Impact of High-Altitude Hypoxia on Mortality from Acute Lymphoblastic Leukemia in Mountain Regions of Ecuador

Impact of High-Altitude Hypoxia on Mortality from Acute Lymphoblastic Leukemia in Mountain Regions of Ecuador | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Impact of High-Altitude Hypoxia on Mortality from Acute Lymphoblastic Leukemia in Mountain Regions of Ecuador Xavier García-León, Esteban Fernandez-Moreira, Manuel Gómez del Moral, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7408518/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose: Acute lymphoblastic leukemia (ALL) is a rare hematological cancer that primary affects children, although its prognosis for survival is better than that of ALL in adults. We investigated the possibility that hypoxia brought on by high altitude might be an AAL-death risk factor by examininghow altitude could modify age-dependent pattern of ALL-mortality. Methods: In Ecuador, an epidemiological investigation was conducted to examine the spatial distribution of ALL mortality by sex and age in relation to altitude. The sample was divided into children (≤ 17 years old) and adults (≥ 18 years old), in addition to sex as a differentiator. ALL age-adjusted mortality rates per 100,000 inhabitants were calculated from 2011 to 2022. Relative Risk was computed to estimate the likelihood of ALL-death for both pediatric and adult groups across altitude categories. For comparisons based on sex, the t -test was applied. Results: When ALL-death rates was analyzed by altitude, the current investigation revealed significant age differences. Adults who lived over 2000 m were almost twice as likely to die from ALL as those who lived at sea level. Low and moderately high altitudes (1000-2000 m) provided a protective benefit in the pediatric group (only boys), while elevations beyond 2000 m appeared to eliminate this effect. Conclusions: Our results highlight altitude as a biometeorological factor influencing ALL mortality. ALL mortality rates were negatively impacted by altitude. Children could be harmed by hypoxia at elevations higher than 2000 m above sea level, although the effect was worse in adults. Our results support the emerging notion that hypoxia-inducible factor pathway contributes to ALL. Age groups Altitude sickness Death Demographic analysis Hypoxia-Inducible Factor 1 Leukemia lymphoid Figures Figure 1 1. INTRODUCTION Acute lymphoblastic leukemia (ALL), also known as acute lymphocytic leukemia, is a rare type of cancer that affects blood and bone marrow and that is characterized by the development of large numbers of immature lymphocytes due to a DNA mutation. Excessive number of immature lymphocytes interfere with the production of new red blood cells, white blood cells, and platelets in the bone marrow resulting in a characteristic disease pattern. Between 75% and 80% of cancers in children and adolescents under 15 years of age are ALL cases, making it the most kind of malignity in this age group in Latin America [ 1 , 2 ]. There are no obvious reasons why children develop the disease, which progresses rapidly in the absence of treatment. Childhood ALL is regarded as a complex disease that results from the interplay of genetic and environmental factors over the course of a multistage sequence [ 3 ]. Although acquired genetic disorders such as Down syndrome, Klinefelter syndrome, Fanconi anemia to say a few are among the risk factors linked with the disease, only a small fraction (less than 10%) can be ascribed to genetics [ 4 ]. Environmental risks factors like prior exposure to chemotherapy, radiation/ionizing therapy, and benzene, infections, a weakened immune system, and diet also have an influence in the development of childhood ALL [ 5 , 6 ]. Data from the Global Cancer Observatory ( https://gco.iarc.fr/en ) show that 29,273 cancer cases were reported in Republic of Ecuador in 2021, with 1,199 of those cases being related with children cancer. The incidence of ALL in Ecuadorian children between 2 to 5 years old has increased relative to the global prevalence; with rates ranging from 20 to 80 cases per 100,000 habitants [ 7 , 8 ]. The study on ALL is especially relevant in the Ecuadorian context. The magnitude of mining and agriculture exploitation in the Republic of Ecuador [ 9 ], as well as the substantial geographical and environmental disparities between the Coast and Andean regions [ 10 ] might have an impact on ALL prevalence. Almost seven million Ecuadorians reside in the Andean region, whose elevations range between 1800 m and 6268 m above sea level. Because malignant behavior and angiogenesis in cancer cells are known to be enhanced by hypoxia [ 11 – 13 ], high altitude-induced hypoxia is likely to affect unfavorable ALL prognosis [ 14 , 15 ]. One of the distinguish characteristics of ALL is that adult survival rates are lower (30–40%) than those for children, where survival surpass 90%. We carried out a nationwide epidemiological and geodemographic study to determine ALL-death prevalence and mortality distribution by age across the high and lowlands of the Republic of Ecuador. Examining how altitude could modify age-dependent pattern of ALL mortality was intended to validate the hypothesis that high altitude-induced hypoxia might be an environmental risk factor for the mortality of the illness. 2. METHODS 2.1 Study design An epidemiological study on spatial distribution was conducted to examine ALL mortality by sex and age according to altitude above sea level (a.s.l.) in the Republic of Ecuador. 2.2 Study zone The Republic of Ecuador, the smallest country in the Andean region of South America (256,370 km²), is located in the northwest of the continent, and borders Colombia to the north, Peru to the southeast, and the Pacific Ocean to the west (Fig. 1 ). The Andes ridge, with altitudes exceeding 5,000 m a.s.l., divides the country geographically. Administratively, the country is divided into 24 provinces, each of which is further subdivided into counties, also known as canton . Parishes are the next level of subdivisions for each canton . Each provincial canton served as the analytical spatial unit (Fig. 1 ), since the parishes assigned to each canton has comparable altitudinal characteristics. A total of 221 cantons were included in the study. 2.3 Population description According to data from the National Institute of Censuses and Statistics (INEC) [ 16 ], in 2022 the Republic of Ecuador was home to 17,082,730 inhabitants (49% women and 51% men). This represents 0.2% of the global population and 2% of the Latin American population. The population under the age of 18 was 36%. Ecuadorian population grew by 2.5 million people (17%) between 2011 and 2022 The demographic profile reflected a higher proportion in urban areas (63%). The most populated areas were the Coast (53%, seven provinces) and the Andes (41%, ten provinces), while the least populous ones were the Amazon (5.8%, six provinces) and the Galapagos Islands (0.2%, a single province). 2.4 Data collection Death certificates with ALL listed as the underlying cause of death (ICD-10: C91.0) were retrieved from the INEC-sponsored Statistical Register of Deaths database [ 16 ], a publicly available online source of information. The time frame covered was 2011–2022. Cases of incomplete data were eliminated from the analysis. To minimize bias and ensured higher accuracy, rather than the place where the death certificate was issued, the deceased person´s canton of residence was taken into account. 2.4 Data categorization Based on earlier studies on age disparities in ALL survival [ 17 – 21 ], as well as the definition of pediatric age [ 22 ], patients sample was divided into two groups: pediatrics (≤ 17 years old) and adults (≥ 18 years old), in addition to sex (women and men) as a differentiator. Oxygen partial pressure decreases with altitude [ 23 ]. The following height levels were considered in order to evaluate the potential association between altitude and ALL-mortality rates [ 24 – 26 ]: Sea Level (< 500 m a.s.l.), Very Low (500 m ‒ < 1000 m a.s.l.), Low (1000 m ‒ < 1500 m a.s.l.), Low Moderate (1500 m ‒ < 2000 m a.s.l.), Moderate High (2000 m ‒ 2500 m a.s.l.). For ALL mortality comparisons between altitudes, the a.s.l. elevation for each canton was obtained from the Military Geographic Institute web site ( https://www.geograficomilitar.gob.ec/ ). 2.6 Statistics Age-adjusted mortality rates per 100,000 inhabitants were calculated for the overall observation period (2011–2022). The rate adjustment was performed using the direct method, and stratifications were made by defined age groups and sex [ 27 ]. The annual projections of the population by age group and sex at the provincial canton level were obtained from the INEC based on the latest census available in the country [ 16 ]. Additionally, Relative Risk (RR) was calculated to estimate the probability of mortality in the population, using the cantons of Sea Level (< 500 m a.s.l.) as the reference for both pediatric and adult groups, with their 95% confidence intervals (CI) to assess globally and by sex. The t -test was applied for binary comparisons while alpha-value was set at 0.05 for statistical significance. 2.7 Ethics An ethics committee review was not required because the study was retrospective in nature and used publically available secondary registers for non-experimental research. The files did not contain identifiable personal information that would violate the Helsinki declaration or international and national best practices recommendations. We followed STROBE guidelines to report this study. 