Stroke in Sierra Leone. the stroke risk factors for people with HIV: A prospective case-control study.

BACKGROUND: HIV infection rates are relatively low in Sierra Leone and in West Africa but the contribution of HIV to the risk factors for stroke and outcomes is unknown. In this study, we examined stroke types, presentation, risk factors and outcome in HIV stroke patients compared with controls. METHODS: We used data from the Stroke in Sierra Leone Study at 2 tertiary hospitals in Freetown, Sierra Leone. A case control design was used to compare stroke type, presentation, risk factors and outcome in sero-positive HIV patients with HIV negative stroke controls. Controls were matched for age and gender and a 1:4 ratio cases to controls was used to optimize power. Analysis was performed using the Pearson x2 for categorical variable, Paired-T test and Mann-Whitney U test for continuous variables. A p-value of less than 0.05 was taken as the level of statistical significance. RESULTS: Of 511 (51.8%) stroke patients tested for HIV, 36 (7.1%) were positive. Univariate unmatched analysis showed a stroke mean age of 49 years in HIV-positive versus 58 years in HIV-negative population (p = <0.001). In the case-control group, ischaemic stroke is the major type reported in both populations, HIV-negative population: 77 (53.5%) versus HIV-positive: 25 (69.4%) (p = 0.084). Hypertension is the most prevalent risk factor in both groups, HIV-positive: 23 (63.9%) versus HIV-negative: 409 (86.1%) (p = 0.001). Lower CD4+ count is associated in-hospital mortality (p = <0.001). CONCLUSION: These findings support the current call for timely management of stroke and HIV through integrated care.

Results of an international survey on the status of prehospital care.

BACKGROUND: Prehospital care including recognition of stroke symptoms by the public and professionals combined with an efficient and effective emergency medical service (EMS) is essential to increase access to effective acute stroke care. We undertook a survey to document the status of stroke prehospital care globally. METHODS: A survey was distributed via email to the World Stroke Organization (WSO) members. Information was sought on the current status of stroke prehospital delay globally, including (1) ambulance availability and whether payment for use is required, (2) ambulance response times and the proportion of patients arriving at hospital by ambulance, (3) the proportion of patients arriving within 3 h and more than 24 h after symptom, (4) whether stroke care training of paramedics, call handlers, and primary care staff, (5) availability of specialist centers, and (6) the proportion of patients taken to specialist centers. Respondents were also asked to identify the top three changes in prehospital care that would benefit their population. Data were analyzed descriptively at both country and continent level. RESULTS: Responses were received from 116 individuals in 43 countries, with a response rate of 4.7%. Most respondents (90%) reported access to ambulances, but 40% of respondents reported payment was required by the patient. Where an ambulance service was available (105 respondents) 37% of respondents reported that less than 50% of patients used an ambulance and 12% less than 20% of patients used an ambulance. Large variations in ambulance response times were reported both within and between countries. Most of the participating high-income countries (HIC) offered a service used by patients, but this was rarely the case for the low- and middle-income countries (LMIC). Time to admission was often much longer in LMIC, and there was less access to stroke training for EMS and primary care staff. CONCLUSIONS: Significant deficiencies in stroke prehospital care exist globally especially in LMIC. In all countries, there are opportunities to improve the quality of the service in ways that would likely result in improved outcomes after acute stroke.

Stroke in Sierra Leone: Case fatality rate and functional outcome after stroke in Freetown.

