INTRODUCTION
Acute infectious gastroenteritis (AGE) is a common reason for outpatient visits and hospitalizations in the United States, with an estimated 179 million cases per year (1,2 ). Diarrheal diseases are the only cause of infectious disease mortality in the United States to exhibit an increase from 2000 to 2014 (3 ). Populations at risk for severe AGE include the young (<5 years old), the elderly (>65 years old), and the immunocompromised (e.g., history of organ transplantation and HIV disease) (4–9 ). AGE-related hospitalizations and deaths are most frequent in the elderly population; furthermore, admission and mortality rates due to AGE among adults have been increasing since 1999 (10–13 ).
With regard to etiology, norovirus and Clostridioides (Clostridium ) difficile are 2 commonly detected pathogens among adults with AGE (12 ). In 2014, the estimated economic burden of C. difficile alone was $5.4 billion for 606,058 total cases (14 ). Norovirus was responsible for 19–21 million illnesses and between 56,000 and 71,000 hospitalizations each year between 2009 and 2015 (15 ). Previous studies in the US adult population have primarily focused on the epidemiology and burden of AGE due to C. difficile and norovirus in inpatient settings (16–20 ), although a recent study of patients at 4 Veterans Affairs Medical Centers found that C. difficile and norovirus are also the leading pathogens in outpatients with AGE (21 ).
However, as the causes in over two-thirds of AGE-related hospitalizations have not been specified, the burden of AGE in the adult population has not been comprehensively ascertained (12 ). New molecular diagnostic assays with increased sensitivity have the potential to identify etiologies of AGE in addition to C. difficile and norovirus (22,23 ). Moreover, the epidemiology and burden of AGE in outpatients may differ from that of inpatients. Hospital-based outpatients with AGE are likely to have less severe illness than inpatients; however, such patients may still require significant health care resource utilization (HRU) and therefore contribute to the economic burden on health care systems (1,4 ).
Using the largest hospital discharge database in the United States, this study aimed to describe the epidemiology, HRU, and cost of AGE-related outpatient visits among adults overall and those with inflammatory bowel disease (IBD). For the subset of patients with stool microbiology data, we examined commonly detected pathogens. To determine whether AGE-related outcomes varied before and during the coronavirus disease 2019 (COVID-19) pandemic, as a result of limited hospital resources that might affect outcomes of non–COVID-19 (including AGE) patients (24,25 ) or social distancing and other hygienic practices that might alter the transmission of AGE pathogens (26 ), study findings for the overall cohort were also analyzed separately for pre–COVID-19 and pandemic periods.
METHODS
Study design and data source
A retrospective cohort study was performed using the Premier PINC AI Healthcare Database (PHD). The PHD is a hospital-based, service-level, all-payer discharge database for geographically diverse inpatient and outpatient visits from more than 1,150 hospitals (27,28 ). The standard hospital discharge files include demographic characteristics, disease states, and a time-stamped log of billed items (e.g., procedures, medications, laboratory, and diagnostic services) of patient visits and hospital characteristics (29 ). A subset of hospitals (∼25%) submit microbiology laboratory data (all available data from clinical microbiology testing regardless of results) to the PHD. Microbiology data include specimen collection date, type of specimen, types of tests performed, and observations for the specimens. Based on the US Title 45 Code of Federal Regulations (Part 46), Institutional Review Board approval for this study was not required because existing deidentified hospital discharge data were used, and recorded information could not be identified directly or through identifiers linked to individuals. Informed consent of study participants was not pursued due to the nature of the deidentified data. The study followed the Strengthening the Reporting of Observational Studies in Epidemiology (30 ) guidelines.
Study population
AGE was defined using the following International Classification of Diseases, 10th revision, Clinical Modification (ICD-10-CM ) codes: A00.x-A05.x, A06.0-A06.3, and A07.x-A09.x. Adults (aged ≥18 years) who had an outpatient visit with a principal discharge diagnosis of AGE and none of the exclusion criteria between April 1, 2016, and June 30, 2021, were included in the study. Exclusion criteria included the following: (i) had a history of AGE within 30 days before the index visit and (ii) had index visit for diagnostic testing, same-day surgery, or presurgical testing. If a patient had multiple AGE-related outpatient visits during the study period, only the first or index visit was included in the analysis to represent patient-level data.
