INTRODUCTION

Helicobacter pylori is a human pathogen that chronically colonizes the stomach of approximately the half of the world's population. Infection with Helicobacter sp. usually occurs during childhood and persists for decades. Infection is linked to various gastric disorders. While infection causes gastritis, it remains asymptomatic in most individuals. However, approximately 5% of individuals with H. pylori develop gastric or duodenal ulcers, and approximately 1% develop gastric cancer, with infection being the most relevant risk factor for both (1–3).

While the long-known epidemiologic association of H. pylori with gastric diseases is well established, novel findings on induction of chronic inflammation and changes in gastric (stem) cell physiology due to infection raise the question whether infection may also be associated with systemic alterations and development of extragastric diseases. Indeed, several disorders have been linked to H. pylori infection, and eradication is suggested in individuals with several extragastric disorders such as unexplained iron deficiency anemia (IDA) and immune thrombocytopenia. However, results are heterogenous, and response to eradication is higher in countries with high H. pylori prevalence in the background population. In patients with IDA, main benefits for eradication are achieved in children in contrast to adults, while for immune thrombocytopenia, the evidence is less compelling for children and benefits are achieved in adults (2,4,5). An association with cardiovascular diseases has also been previously suggested, although the strength of this association is controversial and a definite mechanistic explanation is missing (6,7).

Using the well-characterized, community-based UK Biobank (UKB) that comprises a large dataset of directly measured anti–H.pylori antibodies in serum samples consisting of more than 9,000 participants, we analyzed overall and disease-specific morbidity in a country with rather medium prevalence of H. pylori up to 40% (8). To this end, we explored the association between H. pylori positivity at baseline and 457 PheCodes, available in the dataset over the threshold of 5 observations per PheCode. This approach demonstrates that H. pylori positivity predisposes to specific organ dysfunctions including well-established gastric diseases, anemia, and various cardiovascular and respiratory disorders. Because cardiometabolic diseases were among the strongest associations with H. pylori positivity, we analyzed 143 metabolites measured at the same time as the H. pylori test was performed and analyzed their association with H. pylori positivity, mortality, and morbidity. H. pylori positivity was associated with lower levels of sphingomyelins, total esterified cholesterol, docosahexaenoic acid, large and very large high-density lipoprotein (HDL), and smaller average HDL diameter.

METHODS Study cohort

The UKB is a community-based cohort study conducted in the United Kingdom at 22 participating centers. The baseline examinations were conducted from 2006 to 2010 and recruited 502,505 volunteers aged 37–73 years. All participants gave informed consent for data linkage to medical reports. At the baseline assessment (2006–2010), the participants provided demographic and physical measures. Ongoing inpatient hospital records beginning in 1996 were used to identify diagnoses according to International Classification of Diseases 9th and 10th edition (ICD-10 and ICD-9) codes. All reported ICD codes were assigned to the respective date of their first diagnosis.

The UKB receives death notifications (age at death and primary ICD diagnosis that led to death) through linkage to national death registries. End of follow-up was defined as death or end of hospital inpatient data collection in January 2023. Causes of death included all malignancies (C00–C97), cardiovascular diseases (I00–I99), respiratory diseases (J00–J99), nonmalignant digestive diseases (K00–K93), and COVID-19 (U0). This research has been conducted using the UKB Resource under Application Number 71300.

Case definition

In a subset of UKB participants, seropositivity status of 20 pathogens was measured in a pilot study using multiplex serology (9,10). H. pylori positivity is defined as 2 or more positive antibodies against the following antigens (with the following cutoff values): antigen VacA >100, antigen outer membrane protein >170, antigen GroEL >80, antigen Catalase >180, and antigen UreA >130 (UKB datafield 23074). The descriptive statistics of this cohort are summarized in Supplementary Table 1 (see Supplementary Digital Content, https://links.lww.com/CTG/A973)

Propensity score matching

Propensity score matching was applied using the PsmPy (0.3.13, (11)) python package (python ≥3.7). After logistic regression–based propensity score with k-nearest neighbor (k-NN) allocation, 2 iterations were performed, resulting in a 2:1 balance of controls over cases and a reduced standardized mean effect size by variable shown in Figure 1 and summarized in Table 1. The propensity score was estimated using age, sex, body mass index (BMI), ethnic background, and socioeconomic status (Townsend deprivation index) at baseline as predictive covariates in the regression. In total, 8,898 cases were enrolled in further regressions (See Supplementary Figure 1, Supplementary Digital Content, https://links.lww.com/CTG/A973).