BACKGROUND: There is limited information on long-term outcomes after stroke in sub-Saharan Africa (SSA). Current estimates of case fatality rate (CFR) in SSA are based on small sample sizes with varying study design and report heterogeneous results. AIMS: We report CFR and functional outcomes from a large, prospective, longitudinal cohort of stroke patients in Sierra Leone and describe factors associated with mortality and functional outcome. METHODS: A prospective longitudinal stroke register was established at both adult tertiary government hospitals in Freetown, Sierra Leone. It recruited all patients ⩾ 18 years with stroke, using the World Health Organization definition, from May 2019 until October 2021. To reduce selection bias onto the register, all investigations were paid by the funder and outreach conducted to raise awareness of the study. Sociodemographic data, National Institute of Health Stroke Scale (NIHSS), and Barthel Index (BI) were collected on all patients on admission, at 7 days, 90 days, 1 year, and 2 years post stroke. Cox proportional hazards models were constructed to identify factors associated with all-cause mortality. A binomial logistic regression model reports odds ratio (OR) for functional independence at 1 year. RESULTS: A total of 986 patients with stroke were included, of which 857 (87%) received neuroimaging. Follow-up rate was 82% at 1 year, missing item data were <1% for most variables. Stroke cases were equally split by sex and mean age was 58.9 (SD: 14.0) years. About 625 (63%) were ischemic, 206 (21%) primary intracerebral hemorrhage, 25 (3%) subarachnoid hemorrhage, and 130 (13%) were of undetermined stroke type. Median NIHSS was 16 (9-24). CFR at 30 days, 90 days, 1 year, and 2 years was 37%, 44%, 49%, and 53%, respectively. Factors associated with increased fatality at any timepoint were male sex (hazard ratio (HR): 1.28 (1.05-1.56)), previous stroke (HR: 1.34 (1.04-1.71)), atrial fibrillation (HR: 1.58(1.06-2.34)), subarachnoid hemorrhage (HR: 2.31 (1.40-3.81)), undetermined stroke type (HR: 3.18 (2.44-4.14)), and in-hospital complications (HR: 1.65 (1.36-1.98)). About 93% of patients were completely independent prior to their stroke, declining to 19% at 1 year after stroke. Functional improvement was most likely to occur between 7 and 90 days post stroke with 35% patients improving, and 13% improving between 90 days to 1 year. Increasing age (OR: 0.97 (0.95-0.99)), previous stroke (OR: 0.50 (0.26-0.98)), NIHSS (OR: 0.89 (0.86-0.91)), undetermined stroke type (OR: 0.18 (0.05-0.62)), and ⩾1 in-hospital complication (OR: 0.52 (0.34-0.80)) were associated with lower OR of functional independence at 1 year. Hypertension (OR: 1.98 (1.14-3.44)) and being the primary breadwinner of the household (OR: 1.59 (1.01-2.49)) were associated with functional independence at 1 year. CONCLUSION: Stroke affected younger people and resulted in high rates of fatality and functional impairment relative to global averages. Key clinical priorities for reducing fatality include preventing stroke-related complications through evidence-based stroke care, improved detection and management of atrial fibrillation, and increasing coverage of secondary prevention. Further research into care pathways and interventions to encourage care seeking for less severe strokes should be prioritized, including reducing the cost barrier for stroke investigations and care.

Stroke Outcomes in Women: A Population-Based Cohort Study.

BACKGROUND: Limited data are available on sex-related disparities in long-term outcomes after stroke. We estimated sex differences in various stroke long-term outcomes among survivors after stroke in a prospective 25-year follow-up study. METHODS: Individuals recruited to the South London Stroke Register, an ongoing multi-ethnic urban-based population stroke register, from 1995 onward were included in the analyses (n=6687). The outcomes were death, subsequent stroke, activity of daily living, instrumental activity of daily living, cognitive impairment, depression, anxiety, and health-related quality of life. Kaplan-Meier curves were generated for mortality, stroke recurrence, and recurrence-free survival by sex and Cox proportional hazards model used to model sex differences up to 25 years. Generalized estimating equation were used to model sex differences in risk of self-reported stroke outcomes over 10 years poststroke outcomes, adjusting for age, preexisting activity of daily living, case-mix, stroke subtypes, and other potential confounding risk factors. RESULTS: There were 49% women (mean age, 72 years; SD, 15.6) and 51% men (mean age, 67 years; SD, 14.3) in 6687 participants. Compared with men, women had 9% (95% CI, 3%-15%) lower covariate-adjusted risk of death and 6% (0%-13%) lower risk of stroke recurrence or death. Generally, women had significantly poorer outcomes in activity of daily living and anxiety than men, and the sex differences persisted to up to 5 years after stroke. Women also had poorer health-related quality of life in physical (ß=-2.06 [95% CI, -3.01 to -1.10]) and mental domains (ß=-1.48 [95% CI, -2.44 to -0.52]). Although not significant, there was a suggestive trend for poorer outcomes in cognitive impairment and depression in women. No significant difference in stroke recurrence were found between men and women. CONCLUSIONS: Female patients with stroke tended to have better covariate-adjusted survival but poorer outcomes among survivors than male patients, with deficits persisting to up to 5 years poststroke.

