Person: Munoz Venturelli, Paula
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Munoz Venturelli
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Publication Implementation of a goal-directed Care Bundle for intracerebral hemorrhage: Results of embedded process evaluation in the INTERACT3 trial(2024) Ouyang, Menglu; Anjum, Anila; Gonzalez, Francisca; Wasay, Mohammad; Ma, Lu; Hu, Xin; Chen, Xiaoying; Malavera, Alejandra; Li, Xi; Munoz Venturelli, Paula; De Silva, Asita; Nguyen Huy Thang; Wahab, Kolawole; Pandian, Jeyaraj; Pontes-Neto, Octavio; Abanto, Carlos; Cano-Nigenda, Venessa; Arauz, Antonio; You, Chao; Jan, Stephen; Song, Lili; Anderson, Craig; Liu, Hueiming; INTERACT3 InvestigatorsThe third, stepped-wedge, cluster-randomized, Intensive Care Bundle with Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT3), has shown that a goal-directed multi-faceted Care Bundle incorporating protocols for the management of physiological variables was safe and effective for improving functional recovery in a broad range of patients with acute intracerebral hemorrhage (ICH). The INTERACT3 Care Bundle included time- and target-based protocols for the management of early intensive lowering of systolic blood pressure (SBP, target <140mmHg), glucose control (target 6.1-7.8 mmol/L in those without diabetes and 7.8-10.0 mmol/L in those with diabetes), anti-pyrexia treatment (target body temperature ≤37.5°C), and the rapid reversal of warfarin-related anticoagulation (target international normalized ratio <1.5). An embedded process evaluation was conducted to allow a better understanding of how the Care Bundle was implemented in different countries to enhance the transferability of this evidence in the international context. This study used a mixed-methods approach involving interviews, focus group discussions, and surveys to evaluate the implementation outcomes included fidelity, dose, reach, acceptability, appropriateness, adoption, and sustainability. Interviews (n = 27), focus group discussions (n = 3), and quantitative surveys (n = 48) were conducted in 7 low- and middle-income countries (LMICs) and 1 high-income country during 2019-2022. The Care Bundle was generally delivered as planned and well accepted by stakeholders, although some difficulties were reported in reaching the SBP and glycemic targets. Contextual factors including staff shortage, limited availability of antihypertensive drugs, and delayed systems of care processes, were common barriers to implementing the Care Bundle. Facilitating factors included good communication and collaboration with staff in emergency departments, the development of pathways within available resources, and regular training and monitoring. Our process evaluation provides useful insights into the contextual barriers which need to be addressed for effective scale up of the Care Bundle implementation in a global context. Trial registration: INTERACT3 is registered at Clinicaltrials.gov (NCT03209258) and the Chinese Clinical Trial Registry (ChiCTR-IOC-17011787).Publication Effects of intensive blood pressure lowering on cerebral ischaemia in thrombolysed patients: insights from the ENCHANTED trial(2023) Chen, Chen; Ouyang, Menglu; Ong, Sheila; Zhang, Luyun; Zhang, Guobin; Delcourt, Candice; Mair, Grant; Liu, Leibo; Billot, Laurent; Li, Qiang; Chen, Xiaoying; Parsons, Mark; Broderick, Joseph; Demchuk, Andrew; Bath, Philip; Donnan, Geoffrey; Levi, Christopher; Chalmers, John; Lindley, Richard; Martins, Sheila; Pontes-Neto, Octavio; Munoz Venturelli, Paula; Olavarría, Verónica V.; Lavados, Pablo; Robinson, Thompson; Wardlaw, Joanna; Li, Gang; Wang, Xia; Song, Lili; Anderson, CraigBackground: Intensive blood pressure lowering may adversely affect evolving cerebral ischaemia. We aimed to determine whether intensive blood pressure lowering altered the size of cerebral infarction in the 2196 patients who participated in the Enhanced Control of Hypertension and Thrombolysis Stroke Study, an international randomised controlled trial of intensive (systolic target 130-140 mm Hg within 1 h; maintained for 72 h) or guideline-recommended (systolic target <180 mm Hg) blood pressure management in patients with hypertension (systolic blood pressure >150 mm Hg) after thrombolysis treatment for acute ischaemic stroke between March 3, 2012 and April 30, 2018. Methods: All available brain imaging were analysed centrally by expert readers. Log-linear