell NRC, Lopez-Jaramillo P, Kishore SP, et al. Fixed-dose combination pharmacologic therapy to improve hypertension control worldwide: Clinical perspective and policy implications. J Clin Hypertens. 2018;21(1):4–15.
doi: 10.1111/jch.13426
Fernández LG, Firima E, Gupta R, Sematle M, Khomolishoele M, Molulela M, et al. Awareness, treatment, and control among adults living with arterial hypertension or diabetes mellitus in two rural districts in Lesotho. In Review; 2023 Jul. Available from: https://www.researchsquare.com/article/rs-3189573/v1 [cited 2023 Oct 18]
González Fernández L, Firima E, Gupta R, Sematle MP, Khomolishoele M, Molulela M, et al. Prevalence and determinants of cardiovascular risk factors in Lesotho: a population-based survey. Int Health. 2024;16(3):313–24.
pubmed: 37593886
doi: 10.1093/inthealth/ihad058
Fernández LG, Firima E, Robinson E, Ursprung F, Huber J, Amstutz A, et al. Community-based care models for arterial hypertension management in non-pregnant adults in sub-Saharan Africa: a literature scoping review and framework for designing chronic services. BMC Public Health. 2022;22(1):1126.
pubmed: 35658850
pmcid: 9167524
doi: 10.1186/s12889-022-13467-4
Ministry of Health Lesotho. The Village Health Program Policy. 2020.
Joseph JK, Rigodon J, Cancedda C, Haidar M, Lesia N, Ramanagoela L, et al. Lay health workers and HIV care in rural Lesotho: a report from the field. AIDS Patient Care STDS. 2012;26(3):141–7.
pubmed: 22304374
doi: 10.1089/apc.2011.0209
Amstutz A, Lejone TI, Khesa L, Muhairwe J, Bresser M, Vanobberghen F, et al. Home-based oral self-testing for absent and declining individuals during a door-to-door HIV testing campaign in rural Lesotho (HOSENG): a cluster-randomised trial. Lancet HIV. 2020;7(11):e752–61.
pubmed: 33045193
doi: 10.1016/S2352-3018(20)30233-2
Dunachie S, Chamnan P. The double burden of diabetes and global infection in low and middle-income countries. Trans R Soc Trop Med Hyg. 2019;113(2):56–64.
pubmed: 30517697
doi: 10.1093/trstmh/try124
Vos T, Lim SS, Abbafati C, Abbas KM, Abbasi M, Abbasifard M, et al. 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. The Lancet. 2020;396(10258):1204–22.
doi: 10.1016/S0140-6736(20)30925-9
Geneva: World Health Organization. Noncommunicable Diseases Data Portal: Lesotho NCD Country Profile. 2022. Available from: https://ncdportal.org/CountryProfile/GHE110/LSO#risk-factor6 [cited 2023 Nov 29]
Relton C, Torgerson D, O’Cathain A, Nicholl J. Rethinking pragmatic randomised controlled trials: introducing the “cohort multiple randomised controlled trial” design. BMJ. 2010;19(340): c1066.
doi: 10.1136/bmj.c1066
Van Der Velden JM, Verkooijen HM, Young-Afat DA, Burbach JPM, Van Vulpen M, Relton C, et al. The cohort multiple randomized controlled trial design: a valid and efficient alternative to pragmatic trials? Int J Epidemiol. 2016;25:96–102.
Chan AW, Tetzlaff JM, Gøtzsche PC, Altman DG, Mann H, Berlin JA, et al. SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials. BMJ. 2013;346. Available from: https://www.bmj.com/content/346/bmj.e7586
Caille A, Kerry S, Tavernier E, Leyrat C, Eldridge S, Giraudeau B. Timeline cluster: a graphical tool to identify risk of bias in cluster randomised trials. BMJ. 2016;16(354): i4291.
doi: 10.1136/bmj.i4291
Ministry of Health Lesotho. Standard Treatment Guidelines for Lesotho. 2022.