Risk prediction of 30-day mortality after stroke using machine learning: a nationwide registry-based cohort study.

BACKGROUNDS: We aimed to develop and validate machine learning (ML) models for 30-day stroke mortality for mortality risk stratification and as benchmarking models for quality improvement in stroke care. METHODS: Data from the UK Sentinel Stroke National Audit Program between 2013 to 2019 were used. Models were developed using XGBoost, Logistic Regression (LR), LR with elastic net with/without interaction terms using 80% randomly selected admissions from 2013 to 2018, validated on the 20% remaining admissions, and temporally validated on 2019 admissions. The models were developed with 30 variables. A reference model was developed using LR and 4 variables. Performances of all models was evaluated in terms of discrimination, calibration, reclassification, Brier scores and Decision-curves. RESULTS: In total, 488,497 stroke patients with a 12.3% 30-day mortality rate were included in the analysis. In 2019 temporal validation set, XGBoost model obtained the lowest Brier score (0.069 (95% CI: 0.068-0.071)) and the highest area under the ROC curve (AUC) (0.895 (95% CI: 0.891-0.900)) which outperformed LR reference model by 0.04 AUC (p < 0.001) and LR with elastic net and interaction term model by 0.003 AUC (p < 0.001). All models were perfectly calibrated for low (< 5%) and moderate risk groups (5-15%) and ≈1% underestimation for high-risk groups (> 15%). The XGBoost model reclassified 1648 (8.1%) low-risk cases by the LR reference model as being moderate or high-risk and gained the most net benefit in decision curve analysis. CONCLUSIONS: All models with 30 variables are potentially useful as benchmarking models in stroke-care quality improvement with ML slightly outperforming others.

National implementation of reperfusion for acute ischaemic stroke in England: How should services be configured? A modelling study.

Objectives: To guide policy when planning thrombolysis (IVT) and thrombectomy (MT) services for acute stroke in England, focussing on the choice between 'mothership' (direct conveyance to an MT centre) and 'drip-and-ship' (secondary transfer) provision and the impact of bypassing local acute stroke centres. Design: Outcome-based modelling study. Setting: 107 acute stroke centres in England, 24 of which provide IVT and MT (IVT/MT centres) and 83 provide only IVT (IVT-only units). Participants: 242,874 emergency admissions with acute stroke over 3 years (2015-2017). Intervention: Reperfusion delivered by drip-and-ship, mothership or 'hybrid' models; impact of additional travel time to directly access an IVT/MT centre by bypassing a more local IVT-only unit; effect of pre-hospital selection for large artery occlusion (LAO). Main outcome measures: Population benefit from reperfusion, time to IVT and MT, admission numbers to IVT-only units and IVT/MT centres. Results: Without pre-hospital selection for LAO, 94% of the population of England live in areas where the greatest clinical benefit, assuming unknown patient status, accrues from direct conveyance to an IVT/MT centre. However, this policy produces unsustainable admission numbers at these centres, with 78 out of 83 IVT-only units receiving fewer than 300 admissions per year (compared to 3 with drip-and-ship). Implementing a maximum permitted additional travel time to bypass an IVT-only unit, using a pre-hospital test for LAO, and selecting patients based on stroke onset time, all help to mitigate the destabilising effect but there is still some significant disruption to admission numbers, and improved selection of patients suitable for MT selectively reduces the number of patients who would receive IVT at IVT-only centres, challenging the sustainability of IVT expertise in IVT-only centres. Conclusions: Implementation of reperfusion for acute stroke based solely on achieving the maximum population benefit potentially leads to destabilisation of the emergency stroke care system. Careful planning is required to create a sustainable system, and modelling may be used to help planners maximise benefit from reperfusion while creating a sustainable emergency stroke care system.

A Prospective Stroke Register in Sierra Leone: Demographics, Stroke Type, Stroke Care and Hospital Outcomes.

