Summary
Background
80% of individuals with cancer will require a surgical procedure, yet little comparative data exist on early outcomes in low-income and middle-income countries (LMICs). We compared postoperative outcomes in breast, colorectal, and gastric cancer surgery in hospitals worldwide, focusing on the effect of disease stage and complications on postoperative mortality.
Methods
This was a multicentre, international prospective cohort study of consecutive adult patients undergoing surgery for primary breast, colorectal, or gastric cancer requiring a skin incision done under general or neuraxial anaesthesia. The primary outcome was death or major complication within 30 days of surgery. Multilevel logistic regression determined relationships within three-level nested models of patients within hospitals and countries. Hospital-level infrastructure effects were explored with three-way mediation analyses. This study was registered with ClinicalTrials.gov, NCT03471494.
Findings
Between April 1, 2018, and Jan 31, 2019, we enrolled 15 958 patients from 428 hospitals in 82 countries (high income 9106 patients, 31 countries; upper-middle income 2721 patients, 23 countries; or lower-middle income 4131 patients, 28 countries). Patients in LMICs presented with more advanced disease compared with patients in high-income countries. 30-day mortality was higher for gastric cancer in low-income or lower-middle-income countries (adjusted odds ratio 3·72, 95% CI 1·70–8·16) and for colorectal cancer in low-income or lower-middle-income countries (4·59, 2·39–8·80) and upper-middle-income countries (2·06, 1·11–3·83). No difference in 30-day mortality was seen in breast cancer. The proportion of patients who died after a major complication was greatest in low-income or lower-middle-income countries (6·15, 3·26–11·59) and upper-middle-income countries (3·89, 2·08–7·29). Postoperative death after complications was partly explained by patient factors (60%) and partly by hospital or country (40%). The absence of consistently available postoperative care facilities was associated with seven to 10 more deaths per 100 major complications in LMICs. Cancer stage alone explained little of the early variation in mortality or postoperative complications.
Interpretation
Higher levels of mortality after cancer surgery in LMICs was not fully explained by later presentation of disease. The capacity to rescue patients from surgical complications is a tangible opportunity for meaningful intervention. Early death after cancer surgery might be reduced by policies focusing on strengthening perioperative care systems to detect and intervene in common complications.
Funding
National Institute for Health Research Global Health Research Unit.
Introduction
Cancer prevalence and its associated mortality is increasing in low-income and middle-income countries (LMICs).1 Of the 15·2 million individuals diagnosed with cancer worldwide in 2015, 80% needed surgery.2 Despite this need, fewer than 25% of people worldwide have robust access to effective surgical care.3 In tumours amenable to resection, surgery offers the best chance of cure, particularly in early-stage disease; thus, expanding the availability of surgery is likely to yield large improvements in cancer survival in LMICs.4
Research in context.
Evidence before this study
We searched for evidence of multinational research assessing early outcomes after surgery for three globally common cancers (breast, colorectal, and gastric cancer) focusing on low-income and middle-income countries (LMICs). We searched PubMed, MEDLINE, Google Scholar, and ClinicalTrials.gov for articles published between Jan 1, 1990, and Aug 1, 2020, using the terms “cancer” OR “malignancy” AND “surgery” AND “developing countries” OR “low income” OR “middle-income” OR “low and middle-income”, without language restrictions. Identified studies largely focused on single tumour types and did not compare outcomes across different income settings. No studies systematically collected comparative data examining outcomes after cancer surgery in different income settings.
Added value of this study
To our knowledge, our study is the first to provide comprehensive data across income settings on early outcomes in patients undergoing surgery for three common cancers. We used standardised, validated, and prospective methods to gather global, contemporaneous, and comprehensive data. Even after case-mix adjustment, patients in LMICs had higher postoperative mortality, despite similar complication rates. The capacity to rescue patients from death after the development of common postoperative complications explains a significant part of the disproportionate mortality burden in LMICs.
Implications of all the available evidence
Perioperative mortality is disproportionately greater in LMICs, which contributes to significantly worse cancer survival. Urgent assessment of pragmatic perioperative interventions led by investigators in LMICs is needed to avert avoidable mortality after the development of common complications after surgery.
Direct estimates of the incidence and distribution of cancer by stage are absent for many LMICs, and little is known about variation in access, quality, and outcomes in global cancer care. Breast, colorectal, and gastric cancer represent a significant burden of disease across income settings and, as such, are clear targets for intervention.1, 2 Breast cancer is the most common cancer worldwide, and a leading cause of cancer-related morbidity and mortality in LMICs. Addressing inequities in breast cancer treatment will be essential in meeting gender equality Sustainable Development Goals, as well as health and wellbeing objectives. Colorectal cancer incidence is rising in LMICs and represents the second most common cause of cancer-related death globally. Gastric cancer is the third most common cause of cancer-related death in LMICs. These facts were reflected in a recent LMIC-led research prioritisation exercise, where cancer surgery was identified as a major priority.5
Irrespective of the development status of a country, surgery remains the cornerstone of cancer cure and palliation. Solid tumours are often untreated in LMICs and this carries significant macroeconomic consequences; cumulative gross domestic product losses are estimated to be as high as 1·2% for 2016–30.6 Cancer resection procedures are often highly invasive, leading to postoperative morbidity and mortality. In previous work, we identified significant global disparities in surgical outcomes, with patients in LMICs two to three times more likely to sustain a major complication or to die after surgery.7, 8 These consequences are devasting for patients and their families and, in the context of cancer treatment, complications can lead to long-term morbidity or death, increased treatment costs, and delays in adjuvant treatment. Rescuing patients who sustain a major complication from dying has become an important focus of quality improvement in surgery.9 Not only must complications be minimised, but the timely recognition and management of complications is essential if avoidable mortality is to be minimised. Little is known about factors contributing to early death and complications after cancer surgery in LMICs.
This insufficiency of high-quality data limits global efforts to improve cancer care. Strategic planning mandates detailed and accurate information, so that appropriate resources can be allocated and quality improvement prioritised. Demographic and clinical data, together with details of hospital resources, are needed to help refine public health initiatives, treatment strategies, and quality improvement interventions. To address these issues, we did an international, multicentre, prospective cohort study that aimed to determine the variation in mortality and complication rates for breast, colorectal, and gastric cancers in low-income, middle-income, and high-income countries.
Methods
Study design and setting
This international, multicentre, prospective cohort study was done according to a published protocol.10 The study was designed in a collaborative research prioritisation workshop.5 Breast, colorectal, and gastric cancers were prioritised on the basis of global prevalence and mortality, and relevance to the majority of our collaborators, who are predominantly general surgeons and manage these cancers regularly. To maximise case ascertainment, ensure data quality, and enable engagement across a global network, a pragmatic decision was taken not to collect data on additional cancer types. All Global Surgery study documents, training materials, and language translations are available online. Teams of local investigators undertook the study and were coordinated by a network of national lead investigators. The collaborative network method has been described in detail previously.7, 8 Any health-care facility providing emergency or elective surgery for breast, colorectal, or gastric colorectal cancer worldwide was eligible to participate.
A UK National Health Service (NHS) Research Ethics proportionate review considered this study exempt from formal research registration (South East Scotland Research Ethics Service, reference NR/161AB6) because it was deemed a clinical audit. Individual centres obtained their own audit or institutional approval, together with ethical approval as per local regulations.
Participants
Investigators included consecutive patients undergoing surgery for breast, colorectal, or gastric cancer, from one or more 28-day period between April 1, 2018, and Jan 31, 2019, with validation performed until April 23, 2019. Inclusion criteria were adult patients aged 18 years or older; undergoing their first surgical procedure for the treatment of one of the three cancers; and requiring a skin incision performed under general or neuraxial (eg, regional, epidural or spinal) anaesthesia. All patients fulfilling the inclusion criteria within the defined period were enrolled. A 28-day period was chosen to balance sample size requirements and pragmatism for the working clinicians who were enrolling patients and contributing data.
The inclusion of primary breast, colorectal, and gastric cancer was based on global prevalence, potential for cure with surgical treatment, and relevance to general surgeons working in resource-constrained settings. There was an absolute requirement for all cases in the chosen period to be included, but no minimum number was set to avoid bias against smaller centres. Patients provided consent to participate if required by local research regulations and could withdraw at any time during the study period. Due to potential limitations in preoperative diagnosis in some settings, all patients receiving surgical treatment for suspected cancer were enrolled. Patients subsequently found to have a non-oncological diagnosis were excluded from data analysis. Emergency procedures were defined as unplanned, non-elective operations. Open and minimally invasive procedures (eg, laparoscopic or robotic) were eligible. Patients were excluded if the primary pathology was not suspected to be breast, colorectal, or gastric cancer; if the pathology was a suspected cancer recurrence; or if they were undergoing a procedure that did not require a skin incision.
Data collection and validation
Data variables were selected to be objective, standardised, easily transcribed, and internationally relevant to maximise completeness and accuracy. Local investigators uploaded records to a secure website, provided using the Research Electronic Data Capture system.11 The lead investigator at each site checked the accuracy of all cases before data submission. To ensure data quality, real-time assessment was done on entry into the database and disparities highlighted to the local collaborator for immediate review. The submitted data were then checked centrally and when missing data were identified, the local lead investigator was contacted and asked to complete the record. Online data visualisation tools aided this process. Once vetted, the record was accepted into the dataset for analysis. Records that were vetted but remained incomplete were included in the patient flow chart, but excluded from analysis.
Patient variables included age, sex, performance status according to the Eastern Cooperative Oncology Group, physical status according to the American Society of Anesthesiologists (ASA) grading system, and smoking status. Disease-related variables included cancer type, disease stage, timing of surgery (elective vs emergency), intent of surgery (curative vs palliative), and use of WHO surgical checklist. Presence of preoperative perforation or obstruction, and operative approach (open or minimally invasive) were also included for gastric and colorectal cancers.
Disease stage was defined according to the Essential TNM classification of malignant tumours system,12 to account for differences in local protocols and availability of investigations for preoperative staging. A pragmatic view was taken to the confirmation of cancer diagnosis, because postoperative pathological examination worldwide is dependent on the availability of patient and health-care resources. To reflect this situation, we recorded the basis of cancer diagnosis using a hierarchical scale ranging from clinical diagnosis only to pathological confirmation (appendix p 7).
Data validation was done in three parts across a representative sample of centres, according to a prespecified protocol (appendix pp 47–51). First, centres self-reported the key processes used to identify and follow up patients (appendix p 7). Second, independent validators (ie, doctors, nurses, or medical students who were not part of the recruiting teams) quantitatively reported case ascertainment and sampled data accuracy. Third, validators identified any missing eligible patient within the local cohort and collected the missing information for each omission (age, sex, operation urgency, and 30-day mortality). These data were used to determine whether patient data were missing at random.
Outcomes
The primary outcome measures were 30-day mortality and 30-day major complication, as defined by Clavien-Dindo grade III, IV, or V.13 Death was included in the definition of major complication and therefore was not a competing risk. Capacity to rescue was defined as the absolute risk difference of death in patients sustaining a complication of surgery. Mortality conditional on major complication was analysed post hoc.
The secondary outcome measures were defined in the protocol10 and designed to describe cancer care quality. They included: 30-day any complication (defined by Clavien-Dindo grade I–V); 30-day unplanned reintervention (defined as operative, radiological, or endoscopic reintervention any time until 30 days after surgery); unplanned readmission to a health-care facility; cancer-specific complications including seroma (breast), anastomotic leak (gastric and colorectal), surgical site infection (all),8 abscess formation (all), and postoperative bleed (all); cancer treatment pathways; and hospital-level care processes. Patients were assessed at 30 days to determine postoperative outcomes, with follow-up done in person, by telephone, or by review of medical or re-admission records, dependent on local practices.