Figure 1.:

Manhattan plot of sex, age, body mass index, ethnic background, and socioeconomic status (Townsend deprivation index) adjusted −log10 (P values) for all selected PheCodes comparing their occurrence in Helicobacter pylori–positive individuals with controls. Highlighted are associations with P values <0.05 (corrected for multiple testing by false discovery rate to the threshold [dotted line] 0.0038). Upward/downward pointing triangular markers refer to PheCodes, that are overrepresented or underrepresented, respectively, in H. pylori–positive individuals compared with controls. CHF, congestive heart failure; NOS, not otherwise specified.

Table 1. - Mortality analyses after a mean follow-up of 13.6 years, corrected for age, sex, BMI, and socioeconomic status Helicobacter pylori positive (n = 2,966) Controls (n = 5,932) P OR CI n % n % Mortality (ICD-10 code) 263 8.87 432 7.28 0.39 1.07 0.91 1.23 Neoplasms (C) 136 4.59 240 4.05 0.84 1.02 0.81 1.24 Neurological diseases (G) 14 0.47 20 0.34 0.37 1.36 0.68 2.05 Cardiovascular diseases (I) 52 1.75 91 1.53 0.83 0.96 0.62 1.30 Respiratory diseases (J) 17 0.57 15 0.25 0.026* 2.16 1.48 2.84 Digestive diseases (K) 8 0.27 20 0.34 0.25 0.60 0.29 1.48 Coronavirus disease 2019 (U0) 12 0.4 5 0.08 0.018* 3.53 2.49 4.58

Mortality categories with at least 5 deaths per group are displayed with ICD groups. For categories that are significantly different between H. pylori–positive individuals and controls, the most common subgroups are displayed.

BMI, body mass index; ICD, International Classification of Diseases.

*P < 0.05.

PheWAS analysis

We performed a phenome-wide association study (PheWAS). The coding for clinical diagnoses in our dataset followed the ICD-10 and ICD-9 coding systems. The ICD is a list of codes for diseases, symptoms, findings, and injuries. Most of the world's health expenditures are allocated with ICD (12). For each study subject, ICD codes from the electronic health record diagnoses throughout the study period were collated and duplicates removed. We converted the ICD codes of the 8,898 enrolled participants into 457 associated PheCodes using the pyPheWAS package (13). PheCodes are manually compiled groups of ICD codes used to characterize and scale clinically relevant conditions with wide ranges of diagnoses or symptoms and were created to enable PheWAS (14). PheCodes are maintained by the Center for Precision Medicine at Vanderbilt University Medical Center and are available at https://www.phewascatalog.org/phecodes. A series of case-control tests was performed by fitting multiple logistic regression models, 1 for every PheCode of interest. The influence of the analyzed PheCode was then determined through evaluating the beta and testing for statistical significance. To further reduce the influence of age, sex, BMI, self-reported ethnic background, and socioeconomic status after propensity score matching, they were used as “constant” covariates in every regression (13). We analyzed PheCodes from the following 7 disease groups: digestive, respiratory, neoplasms, infections, circulatory, hematopoietic, endocrine/metabolic.

In total, 457 PheCodes were analyzed (See Supplementary Table 2, Supplementary Digital Content, https://links.lww.com/CTG/A973).

Metabolomics

To further dissect the metabolic effects of H. pylori positivity, we analyzed 143 metabolites that were measured through nuclear magnetic resonance spectroscopy in a subset of 1.436 H. pylori–negative participants and 677 H. pylori–positive participants (See Supplementary Table 3, Supplementary Digital Content, https://links.lww.com/CTG/A973). Details on measurements through nuclear magnetic resonance can be accessed here: https://biobank.ndph.ox.ac.uk/showcase/ukb/docs/nmrm_companion_doc.pdf.