regression was used to determine the effects of intensive blood pressure lowering on the size of cerebral infarction, with adjustment for potential confounders. The primary analysis pertained to follow-up computerised tomography (CT) scans done between 24 and 36 h. Sensitivity analysis were undertaken in patients with only a follow-up magnetic resonance imaging (MRI) and either MRI or CT at 24-36 h, and in patients with any brain imaging done at any time during follow-up. This trial is registered with ClinicalTrials.gov, number NCT01422616. Findings: There were 1477 (67.3%) patients (mean age 67.7 [12.1] y; male 60%, Asian 65%) with available follow-up brain imaging for analysis, including 635 patients with a CT done at 24-36 h. Mean achieved systolic blood pressures over 1-24 h were 141 mm Hg and 149 mm Hg in the intensive group and guideline group, respectively. There was no effect of intensive blood pressure lowering on the median size (ml) of cerebral infarction on follow-up CT at 24-36 h (0.3 [IQR 0.0-16.6] in the intensive group and 0.9 [0.0-12.5] in the guideline group; log Δmean -0.17, 95% CI -0.78 to 0.43). The results were consistent in sensitivity and subgroup analyses. Interpretation: Intensive blood pressure lowering treatment to a systolic target <140 mm Hg within several hours after the onset of symptoms may not increase the size of cerebral infarction in patients who receive thrombolysis treatment for acute ischaemic stroke of mild to moderate neurological severity. Funding: National Health and Medical Research Council of Australia; UK Stroke Association; UK Dementia Research Institute; Ministry of Health and the National Council for Scientific and Technological Development of Brazil; Ministry for Health, Welfare, and Family Affairs of South Korea; Takeda.Publication Sex Differences in Profile and In-Hospital Death for Acute Stroke in Chile: Data From a Nationwide Hospital Registry(2024) Nuñez, Marilaura; Allende, María; González, Francisca; Cavada, Gabriel; Anderson, Craig; Munoz Venturelli, PaulaBackground: Knowledge of local contextual sex differences in the profile and outcome for stroke can improve service delivery. We aimed to determine sex differences in the profile of patients with acute stroke and their associations with in-hospital death in the national hospital database of Chile. Methods and results: We present a retrospective cohort based on the analysis of the 2019 Chilean database of Diagnosis-Related Groups, which represents 70% of the operational expenditure of the public health system. Random-effects multiple logistic regression models were used to determine independent associations of acute stroke (defined by main diagnosis International Classification of Diseases, Tenth Revision [ICD-10] codes) and in-hospital death, and reported with odds ratios (ORs) and 95% CIs. Of 1 048 575 hospital discharges, 15 535 were for patients with acute stroke (7074 [45.5%] in women), and 2438 (15.6%) of them died during hospitalization. Differences by sex in sociodemographic and clinical characteristics were identified for stroke and main subtypes. After fully adjusted model, women with ischemic stroke had lower in-hospital death (OR, 0.79 [95% CI, 0.69-0.91]) compared with men; other independent predictors included age per year increase (OR, 1.03 [95% CI, 1.03-1.04]), chronic kidney disease (OR, 1.47 [95% CI, 1.20-1.80]), atrial fibrillation (OR, 1.50 [95% CI, 1.26-1.80]), and other risk factors. Conversely, for intracerebral hemorrhage, women had a higher in-hospital mortality rate than men (OR, 1.19 [95% CI, 1.02-1.40]); other independent predictors included age per year increase (OR, 1.009 [95% CI, 1.003-1.01]), chronic kidney disease (OR, 1.55 [95% CI, 1.23-1.97]), oral anticoagulant use (OR, 1.88 [95% CI, 1.37-2.58]), and other risk factors. Conclusions: Sex differences in characteristics and in-hospital death of hospitalized patients exist for acute stroke in Chile. In-hospital death is higher for acute ischemic stroke in men and higher for intracerebral hemorrhage in women. Future research is needed to better identify contributing factors.Publication The main Optimal Post rTpa-Iv Monitoring in Ischemic Stroke Trial (OPTIMISTmain): Protocol for a Pragmatic, Stepped Wedge, Cluster Randomized Controlled Trial(2023) Ouyang, Menglu; Faigle, Roland; Wang, Xia; Johnson, Brenda; Summers, Debbie; Khatri, Pooja; Billot, Laurent; Liu, Hueiming; Malavera, Alejandra; Munoz