Sample size
As described in the protocol,10 consideration was given to the sample size needed to compare income groups. Estimates of 30-day mortality for gastrointestinal cancer surgery were determined using data from the GlobalSurg 1 and 2 studies.7, 8 Stratification of results by country income group show differences between high-income countries and LMICs in both emergency surgery (75 [11·6%] of 644 vs 59 [27·3%] of 216, respectively) and elective surgery (30 [2·0%] of 1501 vs 23 [5·5%] of 416, respectively). An indicative sample size calculation using the smaller of these estimates suggests around 500 patients per group at 80% power (2·0% vs 5·5%, α=0·05) or 640 patients per group at 90% power would be required to conclude a difference in 30-day mortality rate between income groups.
Statistical analysis
Variation across different international health settings was assessed by stratifying countries by World Bank country group classifications. Differences between World Bank tertiles were tested with the Pearson χ2 test for categorical variables and with the Kruskal-Wallis test for continuous variables. Multilevel logistic regression models were constructed to account for case mix (differing patient, disease, and operative characteristics), with population stratification by hospital and country of residence incorporated as random intercepts with constrained gradients. Further post hoc analyses were then performed exploring the relationship between primary outcome measures, patient factors, and hospital care facilities.
Models were constructed using the following principles: variables associated with outcome measures in previous studies were accounted for; demographic variables were included in model exploration; population stratification by hospital and country of residence was incorporated as random effects; all first-order interactions were checked and included in final models if found to be influential (reaching statistical significance or resulting in a 10% or greater change in the odds ratio (OR) of the explanatory variable of interest); final model selection was done using a criterion-based approach by minimising the Akaike information criterion and discrimination determined using the C-statistic (area under the receiver operator curve). Effect estimates are presented as ORs and 95% CIs. The variance explained at each level of multilevel models was determined.14 The conditional pseudo R2 was defined as the sum of the variance components of fixed and all random effects divided by total variance. The variance explained by each component (marginal pseudo R2) was expressed as a proportion of the conditional pseudo R2.
Mediation analysis was performed by three-way decomposition of total effects into direct, indirect, and interactive effects.15 The mediators examined were at the level of the hospital, defined as the presence or absence of postoperative care infrastructure, and it was assumed that there was no causal relationship between these and patient-level covariates. Similarly, no mediator-outcome confounders were specified. Uncertainty was determined using bootstrap resampling (5000 draws) and CIs constructed using percentiles.
Quantities of interest were calculated from logistic regression models for different covariate levels (patient and disease characteristics). Absolute risk differences were calculated, and CIs determined using bootstrap resampling. The number needed to treat to benefit was defined as the reciprocal of the absolute risk difference.
All analyses were done using R (version 3.6.3), using the finalfit, tidyverse, and lme4.
This trial was prospectively registered with ClinicalTrials.gov, NCT03471494.
Role of the funding source
National Institute for Health Research (NIHR) Global Health Research Unit Grant (NIHR 17–0799) funded hub development in a subset of contributing countries. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the UK Department of Health and Social Care. The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the Article. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.
Results
Between April 1, 2018, and Jan 31, 2019, 16 838 patient records were submitted for analysis. 880 (5·2%) did not fulfil the inclusion criteria, leaving 15 958 records for the final analysis (figure 1). These patients were from 428 hospitals, across 82 countries—22 in Africa, 17 in Asia, 30 in Europe, five in North America, two in Oceania, and six in South America.
Figure 1.
Patient flow chart
On stratification by World Bank country income groups, 9106 (57·1%) patients were from high-income countries, 2721 (17·0%) from upper-middle-income countries, and 4131 (25·9%) from low-income or lower-middle-income countries (table; appendix p 2). Patients from upper-middle-income countries and low-income or lower-middle-income countries were younger, more likely to have lost weight, and had fewer comorbidities compared with patients from high-income countries. Missingness was low and no patterns were seen when comparing included and missing data (appendix pp 2–3).
Table.
Patient characteristics by country income group
| High (n=9106) | Upper-middle (n=2721) | Low and lower-middle (n=4131) | Total (N=15 958) | ||
|---|---|---|---|---|---|
| Cancer type | |||||
| Breast | 4220 (46·3%) | 1319 (48·5%) | 2867 (69·4%) | 8406 (52·7%) | |
| Colorectal (colon or rectum) | 4174 (45·8%) | 1113 (40·9%) | 928 (22·5%) | 6215 (38·9%) | |
| Gastric | 712 (7·8%) | 289 (10·6%) | 336 (8·1%) | 1337 (8·4%) | |
| Age, years | 65·0 (13·4) | 58·0 (13·6) | 51·9 (12·7) | 60·4 (14·4) | |
| Sex | |||||
| Male | 2864 (31·5%) | 791 (29·1%) | 723 (17·5%) | 4378 (27·4%) | |
| Female | 6231 (68·4%) | 1928 (70·9%) | 3406 (82·4%) | 11565 (72·5%) | |
| Missing | 11 (0·1%) | 2 (0·1%) | 2 (0%) | 15 (0·1%) | |
| ASA grade | |||||
| I | 1148 (12·6%) | 739 (27·2%) | 1285 (31·1%) | 3172 (19·9%) | |
| II | 4769 (52·4%) | 1474 (54·2%) | 2242 (54·3%) | 8485 (53·2%) | |
| III | 2558 (28·1%) | 391 (14·4%) | 412 (10·0%) | 3361 (21·1%) | |
| IV | 217 (2·4%) | 42 (1·5%) | 36 (0·9%) | 295 (1·8%) | |
| V | 17 (0·2%) | 1 (0%) | 10 (0·2%) | 28 (0·2%) | |
| Missing | 397 (4·4%) | 74 (2·7%) | 146 (3·5%) | 617 (3·9%) | |
| Body-mass index | |||||
| <18·5 | 231 (2·5%) | 111 (4·1%) | 234 (5·7%) | 576 (3·6%) | |
| 18·5–24·9 | 3267 (35·9%) | 1148 (42·2%) | 1511 (36·6%) | 5926 (37·1%) | |
| 25–30 | 3079 (33·8%) | 882 (32·4%) | 1354 (32·8%) | 5315 (33·3%) | |
| >30 | 1773 (19·5%) | 470 (17·3%) | 867 (21·0%) | 3110 (19·5%) | |
| Missing | 756 (8·3%) | 110 (4·0%) | 165 (4·0%) | 1031 (6·5%) | |
| >10% weight loss | |||||
| No | 6560 (72·0%) | 1813 (66·6%) | 2896 (70·1%) | 11269 (70·6%) | |
| Yes | 1049 (11·5%) | 673 (24·7%) | 917 (22·2%) | 2639 (16·5%) | |
| Missing | 1497 (16·4%) | 235 (8·6%) | 318 (7·7%) | 2050 (12·8%) | |
| ECOG performance status | |||||
| 0 | 5090 (55·9%) | 1732 (63·7%) | 2136 (51·7%) | 8958 (56·1%) | |
| 1 | 2152 (23·6%) | 639 (23·5%) | 1085 (26·3%) | 3876 (24·3%) | |
| 2 | 961 (10·6%) | 201 (7·4%) | 570 (13·8%) | 1732 (10·9%) | |
| 3 | 299 (3·3%) | 94 (3·5%) | 176 (4·3%) | 569 (3·6%) | |
| 4 | 32 (0·4%) | 9 (0·3%) | 31 (0·8%) | 72 (0·5%) | |
| Missing | 572 (6·3%) | 46 (1·7%) | 133 (3·2%) | 751 (4·7%) | |
| Smoking | |||||
| No, never | 5363 (58·9%) | 1902 (69·9%) | 3631 (87·9%) | 10896 (68·3%) | |
| Stopped >6 weeks ago | 1650 (18·1%) | 322 (11·8%) | 181 (4·4%) | 2153 (13·5%) | |
| Yes, current smoker | 1174 (12·9%) | 347 (12·8%) | 170 (4·1%) | 1691 (10·6%) | |
| Missing | 919 (10·1%) | 150 (5·5%) | 149 (3·6%) | 1218 (7·6%) | |
| Diabetes | |||||
| No | 7594 (83·4%) | 2179 (80·1%) | 3100 (75·0%) | 12873 (80·7%) | |
| Diet controlled | 209 (2·3%) | 42 (1·5%) | 45 (1·1%) | 296 (1·9%) | |
| Medication controlled, non-insulin | 895 (9·8%) | 324 (11·9%) | 422 (10·2%) | 1641 (10·3%) | |
| Insulin dependent | 279 (3·1%) | 120 (4·4%) | 191 (4·6%) | 590 (3·7%) | |
| Missing | 129 (1·4%) | 56 (2·1%) | 373 (9·0%) | 558 (3·5%) | |
| HIV tested | |||||
| No | 8650 (95·0%) | 1626 (59·8%) | 2118 (51·3%) | 12394 (77·7%) | |
| Yes, negative | 404 (4·4%) | 1067 (39·2%) | 2001 (48·4%) | 3472 (21·8%) | |
| Yes, positive | 9 (0·1%) | 26 (1·0%) | 12 (0·3%) | 47 (0·3%) | |
| Missing | 43 (0·5%) | 2 (0·1%) | 0 | 45 (0·3%) | |
| Distance from hospital to home, km | |||||
| <10 | 3497 (38·4%) | 677 (24·9%) | 575 (13·9%) | 4749 (29·8%) | |
| 10 to 19·9 | 1798 (19·7%) | 617 (22·7%) | 673 (16·3%) | 3088 (19·4%) | |
| 20 to 49·9 | 1756 (19·3%) | 479 (17·6%) | 768 (18·6%) | 3003 (18·8%) | |
| 50 to 100 | 738 (8·1%) | 195 (7·2%) | 514 (12·4%) | 1447 (9·1%) | |
| >100 | 576 (6·3%) | 439 (16·1%) | 1409 (34·1%) | 2424 (15·2%) | |
| Missing | 741 (8·1%) | 314 (11·5%) | 192 (4·6%) | 1247 (7·8%) | |
Numbers are n (%) or mean (SD). High income included 31 countries and 241 hospitals. Upper-middle income included 23 countries and 81 hospitals. Lower-middle income or low income included 28 countries and 106 hospitals. The total column therefore includes 82 countries and 428 hospitals. For patient characteristics by cancer type, see appendix p 2. ASA=American Society of Anesthesiologists. ECOG=Eastern Cooperative Oncology Group.
Overall, 8406 (52·7%) patients had surgery for breast cancer, 6215 (38·9%) for colorectal cancer, and 1337 (8·4%) for gastric cancer (figure 1). The distribution of cancer type, unadjusted mortality, and complication rates across country income group are shown in figure 2.
Figure 2.
Patients and outcomes by cancer type and country income group
Data are for 15 958 patients from 82 countries and 428 hospitals. Crude outcome rates are shown for 30-day mortality, 30-day major complication (Clavien-Dindo grade ≥III), and 30-day any complication.
The proportion of patients with later-stage disease who had surgery was greater in upper-middle-income countries and low-income or lower-middle-income countries for all three cancer groups (figure 3; appendix p 8). There was a strong positive correlation between cancer stage and performance status for patients with gastric cancer, and a weaker relationship in patients with breast and colorectal cancer (appendix pp 9–14). No strong relationship between operative risk (ASA grade) and cancer stage was seen.
Figure 3.
Stage of presentation (A), 30-day mortality (B), and 30-day complications (C) by cancer and country income group
(A) Proportion of patients enrolled by cancer stage by country income group. (B) Proportion of patients dying or sustaining a major complication or any complication by day 30 after surgery stratified by country income group. (C) Proportion of patients sustaining a major complication who died within 30 days.
30-day mortality was higher for gastric cancer in the low-income or lower-middle-income group (33 [10·1%] of 326) and for colorectal cancer in the upper-middle-income group (47 [4·3%] of 1102) and low-income or lower-middle-income group (63 [7·0%] of 905), compared with the high-income group (gastric 27 [3·8%] of 702; colorectal 94 [2·3%] of 4142; figure 3; appendix p 20). However, the proportion of patients with a major complication or any complication was similar across all income groups.