Patients with IBD were identified using ICD-10-CM codes for Crohn's disease (K50.x), ulcerative colitis (K51.x), and indeterminate colitis (K52.3) during index outpatient visits and any visit to the same hospital within 180 days before the index visit (31 ). Patients were included in the subgroup analysis if they had available microbiology data in the PHD for any stool tests performed at the hospital during the index visit. The pre–COVID-19 period was defined as the time interval between April 1, 2016, and February 29, 2020, and the COVID-19 period was defined as between March 1, 2020, and June 30, 2021.
Outcome measures
The main outcomes of interest were HRU and health care cost and included (i) utilization of stool testing during the index visit; (ii) outpatient type for the index visit (e.g., emergency department [ED] and clinic); (iii) utilization of postdischarge services for the index visit (e.g., home health, nursing or rehabilitation facility, and hospice); (iv) utilization of ancillary diagnostic tests (e.g., abdominal computed tomography, ultrasound, and fluoroscopy) within 30 days of the index visit; (v) AGE-related hospitalization or outpatient visits within 30 days; (vi) total index visit cost; and (vii) total index plus 30-day AGE-related follow-up cost.
Stool tests were identified if the hospital had charges related to a stool test during the index visit in the itemized billing data using string searches. Stool tests included multiplex gastrointestinal (GI) polymerase chain reaction panels and traditional stool workup (e.g., stool culture, single pathogen polymerase chain reaction test, immunology test, microscopy, C. difficile toxin test, and ova and parasite test) (32 ). Ancillary diagnostic tests were identified using ICD-10-PCS (procedure) codes and Current Procedural Terminology codes (see Supplementary eTable 1, Supplementary Digital Content 1, https://links.lww.com/AJG/C866 ). AGE-related hospitalizations and outpatient visits within 30 days were identified when the patient received inpatient or outpatient care at the same hospital or hospital system with a principal or secondary discharge diagnosis of AGE within 30 days of the index discharge. The index visit cost and index visit plus 30-day AGE-related follow-up cost included the sum of all costs incurred at the hospital including room and board, pharmacy, laboratory, imaging, and central supply. In the subgroup analysis, outcomes of interest were cost of stool tests and types of identified stool pathogens.
Patient, visit, and hospital characteristics
Baseline patient characteristics (i.e., age, sex, and patients' self-reported race and ethnicity) and hospital characteristics including geographical region (i.e., Midwest, Northeast, South, or West), hospital size (i.e., number of beds), urbanicity of population served (rural vs urban) and teaching status (teaching vs nonteaching) were provided by the hospitals. Charlson-Deyo comorbidities were identified using ICD-10-CM and ICD-10-PCS codes (see Supplementary eTable 2, Supplementary Digital Content 1, https://links.lww.com/AJG/C866 ), and the Charlson-Deyo Comorbidity Index score was calculated using a previously validated method (33,34 ). In addition to Charlson-Deyo comorbidities, risk factors for AGE (e.g., malnutrition, immunosuppression, and history of transplantation) (35 ) were identified using ICD-10-CM and ICD-10-PCS codes (see Supplementary eTable 2, Supplementary Digital Content 1, https://links.lww.com/AJG/C866 ). Comorbidities and risk factors were assessed during the index visit and any visit to the same hospital within 180 days before the index visit.
Statistical analysis
Descriptive statistics were used to present baseline patient and hospital characteristics of patients with AGE and their outcomes. Continuous variables were reported as mean (SD) or median (first quartile, third quartile), and categorical variables were reported as counts and percentages. For statistical difference between 2 groups, the Student t test or Mann-Whitney test was used for continuous variables, as indicated, and Pearson's χ2 test or Fisher exact test for categorical variables. For testing statistical differences between more than 2 groups, the Pearson χ2 test was used for categorical variables, and Bonferroni correction was performed to adjust for multiple comparisons when the null hypothesis was rejected. All cost variables were adjusted to and presented as 2021 US dollars based on the Consumer Price Index for urban consumers for hospital and related services (36 ). All analyses and figures were performed and generated using R v.3.6.3 (R Foundation for Statistical Computing, Vienna, Austria).