3. RESULTS 3.1. Absolute distribution of ALL mortality Table 1 shows the demographic characteristics of the sample distributed by heights above sea level in order to find important patterns regarding ALL mortality. The majority of people (51.8% spread throughout 43.4% of the cantons ) live at Sea Level ( 2500 m a.s.l. High Altitude) is the second most inhabited region (28.6%). At Low Altitude cantons (500-1000 m a.s.l.), on the other hand, are the less inhabited (13.6% of the cantons with a population of 7.7%). In terms of age groups distribution, Very Low Altitude cantons (< 500 m a.s.l.) host the highest prevalence of children (18.9% of the pediatric population) and adults (33.2%). Adults and children make up 19.0% and 9.6% of the population at the High Altitude cantons (> 2500 m a.s.l.) respectively. Regarding the distribution of ALL deaths by elevation (Table 1), 46.1% are concentrated at Sea Level (< 500 m a.s.l). The most densely populated areas, the provincial cantons located below 500 m height (Sea Level) and above 2500 m height (High Altitude), had the highest rates of ALL deaths ‒ 46.1% and 36.3%, respectively (Table 1). When compared by age group, Sea Level ( 2500 m a.s.l.) was 11.2%, which is quite high considering that 9.6% of the pediatric population lives at this elevation. Only 19.0% of the adult population lives at high altitudes, while adult ALL-deaths account for 25.1% of the total ALL-death population. Overall, mortality from ALL indicate that in the pediatric group, males had higher death rates than females (21.1% versus 4.9%), while similar death rates were observed in adults (males: 32.2% and females: 31%). 3.2. Adjusted distribution of ALL mortality rates Details on adjusted mortality rates according to altitude by age groups and sex can be found in Table 2. Below 500 m a.s.l. height, the adjusted overall death rate was the lowest (16.1 per 100,000 inhabitants), grew at relatively high elevations (21.4 per 100,000 inhabitants between 2000 and 2500 m a.s.l.), and reached its maximum over 2500 m a.s.l. (23.0 per 100,000 inhabitants). This pattern shows a clear correlation between altitude and higher ALL-mortality. In the pediatric population living below 500 m a.s.l., the adjusted mortality rate was 19.8 per100,000 inhabitants, the highest at Sea Level. While the ALL-death rate in pediatrics drops to 14.7 at Moderately High Altitude (2000-2500 m a.s.l.), it raises to 21.3 at High Altitude (> 2500 m a.s.l.) and then returns to levels comparable to those below 500 m a.s.l. Compared to the pediatric group, the adjusted death rate for adults at Sea Level (500 m a.s.l.) was lower (14.0). Moderately High Altitudes (2000 to 2500 m a.s.l.) had the greatest adult mortality rate (25.0), whereas the High Altitud elevation also had a high rate (23.9). As a result, there was a noticeable rise in the mortality rate above 2000 m a.s.l., suggesting that adults were more susceptible to altitude effects. The adjusted mortality rate was 22.7 for the male pediatrics and 14.7 for male adults at Sea Level (< 500 m a.s.l.). The male pediatric mortality rates dropped to 15.2 at Moderate High Altitude (2000 m to 2500 m a.s.l.), whereas the adult mortality rate raised to 27.5, the highest of all altitude categories. However, death rates for men raised to 23.4 in pediatrics at High Altitude (> 2500 m a.s.l.), while they stay steady at about 25.7 in adults. In females, a similar trend was observed. The adjusted death rate was 13.3 for adults and 16.7 for pediatrics at Sea Level ( 2500 m a.s.l.), the rates increased to 19.0 for pediatric girls, and hardly changed for adult females (22.4). 3.3. Comparisons of ALL-death relative ratios by altitude, sex, and age groups. The prevalence of ALL mortality in adult and children varies with increasing altitude, as Table 3 illustrates. In comparison with Sea Level (< 500 m a.s.l.), the risk of ALL mortality generally increases above 2000 m a.s.l., that is, in the Moderately High Altitude and High Altitude categories. Adults of both sexes had the highest risk of ALL mortality over 2000 m a.s.l. (Moderate High Altitude: RR: 1.8, 95% CI: 1.6-1.1, P < 0.001; High Altitude: RR: 1.7, 95% CI: 1.6-1.9, P < 0.001), but male pediatrics had a lower risk of ALL death at 500-1000 m. a.s.l., as well as at 1500-2500 m a.s.l. (Low Altitude: RR: 0.4, 95% CI: 0.3-0.6, P < 0.001; Moderate Altitude: RR: 0.3, 95% CI: 0.1-0.9, P < 0.05; Moderate High Altitude: RR: 0.7, 95% CI: 0.5-0.9, P < 0.001). At any altitude, no statistically significant differences were seen in pediatric females. Furthermore, the risk for ALL mortality in adults of both sexes did not change between Sea Level (< 500 m a.s.l.) and elevations below 2000 m. a.s.l. 4. DISCUSSION The current study showed notable age disparities when the ALL-death prevalence was broken down by altitude. Adults living over 2000 m a.s.l. had nearly twice the risk of dying from ALL compared to those living at Sea Level (< 500 m a.s.l.). In the pediatric group, low and moderate high altitudes had a protective effect, but it seemed to be lost when elevation exceeded 2000 m a.s.l. and based on sex. The association between ALL-death risk and altitude was supported by the fact that age greatly impacts on the likelihood of recovery from ALL. At heights exceeding 2000 m a.s.l., ALL-mortality rates increased, suggesting that hypoxia derived from altitude could contribute negatively to the evolution of ALL. The body responds to prolonged exposure to environmental induced hypoxia by generating a a protein called hypoxia-inducible factor (HIF-1), which sets off a cascade of adaptive physiological changes to the low oxygen partial pressure [28]. The HIF-1α protein (HIF-1A gene) oxygen-dependent degradation controls its activity [29]. In this regard, it may be concluded that age-based maladaptation to altitude may be the cause of the age-related variations in ALL-death vulnerability at high altitude. Nonetheless, the evidence reviewed indicates that the onset of high altitude illnesses is unrelated to age [30–32]. According to some studies, HIF-1α has a role in leukemia [33]. In particular, in childhood ALL, the HIF pathway is activated [34, 35], which accelerates the diseases´ progression [36, 37]. Because the HIF pathway causes increased, fast, and chaotic vascular development [11, 38] as well as metabolism disruptions [39] in cancer, its role in adult susceptibility to ALL-death is also significant. In ALL, HIF-1α system contributes to chemo-resistance [40–42]. Given that age and HIF functioning are interdependent [43–45], it stands to reason that variations in the risk for ALL mortality that are connected to age and altitude may be explained by the HIF pathway. In line with earlier findings [46], boys have worse ALL survival rate than girls. For this reason, we were surprised to discover that boys in the pediatric group were less affected by ALL-death than girls in the very low, moderate, and moderate-high ranges of altitude (Table 2). This leads to speculate that there may be biological and statistical differences that account for this phenomenon. There are sex-dimorphic HIF physiological responses to altitude-induced hypoxia [47], as well as HIF-mediated responses [48]. Moreover, there is epidemiological evidence that living at moderate altitude is associated with lower death rates [49]. Therefore, complex age-sex interactions that warrant more research could account for the absence of sex-based differences in the adult group, but not in the pediatric one. It could be argued that our results are too particular to the Ecuadorian case to be generalizable to other populations. The Ecuadorian population has the same risk of developing cancer at high altitudes as other populations [15, 50], despite their apparent capacity to adapt to hypoxic environments [51]. Finally, because there is minimal evidence that excessive solar ultraviolet irradiation [52] and Latino/Hispanic ethnicity [53] raises ALL risk, our study ignored their effects in diseases´ mortality rates. To the best of our knowledge, this is the first study to investigate the association between altitude and ALL survival because one of the characteristics that sets ALL apart is its age-dependent survival rate, and height-based ALL-death risk also depended on age. This study has a number of strengths. Using data for all cantons across the Coast, Andean, and Amazonian regions of Ecuador from a long period (2011–2022) led to robust estimates of ALL-mortality rates over a large elevation range. Moreover, we used data from the INEC-sponsored Statistical Register of Deaths database, which undergoes rigorous quality control prior to publishing. Lastly, the Ecuadorian army´s official cartography site was used to ensure the canton ´s topographical and altitude accuracy. The study also has some limitations like the cause of death may be affected by regional variability in certification. Our analysis comparatively large sample size lessened the impact of errors in cause-of-death assignment. In addition, using mean canton elevation is equivalent to measuring the true altitude of residence with random error. The impact of height heterogeneity within each canton , was mitigated by the rather wide altitude categories that were utilized in our analysis. In conclusion, this study revealed that altitude has a negative effect on mortality rates from ALL. Although at altitudes greater than 2000 m a.s.l., hypoxia could also be harmful to children, this effect was much stronger in the adult population. Our findings add additional evidence of the impact of geographical and environmental determinants on the progression and incidence of the ALL disease. Fort the first time ever, our research gives epidemiological support to the impact of hypoxia on ALL. Up-to-date and geographically adapted interventions can reduce mortality from ALL in high-altitude areas. Declarations Funding sources The authors declare that no funds, grants, or other support was received during the preparation of the manuscript. Competing interests The authors have no relevant financial or non-financial interests to disclose. Authors´ contributions X.G-L., E.F-M., and S.B conceived and design the study. X.G-L. and K.C. were in charge on the acquisition of data; A.R.G-G. and K.C. analyzed and interpreted the data; X.G-L., M.G., and S.B. wrote the original draft; E.F-M., M.G., and A.R.G-G. revisited the manuscript critically for important intellectual content. All the authors wrote and approved the final version of the manuscript. Data availability The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation. Ethics approval Due to the retrospective nature of the study ‒ which involved non-experimental research using publicly accesible secondary registries ‒ an ethics committee was not necessary. There was not sensitive or private information in the datasets that would have infringed on the right to personal data protection. 