Outcomes were adjusted in three-level models accounting for patient and disease factors nested within hospitals and country of treatment (figure 4; appendix pp 22–38). Higher 30-day mortality was seen in gastric cancer in low-income or lower-middle-income countries (adjusted OR [aOR] 3·72, 95% CI 1·70–8·16) and in colorectal cancer in upper-middle-income countries (2·06, 1·11–3·83) and low-income or lower-middle-income countries (4·59, 2·39–8·80; figure 4). No difference in mortality was seen in breast cancer.
Figure 4.
Multilevel logistic regression-adjusted outcomes by World Bank country income group
Models were built incorporating patient and disease factors specific to each cancer. Univariable, full multivariable, parsimonious multivariable, and multilevel (patient, hospital, country) models for each outcome in each cancer type are given in the appendix (pp 22–38). Box size proportional to group size (n). WB=World Bank. OR=odds ratio.
The proportion of patients sustaining a major complication or any complication in these adjusted analyses was similar across country income groups, with weak evidence of fewer major complications after breast surgery in the upper-middle-income group (figure 4).
No statistical interactions were seen between patient factors and country income group for mortality or complications; for example, the effect of age, body-mass index, and ASA grade on outcomes did not differ by country income group.
Given similar complication rates across country income groups, we did an analysis defined post hoc to examine factors predicting mortality after major complications in colorectal and gastric cancer, to determine where capacities to rescue patients might exist.
The proportion of patients sustaining a major complication who subsequently died was higher in upper-middle-income and low-income or lower-middle-income countries compared with high-income countries, in both unadjusted (figure 3) and adjusted analyses (appendix p 4). The relationship between mortality and country income group was consistent across cancer stage of presentation, except for stage IV gastric cancer, where mortality was high across all country income groups (appendix p 4). Similarly, the proportion of patients sustaining complications across country income groups was unchanged after stratification by stage of presentation (appendix p 4).
The pattern of complications occurring within cancer types was broadly similar across country income groups (appendix p 5). No systematic differences in the types of complications being sustained (eg, bleeding, infection) were seen in different country income groups.
In a model accounting for patient factors and clustering by country and hospital, patients in upper-middle-income (aOR 3·89, 2·08–7·29) and low-income or lower-middle-income (6·15, 3·26–11·59) groups were more likely to die after a major complication compared with the high-income group (figure 5; appendix p 43). Patient performance status and emergency surgery were strong predictors of death after major complication. Although patients with stage IV cancer had a greater probability of dying after major complication, stage I to III cancer was not associated with an excess mortality when accounting for other variables in the model. A sensitivity analysis using final pathological staging, as opposed to preoperative clinical staging, showed similar findings (appendix pp 15–16).
Figure 5.
Capacity to rescue from major complication
(A) Multilevel logistic regression model for predictors of death after major complication in colorectal and gastric cancer. Box size proportional to group size (n). (B) Three-way decomposition mediation model of the proportion of the effect of country income group on 30-day mortality mediated by postoperative care infrastructure (the consistent presence of a designated postoperative recovery area, the availability of critical care facilities, and the existence of a working CT scanner). (C) Proportion of 30-day mortality variation explained at the level of patient or disease, hospital, country, and country income group, in patients with colorectal or gastric cancer who died after major complication. The variance explained at each of the four levels of the model (marginal pseudo R2) is expressed as a proportion of the total variance explained (conditional pseudo R2). (D) Absolute risk difference for 30-day mortality after major complication in the presence of consistently available postoperative care infrastructure. Estimates for age 55 years, ECOG performance status 1, ASA grade 2, cancer stage II, and elective surgery. WB=World Bank. OR=odds ratio. ECOG=Eastern Cooperative Oncology Group. ASA=American Society of Anesthesiologists.
In a four-level model of patients nested in hospitals, countries, and World Bank income groups, 60% of the variation in outcome captured by the model (pseudo R2 0·42) was explained by patient or disease factors, with the remaining 40% explained by hospital, country, and country income group factors.
We assessed hospital facilities and processes to determine relationships with excess mortality after major complications. Hospitals in high-income (n=232), upper-middle-income (n=72) and low-income or lower-middle-income (n=95) groups were sampled. Hospitals in upper-middle-income and low-income or lower-middle-income groups were less likely to have postoperative care infrastructure (designated postoperative recovery areas, consistently available critical care facilities, and an available and working CT) and cancer care pathways (tumour board, oncology services, and palliative care services; appendix pp 41–42).
The association between country income group and 30-day mortality was examined in a three-way decomposition mediation model of postoperative care infrastructure (figure 5; appendix p 44). No interaction was found between this mediator and country income group. A significant proportion of the excess mortality after major complication was mediated by the absence of postoperative care infrastructure in low-income or lower-middle-income (aOR 1·19, 95% CI 1·01–1·42; 20%) and upper-middle-income (1·19, 1·01–1·42; 22%) groups. The absolute risk differences for 30-day mortality after major complication with and without consistently available postoperative care infrastructure were examined for common patient covariates (figure 5; appendix p 45). The presence of postoperative care infrastructure was associated with fewer deaths in both the low-income or lower-middle-income group (seven to ten fewer deaths per 100 major complications, number needed to treat 10–14) and the upper-middle-income group (five to eight fewer deaths per 100 major complications, number needed to treat 13–20). Cancer care pathways were not shown to mediate any association with 30-day mortality.
In 265 hospitals in 69 countries randomly selected for validation (1060 hospital-weeks of data collection), 3805 patients fulfilled inclusion criteria compared with 3669 (96·4%) in the primary dataset (appendix p 47). Accuracy was high for the validated continuous predictor (Pearson's correlation coefficient 0·99; appendix p 50). Agreement for categorical predictors was good (sex, T stage, urgency, and intent; Cohen's κ coefficients >0·75; appendix p 51) and lower for N stage (κ 0·67). Agreement was very good for 30-day mortality (κ 0·89) and good for 30-day major complication (κ 0·63).
Discussion
Differences in early cancer outcomes in LMICs compared with high-income countries are often attributed to the advanced stage of presentation, together with an absence of access to cancer-specific treatments. In this prospective, international cohort study of 15 958 patients in 82 countries undergoing surgery for breast, colorectal, and gastric cancer, we show that 30-day postoperative mortality is four-times higher in resource-limited settings, despite patients experiencing similar major complication rates. Although patient factors partially explained the higher postoperative mortality rate in LMICs, health system factors, including access to postoperative monitoring, emergent imaging, and critical care facilities also appeared key, resulting in an insufficiency of capacity to rescue after major complications. This excess mortality after cancer surgery will hamper cancer control efforts in LMICs, and prevent cancer patients, communities, and economies from realising the benefits of cancer-specific treatments.
According to Global Cancer Observatory data, cancer is a leading cause of death and disability worldwide, exerting substantial economic effects in countries at all stages of development,16 with a disproportionate burden of disease now emerging in LMICs.2 Surgery is fundamental to the treatment of solid cancers across all income settings, acting as a pivotal component of multidisciplinary care, together with imaging, pathology, chemoradiotherapy, and palliation. Effective surgical care plays a crucial role in the prevention of death from cancer,2 and requires systems of the highest quality throughout the preoperative and postoperative periods.3 If the opportunity to strengthen surgical cancer systems is not taken, an estimated US$6·2 trillion in gross domestic product will be lost by 2030.2
Mortality reported in our study across LMICs for both gastric (7·2%) and colorectal (5·5%) cancer were higher than current global estimates.17 Existing perioperative mortality rates in the literature are limited by the absence of standardised reporting and risk stratification, and are often derived from small, single-centre studies. The 30-day mortality in our study was similar to that in our previous multicentre observational cohorts.7, 8 Across gastric and colorectal cancers, variation in 30-day mortality between high-income countries and LMICs was shown after both emergency (7·1% vs 18·0%, respectively) and elective (1·9 vs 4·0%, respectively) surgery.
There are well described factors that could contribute to an early excess mortality after cancer surgery. Locally advanced or metastatic cancer is a common initial presentation in LMICs, due in part to reduced access to timely and affordable surgical services.2 Delays in presentation result in poorer survival through a combination of cancer progression,18 cancer-related cachexia,19 and the consequences of emergency presentation. Achieving early detection and treatment through cancer screening initiatives is important, and often the focus of public health initiatives and funding.20 However, in this study we show that excess mortality after cancer surgery in LMICs is only partly explained by the later presentation of disease. We have shown an excess in postoperative mortality despite similar rates and patterns of complications. The importance of rescuing patients from common complications is now well established with variation described globally.21 To our knowledge, our study is the first to identify capacity to rescue as an important early determinant of outcomes from cancer surgery in resource-restricted settings. Furthermore, we have shown an association between the consistent presence of postoperative care infrastructure and lower mortality rates after major complications. The capacity to rescue patients is likely to limit expected reductions in mortality from current global development funds and multilateral investments in cancer control. Better perioperative care systems to detect and intervene in common complications are essential if early death after cancer surgery is to be reduced.
A major strength of this study is its prospective design and deep patient-level and hospital-level data collected simultaneously from a wide breadth of global settings. More than 100 variables were included, making it one of the richest datasets in this area, to our knowledge. The use of the Essential TNM system, together with standard TNM 8 classifications, make meaningful comparisons of cancer stage possible in settings with limited access to imaging and pathological services.12 The assessment of cancer stage, treatment, and outcome was standardised, and training provided through an online platform. Data quality was ensured though collaborator-facing web applications and real-time data entry quality assurance. An independent validation study verified data accuracy and case ascertainment. Quantification of surgical cancer care in resource-limited settings has been hindered by an insufficient amount of high-quality data.4, 17, 22 This study therefore contributes to closing this knowledge gap and allows meaningful comparison from multiple income settings with accurate case-mix adjustment.
Limitations of this study include looking at outcomes only in the 30 days after surgery. Oncological outcomes are essential in capturing the effectiveness of cancer treatments, including surgery, and these outcomes are poorly captured and understood in resource-limited settings.2, 4 Disease-free and overall survival after surgery are likely to be significantly lower in LMICs, for many of the reasons described in this study, including the later stage disease across included cancers. The effect of delayed surgery in life-years lost for stage I–III disease is well described in high-income countries;23 however the impact of this in global settings is less clear. The current study will be extended to capture longer-term outcomes and other cancers in the future, which should add significantly to the picture of global surgical cancer care we have provided here.
Only patients undergoing primary surgery for breast, colorectal, or gastric cancers were included in our study, and therefore outcomes in patients receiving non-surgical care were not examined. Furthermore, the relationship between outcomes and hospital-level facilities were associations. Hospitals with CT and critical care facilities are likely to have other differences in infrastructure and processes that might contribute to better outcomes. Although we provide several important measures of hospital facilities (appendix pp 41–42), further detailed analyses of these data are ongoing. Finally, the substantial economic and financial costs to patients undergoing cancer treatment are known to be significant, but were not measured.
Reducing early mortality after surgery is key to improving cancer outcomes and achieving Universal Health Coverage for non-communicable diseases worldwide. The Lancet Commission on Global Cancer Surgery identified the key requirements to scale up surgical cancer services by 2030.3 Improvements in the provision of cancer care remain essential if Sustainable Development Goals are to be met. Yet, detailed global information supporting focused initiatives to develop infrastructure, improve quality, and implement effective interventions remains limited. Although complete analysis of the patient pathway was not possible within this study, we identified multiple components of the surgical health system and patient-level risk factors that could be targeted for further study and intervention. High-quality perioperative care requires appropriate recovery and ward space, a sufficient number of well trained staff, the use of early warning systems, and ready access to imaging, operating theatre space, and critical care facilities to deal with complications when they occur—the delivery of which is even more challenging in the present COVID-19 pandemic.24
Access to cancer surgery is an important barrier to safe and effective care for people with cancer in LMICs.25 Improved access comes with further opportunities for optimisation of individual patients through, for instance, nutritional interventions and neoadjuvant therapies. Addressing these factors with high-quality interventional trials to build a global evidence base for the delivery of safe cancer surgery is likely to have significant effect and improve cancer survival.