RESULTS
We identified 248,896 hospital-based outpatients with AGE with a mean age of 44.3 (19.6) years; more than 40% of the patients were between the ages of 18–34 years (Table 1 ). More women visited hospitals as outpatients (>60%) than men, and the predominance of women remained consistent across age categories (Figure 1a ) and region (Figure 1b ). Two-thirds of the patients self-identified as White (68.5%), 17.8% as Black, and 13.6% as Hispanic. The most common health insurance was private (37.1%), followed by similar proportions of Medicaid (23.6%) and Medicare (23.3%). About 12.9% of the patients did not have health insurance at the time of their index visit. The most common baseline conditions were hypertension (27.5%), chronic pulmonary disease (19.4%), and diabetes (16.1%). However, nearly two-thirds (63.0%) of the patients did not have a risk factor for AGE, and a similar proportion (62.0%) had a zero Charlson-Deyo Comorbidity Index score, suggesting a relatively healthy study population. Nearly half (48.7%) of the outpatient visits occurred at small (1–299 beds) hospitals. Most patients visited nonteaching (60.4%) and urban (77.9%) hospitals.
Table 1.: Demographics, clinical, and hospital characteristics of outpatients visiting hospitals due to acute infectious gastroenteritis, stratified by inflammatory bowel disease (IBD) status
Figure 1.: Sex distribution of hospital-based outpatients with acute infectious gastroenteritis by age group and geographic region. (a ) By age group. (b ) By geographic region.
Among 3,225 patients with IBD, 52.6% (n = 1,697) had Crohn's disease, 49.3% (n = 1,591) had ulcerative colitis, 3.0% (n = 96) had both diagnoses, and 1.0% (n = 33) had indeterminate colitis. Patients with IBD were older (mean age 47.6 vs 44.3 years) and more likely to be White (80.3% vs 68.3%), have Medicare (30.2% vs 23.2%), present with hypertension (36.5% vs 27.4%), and report a previous history of AGE (9.9% vs 1.5%) or other noninfective gastroenteritis and colitis (16.2% vs 4.4%) compared with patients without IBD (all P < 0.01, Table 1 ).
Patients during the COVID-19 period (n = 34,062) were slightly older (mean 45.9 vs 44.1 years) and more likely to present with hypertension (28.8% vs 27.3%) or obesity (10.0% vs 7.2%) than patients in the pre–COVID-19 period (n = 214,834, all P < 0.01, see Supplementary eTable 3, Supplementary Digital Content 1, https://links.lww.com/AJG/C866 ). Of 34,062 patients visiting the hospital due to AGE during the COVID-19 period, only 150 (0.4%) were diagnosed with COVID-19.
HRU and visit cost
Most hospital-based outpatient visits due to AGE occurred in the ED (84.7%, Table 2 ). Consequently, most patients were seen by emergency medicine physicians (62.2%), followed by internists (7.6%), family medicine physicians (7.5%), and hospitalists (5.5%). Only 18.3% of the cohort underwent a stool test during the index visit. Almost all patients were discharged home (96.4%) after the index visit, with a small proportion of patients requiring home health care (0.9%) or discharge to a nursing or rehabilitation facility (0.6%). After the index visit, fewer than 1% underwent any ancillary GI diagnostic testing within 30 days. A small percentage of patients were admitted (1.0%) or had additional outpatient visits (2.8%) for AGE within 30 days. Among patients with IBD, more than a third (38.2%) underwent a stool test during the index visit. After the index visit, a higher percentage of patients were admitted (3.9% vs 1.0%) or had additional AGE-related outpatient visits (7.9% vs 2.8%) compared with patients without IBD within 30 days (all P < 0.01).
Table 2.: Health care resource utilization and cost of outpatients visiting hospitals due to acute infectious gastroenteritis, stratified by inflammatory bowel disease (IBD) status
The total mean and median costs of the index visit were $1,147 ($2,084) and $609 ($340, $1,056), respectively (Table 2 ). The total mean of the index visit plus 30-day AGE-related follow-up cost was $1,338 ($4,317), amounting to a total of $333,060,182 and a mean of $63,440,035 per year for the entire cohort. The mean costs of the index visit and index visit plus 30-day AGE-related follow-up were both significantly higher among patients with IBD ($2,298 and $2,926, respectively) compared with patients without IBD (both P < 0.01, Figure 2a, b ). The mean costs for the index visit and index visit plus 30-day follow-up were higher during the COVID-19 period than during the pre–COVID-19 period (both P < 0.01, see Supplementary eFigure 1a and 1b and eTable 4, Supplementary Digital Content 1, https://links.lww.com/AJG/C866 ).