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Cancer 128:1863-1870. doi: 10.1002/cncr.34150 Raberin A, Burtscher J, Citherlet T, Manferdelli G, Krumm B, Bourdillon N, Antero J, Rasica L, Malatesta D, Brocherie F, Burtscher M, Millet GP (2024) Women at altitude: Sex-related physiological responses to exercise in hypoxia. Sports Med 54:271–287. https://doi.org/10.1007/s40279-023-01954-6 Zampino M, Yuzhakova M, Hansen J, McKinney RD, Goldspink PH, Geenen DL, Buttrick PM (2006) Sex-related dimorphic response of HIF-1 alpha expression in myocardial ischemia. Am J Physiol Heart Circ Physiol 291:H957-64. doi: 10.1152/ajpheart.00580.2005 Burtscher M (2016) Lower mortality rates in those living at moderate altitude. Aging (Albany NY) 8:2603-2604. doi: 10.18632/aging.101057 Garrido DI, Garrido SM (2018) Cancer risk associated with living at high altitude in Ecuadorian population from 2005 to 2014. Clujul Med 91:188-196. doi: 10.15386/cjmed-932 Sánchez, K., Ramírez-Cando, L., Machado, W. Villafuerte A, Ballaz S. (2022) Mean corpuscular haemoglobin concentration (MCHC): a new biomarker for high-altitude pulmonary edema in the Ecuadorian Andes. Sci Rep 12:20740 https://doi.org/10.1038/s41598-022-25040-5 Little MP, Mai JZ, Fang M, Chernyavskiy P, Kennerley V, Cahoon EK, Cockburn MG, Kendall GM, Kimlin MG (2024) Solar ultraviolet radiation exposure, and incidence of childhood acute lymphocytic leukaemia and non-Hodgkin lymphoma in a US population-based dataset. Br J Cancer 130:1441-1452. doi: 10.1038/s41416-024-02629-3 Feng Q, de Smith AJ, Vergara-Lluri M, Muskens IS, McKean-Cowdin R, Kogan S, Brynes R, Wiemels JL (2021) Trends in acute lymphoblastic leukemia incidence in the United States by race/ethnicity from 2000 to 2016. Am J Epidemiol 190:519-527. doi: 10.1093/aje/kwaa215 Tables Table 1. Altitude-based distribution of Ecuadorian population and ALL-death rates . Altitude (a.s.l.) Total Sea Level Very Low Low Moderate Moderate High High < 500 m 500 ‒ < 1000 m 1000 ‒ < 1500 m 1500 ‒ < 2000 m 2000 ‒ 2500 m Average per canton (SD) 113.8 (121.6) 705.1 (151.6) 1182.4 (89.7) 1829.4 (115.5) 2263.8 (132.8) 2623.9 (680.9) 1327.6 (1143.9) Province cantons, n (%) 96 (43.4) 30 (13.6) 21 (9.5) 11 (5.0) 27 (12.2) 36 (16.3) 221 (100) Population n a (%) 8.7 (51.8) 1.3 (7.7) 0.1 (0.6) 0.2 (1.2) 1.7 (10.1) 4.8 (28.6) 16.8 (100) Pediatrics n a (%) 3.2 (18.9) 0.5 (3.0) 0.04 (0.2) 0.1 (0.5) 0.6 (3.5) 1.6 (9.6) 6.1 (35.7) Men 1.7 (9.8) 0.3 (1.6) 0.02 (0.1) 0.05 (0.3) 0.3 (1.8) 0.8 (4.9) 3.1 (37.4) Women 1.6 (9.1) 0.2 (1.4) 0.01 (0.1) 0.04 (0.2) 0.3 (1.7) 0.8 (4.7) 2.9 (34.1) Adults n a (%) 5.6 (33.2) 0.7 (4.4) 0.1 (0.4) 0.1 (0.8) 1.1 (6.5) 3.2 (19.0) 10.9 (64.3) Men 2.8 (16.3) 0.4 (2.1) 0.03 (0.2) 0.07 (0.4) 0.5 (3.1) 1.5 (8.9) 5.2 (62.6) Women 2.9 (16.9) 0.4 (2.3) 0.03 (0.2) 0.1 (0.4) 0.6 (3.4) 1.7 (10.2) 5.6 (65.9) ALL-deaths n (%) 1419 (46.1) 153 (5.0) 8 (0.3) 22 (0.7) 361 (11.7) 1118 (36.3) 3081 (100) Pediatrics 635 (20.6) 60 (1.9) 4 (0.1) 4 (0.1) 87 (2.8) 346 (11.2) 1136 (36.9) Men 376 (12.2) 26 (0.8) 3 (0.1) 3 (0.1) 46 (1.5) 196 (6.4) 650 (21.1) Women 259 (8.4) 34 (1.1) 1 (0.03) 1 (0.03) 41 (1.3) 150 (4.9) 150 (4.9) Adults 784 (25.4) 93 (3.0) 4 (0.1) 18 (0.6) 274 (8.9) 772 (25.1) 1945 (63.1) Men 405 (13.1) 49 (1.6) 2 (0.1) 7 (0.2) 142 (4.6) 386 (12.5) 991 (32.2) Women 379 (12.3) 44 (1.4) 2 (0.1) 11 (0.4) 132 (4.3) 386 (12.5) 954 (31.0) a million inhabitants Table 2. Adjusted ALL-mortality rate per 100,000 habitants according to altitude. Data are shown as relative ratio or RR (95% CI). Altitude (a.s.l.) Total Sea Level Very Low Low Moderate Moderate High High < 500 m 500 ‒ < 1000 m 1000 ‒ < 1500 m 1500 ‒ < 2000 m 2000 ‒ 2500 m Overall 16.1 (15.3-16.9) 12.2 (10.4-14.3) 7.8 (3.9-15.5) 9.9 (6.5-15.0) 21.4 (19.3-23.7) 23.0 (21.7-24.4) 18.2 (17.6-18.8) Pediatrics 19.8 (18.3-21.4) 11.9 (9.3-15.4) 10.8 (4.1-28.9) 4.6 (1.7-12.2) 14.7 (11.9-18.1) 21.3 0.1 19.1 23.6 18.8 (17.7-19.9) Men 22.7 (20.5-25.1)* 9.7 (6.6-14.2) 13.6 (4.4-42.1) 6.5 (2.1-20.1) 15.2 (11.4-20.3) 23.4 (20.4-26.9)* 20.7 (19.2-22.4)* Women 16.7 (14.8-18.9) 14.5 (10.3-20.3) 6.8 (1.0-48.0) 2.5 (0.3-17.4) 14.1 (10.4-19.2) 19.0 (16.2-22.3) 16.6 (15.2-18.2) Adults 14.0 (13.0-15.0) 12.4 (10.1-15.2) 6.1 (2.3-16.1) 13.3 (8.4-21.1) 25.0 (22.2-28.2) 23.9 (22.3-25.7) 17.9 (17.1-18.7) Men 14.7 (13.3-16.2) 13.5 (10.2-17.8) 6.0 (1.5-24.1) 10.8 (5.1-22.6) 27.5 (23.3-32.4) 25.7 (23.2-28.4) 18.9 (17.8-20.1) Women 13.3 (12.0-14.7) 11.4 (8.5-15.4) 6.1 (1.5-24.4) 15.6 (8.7-28.3) 22.8 (19.3-27.1) 22.4 (20.3-24.7) 16.9 (15.8-18.0) Statistical significance: * P < 0.05 compared to Women Table 3. Altitude-dependent prevalence of ALL-deaths. Data are shown as relative ratio or RR (95% CI). Altitude (a.s.l.) Sea Level Very Low Low Moderate Moderate High High < 500 m 500 ‒ < 1000 m 1000 ‒ < 1500 m 1500 ‒ < 2000 m 2000 ‒ 2500 m Overall Ref. 0.8 (0.6-0.9)*** 0.5 (0.2-1.0)* 0.6 (0.4-0.9)* 1.3 (1.2-1.5)*** 1.4 (1.3-1.5)*** Pediatrics Ref. 0.6 (0.5-0.8)*** 0.5 (0.2-1.5) 0.2 (0.1-0.6)** 0.7 (0.6-0.9)** 1.1 (0.9-1.2) Men Ref. 0.4 (0.3-0.6)*** 0.6 (0.2-1.9) 0.3 (0.1-0.9)* 0.7 (0.5-0.9)*** 1.0 (0.9-1.2) Women Ref. 0.9 (0.6-1.2) 0.4 (0.1-2.9) 0.1 (0.0-1.0) 0.8 (0.6-1.2) 1.1 (0.9-1.4) Adults Ref. 0.9 (0.7-1.1) 0.4 (0.2-1.2) 1.0 (0.6-1.5) 1.8 (1.6-2.1)*** 1.7 (1.6-1.9)*** Men Ref. 0.9 (0.7-1.2) 0.4 (0.1-1.6) 0.7 (0.3-1.5) 1.9 (1.5-2.3)*** 1.7 (1.5-2.0)*** Women Ref. 0.9 (0.6-1.2) 0.5 (0.1-1.8) 1.2 (0.6-2.2) 1.7 (1.4-2.1)** 1.7 (1.5 1.9)** Statistical significance: * P < 0.05; ** P < 0.01; *** P < 0.01 compared to Sea Level Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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01:11:03","extension":"html","order_by":14,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":216961,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7408518/v1/75dd9a1fef53eabe7d024bdc.html"},{"id":92682002,"identity":"427ea0b6-0936-42fa-a3c8-8aea87fab4c2","added_by":"auto","created_at":"2025-10-03 01:11:03","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":821300,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eEcuador map. \u003c/strong\u003eHighlighted the Andean ridge (left) and detailed distribution of provincial \u003cem\u003ecantons\u003c/em\u003e (right).\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7408518/v1/6e7bd5d796c3f630b96f6936.jpeg"},{"id":105904439,"identity":"43c4bc54-9b4a-41c9-97de-cb353cfc4d5b","added_by":"auto","created_at":"2026-04-01 10:08:35","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2188449,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7408518/v1/5ee92d61-6e28-4185-a9c4-f6f08f187d86.pdf"}],"financialInterests":"","formattedTitle":"Impact of High-Altitude Hypoxia on Mortality from Acute Lymphoblastic Leukemia in Mountain Regions of Ecuador","fulltext":[{"header":"1. INTRODUCTION","content":"\u003cp\u003eAcute lymphoblastic leukemia (ALL), also known as acute lymphocytic leukemia, is a rare type of cancer that affects blood and bone marrow and that is characterized by the development of large numbers of immature lymphocytes due to a DNA mutation. Excessive number of immature lymphocytes interfere with the production of new red blood cells, white blood cells, and platelets in the bone marrow resulting in a characteristic disease pattern. Between 75% and 80% of cancers in children and adolescents under 15 years of age are ALL cases, making it the most kind of malignity in this age group in Latin America [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThere are no obvious reasons why children develop the disease, which progresses rapidly in the absence of treatment. Childhood ALL is regarded as a complex disease that results from the interplay of genetic and environmental factors over the course of a multistage sequence [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Although acquired genetic disorders such as Down syndrome, Klinefelter syndrome, Fanconi anemia to say a few are among the risk factors linked with the disease, only a small fraction (less than 10%) can be ascribed to genetics [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Environmental risks factors like prior exposure to chemotherapy, radiation/ionizing therapy, and benzene, infections, a weakened immune system, and diet also have an influence in the development of childhood ALL [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eData from the Global Cancer Observatory (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://gco.iarc.fr/en\u003c/span\u003e\u003cspan address=\"https://gco.iarc.fr/en\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) show that 29,273 cancer cases were reported in Republic of Ecuador in 2021, with 1,199 of those cases being related with children cancer. The incidence of ALL in Ecuadorian children between 2 to 5 years old has increased relative to the global prevalence; with rates ranging from 20 to 80 cases per 100,000 habitants [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. The study on ALL is especially relevant in the Ecuadorian context. The magnitude of mining and agriculture exploitation in the Republic of Ecuador [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], as well as the substantial geographical and environmental disparities between the Coast and Andean regions [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] might have an impact on ALL prevalence. Almost seven million Ecuadorians reside in the Andean region, whose elevations range between 1800 m and 6268 m above sea level. Because malignant behavior and angiogenesis in cancer cells are known to be enhanced by hypoxia [\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], high altitude-induced hypoxia is likely to affect unfavorable ALL prognosis [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eOne of the distinguish characteristics of ALL is that adult survival rates are lower (30\u0026ndash;40%) than those for children, where survival surpass 90%. We carried out a nationwide epidemiological and geodemographic study to determine ALL-death prevalence and mortality distribution by age across the high and lowlands of the Republic of Ecuador. Examining how altitude could modify age-dependent pattern of ALL mortality was intended to validate the hypothesis that high altitude-induced hypoxia might be an environmental risk factor for the mortality of the illness.