Introduction: Stroke is the second most common cause of adult death in Africa. This study reports the demographics, stroke types, stroke care and hospital outcomes for stroke in Freetown, Sierra Leone. Methods: A prospective observational register recorded all patients 18 years and over with stroke between May 2019 and April 2020. Stroke was defined according to the WHO criteria. Pearson's chi-squared test was used to examine associations between categorical variables and unpaired t-tests for continuous variables. Multivariable logistic regression, to explain in-hospital death, was reported as odds ratios (ORs) and 95% confidence intervals. Results: Three hundred eighty-five strokes were registered, and 315 (81.8%) were first-in-a-lifetime events. Mean age was 59.2 (SD 13.8), and 187 (48.6%) were male. Of the strokes, 327 (84.9%) were confirmed by CT scan. Two hundred thirty-one (60.0%) were ischaemic, 85 (22.1%) intracerebral haemorrhage, 11 (2.9%) subarachnoid haemorrhage and 58 (15.1%) undetermined stroke type. The median National Institutes of Health Stroke Scale on presentation was 17 [interquartile range (IQR) 9-25]. Haemorrhagic strokes compared with ischaemic strokes were more severe, 20 (IQR 12-26) vs. 13 (IQR 7-22) (p < 0.001), and occurred in a younger population, mean age 52.3 (SD 12.0) vs. 61.6 (SD 13.8) (p < 0.001), with a lower level of educational attainment of 28.2 vs. 40.7% (p = 0.04). The median time from stroke onset to arrival at the principal referral hospital was 25 hours (IQR 6-73). Half of the patients (50.4%) sought care at another health provider prior to arrival. One hundred fifty-one patients died in the hospital (39.5%). Forty-three deaths occurred within 48 hours of arriving at the hospital, with median time to death of 4 days (IQR 0-7 days). Of the patients, 49.6% had ≥1 complication, 98 (25.5%) pneumonia and 33 (8.6%) urinary tract infection. Male gender (OR 3.33, 1.65-6.75), pneumonia (OR 3.75, 1.82-7.76), subarachnoid haemorrhage (OR 43.1, 6.70-277.4) and undetermined stroke types (OR 6.35, 2.17-18.60) were associated with higher risk of in-hospital death. Discussion: We observed severe strokes occurring in a young population with high in-hospital mortality. Further work to deliver evidence-based stroke care is essential to reduce stroke mortality in Sierra Leone.

Stroke Care in the United Kingdom During the COVID-19 Pandemic.

BACKGROUND AND PURPOSE: The coronavirus disease 2019 (COVID-19) pandemic has potentially caused indirect harm to patients with other conditions via reduced access to health care services. We aimed to describe the impact of the initial wave of the pandemic on admissions, care quality, and outcomes in patients with acute stroke in the United Kingdom. METHODS: Registry-based cohort study of patients with acute stroke admitted to hospital in England, Wales, and Northern Ireland between October 1, 2019, and April 30, 2020, and equivalent periods in the 3 prior years. RESULTS: One hundred fourteen hospitals provided data for a study cohort of 184 017 patients. During the lockdown period (March 23 to April 30), there was a 12% reduction (6923 versus 7902) in the number of admissions compared with the same period in the 3 previous years. Admissions fell more for ischemic than hemorrhagic stroke, for older patients, and for patients with less severe strokes. Quality of care was preserved for all measures and in some domains improved during lockdown (direct access to stroke unit care, 1-hour brain imaging, and swallow screening). Although there was no change in the proportion of patients discharged with good outcome (modified Rankin Scale score, ≤2; 48% versus 48%), 7-day inpatient case fatality increased from 6.9% to 9.4% (P<0.001) and was 22.0% in patients with confirmed or suspected COVID-19 (adjusted rate ratio, 1.41 [1.11-1.80]). CONCLUSIONS: Assuming that the true incidence of acute stroke did not change markedly during the pandemic, hospital avoidance may have created a cohort of untreated stroke patients at risk of poorer outcomes or recurrent events. Unanticipated improvements in stroke care quality should be used as an opportunity for quality improvement and to learn about how to develop resilient health care systems.

Effect of stroke early supported discharge on length of hospital stay: analysis from a national stroke registry.