Figure 2.: Mean and median costs of acute infectious gastroenteritis (AGE)-related visits and stool test during the index visit among hospital-based AGE outpatients, stratified by inflammatory bowel disease (IBD) status. (a ) Index visit. (b ) Index + 30-day AGE-related follow-up. (c ) Stool test (among subgroup patients).
Stool test cost and pathogen results: subgroup analysis
From patients with a stool test performed at the hospital during the index visit (n = 45,451), microbiology results were available for 12,469 (27.4%). About a quarter (26.5%) of patients with IBD with a stool test (n = 1,232) had available microbiology results (n = 326). The total mean and median costs of stool testing per patient were $153 ($198) and $98 ($48, $187), respectively. Unlike the index visit and index visit plus 30-day AGE-related follow-up costs, the mean and median costs of stool testing were similar between patients with and without IBD (P = 0.22, Figure 2c ) and between pre–COVID-19 and COVID-19 periods (P = 0.60, see Supplementary eFigure 1c, Supplementary Digital Content 1, https://links.lww.com/AJG/C866 ).
Among the 12,469 patients who underwent stool testing, 47.5% (n = 5,922) had no pathogen detected, and 4.0% (n = 503) had more than 1 pathogen detected by the stool test (see Supplementary eFigure 2a, Supplementary Digital Content 1, https://links.lww.com/AJG/C866 ). Among 326 patients with IBD with a stool test result, 39.3% (n = 128) had no pathogen detected, and 2.8% (n = 9) had more than 1 pathogen detected. Compared with patients without IBD, patients with IBD were more likely to have at least 1 pathogen detected (60.7% vs 52.3%, P < 0.01). During the COVID-19 period, a smaller proportion of patients had no pathogen detected (42.7% vs 48.5%, P < 0.01) or more than 1 pathogen detected (2.0% vs 4.4%, P < 0.01) compared with patients in the pre–COVID-19 period (see Supplementary eFigure 2b, Supplementary Digital Content 1, https://links.lww.com/AJG/C866 ).
Among 6,547 patients with a detected pathogen, the most common pathogens were C. difficile (61.3%), norovirus (12.0%), Campylobacter spp. (jejuni , coli , and upsaliensis , 7.5%), rotavirus (4.0%), Giardia lamblia or Cryptosporidium (3.3%), diarrheagenic Escherichia coli (enteroaggregative, enteropathogenic, enterotoxigenic, and Shiga toxin-producing E. coli/ O157 E.coli , 3.3%), and Salmonella (3.0%). When stratified by different age groups (18–49, 50–74, and 75+ years), Campylobacter spp. and norovirus were most frequently detected among those aged 18–49 years (9.9% and 16.0%, respectively), and C. difficile was most common among those aged 75+ years (77.2%, all P < 0.01, Figure 3a ). Among 198 patients with IBD with a detected pathogen, the most common pathogens were C. difficile (80.8%), Campylobacter spp. (5.1%), norovirus (4.0%), diarrheagenic E. coli (2.5%), and Giardia lamblia or Cryptosporidium (2.5%, Figure 3b ). Compared with patients without IBD, patients with IBD had a significantly higher detection of C. difficile (80.8% vs 60.7%) and a lower detection of Campylobacter spp. (5.1% vs 7.6%) and norovirus (4.0% vs 12.2%, all P < 0.01). Between the pre–COVID-19 (n = 5,355) and COVID-19 (n = 1,192) periods, there was little variation in pathogen type; however, a significant decline in the detection of enteric viruses (adenovirus, astrovirus, norovirus, rotavirus, and sapovirus, 10.1% vs 18.5%, P < 0.01) and an increase in detection of C. difficile (72.3% vs 58.9%, P < 0.01) were observed during the COVID-19 period (see Supplementary eFigure 2c, Supplementary Digital Content 1, https://links.lww.com/AJG/C866 ).
Figure 3.: Types of pathogens among hospital-based outpatients who underwent stool test at the hospital due to acute infectious gastroenteritis and had a detected stool pathogen. (a ) Stratified by age group: 18–49 (n = 2,655), 50–74 (n = 2,631), and 75+ (n = 1,261) years. (b ) Stratified by inflammatory bowel disease (IBD) status: without IBD (n = 6,349) and with IBD (n = 198).