\u003c/p\u003e"},{"header":"2. METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003e2.1 Study design\u003c/h2\u003e\u003cp\u003eAn epidemiological study on spatial distribution was conducted to examine ALL mortality by sex and age according to altitude above sea level (a.s.l.) in the Republic of Ecuador.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003e2.2 Study zone\u003c/h2\u003e\u003cp\u003eThe Republic of Ecuador, the smallest country in the Andean region of South America (256,370 km\u0026sup2;), is located in the northwest of the continent, and borders Colombia to the north, Peru to the southeast, and the Pacific Ocean to the west (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The Andes ridge, with altitudes exceeding 5,000 m a.s.l., divides the country geographically. Administratively, the country is divided into 24 provinces, each of which is further subdivided into counties, also known as \u003cem\u003ecanton\u003c/em\u003e. Parishes are the next level of subdivisions for each \u003cem\u003ecanton\u003c/em\u003e. Each provincial \u003cem\u003ecanton\u003c/em\u003e served as the analytical spatial unit (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e), since the parishes assigned to each \u003cem\u003ecanton\u003c/em\u003e has comparable altitudinal characteristics. A total of 221 \u003cem\u003ecantons\u003c/em\u003e were included in the study.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003e2.3 Population description\u003c/h2\u003e\u003cp\u003eAccording to data from the National Institute of Censuses and Statistics (INEC) [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], in 2022 the Republic of Ecuador was home to 17,082,730 inhabitants (49% women and 51% men). This represents 0.2% of the global population and 2% of the Latin American population. The population under the age of 18 was 36%. Ecuadorian population grew by 2.5\u0026nbsp;million people (17%) between 2011 and 2022 The demographic profile reflected a higher proportion in urban areas (63%). The most populated areas were the Coast (53%, seven provinces) and the Andes (41%, ten provinces), while the least populous ones were the Amazon (5.8%, six provinces) and the Galapagos Islands (0.2%, a single province).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003e2.4 Data collection\u003c/h2\u003e\u003cp\u003eDeath certificates with ALL listed as the underlying cause of death (ICD-10: C91.0) were retrieved from the INEC-sponsored Statistical Register of Deaths database [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], a publicly available online source of information. The time frame covered was 2011\u0026ndash;2022. Cases of incomplete data were eliminated from the analysis. To minimize bias and ensured higher accuracy, rather than the place where the death certificate was issued, the deceased person\u0026acute;s \u003cem\u003ecanton\u003c/em\u003e of residence was taken into account.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003e2.4 Data categorization\u003c/h2\u003e\u003cp\u003eBased on earlier studies on age disparities in ALL survival [\u003cspan additionalcitationids=\"CR18 CR19 CR20\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e], as well as the definition of pediatric age [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e], patients sample was divided into two groups: pediatrics (\u0026le;\u0026thinsp;17 years old) and adults (\u0026ge;\u0026thinsp;18 years old), in addition to sex (women and men) as a differentiator. Oxygen partial pressure decreases with altitude [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. The following height levels were considered in order to evaluate the potential association between altitude and ALL-mortality rates [\u003cspan additionalcitationids=\"CR25\" citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]: Sea Level (\u0026lt;\u0026thinsp;500 m a.s.l.), Very Low (500 m ‒ \u0026lt; 1000 m a.s.l.), Low (1000 m ‒ \u0026lt; 1500 m a.s.l.), Low Moderate (1500 m ‒ \u0026lt; 2000 m a.s.l.), Moderate High (2000 m ‒ \u0026lt; 2500 m a.s.l.) and High (\u0026gt;\u0026thinsp;2500 m a.s.l.). For ALL mortality comparisons between altitudes, the a.s.l. elevation for each \u003cem\u003ecanton\u003c/em\u003e was obtained from the Military Geographic Institute web site (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.geograficomilitar.gob.ec/\u003c/span\u003e\u003cspan address=\"https://www.geograficomilitar.gob.ec/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003e2.6 Statistics\u003c/h2\u003e\u003cp\u003eAge-adjusted mortality rates per 100,000 inhabitants were calculated for the overall observation period (2011\u0026ndash;2022). The rate adjustment was performed using the direct method, and stratifications were made by defined age groups and sex [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. The annual projections of the population by age group and sex at the provincial \u003cem\u003ecanton\u003c/em\u003e level were obtained from the INEC based on the latest census available in the country [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Additionally, Relative Risk (RR) was calculated to estimate the probability of mortality in the population, using the \u003cem\u003ecantons\u003c/em\u003e of Sea Level (\u0026lt;\u0026thinsp;500 m a.s.l.) as the reference for both pediatric and adult groups, with their 95% confidence intervals (CI) to assess globally and by sex. The \u003cem\u003et\u003c/em\u003e-test was applied for binary comparisons while alpha-value was set at 0.05 for statistical significance.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\u003ch2\u003e2.7 Ethics\u003c/h2\u003e\u003cp\u003eAn ethics committee review was not required because the study was retrospective in nature and used publically available secondary registers for non-experimental research. The files did not contain identifiable personal information that would violate the Helsinki declaration or international and national best practices recommendations. We followed STROBE guidelines to report this study.\u003c/p\u003e\u003c/div\u003e"},{"header":"3. RESULTS","content":"\u003cp\u003e\u003cstrong\u003e3.1. Absolute distribution of ALL mortality\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTable 1 shows the demographic characteristics of the sample distributed by heights above sea level \u0026nbsp;in order to find important patterns regarding ALL mortality. The majority of people (51.8% spread throughout 43.4% of the \u003cem\u003ecantons\u003c/em\u003e) live at Sea Level (\u0026lt; 500 m a.s.l.). With 16.3% of the cantons, the Andes (\u0026gt; 2500 m a.s.l. High Altitude) is the second most inhabited region (28.6%). At Low Altitude \u003cem\u003ecantons\u003c/em\u003e (500-1000 m a.s.l.), on the other hand, are the less inhabited (13.6% of the \u003cem\u003ecantons\u003c/em\u003e with a population of 7.7%). In terms of age groups distribution, Very Low Altitude \u003cem\u003ecantons\u003c/em\u003e (\u0026lt; 500 m a.s.l.) host the highest prevalence of children (18.9% of the pediatric population) and adults (33.2%). Adults and children make up 19.0% and 9.6% of the population at the High Altitude \u003cem\u003ecantons\u003c/em\u003e (\u0026gt; 2500 m a.s.l.) respectively.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eRegarding the distribution of ALL deaths by elevation (Table 1), 46.1% are concentrated at Sea Level (\u0026lt; 500 m a.s.l). The most densely populated areas, the provincial\u0026nbsp;\u003cem\u003ecantons\u003c/em\u003e located below 500 m height (Sea Level) and above 2500 m height (High Altitude), had the highest rates of ALL deaths ‒ 46.1% and 36.3%, respectively (Table 1). When compared by age group, Sea Level (\u0026lt; 500 m a.s.l.) constitute 20.6% and 25.4% of pediatric and adult ALL mortality respectively. However, the percentage of pediatric ALL-mortality at high elevations (\u0026gt; 2500 m a.s.l.) was 11.2%, which is quite high considering that 9.6% of the pediatric population lives at this elevation. Only 19.0% of the adult population lives at high altitudes, while adult ALL-deaths account for 25.1% of the total ALL-death population. Overall, mortality from ALL indicate that in the pediatric group, males had higher death rates than females (21.1% versus 4.9%), while similar death rates were observed in adults (males: 32.2% and females: 31%).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.2. Adjusted distribution of ALL mortality rates\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDetails on adjusted mortality rates according to altitude by age groups and sex can be found in Table 2. Below 500 m a.s.l. height, the adjusted overall death rate was the lowest (16.1 per 100,000 inhabitants), grew at relatively high elevations (21.4 per 100,000 inhabitants between 2000 and 2500 m a.s.l.), and reached its maximum over 2500 m a.s.l. (23.0 per 100,000 inhabitants). This pattern shows a clear correlation between altitude and higher ALL-mortality.