This study has produced a unique prospective dataset of patients undergoing breast, colorectal, and gastric cancer surgery worldwide. Future research should focus on the detailed characterisation of perioperative care processes and the implementation of strategies to both reduce complication rates, and to rescue patients from complications when they do occur. Policy makers worldwide must balance investments in the early detection and treatment of cancer with the simultaneous improvement in safe perioperative care. Without these investments, mortality gains in cancer control will not be fully realised.
Correspondence to: Prof Ewen M Harrison, National Institute for Health Research Global Health Research Unit on Global Surgery, Centre for Medical Informatics Usher Institute, University of Edinburgh, Edinburgh EH16 4UX, UK ewen.harrison@ed.ac.uk
For more on the Global Cancer Observatory see https://gco.iarc.fr/
Data sharing
The dataset can be explored using an online visualisation application online. Hospital-level data can be shared by application to the corresponding author. For analyses of patient-level identifiable data within our trusted research environment, please contact the corresponding author.
Acknowledgments
Acknowledgments
This study was funded by the National Institute for Health Research Global Health Research Unit Grant (NIHR 17–0799) in a subset of contributing countries. We would like to pay tribute to Hosni Khairy Salem, a dedicated key member of the GlobalSurg Collaborative, who tragically lost his life in June, 2020.
Contributors
Study design, data collection, data analysis, data interpretation, and writing (SRK, MLAA, EMH, PB, JEF, MIvBH, KAM, FP, ARM, NJS, ST, HST, and TGW); study design, data collection, and writing (AOAde and SWA-S); study design, data interpretation, and writing (AOAdi, TMD, JCAI, TPK, RJL, and DM); data collection, data interpretation, and writing (ISA-S, AJD, FN, and TDP); study design, data collection, data interpretation, and writing (AB, KMC, AC-C, JG, MCML, IL, and DN); study design and writing (BMB); data collection, data interpretation, writing, and revision (ME and BL); study design, data collection, and data interpretation (CJF and RTS); data analysis, data interpretation, and writing (DNG); study design and data interpretation (JM, HKS); data collection (RLM); data analysis and data interpretation (LN and AMR); study design, data analysis, data interpretation, and writing (RP and CAS); study design, data collection, and Article revisions (AUQ); data interpretation and writing (JS); data interpretation, writing, and critical review (MAW); data collection and manuscript revisions (JW); and data verification (EMH, SRK, CAS, RP, TMD, and LN).
GlobalSurg Collaborative and NIHR Global Health Research Unit on Global Surgery writing group
Stephen R Knight, Catherine A Shaw, Riinu Pius, Thomas M Drake, Lisa Norman, Adesoji O Ademuyiwa, Adewale O Adisa, Maria-Lorena Aguilera-Arévalo, Sara W Al-Saqqa, Ibrahim S Al-Slaibi, Aneel Bhangu, Bruce M Biccard, Peter Brocklehurst, Ainhoa Costas-Chavarri, Kathryn M Chu, Anna J Dare, Muhammed Elhadi, Cameron J Fairfield, J Edward Fitzgerald, Dhruv N Ghosh, James Glasbey, Mark I van Berge Henegouwen, J C Allen Ingabire, T Peter Kingham, Marie Carmela M Lapitan, Ismaïl Lawani, Bettina Lieske, Richard J Lilford, Janet Martin, Kenneth A Mclean, Rachel L Moore, Dion Morton, Dmitri Nepogodiev, Faustin Ntirenganya, Francesco Pata, Thomas D Pinkney, Ahmad U Qureshi, Antonio Ramos-De la Medina, Aya M Riad, Hosni Khairy Salem, Joana Simões, Richard T Spence, Neil J Smart, Stephen Tabiri, Hannah S Thomas, Thomas G Weiser, Malcolm A West, John Whitaker, Ewen M Harrison.
Declaration of interests
MIvBH reports personal fees from Mylan, Alesi Surgical, Johnson and Johnson, and Medtronic; grants and non-financial support from Stryker; and grants from Olympus, outside the submitted work. All fees were paid to MIvBH's employing institution. PB reports grants and personal fees from the Medical Research Council (MRC); grants from MRC, National Institute for Health Research Health Technology Assessment, and Wellcome Trust; and personal fees from AG Biotest, outside the submitted work. TPK reports personal fees from Olympus Surgical outside the submitted work. All other authors declare no competing interests.
Contributor Information
GlobalSurg Collaborative and National Institute for Health Research Global Health Research Unit on Global Surgery:
Stephen R Knight, Catherine A Shaw, Riinu Pius, Thomas M Drake, Lisa Norman, Adesoji O Ademuyiwa, Adewale O Adisa, Maria Lorena Aguilera, Sara W Al-Saqqa, Ibrahim Al-Slaibi, Aneel Bhangu, Bruce M Biccard, Peter Brocklehurst, Ainhoa Costas-Chavarri, Kathryn Chu, Anna Dare, Muhammed Elhadi, Cameron J Fairfield, J Edward Fitzgerald, Dhruv Ghosh, James Glasbey, Mark I. van Berge Henegouwen, J.C. Allen Ingabire, T Peter Kingham, Marie Carmela Lapitan, Ismaïl Lawani, Bettina Lieske, Richard Lilford, Janet Martin, Kenneth A Mclean, Rachel Moore, Dion Morton, Dmitri Nepogodiev, Faustin Ntirenganya, Francesco Pata, Thomas Pinkney, Ahmad Uzair Qureshi, Antonio Ramos-De la Medina, Aya Riad, Hosni Khairy Salem, Joana Simões, Richard Spence, Neil Smart, Stephen Tabiri, Hannah Thomas, Thomas G Weiser, Malcolm West, John Whitaker, Ewen M Harrison, Arben Gjata, Maria Marta Modolo, Sebastian King, Erick Chan, Sayeda Nazmun Nahar, Ade Waterman, Dominique Vervoort, Ismaïl Lawani, Alemayehu Ginbo Bedada, Bernardo De Azevedo, Ana Gabriela Figueiredo, Manol Sokolov, Venerand Barendegere, Gerald Ekwen, Arnav Agarwal, Anna Dare, Qinyang Liu, Juan Camilo Correa, Kalisya Luc Malemo, Jacques Bake, Jakov Mihanovic, Kamila Kuncarová, Julius Orhalmi, Hosni Salem, Jyri Teras, Aristotelis Kechagias, Alexis P Arnaud, Judith Lindert, Stephen Tabiri, Vasileios Kalles, Maria-Lorena Aguilera-Arevalo, Gustavo Recinos, Zsolt Baranyai, Basant Kumar, Harish Neelamraju Lakshmi, Sanoop Koshy Zachariah, Philip Alexander, Sunil Kumar Venkatappa, C Pramesh, Radhian Amandito, Christina Fleming, Luca Ansaloni, Francesco Pata, Gianluca Pellino, Ahmed M. Altibi, Ibrahim Nour, Intisar Hamdun, Muhammed Elhadi, Ali M. Ghellai, Donatas Venskutonis, Tomas Poskus, Justas Zilinskas, John Whitaker, Precious Malemia, Yong Yong Tew, Elaine Borg, Sarah Ellul, Antonio Ramos-De la Medina, fatima Zahraa Wafqui, David W Borowski, Anne Sophie van Dalen, Cameron Wells, Harissou Adamou, Adesoji Ademuyiwa, Adewale Adisa, Kjetil Søreide, Ahmad Uzair Qureshi, Ibrahim Al-Slaibi, Sara Al Saqqa, Osaid Alser, Haya Tahboub, Helmut Alfredo Segovia Lohse, Sebastian Shu Yip, Marie Carmela Lapitan, Piotr Major, Joana Simões, António Sampaio Soares, Matei Razvan Bratu, Andrey Litvin, Armen Vardanyan, JC Allen Ingabire, Ainhoa Costas-Chavarri, Ahmad Gudal, Naif Albati, Jovan Juloski, Bettina Lieske, Miran Rems, Sarah Rayne, Stephanie Van Straten, Yoshan Moodley, Kathryn Chu, Rachel Moore, Irene Ortega Vázquez, Jaime Ruiz-Tovar, Kithsiri Janakantha Senanayake, Sujeewa Priyantha Bandara Thalgaspitiya, Omer Abdelbagi Omer, Anmar Homeida, Yucel Cengiz, Daniel Clerc, Muhammad Alshaar, Hanen Bouaziz, Yuksel Altinel, Matthew Doe, Maryna Freigofer, Ella Teasdale, Rakan Kabariti, Joshua Michael Clements, Stephen Richard Knight, Ahsan Ashfaq, Ijeoma Azodo, Gabriela Wagner, Ivan Trostchansky, Mayaba Maimbo, David Linyama, Helidon Nina, Amanda Zeko, Claudio Gabriel Fermani, Maria Marta Modolo, Santiago Villalobos, Federico Carballo, Pablo Farina, Sebastian Guckenheimer, Marilla Dickfos, Ankit Ajmera, Chester Chong, Ralph Gourlay, Sikandar Hussaini, Yi Jia Lee, Adeeb Majid, Peter Martin, Rebecca Miles, Owen James Morris, Jamie Phua, William Ridley, Tarunpreet Saluja, Ryan Renxin Tan, Jen Teh, Anna Wells, Bharti Arora, Qaasim Dollie, Debbie Ho, Yanru Ma, Omattage Mahasha Perera, Anthony Truong, Amanda Caroline Dawson, Bryan Lim, Upuli Pahalawatta, Jacqueline Phan, Xiao-Ming Sarah Woon-Shoo-Tong, Andrea Yeoh, Lillian Charman, Andrew Drane, Sharon Laura, Charmaine Chu Wen Lo, Amy Mozes, Rita Poon, Hao Han Tan, Ellen Wall, Prakshi Chopra, Jasmine De Giovanni, Bal Dhital, Brian Draganic, Alexander Duller, Jonathan Gani, Yao Kuan Goh, Jun Young Jeong, Brendan McManus, Prakash Nagappan, Peter Pockney, Anya Rugendyke, Mahsa Sarrami, Stephen Smith, Vanessa Wills, Hsu Ven