DISCUSSION
This study of the largest hospital discharge database in the United States provides novel insights into the epidemiology of AGE. Among the most striking findings is the female predominance (1.7:1 ratio), seen in all age groups and geographic regions. Our observations confirm that AGE is a common and costly medical condition, which affects adults of all ages (18–89+ years). Although a slightly higher proportion of patients in this cohort were uninsured or had Medicaid, relative to the full PHD cohort (28 ), the burden of illness affected persons of all racial, ethnic, and socioeconomic groups. Only 18% of patients underwent diagnostic stool testing, which accounted for less than 15% of total health care costs associated with the index visit. C. difficile was the most frequently identified pathogen in this setting.
Previous smaller studies have also suggested a female predominance in patients with AGE. Women were overrepresented (62%) among cases of hemolytic-uremic syndrome occurring during the 2011 outbreak of Shiga toxin-producing E. coli in Germany (37 ). A female predominance (62% among individuals aged 22 years or older) was observed in a multicenter evaluation of US outpatients with stool cultures ordered by providers (22 ). Bresee et al (1 ) found a similar sex distribution in their prospective multicenter study of adults with AGE visiting US EDs. Although the reasons for the skewed sex distribution in AGE are presently uncertain, potential contributing factors include differences in exposure to young children, dietary preferences, and health care utilization patterns (37–39 ).
Approximately 2 of 5 patients visiting hospitals due to AGE were aged 40 years or younger in this study. Furthermore, almost two-thirds of the patients lacked an identifiable risk factor for AGE. Although advanced age and immunocompromising conditions are known risk factors for hospitalization and death due to AGE (1,6,8,10,40 ), our study showed that numerous young and relatively healthy patients visited the ED for AGE. Total health care costs amounted to over $333 million 2021 US dollars in our study cohort, in contrast to the estimated $160 million 2014 US dollars attributed by Collier et al (41 ) to domestically acquired waterborne enteric diseases from 2000 to 2015. The cost of stool diagnostic testing was a factor in fewer than a fifth of the patients. Both index visit and index visit plus 30-day AGE-related follow-up costs were significantly higher for patients with IBD, but the costs of stool testing were similar, suggesting that stool testing was not a factor driving cost increases among patients with IBD.
Among hospital-based outpatients with a stool test, C. difficile was the most frequently detected pathogen, followed by norovirus. Previous studies have also reported C. difficile and norovirus as the leading causes of ED visits, hospitalizations, and deaths among adults with AGE (2,10,42,43 ). Our study confirms that C. difficile is increasingly detected in the community and is the predominant pathogen in outpatients seeking medical attention for AGE (38,44,45 ). Similar observations have been reported in other countries; Viprey et al (46 ) found that C. difficile infections in the community were common, and almost half of these infections were undetected across 12 European countries. Bresee et al (1 ) identified Campylobacter spp. as a frequent cause of AGE among ED patients, and these bacteria were the third most commonly found pathogens (8%) in our study. We found 4% of patients to have rotavirus infections, suggesting that rotavirus is underappreciated as a cause of AGE in adults (1,47 ). Detection of diarrheagenic E. coli in our patient cohort was lower in comparison to some published studies and may be attributable to underdiagnosis or underreporting of these pathogens (22,23 ). Further study will be required to determine the contribution of these pathogens to AGE in adult outpatients. We observed that patients with IBD were more likely to have a positive stool test compared with patients without IBD (61% vs 52%). Our findings support those of Limsrivilai et al (48 ) in showing that a significantly higher percentage of patients with active IBD had positive stool tests (31%) compared with healthy patients (14%), even at the time of AGE diagnosis in patients without IBD. Compared with patients without IBD, a higher percentage of patients with IBD had C. difficile detected in our study (81% vs 61% among patients with a positive test). Axelrad et al (49 ) reported that although patients with IBD were less likely to test positive for non–C. difficile enteric infections compared with patients without IBD, such infections were identified in 17% of symptomatic patients with IBD. We also observed that 12% (n = 38) of patients with IBD with microbiology results (n = 326) tested positive for a non–C. difficile enteric infection.