Statistical analysis

All continuous variables were analyzed by unpaired, 2-tailed t tests or the Mann-Whitney U test and by an appropriate multivariable model. The results are presented as mean ± SD (normal distribution) or median [IQR] (non-normal distribution). All categorical variables were displayed as relative (%) frequencies, and the corresponding contingency tables were analyzed using the χ2 test. Odds ratios/hazard ratios (ORs/HRs) were presented with their corresponding 95% confidence intervals (CIs) given in brackets. HRs were calculated using Cox proportional hazard regression models. Multivariable logistic regression was performed to test for independent associations. The PheWAS analysis was performed using the “pyPheWAS” python package (15). Differences were statistically significant when P < 0.05. For PheWAS analyses, an false discovery rate-adjusted significance level of P ≤0.0038 was calculated using the implemented false discovery rate correction for multiple testing. Data were analyzed using Python 3.11.2, R version 4.0.2 (R Foundation for Statistical Computing, Vienna, Austria) and Prism version 8 (GraphPad, LaJolla, CA).

RESULTS

The UKB dataset consists of 9.967 individuals with valid information on the presence of H. pylori antibodies in the serum at baseline, with 2.966 being H. pylori positive (Table 2). Before matching, we found that H. pylori positivity was associated with higher age, male sex, and obesity (See Supplementary Table 1, Supplementary Digital Content, https://links.lww.com/CTG/A973). After propensity score 2:1 matching, age was well balanced, and for all cohort variables, a reduction in mean effect size could be achieved (See Supplementary Figure 1, Supplementary Digital Content, https://links.lww.com/CTG/A973).

Table 2. - Comparison of baseline characteristics and serum parameters in Helicobacter pylori–positive individuals vs controls H. pylori positive (n = 2,966) Controls (n = 5,932) Multivariable P Mean SD Mean SD BMI (kg/m2) 27.4 4.8 27.8 4.9 Age (yr) 57.0 7.9 57.3 8.2 Sex (n, %women) 1,483 50 2,966 50 Townsend deprivation index −1.7 2.9 −0.7 3.4 Ethnicity (n, % White) 2,652 89.4 5,717 96.4 Serum metabolites  Total protein (g/L) 73.1 4.4 72.4 4.1 2.3E-08*  Cholesterol (mmol/L) 5.6 1.2 5.8 1.2 0.009*  IGF-1 (nmol/L) 21.0 6.0 21.6 5.9 0.004*  SHBG (nmol/L) 51.9 27.2 51.7 27.4 0.008*  Alkaline phosphatase (U/L) 85.7 28.4 83.7 24.9 0.023*  Vitamin D (nmol/L) 45.5 21.1 46.2 20.2 0.09  Albumin (g/L) 45.1 2.6 45.3 2.5 0.13  Alanine aminotransferase (U/L) 23.6 12.9 23.6 13.6 0.16  Glucose (mmol/L) 5.1 1.1 5.1 1.1 0.21  Total bilirubin (umol/L) 9.0 4.3 9.1 4.7 0.24  C-reactive protein (mg/L) 2.7 3.9 2.6 4.6 0.31  HbA1c (mmol/mol) 36.6 6.7 35.9 6.3 0.31  Creatinine (umol/L) 73.2 17.3 72.8 21.5 0.38  Aspartate aminotransferase (U/L) 26.6 11.1 26.1 9.5 0.45  Urate (umol/L) 314.3 82.1 310.0 80.0 0.51  Gamma-glutamyltransferase (U/L) 38.9 48.1 37.6 43.5 0.63  Direct bilirubin (umol/L) 1.9 0.8 1.8 0.8 0.80  Urea (mmol/L) 5.5 1.4 5.5 1.5 0.93

Quantitative measures are expressed as mean with SD or relative frequency (%) and their corresponding multivariate P values, sex, age, BMI, ethnic background, and socioeconomic status (Townsend deprivation index) adjusted. Relative measures are expressed as n with percentage of modus.

BMI, body mass index; IGF-1, insulin-like growth factor 1; SHBG, sex hormone binding globulin.

*P < 0.05.

We compared routine serum parameters between H. pylori–positive individuals and controls. H. pylori–positive individuals had higher mean levels of total protein (73.1 vs 72.4 g/L), lower levels of cholesterol (5.6 vs 5.8 mmol/L), and lower levels of insulin-like growth factor 1 (21.0 vs 21.6 nmol/L) compared with controls. H. pylori –positive individuals also had higher levels of sex hormone binding globulin (51.9 vs 51.7 nmol/L) and alkaline phosphatase (85.7 vs 83.7 U/L) compared with controls (Table 2).