OBJECTIVE: The first observational study to investigate the impact of early supported discharge (ESD) on length of hospital stay in real-world conditions. DESIGN: Using historical prospective Sentinel Stroke National Audit Programme (SSNAP) data (1 January 2013-31 December 2016) and multilevel modelling, cross-sectional (2015-2016; 30 791 patients nested within 55 hospitals) and repeated cross-sectional (2013-2014 vs 2015-2016; 49 266 patients nested within 41 hospitals) analyses were undertaken. SETTING: Hospitals were sampled across a large geographical area of England covering the West and East Midlands, the East of England and the North of England. PARTICIPANTS: Stroke patients whose data were entered into the SSNAP database by hospital teams. INTERVENTIONS: Receiving ESD along the patient care pathway. PRIMARY AND SECONDARY OUTCOME MEASURES: Length of hospital stay. RESULTS: When adjusted for important case-mix variables, patients who received ESD on their stroke care pathway spent longer in hospital, compared with those who did not receive ESD. The percentage increase was 15.8% (95% CI 12.3% to 19.4%) for the 2015-2016 cross-sectional analysis and 18.8% (95% CI 13.9% to 24.0%) for the 2013-2014 versus 2015-2016 repeated cross-sectional analysis. On average, the increased length of hospital stay was approximately 1 day. CONCLUSIONS: This study has shown that by comparing ESD and non-ESD patient groups matched for important patient characteristics, receiving ESD resulted in a 1-day increase in length of hospital stay. The large reduction in length of hospital stay overall, since original trials were conducted, may explain why a reduction was not observed. The longer term benefits of accessing ESD need to be investigated further. TRIAL REGISTRATION NUMBER: http://www.isrctn.com/ISRCTN15568163.

Trends in prevalence of acute stroke impairments: A population-based cohort study using the South London Stroke Register.

BACKGROUND: Acute stroke impairments often result in poor long-term outcome for stroke survivors. The aim of this study was to estimate the trends over time in the prevalence of these acute stroke impairments. METHODS AND FINDINGS: All first-ever stroke patients recorded in the South London Stroke Register (SLSR) between 2001 and 2018 were included in this cohort study. Multivariable Poisson regression models with robust error variance were used to estimate the adjusted prevalence of 8 acute impairments, across six 3-year time cohorts. Prevalence ratios comparing impairments over time were also calculated, stratified by age, sex, ethnicity, and aetiological classification (Trial of Org 10172 in Acute Stroke Treatment [TOAST]). A total of 4,683 patients had a stroke between 2001 and 2018. Mean age was 68.9 years, 48% were female, and 64% were White. After adjustment for demographic factors, pre-stroke risk factors, and stroke subtype, the prevalence of 3 out of the 8 acute impairments declined during the 18-year period, including limb motor deficit (from 77% [95% CI 74%-81%] to 62% [56%-68%], p < 0.001), dysphagia (37% [33%-41%] to 15% [12%-20%], p < 0.001), and urinary incontinence (43% [39%-47%) to 29% [24%-35%], p < 0.001). Declines in limb impairment over time were 2 times greater in men than women (prevalence ratio 0.73 [95% CI 0.64-0.84] and 0.87 [95% CI 0.77-0.98], respectively). Declines also tended to be greater in younger patients. Stratified by TOAST classification, the prevalence of all impairments was high for large artery atherosclerosis (LAA), cardioembolism (CE), and stroke of undetermined aetiology. Conversely, small vessel occlusions (SVOs) had low levels of all impairments except for limb motor impairment and dysarthria. While we have assessed 8 key acute stroke impairments, this study is limited by a focus on physical impairments, although cognitive impairments are equally important to understand. In addition, this is an inner-city cohort, which has unique characteristics compared to other populations. CONCLUSIONS: In this study, we found that stroke patients in the SLSR had a complexity of acute impairments, of which limb motor deficit, dysphagia, and incontinence have declined between 2001 and 2018. These reductions have not been uniform across all patient groups, with women and the older population, in particular, seeing fewer reductions.

Effectiveness of Stroke Early Supported Discharge: Analysis From a National Stroke Registry.