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn the pediatric population living below 500 m a.s.l., the adjusted mortality rate was 19.8 per100,000 inhabitants, the highest at Sea Level. While the ALL-death rate in pediatrics drops to 14.7 at Moderately High Altitude (2000-2500 m a.s.l.), it raises to 21.3 at High Altitude (\u0026gt; 2500 m a.s.l.) and then returns to levels comparable to those below 500 m a.s.l. Compared to the pediatric group, the adjusted death rate for adults at Sea Level (500 m a.s.l.) was lower (14.0). Moderately High Altitudes (2000 to 2500 m a.s.l.) had the greatest adult mortality rate (25.0), whereas the High Altitud elevation also had a high rate (23.9). As a result, there was a noticeable rise in the mortality rate above 2000 m a.s.l., suggesting that adults were more susceptible to altitude effects.\u003c/p\u003e\n\u003cp\u003eThe adjusted mortality rate was 22.7 for the male pediatrics and 14.7 for male adults at Sea Level (\u0026lt; 500 m a.s.l.). The male pediatric mortality rates dropped to 15.2 at Moderate High Altitude (2000 m to 2500 m a.s.l.), whereas the adult mortality rate raised to 27.5, the highest of all altitude categories. However, death rates for men raised to 23.4 in pediatrics at High Altitude (\u0026gt; 2500 m a.s.l.), while they stay steady at about 25.7 in adults. In females, a similar trend was observed. The adjusted death rate was 13.3 for adults and 16.7 for pediatrics at Sea Level (\u0026lt; 500 m a.s.l.). The mortality rate for adult females increased to 22.8, although it decreased little for pediatric females (14.1). In the highlands (\u0026gt; 2500 m a.s.l.), the rates increased to 19.0 for pediatric girls, and hardly changed for adult females (22.4).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.3. Comparisons of ALL-death relative ratios by altitude, sex, and age groups.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe prevalence of ALL mortality in adult and children varies with increasing altitude, as Table 3 illustrates. In comparison with Sea Level (\u0026lt; 500 m a.s.l.), the risk of ALL mortality generally increases above 2000 m a.s.l., that is, in the Moderately High Altitude and High Altitude categories.\u003c/p\u003e\n\u003cp\u003eAdults of both sexes had the highest risk of ALL mortality over 2000 m a.s.l. (Moderate High\u0026nbsp;Altitude: RR: 1.8, 95% CI: 1.6-1.1, \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.001; High Altitude: RR: 1.7, 95% CI: 1.6-1.9, \u003cem\u003eP\u0026nbsp;\u003c/em\u003e\u0026lt; 0.001), but male pediatrics had a lower risk of ALL death at 500-1000 m. a.s.l., as well as at 1500-2500 m a.s.l. (Low Altitude: RR: 0.4, 95% CI: 0.3-0.6, \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.001; Moderate Altitude: RR: 0.3, 95% CI: 0.1-0.9, \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.05; Moderate High Altitude: RR: 0.7, 95% CI: 0.5-0.9, \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.001). At any altitude, no statistically significant differences were seen in pediatric females. Furthermore, the risk for ALL mortality in adults of both sexes did not change between Sea Level (\u0026lt; 500 m a.s.l.) and elevations below 2000 m. a.s.l.\u003c/p\u003e"},{"header":"4. DISCUSSION","content":"\u003cp\u003eThe current study showed notable age disparities when the ALL-death prevalence was broken down by altitude. Adults living over 2000 m a.s.l. had nearly twice the risk of dying from ALL compared to those living at Sea Level (\u0026lt; 500 m a.s.l.). In the pediatric group, low and moderate high altitudes had a protective effect, but it seemed to be lost when elevation exceeded 2000 m a.s.l. and based on sex. The association between ALL-death risk and altitude was supported by the fact that age greatly impacts on the likelihood of recovery from ALL.\u003c/p\u003e\n\u003cp\u003eAt heights exceeding 2000 m a.s.l., ALL-mortality rates increased, suggesting that hypoxia derived from altitude could contribute negatively to the evolution of ALL. The body responds to prolonged exposure to environmental induced hypoxia by generating a\u003c/p\u003e\n\u003cp\u003ea protein called hypoxia-inducible factor (HIF-1), which sets off a cascade of adaptive physiological changes to the low oxygen partial pressure [28]. The HIF-1α protein (HIF-1A gene) oxygen-dependent degradation controls its activity [29]. In this regard, it may be concluded that age-based maladaptation to altitude may be the cause of the age-related variations in ALL-death vulnerability at high altitude. Nonetheless, the evidence reviewed indicates that the onset of high altitude illnesses is unrelated to age [30–32]. According to some studies, HIF-1α has a role in leukemia [33]. In particular, in childhood ALL, the HIF pathway is activated [34, 35], which accelerates the diseases´ progression [36, 37]. Because the HIF pathway causes increased, fast, and chaotic vascular development [11, 38] as well as metabolism disruptions [39] in cancer, its role in adult susceptibility to ALL-death is also significant. In ALL, HIF-1α system contributes to chemo-resistance [40–42]. Given that age and HIF functioning are interdependent [43–45], it stands to reason that variations in the risk for ALL mortality that are connected to age and altitude may be explained by the HIF pathway.\u003c/p\u003e\n\u003cp\u003eIn line with earlier findings [46], boys have worse ALL survival rate than girls. For this reason, we were surprised to discover that boys in the pediatric group were less affected by ALL-death than girls in the very low, moderate, and moderate-high ranges of altitude (Table 2). This leads to speculate that there may be biological and statistical differences that account for this phenomenon. There are sex-dimorphic HIF physiological responses to altitude-induced hypoxia [47], as well as HIF-mediated responses [48]. Moreover, there is epidemiological evidence that living at moderate altitude is associated with lower death rates [49]. Therefore, complex age-sex interactions that warrant more research could account for the absence of sex-based differences in the adult group, but not in the pediatric one. It could be argued that our results are too particular to the Ecuadorian case to be generalizable to other populations. The Ecuadorian population has the same risk of developing cancer at high altitudes as other populations [15, 50], despite their apparent capacity to adapt to hypoxic environments [51]. Finally, because there is minimal evidence that excessive solar ultraviolet irradiation [52] and Latino/Hispanic ethnicity [53] raises ALL risk, our study ignored their effects in diseases´ mortality rates. To the best of our knowledge, this is the first study to investigate the association between altitude and ALL survival because one of the characteristics that sets ALL apart is its age-dependent survival rate, and height-based ALL-death risk also depended on age.\u003c/p\u003e\n\u003cp\u003eThis study has a number of strengths. Using data for all \u003cem\u003ecantons\u003c/em\u003e across the Coast, Andean, and Amazonian regions of Ecuador from a long period (2011–2022) led to robust estimates of ALL-mortality rates over a large elevation range. Moreover, we used data from the INEC-sponsored Statistical Register of Deaths database, which undergoes rigorous quality control prior to publishing. Lastly, the Ecuadorian army´s official cartography site was used to ensure the \u003cem\u003ecanton\u003c/em\u003e´s topographical and altitude accuracy. The study also has some limitations like the cause of death may be affected by regional variability in certification. Our analysis comparatively large sample size lessened the impact of errors in cause-of-death assignment. In addition, using mean \u003cem\u003ecanton\u003c/em\u003e elevation is equivalent to measuring the true altitude of residence with random error. The impact of height heterogeneity within each \u003cem\u003ecanton\u003c/em\u003e, was mitigated by the rather wide altitude categories that were utilized in our analysis.\u003c/p\u003e\n\u003cp\u003eIn conclusion, this study revealed that altitude has a negative effect on mortality rates from ALL. Although at altitudes greater than 2000 m a.s.l., hypoxia could also be harmful to children, this effect was much stronger in the adult population. Our findings add additional evidence of the impact of geographical and environmental determinants on the progression and incidence of the ALL disease. Fort the first time ever, our research gives epidemiological support to the impact of hypoxia on ALL. Up-to-date and geographically adapted interventions can reduce mortality from ALL in high-altitude areas.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding sources\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that no funds, grants, or other support was received during the preparation of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no relevant financial or non-financial interests to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors´ contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eX.G-L., E.F-M., and S.B conceived and design the study. X.G-L. and K.C.\u0026nbsp;were in charge on the acquisition of data; A.R.G-G. and K.C. analyzed and interpreted the data; X.G-L., M.G., and S.B. wrote the original draft; E.F-M., M.G., and A.R.G-G.\u0026nbsp;revisited the manuscript critically for important intellectual content. All the authors wrote and approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDue to the retrospective nature of the study ‒ which involved non-experimental research using publicly accesible secondary registries ‒ an ethics committee was not necessary. There was not sensitive or private information in the datasets that would have infringed on the right to personal data protection.