To obtain insight into conditions associated with H. pylori positivity, we performed a multi/mass monovariate PheWAS analysis. Of 457 selected PheCodes, 25 were significantly overrepresented and 2 were underrepresented in H. pylori–positive subjects (Figures 1 and 2, Supplementary Table 2 [see Supplementary Digital Content, https://links.lww.com/CTG/A973]). We found a significant overrepresentation of several gastric disorders that are known to be driven by H. pylori infection such as “bacterial gastritis,” “other specified gastritis,” and “gastric cancer.” Moreover, there was a strong positive association with IDA, which confirmed previous data (16,17). In addition, various other diseases showed a significant correlation. Of the 25 most overrepresented disorders, 11 belonged to circulatory diseases, including congestive heart failure, cardiomegaly, angina pectoris, essential hypertension, hypotension, myocardial infraction, and 7 respiratory disorders such as postinflammatory pulmonary fibrosis and chronic obstructive pulmonary disease (COPD) (Figure 2, Supplementary Table 2 [see Supplementary Digital Content, https://links.lww.com/CTG/A973]). The underrepresented PheCodes included “benign neoplasm of other parts of digestive system” and “ulcer of esophagus” (Figure 2).

Figure 2.:

The 27 most overrepresented/underrepresented PheCodes in individuals with Helicobacter pylori, adjusted for age, sex, BMI, ethnic background, and socioeconomic status. ORs are given as log (OR) and 95% confidence intervals. Only PheCodes that remained significant after adjustment for multiple testing are displayed and have thereby a P value of ≤0.0038. BMI, body mass index; CI, confidence interval; NOS, not otherwise specified; OR, odds ratio.

Next, we analyzed whether increased morbidity in H. pylori–positive individuals is also linked to increased mortality (Table 1). During the mean follow-up of 13.6 years, 263 of the H. pylori–positive participants (8.8%) and 432 (7.2%, Table 1) of H. pylori–negative individuals died. The univariate analysis revealed a significant increase in the overall mortality of the H. pylori–positive participants (univariate P value 0.012; See Supplementary Figure 2, Supplementary Digital Content, https://links.lww.com/CTG/A973), which did not stay significant after adjustment for age, sex, BMI, ethnicity, and socioeconomic status (multivariate P value 0.4, Table 1). However, H. pylori positivity was associated with a significant increase in respiratory-associated mortality (HR 2.16; 95%CI [1.48–2.84], Table 1) and increased death due to COVID-19 (HR 3.53; 95%CI [2.49–4.58]).

Last, we dissected the effect of H. pylori positivity on 143 serum metabolites (Figure 3). H. pylori positivity was associated with lower levels of sphingomyelins, total esterified cholesterol, docosahexaenoic acid, large and very large HDL, and smaller average HDL diameter (Figure 3).

Figure 3.:

Circle plot for lipidomic analysis for Helicobacter pylori–positive UKB participants compared with controls. Lipidomic parameters were measured through NMR spectroscopy. Hazard ratios (with 95% confidence intervals) are presented per 1-SD higher metabolic biomarker on the natural log scale, stratified by age, sex, body mass index, and Townsend deprivation index. *P < 0.05. Original code by Diego J Aguilar-Ramirez. DHA, docosahexaenoic acid; FAs, fatty acids; FAw3, omega-3 fatty acids; FAw6, omega-6 fatty acids; HDL-D, high-density lipoprotein particle diameter; LA, linoleic acid; LDL, low-density lipoproteins; LDL-D, low-density lipoprotein particle diameter; LP, lipoprotein; MUFA, monounsaturated fatty acids; NMR, nuclear magnetic resonance; PUFA, polyunsaturated fatty acids; SFA, saturated fatty acids; VLDL-D, very low-density lipoprotein particle diameter.

DISCUSSION

We aimed to analyze the UKB database to delineate the relevance of H. pylori positivity for human health. Our data demonstrate that H. pylori positivity plays an organ- and disease entity–specific role in the development of cardiovascular, digestive, and metabolic diseases. Given the large number of recruited individuals, the long follow-up period (>10,000 person-years) and a precise collection of disease phenotypes, we were able to gain unprecedented insights and discovered 27 PheCodes that are significantly associated with H. pylori positivity.