Williams B, Mancia G, Spiering W, Agabiti Rosei E, Azizi M, Burnier M, et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension. Eur Heart J. 2018;39(33):3021–104.
pubmed: 30165516
doi: 10.1093/eurheartj/ehy339
Unger T, Borghi C, Charchar F, Khan NA, Poulter NR, Prabhakaran D, et al. 2020 International Society of Hypertension Global Hypertension Practice Guidelines. 2020;75(6):1334–57.
ICHOM International Consortium for Health Outcomes Measurement. Hypertension in low- and middle-income countries Data collection reference guide V 4.0.0. 2022. Available from: https://connect.ichom.org/wp-content/uploads/2022/08/17-Hypertension_in_LMIC_Reference_Guide_V4.0_30.03.2022.pdf [cited 2023 Nov 5]
WHO Cvd Risk Charts Working Group. World Health Organization cardiovascular disease risk charts: revised models to estimate risk in 21 global regions. Lancet Glob Health. 2019;7(10):e1332–45.
doi: 10.1016/S2214-109X(19)30318-3
Craig CL, Marshall AL, Sjöström M, Bauman AE, Booth ML, Ainsworth BE, et al. International Physical Activity Questionnaire: 12-Country Reliability and Validity: Med Sci Sports Exerc. 2003 Aug;35(8):1381–95.
Okeyo AP, Seekoe E, de Villiers A, Faber M, Nel JH, Steyn NP. Dietary Practices and Adolescent Obesity in Secondary School Learners at Disadvantaged Schools in South Africa: Urban-Rural and Gender Differences. Int J Environ Res Public Health. 2020;17(16):5864.
pubmed: 32823510
pmcid: 7460370
doi: 10.3390/ijerph17165864
Feng YS, Kohlmann T, Janssen MF, Buchholz I. Psychometric properties of the EQ-5D-5L: a systematic review of the literature. Qual Life Res. 2021;30(3):647–73.
pubmed: 33284428
doi: 10.1007/s11136-020-02688-y
Horne R, Weinman J, Hankins M. The beliefs about medicines questionnaire: The development and evaluation of a new method for assessing the cognitive representation of medication. Psychol Health. 1999;14(1):1–24.
doi: 10.1080/08870449908407311
Mostafavi F, Najimi A, Sharifirad G, Golshiri P. Beliefs About Medicines in Patients with Hypertension: the Instrument Validity and Reliability in Iran. Mater Socio Medica. 2016;28(4):298.
doi: 10.5455/msm.2016.28.298-302
Hajifathalian K, Ueda P, Lu Y, Woodward M, Ahmadvand A, Aguilar-Salinas CA, et al. A novel risk score to predict cardiovascular disease risk in national populations (Globorisk): a pooled analysis of prospective cohorts and health examination surveys. Lancet Diabetes Endocrinol. 2015;3(5):339–55.
pubmed: 25819778
pmcid: 7615120
doi: 10.1016/S2213-8587(15)00081-9
D’Agostino RB, Vasan RS, Pencina MJ, Wolf PA, Cobain M, Massaro JM, et al. General Cardiovascular Risk Profile for Use in Primary Care: The Framingham Heart Study. Circulation. 2008;117(6):743–53.
pubmed: 18212285
doi: 10.1161/CIRCULATIONAHA.107.699579
Takahashi H, Yoshika M, Yokoi T. Validation of two automatic devices for the self-measurement of blood pressure according to the ANSI/AAMI/ISO81060–2:2009 guidelines: the Omron BP765 (HEM-7311-ZSA) and the Omron BP760N (HEM-7320-Z). Vasc Health Risk Manag. 2015 Jan;49.
Rotondi M, Donner A. Sample size estimation in cluster randomized trials: An evidence-based perspective. Comput Stat Data Anal. 2012;56(5):1174–87.
doi: 10.1016/j.csda.2010.12.010
Amstutz A, Lejone TI, Khesa L, Kopo M, Kao M, Muhairwe J, et al. Offering ART refill through community health workers versus clinic-based follow-up after home-based same-day ART initiation in rural Lesotho: The VIBRA cluster-randomized clinical trial. Newell ML, editor. PLOS Med. 2021 Oct 21;18(10):e1003839.