Wong, Geoffrey Ye, Geoffrey Zhang, Ethan Brooker, Daniel Feng, Bonnie Lau, Carlin Ngai, Sarah Birks, David Gyorki, Jaime Otero de Pablos, Ali Abbosh, Chris Gillespie, Ahmed Mahmoud, Bianca Kwan, Joshua Lawson, Andrea Warwick, Janne Bingham, Andrew J Cockbain, Nagendra Naidu Dudi-Venkata, Jordan Ellaby-Hall, Ben Finlay, Emily Humphries, Jade Pisaniello, Monique Pisaniello, Salma Salih, Tarik Sammour, Haidar Hadri Abd Wahab, April De Silva, Nicola Hayward, Kartik Iyer, Guy Maddern, Gian Andrea Prevost, Naga Annapureddy, Krishna Pranathi Settipalli, Jeremy Yeo, Lucy Hempenstall, Lily Pham, Shaun Purcell, Cherry Talavera, Ashish I Vaska, Gurpreet Chaggar, Phillip Chrapko, Annelise Cocco, Sarah Michelle Crystal Jade Coulter-Nile, Grahame Ctercteko, James French, Houchen Gong, Martijn Gosselink, Thuvarahan Jegathees, Ivan Jin, Michelle Kalachov, Kathryn Kiefhaber, Katherine Lee, Jason Luong, Steven Phan, Henry Pleass, Kelly Veale, Zhi Zeng, Angela Au, Ashe DeBiasio, Idy Deng, Jananee Myooran, Amrita Nair, Peter Stewart, Anton Stift, Lukas Walter Unger, Kerstin Wimmer, Nabila Ahmed, Syed Hasan, Saber Rahman, Margaret O'Shea, Greg Padmore, Adrian Peters, Pietro Perduca, Guenda Pulcina, Nicolas Tinton, Frederic Buxant, Elsa Dabin, Giulia Garofalo, Francis Dossou, Ismaïl Lawani, Freddy Houehanou Rodrigue Gnangnon, Yacoubou Imorou Souaibou, Alemayehu Ginbo Bedada, Pako Motlaleselelo, Omphile Tlhomelang, Igor Lima Buarque, Gustavo Mendonça Ataíde Gomes, Aldo Vieira Barros, Ilia Batashki, Nikolai Damianov, Vladislav Stoyanov, Dragomir Dardanov, Svilen Maslyankov, Plamen Petkov, Manol Sokolov, George Todorov, Evgeni Zhivkov, Aygulya Akisheva, Miguel Angel Castilla Moreno, Geno Genov, Ivelina Ilieva, Tsvetomir Ivanov, Martin Karamanliev, Azhar Khan, Emil Mitkov, Tsanko Yotsov, Boyko Atanasov, Nikolay Belev, Mihail Slavchev, Carlos Nsengiyumva, Elgan Jones, Simon Stock, Gerald Ekwen, Steve Kyota, James Brown, Tresor Mabanza K., Lemery Nigo Samuel, Chidi Otuneme, Ngwang Prosper, Franklin Umenze, Marylise Boutros, Natasha Caminsky, Sinziana Dumitra, Richard Garfinkle, Dominique Morency, Ebram Salama, Alexander Banks, Lorenzo Ferri, Haitian He, Amit Katz, Alexander Sender Liberman, Sarkis Meterissian, Allison Pang, Elena Parvez, Arnav Agarwal, Anna Dare, Usmaan Hameed, Fahima Osman, Sangita Sequeira, Natalie Coburn, Anna Dare, Alisha Jaffer, Paul Karanicolas, Matthew Mosseler, Reilly Musselman, Xinyuan Liu, Ching Wan Yip, Juan Sebastian Garces-Otero, Carolina Guzman, Sebastian Sierra, Andres Uribe Valencia, Paulo Andrés Cabrera Rivera, Saul Camelo, Andrea Gonzalez, Alejandro González-Orozco, Manuel Santiago Mosquera Paz, Carlos J- Perez Rivera, Felipe Gonzalez, Andres Isaza-Restrepo, Laura Nino- Torres, Natalia Arias Madrid, Maria Clara Mendoza Arango, Sebastian Sierra, Jacques Bake, Justin Tsandiraki, Damir Jemendžic, Branislav Kocman, Oliver Šuman, Renata Canic, Darko Jurišic, Ivana Karakas, Ana Krizanovic Rupcic, Vlatka Pitlovic, Josip Samardžic, Mario Kopljar, Ivan Bacic, Edgar Domini, Robert Karlo, Jakov Mihanovic, Danijela Miljanic, Andrea Simic, Mariam Ahmed, Majdi Al Nassrallah, Rabiya Altaf, Talal Amjad, Ruba Eltoum, Heba Haidar, Alhassan Hassan, Omar Khalil, Marwan Qasem, Rommel Ramesh, Gautham Sajith, Maham Wisal, Jan Žatecký, Michele Bujda, Katerina Jirankova, Ales Paclik, Aya Abdallah, Mariam Abdulgawad Almogy, Esraa Ayman El-sawy, Ahmed Moustafa ElFayoumy, Nourhan Elghareeb, Nourhan Ahmed Esmat, Ahmed Fadel, Abdullah Habater, Heba Hamdy, Amr Hefni, Marwa Kamal, Norhan Mohamed Abobakr, Ahmed Sayed, Nancy Shaker, Ehab Taha, Hoda Tharwat, Omar Zakaria, Ibrahem Abdelmotaleb, Ali Al-Dhufri, Hamza S. Al-Himyari, Enas El sheikh, Asmaa Eldmaty, Aya Elkhalawy, Ahmed M.Elkhashen, Kithara Magdy, Safa Mostafa, Habib Doutoum Sadia, Mohamed mahmoud Saleh, Dina Samir, Mohamed Yahia Mohamed Ali, Mahmoud A. Nassar, Samar Abdelhady, Aly Abdelrazek, Israa Abdelsalam, Aya El-Sawy, Eman Essam, Mohamed Gadelkarim, Khaled Ghaly, Mohamed Hassabalnaby, Rana Masarani, Nourhan Mohamed Shaaban, Ahmed Sabry, Menatalla Salem, Nourhan Akram Soliman, Diaaaldin Zahran, Moustafa Ramadan Abou El.soud, Esraa Tarek Badr, Hala Borham, Nehal Elmeslemany, Mohammad Elsayed, Fawzia Elsherif, Sara Eslam, Gehad Gaber, Sondos Ibrahim, Yara Kamh, Abdelrahman Mahmoud, Shimaa gamal Mohamed, Eman Morshedy, Cinderella Omar, Fatima Salem Soliman, Shaza Abdelkawy, Naglaa Abdelmohsen, Mahmoud Abdelshakour, Ahmed Dahy, Norhan Gamal, Mohammed Gamal, Ahmad Hasan, Helal Hetta, Nehad Mousa, Mohamed Omar, Somia Rabie, Mahmoud Saad, Bakeer Saleh, Marwa Sayed Mohamed, Muhammad Shawqi, Heba Abdelhady Mousa, Mostafa Alnoury, Mohamed Elbealawy, Ahmed Elshafey, Muhammad Essam Ibrahim El Desouki Muhammad Ahmed, Mennatullah Ghonaim, Fawzy Hgag, Mohamed Ibrahim, Mahmoud Morsy, Mohamed Reda Loaloa, Ahmed Refaat, Hadeer Samir, Fatma Shahien, Mohamed Sobhy, Fathy Sroor, Esraa Abdellatif, Marina Adel, Amr Abdelghani Afifi, Eman Afifi, Marco Antaky, Amr Dawoud, Naira El Zoghby, Amira El-remaily, Ali Abdelazez Elzanfaly, Ahmed Gadallah, Fatma Alzahraa Gamal, Omar Hashem, Shrouk Medhat Youssef, Aliaa Muhammad Attyah, Malak Munir, Omar Shazly, Esraa Taha, Karim Wilson, Sawsan Adel, Asmaa Ali, Esraa Eid, Esraa Elhelow, Marwa Elmahdy, Bassant Elshatby, Amany Hossam el-din Zakaria, Ahmad Hossny, Eman Ibrahim, Ahmed M.Yonis, Maram Metwalli, Basant Yousry, Esraa Zid, Mina A Yacoub, Ahmed Abdelhakim, Nervana Abouelsoad, Mo'min Alkhatib, Ahmed Ashraf, Alaa Ashraf, Yasmin Elazab, Mahmoud Elfanty, Osama Elkabir, Mai Elsayed, Ahmed Elshimy, Hager Elsobky, John Eskander, Ahmed Gad, Ward Hamsho, Noura Khaled Abdelwahed, Menna Magdy, Dalia Moharam, Abeer Osama, Shereen Ramadan, Radwa Roum, Taqwa Sayed, Tarneem Shehada, Ahmed Mohy Zidan, Khalid Abbas, Amr Ali, Mohamed Attia, Mohamed Balata, Ayman El Nakeeb, Mohamed Ibrahim Elsayed Elewaily, Ahmed Elfallal, Hossam Elfeki, Ahmed Elkhadragy, Sameh Emile, Helmy Ezzat, Hasnaa Hosni, Islam Mansour, Waleed Omar, Gehad Othman, Kareem Sadek, Mostafa Shalaby, Noura Shehab-Eldeen, Rawda Anas khalifa, Helmy Badr, Mostafa Eldeep, Ahmed Eldeep, Amany Eldoseuky mohammed, Salwa Khallaf, Eman Magdy Hegazy, Rokia Mahmoud, Pola Mikhail, Mahmoud Morsi, Sara Mowafy, Dina Raafat, Amina Safy, Marwa Sera, Ahmed shible Sera, Mostafa Salim Mohamed AbdAllah, Muhammad Abdelkader, Abdulrahman Osama Abdou, Ahmedgaber Ahmed, Shireen Gaafar, Fatma Ibrahim negm, Mina Lapic, Ahmed Maher, Hagar Mahmoud, Ahmed Mostafa, Mohamed Samir, Fatma Samy, Nourhan Semeda, Hind I. Shalaby, Alaa El-taweel, Ahmed Galal Elnagar, Ahmed Gamal Hemidan, Mohamed Hussein, Ahmed. A. Kandil, Mf Moawad, Ayat Allah Nasser Hamamah, Mostafa Soliman, Mohamed Abdelkhalek, Noura Abdelmaksoud Tawakel, Ahmed Mohamed Abdelwahed, Alrawy Abdou, Khalid Atallah, Mohammed Yasser Elsherbeny, Eman Emara, Mohamed Hamdy, Omar Hamdy, Amira Haron, Salma Ismail, Islam Hany Metwally, Nihal Mohamed Hamed Elgaml, Ahmed Nassar, Basel Refky, Mirna Sadek, Mahmoud Saleh, Asmaa Yunes, Mai Zakaria, Mohammed Zuhdy, Notila Fayed, Mohammed Mustafa Hassan Mohammed, Sander Kütner, Priit Melnik, Indrek Seire, Jyri Teras, Toomas Ümarik, Eppu Ainoa, Verner Eerola, Hanna Koppatz, Laura Koskenvuo, Ville Sallinen, Sini Takala, Jevgeni Katunin, Aristotelis Kechagias, Arto Turunen, Niki Christou, Muriel Mathonnet, Vincent Lavoue, Krystel Nyangoh Timoh, Lucie Soulabaille, Romain Lesourd, Aude Merdrignac, Laurent Sulpice, Benoît André, Elodie Chantalat, Charlotte Vaysse, Bertrand Dousset, Sebastien Gaujoux, Gregory Martin, Octavian Clonda, Domantas Juodis, Klaus Kienle, Andras Mravik, Samuel Palmer, Gabor Szabadhegyi, Anita Eseenam Agbeko, Solomon Gyabaah, Frank Enoch Gyamfi, Nuhu Naabo, Atta Owusu senior, Joseph Yorke, Frank Owusu, Francis Abantanga, Theophilus Teddy Kojo Anyomih, Abdul-Jalilu Mohammed Muntaka, Emmanuel Owusu Abem, Mohammed Sheriff, Stephen Tabiri, Paul M. Wondoh, Dimitrios Balalis, Dimitrios Korkolis, Georgios Gkiokas, Eirini Pantiora, Theodosios Theodosopoulos, Argyrios Ioannidis, Konstantinos Konstantinidis, Sofia Konstantinidou, Nikolaos Machairas, Anna Paspala, Anastasia Prodromidou, Christos Chouliaras, Konstantinos Papadopoulos, Ioannis Baloyiannis, Ioannis Mamaloudis, George Tzovaras, Ioanna Akrida, Maria-Ioanna Argentou, Stylianos Germanos, Evangelos Iliopoulos, Ioannis Maroulis, George