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eFuentes L, Flores M, Iglesias A, Luzuriaga A, Rend\u0026oacute;n N, Ord\u0026oacute;\u0026ntilde;ez R, Sol\u0026oacute;rzano F, A\u0026ntilde;ez R (2018) Characteristics of acute lymphoblastic leukemia and febrile neutropenia in children and adolescents treated at a hospital in Guayaquil, Ecuador. Rev Peru Exp Med salud p\u0026uacute;blica 35:272-278. https://doi.org/10.17843/rpmesp.2018.352.2862\u003c/li\u003e\n\u003cli\u003eDuffy C, Graetz D, L\u0026oacute;pez A, Carrillo A, Job G, Chen Y, Devidas M, Le\u0026oacute;n S, Bonzi S, Flores P, Torres L, Broncano E, Jaramillo S, Zelada M, Novoa R, Samudio A, S\u0026aacute;nchez-Fernandez G, Villanueva E, Metzger M, Friedrich P, Jeha S (2023) Retrospective analysis of the results of pediatric acute lymphoblastic leukemia in South American centers. Front Oncol 13:1254233. https://doi.org/10.3389/fonc.2023.1254233\u003c/li\u003e\n\u003cli\u003eSchmidt JA, Hornhardt S, Erdmann F, S\u0026aacute;nchez-Garc\u0026iacute;a I, Fischer U, Sch\u0026uuml;z J, Ziegelberger G (2021) Risk factors for childhood leukemia: Radiation and beyond. Front Public Health 9:805757. doi: 10.3389/fpubh.2021.805757\u003c/li\u003e\n\u003cli\u003eNematollahi P, Arabi S, Mansourian M, Yousefian S, Moafi A, Mostafavi S, Naeini A, Ebrahimi A, Ebrahimpour K, Amin M, Kavosh A, Radfar N, Naimi A, Kelishadi R (2023) Environmental Risk Factors for Pediatric Acute Leukemia: Methodology and Early Findings. Int J Prev Med 14:103. doi: 10.4103/ijpvm.ijpvm_348_22\u003c/li\u003e\n\u003cli\u003eLin K, Zhou G, Guo H, Niu Q, Guo H, Song G, Hu Y, Liu J, Yan Y (2023) Exposure to air pollution and risk of haematological malignancies: a systematic review and dose-response meta-analysis of epidemiologic evidence. Environ Res Lett 18: 093001. \u003cstrong\u003edoi\u003c/strong\u003e: 10.1088/1748-9326/aceb7a\u003c/li\u003e\n\u003cli\u003ePuckett Y, Chan O, Doerr C. Acute Lymphocytic Leukemia (Nursing). In: StatPearls. Treasure Island (FL): StatPearls Publishing; (2024) Jan-. https://www.ncbi.nlm.nih.gov/books/NBK568716/. Accessed 26 August 2023.\u003c/li\u003e\n\u003cli\u003eTorres-Roman JS, Valcarcel B, Guerra-Canchari P, Dos Santos Alves CA, Ribeiro-Barbosa I, La Vecchia C, Mcglynn KA, Bezerra-De Sousa DL (2020) Leukemia mortality in children from Latin America: trends and predictions to 2030. BMC Pediatr 20:511. https://doi.org/10.1186/s12887-020-02408-y\u003c/li\u003e\n\u003cli\u003eDong Y, Shi O, Zeng Q, Lu X, Wang W, Li Y, Wang Q (2020) Leukemia incidence trends at the global, regional, and national level between 1990 and 2017. Exp Hematol Oncol 9:14. https://doi.org/10.1186/s40164-020-00170-6\u003c/li\u003e\n\u003cli\u003eOnyije F, Olsson A, Baaken D, Erdmann F, Stanulla M, Wollschl\u0026auml;ger D, Sch\u0026uuml;z J (2022) Environmental risk factors for childhood acute lymphoblastic leukemia: An umbrella review. Cancers 14:382. https://doi.org/10.3390/cancers14020382\u003c/li\u003e\n\u003cli\u003ePan W, Erlien C, Bilsborrow R. 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Expert Opin Ther Targets 22:917-928. doi: 10.1080/14728222.2018.1538357\u003c/li\u003e\n\u003cli\u003eWellmann S, Guschmann M, Griethe W, Eckert C, von Stackelberg A, Lottaz C, Moderegger E, Einsiedel HG, Eckardt KU, Henze G, Seeger K (2004) Activation of the HIF pathway in childhood ALL, prognostic implications of VEGF. Leukemia 18:926\u0026ndash;933. https://doi.org/10.1038/sj.leu.2403332\u003c/li\u003e\n\u003cli\u003eSilveira VS, Freire BM, Borges KS, Andrade AF, Cruzeiro GA, Sabino JP, Glass ML, Yunes JA, Brandalise SR, Tone LG, Scrideli CA (2014) Hypoxia-related gene expression profile in childhood acute lymphoblastic leukemia: prognostic implications. Leuk Lymphoma 55:1751-1757. doi: 10.3109/10428194.2013.858812\u003c/li\u003e\n\u003cli\u003eSteele M, Narendran A (2012) Mechanisms of defective erythropoiesis and anemia in pediatric acute lymphoblastic leukemia (ALL). Ann Hematol 91:1513\u0026ndash;1518. https://doi.org/10.1007/s00277-012-1475-5\u003c/li\u003e\n\u003cli\u003eYou H, Wang D, Wei L, Chen J, Li H, Liu Y (2022) Deferoxamine inhibits acute lymphoblastic leukemia progression through repression of ROS/HIF-1\u003cem\u003e\u0026alpha;\u003c/em\u003e, Wnt/\u003cem\u003e\u0026beta;\u003c/em\u003e-catenin, and p38MAPK/ERK pathways. J Oncol 2022:8281267. doi: 10.1155/2022/8281267\u003c/li\u003e\n\u003cli\u003eKrock BL, Skuli N, Simon MC (2011) Hypoxia-induced angiogenesis: good and evil. Genes Cancer. 2:1117-1133. doi: 10.1177/1947601911423654\u003c/li\u003e\n\u003cli\u003eSharma A, Sinha S and Shrivastava N (2022) Therapeutic targeting hypoxia-inducible factor (HIF-1) in cancer: Cutting gordian knot of cancer cell metabolism. Front. 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Am J Epidemiol 190:519-527. doi: 10.1093/aje/kwaa215\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1. Altitude-based distribution of Ecuadorian population and ALL-death rates\u003c/strong\u003e\u003cstrong\u003e.\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 171px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"11\" style=\"width: 655px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAltitude\u0026nbsp;\u003c/strong\u003e(a.s.l.)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTotal\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 171px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSea Level\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eVery Low\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLow\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eModerate\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eModerate High\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHigh\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 171px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e\u0026lt; 500 m\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e500 ‒ \u0026lt; 1000 m\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e1000\u0026nbsp;‒\u0026nbsp;\u0026lt; 1500 m\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e1500\u0026nbsp;‒\u0026nbsp;\u0026lt; 2000 m\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e2000\u0026nbsp;‒\u0026nbsp;\u0026lt; 2500 m\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u0026gt; 2500 m\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 171px;\"\u003e\n \u003cp\u003eAverage per canton (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e113.8 (121.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e705.1 (151.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e1182.4 (89.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e1829.4 (115.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e2263.8 (132.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003e2623.9 (680.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e1327.6 (1143.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 171px;\"\u003e\n \u003cp\u003eProvince cantons, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e96 (43.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e30 (13.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e21 (9.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e11 (5.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e27 (12.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003e36 (16.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e221 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 171px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePopulation n\u003csup\u003ea\u003c/sup\u003e (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e8.7 (51.8)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.3 (7.7)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.1 (0.6)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.2 (1.2)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.7 (10.1)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e4.8 (28.6)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e16.8 (100)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 171px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePediatrics n\u003csup\u003ea\u003c/sup\u003e (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e3.2 (18.9)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.5 (3.0)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.04 (0.2)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.1 (0.5)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.6 (3.5)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.6 (9.6)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e6.1 (35.7)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 171px;\"\u003e\n \u003cp\u003eMen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e1.7 (9.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e0.3 (1.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e0.02 (0.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e0.05 (0.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e0.3 (1.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003e0.8 (4.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e3.1 (37.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 171px;\"\u003e\n \u003cp\u003eWomen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e1.6 (9.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e0.2 (1.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e0.01 (0.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e0.04 (0.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e0.3 (1.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003e0.8 (4.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e2.9 (34.