Social distancing and improved hygienic measures (e.g., frequent handwashing) during the COVID-19 pandemic were effective in decreasing rates of transmission of severe acute respiratory syndrome coronavirus 2 and other respiratory pathogens and nonrespiratory pathogens. Nawrocki et al (26 ) and Palmer et al (50 ) reported that detection rates of enteric viruses decreased during the early periods of COVID-19 pandemic, with norovirus showing the most notable drop. Similar to the findings of Nawrocki et al (26 ), no differences were found among detection rates for most GI bacterial pathogens between the pre–COVID-19 and COVID-19 periods, although our study defined the COVID-19 period in a broader sense and included periods when strict social distancing policies had been lifted in the United States. However, increased detection of C. difficile (P < 0.01) and Campylobacter spp. (P = 0.07) was observed (51,52 ). As disturbance of the host microbiome is essential for C. difficile pathogenesis, inappropriate prescription of antibiotics during the initial phase of the pandemic might have contributed to the increased prevalence of this pathogen (53 ), although positivity rates of pathogens detected by a commercial multiplex panel suggest that the rise in C. difficile observed during COVID-19 was relative rather than absolute (54 ). Because of a reluctance of patients to seek health care during the pandemic, it is also possible that only those with more severe symptoms of AGE presented for care (55 ).
This study has several limitations. First, this was a secondary data analysis using a hospital administrative database. AGE and IBD statuses were captured by ICD-10-CM codes, and potential coding errors may affect the accuracy of patient identification. Second, procedures (e.g., stool test and ancillary diagnostic test) were identified using chargemaster descriptions and procedure codes, which may have resulted in underreporting. We also were unable to capture tests performed outside of the hospital, which may have underestimated the number of diagnostic tests ordered and the costs of care in the study population. Of 45,451 patients with a stool test, only 27% had available microbiology results. Because only a subset of hospitals submits microbiology data to PHD, microbiology results in this study may not be generalizable to all patients with a stool test. Finally, the study cohort was limited to hospital-based outpatients who were primarily evaluated in the ED setting; additional research is needed to understand the generalizability of the results to the overall AGE outpatient population.
This is one of the few studies to assess the epidemiology and economic burden of AGE in hospital-based outpatient settings in a large US cohort. AGE is a common condition that affects adults of all ages, including young and healthy adults, and persons of all racial, ethnic, and socioeconomic groups. AGE is considerably more common in women than in men, among individuals seeking medical attention in the outpatient setting, and is associated with a substantial economic burden, exceeding US $330 million for the total study population. Stool diagnostic testing to identify the etiology of AGE was infrequently performed at the hospital in this cohort, but when testing was performed, C. difficile and norovirus were the most frequently detected pathogens. These results will be useful for clinicians and administrators responsible for the allocation of health care resources for adult outpatients with AGE. Patients with IBD who underwent stool testing were more likely to have a pathogen detected and more likely to harbor C. difficile . Further studies can assess the utility of stool diagnostic testing in this population.
CONFLICTS OF INTEREST
Guarantor of the article: Rena C. Moon, MD, MPH.
Specific author contributions: Concept and design: all authors. Acquisition, analysis, or interpretation of data: R.C.M., N.R., H.B., T.C.B., and F.C.F. Drafting of the manuscript: R.C.M. Critical revision of the manuscript for important intellectual content: R.C.M., T.C.B., N.R., R.H., B.C., T.T.T., and F.C.F. Statistical analysis: R.C.M. and N.R. Administrative, technical, or material support: N.R., T.T.T., and F.C.F. Supervision: N.R., T.T.T., and F.C.F.
Financial support: This study was funded by bioMérieux. The funder had a role in the design and conduct of the study; management, analysis, and interpretation of the data; preparation, review, and approval of the manuscript, and the decision to submit the manuscript for publication. However, the funder had no role in collection of the data.
Potential competing interests: R.C.M., N.R., and H.B. worked on the study as full-time employees and stockholders of Premier. T.C.B., B.C., R.H., and T.T.T worked on the study as full-time employees of bioMérieux. F.C.F. worked on the study as a paid consultant to bioMérieux.
ACKNOWLEDGEMENT
We thank Manon Nitta for assisting with literature review, Isabel Gomez for improving figure aesthetics, and Cate Polacek for administrative support.
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