Skroubis, George Theofanis, Christos Chatzakis, Orestis Ioannidis, Lydia Loutzidou, Vasileios Kalles, Panagiotis Karathanasis, Nikolaos Michalopoulos, Charalampos Theodoropoulos, Dimitrios Theodorou, Tania Triantafyllou, Zoe Garoufalia, Natasha Hasemaki, Michalis Kontos, Gregory Kouraklis, Stylianos Kykalos, Theodore Liakakos, Eustratia Mpaili, Alexandros Papalampros, Dimitrios Schizas, Athanasios Syllaios, Ekaterini Christina Tampaki, Antonios Tsimpoukelis, Maria Ioanna Antonopoulou, Eirini Deskou, Dimitrios K. Manatakis, Dimitrios Papageorgiou, Menelaos Zoulamoglou, Christos Anthoulakis, Michalis Margaritis, Nikolaos Nikoloudis, Veronica Campo, André Ceballos, Mario-Andrés Flores, Waleska Giron, Donghyun Ko, Gabriel Martinez, Gustavo Recinos, Verónica Rivera Lara, Nataly Rueda, Andres Sanchez, Jorge Carlos Guillermo Tejeda Garrido, Maria-Lorena Aguilera-Arevalo, Alvaro Eduardo Alvarez Rivera, Elvis Benjamin Bamaca Ixcajoc, Lilian Elizabeth Barreda Zelaya, Patricia Chacòn-Herrera, Ligia Margarita Corea Ruiz, Guillermo Echeverria-Davila, Mario Garcia, Danilo García, Edgar Fernando Gutiérrez Mayen, Noriega José, Nery Mazariegos, Diego Méndez, Michael Paniagua Espinoza, Zsolt Baranyai, David Bardos, Marton Benke, Kristof Illes, Balint András Kokas, Réka Szabó, Akhila Appukuttan, Anjitha Asok, Vijaykumar D.K., Kapil Malik, Praveen Ravishankaran, Ritesh Tapkire, Guru Moorthy, Joyner Abraham, Ramesh Muthuvel, John Alapatt, Abhay Kattepur, Nizamudheen Pareekutty, Mebanshanbor Garod, Caleb Harris, Cliff Wanniang, Ashish Gupta, Deepak Nehra, Sanjeev Parshad, Rajgopal Acharya, Rajendra Badwe, Manish Bhandare, Urvashi Jain, Karishma Kirti, Nita Nair, Shailesh Shrikhande, Purvi Thakkar, Premkumar Anandan, Archana C S, Arun Holenarasipur Narasannaiah, Tejaswi Jagarlamudi, Sunil Kumar Venkatappa, Rashmi M R, Mallikarjuna Manangi, Abhishek Raghavendra, K. Seshagiri Rao, Vinay S, Vinay Sajjan, Aneesh Shenoy, Santhosh Shivashankar Chikkanayakanahalli, Kavya Tharanath, Sushmita V, Peter Adidharma, Raksheeth Agarwal, Radhian Amandito, Phebe Anggita Gultom, Ghafur Rasyid Arifin, Matthew Billy, Zatira Elfizri, Alessa Fahira, Devi Felicia, Triana Hardianti Gunardi, Nadya Johanna, Nadia Rahmadiani Nugrahadi, Sonar Soni Panigoro, Siti Rahmayanti, Retta Catherina Sihotang, Santi Yuanita Brata, Hadi Winoto, Nastaran Barati, Manoochehr Karami, Hamidreza Khorshidi, Homa Naderifar, Mazin A. Abdulla, Maggie Coleman, Ronan J Doherty, Rob Hannon, Brenda Murphy, Aine Stakelum, Des Winter, Lylas Aljohmani, Richard Farnan, Yeshey Seldon, Tanna Tan, Shriya Varghese, Mohammad Alherz, Muaaz Ather, Mohammad Bajilan, Vivien Graziadei, Isobel Pilkington, Omar Quidwai, Paul Ridgway, Haaris Shiwani, Abd al-Rahman Tahir, Eimear Blunnie, Daniel Burke, Niall Kennedy, Kate Macdonagh, Maeve O'Neill, Siobhan Rooney, Giuseppe Falco, Guglielmo Ferrari, Simone Mele, Gabriela Elisa Nita, Lara Ugoletti, Maurizio Zizzo, Gianmaria Confalonieri, Giovanni Pesenti, Fulvio Tagliabue, Gianluca Baronio, Deborah Ongaro, Giacomo Pata, Bruno Compagnoni, Renato Salvadori, Lucio Taglietti, Nicola D'Alessandro, Pierpaolo Di Lascio, Giovanni Pascale, Luca Bortolasi, Tommaso Campagnaro, Massimo Carlini, Giorgio Lisi, Davide Lombardi, Corrado Pedrazzani, Domenico Spoletini, Giulia Turri, Paola Violi, Donato Francesco Altomare, Fabrizio Aquilino, Nicola Musa, Vincenzo Papagni, Arcangelo Picciariello, Leonardo Vincenti, Dario Andreotti, Savino Occhionorelli, Matteo Tondo, Stefano Maria Massimiliano. Basso, Riccardo Cirelli, Marco Enrico Mario Maino, Guglielmo Niccolò Piozzi, Emanuele Picone, Rosa Scaramuzzo, Giovanni Sinibaldi, Alfonso Amendola, Lorenzo Anastasio, Luigi Bucci, Emanuele Caruso, Antonio Castaldi, Sara Di Maso, Vincenza Paola Dinuzzi, Giovanni Esposito, Maria Gaudiello, Mariano Cesare Giglio, Paola Antonella Greco, Gaetano Luglio, Andrea Manfreda, Ester Marra, Federica Mastella, Gianluca Pagano, Roberto Peltrini, Vincenzo Pepe, Michele Sacco, Viviana Sollazzo, Giovanni Spiezio, Ettore Cianchetti, Nunzia Menduni, Michele Maria Carvello, Francesca Di Candido, Antonino Spinelli, Fabio Corsi, Luca Sorrentino, Fabio Marino, Emanuele Luigi Giuseppe Asti, Luigi Bonavina, Emanuele Rausa, Martina Asta, Andrea Belli, Francesco Bianco, Carmela Cervone, Paolo Delrio, Armando Falato, Andrea Fares Bucci, Rita Guarino, Ugo Pace, Daniela Rega, Emilia De Luca, Gaetano Gallo, Giuseppe Sammarco, Giuseppe Sena, Giuseppina Vescio, Letizia Santandrea, Giampaolo Ugolini, Davide Zattoni, Nicola Chetta, Gaetano Logrieco, Serafino Vanella, Gianluca Garulli, Nicola Zanini, Andrea Bondurri, Francesco Cammarata, Francesco Colombo, Diego Foschi, Giulia Maria Beatrice Lamperti, Anna Maffioli, Gianluca Matteo Sampietro, Al'ona Yakushkina, Gloria Zaffaroni, Luca Ansaloni, Enrico Cicuttin, Maria Grazia Sibilla, Harmony Impellizzeri, Marco Inama, Gianluigi Moretto, Sylvie Mochet, Elisa Ponte, Antonella Usai, Stefano Mancini, Andrea Sagnotta, Luigi Solinas, Elisa Bolzonaro, Nicolò Tamini, Gianluca Curletti, Raffaele Galleano, Michele Malerba, Sofia Campanella, Gianfranco Cocorullo, Francesco Colli, Paolino De Marco, Nicolò Falco, Tommaso Fontana, Leonel jospin Kamdem Mambou, Antonella La Brocca, Leo Licari, Brenda Randisi, Giovanna Rizzo, Giulia Rotolo, Giuseppe Salamone, Roberta Tutino, Paolina Venturelli, Stefano Malabarba, Alessandro Sgrò, Ivan Vella, Bruno Cirillo, Daniele Crocetti, Giorgio De Toma, Pierfrancesco Lapolla, Andrea Mingoli, Paolo Sapienza, Angela Belvedere, Stefania Bianchini, Margherita Binetti, Arianna Birindelli, Valeria Tonini, Mauro Podda, Fabio Pulighe, Michele De Rosa, Lorenzo Bono, Felice Borghi, Paolo Geretto, Maria Carmela Giuffrida, Corrado Lauro, Alessandra Marano, Luca Pellegrino, Paola Salusso, Diego Sasia, Michela Campanelli, Alberto Realis Luc, Mario Trompetto, Roberto Cardia, Nicola Cillara, Antonio Nicola Giordano, Antonio Costanzo, Mario Alessandro Giovilli, Luca Turati, Silvestro Canonico, Gianluca Pellino, Guido Sciaudone, Francesco Selvaggi, Lucio Selvaggi, Nader Albsoul, Ahmad AlBsoul, Ala'a Aldeen Alkhatib, Osama Alsallaq, Justin Z. Amarin, Rami Ayoub, Isam Bsisu, M S El Muhtaseb, Mohammad Jabaiti, Jamal Melhem, Ibrahim Nour, Yasmeen Z. Qwaider, Mohammad Hasan Salameh, Ahmad Suleihat, Haya H. Suradi, Mohammad Alammarin, Almoutuz Aljaafreh, Mohammad Bani hani, Zeina Bani hani, Farah Bani Hani, Toqa Fahmawee, Shadi Hamouri, Cyrine Katanani, Ra'fat Tawalbeh, Tamara Tawalbeh, Hassan Zawahrah, Mohamad K. Abou Chaar, Lana Abusalem, Mahmoud Al-Masri, Hani Al-Najjar, Lutfi Barghuthi, Zahra Ahmed, Adnan Maulana, Omar Ngotho, Charbel Kamau, Aruyaru Stanley Mwenda, Fridah Bosire, Elizabeth Mwachiro, Robert Parker, Ian Simel, Kimutai Sylvester, Abdulmunem Ahmed Mustafa Althini, Sofian Elbarouni, Aya Elseed Elbeshina, Ahmed Gwea, Ans Malek, Wedad Albashir Masoud Farag, Abdulwahab Abdalei, Abu Baker Abdel Malik, Areej Abo-khammash, Ma'aly Abuhlaiga, Nour Adnan, Marwa Albaggar, Asma Alfitory, Asma Aljanfi, Fakhruddin Almuzghi, Zohoor Altumei, Fatima Alzabti, Hana Ashoushan, Mohamed Assalhi, Joma Azzubia, Sondos Bnhameida, Malik Delhen, Houssein Elshafei, Hana Elteir, Fatima Esbaga, Abdel Aziz Gobbi, Fatma Hamouda, Hamdan Hilan, Rania Ismail, Fieruz Jebran, Muataz Kasbour, Galia Maderi, Saja Mohammad, Burooj Mohammed, Habib Murtadi, Hamassat Mustafa, Mohamed Rajab, Sarah Trenba, Mariam Wafaa, Eman Al Sagheir, Alabas Almigheerbi, Ahmed Alzahaf, Sumayyah Ghayth Bahroun, Najah Ben Dallah, Mahmoud Elshaibani, Haitem Eswaye, Maha Karar, Samah Omar, Eman Younes, Maha Younes, Dafer Zreeg, Saleh Abujamra, Firas Ashour, Mala Elgammudi, Wesal Omar F. Aljadidi, Enas Saddouh, Randa Sharif, Aya Alabuzidi, AbdulMawlay Alwerfally, Sarra Aribi, Fatma Bibas, Taha Elfaituri, Yasmine Elhajjaji, Ala Khaled, Wegdan Khalil, Tesneem Layas, Enas Soula, Ahmed Tarek, Muad fathi khalleefah Abu hallalah, Saleh Abujamra, Hazem Abdelkarem Ahmed, Tagwa Alsharef, Abdulsalam Ali Ben Saoud, Tasnim El Gharmoul, Ahmed Elhadi, Safa Elrais, Abdulhalim Shebani, Heba Zarti, Asaid Zeiton, Marijus Ambrazevicius, Nerijus Kaselis, Migle Stakyte, Oleg Aliosin, Agne Cizauskaite, Sarunas Dailidenas, Vitalijus Eismontas, Migle Kybransiene, Vitalija Nutautiene, Narimantas Samalavicius, Dainius Simcikas, Algirdas Slepavicius, Albinas Tamosiunas, Nerijus Ubartas, Paulius