Venturelli, Paula; Gonzalez, Francisca; Urrutia, Francisca; Day, Diana; Songa, Lili; Sui, Yi; Delcourt, Candice; Robinson, Thompson; Durham, Alice; Ebraimo, Ahtasam; Wan Asyraf Wan Zaidin; Jan, Stephen; Lindley, Richard; Urrutia, Victor; Anderson, CraigIntroduction Careful monitoring of patients who receive intravenous thrombolysis (IVT) for acute ischemic stroke (AIS) is resource-intensive, and potentially less relevant in those with mild degrees of neurological impairment who are at low-risk of symptomatic intracerebral hemorrhage (sICH) and other complications. \ Methods OPTIMISTmain is an international, multicenter, prospective, stepped wedge, cluster randomized, blinded outcome assessed trial aims to determine whether a less-intensity monitoring protocol is at least as effective, safe and efficient as standard post-IVT monitoring in patients with mild deficits post-AIS. Clinically-stable adult patients with mild AIS (defined by a NIHSS <10) who do not require intensive care within 2 hours post-IVT are recruited at hospitals in Australia, Chile, China, Malaysia, Mexico, UK, US and Vietnam. An average of 15 patients recruited per period (overall 60 patient participants) at 120 sites for a total of 7200 IVT-treated AIS patients will provide 90% power (one-sided α 0.025). The initiation of eligible hospitals is based on a rolling process whenever ready, stratified by country. Hospitals are randomly allocated using permuted blocks into 3 sequences of implementation, stratified by country and the projected number of patients to be recruited over 12 months. These sequences have four periods that dictate the order in which they are to switch from control (usual care) to intervention (implementation of low intensity monitoring protocol) to different clusters of patients in a stepped manner. Compared to standard monitoring, the low-intensity monitoring protocol includes assessments of neurological and vital signs every 15 minutes for 2 hours, 2 hourly (versus every 30 minutes) for 8 hours, and 4 hourly (versus every 1 hour) until 24 hours, post-IVT. The primary outcome measure is functional recovery, defined by the modified Rankin scale (mRS) at 90 days, a seven-point ordinal scale (0 [no residual symptom] to 6 [death]). Secondary outcomes include death or dependency, length of hospital stay, and health-related quality of life, sICH and serious adverse events. Conclusion OPTIMISTmain will provide Level I evidence for the safety and effectiveness of a low-intensity post-IVT monitoring protocol in patients with mild severity of AIS.Publication Disparities in Stroke Incidence Over Time by Sex and Age in Latin America and the Caribbean Region 1997 to 2021: A Systematic Review and Meta-Analysis(2023) Nuñez, Marilaura; Delfino, Carlos; Asenjo, Claudia; Schilling, Andrea; Lavados, Pablo; Anderson, Craig; Munoz Venturelli, PaulaBackground High-income country studies show unfavorable trends in stroke incidence (SI) in younger populations. We aimed to estimate temporal change in SI disaggregated by age and sex in Latin America and the Caribbean region. Methods and Results A search strategy was used in MEDLINE, WOS, and LILACS databases from 1997 to 2021, including prospective population-based observational studies with first-ever stroke incidence in Latin America. Reports without data broken down by age and sex were excluded. Risk of bias was assessed with The Joanna Briggs Institute's guide. The main outcomes were incidence rate ratio and relative temporal trend ratio of SI, comparing time periods before 2010 with after 2010. Pooled relative temporal trend ratios considering only studies with 2 periods in the same population were calculated by random-effects meta-analysis. Meta-regression analysis was used to evaluate incidence rate determinants. From 9242 records identified, 6 studies were selected including 4483 first-ever stroke in 4 101 084 individuals. Crude incidence rate ratio in younger subjects (<55 years) comparing before 2010:after 2010 periods showed an increase in SI in the past decade (incidence rate ratio, 1.37 [95% CI, 1.23-1.50]), in contrast to a decrease in older people during the same period (incidence rate ratio, 0.83 [95% CI, 0.76-0.89]). Overall relative temporal trend ratio (<55:≥55 years) was 1.65 (95 CI%, 1.50-1.80), with higher increase in young women (pooled relative temporal trend ratio, 3.08 [95% CI, 1.18-4.97]; P for