Our data confirm previous well-established links between H. pylori and gastric disorders, which are based on bacterial lifelong persistence in the human gastric mucosa of approximately 50% of the world's population (18–21). Using a potent flagellar system and chemotactic receptors, H. pylori can penetrate the mucus and colonize gastric epithelial cells in the pit and deep in gastric glands (20,22,23). Recent studies have revealed the interplay between bacterium and host epithelium, demonstrating key mechanisms in activation of stem cells leading to hyperplasia and a robust and sustained innate and adaptive immune response that fails to clear H. pylori, rather supporting a chronic inflammatory condition, laying ground for cancer initiation and progression (20,24–29). In addition to being linked to gastritis and gastroduodenal ulcers, our data confirm an association between H. pylori positivity and IDA. Experimental data from mice studies revealed that CagA+ H. pylori acquire iron from host cells through transfer of transferrin receptors from the basolateral membrane to the apical surface where the bacteria locate (30). This and gastric hypochlorhydria in chronic gastritis, which interferes with iron reduction and absorption, may affect the systemic iron level leading to anemia (31). Notably, iron deficiency has been associated with accelerated premalignant and malignant gastric lesions in mice and humans (32). The link between infection and noncardia gastric cancer has been demonstrated in various studies, and H. pylori is considered a WHO type I carcinogen (1). It should be noted that most datasets that link H. pylori infection and gastric cancer risk are from Asian countries, an area with high prevalence of H. pylori infection (33). While large cohort studies from the United States have also demonstrated this association (34,35), there is still a debate on whether this applies to European countries because the reduction for H. pylori is larger than the reduction in gastric cancer from 1993 to 2007 (36). Still most patients with noncardia gastric cancer were tested H. pylori positive in a European case-control study and 2 studies in the Swedish population reported a high association of H. pylori seropositivity with noncardia gastric cancer (37–39). Our data now clearly demonstrate an association between H. pylori positivity and gastric cancer in the UK, together supporting the critical role of H. pylori for this disorder also in Europe. Heterogeneity of the strength of the association with gastric cancer may be explained by the not yet routinely analyzed genetic risk status of infected individuals (40). Whether H. pylori infection is associated with other extragastric cancers remains controversial. We found no clear association with extragastric cancers.

Our study found a positive association of H. pylori infection with several cardiovascular disorders such as heart failure, angina pectoris, or cerebrovascular disease, consistent with recent meta-analyses: H. pylori infection in >20,000 patients was associated with an increased risk of myocardial infarction, OR: 2.10 (CI: 1.75–2.53) (6); second, an increased risk of acute coronary syndrome, OR: 2.03 (CI: 1.66–2.47) (41), and third, an increased risk by 51% of adverse cardiovascular events, including foremost myocardial infarction and cerebrovascular disease (42). A recent meta-analysis of observational studies in >270,000 individuals further linked H. pylori infection to an increased risk of stroke (43). The latest meta-analysis of cohort studies on H. pylori infection and the risk of cardiovascular disease including 230,288 patients found only a mild increase of cardiovascular risk (relative risk 1.10, 95% CI 1.03, 1.18), much smaller than previous meta-analyses and our data and no significant association with the risk of stroke (7). The cardiovascular risk, even if limited, has significant impact on public health and might become evident because H. pylori, especially CagA-positive strains, may contribute synergistically with a high-fat diet to the development of atherosclerosis and cardiovascular disease through chronic inflammatory and immunological processes (44–46). In addition, a correlation of H. pylori infection with changes in lipids might contribute to a higher cardiovascular risk (47). In accordance with previous publications (44,48,49), we found a prominent decrease in HDL cholesterol, contributing to dyslipidemia as an important factor for atherosclerosis. Of importance, eradication was successful in restoring HDL levels (50), indicating that eradication could have an inhibitory effect on the onset of cardiovascular disease, although this is yet unknown. We also found a negative association with docosahexaenoic acid, an omega-3 fatty acid that has been found to protect cardiovascular health (51). Bacterial properties enable H. pylori also to directly extract cholesterol from epithelial cells, which may also affect the systemic lipid levels (29,52). This and the atherogenic modification in lipid metabolism may be associated with proinflammatory signaling (53). The proinflammatory signaling may explain the positive correlation with type 2 diabetes mellitus found in the H. pylori–positive cohort and elsewhere (54), which in turn drives further unfavorable effects on cardiovascular disease. While our data provide additional evidence for an increased cardiometabolic risk in individuals infected with H. pylori, less biased studies as randomized controlled trials are needed for definite conclusion on this association. Further prospective studies should also address whether eradication prevents the development of atherosclerosis and its complications to clarify the role of this bacterium in cardiovascular pathology.