Lee YL, Lim YMF, Law KB, Sivasampu S. Intra-cluster correlation coefficients in primary care patients with type 2 diabetes and hypertension. Trials. 2020;16(21):530.
doi: 10.1186/s13063-020-04349-4
Donner A, Klar N. Design and analysis of cluster randomization trials in health research. London: Wiley; 2000.
Community Health Toolkit. Community Health Toolkit. Available from: https://communityhealthtoolkit.org [cited 2023 May 29]
Bhutta ZA, Lassi ZS, Pariyo G, Huicho L. Global Experience of Community Health Workers for Delivery of Health Related Millennium Development Goals: A Systematic Review, Country Case Studies, and Recommendations for Integration into National Health Systems. World Health Organization, Global Health Workforce Alliance; 2010. Available from: https://chwcentral.org/wp-content/uploads/2013/07/Global-Experience-of-Community-Health-Workers-for-Delivery-of-Health-Related-Millennium-Development-Goals.pdf
Augustovski F, Chaparro M, Palacios A, Shi L, Beratarrechea A, Irazola V, et al. Cost-Effectiveness of a Comprehensive Approach for Hypertension Control in Low-Income Settings in Argentina: Trial-Based Analysis of the Hypertension Control Program in Argentina. Value Health. 2018;21(12):1357–64.
pubmed: 30502778
pmcid: 6457112
doi: 10.1016/j.jval.2018.06.003
Ogedegbe G, Gyamfi J, Plange-Rhule J, Surkis A, Rosenthal DM, Airhihenbuwa C, et al. Task shifting interventions for cardiovascular risk reduction in low-income and middle-income countries: a systematic review of randomised controlled trials. BMJ Open. 2014;4(10): e005983.
pubmed: 25324324
pmcid: 4202019
doi: 10.1136/bmjopen-2014-005983
Schwalm JD, McCready T, Lopez-Jaramillo P, Yusoff K, Attaran A, Lamelas P, et al. A community-based comprehensive intervention to reduce cardiovascular risk in hypertension (HOPE 4): a cluster-randomised controlled trial. The Lancet. 2019;394(10205):1231–42.
doi: 10.1016/S0140-6736(19)31949-X
Sun Y, Mu J, Wang DW, Ouyang N, Xing L, Guo X, et al. A village doctor-led multifaceted intervention for blood pressure control in rural China: an open, cluster randomised trial. The Lancet. 2022;399(10339):1964–75.
doi: 10.1016/S0140-6736(22)00325-7
Hendriks M, van Andel J, Asiki G, Kyobutungi C. Cardiovascular risk in hypertension: open questions about HOPE 4. The Lancet. 2020;396(10247):309–10.
doi: 10.1016/S0140-6736(20)30612-7
Gerber F, Gupta R, Lejone TI, Tahirsylaj T, Lee T, Kohler M, et al. Community-based type 2 diabetes care by lay village health workers in rural Lesotho: protocol for a cluster-randomized trial within the ComBaCaL cohort study (ComBaCaL T2D TwiC). Trials. 2023;24(1):688.
pubmed: 37875943
pmcid: 10598965
doi: 10.1186/s13063-023-07729-8
World Health Organization. WHO guideline: recommendations on digital interventions for health system strengthening. Geneva: World Health Organization; 2019. Available from: https://apps.who.int/iris/handle/10665/311941 [cited 2023 Jun 5]
Aovare P, Abdulai K, Laar A, van der Linden EL, Moens N, Richard E, et al. Assessing the Effectiveness of mHealth Interventions for Diabetes and Hypertension Management in Africa: Systematic Review and Meta-Analysis. JMIR MHealth UHealth. 2023;29(11): e43742.
doi: 10.2196/43742
Giraudeau B, Ravaud P. Preventing Bias in Cluster Randomised Trials. PLoS Med. 2009;6(5): e1000065.
pubmed: 19536323
pmcid: 2668175
doi: 10.1371/journal.pmed.1000065