Zeromskas, Saulius Bradulskis, Edvinas Dainius, Juozas Juocas, Egle Kubiliute, Juozas Kutkevicius, Aurimas Opolskis, Audrius Parseliunas, Andrejus Subocius, Donatas Venskutonis, Egle Virbickaite, Diana Zuikyte, Algirdas Bogusevicius, Kristina Buzaite, Daiva Cepuliene, Ieva Cesleviciene, Vaidotas Cesna, Jolanta Gribauskaite, Povilas Ignatavicius, Mantas Jokubauskas, Monika Liugailaite, Ernest Margelis, Ruta Mazelyte, Lina Pankratjevaite, Matas Pažusis, Agne Rackeviciute, Justina Saladyte, Monika Škimelyte, Vygintas Šlenfuktas, Monika Sudeikyte, Algimantas Tamelis, Tomas Vanagas, Žygimantas Žumbakys, Aivaras Atkociunas, Audrius Dulskas, Justas Kuliavas, Justas Birutis, Sigitas Paškevicius, Mindaugas Šatkauskas, Donatas Danys, Matas Jakubauskas, Lina Jakubauskiene, Marius Kryzauskas, Vytautas Lipnickas, Gabija Makunaite, Fanjandrainy Rasoaherinomenjanahary, Herizo Rasolofonarivo, Luc Hervé Samison, Bitiel Banda, Precious Malemia, Vanessa Msosa, Ahmad Imran Ahmad Izzuddin, Andre Das, Ying Yee Gan, Tan Shong Sheng, Jia yng Siaw, Mohd Fadliyazid Ab Rahim, Dyg Zahratul Hamrak Abang Jamari, Nurfariza Che Husin, Muhd Yusairi Kamarulzaman, Yi Ping Lim, Nil Amri Mohamed Kamil, Mohd Razeen Mohd Hassan, Saidah Mohd Sahid, Johari Mustafa, Elaine Hui Been Ng, Wan Khamizar Wan Khazim, Ng Chang Ern, P.G. Lingeshan, Syariz Ezuan Sulaiman, Sue Ean Ang, Muhammad Navid Bin Mohamad Sithik, Yih Jeng Cheong, Mahadevan Deva Tata, Law Jia Xian, Aravinthan Kadravello, I-Ern Koh, Li-Yen Ng, Yuki Julius Ng We Yong, Kandasami Palayan, Chi Xuan Sam, Phuah Siow Jin, Jeremy Tan Ern Hwei, Yita Tang, Alvin Zubin Ter, Michael Pak-Kai Wong, Andee Dzulkarnaen Zakaria, Zaidi Zakaria, Fitjerald Henry, Thyivya Kalaiselvan, Muhammad Fairuz Shah Abd Karim, Mohamed Rezal Abdul Aziz, Nora Abdul Aziz, Tak Loon Khong, Peng Choong Lau, Hiong Chin Lim, April Camilla Roslani, Jonathan Chen Ken Seak, Sui-Weng Wong, Lai Fen Wong, Leow Yeen Chin, Mercy Chinemerem Anyanwu, Elaine Borg, Zachary Busuttil, Thomas Calleja, Kurt Lee Chircop, Ruth Cutajar, Andrew Michael Dimech, Sarah Ellul, Joseph Galea, Kiara Gascon Perai, Ruth Gatt, Lisa Kelman, Elizabeth Micallef, Favour Nwolu, Kim Sammut, Joanna Thompson, Sean Warwicker, Matthew Zammit, Fernando Cordera, Efraín Cruz González, Jorge Sánchez-García, Francisco José Barbosa Camacho, Francisco Javier Barrera López, Carlos Jose Zuloaga Fernandez del Valle, Eric Acosta, Iván Romarico González Espinoza, Perla Moreno, Ana Olivia Cortes-Flores, Clotilde Fuentes Orozco, Alejandro Gonzalez Ojeda, Samantha Corro Díaz González, Laura Martinez, Antonio Ramos-De la Medina, Bonifacio Mosqueda Amador, Armando Novoa, Dennet Arturo Olazo Espejo, Alejandro Jimenez, Federico Lopez Rosales, Elva Gabriela Vanoye, Luis Alberto Garcia Gonzalez, Roberto Carlos Miranda-Ackerman, Manuel Solano-Genesta, Alethia Alvarez-Cano, Hector Hugo Romero-Garza, Heriberto Medina-Franco, Lorelí Mejía-Fernández, Noel Salgado-Nesme, Omar Vergara-Fernandez, Guadalupe Montserrat Gutiérrez-Mota, Francisco Xavier Hernandez Vera, Anabella Llantada Lopez, Gilberto Morgan Villela, Felipe de Jesus Ramirez Padilla, Walezka Tapia Marin, Mónica Martínez Maldonado, Ramses Sánchez Suárez, José Manuel Troche, Chaymae Benyaiche, Oumaima Outani, Souadka Amine, Amine Benkabbou, Anass Mohammed Majbar, Raouf Mohsine, Ali Rafik, Thida Oung, Moe Moe Tin, David W Borowski, Philipp Plarre, David W Borowski, Philipp Plarre, Anna Alberga, Nina Sluiter, Jurriaan Tuynman, Robin Blok, Didem Cömert, Roel Hompes, Marianne Kalff, Merel Elisabeth Stellingwerf, Pieter Tanis, Mark van Berge Henegouwen, Elise Maria van Praag, Daan Wisselink, Michael Gerhards, Josephine Lopes Cardozo, Emma Westerduin, Joske de Jonge, Aaw van Geloven, Kaz van Schilt, Frank den Boer, Simone Stoots, Stijn Vlek, Jamie Adams, Ibrahim S. Al-Busaidi, Gabrielle Budd, Seung il Choi, Michael Jen Jie Chu, Anurag Ganugapati, Lucy McKinstry, Rebecca Pascoe, Simon Richards, Kenrick Rosser, Annie Stevenson, Rebecca White, Shebani Farik, Jin Kwun, Ahmed Murad, Sarah Cowan, Timothy Hall, Michael Hayton, Laminou Malam Sani, Souleymane Oumarou Garba, Harissou Adamou, Ibrahim Amadou Magagi, Oumarou Habou, Halima Aliyu, Muhammad Daniyan, Tunde T. Sholadoye, Lawal Abdullahi, Lofty-John Anyanwu, Aminu Mohammad Mohammad, Abubakar Bala Muhammad, Abdurrahman Abba Sheshe, Ibrahim Suleiman, Alaba Adesina, Ajibola Awolowo, Clement Onuoha, Omotayo Salami, Ogechukwu Taiwo, Agboola Taiwo, Stephen Kache, Jerry Godfrey Makama, Danjuma Sale, Olajide Abiola, Akinlabi Ajao, Anthony Ajiboye, Amarachukwu Etonyeaku, Julius Olaogun, Ademola Adebanjo, Opeoluwa Adesanya, Michael Olatunji Afolayan, Olanrewaju Balogun, Ayomide Makanjuola, Samuel Nwokocha, Rufus Wale Ojewola, Thomas Olagboyega Olajide, Adewale Aderounmu, Abdul-Rashid Adesunkanmi, Adewale Adisa, Augustine Agbakwuru, Adeleke Akeem Aderogba, Olusegun Isaac Alatise, Olukayode Arowolo, Oladejo Lawal, Tajudeen Mohammed, Chinedu Ndegbu, Olalekan Olasehinde, Funmilola Wuraola, Akinbolaji Akinkuolie, Amarachukwu Etonyeaku, Arinzechukwu Mosanya, Omobolaji Ayandipo, Peter Elemile, Taiwo Akeem Lawal, Samuel Ali SANI, Stephen Garba, Rebecca Hauwa SANI, Samson Olori, Henry Onyebuashi, Ifeanyi Umoke, Adedire Adenuga, Ademola Adeyeye, Olufemi Habeeb, Bashir Lawal, Abdulrasheed Nasir, Eirik Kjus Aahlin, Didrik Kjønås, Elisabeth Myrseth, Jibran Abbasy, Abdul Alvi, Omair Saleem, Asma Afzal, Anam Nazir, Muhammad Farooq, Ayesha Liaqat, Syed Asghar Naqi, Ali Raza, Muzna Sarfraz, Muhammad Sarwar, Muntaha Banglani, Ambreen Munir, Rahmat Sehrish, Bushra Ayub, Raza Sayyed, Amna Altaf, Saima Ayub, Ahmad Uzair Qureshi, Komal Saeed, Bilal Syed, Sana Amir Akbar, Abdul Wahid Anwer, Ruqayya Naheed Khan, Amina Iqbal Khan, Shahid Khattak, Sameen Mohtasham, Muhammad Asad Parvaiz, Aamir Ali Syed, Abdul Basit Ansari, Noman Shahzad, Tanwir Khaliq, Isbah Rashid, Shahzad Hussain Waqar, Hasan Abu Al-saleem, Amjad Abu Alqumboz, Mohammad Alqadi, Adham Amro, Rawan Assa, Eman Awesat, Rawan Ayyad, Mohammed Hammad, Ayat Haymony, Bassel Hijazi, Bara Hmeidat, Rowaa Lahaseh, Aseel Qawasmi, Alaa Rajabi, Mohammed Shehada, Sundus Shkokani, Yasmine Yaghi, Nadine Yaghi, Mohammad AlZohour, Mohammad Farid, Yousef Mahmoud Habes, Wesam Juba, Yanal Nubani, Abdelrahman Rabee, Mohammad Sa'deh, Saeed Abed, Iyad Al basos, Mohammad Alswerki, Dina Ashour, Israa Awad, Samar Diab, Alaa El Jamassi, Sahar El-Kahlout, Somaya Elhout, Ahmed N K Hajjaj, Doaa Hasanain, Baraa Nabil hajjaj, Mohammed Obaid, Eman Saikaly, Ahmed Salhi, Hiba Al-Tammam, Murad Almasri, Muath Baniowda, Doha Beshtawi, Ali Horoub, Rami Misk, Bayan Mohammad, Rami Qasrawi, Tasnim Sholi, Samar Abu-Nimeh, Abrar Abu-srour, Sadi A. Abukhalaf, Samer Adawi, Barah Alsalameh, Kholoud Ayesh, Muawiyah Elqadi, Ahmad Hammouri, Fatima Karim Mustafa, Natalie Marzouqa, Shatha Melhem, Dima Miqdad, Balqees Mohamad, Mhammed Rawhi, Ayman B. Abu Ahammala, Ahmed Abu Ataya, Israa Abu Jayyab, Samar Al-Shwaikh, Othman Alagha, Mohammed Alasttal, Haneen Awadallah, Mahmood Elblbessy, Jehad Fares, Akram Jarbou, Ibtisam Mahfouz, Moath A. Albahnasawi, Asmaa' Abo mahadi, Hasan Abuelhatal, Ayham Abuelqomboz, Abdelrahman Almoqayyad, Abdallah Alwali, Reem Balaawi, Mahmoud Hamouda, Mohammed Humeid, Abdullah Jedyan, Tasneem Mahmoud Abu hamam, Ghadeer Matar, ALi Salem, Tahani Samra, Nureddin Shaheen, Karam Shihada, Ayoob A.Nemer, Mahmoud Abu Al Amrain, Abdulwhhab Abu Alamrain, Najlaa Abu Jamie, Mohammed R. Abu-Rous, Nada Alfarra, Mohammed AlTaweel, Noor Alwhaidi, Ramadan Hamed, Bader Saqqa, Ahmad Shaheen, Dana Aljaber, Loay Aljaberi, Malak Alwaheidi, Assef Jawaada, Hani Khaldi, Rami Qahoush, Jalil Qari, Rana Saadeh, Ahlam Salim, Aseel Yacoub, Abbas Abbas, Rana Abu shua'ib, Baraa Abu Zainah, Mahmoud AbuSirrees, Basheer Babaa, Ola Barhoush, Asef Belal qadomi, Laith Daraghmeh, Reema Haji, Alaa Khatatbeh, Lana Khatib, Salsabeel Qarariah, Yara Quzmar, Khalil Safadi, Roqaya Salameh, Mohammad Hassan, Shifaa Herzallah, Loai Massad, Ahmed Nazzal, Ranin Nazzal, Dennis Escobar, Gustavo Miguel Machain V, Agustin Rodriguez Gonzalez, Jorge Emerson Chachaima Mar, Nathaly Olga Chinchihualpa Paredes, Vicente Cuba, Walter Lopez, Maria Milagros Niquen Jimenez, Nestor Alberto Sanchez Bartra, Olenka Sapallanay Ojeda, Diego Sequeiros, Andrea Toscano Pacheco, María Vergara, Sol Abarca, Rodrigo Alcorta, Giuliano