The potential involvement of H. pylori infection in respiratory diseases is still under debate. We found a positive association for 7 respiratory disorders such as postinflammatory pulmonary fibrosis, and COPD. A recent review summarized predominantly case-control studies with controversial findings on respiratory diseases concluding that so far in face of missing prospective studies, no clear evidence supports a casual relation between infection and respiratory diseases (55). Still inflammatory and endothelial changes associated with lung injury have been described in mice (56). Besides proving data on a larger sample size, we, in this study, report data on a significant increase in respiratory-associated mortality in individuals with positive H. pylori serology, which is in line with a previous report in individuals with COPD (57). The association with lung cancer is under debate (58) and was not specifically obvious in our study. Noteworthy, we found a positive association of H. pylori positivity with deaths of individuals with COVID-19 (SARS-CoV-2) infection, although limited by small death rate. Previous data suggested that H. pylori–infected people may be more susceptible to COVID-19, which may be explained by the increased expression of SARS-CoV-2 entry receptors such as angiotensin-converting enzyme 2 in the affected gastric mucosa or elevated gastric pH that no longer inactivates SARS-CoV-2 (59,60). In addition, as found in this study, the H. pylori–associated inflammatory response and cardiocirculatory and respiratory morbidity may promote a risk status for COVID-19. The understanding of gastrointestinal and respiratory disease course in the complex interplay of both highly prevalent human infectious diseases is of emerging interest.

While the PheWAS analysis is well suited to identify an extensive repertoire of H. pylori positivity–associated conditions, our analysis has some limitations. First, a causal link between diseases and mechanisms cannot be explained. Second, the UKB is not an entirely representative population sample because 94% of subjects are White British and from higher-income classes. Moreover, outcomes based on ICD codes may experience some degree of misclassification or underdiagnosis. We were not able to distinguish active or past H. pylori infection and to analyze the influence of eradication treatment on gastric and extragastric disease because patients were enrolled based on anti-H. pylori antibodies, and data on H. pylori eradication in the past or during follow-up were not available. In summary, our large study of H. pylori positivity demonstrates that it plays an organ- and disease entity–specific role in the development of human disease. However, an association study cannot distinguish between causes and consequences. Although this study design is based on a correlational relationship, our findings might help to provide a framework for patient recommendations.

CONFLICTS OF INTEREST

Guarantor of the article: Carolin V. Schneider, MD.

Specific author contributions: C.V.S. had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. P.K. and C.V.S. analyzed the data. J.W., M.S., and C.V.S. conceptualized and drafted the manuscript. C.V.S. and M.S. supervised the work. All authors agreed to submit the manuscript, read, edited, and approved the final draft.

Financial support: C.V.S. is supported NRW Rueckkehr Program. M.S. is supported by the DFG Emmy Noether Program (Si1983 41), ERC (Starting Grant REVERT, Einstein Foundation Berlin (EC3R Consortium). K.M.S. is supported by the Federal Ministry of Education and Research (BMBF) and the Ministry of Culture and Science of the German State of North Rhine-Westphalia (MKW) under the Excellence strategy of the federal government and the Laender.

Potential competing interests: None to report.

Study Highlights

WHAT IS KNOWN ✓ Helicobacter pylori colonizes the human stomach and increases the risk of gastroduodenal ulcer and gastric cancer.

WHAT IS NEW HERE ✓ H. pylori positivity is associated with specific cardiovascular, respiratory, and metabolic disorders. ✓ Multivariate analysis shows no change in overall mortality in H. pylori–positive participants. ✓ Lipidomic analysis reveals dyslipidemic profile in H. pylori–positive participants, which may link H. pylori to systemic inflammation and disease. ACKNOWLEDGEMENT

We thank Diego J. Aguilar-Ramirez, Oxford Population Health, University of Oxford, for the code for Figure 3 of this article.

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