heterogeneity <0.001). Conclusions An unfavorable change in SI in young people, especially in women, was detected in population-based studies in the past decade in Latin America and the Caribbean. Further investigation of the explanatory variables is required to ameliorate stroke prevention and inform local decision-makers. Registration URL: https://www.crd.york.ac.uk/prospero/ Identifier: CRD42022332563.Publication Risk and impact of stroke across 38 countries and territories of the Americas from 1990 to 2021: a population-based trends analysis from the Global Burden of Disease Study 2021(2025) Martinez, Ramón; Munoz Venturelli, Paula; Ordunez, Pero; Fregni, Felipe; Abanto, Carlos; Alet, Matias; Alvarez, Tony; Amaya, Pablo; Ameriso, Sebastian; Arauz, Antonio; Barboza, Miguel; Bayona, Hernán; Ortiz, Antonio; Calleja, Juan; Cano, Vanessa; Carbonera, Leonardo; Carrillo, Rodrigo; Corredor, Angel; De Souza, Ana; Jimenez, Claudio; Lanas, Fernando; Martins, Sheila; Navia, Víctor; Novarro, Nelson; Olavarría, Verónica V.; Ovbiagele, Bruce; Pachecho, Kevin; Pontes, Octavio; Pujol, Virginia; Rabinstein, Alejandro; Rosales, Julieta; Rosende, Andrés; Sampaio, Gisele; Saposnik, Gustavo; Sen, Souvik; Testai, Fernando; Urrutia, Victor; Anderson, Craig; Lavados, PabloBackground: Despite substantial declines in burden over time, stroke remains a public health threat in the Americas. This study aimed to assess the current magnitude, trends, and disparities in the estimates of stroke burden by sex and age in the Americas from 1990 to 2021. Methods: Estimates from the Global Burden of Disease, Injuries and Risk Factors Study 2021 were used to analyze incidence, prevalence, mortality, years of life lost due to premature death, years lived with disabilities, and disability-adjusted life years (DALYs) caused by stroke and its major subtypes stratified by age, and sex in the Americas from 1990 to 2021. We used Joinpoint regression analysis to estimate the average annual percent change (AAPC) of stroke mortality and disease burden outcomes and assessed trends. Findings: In 2021, there were 1.1 million (95% uncertainty interval: 1.0-1.2) new cases, 12.9 million (12.3-13.7) prevalent cases, 0.5 million (0.5-0.6) deaths, and 11.4 million (10.6-12.1) DALYs due to stroke in the Americas. The absolute number of stroke burden outcomes increased from 1990 to 2021, but their corresponding age-standardized rates significantly declined. A deceleration in reduction rates of burden outcomes for all strokes and most stroke subtypes occurred over the last decade, with pronounced difference between sexes mainly in incidence among younger groups. From 2015 to 2021, trends in incidence rates from all stroke and stroke subtypes reversed to increase in most age groups, and strikingly, trends in mortality and DALY rates from ischemic stroke among younger populations reversed to upward with AAPC over 1.4%. A substantial number of countries contributed to these increasing trends. Interpretation: Regionally, the annual number of stroke cases and deaths significantly increased from 1990 to 2021, despite reductions in age-standardized rates. The declining pace in age-standardized stroke rates has decelerated in recent years, while trends in incidence, and ischemic stroke mortality and DALY among middle-aged adults and adults, reversed towards upward in the period 2015-2021. Further studies are needed to understand the determinants of this recent pattern and identify the most cost-effective interventions to stem this alarming trend. Funding: There was no funding source for this study.Publication STatin TReatment for COVID- 19 to Optimise NeuroloGical recovERy (STRONGER): study protocol for a randomised, open label clinical trial in patients with persistent neurological symptoms after COVID- 19 infection(2025) Delfino, Carlos; Carcel, Cheryl; Lin, Xiaolei; Munoz Venturelli, Paula; Naismith, Sharon; Woodward, Mark; Peters, Ruth; Wijesuriya, Nirupama; Law, Meng; Harding, Ian; Wang, Xia; Elliott, Julian; Leder, Karin; Hutchings, Owen; Stecher, Ximena; Zoungas, Sophia; Anderson, CraigIntroduction Increasing awareness of the high frequency, wide spectrum and disabling nature of symptoms that can persist following COVID-19 infection has prompted the investigation of management strategies. Our study aims to determine the effectiveness of atorvastatin on cognitive function, physical activity, mood, health-related quality of