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 171px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAdults n\u003csup\u003ea\u003c/sup\u003e (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e5.6 (33.2)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.7 (4.4)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.1 (0.4)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.1 (0.8)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.1 (6.5)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e3.2 (19.0)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e10.9 (64.3)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 171px;\"\u003e\n \u003cp\u003eMen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e2.8 (16.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e0.4 (2.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e0.03 (0.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e0.07 (0.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e0.5 (3.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003e1.5 (8.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e5.2 (62.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 171px;\"\u003e\n \u003cp\u003eWomen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e2.9 (16.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e0.4 (2.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e0.03 (0.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e0.1 (0.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e0.6 (3.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003e1.7 (10.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e5.6 (65.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 171px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eALL-deaths n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1419 (46.1)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e153 (5.0)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e8 (0.3)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e22 (0.7)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e361 (11.7)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1118 (36.3)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e3081 (100)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 171px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePediatrics\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e635 (20.6)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e60 (1.9)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e4 (0.1)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e4 (0.1)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e87 (2.8)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e346 (11.2)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1136 (36.9)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 171px;\"\u003e\n \u003cp\u003eMen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e376 (12.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e26 (0.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e3 (0.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e3 (0.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e46 (1.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003e196 (6.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e650 (21.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 171px;\"\u003e\n \u003cp\u003eWomen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e259 (8.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e34 (1.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e1 (0.03)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e1 (0.03)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e41 (1.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003e150 (4.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e150 (4.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 171px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAdults\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e784 (25.4)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e93 (3.0)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e4 (0.1)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e18 (0.6)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e274 (8.9)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e772 (25.1)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1945 (63.1)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 171px;\"\u003e\n \u003cp\u003eMen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e405 (13.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e49 (1.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e2 (0.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e7 (0.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e142 (4.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003e386 (12.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e991 (32.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 171px;\"\u003e\n \u003cp\u003eWomen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e379 (12.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e44 (1.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e2 (0.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e11 (0.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e132 (4.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003e386 (12.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e954 (31.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003e\u003csup\u003ea\u0026nbsp;\u003c/sup\u003e\u003c/strong\u003emillion inhabitants\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2.\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eAdjusted ALL-mortality rate per 100,000 habitants according to altitude.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData are shown as relative ratio or RR (95% CI).\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 148px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"11\" style=\"width: 670px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAltitude\u0026nbsp;\u003c/strong\u003e(a.s.l.)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" style=\"width: 103px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTotal\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 148px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 103px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSea Level\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eVery Low\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLow\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eModerate\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eModerate High\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHigh\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 148px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 103px;\"\u003e\n \u003cp\u003e\u0026lt; 500 m\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e500 ‒ \u0026lt; 1000 m\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003e1000\u0026nbsp;‒\u0026nbsp;\u0026lt; 1500 m\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003e1500\u0026nbsp;‒\u0026nbsp;\u0026lt; 2000 m\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003e2000\u0026nbsp;‒\u0026nbsp;\u0026lt; 2500 m\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u0026gt; 2500 m\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 148px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOverall\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 103px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e16.1 (15.3-16.9)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e12.2 (10.4-14.3)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e7.8 (3.9-15.5)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e9.9 (6.5-15.0)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e21.4 (19.3-23.7)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e23.0 (21.7-24.4)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 103px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e18.2 (17.6-18.8)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 148px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePediatrics\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 103px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e19.8 (18.3-21.4)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e11.9 (9.3-15.4)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e10.8 (4.1-28.9)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e4.6 (1.7-12.2)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e14.7 (11.9-18.1)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e21.3 0.1 19.1 23.6\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 103px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e18.8 (17.7-19.9)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 148px;\"\u003e\n \u003cp\u003eMen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 103px;\"\u003e\n \u003cp\u003e22.7 (20.5-25.1)*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e9.7 (6.6-14.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003e13.6 (4.4-42.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003e6.5 (2.1-20.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003e15.2 (11.4-20.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106px;\"\u003e\n \u003cp\u003e23.4 (20.4-26.9)*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 103px;\"\u003e\n \u003cp\u003e20.7 (19.2-22.4)*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 148px;\"\u003e\n \u003cp\u003eWomen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 103px;\"\u003e\n \u003cp\u003e16.7 (14.8-18.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e14.5 (10.3-20.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003e6.8 (1.0-48.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003e2.5 (0.3-17.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003e14.1 (10.4-19.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106px;\"\u003e\n \u003cp\u003e19.0 (16.2-22.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 103px;\"\u003e\n \u003cp\u003e16.6 (15.2-18.