Borda-Luque, Ivan Edward Eusebio Zegarra, Claudia Luján López, Mirella Marrufo, Cinthya Mogrovejo, Andrea Nomura, Yamile Rodríguez Angeles, Maitza Rosario Vidal Meza, Gabriela Zavala, José Neiser Castillo Arrascue, Jomara Caroline Hidrogo Cabrera, José Julio Mariano Larrea vera, Miguel Osorio, Edgar Alcides Ylatoma Díaz, Mark Anthony Fontanilla, Joseph Roy Fuentes, Anna Leah Salazar, Genieve Dominguez, Marc Paul Lopez, Shiela Macalindong, Mark Augustine Onglao, Arjel Ramirez, Marie Dione Sacdalan, Mayou Martin Tampo, Gemma Leonora Uy, Jeremiah Mangahas, Kenneth Yabut, Joannes Paul Cañete, Bernalynn Eris Cansana, Ernes John Castro, Maria Kaiserin Lipana, Manuel Francisco Roxas, Vlu Jean Zara, Maciej Chrol, Paula Franczak, Michal Orlowski, Piotr Budzynski, Andrzej Budzynski, Pawel Bury, Agata Czerwinska, Jadwiga Dworak, Jacek Dziedzic, Michal Kisielewski, Jan Kulawik, Anna Lasek, Piotr Major, Piotr Malczak, Marcin Migaczewski, Michal Pedziwiatr, Magdalena Pisarska, Dorota Radkowiak, Mateusz Rubinkiewicz, Anna Rzepa, Tomasz Skoczylas, Maciej Stanek, Katarzyna Truszkiewicz, Mateusz Wierdak, Marek Winiarski, Piotr Zarzycki, Anna Zub-Pokrowiecka, Piotr Kowalewski, Rafal Roszkowski, Maciej Waledziak, Miguel Tomé, Sara Patrocinio, Ines Guerreiro, Filipe Almeida, Xavier de Sousa, Nuno Monteiro, Maria Teresa Costa Santos, Daniela de Oliveira, Marta Lopes Serra, Daniela Morgado, Christian Neves, Ana Carolina Oliveira, Alice Pimentel, Sofia Silva, Márcia Carvalho, Lúcia Carvalho, Joana Magalhães, Leonor Matos, Tânia Monteiro, Carlota Ramos, Vanessa Santos, José Barbosa, Jose Costa-Maia, Vítor Devezas, Ana Fareleira, Cristina Fernandes, Diana Gonçalves, Henrique Mora, Marina Morais, Fabiana Silva de Sousa, Sara Catarino Santos, Ana Logrado, André Tojal, Edgar Amorim, Miguel F. 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Nsengimana, Carine Uwakunda, Mohammad Monir Abbas, Nouf Akeel, Murad Aljiffry, Kholoud Awaji, Ali Farsi, Ghader Jamjoum, Ahmad Khoja, Ashraf Maghrabi, Nadim Malibary, Mohammed Nassif, Abdulaziz Saleem, Abdullah Sultan, Wail Tashkandi, Hanaa Tashkandi, Nora Trabulsi, Mouhamadou Bachir Ba, Adja Coumba Diallo, Abdourahmane Ndong, Vladica Cuk, Uroš Jankovic, Jovan Juloski, Sharon Zhiling Koh, Frederick Koh, Kuok Chung Lee, Kai Yin Lee, Sean Lee, Wei Qi Leong, Bettina Lieske, Su Ann Lui, Prajwala Prakash, Jan Grosek, Gregor Norcic, Ales Tomazic, Nicolas Fitchat, Robert Jaich, Devorah Wineberg, Modise Zacharia Koto, Daniella Baiocchi, Damian Clarke, Christina Johanna Steenkamp, Stephanie Van Straten, Sharon Bannister, Adam Boutall, Galya Chinnery, Anna Coccia, Angela Dell, Parveen Karjiker, Christo Kloppers, Nicholas Loxton, Tumi Mabogoane, Francois Malherbe, Eugenio Panieri, Shreya Rayamajhi, Richard Spence, Tirsa van Wyngaard, Claire Warden, T E Madiba, Yoshan Moodley, Nivashen Pillay, Savannah Brooks, Charlise Kruger, Lisa Hannah Van Der Merwe, Ferhana Gool, Maahir Kariem, Heather Bougard, Kathryn Chu, Nazmie Kariem, Fazlin Noor, Reantha Pillay, Leandi Steynfaardt, Lucía González González, José Miguel Marín Santos, Paula Martín-Borregón, Javier Martínez Caballero, Cristina Nevado García, Pastora Rodriguez Fraga, Gonzalo De Castro Parga, Maria Pilar Fernández Veiga, Lucía Garrido López, Hugo Infante Pino, Irene Lages Cal, Marta López Otero, Manuel Nogueira Sixto, Marta Paniagua García Señorans, Laura Rodríguez Fernández, Alejandro Ruano Poblador, Erika Rufo Crespo, Raquel Sanchez-Santos, Vincenzo Vigorita, Ester Alonso Batanero, Dorisme Asnel, Isabel Cifrian Canales, Elisa Contreras Saiz, Irene De Santiago Alvarez, Tamara Díaz Vico, Sebastian Fernandez Arias, Daniel Fernández Martínez, Carmen García Bernardo, Luis Joaquín García Flórez, Carmen Garcia Gutierrez, Manuel García Munar, Carlos Alberto Márquez Zorrilla Molina, Marta Merayo, José Luis Michi Campos, Maria Moreno Gijon, Jorge L. 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Eimear Monaghan, James Crawford, Susan Moug, James Blackwell, Hannah Boyd-Carson, Philip Herrod, Omar Al-Allaf, Miriam Beattie, Cameron Bullock, Shivang Burman, Gemma Clark, Nicolas Flamey, Oliver Flannery, Alexander Harding, Ben Kodiatt, Samuel Lawday, Shivani Mahapatra, Navin Mukundu Nagesh, Michael Ng, Dupinderjit Rye, Andrel Yoong, Laura Clark, Chris Deans, Monisha Edirisooriya, Cameron J Fairfield, Ewen M Harrison, Emma Victoria Carrington, Tsz Lun Ernest Wong, Baasil Yusuf, Carla Chamberlain, Kathryn Duke, Elizabeth Kmiotek, Azel Botes, Natalie Condie, Timothy Schrire, Reena Shah, Iolo Thomas-Jones, Charlotte Yates, Natasha Anthony, Edward Matthews, Kapil Sahnan, James Tankel, Sally Tucker, Jasmine Winter Beatty, Paul Ziprin, William Duggan, Anastasia Kantartzi, Shruthi Sridhar, Rachel Alys Khaw, Prakhar Srivastava, Charlotte Underwood, Homero Alves do Canto Brum, Sharat Chopra, Laura Davis, Rebecca Hughes, Joshua Tulley, Justin Alberts, Thomas Athisayaraj, Mojolaoluwa Olugbemi, Kasim Ahmad, Claudia Chan, Gavin Chapman, Hannah Fleming, Benjamin Fox, Julia Grewar, Kate Hulse, Duncan Rutherford, Mackay Sinead, Scott Smith, Doug Speake, Peter G Vaughan-Shaw, Natasha Christodoulides, Simrit Kudhail, Matthew Welch, Syed Muhibullah Husaini, Simon Lambracos, Chikamuche Anyanwu, Rishi Suresh, Jimmy Scott Thomas, Elizabeth Gleeson, Rebecca Platoff, Areeba Saif, Zachary Enumah, Eric Etchill, Alodia Gabre-Kidan, Mitchell Bernstein, Francesco Maria Carrano, Joseph Connors, Patricio Lynn, Marcovalerio Melis, Elliot Newman, Deshka S Foster, Kenneth Perrone, Ashley Titan, Thomas G Weiser, Sarwat Ahmad, Andrea Chao M.D. Bafford, Marco Dal Molin, Nader Hanna, Syed Nabeel Zafar, Mark Hemmila, Lena Napolitano, Jane J Wong, Julia Chandler, Lauren Wood, Sherry Wren, Taylor Ottesen, Lucia You, Kristin Yu, María del pilar Arciénega Yañez, Martin Ferreira Fernandes, Daniel González, Santiago Cubas, María Catalina González, Vanessa Zubiaurre, Rodrigo Demolin, Nicolas Giroff, Pablo Sciuto, Maite Campos, Gabriela Rodríguez Cantera, Gabriela Wagner, Garg Deepika, Mayaba Maimbo, Elliot Simuchimba, Anadi Bulaya, Chali Chibuye, Bright Chirengendure, Mary-Rose Kabale, Kizito Kabongo, David Linyama, James Munthali, Oliver Mweso, Francis Pikiti, James Otieno, Erick Chan, Log Tung Lai, Brighid Blackman, Sophie Richards, Suren Subramaniam, Rafid Karim, Nathan Kok, Yanni Dion Lee, Shabina Ali, Aanjaneya Sinha, Robert Corrigan, Nicole Barnes, Florence Wong, Grace Dennis, Julia Jedamzik, Emil Phillips, Wivine Piette, Marie Van hentenryck, Houenoukpo Koco, Souliath Lawani, Mamo Woldu Kassa, Tainá Santos Bezerra, Petar Gribnev, Dobromir Dimitrov, Panche Krastev, Sovannarith Oum, Divine Tim Bonghaseh, Maryam Al Farsi, Nourah Alsharqawi, Arnav Agarwal, Veronica Acevedo, Andrea Carolina Castillo Barbosa, Felipe Giron, Jimmy Paul Leon Rodriguez, Darko Kucan, Damir Rosko, Neven Barsic, Domagoj Župan, Amgad Hegazi, Vendula Truncíková, Vladimir Fryba, Mostafa Mohamed, Ahmed Sultan, Ahmed Nagi, Abdallah Rashad Temerik, Mohamed Elemam Elshawy, Moustafa Ibrahim Mahmoud, Shrouk Omar, Mohamed Anwar, Tarek Rageh, Aya Elmokadem, Khaled Gaballa, Sandra Teppo, Antti Turunen, Pasi Pengermä, Quentin Ballouhey, Damien Bergeat, Ariane Weyl, Elisabeth Hain, Adam Gyedu, Edwin Yenli, Dorcas Osei-Poku, Vaia-Aliki Rompou, Athanasios Zoikas, Apostolos Gaitanidis, Georgios Koukis, Konstantinos Perivoliotis, Panagiotis Tavlas, Konstantinos Galanos-Demiris, George Zografos, Ioannis Karavokyros, Georgia Xanthopoulou, Eirini Iordanidou, Fernanda Ayau, Allan Garcia, Pekli Damján, Deepender Wason, Ashika B L, Ervandy Rangganata, Prerna Kamath, Donal B O'Connor, Margherita Pinto, Fabrizio Perrone, Francesca Paola Tropeano, Francesca Troilo, Daniela Bossi, Dario Scala, Lucrezia Pulitanò, Marcella Carella, Andrea Pietrabissa, Alice Gori, Giorgio Giraudo, Veronica De Simone, Alfio Alessandro Russo, Bartolomeo Braccio, Raed Al-Taher, Sarah Athamneh, Andrea Parker, Adnan Sawiee, Amina Kattia, 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Supplementary Material
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The dataset can be explored using an online visualisation application online. Hospital-level data can be shared by application to the corresponding author. For analyses of patient-level identifiable data within our trusted research environment, please contact the corresponding author.