BACKGROUND: Implementation of stroke early supported discharge (ESD) services has been recommended in many countries' clinical guidelines, based on clinical trial evidence. This is the first observational study to investigate the effectiveness of ESD service models operating in real-world conditions, at scale. METHODS AND RESULTS: Using historical prospective data from the United Kingdom Sentinel Stroke National Audit Programme (January 1, 2016-December 31, 2016), measures of ESD effectiveness were "days to ESD" (number of days from hospital discharge to first ESD contact; n=6222), "rehabilitation intensity" (total number of treatment days/total days with ESD; n=5891), and stroke survivor outcome (modified Rankin scale at ESD discharge; n=6222). ESD service models (derived from Sentinel Stroke National Audit Programme postacute organizational audit data) were categorized with a 17-item score, reflecting adoption of ESD consensus core components (evidence-based criteria). Multilevel modeling analysis was undertaken as patients were clustered within ESD teams across the Midlands, East, and North of England (n=31). A variety of ESD service models had been adopted, as reflected by variability in the ESD consensus score. Controlling for patient characteristics and Sentinel Stroke National Audit Programme hospital score, a 1-unit increase in ESD consensus score was significantly associated with a more responsive ESD service (reduced odds of patient being seen after ≥1 day of 29% [95% CI, 1%-49%] and increased treatment intensity by 2% [95% CI, 0.3%-4%]). There was no association with stroke survivor outcome measured by the modified Rankin Scale. CONCLUSIONS: This study has shown that adopting defined core components of ESD is associated with providing a more responsive and intensive ESD service. This shows that adherence to evidence-based criteria is likely to result in a more effective ESD service as defined by process measures. Registration: URL: http://www.isrctn.com/; Unique identifier: ISRCTN15568163.

A systematic review of machine learning models for predicting outcomes of stroke with structured data.

BACKGROUND AND PURPOSE: Machine learning (ML) has attracted much attention with the hope that it could make use of large, routinely collected datasets and deliver accurate personalised prognosis. The aim of this systematic review is to identify and critically appraise the reporting and developing of ML models for predicting outcomes after stroke. METHODS: We searched PubMed and Web of Science from 1990 to March 2019, using previously published search filters for stroke, ML, and prediction models. We focused on structured clinical data, excluding image and text analysis. This review was registered with PROSPERO (CRD42019127154). RESULTS: Eighteen studies were eligible for inclusion. Most studies reported less than half of the terms in the reporting quality checklist. The most frequently predicted stroke outcomes were mortality (7 studies) and functional outcome (5 studies). The most commonly used ML methods were random forests (9 studies), support vector machines (8 studies), decision trees (6 studies), and neural networks (6 studies). The median sample size was 475 (range 70-3184), with a median of 22 predictors (range 4-152) considered. All studies evaluated discrimination with thirteen using area under the ROC curve whilst calibration was assessed in three. Two studies performed external validation. None described the final model sufficiently well to reproduce it. CONCLUSIONS: The use of ML for predicting stroke outcomes is increasing. However, few met basic reporting standards for clinical prediction tools and none made their models available in a way which could be used or evaluated. Major improvements in ML study conduct and reporting are needed before it can meaningfully be considered for practice.

Re-engineering the Cypriot healthcare service system.

BACKGROUND: The Cypriot healthcare system has undergone a number of major transformations since the induction of the Republic of Cyprus in the European Union over 10 years ago. Currently Cyprus is undergoing a major reform, namely the introduction of a primary care driven national healthcare system. The aim of the study was to assess the existing state of training, support, quality, guidelines and infrastructure towards a better healthcare system in Cyprus. METHODS: This is a mixed-methods study combining statistical data until October 2016 and workshop discussions delivered in Cyprus in November 2015. We used anonymised data provided: (1a) by the Cyprus Medical Association of all registered medical doctors up to October 2016; (1b); by the Ministry of Health (MoH) Health Monitoring Unit up to October 2016; (2) during a workshop organised with representatives from the Royal College of Physicians, the European Commission and the Health Insurance Organization. RESULTS: The gender ratio of men over women is disproportionate, with over 85% of the medical doctors undertaking their training in Greece, Eastern Europe and neighbouring countries, while the current record does not hold a relevant specialty information for 4 out of 10 doctors. The results show lack of statutory inspection systems, application of revalidation principles or implementation of peer-review clinical services on the island. There are eight proposed recommendations made by the workshop participants towards the transformation of the Cypriot healthcare system and the development of the Cyprus Quality Improvement Institute. These are aimed at addressing gaps in quality of care, adherence to clinical guidelines and implementation of audits, development of doctors' revalidation and peer-review of clinical services, accreditation of service implementation, establishment of a statutory inspection system as well as the set-up of an incentives program as part of the general healthcare system (GHS) of Cyprus. CONCLUSIONS: Current efforts for the implementation of the new GHS in Cyprus call for adequate training and support of the medical workforce, transparent and safer quality of care provision through the implementation of clinical guidelines and capacity-building infrastructure.