life and features of neurovascular impairment and neuroinflammation in adults with ongoing neurological symptoms after COVID-19 infection. Methods and analysis The STatin TReatment for COVID-19 to Optimise NeuroloGical recovERy study is an ongoing international, investigator-initiated and conducted, multicentre, prospective, randomised, open label, blinded endpoint trial with fixed time points for outcome assessments. A total of 410 participants with long covid neurological symptoms were planned to be randomly assigned to either the intervention group to receive 40 mg atorvastatin for 12 months or to a control group of no treatment, on top of usual care. Ethics and dissemination This study protocol was designed, implemented and reported, in accordance with the International Conference on Harmonisation guidelines for Good Clinical Practice, the National Health and Medical Research Council of Australia, the National Statement on Ethical Conduct in Human Research and with the ethical principles laid down in the World Medical Association Declaration of Helsinki. Central ethics committee approval was obtained from Sydney Local Health District Royal Prince Alfred Hospital Ethics (No: X21-0113 and 2021/ETH00777 10) in Australia. Site-specific ethics committee approvals were obtained elsewhere before any local study activities. All participants provided written informed consent.Publication Recommendations for Implementing the INTERACT3 Care Bundle for Intracerebral Hemorrhage in Latin America: Results of a Delphi Method(2025) Allende, María; Munoz Venturelli, Paula; Gonzalez, Francisca; Bascur, Francisca; Anderson, Craig; Ouyang, Menglu; Cabieses, Báltica; Obach, Alexandra; Cano, Vanessa; Arauzg, AntonioIntroduction: The third Intensive Care Bundle with Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT3) showed that the implementation of a care bundle improves outcomes after acute intracerebral hemorrhage (ICH). We aimed to establish consensus-based recommendations for the broader integration of the care bundle across Latin American countries (LAC). Methods: A 3-phase Delphi study allowed a panel of 32 healthcare workers from 14 LAC to sequentially rank statements relevant to 7 domains (training, resources/infrastructure, patient education, blood pressure, temperature, glycemic control, and anticoagulation reversal). The pre-defined consensus threshold was 75%. Results: A total of 43 statements reached consensus by the third round, with 12 new statements emerging through rounds. The highest-ranked statements in each domain emphasized critical aspects, but successful implementation requires appropriate resourcing. Key priorities were continuous training of all healthcare workers in ICH management, establishing protocols aligned with available resources, and collaborative interdisciplinary care supported by institutional networks. Statements related to anticoagulation reversal had the highest priority. Conclusions: Consensus statements are provided to facilitate integration of the INTERACT3 care bundle to reduce disparities in ICH outcomes in LAC.Publication Multimorbidity in acute ischemic stroke and its impact on short-term mortality: A Chilean nationwide database analysis(2025) González, Francisca; Allende, María; Nuñez, Marilaura; Delgado, Iris; Jakszyn, Paula; Delfino, Carlos; Anderson, Craig; Munoz Venturelli, PaulaBackground: Multimorbidity predicts a worse prognosis for various diseases but its impact in people after an acute ischemic stroke (AIS) in developing societies is not well established. We aimed to characterize the pattern of multimorbidity and determine its association with in-hospital mortality after AIS in the nationwide Chilean database. Methods: A retrospective analysis of the Diagnosis-Related Groups database for hospitalized adult patients in Chile in 2019 was conducted. Association of multimorbidity, defined as the presence of ≥2 health conditions, in patients with AIS (ICD-10 code I63) on in-hospital mortality was determined in logistic regression models adjusted for confounding variables. Results: Of 1,048,575 recorded ICD-10 codes, there were 10,440 AIS episodes in whom 7,696 (73.7 %) patients had multimorbidity. Age, female sex, and low socioeconomic status were associated with a higher multimorbidity, and the combination of comorbidities differed across age groups. Cardiometabolic multimorbidity was associated with higher in-hospital mortality (odds ratio [OR] 1.39, 95 % confidence interval [CI] 1.16-1.66; p<0.001). Stage 5 chronic kidney disease combined with ischemic heart disease was the comorbidity with the highest risk of death (OR 4.20, 95 %CI 1.58-11.16; p = 0.004). Obesity, which exhibited a predominance in early to mid-life, had the highest association with mortality when combined with other conditions. Conclusions: Multimorbidity is common in patients with AIS and its components vary by age and sex. Cardiometabolic multimorbidity increases the likelihood of in-hospital mortality. Adopting a multimorbidity-focused approach to stroke care could improve outcomes.Publication Surgical outcomes from haematoma evacuation for intracerebral haemorrhage in the INTERACT3 study(2025) Hu, Xin; Ouyang, Menglu; Xu, Jianguo; Liu, Yi; Li, Xi; Jiang, Yan; Chen, Xiaoying; Billot, Laurent; Qiang, Li; Malavera, Alejandra; Munoz Venturelli, Paula; Thang, Nguyen; Wahab, Kolawole; Pandian, Jeyaraj; Wasay, Mohammad; Pontes-Neto, Octavio; Abanto, Carlos; Arau, Antonio; Li, Zongping; Chen, Minhui; Wang, Xiaofeng; Yang, Chengyi; Xin, Xiaodong; Jiang, Dehua; Zheng, Jun; Yu, Zhiyuan; Xiao, Anqi; Tao, Chuanyuan; Chen, Lei; Wu, Bo; Li, Hao; Anderson, Craig; You, Chao; Song, Lili; Ma, Lu; INTERACT3 InvestigatorsBackground: There is ongoing controversy as to whether surgical intervention to haematoma evacuation benefits patients with acute intracerebral haemorrhage (ICH). This study aimed to evaluate the association of surgical intervention to evacuate the haematoma and 6-month functional outcome in participants of the third Intensive Care Bundle with Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial (INTERACT3). Methods: This was a secondary analysis of INTERACT3, which enrolled adults (age ≥18 years) spontaneous ICH patients within 6 h after onset. INTERACT3 was an international, multicentre, prospective, stepped-wedge, cluster randomised, blinded outcome assessed, clinical trial undertaken at 121 hospitals in 10 countries between December 12, 2017 and December 31, 2021. To limit heterogeneity in the results, we restricted analyses to participants in China. The primary outcome was poor functional outcome, defined by a score of 5-6 on the modified Rankin scale (mRS), at 6 months. Secondary outcomes include a mRS score of 4-6 and mortality at 6 months. Sensitivity analysis included propensity score matched analysis and the imputation of missing outcome variables. The effect of timing on surgical outcome was also evaluated. The INTERACT3 trial was registered at ClinicalTrials.gov (NCT03209258) and CHiCTR.org.cn (ChiCTR-IOC-17011787). Findings: Of 5772 participants (mean age 62.0 ± 12.5 years) at 82 sites in China, 1411 (24.4%) received surgery in which craniotomy (72.6%) was the most common approach. After adjustment for confounding variables, surgery to evacuate the haematoma was associated with lower odds of a poor functional outcome (odds ratio 0.71, 95% CI 0.55-0.92; p = 0.010) and mortality (odds ratio 0.55, 95% CI 0.40-0.75; p = 0.0001) at 6 months. The association was consistent in propensity score matching analysis and sensitivity analysis by imputation. We did not detect significant differences in outcome between those who received surgery on the same day of hospital arrival compared to those who received surgery on the second or later days. In analysis limited to participants with supratentorial ICH and with a haematoma volume 30 mL or more, evacuation of the haematoma was associated with lower odds of poor functional outcome (n = 1234, odds ratio 0.68, 95% CI 0.46-0.99; p = 0.042) and mortality (n = 1291, OR 0.45, 95% CI 0.29-0.69; p = 0.0003). Interpretation: This secondary analysis of the INTERACT3 indicates that evacuation of the haematoma is associated with better chances of surviving free of severe disability after acute ICH. With the evolution of instrument and techniques, further trial should address the role of haematoma evacuation in deep ICH patients, the time window and difference between mini-invasive techniques. Funding: Joint Global Health Trials (JGHT) funding scheme from the Department of Health and Social Care, the Foreign, Commonwealth & Development Office, the Medical Research Council and Wellcome Trust; the West China Hospital Outstanding Discipline Development 1-3-5 programme; National Health and Medical Research Council of Australia; Sichuan Credit Pharmaceutical; and Takeda (China).