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 148px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAdults\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 103px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e14.0 (13.0-15.0)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e12.4 (10.1-15.2)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e6.1 (2.3-16.1)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e13.3 (8.4-21.1)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e25.0 (22.2-28.2)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e23.9 (22.3-25.7)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 103px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e17.9 (17.1-18.7)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 148px;\"\u003e\n \u003cp\u003eMen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 103px;\"\u003e\n \u003cp\u003e14.7 (13.3-16.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e13.5 (10.2-17.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003e6.0 (1.5-24.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003e10.8 (5.1-22.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003e27.5 (23.3-32.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106px;\"\u003e\n \u003cp\u003e25.7 (23.2-28.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 103px;\"\u003e\n \u003cp\u003e18.9 (17.8-20.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 148px;\"\u003e\n \u003cp\u003eWomen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 103px;\"\u003e\n \u003cp\u003e13.3 (12.0-14.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e11.4 (8.5-15.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003e6.1 (1.5-24.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003e15.6 (8.7-28.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003e22.8 (19.3-27.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106px;\"\u003e\n \u003cp\u003e22.4 (20.3-24.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 103px;\"\u003e\n \u003cp\u003e16.9 (15.8-18.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eStatistical significance: *\u003cem\u003eP\u003c/em\u003e \u0026lt; 0.05 compared to Women\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3. Altitude-dependent prevalence of ALL-deaths.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData are shown as relative ratio or RR (95% CI).\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 193px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"11\" style=\"width: 741px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAltitude\u0026nbsp;\u003c/strong\u003e(a.s.l.)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 193px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSea Level\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eVery Low\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLow\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eModerate\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eModerate High\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHigh\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 193px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106px;\"\u003e\n \u003cp\u003e\u0026lt; 500 m\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110px;\"\u003e\n \u003cp\u003e500 ‒ \u0026lt; 1000 m\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e1000\u0026nbsp;‒\u0026nbsp;\u0026lt; 1500 m\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e1500\u0026nbsp;‒\u0026nbsp;\u0026lt; 2000 m\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e2000\u0026nbsp;‒\u0026nbsp;\u0026lt; 2500 m\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u0026gt; 2500 m\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 193px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOverall\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106px;\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.8 (0.6-0.9)***\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.5 (0.2-1.0)*\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.6 (0.4-0.9)*\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.3 (1.2-1.5)***\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.4 (1.3-1.5)***\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 193px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePediatrics\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106px;\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.6 (0.5-0.8)***\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.5 (0.2-1.5)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.2 (0.1-0.6)**\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.7 (0.6-0.9)**\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.1 (0.9-1.2)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 193px;\"\u003e\n \u003cp\u003eMen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106px;\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110px;\"\u003e\n \u003cp\u003e0.4 (0.3-0.6)***\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e0.6 (0.2-1.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e0.3 (0.1-0.9)*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e0.7 (0.5-0.9)***\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n 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style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e0.8 (0.6-1.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e1.1 (0.9-1.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 193px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAdults\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106px;\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.9 (0.7-1.1)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n 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(1.6-1.9)***\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 193px;\"\u003e\n \u003cp\u003eMen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106px;\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110px;\"\u003e\n \u003cp\u003e0.9 (0.7-1.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e0.4 (0.1-1.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e0.7 (0.3-1.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e1.9 (1.5-2.3)***\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e1.7 (1.5-2.0)***\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 193px;\"\u003e\n \u003cp\u003eWomen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106px;\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110px;\"\u003e\n \u003cp\u003e0.9 (0.6-1.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e0.5 (0.1-1.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e1.2 (0.6-2.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e1.7 (1.4-2.1)**\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e1.7 (1.5 1.9)**\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eStatistical significance: *\u003cem\u003eP\u003c/em\u003e \u0026lt; 0.05; **\u003cem\u003eP\u003c/em\u003e \u0026lt; 0.01; ***\u003cem\u003eP\u003c/em\u003e \u0026lt; 0.01 compared to Sea Level\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Age groups, Altitude sickness, Death, Demographic analysis, Hypoxia-Inducible Factor 1, Leukemia, lymphoid","lastPublishedDoi":"10.21203/rs.3.rs-7408518/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7408518/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose: \u003c/strong\u003eAcute lymphoblastic leukemia (ALL) is a rare hematological cancer that primary affects children, although its prognosis for survival is better than that of ALL in adults. We investigated the possibility that hypoxia brought on by high altitude might be an AAL-death risk factor by examininghow altitude could modify age-dependent pattern of ALL-mortality.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eIn Ecuador, an epidemiological investigation was conducted to examine the spatial distribution of ALL mortality by sex and age in relation to altitude. The sample was divided into children (≤ 17 years old) and adults (≥ 18 years old), in addition to sex as a differentiator. ALL age-adjusted mortality rates per 100,000 inhabitants were calculated from 2011 to 2022. Relative Risk was computed to estimate the likelihood of ALL-death for both pediatric and adult groups across altitude categories. For comparisons based on sex, the \u003cem\u003et\u003c/em\u003e-test was applied.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eWhen ALL-death rates was analyzed by altitude, the current investigation revealed significant age differences. Adults who lived over 2000 m were almost twice as likely to die from ALL as those who lived at sea level. Low and moderately high altitudes (1000-2000 m) provided a protective benefit in the pediatric group (only boys), while elevations beyond 2000 m appeared to eliminate this effect.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions: \u003c/strong\u003eOur results highlight altitude as a biometeorological factor influencing ALL mortality. ALL mortality rates were negatively impacted by altitude. Children could be harmed by hypoxia at elevations higher than 2000 m above sea level, although the effect was worse in adults. Our results support the emerging notion that hypoxia-inducible factor pathway contributes to ALL.\u003c/p\u003e","manuscriptTitle":"Impact of High-Altitude Hypoxia on Mortality from Acute Lymphoblastic Leukemia in Mountain Regions of Ecuador","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-03 01:10:58","doi":"10.21203/rs.3.rs-7408518/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"48fcadd2-b8be-44ac-aa4b-1b1f72b7c647","owner":[],"postedDate":"October 3rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-03-31T08:52:55+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-03 01:10:58","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7408518","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7408518","identity":"rs-7408518","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}